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WO2005117847A2 - Methods and compounds for the treatment of neoplasms - Google Patents

Methods and compounds for the treatment of neoplasms Download PDF

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Publication number
WO2005117847A2
WO2005117847A2 PCT/US2005/019324 US2005019324W WO2005117847A2 WO 2005117847 A2 WO2005117847 A2 WO 2005117847A2 US 2005019324 W US2005019324 W US 2005019324W WO 2005117847 A2 WO2005117847 A2 WO 2005117847A2
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Prior art keywords
group
alkyl
independently
carbon atoms
aryl
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PCT/US2005/019324
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French (fr)
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WO2005117847A3 (en
Inventor
Curtis Keith
Margaret S. Lee
Michael A. Foley
Brent R. Stockwell
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Combinatorx, Incorporated
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Publication of WO2005117847A2 publication Critical patent/WO2005117847A2/en
Publication of WO2005117847A3 publication Critical patent/WO2005117847A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
    • C07D279/28—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
    • 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 features compounds useful in the treatment of neoplasms. Accordingly, the invention features compounds having the formula I:
  • X 1 is CH 2 or NR 16 , where NR 16 is H or C, -6 alkyl; X 2 is CH or N; each of Y and Z is, independently, O, CH 2 , or NR 17 , where NR 17 is H or C ⁇ -6 alkyl; each of A and B is, independently, an optionally substituted C 6 or Cio aryl or an optionally substituted C 2- heteroaryl; each of R 10 and R 11 is, independently
  • R 13 is H, C C 6 alkyl, C r C 8 cycloalkyl, C 2 -C 12 alkoxyalkyl, C 2 -C 6 hydroxyalkyl, C ⁇ -C 6 alkylamino C 2 -C 6 alkyl, amino C C 6 alkyl, or C or C 10 aryl
  • R 14 is H, C r C 6 alkyl, C r C 8 cycloalkyl, C r C 6 alkyloxy, C 2 -C, 2 alkoxyalkyl, C 2 -C 6 hydroxyalkyl, C 3 -C 1 alkylaminoalkyl, C 4 -C ⁇ 2 dialkylaminoalkyl, C 2 -C 6 aminoalkyl, or C orCio aryl
  • R is H, OH, or d- C 6 alkyloxy, carbonyl(CrC 6 alkoxy), carbonyl(C - ⁇ aralkoxy), carbony
  • each of R 15 , R 16 , and R 17 is, independently, H, C C 6 alkyl, halogen, or trifluoromethyl
  • each of R 18 , R 19 , R 20 , and R 21 is, independently, H or C r C 6 alkyl
  • R 22 is H, halogen, trifluoromethyl, OCF 3 , NO 2 , C,-C 6 alkyl, C,-C 8 cycloalkyl, C ⁇ -C 6 alkyloxy, C 2 -C 12 alkoxyalkyl, C 2 -C 6 hydroxyalkyl, C 3 -C 12 alkylaminoalkyl, C 4 -C 12 dialkylaminoalkyl, C 2 -C 6 aminoalkyl, or C 6 or C 10 aryl; q is 2 or 3; each of m and o is, independently, 2 or 3; and each of n and p is, independently, 0 or 1.
  • W is S, NH, S(O), S
  • R 9 is
  • R is
  • each of n and p is 0; q is 3; each of Y and Z is O; X is NR 16 , and each of
  • A-R 10 and -B-R 11 is
  • Examples of preferred compounds include compounds of Formula III:
  • R 9 is
  • Preferred compounds of this embodiment are those in which m and n is 2; each of n and p is 0; q is 3; each of Y and Z is O; X is N; and each of-A- R 10 and -B-R ⁇ is
  • Examples of preferred compounds include compounds of Formula III:
  • R 2 is H, CI or CF 3 and R 16 is H or CH 3 .
  • R 2 is CF 3 (compound 1).
  • R is H (compound 2).
  • R is CI (compound 3).
  • the invention also features compositions that include a compound of formula (I) a pharmaceutically acceptable carrier.
  • the invention features another method for treating a patient having a neoplasm, by administering to the patient a first compound having the formula I:
  • each of R 15 , R 16 , and R 17 is, independently, H, C ⁇ -C 6 alkyl, halogen, or trifluoromethyl
  • each of R 18 , R 19 , R 20 , and R 21 is, independently, H or C C 6 alkyl
  • R 22 is H, halogen, trifluoromethyl, OCF 3 , NO 2 , C r C 6 alkyl, C r C 8 cycloalkyl, CpC 6 alkyloxy, C 2 -C ]2 alkoxyalkyl, C 2 -C 6 hydroxyalkyl, C 3 -C ⁇ 2 alkylaminoalkyl, C 4 -C 12 dialkylaminoalkyl, C 2 -C 6 aminoalkyl, or C or Cio aryl; q is 2 or 3; each of m and o is, independently, 2 or 3; and each of n and p is, independently, 0 or 1.
  • the methods of the invention can include administration to a patient a compound of formula (I) by intravenous, intramuscular, inhalation, rectal, or oral administration.
  • the invention features a method for treating a patient having a neoplasm, such as cancer, that further includes, in a additon to administering to the patient a compound of formula (I), administering to the patient an additional treatment for cancer, with the additional treatment and the treatment with a compound of formula (I) within six months of each other.
  • the additional treatment can be surgery, radiation therapy, chemotherapy, immunotherapy, anti-angiogenesis therapy, or gene therapy.
  • the additional treatment is chemotherapy with an antiproliferative agent.
  • the additional treatment includes administering to a patient a Group A anti-proliferative agent, as defined below.
  • Preferred agents include bleomycin, carmustine, cisplatin, daunorubicin, etoposide, melphalan, mercaptopurine, methotrexate, mitomycin, vinblastine, paclitaxel, docetaxel, vincristine, vinorelbine, cyclophosphamide, chlorambucil, gemcitabine, capecitabine, 5-fluorouracil, fludarabine, raltitrexed, irinotecan, topotecan, doxorubicin, epirubicin, letrozole, anastrazole, formestane, exemestane, tamoxifen, toremofine, goserelin, leuporelin, bicalutamide, flutamide, nilutamide, hypericin, trastuzumab, or
  • cancers treated according to any of the methods of the invention can be, for example, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosar
  • the cancer being treated is lung cancer, especially lung cancer attributed to squamous cell carcinoma, adenocarinoma, or large cell carcinoma, colorectal cancer, ovarian cancer, especially ovarian adenocarcinoma, or prostate cancer.
  • the invention features a method for treating a patient who has a neoplasm, or inhibiting the development of a neoplasm in a patient who is at risk for developing a neoplasm by administering to the patient a pharmaceutical composition that includes a compound of formula (I) and a pharmaceutically acceptable carrier.
  • cancer or “neoplasm” or “neoplastic cells” is meant a collection of cells multiplying in an abnormal manner. Cancer growth is uncontrolled and progressive, and occurs under conditions that would not elicit, or would cause cessation of, multiplication of normal cells.
  • inhibits the growth of a neoplasm is meant measurably slows, stops, or reverses the growth rate of the neoplasm or neoplastic cells in vitro or in vivo. Desirably, a slowing of the growth rate is by at least 20%, 30%, 50%, or even 70%, as determined using a suitable assay for determination of cell growth rates (e.g., a cell growth assay described herein).
  • an effective amount is meant the amount of a compound, in a combination according to the invention, required to inhibit the growth of the cells of a neoplasm in vivo.
  • the effective amount of active compound(s) used to practice the present invention for therapeutic treatment of neoplasms varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount.
  • acyl or "alkanoyl,” as used interchangeably herein, represent an alkyl group, as defined herein, or hydrogen attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl, acetyl, propionyl, butanoyl and the like. Exemplary unsubstituted acyl groups are of from 2 to 7 carbons.
  • acylamino represents an acyl group attached to the parent molecular group through a nitrogen atom. Exemplary unsubstituted acylamino groups are of from 2 to 7 carbons.
  • acyloxy represents an acyl group attached to the parent molecular group through an oxygen atom.
  • exemplary unsubstituted acyloxy groups are of from 2 to 7 carbons.
  • alkenyl represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 6 carbons containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl and the like and may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of: (1) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) amino; (5) aryl; (6) arylalkoxy, wherein the alkylene group is
  • alkoxy or "alkyloxy,” as used interchangeably herein, represent an alkyl group attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted alkoxy groups are of from 1 to 6 carbons.
  • alkoxyalkyl or “alkyloxyalkyl,” as used interchangeably herein, represent an alkyl group to which is attached an alkoxy group. Exemplary unsubstituted alkoxyalkyl groups are of from 2 to 12 carbons.
  • alkoxycarbonyl or “alkyloxycarbonyl,” as used interchangeably herein, represent an ester group; i.e.
  • alkoxy group attached to the parent molecular group through a carbonyl group and is exemplified by methoxycarbonyl, ethoxycarbonyl and the like.
  • exemplary unsubstituted alkoxycarbonyl groups are of from 2 to 7 carbons.
  • alkyl represents a monovalent group derived from a straight or branched chain saturated hydrocarbon of, unless otherwise specified, from 1 to 6 carbons and is exemplified by methyl, ethyl, n- and iso- propyl, n-, sec-, iso- and tert-butyl, neopentyl and the like and may be optionally substituted with one, two, three or, in the case of alkyl groups of two carbons or more, four substituents independently selected from the group consisting of: (1) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) amino; (5) aryl; (6) arylalkoxy; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atom
  • alkylamino represents an alkyl group attached to the parent molecular group through a nitrogen atom. Exemplary unsubstituted alkylamino groups are of from 1 to 6 carbons.
  • alkylaminocarbonyl represents an alkylamino group attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted alkylaminocarbonyl groups are of from 2 to 7 carbons.
  • alkylaminosulfonyl represents an alkylamino group attached to the parent molecular group through an -SO 2 - group.
  • alkylaminosulfonyl groups are of from 1 to 6 carbons.
  • alkylene represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene and the like.
  • alkylsulfinyl represents an alkyl group attached to the parent molecular group through an -S(O)- group.
  • Exemplary unsubstituted alkylsulfinyl groups are of from 1 to 6 carbons.
  • alkylsulfinylalkyl represents an alkyl group, as defined herein, substituted by an alkylsulfinyl group.
  • exemplary unsubstituted alkylsulfinylalkyl groups are of from 2 to 12 carbons.
  • alkylsulfonyl represents an alkyl group attached to the parent molecular group through an -SO 2 - group.
  • Exemplary unsubstituted alkylsulfonyl groups are of from 1 to 6 carbons.
  • alkylsulfonylalkyl represents an alkyl group, as defined herein, substituted by a alkylsulfonyl group.
  • exemplary unsubstituted alkylsulfonylalkyl groups are of from 2 to 12 carbons.
  • alkylthio represents an alkyl group attached to the parent molecular group through a sulfur atom. Exemplary unsubstituted alkylthio groups are of from 1 to 6 carbons.
  • alkynyl represents monovalent straight or branched chain groups of from two to six carbon atoms containing a carbon- carbon triple bond and is exemplified by ethynyl, 1-propynyl, and the like and may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of: (1) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) amino; (5) aryl; (6) arylalkoxy, wherein the alkylene group is of one to six carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (11) halo; (12) heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oy
  • amino represents an -NH 2 group.
  • aminoalkyl represents an alkyl group, as defined herein, substituted by an amino group.
  • aryl represents a mono- or bicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like and may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms;
  • R and R are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluor
  • arylalkenyl or “aralkenyl,” as used interchangeably herein, represent an aryl group attached to the parent molecular group through an alkenyl group.
  • exemplary unsubstituted arylalkenyl groups are of from 8 to 16 carbons.
  • arylalkoxy or “aralkoxy,” as used interchangeably herein, represent an arylalkyl group attached to the parent molecular group through an oxygen atom.
  • exemplary unsubstituted arylalkoxy groups are of from 7 to 16 carbons.
  • arylalkoxycarbonyl or “aralkoxycarbonyl,” as used interchangeably herein, represent an arylalkoxy group attached to the parent molecular group through a carbonyl group.
  • exemplary unsubstituted arylalkoxycarbonyl groups are of from 8 to 17 carbons.
  • arylalkyl or “aralkyl,” as used interchangeably herein, represent an aryl group attached to the parent molecular group through an alkyl group.
  • Exemplary unsubstituted arylalkyl groups are of from 7 to 16 carbons.
  • arylalkylamino or “aralkylamino,” as used interchangeably herein, represent an arylalkyl group attached to the parent molecular group through a nitrogen atom. Exemplary unsubstituted arylalkylamino groups are of from 7 to 16 carbons.
  • arylalkylaminocarbonyl or “aralkylaminocarbonyl,” as used interchangeably herein, represents an arylalkylamino group attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted arylalkylaminocarbonyl groups are of from 8 to 17 carbons.
  • arylalkylsulfinyl or “aralkylsulfinyl,” as used interchangeably herein, represent an arylalkyl group attached to the parent molecular group through an -SO- group.
  • exemplary unsubstituted arylalkylsulfinyl groups are of from 7 to 16 carbons.
  • arylalkylsulfonyl or “aralkylsulfonyl,” as used interchangeably herein, represent an aralkyl group attached to the parent molecular group through an -SO 2 - group.
  • Exemplary unsubstituted arylalkylsulfonyl groups are of from 7 to 16 carbons.
  • arylalkylthio or " aralkylthio,” as used interchangeably herein, represents an arylalkyl group attached to the parent molecular group through a sulfur atom. Exemplary unsubstituted arylalkylthio groups are of from 7 to 16 carbons.
  • arylamino represents an aryl group which is attached to the parent molecular group through a nitrogen atom. Exemplary unsubstituted arylamino groups are of 6 or 10 carbons.
  • arylaminocarbonyl represents an arylamino group attached to the parent molecular group through a carbonyl group.
  • Exemplary unsubstituted arylaminocarbonyl groups are of from from 7 or 11 carbons.
  • arylaminosulfonyl represents an arylamino group attached to the parent molecular group through an -SO 2 - group.
  • exemplary unsubstituted arylaminosulfonyl groups are of 6 or 10 carbons.
