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WO2006069096A1 - Derives de silanol en tant qu'inhibiteurs d'histone deacetylase - Google Patents

Derives de silanol en tant qu'inhibiteurs d'histone deacetylase Download PDF

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Publication number
WO2006069096A1
WO2006069096A1 PCT/US2005/046255 US2005046255W WO2006069096A1 WO 2006069096 A1 WO2006069096 A1 WO 2006069096A1 US 2005046255 W US2005046255 W US 2005046255W WO 2006069096 A1 WO2006069096 A1 WO 2006069096A1
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Prior art keywords
alkyl
hydrogen
aralkyl
hydroxyalkyl
heteroaralkyl
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PCT/US2005/046255
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Inventor
Dana Davis
Hyunjin M. Kim
John Y. Ramphal
Jeffrey R. Spencer
Vincent W. F. Tai
Erik J. Verner
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Pharmacyclics LLC
Axys Pharmaceuticals Inc
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Pharmacyclics LLC
Axys Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0834—Compounds having one or more O-Si linkage
    • C07F7/0836—Compounds with one or more Si-OH or Si-O-metal linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is directed to certain silanol derivatives that are inhibitors of histone deacetylase and are therefore useful in the treatment of diseases associated with histone deacetylase activity.
  • Pharmaceutical compositions and processes for preparing these compounds are also disclosed.
  • HDACs histone deacetylase enzymes
  • HDAC inhibitors can lead to growth inhibition, growth arrest, terminal differentiation and/or apoptosis.
  • In vivo studies have demonstrated growth inhibition of tumors and a reduction in tumor metastasis as a result of treatment with HDAC inhibitors.
  • the PLZF -RAR ⁇ form of the disease is treatable with retinoic acid
  • the PLZF -RAR ⁇ form is resistant to this treatment.
  • HDAC inhibitor sodium butyrate to the dosing regimen led to complete clinical and cytogenic remission (Warrell et al. J. Natl. Cancer. Inst. 90, 1621- 1625, (1998)).
  • HDACs have also been associated with Huntington's disease (Steffan, et al., Nature 413:739-744, "Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila").
  • an increase in HDAC activity contributes to the pathology and/or symptomatology of a number of diseases. Accordingly, molecules that inhibit the activity of HDAC are useful as therapeutic agents in the treatment of such diseases.
  • this invention is directed to a method for treating a disease in a patient which is mediated by HDAC which method comprises administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I):
  • R a and R b are independently hydrogen, alkyl, alkylcarbonyl, or aralkylcarbonyl; or R a and R b together form alkylene or -CO[CH(R)] 2 CO- where each R is hydrogen or alkyl;
  • R 1 is alkyl, alkenyl, or cycloalkyl each of which is optionally substituted with alkoxy, hydroxy, halo, thiol, or amino or R 1 is phenyl optionally substituted with halo, haloalkyl, carboxy, cyano or nitro;
  • X is (C]. 8 )alkylene, (C 2-8 )alkenylene, or (C 2-8 )alkynylene each of which is optionally substituted with one to five halo or one or two R c independently selected from: (a) aryl; (b) heteroaryl;
  • R 5 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl
  • R 6 and R 7 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 8 R 9 (where R 8 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 9 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
  • R 12 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl and R 13 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, -(alkylene)- NR 14 R 15 (where R 14 and R 15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form heterocycloamino), aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 16 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 18 R 19 (where R 18 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 19 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 17 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 20 R 21 (where R 20 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 21 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl
  • R 22 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 24 R 25 (where R 24 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 25 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 23 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 26 R 27 (where R 26 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 27 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); or R 22 and R 23 together with the nitrogen atom to which they
  • R 28 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl and R 29 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 31 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl
  • R 32 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 34 R 35 (where R 34 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 35 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl)
  • R 33 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or -(alkylene)-NR 36 R 37 (where R 36 is hydrogen, alkyl, hydroxyalkyl, or alkoxy
  • R 38 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl
  • R 39 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 41
  • R 42 (where R 41 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 42 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 40 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 43 R 44 (where R 43 is hydrogen, alkyl, hydroxyalkyl, or alkoxyal
  • R 45 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 47 R 48 (where R 47 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 48 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 46 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 49 R 50 (where R 49 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 50 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); or R 45 and R 46 together with the nitrogen atom to which
  • Y is a single bond, -O-, -SO 2 -, -C(O)NR 70 -, -NR 71 C(O)-, -NR 72 SO 2 -, -SO 2 NR 73 -, -NR 74 C(O)NR 75 -, -NR 76 SO 2 NR 77 -, -NHC(O)O-, -OC(O)NH-, -NHCHR, or -CHRNH-
  • R 70 , R 71 , R 72 , and R 73 are hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aralkyl
  • R 74 and R 75 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aralkyl
  • R 76 and R 77 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or
  • Ar is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkenyl, heterocycloalkenylalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, or cycloalkenylalkyl each of which is substituted with R 2 , R 3 and R 4 groups on the aromatic or alicyclic ring;
  • R 2 is hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or haloalkoxy;
  • R 3 and R 4 are independently:
  • R 78 is hydrogen, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aryloxyalkyl, aralkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, heteroaralkyl, heteroaralkyloxyalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl, -(alkylene)-NR 80 R 81 (where R 80 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 81 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or -C(O)R 82 where R 82 is alkyl,
  • R 91 is hydrogen, alkyl, or aralkyl and R 92 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R 91 and R 92 together with the nitrogen atom to which they are attached form heterocycloalkylamino;
  • R 93 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or heterocycloalkyl;
  • R 94 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, aralkyloxyalkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, -(alkylene)-NR 96 R 97 (where R 96 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 97 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -C(O)R 98 , -(alkylene)-C(O)R 99 , -OC(O)R 100 , or -(alkylene)- OC(O)R 101 (where R 98 , R 99 , R 100 and R 101 are alkyl, aryl, aralkyl,
  • R 104 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, -(alkylene)-NR 106 R 107 (where R 106 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 107 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-C(O)R 108 , or -(alkylene)-OC(O)R 109 (where R 108 and R 109 are alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, or alkoxy) and R 105 is alkyl, haloalkyl, aryl, aralkyl, hydroxyalkyl, or alkoxy) and R 105 is alkyl, haloalkyl, aryl, a
  • R 200c is aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl; or
  • R 200b and R 200c together with the nitrogen to which they are attached form heterocycloamino ; wherein any aromatic or alicyclic ring in R 3 and R 4 is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, nitro, cyano, carboxy, alkoxycarbonyl, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, phenyl, amino, alkylamino, and dialkylamino; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the disease is a proliferative disorder such as cancer and bipolar disorders.
  • the cancer is prostate cancer, breast cancer, lung melanoma, stomach cancer, neuroblastoma, colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, AML, MML, CML, and T-cell lymphoma.
  • this invention is directed to a method for treating cancer in an animal which method comprises administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in combination with radiation therapy and optionally in combination with one or more compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, and an angiogenesis inhibitor. Most preferably, in combination with a retinoid receptor modulator.
  • this invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.
  • the medicament is useful in the treatment of a disease mediated by HDAC. More preferably, the disease is cancer.