  • aryloxy represents an aryl group which is attached to the parent molecular group through an oxygen atom.
  • Exemplary unsubstituted aryloxy groups are of 6 or 10 carbons.
  • aryloxycarbonyl represents an aryloxy group which is attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted aryloxycarbonyl groups are of 7 or 11 carbons.
  • aryloyl or “aroyl,” as used interchangeably herein, represent an aryl group which is attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted aryloxycarbonyl groups are of 7 or 11 carbons.
  • aryloylamino or “aroylamino,” as used interchangeably herein, represent an aroyl group which is attached to the parent molecular group through a nitrogen atom.
  • Exemplary unsubstituted aryloylamino groups are of 7 or 11 carbons.
  • arylsulfinyl as used herein, represens an aryl group attached to the parent molecular group through an -SO- group.
  • Exemplary unsubstituted arylsulfinyl groups are of 6 or 10 carbons.
  • arylsulfonyl as used herein, represens an aryl group attached to the parent molecular group through an -SO 2 - group.
  • Exemplary unsubstituted arylsulfonyl groups are of 6 or 10 carbons.
  • arylthio represents an aryl group which is attached to the parent molecular group through a sulfur atom. Exemplary unsubstituted arylthio groups are of 6 or 10 carbons.
  • azido represents an -N 3 group.
  • azidoalkyl represents an alkyl group, as defined herein, substituted by an azido group.
  • cancer or “neoplasm” or “neoplastic cells” is meant a collection of cells multiplying in an abnormal manner. Cancer growth is uncontrolled and progressive, and occurs under conditions that would not elicit, or would cause cessation of, multiplication of normal cells.
  • carbamate or “carbamyl,” as used interchangeably herein, represent a R A OC(O)NR B - group, or a -OC(O)NR B - linkage, depending on the chemical context in which this term is used, wherein R A is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl; and R B is selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, as defined herein.
  • carbonate represents a -R A OC(O)O- group, or a - OC(O)O- linkage, depending on the chemical context in which this term is used, wherein R A is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, as defined herein.
  • carboxydehyde represents a -CHO group.
  • (carboxaldehyde)alkyl represents an alkyl group, as defined herein, substituted by a carboxaldehyde group.
  • Carboxy represents a -CO 2 H group.
  • Carboxyalkyl represents an alkyl group, as defined herein, substituted by a carboxy group.
  • cycloalkenyl represents a monovalent cyclic hydrocarbon of from three to eight carbons, unless otherwise specified, having at least one carbon-carbon double bond.
  • the cycloalkenyl groups of this invention can be optionally substituted with (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein die alkyl and alkylene groups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atom
  • cycloalkyl represents a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group of from three to eight carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1.]heptyl and the like.
  • the cycloalkyl groups of this invention can be optionally substituted with (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms
  • Exemplary unsubstituted cycloalkylamino groups are of from 3 to 8 carbons.
  • the term "cycloalkylaminocarbonyl,” as used herein, represents a cycloalkylamino group attached to the parent molecular group through a carbonyl group.
  • Exemplary unsubstituted cycloalkylaminocarbonyl groups are of from 4 to 9 carbons.
  • Exemplary unsubstituted cycloalkyloxy groups are of from 3 to 8 carbons.
  • cycloalkyloxycarbonyl or “cycloalkoxycarbonyl,” as used interchangeably herein, represent a cycloalkyloxy group, as defined herein, attached to the parent molecular group through a carbonyl group.
  • exemplary unsubstituted cycloalkyloxycarbonyl groups are of from 4 to 9 carbons.
  • cycloalkylalkoxy represents an alkoxy group, as defined herein, to which is attached a cycloalkyl group.
  • Exemplary unsubstituted cycloalkylalkoxy groups are of from 4 to 14 carbons.
  • cycloalkylalkyl represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an alkyl group.
  • exemplary unsubstituted cycloalkylalkyl groups are of from 4 to 14 carbons.
  • cycloalkylsulfinyl represents a cycloalkyl group attached to the parent molecular group through an -SO- group.
  • Exemplary unsubstituted cycloalkylsulfinyl groups are of from 3 to 8 carbons.
  • cycloalkylsulfonyl represents a cycloalkyl group attached to the parent molecular group through an -SO 2 - group.
  • exemplary unsubstituted cycloalkylsulfonyl groups are of from 3 to 8 carbons.
  • dialkylamino represents an N,N- dialkylsubstituted amine attached to the parent molecular group through the nitrogen atom.
  • the two alkyl substituents of a dialkylamino group can be the same or different, or can be joined together to form a ring.
  • dialkylamino groups are of from 2 to 12 carbons and include dimethylamino, diethylamino, pyrrolidino, and piperidino.
  • an effective amount is meant the amount of a compound, in a combination according to the invention, required to inhibit the growth of the cells of a neoplasm in vivo.
  • the effective amount of active compound(s) used to practice the present invention for therapeutic treatment of neoplasms varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount.
  • haloalkyl represents an alkyl group, as defined herein, substituted by one, two, or three halogen atoms and is exemplified by chloromethyl, bromoethyl, trifluoromethyl and the like.
  • halo or halogen
  • heteroaryl represents that subset of heterocycles, as defined herein, which are aromatic: i.e., they contain 4n+2 pi electrons within the mono- or multicyclic ring system. Exemplary unsubstituted heteroaryl groups are of from 1 to 9 carbons.
  • heteroarylalkenyl or “heteroaralkenyl,” or as used interchangeably herein, represent a heteroaryl group, as defined herein, attached to the parent molecular group through an alkenyl group.
  • exemplary unsubstituted heteroarylalkenyl groups are of from 3 to 15 carbons.
  • heteroarylalkyl or “heteroaralkyl,” as used interchangeably herein, represent a heteroaryl group, as defined herein, attached to the parent molecular group through an alkyl group.
  • Exemplary unsubstituted heteroarylalkyl groups are of from 2 to 15 carbons.
  • heteroarylalkylamino or “heteroaralkylamino,” as used interchangeably herein, represent a heteroarylalkyl group, as defined herein, attached to the parent molecular group through a nitrogen atom.
  • exemplary unsubstituted heteroarylalkylamino groups are of from 2 to 15 carbons.
  • heteroarylalkylaminocarbonyl or “heteroaralkylaminocarbonyl,” or as used interchangeably herein, represent a heteroarylalkylamino group, as defined herein, attached to the parent molecular group through a carbonyl group.
  • Exemplary unsubstituted heteroarylalkylaminocarbonyl groups are of from 3 to 16 carbons.
  • heteroaryloyl or “heteroaroyl,” or as used interchangeably herein, represent a heteroaryl group, as defined herein, attached to the parent molecular group through a carbonyl group.
  • exemplary unsubstituted heteroaryloyl groups are of from 2 to 10 carbons.
  • heteroarylalkyloxy or “heteroaralkoxy,” or as used interchangeably herein, represent a heteroarylalkyl group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • Exemplary unsubstituted heteroarylalkyloxy groups are of from 2 to 15 carbons.
  • heteroarylalkyloxycarbonyl or “heteroaralkoxycarbonyl,” as used interchangeably herein, represent a heteroaralkoxy group, as defined herein, attached to the parent molecular group through a carbonyl group.
  • exemplary unsubstituted heteroarylalkyloxycarbonyl groups are of from 3 to 16 carbons.
  • heteroarylalkylsulfonyl or “heteroaralkylsulfonyl,” as used interchangeably herein, represent a heteroarylalkyl group attached to the parent molecular group through an -SO 2 - group.
  • Exemplary unsubstituted heteroarylalkylsulfonyl groups are of from 2 to 15 carbons.
  • heteroarylamino represents a heteroaryl group attached to the parent molecular group through a nitrogen atom. Exemplary unsubstituted heteroarylamino groups are of from 1 to 9 carbons.
  • heteroarylaminocarbonyl represents a heteroarylamino group attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted heteroarylaminocarbonyl groups are of from 2 to 10 carbons.
  • heteroarylaminosulfonyl represents a heteroarylamino group attached to the parent molecular group through an -SO 2 - group.
  • Exemplary unsubstituted heteroarylaminosulfonyl groups are of from 1 to 9 carbons.
  • heteroaryloxy represents a heteroaryl group attached to the parent molecular group through an oxygen atom.
  • exemplary unsubstituted heteroaryloxy groups are of from 1 to 9 carbons.
  • heteroaryloxycarbonyl represents a heteroaryloxy group attached to the parent molecular group through a carbonyl group.
  • Exemplary unsubstituted heteroaryloxycarbonyl groups are of from 1 to 9 carbons.
  • heteroarylsulfonyl represents a heteroaryl group attached to the parent molecular group through an -SO 2 - group.
  • exemplary unsubstituted heteroarylsulfonyl groups are of from 1 to 9 carbons.
  • heteroarylthio represents a heteroaryl group attached to the parent molecular group through a sulfur atom.
  • Exemplary unsubstituted heteroaryloxy groups are of from 1 to 9 carbons.
  • heterocycle or “heterocyclyl,” as used interchangeably herein represent a 5-, 6- or 7-membered ring, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • the 5-membered ring has zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds.
  • heterocycle also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring and another monocyclic heterocyclic ring such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like.
  • Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidin
  • F' is selected from the group consisting of -CH 2 -, -CH 2 O- and -O-
  • G' is selected from the group consisting of -C(O)- and -(C(R')(R")) V -
  • R' and R" are independently selected from the group consisting of hydrogen or alkyl of one to four carbon atoms
  • v is one to three and includes groups such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like.
  • any of the heterocycle groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms
  • R and R are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluor
  • heterocyclylalkyl represents a heterocyclyl group attached to the parent molecular group through an alkyl group.
  • exemplary unsubstituted heterocyclylalkyl groups are of from 2 to 15 carbons.
  • heterocyclylamino or “(heterocycle)amino,” as used interchangeably herein, represents a heterocycle group, as defined herein, attached to the parent molecular group through nitrogen.
  • exemplary unsubstituted heterocyclylamino groups are of from 1 to 9 carbons.
  • heterocyclyloxy or “ (heterocycle) oxy,” as used interchangeably herein, represents a heterocycle group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • exemplary unsubstituted heterocyclyloxy groups are of from 1 to 9 carbons.
  • heterocyclyloxycarbonyl or “(heterocycle)oxycarbonyl,” as used interchangeably herein, represents a heterocycloxy group, as defined herein, attached to the parent molecular group through a carbonyl group.
  • Exemplary unsubstituted heterocyclyloxycarbonyl groups are of from 2 to 10 carbons.
  • heterocyclyloyl or “(heterocycle)oyl,” as used interchangeably herein, represents a heterocycle group, as defined herein, attached to the parent molecular group through a carbonyl group.
  • exemplary unsubstituted heterocyclyloyl groups are of from 2 to 10 carbons.
  • heterocyclylsulfonyl represents a heterocyclyl group attached to the parent molecular group through an -SO 2 - group.
  • Exemplary unsubstituted heterocyclylsulfonyl groups are of from 1 to 9 carbons.
  • heterocyclylthio represents a heterocyclyl group attached to the parent molecular group through a sulfur atom.
  • Exemplary unsubstituted heteroaryloxy groups are of from 1 to 9 carbons.
  • hydroxy as used herein, represents an -OH group.
  • hydroxyalkyl as used herein, represents an alkyl group, as defined herein, substituted by one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group and is exemplified by hydroxymethyl, dihydroxypropyl and the like.
  • inhibitts the growth of a neoplasm is meant measurably slows, stops, or reverses the growth rate of the neoplasm or neoplastic cells in vitro or in vivo.
  • a slowing of the growth rate is by at least 20%, 30%, 50%, or even 70%, as determined using a suitable assay for determination of cell growth rates (e.g., a cell growth assay described herein).
  • a reversal of growth rate is accomplished by initiating or accelerating necrotic or apoptotic mechanisms of cell death in the neoplastic cells, resulting in a shrinkage of the neoplasm.
  • a low dosage is meant at least 10% less than the lowest standard recommended dosage of an anti-proliferative agent as recommended by the Physician 's Desk Reference, 57 l Edition (2003).
  • a “high dosage” is meant at least 5% more than the highest standard dosage of an anti-proliferative agent.
  • a “moderate dosage” is meant the dosage between the low dosage and the high dosage.
  • N-protected amino refers to an amino group, as defined herein, to which is attached an N-protecting or nitrogen-protecting group, as defined herein.
  • N-protected aminoalkyl refers to an alkyl group, as defined herein, which is substituted by an N-protecting or nitrogen- protecting group, as defined herein.
  • N-protecting group or “nitrogen protecting group” as used herein, represent those groups intended to protect an amino group against undersirable reactions during synthetic procedures.
  • N-protecting groups comprise acyl, aroyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine and the like; sulfonyl groups
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t- butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • nitro represents an -NO group.
  • nitroalkyl represents an alkyl group substituted by an -NO 2 group.
  • non- vicinal O, S, or N is meant an oxygen, sulfur, or substituted or unsubstituted nitrogen heteroatom substituent in a linkage, wherein the heteroatom substituent does not form a bond to a saturated carbon that is bonded to another heteroatom.
  • perfluoroalkyl represents an alkyl group, as defined herein, wherein each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical. Perfluoroalkyl groups are exemplified by trifluoromethyl, pentafluoroethyl, and the like.
  • perfluoroalkoxy refers to a perfluoroalkyl group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • pharmaceutically acceptable salt represents those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences 66: 1-19, 1977.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base group with a suitable organic acid.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- na
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.
  • pharmaceutically acceptable ester represents esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl group preferably has not more than 6 carbon atoms.
  • Examples of particular esters includes formates, acetates, propionates, butyates, acrylates and ethylsuccinates.
  • prodrugs represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with with the tissues of humans and animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.
  • ring system substituent is meant a substituent attached to an aromatic or non-aromatic ring system. When a ring system is saturated or partially saturated the “ring system substituent” further includes methylene (double bonded carbon), oxo (double bonded oxygen) or thioxo (double bonded sulfur).
  • spiroalkyl represents an alkylene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group.
  • sulfonyl represents an -SO 2 - group.
  • thioalkoxy represents represents an alkyl group attached to the parent molecular group through a sulfur atom. Exemplary unsubstituted thioalkoxy groups are of from 1 to 6 carbons.
  • thioalkoxyalkyl represents an alkyl group substituted by a thioalkoxy group.
  • Exemplary unsubstituted thioalkoxyalkyl groups are of from 2 to 12 carbons.
  • thiocarbonyl is meant a -C(S)- group.
  • thiol is meant an -SH group.
  • Asymmetric or chiral centers may exist in the compounds of the present invention.
  • the present invention contemplates the various stercoisomers and mixtures thereof. Individual stereoisomers of compounds or the present invention are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of mixtures of enantiometic compounds followed by resolution well-known to those of ordinary skill in the art.
  • the present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond and designates such isomers as of the Z or E configuration, wherein the term "Z" represents substituents on the same side of the carbon-carbon double bond and the term “E” represents substituents on opposite sides of the carbon-carbon double bond. It is also recognized that for structures in which tautomeric forms are possible, the description of one tautomeric form is equivalent to the description of both, unless otherwise specified.
  • Group A antiproliferative agent is meant an agent listed in Table 1. Table 1.
  • Platinum agents cisplatin carboplatinum oxaliplatin ZD-0473 (AnorMED) spiroplatinum, lobaplatin (Aetema) carboxyphthalatoplatinum, satraplatin (Johnson Matthey) tetraplatin BBR-3464 (Hoffmann-La Roche) ormiplatin SM- 11355 (Sumitomo) iproplatin AP-5280 (Access)
  • Topoisomerase Amsacrine rubitecan (SuperGen) inhibitors epirubicin exatecan mesylate (Daiichi) etoposide quinamed (ChemGenex) teniposide or mitoxantrone gimatecan (Sigma-Tau) irinotecan (CPT-l l) diflomotecan (Beaufour-Ipsen) 7-ethyl- 10-hydroxy-camptothecin TAS-103 (Taiho) topotecan elsamitrucin (Spectrum) dexrazoxanet (TopoTarget) J-107088 (Merck & Co) pixantrone (Novuspharma) BNP-1350 (BioNumerik) rebeccamycin analogue (Exelixis) CKD-602 (Chong Kun Dang) BBR-3576 (Novuspharma) KW-2170 (Kyowa Hakko) Table 1 (cont.)
  • Anti tumor dactinomycin (actinomycin D) amonafide antibiotics doxorubicin (adriamycin) azonafide deoxyrubicin anthrapyrazole valrubicin oxantrazole daunorubicin (daunomycin) losoxantrone epirubicin bleomycin sulfate (blenoxane) therarubicin bleomycinic acid idarubicin bleomycin A rubidazone bleomycin B plicamycinp mitomycin C porfiromycin MEN-10755 (Menarini) cyanomorpholinodoxorubicin GPX-100 (Gem Pharmaceuticals) mitoxantrone (novantrone)
  • Antimitotic paclitaxel SB 408075 (GlaxoSmithKline) agents docetaxel E7010 (Abbott) colchicine PG-TXL (Cell Therapeutics) vinblastine IDN 5109 (Bayer) vincristine A 105972 (Abbott) vinorelbine A 204197 (Abbott) vindesine LU 223651 (BASF) dolastatin 10 (NCI) D 24851 (ASTAMedica) rhizoxin (Fujisawa) ER-86526 (Eisai) mivobulin (Warner-Lambert) combretastatin A4 (BMS) cemadotin (BASF) isohomohalichondrin-B (PharmaMar) RPR 109881A (Aventis) ZD 6126 (AstraZeneca) TXD 258 (Aventis) PEG-paclitaxel (Enzon) epothilone B (Novartis) AZ 109
  • Thymidylate pemetrexed (Eli Lilly) nolatrexed (Eximias) synthase inhibitors ZD-9331 (BTG) CoFactorTM (BioKeys)
  • DNA antagonists trabectedin (PharmaMar) mafosfamide (Baxter International) glufosfamide (Baxter International) apaziquone (Spectrum albumin + 32P (Isotope Solutions) Pharmaceuticals) thymectacin (NewBiotics) 06 benzyl guanine (Paligent) edotreotide (Novartis)
  • Histone tacedinaline Pfizer
  • pivaloyloxymethyl butyrate Tian
  • acetyltransferase SAHA Adijisawa
  • Depsipeptide Fujisawa
  • TNF alpha virulizin (Lorus Therapeutics) revimid (Celgene) agonists/antagonists CDC-394 (Celgene)
  • Immuno- interferon dexosome therapy (Anosys) modulators oncophage (Antigenics) pentrix (Australian Cancer GMK (Progenies) Technology) adenocarcinoma vaccine (Biomira) ISF-154 (Tragen) CTP-37 (AVI BioPharma) cancer vaccine (Intercell) IRX-2 (Immuno-Rx) norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) synchrovax vaccines (CTL Immuno) MGV (Progenies) melanoma vaccine (CTL Immuno) ⁇ -alethine (Dovetail) p21 RAS vaccine (GemVax) CLL therapy (Vasogen)
  • Photodynamic talaporfin (Light Sciences) Pd-bacteriopheophorbide (Yeda) agents Theralux (Theratechnologies) lutetium texaphyrin (Pharmacyclics) motexafin gadolinium (Pharmacyclics) hypericin Table 1 (cont.)
  • Inhibitors leflunomide (Sugen/Pharmacia) CEP-701 (Cephalon) ZD1839 (AstraZeneca) CEP-751 (Cephalon) erlotinib (Oncogene Science) MLN518 (Millenium) canertinib (Pfizer) PKC412 (Novartis) squalamine (Genaera) phenoxodiol () SU5416 (Pharmacia) trastuzumab (Genentech) SU6668 (Pharmacia ) C225 (ImClone) ZD4190 (AstraZeneca) rhu-Mab (Genentech) ZD6474 (AstraZeneca) MDX-H210 (Medarex) vatalanib (Novartis) 2C4 (Genentech) PKI166 (Novartis) MDX-447 (Medarex) GW2016 (GlaxoSmithKline) ABX-
  • SR-27897 CCK A inhibitor, Sanofi-Synthelabo
  • BCX- 1777 PNP inhibitor, BioCryst
  • tocladesine cyclic AMP agonist, Ribapharm
  • ranpimase ribonuclease stimulant, Alfacell
  • alvocidib CDK inhibitor, Aventis
  • galarubicin RNA synthesis inhibitor, Dong-A
  • CapCellTM (CYP450 stimulant, Bavarian Nordic)
  • R-flurbiprofen (NF-kappaB inhibitor, Encore)
  • GCS-100 gal3 antagonist, GlycoGenesys
  • 3CPA NF-kappaB inhibitor, Active Biotech
  • G17DT immunogen (gastrin inhibitor, Aphton) seocalcitol (vitamin D receptor agonist, Leo) efaproxiral (oxygenator, Allos Therapeutics) 131-I-TM-601 (DNA antagonist, TransMolecular)
  • PI-88 heparanase inhibitor, Progen
  • ODC inhibitor eflornithine
  • tesmilifene histamine antagonist
  • YM minodronic acid osteoclast inhibitor
  • SR-31747 IL-1 antagonist, Sanofi-Synthelabo
  • PG2 hematopoiesis enhancer, Pharmagenesis
  • CCI-779 mTOR kinase inhibitor, Wyeth
  • ImmunolTM triclosan oral rinse, Endo
  • exisulind PDE V inhibitor, Cell Pathways
  • triacetyluridine uridine prodrug , Wellstat
  • CP-461 PDE V inhibitor, Cell Pathways
  • SN-4071 sarcoma agent, Signature BioScience
  • WX-UK1 plasmaogen activator inhibitor, PCK-3145 (apoptosis promotor, Procyon)
  • PBI-1402 PMN stimulant, ProMetic CHS-828 (cytotoxic agent, Leo)
  • trans-retinoic acid differentiated, NIH
  • bortezomib proteasome inhibitor, Millennium
  • MX6 apoptosis promotor, MAXIA
  • SRL-172 T cell stimulant, SR Pharma
  • apomine apoptosis promotor, ILEX Oncology
  • TLK-286 glutthione S transferase inhibitor, urocidin (apoptosis promotor, Bioniche)
  • PT-100 growth factor agonist
  • Point brostallicin apoptosis promotor, Pharmacia
  • CDA-II apoptosis promotor, Everlife
  • X is N and m, n, o, p, q, Y, Z, A,
  • nucleophile is a primary amine, resulting in compounds of formula I where R 9 is
  • X 1 is NH and m, n, o, p, q, Y,
  • Z, A, B R 10 and R 1 ' are as previously defined herein.
  • Compounds of formula VIII can be also be used to form organometallic compounds, such as cuprates, which can be subsequently reacted with activated olefins, such as ⁇ , ⁇ -unsaturated ketones or esters.
  • the cuprate is reacted with an ⁇ , ⁇ -unsaturated ester of the formula XI: H ⁇ O ⁇ -v ⁇ O-Protecting group O (XI), which can be subsequently refunctionalized and carried on synthetically by reactions known to those skilled in the art to produce compounds of formula I where R 9 is where X 2 is CH and m, n, o, p, q, Y, Z, A, B R 10 and R 1 ' are as previously defined herein.
  • R 9 is where X 2 is CH and m, n, o, p, q, Y, Z, A, B R 10 and R 1 ' are as previously defined herein.
  • compounds of formula V can be oxidized to aldehydes of formula VI.
  • W is S
  • oxidants such as Dess-Martin reagent are particularly preferred.
  • a compound of formula VI can then be reacted with a secondary amine (each of R a and R is, independently an optionally substituted alkyl, aryl, or heteroaryl as shown in Scheme 1) or with a primary amine (R a is an optionally substituted alkyl, aryl, or heteroaryl and R b is H) in a reductive amination procedure to produce compounds of formula VII.
  • a secondary amine each of R a and R is, independently an optionally substituted alkyl, aryl, or heteroaryl as shown in Scheme 1
  • R a is an optionally substituted alkyl, aryl, or heteroaryl and R b is H
  • the compound dilution matrix was assayed using the bromodeoxyuridine (BrdU) cytoblot method.
  • the assay was performed using both A549 and HCT cells. Forty-five microliters of a suspension containing A549 lung adenocarcinoma cells (ATCC# CCL-185) was seeded in a white opaque polystyrene cell culture treated sterile 384- well plate (NalgeNunc #164610) using a multidrop (Labsystems) to give a density of 3000 cells per well.
  • the fixative was aspirated and 2N HC1 with Tween 20 (polyoxyethylene sorbitan monolaurate) was added to each well and the plates were incubated for 20 minutes at room temperature.
  • the HC1 was neutralized with a solution of 2N NaOH and the cells were washed twice with Hank's Balanced Salt Solution (HBSS) and once with PBS containing 0.5% bovine serum albumin (BSA) and 0.1% Tween 20.
  • HBSS Hank's Balanced Salt Solution
  • BSA bovine serum albumin
  • Tween 20 The wash solution was removed and mouse anti-BrdU primary antibody (PharMingen #555627) was diluted 1: 1000 in PBS containing BSA, Tween 20, and secondary antibody at a dilution of 1 :2000 (Amersham #NA931).
  • the secondary antibody recognizes the mouse antibody and it is conjugated to the enzyme horseradish peroxidase (HRP). After one hour of incubation, the antibody solution was removed and the cells washed once with PBS. After the PBS wash, the HRP substrate (which contains luminol, hydrogen peroxide, and an enhancer such as para- iodophenol) was added to each well. The plates were read using an LJL Analyst. All aspirations as well as the washes with PBS and HBSS were performed using a TEC AN Power Washer 384. The amount of light output from each well indicates the amount of DNA synthesis that occurred in that well. Decreased light indicates antiproliferative action of the compounds.
  • HRP substrate which contains luminol, hydrogen peroxide, and an enhancer such as para- iodophenol
  • Luminescence for each position in the dilution matrix was divided into the luminescence values for A549 or HCT cells treated with only DMSO vehicle, providing antiproliferative ratios for each position in the dilution matrix for compounds 1, 2, and 3, respectively.
  • the anti-proliferative effect demonstrated with A459 cells can be similarly demonstrated using other cancer cell lines, such as MCF7 mammary adenocarcinoma, PA-1 ovarian teratocarcinoma, HT29 colorectal adenocarcinoma, HI 299 large cell carcinoma, U-2 OS osteogenic sarcoma, U- 373 MG glioblastoma, Hep-3B hepatocellular carcinoma, BT-549 mammary carcinoma, T-24 bladder cancer, C-33 A cervical carcinoma, HT-3 metastatic cervical carcinoma, SiHa squamous cervical carcinoma, CaSki epidermoid cervical carcinoma, NCI-H292 mucoepidermoid lung carcinoma, NCI-2030, non small cell
  • the specificity can be tested by using cells such as NHLF lung fibroblasts, NHDF dermal fibroblasts, HMEC mammary epithelial cells, PrEC prostate epithelial cells, HRE renal epithelial cells, NHBE bronchial epithelial cells, CoSmC Colon smooth muscle cells, CoEC colon endothelial cells, NHEK epidermal keratinocytes, and bone marrow cells as control cells.
  • cells such as NHLF lung fibroblasts, NHDF dermal fibroblasts, HMEC mammary epithelial cells, PrEC prostate epithelial cells, HRE renal epithelial cells, NHBE bronchial epithelial cells, CoSmC Colon smooth muscle cells, CoEC colon endothelial cells, NHEK epidermal keratinocytes, and bone marrow cells as control cells.
  • the compounds of the invention are useful for the treatment of neoplasms. Therapy may be performed alone or in conjunction with another therapy (e.g., surgery, radiation therapy, chemotherapy, immunotherapy, anti- angiogenesis therapy, or gene therapy).
  • another therapy e.g., surgery, radiation therapy, chemotherapy, immunotherapy, anti- angiogenesis therapy, or gene therapy.
  • useful chemotherapeutic agents that can be used in a compound of formula I are listed in Table (I) and are referred to a "Group A antiproliferative agents.”