  • this invention provides a compound of Formula (Ia):
  • R 1 is alkyl or alkenyl, or R 1 is phenyl optionally substituted with halo, haloalkyl, carboxy, cyano or nitro;
  • X is (C 1-8 )alkylene, (C 2-8 )alkenylene, or (C 2-8 )alkynylene each of which is optionally substituted with one to five halo or one or two R c independently selected from:
  • R 12 is alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, cycloalkyl, or heterocycloalkylalkyl and R 13 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, -(alkylene)- NR 14 R 15 (where R 14 and R 15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form heterocycloamino), aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 16 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkylalkyl, or -(alkylene)-NR 18 R 19 (where R 18 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 19 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 17 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 20 R 21 (where R 20 Js hydrogen, alkyl, hydroxyalkyl, or alkoxyal
  • R 22 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 24 R 25 (where R 24 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 25 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 23 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 26 R 27 (where R 26 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 27 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); or R 22 and R 23 together with the nitrogen atom to which they
  • R 28 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl and R 29 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 31 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl
  • R 32 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 34 R 35 (where R 34 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 35 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl)
  • R 33 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or -(alkylene)-NR 36 R 37 (where R 36 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl,
  • R 38 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl
  • R 39 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 41
  • R 42 (where R 41 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 42 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 40 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 43 R 44 (where R 43 is hydrogen, alkyl, hydroxyalkyl, or alkoxyal
  • R 45 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 47 R 48 (where R 47 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 48 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 46 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 49 R 50 (where R 49 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 50 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); or R 45 and R 46 together with the nitrogen atom to which
  • R 51 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl and R 52 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 53 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 54 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 55 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 56 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 57 R 58 (where R 57 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 58 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); and (u) -SR 59 where R 59 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 61 R 62 (where R 61 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 62 is hydrogen, alkyl, hydroxyalkyl, aryl
  • R 3 is:
  • R is hydrogen, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aryloxyalkyl, aralkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, heteroaralkyl, heteroaralkyloxyalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl, -(alkylene)-NR R (where R is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 81 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or -C(O)R 82 where R 82 is alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkylalkyl, aryl, aralkyl,
  • R 91 is hydrogen, alkyl, or aralkyl and R 92 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R 91 and R 92 together with the nitrogen atom to which they are attached form heterocycloalkylamino;
  • R 93 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or heterocycloalkyl;
  • R 94 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, aralkyloxyalkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, -(alkylene)-NR 96 R 97 (where R 96 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 97 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -C(O)R 98 , -(alkylene)-C(O)R 99 , -OC(O)R 100 , or -(alkylene)- OC(O)R 101 (where R 98 , R 99 , R 100 and R 101 are alkyl, aryl, aralkyl,
  • R 104 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, -(alkylene)-NR 106 R 107 (where R 106 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 107 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-C(O)R 108 , or -(alkylene)-OC(O)R 109 (where R 108 and R 109 are alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, or alkoxy) and R 105 is alkyl, haloalkyl, aryl, aralkyl, hydroxyalkyl, or alkoxy) and R 105 is alkyl, haloalkyl, aryl, a
  • R 200c is aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl; or
  • R 200b and R 200c together with the nitrogen to which they are attached form heterocycloamino
  • R 78 is hydrogen and R 79 is alkoxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryloxyalkyl, aralkyl, aralkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, heteroaralkyl, heteroaralkyloxyalkyl, heterocycloalkyl, heterocycloalkylalkyl, or heterocycloalkyloxyalkyl; or R 78 is alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aryloxyalkyl, aralkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, heteroaralkyl, heteroaralkyloxyalkyl, heterocycloalkyl, heterocycloalkyl, heterocycloalkyl, heterocycloalkyl, heterocycloalkyl, hetero
  • R 93 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or heterocycloalkyl;
  • R 94 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, aralkyloxyalkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, -(alkylene)-NR 96 R 97 (where R 96 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 97 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -C(O)R 98 , -(alkylene)-C(O)R 99 , -OC(O)R 100 , or -(alkylene)- OC(O)R 101 (where R 98 , R 99 , R 100 and R 101 are alkyl, aryl, aralkyl,
  • R 104 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, -(alkylene)-NR 106 R 107 (where R 106 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 107 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-C(O)R 108 , or -(alkylene)-OC(O)R 109 (where R 108 and R 109 are alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, or alkoxy) and R 105 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaryl, hydroxy, or alkoxy) and R 105 is alkyl, haloalkyl,
  • R 110 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl
  • R 111 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or heterocycloalkyl; or
  • n6 is O or 1
  • R 200a and R 200b are independently hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, or haloalkoxy
  • R 200c is aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl; or
  • R 200b and R 200c together with the nitrogen to which they are attached form heterocycloamino; wherein any aromatic or alicyclic ring in R 3 and R 4 is optionally substituted with one, two, or three substituents selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, nitro, cyano, carboxy, alkoxycarbonyl, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, phenyl, amino, alkylamino, and dialkylamino; or a pharmaceutically acceptable salt thereof.
  • this invention provides a compound of Formula (Ib):
  • R 1 is alkyl or alkenyl, or R 1 is phenyl optionally substituted with halo, haloalkyl, carboxy, cyano or nitro;
  • X is (Ci -8 )alkylene, (C 2-8 )alkenylene, or (C 2-8 )alkynylene each of which is optionally substituted with one to five halo or one or two R c independently selected from:
  • R 6 and R 7 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 8 R 9 (where R 8 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 9 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
  • R 12 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, cycloalkyl, or heterocycloalkylalkyl and R 13 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, -(alkylene)-NR 14 R 15 (where R 14 and R 15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form heterocycloamino), aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl; (c) -C(O)NR 16 R 17 where R 16 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alk
  • R 22 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 24 R 25 (where R 24 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 23 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 26 R 27 (where R 26 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 27 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); or R 22 and R 23 together with the nitrogen atom to which they are
  • R 28 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl and R 29 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 31 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl
  • R 32 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 34 R 35 (where R 34 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 35 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl)
  • R 33 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 36 R 37 (where R 36 is hydrogen, alkyl, hydroxyalkyl, or alkoxy
  • R 45 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 47 R 48 (where R 47 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 48 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 46 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 49 R 50 (where R 49 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 50 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); or R 45 and R 46 together with the nitrogen atom to which
  • R 51 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl and R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 53 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 54 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 55 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 56 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 57 R 58 (where R 57 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 58 is hydrogen, alkyl, or hydroxyalkyl); and (n) -SR 59 where R 59 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 61 R 62 (where R 61 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 62 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); and further wherein any aromatic or alicyclic ring present in R c is optionally substituted
  • Y is -C(O)NR 70 - and Ar is aryl or Y is -NR 71 C(O)- and Ar is aryl, aralkyl, or aralkenyl and R 70 and R 71 are hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aralkyl; and Ar is substituted with R 2 , R 3 and R groups on the aromatic or alicyclic ring portion;
  • R 2 is hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or haloalkoxy;
  • R 3 and R 4 are independently:
  • R 78 is hydrogen, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aryloxyalkyl, aralkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, heteroaralkyl, heteroaralkyloxyalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl, -(alkylene)-NR 80 R 81 (where R 80 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or -C(O)R where R is alkyl, haloalkyl
  • R 91 is hydrogen, alkyl, or aralkyl and R 92 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R 91 and R 92 together with the nitrogen atom to which they are attached form heterocycloalkylamino;
  • R 93 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or heterocycloalkyl;
  • R 94 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, aralkyloxyalkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, -(alkylene)-NR 96 R 97 (where R 96 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 97 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -C(O)R 98 , -(alkylene)-C(O)R 99 , - OC(O)R 100 , or -(alkylene)-OC(O)R 101 (where R 98 , R 99 , R 100 and R 101 are alkyl, aryl, aralkyl,
  • R 104 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, -(alkylene)-NR 106 R 107 (where R 106 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 107 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-C(O)R 108 , or -(alkylene)-OC(O)R 109 (where R 108 and R 109 are alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, or alkoxy) and R 105 is alkyl, haloalkyl, aryl, aralkyl,
  • n6 is 0 or 1
  • R 200a and R 200b are independently hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, or haloalkoxy
  • R 200c is aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl; or R 200b and R 200c together with the nitrogen to which they are attached form heterocycloamino; wherein any aromatic or alicyclic ring in R , R and R 4 is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, nitro, cyano, carboxy, alkoxycarbonyl, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, phenyl
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
  • the invention is directed to a method of making a compound of Formula (I) where all groups are as defined in the Summary of the Invention:
  • the invention is directed to a method of making a compound of Formula I (where Y is a single bond) or I(a) where R 4 is -(alkylene) n -NR 78 R 79 , where n, R 78 , and R 79 are as defined in the Summary of the Invention :
  • Alicyclic means a moiety characterized by arrangement of the carbon atoms in closed non-aromatic ring structures e.g., cycloalkyl and heterocycloalkyl rings as defined herein.
  • Alkenyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing one or two double bonds, e.g., ethenyl, propenyl, 2-propenyl, butenyl (including all isomeric forms), and the like.
  • Alkenylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms containing one or two double bonds, e.g., ethenylene, propenylene, 2-propenylene, butenylene (including all isomeric forms), and the like.
  • Alkoxy means a -OR radical where R is alkyl as defined herein, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, «-, iso-, or tert-butoxy, and the like.
  • Alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, preferably one or two alkoxy groups, as defined herein, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.
  • Alkoxycarbonyl means a -C(O)OR radical where R is alkyl as defined herein, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
  • Alkoxycarbonylalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxycarbonyl group as defined herein, preferably one or two alkoxycarbonyl group(s), as defined herein, e.g., 2-methoxycarbonylethyl, 1-, 2-, or 3-methoxycarbonylpropyl, 2-ethoxycarbonylethyl, and the like.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1 -methylpropylene, 2-methylpropylene, butylene, pentylene, 2,2-dimethylethylene, and the like.
  • Alkylamino means a -NHR radical where R is alkyl as defined herein, e.g., methylamino, ethylamino, «-, /s ⁇ -propylamino, n-, iso-, tert-butylamino, and the like.
  • Alkylaminoalkyl means an alkyl radical substituted with at least one, preferably one or two, alkylamino group(s) as defined herein.
  • Alkylaminoalkyloxy means an -OR radical where R is alkylaminoalkyl as defined herein.
  • Alkylcarbonyl means a -C(O)R radical where R is alkyl as defined herein, e.g., methylcarbonyl, ethylcarbonyl, and the like.