  • the duration of the combination therapy depends on the type of disease or disorder being treated, the age and condition of the patient, the stage and type of the patient's disease, and how the patient responds to the treatment. Therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recovery from any as yet unforeseen side- effects.
  • cancers and other neoplasms include, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma
  • each compound of the combination may be by any suitable means that results in a concentration of the compound that, combined with the other component, is anti-neoplastic upon reaching the target region.
  • the compound may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition.
  • the composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route.
  • the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.
  • the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A.R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
  • each compound of the claimed combinations depends on several factors, including: the administration method, the neoplasm to be treated, the severity of the neoplasm, whether the neoplasm is to be treated or prevented, and the age, weight, and health of the patient to be treated.
  • the recommended dosage for the anti- proliferative agent is desirably less than or equal to the recommended dose as given in the Physician 's Desk Reference, 57 th Edition (2003).
  • the compound in question may be administered orally in the form of tablets, capsules, elixirs or syrups, or rectally in the form of suppositories.
  • Parenteral administration of a compound is suitably performed, for example, in the form of saline solutions or with the compound incorporated into liposomes.
  • a solubilizer such as ethanol can be applied.
  • a chemotherapeutic agent of the invention is usually given by the same route of administration that is known to be effective for delivering it as a monotherapy.
  • a compound of formula I a Group A antiproliferative agent is dosed in amounts and frequencies equivalent to or less than those that result in its effective monotherapeutic use.

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Abstract

The invention features compounds of 'formula (I) and their use in preparing 'medicaments for treating a patient having a cancer or other neoplasm. R' R9 R8 R N R7

Description

METHODS AND COMPOUNDS FOR THE TREATMENT OF NEOPLASMS The present invention features compounds useful in the treatment of neoplasms. Accordingly, the invention features compounds having the formula I:
Figure imgf000002_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein R is selected from the group consisting of: H, CF3, halo, OCH3, COCH3, CN, OCF3, COCH2CH3, CO(CH2)2CH3, and SCH2CH3; each of R1, R3, R4, R5, R6, R7, and R8 is independently H, OH, F, OCF3, or OCH3; W is selected from the group consisting of: O, S, NH, S(O), S(O)2, CH2, and CH=CH; and R9 is selected from the group consisting of:
Figure imgf000002_0002
wherein X1 is CH2 or NR16, where NR16 is H or C,-6 alkyl; X2 is CH or N; each of Y and Z is, independently, O, CH2, or NR17, where NR17 is H or Cι-6 alkyl; each of A and B is, independently, an optionally substituted C6 or Cio aryl or an optionally substituted C2- heteroaryl; each of R10 and R11 is, independently
A'2 R14 , where R13 is H, C C6 alkyl, CrC8 cycloalkyl, C2-C12 alkoxyalkyl, C2-C6 hydroxyalkyl, Cι-C6 alkylamino C2-C6 alkyl, amino C C6 alkyl, or C or C10 aryl, R14 is H, CrC6 alkyl, CrC8 cycloalkyl, CrC6 alkyloxy, C2-C,2 alkoxyalkyl, C2-C6 hydroxyalkyl, C3-C1 alkylaminoalkyl, C4-Cι2 dialkylaminoalkyl, C2-C6 aminoalkyl, or C orCio aryl, and R is H, OH, or d- C6 alkyloxy, carbonyl(CrC6 alkoxy), carbonyl(C -ι aralkoxy), carbonyl(C6 or Cio aryloxy), or R and R together represent
Figure imgf000003_0001
where each of R15, R16, and R17 is, independently, H, C C6 alkyl, halogen, or trifluoromethyl, each of R18, R19, R20, and R21 is, independently, H or CrC6 alkyl, and R22 is H, halogen, trifluoromethyl, OCF3, NO2, C,-C6 alkyl, C,-C8 cycloalkyl, Cι-C6 alkyloxy, C2-C12 alkoxyalkyl, C2-C6 hydroxyalkyl, C3-C12 alkylaminoalkyl, C4-C12 dialkylaminoalkyl, C2-C6 aminoalkyl, or C6 or C10 aryl; q is 2 or 3; each of m and o is, independently, 2 or 3; and each of n and p is, independently, 0 or 1. Preferably W is S, NH, S(O), S(O)2, and most preferably, W is S. In one embodiment, R9 is
Figure imgf000003_0002
In another embodiment, R9 is
Figure imgf000004_0001
In another embodiment, R is
Figure imgf000004_0002
Preferred compounds of this embodiment are those in which m and n is
2; each of n and p is 0; q is 3; each of Y and Z is O; X is NR 16 , and each of
A-R10 and -B-R11 is
Figure imgf000004_0003
Examples of preferred compounds include compounds of Formula III:
Figure imgf000004_0004
(III), where R2 is H, CI or CF3 and R , 1'6° is H or CH3. In yet another embodiment, R9 is
Figure imgf000004_0005
Preferred compounds of this embodiment are those in which m and n is 2; each of n and p is 0; q is 3; each of Y and Z is O; X is N; and each of-A- R10 and -B-Rπ is
Figure imgf000005_0001
Examples of preferred compounds include compounds of Formula III:
Figure imgf000005_0002
where R2 is H, CI or CF3 and R16 is H or CH3. In one example R2 is CF3 (compound 1). In another example R is H (compound 2). In yet another example, R is CI (compound 3). The invention also features compositions that include a compound of formula (I) a pharmaceutically acceptable carrier. In a related aspect, the invention features another method for treating a patient having a neoplasm, by administering to the patient a first compound having the formula I:
Figure imgf000005_0003
or a pharmaceutically acceptable salt or prodrug thereof, wherein R is selected from the group consisting of: H, CF3, halo, OCH3, COCH3, CN, OCF3, COCH2CH3, CO(CH2)2CH3, and SCH2CH3; each of R1, R3, R4, R5, R6, R7, and R8 is independently H, OH, F, OCF3, or OCH3; W is selected from the group consisting of: O, S, NH, S(O), S(O)2, CH2, and CH=CH; and R9 is selected from the group consisting of:
Figure imgf000006_0001
(CH2)— Y-(CH2)-A _-τR> 10
( rC q > (CH2)-Z-(CH2)p-B-R π and wherein X1 is CH2 or NR16, where NR16 is H or C1-6 alkyl; X2 is CH or N; each of Y and Z is, independently, O, CH2, or NR17, where NR17 is H or C,-6 alkyl; each of A and B is, independently, an optionally substituted C6 or o aryl or an optionally substituted C2-9 heteroaryl; each of R10 and R11 is, independently 12 R14 , where R13 is H, CrC6 alkyl, CrC8 cycloalkyl, C2-C12 alkoxyalkyl, C2-C6 hydroxyalkyl, C C6 alkylamino C2-C6 alkyl, amino C C6 alkyl, or C6 or C10 aryl, R14 is H, C C6 alkyl, CrC8 cycloalkyl, CrC6 alkyloxy, C2-C,2 alkoxyalkyl, C2-C6 hydroxyalkyl, C3-Cι2 alkylaminoalkyl, C4-C]2 dialkylaminoalkyl, C2-C6 aminoalkyl, or C6 orCio aryl, and R12 is H, OH, or d C6 alkyloxy, carbonyl(C]-C6 alkoxy), carbonyl(C7-ι6 aralkoxy), carbonyl(C6 or C10 aryloxy), or R and R together represent
Figure imgf000006_0002
where each of R15, R16, and R17 is, independently, H, Cι-C6 alkyl, halogen, or trifluoromethyl, each of R18, R19, R20, and R21 is, independently, H or C C6 alkyl, and R22 is H, halogen, trifluoromethyl, OCF3, NO2, CrC6 alkyl, CrC8 cycloalkyl, CpC6 alkyloxy, C2-C]2 alkoxyalkyl, C2-C6 hydroxyalkyl, C3-Cι2 alkylaminoalkyl, C4-C12 dialkylaminoalkyl, C2-C6 aminoalkyl, or C or Cio aryl; q is 2 or 3; each of m and o is, independently, 2 or 3; and each of n and p is, independently, 0 or 1. The methods of the invention can include administration to a patient a compound of formula (I) by intravenous, intramuscular, inhalation, rectal, or oral administration. In another aspect, the invention features a method for treating a patient having a neoplasm, such as cancer, that further includes, in a additon to administering to the patient a compound of formula (I), administering to the patient an additional treatment for cancer, with the additional treatment and the treatment with a compound of formula (I) within six months of each other. The additional treatment can be surgery, radiation therapy, chemotherapy, immunotherapy, anti-angiogenesis therapy, or gene therapy. Preferably, the additional treatment is chemotherapy with an antiproliferative agent. Most preferably, the additional treatment includes administering to a patient a Group A anti-proliferative agent, as defined below. Preferred agents include bleomycin, carmustine, cisplatin, daunorubicin, etoposide, melphalan, mercaptopurine, methotrexate, mitomycin, vinblastine, paclitaxel, docetaxel, vincristine, vinorelbine, cyclophosphamide, chlorambucil, gemcitabine, capecitabine, 5-fluorouracil, fludarabine, raltitrexed, irinotecan, topotecan, doxorubicin, epirubicin, letrozole, anastrazole, formestane, exemestane, tamoxifen, toremofine, goserelin, leuporelin, bicalutamide, flutamide, nilutamide, hypericin, trastuzumab, or rituximab, or any combination thereof. Cancers treated according to any of the methods of the invention can be, for example, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. Preferably, the cancer being treated is lung cancer, especially lung cancer attributed to squamous cell carcinoma, adenocarinoma, or large cell carcinoma, colorectal cancer, ovarian cancer, especially ovarian adenocarcinoma, or prostate cancer. In another aspect, the invention features a method for treating a patient who has a neoplasm, or inhibiting the development of a neoplasm in a patient who is at risk for developing a neoplasm by administering to the patient a pharmaceutical composition that includes a compound of formula (I) and a pharmaceutically acceptable carrier.
Definitions As used herein, the terms "cancer" or "neoplasm" or "neoplastic cells" is meant a collection of cells multiplying in an abnormal manner. Cancer growth is uncontrolled and progressive, and occurs under conditions that would not elicit, or would cause cessation of, multiplication of normal cells. By "inhibits the growth of a neoplasm" is meant measurably slows, stops, or reverses the growth rate of the neoplasm or neoplastic cells in vitro or in vivo. Desirably, a slowing of the growth rate is by at least 20%, 30%, 50%, or even 70%, as determined using a suitable assay for determination of cell growth rates (e.g., a cell growth assay described herein). Typically, a reversal of growth rate is accomplished by initiating or accelerating necrotic or apoptotic mechanisms of cell death in the neoplastic cells, resulting in a shrinkage of the neoplasm. By "an effective amount" is meant the amount of a compound, in a combination according to the invention, required to inhibit the growth of the cells of a neoplasm in vivo. The effective amount of active compound(s) used to practice the present invention for therapeutic treatment of neoplasms (i.e., cancer) varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount. The terms "acyl" or "alkanoyl," as used interchangeably herein, represent an alkyl group, as defined herein, or hydrogen attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl, acetyl, propionyl, butanoyl and the like. Exemplary unsubstituted acyl groups are of from 2 to 7 carbons. The term "acylamino," as used herein, represents an acyl group attached to the parent molecular group through a nitrogen atom. Exemplary unsubstituted acylamino groups are of from 2 to 7 carbons. The term "acyloxy," as used herein, represents an acyl group attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted acyloxy groups are of from 2 to 7 carbons. The term "alkenyl," as used herein, represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 6 carbons containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl and the like and may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of: (1) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) amino; (5) aryl; (6) arylalkoxy, wherein the alkylene group is of one to six carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (11) halo; (12) heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxy; (16) N-protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one to six carbon atoms; (21) thiol; (22) - CO2RA, wherein R is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (23) -C(O)NRBRc, wherein RB and Rc are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (24) -SO2RD, wherein RD is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (25) -SO2NR R , wherein R and R are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; and (26) -NR R , wherein R and R are independently selected from the group consisting of (a) hydrogen; (b) an N- protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group. The terms "alkoxy" or "alkyloxy," as used interchangeably herein, represent an alkyl group attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted alkoxy groups are of from 1 to 6 carbons. The terms "alkoxyalkyl" or "alkyloxyalkyl," as used interchangeably herein, represent an alkyl group to which is attached an alkoxy group. Exemplary unsubstituted alkoxyalkyl groups are of from 2 to 12 carbons. The terms "alkoxycarbonyl" or "alkyloxycarbonyl," as used interchangeably herein, represent an ester group; i.e. an alkoxy group, attached to the parent molecular group through a carbonyl group and is exemplified by methoxycarbonyl, ethoxycarbonyl and the like. Exemplary unsubstituted alkoxycarbonyl groups are of from 2 to 7 carbons. The term "alkyl," as used herein, represents a monovalent group derived from a straight or branched chain saturated hydrocarbon of, unless otherwise specified, from 1 to 6 carbons and is exemplified by methyl, ethyl, n- and iso- propyl, n-, sec-, iso- and tert-butyl, neopentyl and the like and may be optionally substituted with one, two, three or, in the case of alkyl groups of two carbons or more, four substituents independently selected from the group consisting of: (1) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) amino; (5) aryl; (6) arylalkoxy; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (11) halo; (12) heterocyclyl; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxyl; (16) N-protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one to six carbon atoms; (21) thiol; (22) -CO2RA, wherein RA is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (23) -C(O)NR R , R C wherein R and R are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (24) -SO2RD, wherein RD is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (25) -SO2NRERF, wherein RE and RF are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; and (26) -NRGRH, wherein RG and RH are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group. The term "alkylamino," as used herein, represents an alkyl group attached to the parent molecular group through a nitrogen atom. Exemplary unsubstituted alkylamino groups are of from 1 to 6 carbons. The term "alkylaminocarbonyl," as used herein, represents an alkylamino group attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted alkylaminocarbonyl groups are of from 2 to 7 carbons. The term "alkylaminosulfonyl," as used herein, represents an alkylamino group attached to the parent molecular group through an -SO2- group. Exemplary unsubstituted alkylaminosulfonyl groups are of from 1 to 6 carbons. The term "alkylene," as used herein, represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene and the like. The term "alkylsulfinyl," as used herein, represents an alkyl group attached to the parent molecular group through an -S(O)- group. Exemplary unsubstituted alkylsulfinyl groups are of from 1 to 6 carbons. The term "alkylsulfinylalkyl," as used herein, represents an alkyl group, as defined herein, substituted by an alkylsulfinyl group. Exemplary unsubstituted alkylsulfinylalkyl groups are of from 2 to 12 carbons. The term "alkylsulfonyl," as used herein, represents an alkyl group attached to the parent molecular group through an -SO2- group. Exemplary unsubstituted alkylsulfonyl groups are of from 1 to 6 carbons. The term "alkylsulfonylalkyl," as used herein, represents an alkyl group, as defined herein, substituted by a alkylsulfonyl group. Exemplary unsubstituted alkylsulfonylalkyl groups are of from 2 to 12 carbons. The term "alkylthio," as used herein, represents an alkyl group attached to the parent molecular group through a sulfur atom. Exemplary unsubstituted alkylthio groups are of from 1 to 6 carbons. The term "alkynyl," as used herein, represents monovalent straight or branched chain groups of from two to six carbon atoms containing a carbon- carbon triple bond and is exemplified by ethynyl, 1-propynyl, and the like and may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of: (1) alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) amino; (5) aryl; (6) arylalkoxy, wherein the alkylene group is of one to six carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (11) halo; (12) heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxy; (16) N-protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one to six carbon atoms; (21) thiol; (22) -CO2RA, wherein RA is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (23) - C(O)NRBRc, wherein RB and Rc are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (24) -SO2RD, wherein RD is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (25) -SO2NRERF, P F • wherein R and R are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; and (26) -NRGRH, wherein RG and RH are independently selected from the group consisting of (a) hydrogen; (b) an N- protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group. The term "amino," as used herein, represents an -NH2 group. The term "aminoalkyl," as used herein, represents an alkyl group, as defined herein, substituted by an amino group. The term "aryl," as used herein, represents a mono- or bicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like and may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylene group is of one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocyclyl; (25) (heterocyclyl)oxy; (26) (heterocyclyl)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32) N-protected aminoalkyl, wherein the alkylene group is of one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (36) - (CH2)qCO2RA, wherein q is zero to four and RA is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (37) -(CH2)qCONRBRc, wherein RB and Rc are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (38) -(CH2)qSO2RD, wherein RD is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (39) -(CH2)qSO2NRERF, , wherein RE and RF are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (40) -
(CH2)qNR R , wherein R and R are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluoroalkoxy; (45) aryloxy; (46) cycloalkoxy; (47) cycloalkylalkoxy; and (48) arylalkoxy. The terms "arylalkenyl" or "aralkenyl," as used interchangeably herein, represent an aryl group attached to the parent molecular group through an alkenyl group. Exemplary unsubstituted arylalkenyl groups are of from 8 to 16 carbons. The terms "arylalkoxy" or "aralkoxy," as used interchangeably herein, represent an arylalkyl group attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted arylalkoxy groups are of from 7 to 16 carbons. The terms "arylalkoxycarbonyl" or "aralkoxycarbonyl," as used interchangeably herein, represent an arylalkoxy group attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted arylalkoxycarbonyl groups are of from 8 to 17 carbons. The terms "arylalkyl" or "aralkyl," as used interchangeably herein, represent an aryl group attached to the parent molecular group through an alkyl group. Exemplary unsubstituted arylalkyl groups are of from 7 to 16 carbons. The terms "arylalkylamino" or "aralkylamino," as used interchangeably herein, represent an arylalkyl group attached to the parent molecular group through a nitrogen atom. Exemplary unsubstituted arylalkylamino groups are of from 7 to 16 carbons. The terms "arylalkylaminocarbonyl" or "aralkylaminocarbonyl," as used interchangeably herein, represents an arylalkylamino group attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted arylalkylaminocarbonyl groups are of from 8 to 17 carbons. The terms "arylalkylsulfinyl" or "aralkylsulfinyl," as used interchangeably herein, represent an arylalkyl group attached to the parent molecular group through an -SO- group. Exemplary unsubstituted arylalkylsulfinyl groups are of from 7 to 16 carbons. The terms "arylalkylsulfonyl" or "aralkylsulfonyl," as used interchangeably herein, represent an aralkyl group attached to the parent molecular group through an -SO2- group. Exemplary unsubstituted arylalkylsulfonyl groups are of from 7 to 16 carbons. The term "arylalkylthio" or " aralkylthio," as used interchangeably herein, represents an arylalkyl group attached to the parent molecular group through a sulfur atom. Exemplary unsubstituted arylalkylthio groups are of from 7 to 16 carbons. The term "arylamino," as used herein, represents an aryl group which is attached to the parent molecular group through a nitrogen atom. Exemplary unsubstituted arylamino groups are of 6 or 10 carbons. The term "arylaminocarbonyl," as used herein, represents an arylamino group attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted arylaminocarbonyl groups are of from from 7 or 11 carbons. The term "arylaminosulfonyl," as used herein, represents an arylamino group attached to the parent molecular group through an -SO2- group. Exemplary unsubstituted arylaminosulfonyl groups are of 6 or 10 carbons. The term "aryloxy," as used herein, represents an aryl group which is attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted aryloxy groups are of 6 or 10 carbons. The term "aryloxycarbonyl," as used herein, represents an aryloxy group which is attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted aryloxycarbonyl groups are of 7 or 11 carbons. The terms "aryloyl" or "aroyl," as used interchangeably herein, represent an aryl group which is attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted aryloxycarbonyl groups are of 7 or 11 carbons. The terms "aryloylamino" or "aroylamino," as used interchangeably herein, represent an aroyl group which is attached to the parent molecular group through a nitrogen atom. Exemplary unsubstituted aryloylamino groups are of 7 or 11 carbons. The term "arylsulfinyl," as used herein, represens an aryl group attached to the parent molecular group through an -SO- group. Exemplary unsubstituted arylsulfinyl groups are of 6 or 10 carbons. The term "arylsulfonyl," as used herein, represens an aryl group attached to the parent molecular group through an -SO2- group. Exemplary unsubstituted arylsulfonyl groups are of 6 or 10 carbons. The term "arylthio," as used herein, represents an aryl group which is attached to the parent molecular group through a sulfur atom. Exemplary unsubstituted arylthio groups are of 6 or 10 carbons. The term "azido," as used herein, represents an -N3 group. The term "azidoalkyl," as used herein, represents an alkyl group, as defined herein, substituted by an azido group. As used herein, the terms "cancer" or "neoplasm" or "neoplastic cells" is meant a collection of cells multiplying in an abnormal manner. Cancer growth is uncontrolled and progressive, and occurs under conditions that would not elicit, or would cause cessation of, multiplication of normal cells. The terms "carbamate" or "carbamyl," as used interchangeably herein, represent a RAOC(O)NRB- group, or a -OC(O)NRB- linkage, depending on the chemical context in which this term is used, wherein RA is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl; and RB is selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, as defined herein. The term "carbonate," as used herein represents a -RAOC(O)O- group, or a - OC(O)O- linkage, depending on the chemical context in which this term is used, wherein RA is selected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, as defined herein. The term "carbonyl," as used herein, represents a C=O group. The term "carboxaldehyde," as used herein, represents a -CHO group. The term "(carboxaldehyde)alkyl," as used herein, represents an alkyl group, as defined herein, substituted by a carboxaldehyde group. The term "carboxy," as used herein, represents a -CO2H group. The term "carboxyalkyl," as used herein, represents an alkyl group, as defined herein, substituted by a carboxy group. The term "cycloalkenyl," as used herein represents a monovalent cyclic hydrocarbon of from three to eight carbons, unless otherwise specified, having at least one carbon-carbon double bond. The cycloalkenyl groups of this invention can be optionally substituted with (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein die alkyl and alkylene groups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylene group is of one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocyclyl; (25) (heterocyclyl)oxy; (26) (heterocyclyl)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32) N-protected aminoalkyl, wherein the alkylene group is of one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (36) -(CH2)qCO2RA, wherein q is zero to four and RA is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (37) -(CH2)qCONRBRc, wherein RB and Rc are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (38) -(CH2)qSO2RD, wherein RD is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (39) - (CH2)qSO2NRERF, , wherein RE and RF are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (40) -(CH2)qNRGRH, wherein RG and RH are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluoroalkoxy; (45) aryloxy; (46) cycloalkoxy; (47) cycloalkylalkoxy; and (48) arylalkoxy. The term "cycloalkyl," as used herein represents a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group of from three to eight carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1.]heptyl and the like. The cycloalkyl groups of this invention can be optionally substituted with (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylene group is of one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocyclyl; (25) (heterocyclyl)oxy; (26) (heterocyclyl)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32) N-protected aminoalkyl, wherein the alkylene group is of one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (36) - (CH2)qCO2RA, wherein q is zero to four and RA is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (37) -(CH2)qCONRBRc, wherein RB and Rc are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (38) -(CH2)qSO2RD, wherein RD is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (39) -(CH2)qSO2NRERF, , wherein RE and RF are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (40) - (CH2)qNR R , wherein R and R are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluoroalkoxy; (45) aryloxy; (46) cycloalkoxy; (47) cycloalkylalkoxy; and (48) arylalkoxy. The term "cycloalkylamino," as used herein, represents a cycloalkyl group attached to the parent molecular group through a nitrogen atom.