  • Alkylsulfonyl means a -SO 2 R radical where R is alkyl as defined herein, e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • Alkylsulfonylamino refers to a -NHSO 2 R radical where R is an alkyl group as defined herein e.g., methylsulfonylamino, ethylsulfonylamino, and the like.
  • Alkylthio means a -SR radical where R is alkyl as defined herein, e.g., methylthio, ethylthio, propylthio (including all isomeric forms), butylthio (including all isomeric forms), and the like.
  • Alkynylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms containing one or two triple bonds, e.g., ethynylene, propynylene, 2-propynylene, butynylene (including all isomeric forms), and the like.
  • Amino means a -NH 2 , or an TV-oxide derivative.
  • Aminoalkyl means an alkyl radical substituted with at least one, preferably one or two, amino group(s) as defined herein.
  • Aminoalkyloxy means an -OR radical where R is aminoalkyl as defined herein.
  • Alkenyl means a -(alkenylene)-R radical where R is aryl as defined herein.
  • Alkoxy means a -OR radical where R is aralkyl as defined herein.
  • Alkyl means a -(alkylene)-R radical where R is aryl as defined herein.
  • Alkylcarbonyl means a -C(O)R group where R is aralkyl as defined herein.
  • Alkyloxy means an -OR radical where R is aralkyl as defined herein.
  • Alkyloxyalkyl means an alkyl radical substituted with at least one, preferably one or two, aralkyloxy group(s), as defined herein.
  • Alkyloxycarbonyl means a -C(O)R radical where R is aralkoxy as defined herein e.g., benzyloxycarbonyl, and the like.
  • Aromatic refers to a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp 2 hybridized and the total number of pi electrons is equal to 4n+2.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms i.e., phenyl or naphthyl.
  • Aryloxycarbonyl means a -C(O)OR radical where R is aryl as defined herein, e.g., phenoxycarbonyl, naphthyloxycarbonyl, and the like.
  • Aryloxy alkyl means a -(alkylene)-OR radical where R is aryl as defined herein e.g., phenoxymethyl, phenoxyethyl, and the like.
  • Arylsulfonyl means a -SO 2 R radical where R is aryl as defined herein, e.g., phenylsulfonyl, naphthylsulfonyl, and the like.
  • Arylsulfonylamino refers to a -NHSO 2 R radical where R is aryl as defined herein e.g., phenylsulfonylamino, and the like.
  • Benzylcarbonyl means a -C(O)benzyl radical.
  • Carboxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one carboxy group, preferably one or two carboxy group(s), as defined herein, e.g., 2-carboxyethyl, 1-, 2-, or 3-carboxypropyl, 2-carboxyethyl, and the like.
  • Cycloalkenyl means an cyclic partially unsaturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., cyclopropenyl, cyclobutenyl, cyclohexenyl, and the like.
  • Cycloalkenylalkyl means a -(alkylene)-R radical where R is cycloalkenyl as defined herein; e.g., cyclopropenylmethyl, cyclobutenylmethyl, cyclopentenylethyl, or cyclohexenylmethyl, and the like.
  • Cycloalkyl means a mono or bicyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or admantyl.
  • Cycloalkylalkyl means a -(alkylene)-R radical where R is cycloalkyl as defined herein; e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl, and the like.
  • Dialkylamino means a -NRR' radical where R and R' are alkyl as defined herein, e.g., dimethylamino, diethylamino, methylpropylamino, methylethylamino, n-, iso-, or tert-butylamino, and the like.
  • Dialkylaminoalkyl means an alkyl radical substituted with at least one, preferably one or two, dialkylamino group(s) as defined herein.
  • Dialkylaminoalkyloxy means an -OR radical where R is dialkylaminoalkyl as defined herein.
  • Halo means fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.
  • Haloalkoxy means a -OR radical where R is haloalkyl as defined herein e.g., -OCF 3 , -OCHF 2 , and the like.
  • Haloalkyl means alkyl as defined herein which is substituted with one or more halogen atoms, preferably one to five halogen atoms, preferably fluorine or chlorine, including those substituted with different halogens, e.g., -CH 2 Cl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF(CH 3 ) 3 , and the like.
  • Heteroaralkenyl means a -(alkenylene)-R radical where R is heteroaryl as defined herein.
  • Heteroaralkyl means a -(alkylene)-R radical where R is heteroaryl as defined herein.
  • Heteroaralkyloxycarbonyl means a -C(O)OR radical where R is heteroaralkyl as defined herein e.g., pyridinylmethoxycarbonyl, furanylmethoxycarbonyl, and the like.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one or more, preferably one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being carbon.
  • heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, benzoxazolyl, benzothiophenyl, benzthiazolyl, quinolinyl, isoquinolinyl, benzopyranyl, benzo[l,3]dioxol-5-yl, and thiazolyl provided that pyridyl is not attached via the nitrogen ring atom.
  • Heteroaryl oxyalkyl means a -(alkylene)-OR radical where R is heteroaryl as defined herein e.g., pyridinyloxymethyl, furanyloxyethyl, and the like.
  • Heteroaryloxycarbonyl means a -C(O)OR radical where R is heteroaryl as defined herein, e.g., pyridinyloxycarbonyl, furanyloxycarbonyl, and the like.
  • Heteroarylsulfonyl means a -SO 2 R radical where R is heteroaryl as defined herein, e.g., pyridinylsulfonyl, pyrimidinylsulfonyl, quinolinylsulfonyl, and the like.
  • Heterocycloalkenyl means an unsaturated monovalent monocyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from -N-, -0-, or -S(O)n-, where n is an integer from O to 2, the remaining ring atoms being C provided that the ring is not aromatic. More specifically the term heterocycloalkenyl includes rings such as tetahyropiperidino, and the like. The heterocycloalkenyl ring optionally contains a keto group within the ring and is optionally fused to phenyl or a heteroaryl ring.
  • Heterocycloalkenylalkyl means a -(alkylene)-R radical where R is heterocycloalkenyl as defined herein.
  • Heterocycloalkyl means a saturated monovalent monocyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from -N-, -0-, or -S(O)n-, where n is an integer from O to 2, the remaining ring atoms being C. More specifically the term heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino.
  • the heterocycloalkyl ring optionally contains a keto group within the ring and is optionally fused to phenyl or heteroaryl, e.g.
  • heterocycloalkylalkyl means a -(alkylene)-R radical where R is heterocycloalkyl as defined herein e.g., tetrahydrofuranmethyl, piperazinylmethyl, morpholinylethyl, and the like.
  • Heterocycloalkylalkyloxycarbonyl means a -C(O)OR radical where R is heterocycloalkylalkyl as defined herein e.g., tetrahydrofuranylmethoxycarbonyl, and the like.
  • Heterocycloalkyloxyalkyl means a -(alkylene)-OR radical where R is heterocycloalkyl as defined herein e.g., piperidinyloxymethyl, tetrahydrofuranyloxyethyl, and the like.
  • Heterocycloalkyloxycarbonyl means a -C(O)OR radical where R is heterocycloalkyl as defined herein, e.g., tetrahydrofuranyloxycarbonyl, piperidinyloxycarbonyl, and the like.
  • Heterocycloalkylsulfonyl means a -SO 2 R radical where R is heterocycloalkyl as defined herein, e.g., piperidinylsulfonyl, morpholin-4-ylsulfonyl, and the like.
  • Hydroalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1 -(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and l-(hydroxymethyl)-2-hydroxyethyl.
  • “Isomer” or “isomers” means compounds of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes "optical isomers”. An atom bonded to four nonidentical substituents is termed a "chiral center".
  • a compound with one chiral center has two enantiomeric forms of opposite chirality; and a mixture of both enatiomeric forms in equal amounts is termed racemic.
  • a compound that has one or more chiral centers has 2" "1 enantiomeric pair(s), where n is the number of chiral centers, unless the compound is meso (i.e. the compound has 2 or more assymetric or chiral centers but which is achiral because it contains an internal plane of symmetry).
  • Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture".
  • a stereoisomer When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see “Advanced Organic Chemistry," 4th edition, March, Jerry, John Wiley & Sons, New York, 1992). It is understood that the names and illustration used in this Application to describe compounds of Formula I are meant to be encompassed all possible stereoisomers and any mixture, racemic or otherwise, thereof.
  • the present invention also includes the prodrugs of compounds of Formula (I).
  • prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula (I) when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo.
  • Prodrugs of compounds of Formula (I) include compounds wherein a hydroxy, amidino, guanidino, amino, carboxylic, or a similar group is modified.
  • prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., jV,N-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g, trifluoroacetylamino, acetylamino, and the like), and the like.
  • esters e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g., jV,N-dimethylaminocarbonyl
  • amides e.g, trifluoroacetylamino, acetylamino, and the like
  • Prodrugs of compounds of Formula (I) are also within the scope of this invention.
  • the present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula (I).
  • compounds of Formula (I) when compounds of Formula (I) contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art.
  • compounds of Formula (I) when compounds of Formula (I) contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups.
  • a comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1999, the disclosure of which is incorporated herein by reference in its entirety.
  • the protected derivatives of compounds of Formula (I) can be prepared by methods well known in the art.
  • a "pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulf
  • the compounds of the present invention may have asymmetric centers.
  • Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, racemic forms are within the scope of this invention, unless the specific stereochemistry or isomeric form is specifically indicated.
  • alkyl, alkylene, alkenylene, and alkynylene includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth.
  • cyclic groups such as aryl, heteroaryl, heterocycloalkyl are substituted, they include all the positional isomers albeit only a few examples are set forth.
  • heterocycloalkyl group optionally mono- or di-substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocycloalkyl group is mono- or disubstituted with an alkyl group and situations where the heterocycloalkyl group is not substituted with the alkyl group.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • Treating" or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease;
  • treating cancer refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.
  • a “therapeutically effective amount” means the amount of a compound of Formula (I) that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • the present invention is directed to a compound of Formula (Ia) or (Ib) where R 1 is alkyl; and X is (C 2-8 )alkylene.
  • R 1 is methyl, ethyl, «-, or wo-propyl, wo-butyl, sec-butyl, or tert-butyl and X is (C 2 . 8 )alkylene. More preferably, R 1 is ethyl, isopropyl, sec-butyl, or tert-butyl and X is ethylene, ⁇ -propylene, w-butylene, w-pentylene, or H-hexylene.
  • R 1 is ethyl, isopropyl, /so-butyl, sec-butyl, or tert-buty ⁇ and X ethylene or pentylene. Most preferably, R 1 is isopropyl or tert-butyl and X is ethylene.
  • the present invention is directed to a compound of Formula (Ia) or (Ib) where R 1 is alkenyl; and X is (C 2 .s)alkylene.
  • the present invention is directed to a compound of Formula I(a) or (Ib) where R 1 is alkyl; and X is (C 2-8 )alkenylene.
  • R 1 is methyl, ethyl, n- or wo-propyl, wo-butyl, sec-butyl, or ter/-butyl and X is (C 2 .g)alkenylene.
  • R 1 is ethyl, isopropyl, wo-butyl, sec-butyl, or te/Y-butyl and X is ethenylene, n-prop-1-enylene, H-prop-2-enylene, w-but-1-enylene, n-pent-1-enylene, or /7-hex-l-enylene.
  • R 1 is isopropyl or tert-butyl and X is ethenylene.
  • the present invention is directed to a compound of Formula I(a) where R 1 is alkyl, preferably ethyl, n- or /s ⁇ -propyl, or tert-butyl; and X is -CH[(CH 2 ) 0-3 R c ]-(CH 2 ) 1-4 - where R c is:
  • R 5 is alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, or heterocycloalkyl;
  • R 6 and R 7 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR R (where R is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 9 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
  • R 12 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl and R 13 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, -(alkylene)-NR 14 R 15 (where R 14 and R 15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form heterocycloamino), aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 16 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 18 R 19 (where R 18 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 19 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R I7 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkyl ene)-NR 20 R 21 (where R 20 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 21 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroa
  • R 28 is alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl and R 29 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl; and further wherein any aromatic or alicyclic ring present in R c is optionally substituted with one, two, or three substitutents independently selected from alkyl, alkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, halo, haloalkyl, haloalkoxy, cyano, alkylthio, alkylsulfonyl, alkoxycarbonyl, carboxy, amino, alkylamino, dialkylamino, -(alkylene)-NR 63 R 64 (where R 63 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,
  • R 1 is methyl, ethyl, wo-propyl, w ⁇ -butyl, sec-butyl, or tert-butyl. More preferably, R 1 is /.s ⁇ -propyl or tert-buty ⁇ and X is -CH[(CH 2 )i -3 R c ]-(CH 2 )i -3 - where R ⁇ is -NR 12 COR 13 where R 12 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl, and R 13 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, -(alkylene)-NR 14 R 15 (where R 14 and R 15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or hetero
  • R 1 is isopropyl or tert-butyl and X is -CH [(CH 2 ) 1-2 R C ] -(CH 2 ) i. 3 - where R c is -NHCOR 1 where R 1 is aryl or heteroaryl optionally substituted with one, two, or three substitutents independently selected from alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, alkylsulfonyl, alkoxycarbonyl, carboxy, amino, alkylamino, and dialkylamino.
  • the present invention is directed to a compound of Formula (Ib) where R 1 is alkyl, preferably ethyl, n- or /s ⁇ -propyl, or tert-buXy ⁇ ; and X is -CH[(CH 2 ) 0-3 R c ]-(CH 2 )i -4 - where R c is:
  • R 6 and R 7 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 8 R 9 (where R 8 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 9 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
  • R 12 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, cycloalkyl, or heterocycloalkylalkyl and R 13 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, -(alkylene)-NR I4 R 15 (where R 14 and R 15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form heterocycloamino), aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl; (c) -C(O)NR 16 R 17 where R 16 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, al
  • R 22 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 24 R 25 (where R 24 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 25 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 23 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 26 R 27 (where R 26 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 27 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); or R 22 and R 23 together with the nitrogen atom to which they
  • R 28 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl and R 29 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl; and further wherein any aromatic or alicyclic ring present in R c is optionally substituted with one, two, or three substitutents independently selected from alkyl, alkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, halo, haloalkyl, haloalkoxy, cyano, alkylthio, alkylsulfonyl, alkoxycarbonyl, carboxy, amino, alkylamino, dialkylamino, -(alkylene)-NR 63 R 64 (where R 63 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl
  • R 1 is methyl, ethyl, wo-propyl, /so-butyl, sec-butyl, or tert-butyl. More preferably, R 1 is /.s ⁇ -propyl or tert-butyl and X is -CH[(CH 2 )o -2 R e ]-(CH 2 ) 1-4 - where R c is -NR 12 COR 13 where R 12 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl, and R 13 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, -(alkylene)-NR 14 R 15 (where R 14 and R 15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or hetero
  • R 1 is isopropyl or tert-butyl and X is -CH[(CH 2 ) 0-2 R c ]-(CH 2 )i -4 - where R c is -NHCOR 13 where R 13 is aryl or heteroaryl optionally substituted with one, two, or three substitutents independently selected from alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, alkylsulfonyl, alkoxycarbonyl, carboxy, amino, alkylamino, and dialkylamino.
  • an even more preferred group of compounds of Formula I(b) is that wherein Ar-Y is Ar-CONH-;
  • Ar-Y is a Ar-NHCO-.
  • an even more preferred group of compounds of Formula I(b) is that wherein Ar is unsubstituted aryl, preferably phenyl.
  • an even more preferred group of compounds is that wherein Ar is phenyl, R 2 is hydrogen; R 3 is selected from alkyl, alkoxy, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxy, alkylsulfonyl, arylsulfonyl, heterocycloalkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, or heteroaryloxycarbonyl wherein any aromatic or alicyclic ring in R 3 is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, nitro, cyano, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino.
  • R 3 is methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, trifluoromethyl, trifluoromethoxy, methylsulfonyl, phenylsulfonyl, piperidinylsulfonyl, pyrrolidinylsulfonyl, methoxycarbonyl, phenoxycarbonyl, or benzyloxycarbonyl wherein any aromatic or alicyclic ring in R 3 is optionally substituted with one or two substituents independently selected from methyl, hydroxy, alkoxy, chloro, fluoro, trifluoromethyl, and trifluoromethoxy.
  • an even more preferred group of compounds of Formula I(a) is that wherein Ar is phenyl, R 2 is hydrogen, R 3 is hydrogen, alkyl, alkoxy, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, or haloalkoxy, and R 4 is -(alkylene) n -NR 78 R 79 where n is 0 or 1, preferably 1, R 78 is alkyl, heteroaralkyl, aralkyl, or aralkyloxyalkyl, and R 79 is heteroaralkyl, aralkyl, or aralkyloxyalkyl.
  • R 4 is N-(methyl)-jV-(2-indol-3- ylethyl)aminomethyl, N-(methyl)-N-(phenethyl)-aminomethyl, 7V-(phenethyl)-iV-(2-indol- 3-ylethyl)-aminomethyl, or jV-(2-benzyloxyethyl)-iV-(2-indol-3-ylethyl)-aminomethyl.
  • R 4 is 7V-(methyl)-N-(2-indol-3-ylethyl)aminomethyl or 7V-(phenethyl)- iV-(2-indol-3-ylethyl)-aminomethyl. Even more preferably, R 4 is N-(methyl)-N-(2-indol- 3-ylethyl)-aminomethyl.