Exemplary unsubstituted cycloalkylamino groups are of from 3 to 8 carbons. The term "cycloalkylaminocarbonyl," as used herein, represents a cycloalkylamino group attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted cycloalkylaminocarbonyl groups are of from 4 to 9 carbons. The terms "cycloalkyloxy" or "cycloalkoxy," as used interchangeably herein, represent a cycloalkyl group, as defined herein, attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted cycloalkyloxy groups are of from 3 to 8 carbons. The terms "cycloalkyloxycarbonyl" or "cycloalkoxycarbonyl," as used interchangeably herein, represent a cycloalkyloxy group, as defined herein, attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted cycloalkyloxycarbonyl groups are of from 4 to 9 carbons. The term "cycloalkylalkoxy," as used herein, represents an alkoxy group, as defined herein, to which is attached a cycloalkyl group. Exemplary unsubstituted cycloalkylalkoxy groups are of from 4 to 14 carbons. The term "cycloalkylalkyl," as used herein, represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an alkyl group. Exemplary unsubstituted cycloalkylalkyl groups are of from 4 to 14 carbons. The term "cycloalkylsulfinyl," as used herein, represents a cycloalkyl group attached to the parent molecular group through an -SO- group. Exemplary unsubstituted cycloalkylsulfinyl groups are of from 3 to 8 carbons. The term "cycloalkylsulfonyl," as used herein, represents a cycloalkyl group attached to the parent molecular group through an -SO2- group. Exemplary unsubstituted cycloalkylsulfonyl groups are of from 3 to 8 carbons. The term "dialkylamino," as used herein, represents an N,N- dialkylsubstituted amine attached to the parent molecular group through the nitrogen atom. The two alkyl substituents of a dialkylamino group can be the same or different, or can be joined together to form a ring. Exemplary dialkylamino groups are of from 2 to 12 carbons and include dimethylamino, diethylamino, pyrrolidino, and piperidino. By "an effective amount" is meant the amount of a compound, in a combination according to the invention, required to inhibit the growth of the cells of a neoplasm in vivo. The effective amount of active compound(s) used to practice the present invention for therapeutic treatment of neoplasms (i.e., cancer) varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount. The term "haloalkyl," as used herein, represents an alkyl group, as defined herein, substituted by one, two, or three halogen atoms and is exemplified by chloromethyl, bromoethyl, trifluoromethyl and the like. The terms "halo" or "halogen," as used interchangeably herein, represent F, CI, Br or I. The term "heteroaryl," as used herein, represents that subset of heterocycles, as defined herein, which are aromatic: i.e., they contain 4n+2 pi electrons within the mono- or multicyclic ring system. Exemplary unsubstituted heteroaryl groups are of from 1 to 9 carbons. The terms "heteroarylalkenyl" or "heteroaralkenyl," or as used interchangeably herein, represent a heteroaryl group, as defined herein, attached to the parent molecular group through an alkenyl group. Exemplary unsubstituted heteroarylalkenyl groups are of from 3 to 15 carbons. The terms "heteroarylalkyl" or "heteroaralkyl," as used interchangeably herein, represent a heteroaryl group, as defined herein, attached to the parent molecular group through an alkyl group. Exemplary unsubstituted heteroarylalkyl groups are of from 2 to 15 carbons. The terms "heteroarylalkylamino" or "heteroaralkylamino," as used interchangeably herein, represent a heteroarylalkyl group, as defined herein, attached to the parent molecular group through a nitrogen atom. Exemplary unsubstituted heteroarylalkylamino groups are of from 2 to 15 carbons. The terms "heteroarylalkylaminocarbonyl" or "heteroaralkylaminocarbonyl," or as used interchangeably herein, represent a heteroarylalkylamino group, as defined herein, attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted heteroarylalkylaminocarbonyl groups are of from 3 to 16 carbons. The terms "heteroaryloyl" or "heteroaroyl," or as used interchangeably herein, represent a heteroaryl group, as defined herein, attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted heteroaryloyl groups are of from 2 to 10 carbons. The terms "heteroarylalkyloxy" or "heteroaralkoxy," or as used interchangeably herein, represent a heteroarylalkyl group, as defined herein, attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted heteroarylalkyloxy groups are of from 2 to 15 carbons. The terms "heteroarylalkyloxycarbonyl" or "heteroaralkoxycarbonyl," as used interchangeably herein, represent a heteroaralkoxy group, as defined herein, attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted heteroarylalkyloxycarbonyl groups are of from 3 to 16 carbons. The terms "heteroarylalkylsulfonyl" or "heteroaralkylsulfonyl," as used interchangeably herein, represent a heteroarylalkyl group attached to the parent molecular group through an -SO2- group. Exemplary unsubstituted heteroarylalkylsulfonyl groups are of from 2 to 15 carbons. The term "heteroarylamino," as used herein, represents a heteroaryl group attached to the parent molecular group through a nitrogen atom. Exemplary unsubstituted heteroarylamino groups are of from 1 to 9 carbons. The term "heteroarylaminocarbonyl," as used herein, represents a heteroarylamino group attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted heteroarylaminocarbonyl groups are of from 2 to 10 carbons. The term "heteroarylaminosulfonyl," as used herein, represents a heteroarylamino group attached to the parent molecular group through an -SO2- group. Exemplary unsubstituted heteroarylaminosulfonyl groups are of from 1 to 9 carbons. The term "heteroaryloxy," as used herein, represents a heteroaryl group attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted heteroaryloxy groups are of from 1 to 9 carbons. The term "heteroaryloxycarbonyl," as used herein, represents a heteroaryloxy group attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted heteroaryloxycarbonyl groups are of from 1 to 9 carbons. The term "heteroarylsulfonyl," as used herein, represents a heteroaryl group attached to the parent molecular group through an -SO2- group. Exemplary unsubstituted heteroarylsulfonyl groups are of from 1 to 9 carbons. The term "heteroarylthio," as used herein, represents a heteroaryl group attached to the parent molecular group through a sulfur atom. Exemplary unsubstituted heteroaryloxy groups are of from 1 to 9 carbons. The terms "heterocycle" or "heterocyclyl," as used interchangeably herein represent a 5-, 6- or 7-membered ring, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The 5-membered ring has zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds. The term "heterocycle" also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring and another monocyclic heterocyclic ring such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, isoindazoyl, triazolyl, tetrazolyl, oxadiazolyl, uricyl, thiadiazolyl, pyrimidyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroinidolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothienyl and the like. Heterocyclic groups also include compounds of the formula
Figure imgf000027_0001
F' is selected from the group consisting of -CH2-, -CH2O- and -O-, and G' is selected from the group consisting of -C(O)- and -(C(R')(R"))V-, wherein R' and R" are independently selected from the group consisting of hydrogen or alkyl of one to four carbon atoms, and v is one to three and includes groups such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Any of the heterocycle groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylene group is of one to six carbon atoms; (20) cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24) heterocycle; (25) (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32) N-protected aminoalkyl, wherein the alkylene group is of one to six carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms; (36) - (CH2)qCO2RA, wherein q is zero to four and RA is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (37) -(CH2)qCONRBRc, wherein RB and Rc are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (38) -(CH2)qSO2RD, wherein RD is selected from the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (39) -(CH2)qSO2NRERF, , wherein RE and RF are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (40) - TJ c ι_ι
(CH2)qNR R , wherein R and R are independently selected from the group consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms; (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group; (41) oxo; (42) thiol; (43) perfluoroalkyl; (44) perfluoroalkoxy; (45) aryloxy; (46) cycloalkoxy; (47) cycloalkylalkoxy; and (48) arylalkoxy. The term "heterocyclylalkyl" represents a heterocyclyl group attached to the parent molecular group through an alkyl group. Exemplary unsubstituted heterocyclylalkyl groups are of from 2 to 15 carbons. The terms "heterocyclylamino" or "(heterocycle)amino," as used interchangeably herein, represents a heterocycle group, as defined herein, attached to the parent molecular group through nitrogen. Exemplary unsubstituted heterocyclylamino groups are of from 1 to 9 carbons. The terms "heterocyclyloxy" or " (heterocycle) oxy," as used interchangeably herein, represents a heterocycle group, as defined herein, attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted heterocyclyloxy groups are of from 1 to 9 carbons. The terms "heterocyclyloxycarbonyl" or "(heterocycle)oxycarbonyl," as used interchangeably herein, represents a heterocycloxy group, as defined herein, attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted heterocyclyloxycarbonyl groups are of from 2 to 10 carbons. The term "heterocyclyloyl" or "(heterocycle)oyl," as used interchangeably herein, represents a heterocycle group, as defined herein, attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted heterocyclyloyl groups are of from 2 to 10 carbons. The term "heterocyclylsulfonyl," as used herein, represents a heterocyclyl group attached to the parent molecular group through an -SO2- group. Exemplary unsubstituted heterocyclylsulfonyl groups are of from 1 to 9 carbons. The term "heterocyclylthio," as used herein, represents a heterocyclyl group attached to the parent molecular group through a sulfur atom.
Exemplary unsubstituted heteroaryloxy groups are of from 1 to 9 carbons. The term "hydroxy" as used herein, represents an -OH group. The term "hydroxyalkyl," as used herein, represents an alkyl group, as defined herein, substituted by one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group and is exemplified by hydroxymethyl, dihydroxypropyl and the like. By "inhibits the growth of a neoplasm" is meant measurably slows, stops, or reverses the growth rate of the neoplasm or neoplastic cells in vitro or in vivo. Desirably, a slowing of the growth rate is by at least 20%, 30%, 50%, or even 70%, as determined using a suitable assay for determination of cell growth rates (e.g., a cell growth assay described herein). Typically, a reversal of growth rate is accomplished by initiating or accelerating necrotic or apoptotic mechanisms of cell death in the neoplastic cells, resulting in a shrinkage of the neoplasm. By a "low dosage" is meant at least 10% less than the lowest standard recommended dosage of an anti-proliferative agent as recommended by the Physician 's Desk Reference, 57l Edition (2003). By a "high dosage" is meant at least 5% more than the highest standard dosage of an anti-proliferative agent. By a "moderate dosage" is meant the dosage between the low dosage and the high dosage. The term "methine" as used herein, represents a =C(H)- group. The term "N-protected amino," as used herein, refers to an amino group, as defined herein, to which is attached an N-protecting or nitrogen-protecting group, as defined herein. The term "N-protected aminoalkyl," as used herein, refers to an alkyl group, as defined herein, which is substituted by an N-protecting or nitrogen- protecting group, as defined herein. The terms "N-protecting group" or "nitrogen protecting group" as used herein, represent those groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N- protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis, 3rd Edition" (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. N-protecting groups comprise acyl, aroyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5- dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5- trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)- 1 -methyl ethoxycarbonyl, α, - dimethyl-3 ,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t- butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,- trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like, arylalkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t- butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The term "nitro," as used herein, represents an -NO group. The term "nitroalkyl," as used herein, represents an alkyl group substituted by an -NO2 group. By "non- vicinal O, S, or N" is meant an oxygen, sulfur, or substituted or unsubstituted nitrogen heteroatom substituent in a linkage, wherein the heteroatom substituent does not form a bond to a saturated carbon that is bonded to another heteroatom. The term "oxo," as used herein, represents =0. The term "perfluoroalkyl," as used herein, represents an alkyl group, as defined herein, wherein each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical. Perfluoroalkyl groups are exemplified by trifluoromethyl, pentafluoroethyl, and the like. The term "perfluoroalkoxy," as used herein, refers to a perfluoroalkyl group, as defined herein, attached to the parent molecular group through an oxygen atom. The term "pharmaceutically acceptable salt," as use herein, represents those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences 66: 1-19, 1977. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. The term "pharmaceutically acceptable ester," as used herein, represents esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl group preferably has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyates, acrylates and ethylsuccinates. The term "pharmaceutically acceptable prodrugs" as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with with the tissues of humans and animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug," as used herein, represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and Judkins et al., Synthetic Communications 26(23):4351-4367, 1996), each of which is incorporated herein by reference. By "ring system substituent" is meant a substituent attached to an aromatic or non-aromatic ring system. When a ring system is saturated or partially saturated the "ring system substituent" further includes methylene (double bonded carbon), oxo (double bonded oxygen) or thioxo (double bonded sulfur). The term "spiroalkyl," as used herein, represents an alkylene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group. The term "sulfonyl," as used herein, represents an -SO2- group. The term "thioalkoxy," as used herein, represents represents an alkyl group attached to the parent molecular group through a sulfur atom. Exemplary unsubstituted thioalkoxy groups are of from 1 to 6 carbons. The term "thioalkoxyalkyl," as used herein, represents an alkyl group substituted by a thioalkoxy group. Exemplary unsubstituted thioalkoxyalkyl groups are of from 2 to 12 carbons. By "thiocarbonyl" is meant a -C(S)- group. By "thiol" is meant an -SH group. Asymmetric or chiral centers may exist in the compounds of the present invention. The present invention contemplates the various stercoisomers and mixtures thereof. Individual stereoisomers of compounds or the present invention are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of mixtures of enantiometic compounds followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a racemic mixture of enantiomers, designated (+/-), to a chiral auxiliary, separation of the resulting diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Enantiomers are designated herein by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. Geometric isomers may also exist in the compounds of the present invention. The present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond and designates such isomers as of the Z or E configuration, wherein the term "Z" represents substituents on the same side of the carbon-carbon double bond and the term "E" represents substituents on opposite sides of the carbon-carbon double bond. It is also recognized that for structures in which tautomeric forms are possible, the description of one tautomeric form is equivalent to the description of both, unless otherwise specified. For example, ami dine structures of the formula -C(=NRQ)NHRT and -C(NHRQ)=NRT, where Rτ and RQ are different, are equivalent tautomeric structures and the description of one inherently includes the other. By "Group A antiproliferative agent" is meant an agent listed in Table 1. Table 1.
Alkylating agents cyclophosphamide lomustine busulfan procarbazine ifosfamide altretamine melphalan estramustine phosphate hexamethylmelamine mechlorethamine thiotepa streptozocin chlorambucil temozolomide dacarbazine semustine. carmustine
Platinum agents cisplatin carboplatinum oxaliplatin ZD-0473 (AnorMED) spiroplatinum, lobaplatin (Aetema) carboxyphthalatoplatinum, satraplatin (Johnson Matthey) tetraplatin BBR-3464 (Hoffmann-La Roche) ormiplatin SM- 11355 (Sumitomo) iproplatin AP-5280 (Access)
Antimetabolites azacytidine tomudex gemcitabine trimetrexate capecitabine deoxycoformycin 5-fluorouracil fludarabine floxuridine pentostatin 2-chlorodeoxyadenosine raltitrexed 6-mercaptopurine hydroxyurea 6-thioguanine decitabine (SuperGen) cytarabin clofarabine (Bioenvision) 2-fluorodeoxy cytidine irofulven (MGI Pharma) methotrexate DMDC (Hoffmann-La Roche) idatrexate ethynylcytidine (Taiho)
Topoisomerase Amsacrine rubitecan (SuperGen) inhibitors epirubicin exatecan mesylate (Daiichi) etoposide quinamed (ChemGenex) teniposide or mitoxantrone gimatecan (Sigma-Tau) irinotecan (CPT-l l) diflomotecan (Beaufour-Ipsen) 7-ethyl- 10-hydroxy-camptothecin TAS-103 (Taiho) topotecan elsamitrucin (Spectrum) dexrazoxanet (TopoTarget) J-107088 (Merck & Co) pixantrone (Novuspharma) BNP-1350 (BioNumerik) rebeccamycin analogue (Exelixis) CKD-602 (Chong Kun Dang) BBR-3576 (Novuspharma) KW-2170 (Kyowa Hakko) Table 1 (cont.)
Anti tumor dactinomycin (actinomycin D) amonafide antibiotics doxorubicin (adriamycin) azonafide deoxyrubicin anthrapyrazole valrubicin oxantrazole daunorubicin (daunomycin) losoxantrone epirubicin bleomycin sulfate (blenoxane) therarubicin bleomycinic acid idarubicin bleomycin A rubidazone bleomycin B plicamycinp mitomycin C porfiromycin MEN-10755 (Menarini) cyanomorpholinodoxorubicin GPX-100 (Gem Pharmaceuticals) mitoxantrone (novantrone)
Antimitotic paclitaxel SB 408075 (GlaxoSmithKline) agents docetaxel E7010 (Abbott) colchicine PG-TXL (Cell Therapeutics) vinblastine IDN 5109 (Bayer) vincristine A 105972 (Abbott) vinorelbine A 204197 (Abbott) vindesine LU 223651 (BASF) dolastatin 10 (NCI) D 24851 (ASTAMedica) rhizoxin (Fujisawa) ER-86526 (Eisai) mivobulin (Warner-Lambert) combretastatin A4 (BMS) cemadotin (BASF) isohomohalichondrin-B (PharmaMar) RPR 109881A (Aventis) ZD 6126 (AstraZeneca) TXD 258 (Aventis) PEG-paclitaxel (Enzon) epothilone B (Novartis) AZ 10992 (Asahi) T 900607 (Tularik) IDN-5109 (Indena) T 138067 (Tularik) AVLB (Prescient NeuroPharma) cryptophycin 52 (Eli Lilly) azaepothilone B (BMS) vinflunine (Fabre) BNP-7787 (BioNumerik) auristatin PE (Teikoku Hormone) CA-4 prodrug (OXiGENE) BMS 247550 (BMS) dolastatin- 10 (NIH) BMS 184476 (BMS) CA-4 (OXiGENE) BMS 188797 (BMS) taxoprexin (Protarga)
Aromatase Aminoglutethimide exemestane inhibitors letrozole atamestane (BioMedicines) anastrazole YM-511 (Yamanouchi) formestane
Thymidylate pemetrexed (Eli Lilly) nolatrexed (Eximias) synthase inhibitors ZD-9331 (BTG) CoFactor™ (BioKeys)
DNA antagonists trabectedin (PharmaMar) mafosfamide (Baxter International) glufosfamide (Baxter International) apaziquone (Spectrum albumin + 32P (Isotope Solutions) Pharmaceuticals) thymectacin (NewBiotics) 06 benzyl guanine (Paligent) edotreotide (Novartis)
Famesyltransferase arglabin (NuOncology Labs) tipifarnib (Johnson & Johnson) inhibitors lonafarnib (Schering-Plough) perillyl alcohol (DOR BioPharma) BAY-43-9006 (Bayer) Table 1 (cont.)