  • an even more preferred group of compounds of Formula (Ia) is that wherein Ar is phenyl, R 2 is hydrogen, R 3 is hydrogen, alkyl, alkoxy, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, or haloalkoxy, and R 4 is -(alkylene) n i -C(O)NR 94 R 95 where nl is 0 or 1 , R 94 is hydrogen, alkyl, alkoxyalkyl, aralkyl, or aralkyloxyalkyl, and R 95 is alkoxyalkyl, heteroaralkyl, aryl, aralkyl, or heterocycloalkylalkyl.
  • R 4 is N-(2-indol-3-ylethyl)-aminocarbonyl, 7V-methyl-iV-(2-indol-3-ylethyl)-aminocarbonyl, JV-phenethyl-iV-benzyl-aminocarbonyl, N-(3-methoxyphenylmethyl)-N-(tetrahydrofuran- 2-ylmethyl)-aminocarbonyl, N-(2-benzyloxyethyl)-iV-(2-indol-3-ylethyl)-aminocarbonyl, 7V,iV-dibenzyl-aminocarbonyl, 7V-phenethyl-N-methyl-aminocarbonyl, N-benzyl- aminocarbonyl, phenylaminocarbonyl, N-(2-indol-3-ylethyl)-aminocarbonyl, N,N-bis- (2-meth
  • an even more preferred group of compounds of Formula (Ia) is that wherein Ar is phenyl, R is hydrogen, R is hydrogen, alkyl, alkoxy, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, or haloalkoxy, and R 4 is -(alkylene) n2 ⁇ R 104 C(O)R 105 (where n2 is 0 or 1, R 104 is hydrogen, and R 105 is heteroaralkyl or heteroaryl).
  • R 4 is (indol- 3-ylmethyl)carbonylaminomethyl, benzofuran-2-ylcarbonylamino, 5-methoxy- benzofuran-2-ylcarbonylamino, or indol-3-ylcarbonylamino.
  • an even more preferred group of compounds of Formula (Ia) is that wherein Ar is phenyl, R 2 is hydrogen, R 3 is hydrogen, alkyl, alkoxy, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, or haloalkoxy, and R 4 is -NR 200a C(O)NR 200b R 200c (where R 200a and R 200c are hydrogen and R 2OOb is aryl).
  • R 4 is 3-methoxy-phenyl- aminocarbonylamino.
  • an even more preferred group of compounds of Formula (Ib) is that wherein Ar is phenyl, R 2 is hydrogen, and R 3 and R 4 are independently hydrogen, alkyl, alkoxy, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, or haloalkoxy.
  • Ar is phenyl
  • R 2 is hydrogen
  • R 3 and R 4 are independently hydrogen, alkyl, alkoxy, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, or haloalkoxy.
  • the present invention is directed to a compound of
  • R 1 is isopropyl or tert-butyl.
  • the present invention is directed to a compound of
  • R 1 is isopropyl or tert-butyl.
  • the present invention is directed to a compound of
  • R 1 is phenyl optionally substituted with halo, haloalkyl, carboxy, cyano or nitro.
  • X is (C 2-8 )alkenylene, preferably, ethenylene
  • Ar is phenyl where R 2 , R 3 and R 4 are as defined in the Summary of the Invention for a compound of Formula (Ia).
  • R 2 and R 3 are hydrogen and R 4 is -(alkylene) n -NR 78 R 79 ), -(alkylene)m -C(O)NR 94 R 95 , -(alkylene) n2 NR 104 C(O)R 105 , or -(alkylene ⁇ NR 110 SO 2 R 111 where n, nl, n2, n3, R 78 , R 79 , R 94 , R 95 , R 104 , R 105 , R 110 , and R 111 are as defined in the Summary of the Invention for a compound of Formula I(a).
  • S In another embodiment, the present invention is directed to a compound of Formula (Ia).
  • the present invention is directed to a compound of Formula (Ib).
  • the present invention is directed to a compound of Formula (Ia) or (Ib) where R 1 is alkyl or alkenyl, or R 1 is phenyl optionally substituted with halo, haloalkyl, carboxy, cyano or nitro.
  • the present invention is directed to a compound of Formula (Ia) where X is (Ci -8 )alkylene, (C 2- g)alkenylene, or (C 2-8 )alkynylene each of which is optionally substituted with one to five halo or one or two R c independently selected from:
  • R 5 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl
  • R 6 and R 7 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 8 R (where R 8 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 9 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
  • R 12 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, cycloalkyl, or heterocycloalkylalkyl and R 13 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, -(alkylene)-NR 14 R 15 (where R 14 and R 15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form heterocycloamino), aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 16 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkylalkyl, or -(alkylene)-NR 18 R 19 (where R 18 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 19 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 17 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 20 R 21 (where R 20 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl
  • R 22 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 24 R 25 (where R 24 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 5 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 26 R 27 (where R 26 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 27 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); or R 22 and R 23 together with the nitrogen atom to which they are
  • R 28 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl and R 29 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 31 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl
  • R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 34 R 35 (where R 34 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 35 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl)
  • R 33 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or -(alkylene)-NR 36 R 37 (where R 36 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl, R 37 (where R 36 is hydrogen, al
  • R 38 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl
  • R 39 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 41
  • R 42 (where R 41 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 42 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 40 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 43 R 44 (where R 43 is hydrogen, alkyl, hydroxyalkyl, or alkoxyal
  • R 45 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 47 R 48 (where R 47 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 48 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 46 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 49 R 50 (where R 49 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 50 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); or R 45 and R 46 together with the nitrogen atom to which
  • the present invention is directed to a compound of Formula (Ib) where X is (C ⁇ alkylene, (C 2-8 )alkenylene, or (C 2- g)alkynylene each of which is optionally substituted with one to five halo or one or two R c independently selected from:
  • R 6 and R 7 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 8 R 9 (where R 8 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 9 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
  • R 12 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, cycloalkyl, or heterocycloalkylalkyl and R 13 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, -(alkylene)-NR 14 R 15 (where R 14 and R 15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form heterocycloamino), aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 16 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkylalkyl, or -(alky lene)-NR 18 R 19 (where R 18 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 1 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 17 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 20 R 21 (where R 20 is hydrogen, alkyl, hydroxyalkyl, or alkoxy
  • R 22 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 24 R 25 (where R 24 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 25 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 23 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 26 R 27 (where R 26 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 27 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); or R and R together with the nitrogen atom to which they are attached
  • R 28 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl and R 29 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl;
  • R 31 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl
  • R 32 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 34 R 35 (where R 34 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 35 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl)
  • R 33 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 36 R 37 (where R 36 is hydrogen, alkyl, hydroxyalkyl, or alkoxy
  • R 38 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aralkyl, heteroaralkyl, or heterocycloalkylalkyl
  • R 39 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 41
  • R 42 (where R 41 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 42 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 40 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 43 R 44 (where R 43 is hydrogen, alkyl, hydroxyalkyl, or alkoxyal
  • R 45 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 47 R 48 (where R 47 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 48 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) and R 46 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 49 R 50 (where R 49 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 50 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); or R 45 and R 46 together with the nitrogen atom to which
  • R 56 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 57 R 58 (where R 57 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 58 is hydrogen, alkyl, or hydroxyalkyl); and (n) -SR 59 where R 59 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, or -(alkylene)-NR 61 R 62 (where R 61 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 62 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); and further wherein any aromatic or alicyclic ring present in R c is optionally substituted
  • R 2 is hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or haloalkoxy.