Pump inhibitors CBT-l (CBA Pharma) zosuquidar trihydrochloride (Eli Lilly) tariquidar (Xenova) biricodar dicitrate (Vertex) MS-209 (Schering AG)
Histone tacedinaline (Pfizer) pivaloyloxymethyl butyrate (Titan) acetyltransferase SAHA (Aton Pharma) depsipeptide (Fujisawa) inhibitors MS-275 (Schering AG)
Metalloproteinase Neovastat (Aeterna Laboratories) CMT-3 (CollaGenex) inhibitors marimastat (British Biotech) BMS-275291 (Celltech)
Ribonucleoside gallium maltolate (Titan) tezacitabine (Aventis) reductase inhibitors triapine (Vion) didox (Molecules for Health)
TNF alpha virulizin (Lorus Therapeutics) revimid (Celgene) agonists/antagonists CDC-394 (Celgene)
Endothelin A atrasentan (Abbott) YM-598 (Yamanouchi) receptor antagonist ZD-4054 (AstraZeneca)
Retinoic acid fenretinide (Johnson & Johnson) alitretinoin (Ligand) receptor agonists LGD-1550 (Ligand)
Immuno- interferon dexosome therapy (Anosys) modulators oncophage (Antigenics) pentrix (Australian Cancer GMK (Progenies) Technology) adenocarcinoma vaccine (Biomira) ISF-154 (Tragen) CTP-37 (AVI BioPharma) cancer vaccine (Intercell) IRX-2 (Immuno-Rx) norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) synchrovax vaccines (CTL Immuno) MGV (Progenies) melanoma vaccine (CTL Immuno) β-alethine (Dovetail) p21 RAS vaccine (GemVax) CLL therapy (Vasogen)
Hormonal and estrogens prednisone antihormonal conjugated estrogens methylprednisolone agents ethinyl estradiol prednisolone chlortrianisen aminoglutethimide idenestrol leuprolide hydroxyprogesterone caproate goserelin medroxyprogesterone leuporelin testosterone bicalutamide testosterone propionate; flutamide fluoxymesterone octreotide methyltestosterone nilutamide diethylstilbestrol mitotane megestrol P-04 (Novogen) tamoxifen 2-methoxyestradiol (EntreMed) toremofϊne arzoxifene (Eli Lilly) dexamethasone
Photodynamic talaporfin (Light Sciences) Pd-bacteriopheophorbide (Yeda) agents Theralux (Theratechnologies) lutetium texaphyrin (Pharmacyclics) motexafin gadolinium (Pharmacyclics) hypericin Table 1 (cont.)
Tyrosine Kinase imatinib (Novartis) kahalide F (PharmaMar)
Inhibitors leflunomide (Sugen/Pharmacia) CEP-701 (Cephalon) ZD1839 (AstraZeneca) CEP-751 (Cephalon) erlotinib (Oncogene Science) MLN518 (Millenium) canertinib (Pfizer) PKC412 (Novartis) squalamine (Genaera) phenoxodiol () SU5416 (Pharmacia) trastuzumab (Genentech) SU6668 (Pharmacia ) C225 (ImClone) ZD4190 (AstraZeneca) rhu-Mab (Genentech) ZD6474 (AstraZeneca) MDX-H210 (Medarex) vatalanib (Novartis) 2C4 (Genentech) PKI166 (Novartis) MDX-447 (Medarex) GW2016 (GlaxoSmithKline) ABX-EGF (Abgenix) EKB-509 (Wyeth) IMC-1C11 (ImClone) EKB-569 (Wyeth)
Miscellaneous agents
SR-27897 (CCK A inhibitor, Sanofi-Synthelabo) BCX- 1777 (PNP inhibitor, BioCryst) tocladesine (cyclic AMP agonist, Ribapharm) ranpimase (ribonuclease stimulant, Alfacell) alvocidib (CDK inhibitor, Aventis) galarubicin (RNA synthesis inhibitor, Dong-A)
CV-247 (COX-2 inhibitor, Ivy Medical) tirapazamine (reducing agent, SRI International)
P54 (COX-2 inhibitor, Phytopharm) N-acetylcysteine (reducing agent, Zambon)
CapCell™ (CYP450 stimulant, Bavarian Nordic) R-flurbiprofen (NF-kappaB inhibitor, Encore)
GCS-100 (gal3 antagonist, GlycoGenesys) 3CPA (NF-kappaB inhibitor, Active Biotech)
G17DT immunogen (gastrin inhibitor, Aphton) seocalcitol (vitamin D receptor agonist, Leo) efaproxiral (oxygenator, Allos Therapeutics) 131-I-TM-601 (DNA antagonist, TransMolecular)
PI-88 (heparanase inhibitor, Progen) eflornithine (ODC inhibitor , ILEX Oncology) tesmilifene (histamine antagonist, YM minodronic acid (osteoclast inhibitor,
BioSciences) Yamanouchi) histamine (histamine H2 receptor agonist, indisulam (p53 stimulant, Eisai)
Maxim) aplidine (PPT inhibitor, PharmaMar) tiazofurin (IMPDH inhibitor, Ribapharm) rituximab (CD20 antibody, Genentech) cilengitide (integrin antagonist, Merck KGaA) gemtuzumab (CD33 antibody, Wyeth Ayerst)
SR-31747 (IL-1 antagonist, Sanofi-Synthelabo) PG2 (hematopoiesis enhancer, Pharmagenesis)
CCI-779 (mTOR kinase inhibitor, Wyeth) Immunol™ (triclosan oral rinse, Endo) exisulind (PDE V inhibitor, Cell Pathways) triacetyluridine (uridine prodrug , Wellstat)
CP-461 (PDE V inhibitor, Cell Pathways) SN-4071 (sarcoma agent, Signature BioScience)
AG-2037 (GART inhibitor, Pfizer) TransMID-107™ (immunotoxin, KS Biomedix)
WX-UK1 (plasminogen activator inhibitor, PCK-3145 (apoptosis promotor, Procyon)
Wilex) doranidazole (apoptosis promotor, Pola)
PBI-1402 (PMN stimulant, ProMetic CHS-828 (cytotoxic agent, Leo)
LifeSciences) trans-retinoic acid (differentiator, NIH) bortezomib (proteasome inhibitor, Millennium) MX6 (apoptosis promotor, MAXIA)
SRL-172 (T cell stimulant, SR Pharma) apomine (apoptosis promotor, ILEX Oncology)
TLK-286 (glutathione S transferase inhibitor, urocidin (apoptosis promotor, Bioniche)
Telik) Ro-31-7453 (apoptosis promotor, La Roche)
PT-100 (growth factor agonist, Point brostallicin (apoptosis promotor, Pharmacia)
Therapeutics) midostaurin (PKC inhibitor, Novartis) bryostatin-1 (PKC stimulant, GPC Biotech)
CDA-II (apoptosis promotor, Everlife)
SDX-101 (apoptosis promotor, Salmedix) ceflatonin (apoptosis promotor, ChemGenex) BRIEF DESCRIPTION OF THE DRAWING Figure 1 is three plots showing compound concentration vs. cell proliferation inhibition for compound 1 [plot A, EC50 (HCT cells) = 10 μM, EC50 (A549 cells) = 16 μM], compound 2 (plot B, EC50 (HCT cells) = 12 μM, EC50 (A549 cells) = 19 μM], and compound 3 [EC50 (HCT cells) = 11 μM, EC5o (A549 cells) = 7 μM]. Peak concentrations and dilution factors are listed on the top of each graph set.
DETAILED DESCRIPTION Compounds of formula I can be prepared as shown in Scheme 1.
Scheme I
n
Figure imgf000041_0001
(VII) Compounds of formula V and VIII can be prepared as described by Lin et al., in U.S. Patent Application Serial No. 09/849,000, using the phenothiazines of formula IV as a starting point. Compounds of formula VIII can then be reacted with nucleophiles to displace the chloro group resulting in compounds of formula X. In one example, the nucleophile is a secondary amine, resulting in compounds of formula I where R9 is
Figure imgf000042_0001
X is N and m, n, o, p, q, Y, Z, A,
B R10 and R11 are as previously defined herein. In another example, the nucleophile is a primary amine, resulting in compounds of formula I where R9 is
Figure imgf000042_0002
where X1 is NH and m, n, o, p, q, Y,
Z, A, B R10 and R1 ' are as previously defined herein. Compounds of formula VIII can be also be used to form organometallic compounds, such as cuprates, which can be subsequently reacted with activated olefins, such as α,β-unsaturated ketones or esters. In one example, the cuprate is reacted with an α,β-unsaturated ester of the formula XI: H^O^^^-v^O-Protecting group O (XI), which can be subsequently refunctionalized and carried on synthetically by reactions known to those skilled in the art to produce compounds of formula I where R9 is
Figure imgf000043_0001
where X2 is CH and m, n, o, p, q, Y, Z, A, B R10 and R1 ' are as previously defined herein. In an alternate synthesis of compounds of formula I where R9 is
Figure imgf000043_0002
compounds of formula V can be oxidized to aldehydes of formula VI. In examples where W is S, oxidants such as Dess-Martin reagent are particularly preferred. A compound of formula VI can then be reacted with a secondary amine (each of Ra and R is, independently an optionally substituted alkyl, aryl, or heteroaryl as shown in Scheme 1) or with a primary amine (Ra is an optionally substituted alkyl, aryl, or heteroaryl and Rb is H) in a reductive amination procedure to produce compounds of formula VII.
Assay for Antiproliferative Activity The compound dilution matrix was assayed using the bromodeoxyuridine (BrdU) cytoblot method. In the present invention, the assay was performed using both A549 and HCT cells. Forty-five microliters of a suspension containing A549 lung adenocarcinoma cells (ATCC# CCL-185) was seeded in a white opaque polystyrene cell culture treated sterile 384- well plate (NalgeNunc #164610) using a multidrop (Labsystems) to give a density of 3000 cells per well. Fifteen microliters of the compound mixture matrix for compounds 1, 2, and 3 was added to each well of the plate containing the cells at concentrations ranging from 0.02 μM to 70 μM (2X dilutions). The compound mixture matrix was transferred using a 16-channel pipettor (Finnpipette). Each experiment was conducted in triplicate plates. After incubation for 72 hours at 37°C, BrdU was added to each well at a concentration of 10 μM. After 16 hours, the media was aspirated and the cells were fixed by the addition of 70% ethanol and phosphate-buffered saline (PBS) at room temperature for 1 hour. The fixative was aspirated and 2N HC1 with Tween 20 (polyoxyethylene sorbitan monolaurate) was added to each well and the plates were incubated for 20 minutes at room temperature. The HC1 was neutralized with a solution of 2N NaOH and the cells were washed twice with Hank's Balanced Salt Solution (HBSS) and once with PBS containing 0.5% bovine serum albumin (BSA) and 0.1% Tween 20. The wash solution was removed and mouse anti-BrdU primary antibody (PharMingen #555627) was diluted 1: 1000 in PBS containing BSA, Tween 20, and secondary antibody at a dilution of 1 :2000 (Amersham #NA931). The secondary antibody recognizes the mouse antibody and it is conjugated to the enzyme horseradish peroxidase (HRP). After one hour of incubation, the antibody solution was removed and the cells washed once with PBS. After the PBS wash, the HRP substrate (which contains luminol, hydrogen peroxide, and an enhancer such as para- iodophenol) was added to each well. The plates were read using an LJL Analyst. All aspirations as well as the washes with PBS and HBSS were performed using a TEC AN Power Washer 384. The amount of light output from each well indicates the amount of DNA synthesis that occurred in that well. Decreased light indicates antiproliferative action of the compounds. Luminescence for each position in the dilution matrix was divided into the luminescence values for A549 or HCT cells treated with only DMSO vehicle, providing antiproliferative ratios for each position in the dilution matrix for compounds 1, 2, and 3, respectively. The anti-proliferative effect demonstrated with A459 cells can be similarly demonstrated using other cancer cell lines, such as MCF7 mammary adenocarcinoma, PA-1 ovarian teratocarcinoma, HT29 colorectal adenocarcinoma, HI 299 large cell carcinoma, U-2 OS osteogenic sarcoma, U- 373 MG glioblastoma, Hep-3B hepatocellular carcinoma, BT-549 mammary carcinoma, T-24 bladder cancer, C-33 A cervical carcinoma, HT-3 metastatic cervical carcinoma, SiHa squamous cervical carcinoma, CaSki epidermoid cervical carcinoma, NCI-H292 mucoepidermoid lung carcinoma, NCI-2030, non small cell lung carcinoma, HeLa, epithelial cervical adenocarcinoma, KB epithelial mouth carcinoma, HT1080 epithelial fibrosarcoma, Saos-2 epithelial osteogenic sarcoma, PC3 epithelial prostate adenocarcinoma, SW480 colorectal carcinoma, CCL-228, and MS-751 epidermoid cervical carcinoma cell lines. The specificity can be tested by using cells such as NHLF lung fibroblasts, NHDF dermal fibroblasts, HMEC mammary epithelial cells, PrEC prostate epithelial cells, HRE renal epithelial cells, NHBE bronchial epithelial cells, CoSmC Colon smooth muscle cells, CoEC colon endothelial cells, NHEK epidermal keratinocytes, and bone marrow cells as control cells.
Therapy The compounds of the invention are useful for the treatment of neoplasms. Therapy may be performed alone or in conjunction with another therapy (e.g., surgery, radiation therapy, chemotherapy, immunotherapy, anti- angiogenesis therapy, or gene therapy). For example, useful chemotherapeutic agents that can be used in a compound of formula I are listed in Table (I) and are referred to a "Group A antiproliferative agents." The duration of the combination therapy depends on the type of disease or disorder being treated, the age and condition of the patient, the stage and type of the patient's disease, and how the patient responds to the treatment. Therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recovery from any as yet unforeseen side- effects. Examples of cancers and other neoplasms include, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodenriglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).