  • the present invention is directed to a compound of
  • R 78 is hydrogen, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aryloxyalkyl, aralkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, heteroaralkyl, heteroaralkyloxyalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl, -(alkylene)-NR R (where R is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or -C(O)R where R is alkyl, haloalkyl, aryl
  • R 91 is hydrogen, alkyl, or aralkyl and R 92 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, or R 91 and R 92 together with the nitrogen atom to which they are attached form heterocycloalkylamino;
  • R 93 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or heterocycloalkyl;
  • R 94 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, aralkyloxyalkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, -(alkylene)-NR 96 R 97 (where R 96 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 97 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -C(O)R 98 , -(alkylene)-C(O)R 99 , - OC(O)R 100 , or -(alkylene)-OC(O)R 101 (where R 98 , R 99 , R 100 and R 101 are alkyl, aryl, aralkyl,
  • R 104 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, -(alkylene)-NR 106 R 107 (where R 106 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 107 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-C(O)R 108 , or -(alkylene)-OC(O)R 109 (where R 108 and R 109 are alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, or alkoxy) and R 105 is alkyl, haloalkyl, aryl, aralkyl,
  • n6 is 0 or 1
  • R 200a and R 200b are independently hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, or haloalkoxy
  • R 200c is aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl; or R 200b and R 200c together with the nitrogen to which they are attached form heterocycloamino; wherein any aromatic or alicyclic ring in R , R and R is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, nitro, cyano, carboxy, alkoxycarbonyl, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, phenyl,
  • R 78 is hydrogen and R 79 is alkoxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryloxyalkyl, aralkyl, aralkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, heteroaralkyl, heteroaralkyloxyalkyl, heterocycloalkyl, heterocycloalkylalkyl, or heterocycloalkyloxyalkyl; or R 78 is alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aryloxyalkyl, aralkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, heteroaralkyl, heteroaralkyloxyalkyl, heterocycloalkyl, heterocycloalkyl, heterocycloalkyl, heterocycloalkyl, heterocycloalkyl, hetero
  • R 93 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or heterocycloalkyl;
  • R 94 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, aralkyloxyalkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, -(alkylene)-NR 96 R 97 (where R 96 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 97 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -C(O)R 98 , -(alkylene)-C(O)R 99 , - OC(O)R 100 , or -(alkylene)-OC(O)R 101 (where R 98 , R 99 , R 100 and R 101 are alkyl, aryl, aralkyl,
  • R 104 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, alkoxyalkyl, -(alkylene)-NR 106 R 107 (where R 106 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R 107 is hydrogen, alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-C(O)R 108 , or -(alkylene)-OC(O)R 109 (where R 108 and R 109 are alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, or alkoxy) and R 105 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, or alkoxy) and R 105 is alkyl, haloalkyl
  • n6 is 0 or 1
  • R 200a and R 200b are independently hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, or haloalkoxy
  • R 200c is aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl; or R 200b and R 200c together with the nitrogen to which they are attached form heterocycloamino; wherein any aromatic or alicyclic ring in R 3 and R 4 is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, nitro, cyano, carboxy, alkoxycarbonyl, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, phenyl, amino
  • the present invention is directed to a compound of Formula (Ib) where R 4 is R 3 as described in embodiment (AA).
  • the present invention is directed to a method of treating a disease which is mediated by HDAC which method comprises administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I).
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I).
  • the compound is of Formula I(a). More preferably, the compound is selected from the above groups (A)-(D) and (J)-(M).
  • R a , R b , and R 2 are hydrogen, R 1 , Ar, X and Y are as defined in Table 1 below are:
  • Compounds 110-125 are named: ethyl-6-(phenylaminocarbonyl)hexylsilanediol; ethyl-5-(phenylaminocarbonyl)pentylsilanediol; isopropyl-5-[(benzoftnan-2-yl)-carbonylamino]-pentylsilanediol; isopropyl-5-(phenylcarbonylamino)-5-(phenylaminocarbonyl)-pentylsilanediol; isopropyl-6-(phenylaminocarbonyl)hexyl-silanediol; isopropyl-4-(7V,N-dibenzylaminocarbonyl)butenyl-silanediol; isopropyl-4-(7V, ⁇ r -dibenzy
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
  • the reactions described herein take place at atmospheric pressure over a temperature range from about -78 0 C to about 150 0 C, more preferably from about 0 0 C to about 125 0 C and most preferably at about room (or ambient) temperature, e.g., about 2O 0 C.
  • Reaction of an alkene or alkyne intermediate of formula 1 or 2 respectively, with a dichlorosilyl intermediate of formula 3 in the presence of a suitable catalyst such as PtH 2 Cl 6 provides a intermediate of formula 4 or 5, respectively.
  • the reaction is carried out in a suitable organic solvent such as tetrahydrofuran.
  • Intermediates of formula 1, used in the preparation of a compound of Formula I(b), can be prepared from commercially available starting materials such as 5-hexyn-l-ol, l-amino-5-hexene, 5-hexen-l-ol, 6-heptenenitrile, ethyl propargyl propionate, 5-hexynoic acid, 3-butynyl-l -acetate, 6-heptyn-l-ol, 5-hexenoic acid, ethyl allylpropionate, acetic acid 3-buten-l-yl ester, 3-butenylurea, l-hepten-4-ol, 6- hepten-3-ol, 6-hepten-l-ol, hex-5-ene-l,2-diol, N-allyl-2-pyrrolidone, JV- butylenepyrrolidine, 4-methyl-l-heptyn-4-ol, 1 ,2-epoxy-7-oc
  • the reaction is typically carried out in the presence of a base.
  • the reaction is carried out in the presence of a coupling agent such as benzotriazole-1-yl-oxy- trispyrrolidino-phosphonium hexafluorophosphate (PyBOP®), bromo-tra-pyrrolidino- phosphonium hexafluorophosphate (PyBrop®), O-benzotriazol-1-yl- N, ⁇ yV',N'-tetramethyl-uronium hexafluorophosphate (HBTU), 0-(7-azabenzotriazol- 1 -y I)-JV ⁇ VJV 'JV '-tetramethyluronium hexafluorophosphate (HATU), or 1,3-dicyclohexylcarbodiimide (DCC) or l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDC) optionally in the presence of 1-hydroxy- benzotriazole (HO
  • a base such as ⁇ yV-diisopropylethylamine, triethylamine, or N-methylmorpholine can be used.
  • the reaction is typically carried out at 20 to 30 0 C, preferably at about 25 0 C, and requires 2 to 24 h to complete.
  • Suitable reaction solvents are inert organic solvents such as halogenated organic solvents (e.g., methylene chloride, chloroform, and the like), acetonitrile, iV ⁇ /V-dimethylformamide, ethereal solvents such as tetrahydrofuran, dioxane, and the like.
  • the above reactions can be carried out in the presence of a base such as triethylamine, N ⁇ /V-diisopropyethylamine, pyridine, and the like and in a suitable solvent such as dichloromethane, tetrahydrofuran, dioxane, N,N-dimethylformamide, and the like.
  • a base such as triethylamine, N ⁇ /V-diisopropyethylamine, pyridine, and the like
  • a suitable solvent such as dichloromethane, tetrahydrofuran, dioxane, N,N-dimethylformamide, and the like.
  • An intermediate of formula 3 such as dichloroethylsilane is commercially available. Others can be prepared by reacting trichlorosilane with an organometallic reagent of formula R 1 Cu, R 1 Li, or R 1 MgZ where R 1 is as defined in the Summary of the Invention and Z is halo as described in U.S. Patent Application Publication No. US2003/0166958, U.S. Patent No. 5,294,724, J. Am. Chem. Soc, 125, 2158, 2168, (2003), and J. Org. Chem., 13(3), 552, (1950).
  • Reaction of a Grignard reagent of formula 6 where Z is halo or an organo lithium intermediate of formula 7 with a fluorodiphenylsilane compound of formula 8 where R 1 is as defined in the Summary of the Invention for a compound of Formula I provides an intermediate of formula 9.
  • the reaction is carried out at low temperature, preferably -78 0 C, and in a suitable organic solvent such as tetrahydrofuran, and the like.
  • Intermediates of formula 6 and 7 are either commercially available or they can be prepared from commercially available starting materials by methods well known in the art.
  • Intermediates of formula 8 can be prepared from difluorodiphenylsilane as described in J. Am. Chem. Soc, 124, 7635-7375, (2002).
  • Intermediate 9 is then converted to a compound of Formula (I) by treatment with triflic acid and ammonium hydroxide.
  • the reaction is carried out in a suitable organic solvent such as dichloromethane, and the like.
  • Reaction of a styrene of formula 10 with dichloro-phenyl-vinyl-silane (11) provides a compound of formula 12.
  • the reaction is carried out in an inert atmosphere in the presence of [l,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]- dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium (Grubbs Catalyst 2 nd Generation) in a suitable organic solvent such as dichloromethane, and the like, at reflux temperature.
  • the reaction is then worked up and washed with aqueous NaHCO 3 to yield a compound of formula I(a).
  • the compounds of this invention are inhibitors of histone deacetylase enzymes and are therefore useful in the treatment of proliferative diseases such as cancer such as lung, colon, rectal, skin, breast, ovarian, prostate, liver, brain and skin cancers; psoriasis; fibroproliferative disorder such as liver fibrosis; smooth muscle proliferative disorder such as atherosclerosis and restenosis; inflammatory diseases such as arthritis; diseases involving angiogenesis such as cancer; diabetic retinopathy; haematopoietic disorder such as anaemia; fungal, parasitic, viral, and bacterial infections; autoimmune diseases such as arthritis, multiple sclerosis, lupus, allergies, asthma, allergic rhinitis, and organ transplant; and bipolar disorders.
  • proliferative diseases such as cancer such as lung, colon, rectal, skin, breast, ovarian, prostate, liver, brain and skin cancers; psoriasis; fibroproliferative disorder such as liver fibrosis; smooth muscle pro
  • the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
  • Therapeutically effective amounts of compounds of Formula (I) may range from approximately 0.1 to 50 mg per kilogram body weight of the recipient per day; preferably about 0.5 to 20 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 35 mg to 1.4 g per day.
  • compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • the preferred manner of administration is oral or parenteral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction.
  • Oral compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I).
  • excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of Formula (I) are described below.
  • the compounds of this invention can be administered in combination with known anti-cancer agents.
  • known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, DNA methyl tranferase inhibitors, and other angiogenesis inhibitors.
  • the compound of the present invention compounds are particularly useful when administered in combination with radiation therapy.
  • Preferred angiogenesis inhibitors are selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP (matrix metalloprotease) inhibitor, an integrin blocker, interferon- ⁇ , interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, - carboxyamidotriazole, combretastatin A-4, squalamine, 6-(o-chloroacetylcarbonyl)- fumagillol, thalidomide, angiostatin, troponin- 1, and an antibody to VEGF such as avastin.
  • a tyrosine kinase inhibitor an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP (matrix metalloprotease)
  • Preferred estrogen receptor modulators are tamoxifen and raloxifene.
  • Estrogen receptor modulators refers to compounds that interfere or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LYl 17081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l-oxopropoxy- 4-methyl-2-[4-[2-(l-piperidinyl)ethoxy]phenyl]-2H-l-benzopyran-3-yl]-phenyl- 2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and S ⁇ 646.
  • Androgen receptor modulators refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism.
  • Examples of androgen receptor modulators include finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • Retinoid receptor modulators refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • retinoid receptor modulators examples include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, ⁇ -difluoromethylornithine, ILX23-7553, trans-iV-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
  • Cytotoxic agents refer to compounds which cause cell death primarily by interfering directly with the cell's functioning or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.
  • cytotoxic agents include, but are not limited to, tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosylate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine) platinum, benzylguanine, glufosfamide, GPXlOO, (trans, trans, trans)-bis-mu-(hexane-l,6-d
  • microtubulin inhibitors include paclitaxel, vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPRl 09881, BMS 184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, anhydrovinblastine, 7V,N-dimethyl-L-valyl-L-valyl-jV-methyl-L-valyl-L-prolyl-L-proline- /-butylamide, TDX258, and BMS 188797.
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ' ,4 ' -O-exo-benzylidene-chartreusin, 9-methoxy-N ) N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine, 1 -amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl- IH, 12H- benzo[de]pyrano[3',4' :b,7]-indolizino[ 1 ,2b]quinoline- 10, 13(9 ⁇ , 15H)dione, lurtotecan, 7-[2-(N-isopropylamino)-ethyl]-(20S)camptothecin, BNP1350, BNPII lOO, BN80915,
  • Antiproliferative agents includes antisense R ⁇ A and D ⁇ A oligonucleotides such as G3139, OD ⁇ 698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N'-(3,4-dichlorophen
  • Antiproliferative agents also includes monoclonal antibodies to growth factors, other than those listed under “angiogenesis inhibitors”, such as trastuzumab, and tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134, for example).
  • angiogenesis inhibitors such as trastuzumab
  • tumor suppressor genes such as p53
  • HMG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3- methylglutaryl-CoA reductase.
  • Compounds which have inhibitory activity for HMG- CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33.
  • the terms "HMG-CoA reductase inhibitor” and “inhibitor of HMG-CoA reductase” have the same meaning when used herein. It has been reported that ⁇ Int. J.
  • HMG-CoA reductase inhibitors examples include but are not limited to lovastatin (MEV ACOR ® ; see U.S. Pat. Nos. 4,231,938; 4,294,926; 4,319,039), simvastatin (ZOCOR ® ; see U.S. Pat. Nos. 4,444,784; 4,820,850; 4,916,239), pravastatin (PRAVACHOL ® ; see U.S. Pat. Nos. 4,346,227; 4,537,859; 4,410,629; 5,030,447 and 5,180,589), fluvastatin (LESCOL ® ; see U.S. Pat. Nos.
  • HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and colchicine the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
  • HMG-CoA reductase inhibitors where an open-acid form can exist
  • salt and ester forms may preferably be formed from the open-acid, and all such forms are included within the meaning of the term "HMG-CoA reductase inhibitor" as used herein.
  • the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin, and most preferably simvastatin.
  • the term "pharmaceutically acceptable salts" with respect to the HMG- CoA reductase inhibitor shall mean non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, iV-benzylphenethylamine, 1 -j7-chlorobenzyl-2-pyrrolidine- l'-yl-methylbenzimidazole, diethylamine, piperazine, and tris(hydroxymethyl) aminomethane.
  • a suitable organic or inorganic base particularly those formed
  • salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium hydroxy, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, hydroxy, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palm
  • Ester derivatives of the described HMG-CoA reductase inhibitor compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
  • Prenyl-protein transferase inhibitor refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • FPTase farnesyl-protein transferase
  • GGPTase-I geranylgeranyl-protein transferase type I
  • GGPTase-II geranylgeranyl-protein transferase type-II
  • prenyl-protein transferase inhibiting compounds examples include (+)-6-[amino(4- chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-l-methyl-2(lH)- quinolinone, (-)-6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]- 4-(3-chloro phenyl)- 1 -methyl-2(lH)-quinolinone, (+)-6-[amino(4-chlorophenyl)- ( 1 -methyl- 1 H-imidazol-5-yl)methyl] -4-(3 -chloro phenyl)- 1 -methyl-2( 1 H)-quinolinone, 5(S)-n-butyl- 1 -(2,3-dimethylphenyl)-4-[ 1 -(4-cyanobenzyl
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. Nos. 5,420,245, 5,523,430, 5,532,359, 5,510,510, 5,589,485, 5,602,098, European Patent Publ. 0 618 221, European Patent Publ. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.
  • HIV protease inhibitors examples include amprenavir, abacavir, CGP-73547, CGP-61755, DMP -450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232, 632.
  • reverse transcriptase inhibitors examples include delaviridine, efavirenz, GS-840, HB Y097, lamivudine, nevirapine, AZT, 3TC, ddC, and ddl. It has been reported (Nat. M?c/.;8(3):225-32, 2002) that HIV protease inhibitors, such as indinavir or saquinavir, have potent anti-angiogenic activities and promote regression of Kaposi sarcoma
  • Angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors FIt-I (VEGFRl) and FIk-I /KDR (VEGFR20), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-oc, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal antiinflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxygenase-2 inhibitors like celecoxib, valecoxib, and rofecoxib (PNAS, Vol.
  • NSAIDs nonsteroidal antiinflammatories
  • NSAID's which are potent COX-2 inhibiting agents.
  • an NSAID is potent if it possess an IC 50 for the inhibition of COX-2 of 1 ⁇ M or less as measured by the cell or microsomal assay known in the art.
  • NSAID's which are selective COX-2 inhibitors are defined as those which possess a specificity for inhibiting COX-2 over COX-I of at least 100 fold as measured by the ratio of IC 50 for COX-2 over IC 50 for COX-I evaluated by the cell or microsomal assay disclosed hereinunder.
  • Such compounds include, but are not limited to those disclosed in U.S. Pat. No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan. 19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat. No. 6,020,343, issued Feb.
  • angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl- 2-butenyl)oxiranyl]-l-oxaspiro[2,5]oct-6 -yl(chloroacetyl)carbamate, acetyldinaline, 5 -amino- 1 - [ [3 , 5 -dichloro-4-(4-chlorobenzoyl)pheny 1] -methyl] - 1 H- 1 ,2 ,3 -triazole- 4-carboxamide, CMlOl, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonyl- imino[iV-methyl-4,2-pyr
  • integral blockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ 3 integrin, to compounds which selectively antagonize, inhibit or counter-act binding of a physiological ligand to the ⁇ v ⁇ 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the ⁇ v ⁇ 3 integrin and the ⁇ v ⁇ 5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the ⁇ v ⁇ 6 ; ⁇ v ⁇ 8 , oti ⁇ i, ⁇ 2 ⁇ l5 ⁇ 5 ⁇ l5 ⁇ 6 ⁇ !, and ⁇ 6 ⁇ 4 integrins.
  • the term also refers to antagonists of any combination of ⁇ v ⁇ 3 , ocv ⁇ s, ⁇ v ⁇ 6 , ⁇ v ⁇ 8, ⁇ i ⁇ i, ⁇ 2 ⁇ 1; ⁇ 5 ⁇ i, ⁇ 6 ⁇ j and ⁇ 6 ⁇ 4 integrins.
  • tyrosine kinase inhibitors include iV-(trifluoromethyl- phenyl)-5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)- indolin-2-one, 17-(allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenyl- amino)-7-methoxy-6-[3-(4-mo ⁇ holinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)- 6,7-bis(2-methoxyethoxy)-4-quinazolinamine, BIBX 1382, 2,3,9,10,11,12-hexahydro- 10-(hydroxymethyl)-l 0-hydroxy-9-methyl-9, 12-epoxy -lH-diindolo[l ,2,3- fg:3',2',l
  • the instant compounds are also useful, alone or in combination with platelet fibrinogen receptor (GP Ilb/IIIa) antagonists, such as tirofiban, to inhibit metastasis of cancerous cells.