Formulation of Pharmaceutical Compositions The administration of each compound of the combination may be by any suitable means that results in a concentration of the compound that, combined with the other component, is anti-neoplastic upon reaching the target region. The compound may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route. Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A.R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
Dosages The dosage of each compound of the claimed combinations depends on several factors, including: the administration method, the neoplasm to be treated, the severity of the neoplasm, whether the neoplasm is to be treated or prevented, and the age, weight, and health of the patient to be treated. For combinations that include a compound of formula I and another anti-proliferative agent of Group A, the recommended dosage for the anti- proliferative agent is desirably less than or equal to the recommended dose as given in the Physician 's Desk Reference, 57th Edition (2003). As described above, the compound in question may be administered orally in the form of tablets, capsules, elixirs or syrups, or rectally in the form of suppositories. Parenteral administration of a compound is suitably performed, for example, in the form of saline solutions or with the compound incorporated into liposomes. In cases where the compound in itself is not sufficiently soluble to be dissolved, a solubilizer such as ethanol can be applied. A chemotherapeutic agent of the invention is usually given by the same route of administration that is known to be effective for delivering it as a monotherapy. For example, when used in combination therapy a compound of formula I, a Group A antiproliferative agent is dosed in amounts and frequencies equivalent to or less than those that result in its effective monotherapeutic use. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. What is claimed is:

Claims

1. A compound having the formula I:
Figure imgf000049_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein R2 is selected from the group consisting of: H, CF3, halo, OCH3, COCH3, CN, OCF3, COCH2CH3, CO(CH2)2CH3, and SCH2CH3; each of R1, R3, R4, R5, R6, R7, and R8 is independently H, OH, F, OCF3, or OCH3; W is selected from the group consisting of: O, S, NH, S(O), S(O)2, CH2, and CH=CH; and R9 is selected from the group consisting of:
Figure imgf000049_0002
(CH2)— Y-(CH2)n-A _-DR!0
X1 (CH2)5-Z-(CH2)-B-R11
Figure imgf000049_0003
X1 is CH2 or NR16, wherein NR16 is H or C1-6 alkyl; X2 is CH or N; each of Y and Z is, independently, O, CH2, or NR17, wherein NR17 is H or C1-6 alkyl; each of A and B is, independently, an optionally substituted C6 or Cι0 aryl or an optionally substituted C2-9 heteroaryl, each of R10 and R11 is, independently
Figure imgf000050_0001
wherein R13 is H, C C6 alkyl, C C8 cycloalkyl, C2-C12 alkoxyalkyl, C2-C6 hydroxyalkyl, CrC6 alkylamino C2-C6 alkyl, amino Cι-C6 alkyl, or C6 or Cio aryl, R14 is H, CrC6 alkyl, C C8 cycloalkyl, C C6 alkyloxy, C2- C12 alkoxyalkyl, C2-C6 hydroxyalkyl, C3-C]2 alkylaminoalkyl, C -Cι2 1 7 dialkylaminoalkyl, C2-C6 aminoalkyl, or C6 orCio aryl, and R is H, OH, or C C6 alkyloxy, carbonyl(CrC6 alkoxy), carbonyl(C7-ι6 aralkoxy), carbonyl(C6 or Cio aryloxy), or R and R together represent
Figure imgf000050_0002
wherein each of R15, R16, and R17 is, independently, H, Cι-C6 alkyl, halogen, or trifluoromethyl, each of R18, R19, R20, and R21 is, independently, H or Cι-C6 alkyl, and R22 is H, halogen, trifluoromethyl, OCF3, NO2, C,-C6 alkyl, CrC8 cycloalkyl, C C6 alkyloxy, C2-C12 alkoxyalkyl, C2-C6 hydroxyalkyl, C3-C]2 alkylaminoalkyl, C4-Cι2 dialkylaminoalkyl, C2-C6 aminoalkyl, or C6 or Cι0 aryl; q is 2 or 3; each of m and o is, independently,
2 or 3; and each of n and p is, independently, 0 or 1.
The compound of claim 1, wherein W is S, NH, S(O), S(O)2.
3. The compound of claim 2, wherein W is S
4. The compound of claim 1 , wherein R is
Figure imgf000051_0001
5. The compound of claim 1 , wherein R9 is
Figure imgf000051_0002
The compound of claim 1 , wherein R9 is
Figure imgf000051_0003
7. The compound of claim 6, wherein each of m and n is 2; each of n and p is 0; q is 3; each of Y and Z is O; and each of -A-R10 and -B-R1 x is
Figure imgf000051_0004
The compound of claim 1 , wherein R9 is
Figure imgf000051_0005
9. The compound of claim 8, wherein each of m and n is 2; each of n and p is 0; q is 3; each of Y and Z is O; X2 is N; and each of -A-R10 and -B-R11 is
Figure imgf000052_0001
10. Use of a compound of formula I in the preparation of a medicament for treating a patient having a neoplasm, wherein said compound of formula I is:
Figure imgf000052_0002
or a pharmaceutically acceptable salt or prodrug thereof, wherein R is selected from the group consisting of: H, CF3, halo, OCH3, COCH3, CN, OCF3, COCH2CH3, CO(CH2)2CH3, and SCH2CH3; each of R1, R3, R4, R5, R6, R7, and R8 is independently H, OH, F, OCF3, or OCH3; W is selected from the group consisting of: O, S, NH, S(O), S(O)2, CH2, and CH=CH; and R9 is selected from the group consisting of:
Figure imgf000052_0003
Figure imgf000053_0001
X1 is CH2 or NR16, wherein NR16 is H or C1-6 alkyl; X2 is CH or N; each of Y and Z is, independently, O, CH2, or NR17, wherein NR17 is H or C)-6 alkyl; each of A and B is, independently, an optionally substituted C6 or C)0 aryl or an optionally substituted C2-9 heteroaryl, each of R10 and R11 is, independently
Figure imgf000053_0002
wherein R1 is H, Cι-C6 alkyl, Cj-Cg cycloalkyl, C2- 2 alkoxyalkyl, C2-C6 hydroxyalkyl, Cι-C alkylamino C2-C6 alkyl, amino C]-C6 alkyl, or C6 or Cio aryl, R14 is H, CrC6 alkyl, C C8 cycloalkyl, C C6 alkyloxy, C2- C12 alkoxyalkyl, C2-C6 hydroxyalkyl, C3-Cj2 alkylaminoalkyl, C -Cι2 1 9 dialkylaminoalkyl, C2-C6 aminoalkyl, or C6 orCio aryl, and R is H, OH, or C]-C6 alkyloxy, carbonyl(C C6 alkoxy), carbonyl(C7-ι6 aralkoxy), carbonyl(C6 or Cio aryloxy), or R and R together represent
Figure imgf000053_0003
wherein each of R15, R16, and R17 is, independently, H, Cι-C6 alkyl, halogen, or trifluoromethyl, each of R18, R19, R20, and R21 is, independently, H or Cι-C6 alkyl, and R22 is H, halogen, trifluoromethyl, OCF3, NO2, CrC6 alkyl, CrC8 cycloalkyl, C,-C6 alkyloxy, C2-C,2 alkoxyalkyl, C2-C6 hydroxyalkyl, C3-Cι2 alkylaminoalkyl, C4-Cι2 dialkylaminoalkyl, C2-C6 aminoalkyl, or C6 or o aryl; q is 2 or 3; each of m and o is, independently, 2 or 3; and each of n and p is, independently, 0 or 1.
11. The use of claim 10, wherein said neoplasm is cancer.
12. The use of claim 11, wherein said cancer is selected from the group consisting of acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's disease, non- Hodgkin's disease, Waldenstrom's macroglobulinemia, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendriglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.
13. The use of claim 11 , wherein said medicament is administered to said patient in addition to a second treatment for cancer, wherein said medicament and said second treatment are administered within 6 months of each other.
14. The use of claim 13, wherein said second treatment comprises surgery, radiation therapy, chemotherapy, immunotherapy, anti-angiogenesis therapy, or gene therapy.
15. The use of claim 13, wherein said second treatment comprises chemotherapy with one or more Group A antiproliferative agents.
16. The use of claim 15, wherein said antiproliferative agent is selected from bleomycin, carmustine, cisplatin, daunorubicin, etoposide, melphalan, mercaptopurine, methotrexate, mitomycin, vinblastine, paclitaxel, docetaxel, vincristine, vinorelbine, cyclophosphamide, chlorambucil, gemcitabine, capecitabine, 5-fluorouracil, fludarabine, raltitrexed, irinotecan, topotecan, doxorubicin, epirubicin, letrozole, anastrazole, formestane, exemestane, tamoxifen, toremofine, goserelin, leuporelin, bicalutamide, flutamide, nilutamide, hypericin, trastuzumab, and rituximab, or any combination thereof.
17. The use of claim 16, wherein said cancer is lung cancer.
18. The use of claim 17, wherein said lung cancer is selected from the group consisting of squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.
19. The use of claim 11, wherein said cancer is colon cancer.
20. The use of claim 11, wherein said cancer is a cancer of the ovary.
21. The use of claim 20, wherein said cancer of the ovary is adenocarcinoma.
22. The use of claim 11 , wherein said cancer is prostate cancer.
23. Use of a compound of formula I in the preparation of a medicament for inhibiting the development of a neoplasm in a patient, wherein said compound of formula I is:
Figure imgf000056_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein R2 is selected from the group consisting of: H, CF3, halo, OCH3, COCH3, CN, OCF3, COCH2CH3, CO(CH2)2CH3, and SCH2CH3; each of R1, R3, R4, R5, R6, R7, and R8 is independently H, OH, F, OCF3, or OCH3; W is selected from the group consisting of: O, S, NH, S(O), S(O)2, CH2, and CH=CH; and R9 is selected from the group consisting of:
( r 'q ( rl q x, (CH2)0-Z-(CH2)-A-R1
Figure imgf000056_0002
Figure imgf000057_0001
wherein X1 is CH2 or NR16, wherein NR16 is H or C1-6 alkyl; X2 is CH or N; each of Y and Z is, independently, O, CH2, or NR17, wherein NR17 is H or Cι_6 alkyl; each of A and B is, independently, an optionally substituted C6 or o aryl or an optionally substituted C2- heteroaryl, each of R10 and R11 is, independently
Figure imgf000057_0002
wherein R is H, Cι-C6 alkyl, C C8 cycloalkyl, C2-C)2 alkoxyalkyl, C2-C6 hydroxyalkyl, C C6 alkylamino C2-C6 alkyl, amino C C6 alkyl, or C6 or Cio aryl, R14 is H, CrC6 alkyl, CrC8 cycloalkyl, C,-C6 alkyloxy, C2- C12 alkoxyalkyl, C2-C6 hydroxyalkyl, C3-Cι2 alkylaminoalkyl, C -Cι dialkylaminoalkyl, C2-C6 aminoalkyl, or C6 orCio aryl, and R12 is H, OH, or C C6 alkyloxy, carbonyl(C C6 alkoxy), carbonyl(C7-ι6 aralkoxy), carbonyl(C6 or Cio aryloxy), or R12 and R13 together represent
R15 R16, R17, N=N , R19 R20 , or R22 , wherein each of R15, R16, and R17 is, independently, H, C C6 alkyl, halogen, or trifluoromethyl, each of R18, R19, R20, and R21 is, independently, H or C C6 alkyl, and R22 is H, halogen, trifluoromethyl, OCF3, NO2, C,-C6 alkyl, C,-C8 cycloalkyl, CrC6 alkyloxy, C2-C,2 alkoxyalkyl, C2-C6 hydroxyalkyl, C3-Cι2 alkylaminoalkyl, C4-Cι2 dialkylaminoalkyl, C2-C6 aminoalkyl, or C6 or Cio aryl; q is 2 or 3; each of m and o is, independently, 2 or 3; and each of n and p is, independently, 0 or 1.
24. A pharmaceutical composition comprising a compound having the formula:
Figure imgf000058_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein R2 is selected from the group consisting of: H, CF3, halo, OCH3, COCH3, CN, OCF3, COCH2CH3, CO(CH2)2CH3, and SCH2CH3; each of R1, R3, R4, R5, R6, R7, and R8 is independently H, OH, F, OCF3, or OCH3; W is selected from the group consisting of: O, S, NH, S(O), S(O)2, CH2, and CH=CH; and R9 is selected from the group consisting of:
Figure imgf000058_0002
and
Figure imgf000059_0001
wherein X1 is CH2 or NR16, wherein NR16 is H or C,-6 alkyl; X2 is CH or N; each of Y and Z is, independently, O, CH2, or NR17, wherein NR17 is H or Cι-6 alkyl; each of A and B is, independently, an optionally substituted C6 or C]0 aryl or an optionally substituted C2-9 heteroaryl, each of R10 and R11 is, independently
Figure imgf000059_0002
wherein R13 is H, C C6 alkyl, Cι-C8 cycloalkyl, C2-Cι2 alkoxyalkyl, C2-C6 hydroxyalkyl, Cι-C6 alkylamino C2-C6 alkyl, amino Cι-C6 alkyl, or C6 or Cio aryl, R14 is H, CrC6 alkyl, CrC8 cycloalkyl, CrC6 alkyloxy, C2- C12 alkoxyalkyl, C2-C6 hydroxyalkyl, C3-Cj2 alkylaminoalkyl, C4-Cι2 19 dialkylaminoalkyl, C2-C6 aminoalkyl, or C6 orCio aryl, and R is H, OH, or Cι-C6 alkyloxy, carbonyl(Cι-C6 alkoxy), carbonyl(C7-ι6 aralkoxy), carbonyl(C6 or Cio aryloxy), or R12 and R13 together represent
Figure imgf000059_0003
wherein each of R15, R16, and R17 is, independently, H, Cι-C6 alkyl, 1 R 10 9fl 91 halogen, or trifluoromethyl, each of R , R , R , and R is, 99 independently, H or Cι-C6 alkyl, and R is H, halogen, trifluoromethyl, OCF3, NO2, C,-C6 alkyl, - cycloalkyl, CrC6 alkyloxy, C2-Cι2 alkoxyalkyl, C2-C6 hydroxyalkyl, C3-Cι2 alkylaminoalkyl, C4-Cι2 dialkylaminoalkyl, C2-C6 aminoalkyl, or C6 or Cio aryl; q is 2 or 3; each of m and o is, independently, 2 or 3; and each of n and p is, independently, 0 or 1.
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