  • Tumor cells can activate platelets largely via thrombin generation. This activation is associated with the release of VEGF.
  • the release of VEGF enhances metastasis by increasing extravasation at points of adhesion to vascular endothelium (Amirkhosravi, Platelets 10, 285-292, 1999). Therefore, the present compounds can serve to inhibit metastasis, alone or in combination with GP Ilb/IIIa) antagonists.
  • fibrinogen receptor antagonists include abciximab, eptifibatide, sibrafiban, lamifiban, lotrafiban, cromofiban, and CT50352.
  • DNA methyltransferase inhibitor refers to compounds which inhibit the methylation of the DNA base cytosine at the C-5 position of that base by the DNA methyltransferase enzyme.
  • DNA methyltransferase inhibitor examples include compounds disclosed in US Patents 6,329,412 and 6,268,137.
  • Specific DNA methy transferase inhibitors include 5-azacytosine and zebularine®.
  • Such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range.
  • Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
  • administration and variants thereof in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.)
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the compounds of the instant invention may also be co-administered with other well known cancer therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • Included in such combinations of therapeutic agents are combinations of the farnesyl-protein transferase inhibitors disclosed in US Patent 6,313,138 and an antineoplastic agent. It is also understood that such a combination of antineoplastic agent and inhibitor of farnesyl- protein transferase may be used in conjunction with other methods of treating cancer and/or tumors, including radiation therapy and surgery.
  • antineoplastic agent examples include, in general, microtubule-stabilizing agents (such as paclitaxel (also known as Taxol ® ), docetaxel (also known as Taxotere ® , epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives); microtubule-disruptor agents; alkylating agents, anti-metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.
  • microtubule-stabilizing agents such as paclitaxel (also known as Taxol ® ), docetaxel (also known as Taxotere ® , epothilone A, epothilone B, desoxyepothilone
  • Example classes of antineoplastic agents include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins.
  • Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as colchicines, etoposide, etoposide phosphate or teniposide, vinblastine, vincristine, leurosidine, vindesine, leurosine, and the like.
  • antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabine, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
  • the preferred class of antineoplastic agents is the taxanes and the preferred antineoplastic agent is paclitaxel.
  • Radiation therapy including x-rays or gamma rays that are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with the compounds of this invention alone to treat cancer.
  • Example 14 ethyl-3-(N-benzyl-N-methyl-aminocarbonyl)-phenethyl-silanediol; 1 HNMR (400MHz, DMSO) ⁇ 7.33-7.18 (m, 9H), 4.69 (bs, 2H), 3.49 (s, 2H), 2.89- 2.58(m, 5H), 0.95(m, 4H), 0.46 (m, 3H); ESMS (m/z): found, 344 (M+l) + ;
  • Example 15 ethyl-3-[jV-methyl-N-(phenethyl)aminocarbonyl]-phenethyl- silanediol; 'H ⁇ MR(400MHZ, DMSO) ⁇ 6.94-6.45 (m, 9H), 3.39 (bs, 2H), 2.65 (bs, 2H), 2.45 (bs, 2H), 2.25 (bs, 2H), 0.59(m, 2H), 0.1 l(m, 2H), 0.02(m; 3H); ESMS (m/z): found, 358 (M+l) + ; and
  • N-Methyltryptamine (0.25 g, 1.46 mmol), 4-ethynylbenzaldehyde (0.19 g, 1.46 mmol) and sodium triacetoxyborohydride (0.46 g, 2.17 mmol) were stirred at ambient temperature in 1 ,2-dichloroethane (7 mL) for 18 h.
  • the reaction solution was then diluted with ethyl acetate (100 mL) and washed with aq. NaHCO 3 (100 mL).
  • the organic layer was dried (MgSO 4 ), filtered and concentrated.
  • the HDAC inhibitory activity of the compounds of this invention in vitro was determined as follows.
  • HDAC-I 200 pM final concentration
  • reaction buffer 50 mM HEPES, 100 mM KCl, 0.001% Tween-20, 5% DMSO, pH 7.4
  • trypsin and acetyl- Gly-Ala-(N-acetyl-Lys)-AMC were added to final concentrations of 50 nM and 25 ⁇ M, respectively, to initiate the reaction.
  • Negative control reactions were performed in the absence of inhibitor in replicates of eight.
  • the reactions were monitored in a fluorescence plate reader. After a 30 min lag time, the fluorescence was measured over a 30 min time frame using an excitation wavelength of 355 nm and a detection wavelength of 460 nm. The increase in fluorescence with time was used as the measure of the reaction rate. Inhibition constants were obtained using the program BatchKi (Kuzmic et al. Anal. Biochem. 2000, 286, 45-50).
  • the HDAC8 inhibitory activity of the compounds of this invention in vitro was determined as follows.
  • HDAC8 28 nM final concentration
  • reaction buffer 50 mM HEPES, 100 mM KCl, 0.001% Tween-20, 0.01% bovine serum albumin, 5% DMSO, pH 7.4
  • trypsin and acetyl-Gly-Ala-(N-acetyl-Lys)-AMC were added to final concentrations of 50 nM and 100 ⁇ M, respectively, to initiate the reaction.
  • Negative control reactions were performed in the absence of inhibitor in replicates of eight. The reactions were monitored in a fluorescence plate reader.
  • Stock cultures of the DU 145 prostate carcinoma cell line were maintained in RPMI medium 1640 containing 10% (v/v) fetal bovine serum, 2 mM L-glutamine, 1 mM sodium pyruvate, 50 units/mL penicillin, and 50 ⁇ g/mL streptomycin at 37 °C in 5% CO 2 humidified atmosphere. Cells were cultured in 75-cm 2 culture flasks and subcultures were established every 3 to 4 days so as not to allow the cells to exceed 90% confluence.
  • DU 145 cells were harvested for proliferation assays by trypsinization (0.05% trypsin/0.53 mM EDTA), washed twice in culture medium, resuspended in appropriate volume of medium, and then counted using a hemacytometer. Cells were seeded in wells of flat-bottom 96-well plates at a density of 5,000 cell/well in 100 ⁇ l. Cells were allowed to attach for 1.5 to 2 h at 37 °C.
  • Cell proliferation was assessed by measuring fluorescence after the addition of the fluorogenic redox indicator, Alamar BlueTM (BioSource International). Ten ⁇ l of Alamar BlueTM was added to each well of the 96-well plate(s) 3 to 4 h prior to the end of the incubation period. Assay plates were read in a fluorescence plate reader (excitation, 530 nm; emission, 620 nm). GI 50 values (concentration at which the growth of the tumor cells was inhibited by 50%) for compounds were determined by plotting the percent control fluorescence against the logarithm of the compound concentration. The compounds of this invention inhibited the growth of the tumor cells.
  • Ingredient tablet mg compound of this invention 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5
  • Suspension Formulation The following ingredients are mixed to form a suspension for oral administration.
  • Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 g sodium chloride 2.O g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g
  • Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 mL colorings 0.5 mg distilled water q.s. to 100 mL
  • Ingredient Amount compound of this invention 1.2 g sodium acetate buffer solution, 0.4M 2.0 mL
  • a suppository of total weight 2.5 g is prepared by mixing the compound of the invention with WitepsolTM H- 15 (triglycerides of saturated vegetable fatty acid; Riches- Nelson, Inc., New York), and has the following composition: compound of the invention 500 mg WitepsolTM H- 15 balance

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Abstract

L'invention concerne certains dérivés de silanol qui sont des inhibiteurs d'histone déacétylase et qui sont par conséquent utiles dans le traitement de maladies associées à l'activité de l'histone déacétylase. L'invention concerne également des compositions pharmaceutiques et des procédés de préparation de ces composés.
PCT/US2005/046255 2004-12-20 2005-12-20 Derives de silanol en tant qu'inhibiteurs d'histone deacetylase Ceased WO2006069096A1 (fr)

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US8222286B2 (en) 2009-11-20 2012-07-17 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8263629B2 (en) 2009-05-28 2012-09-11 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
US8394853B2 (en) 2009-05-28 2013-03-12 Novartis Ag Substituted aminopropionic derivatives as neprilysin inhibitors
US9102635B2 (en) 2013-02-14 2015-08-11 Novartis Ag Substituted bisphenyl butanoic acid derivatives as NEP inhibitors with improved in vivo efficacy
US9163040B2 (en) 2013-02-14 2015-10-20 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
WO2017214491A1 (fr) * 2016-06-09 2017-12-14 Blinkbio, Inc. Charges utiles thérapeutiques à base de silanol

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US9603819B2 (en) 2009-05-28 2017-03-28 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
US8263629B2 (en) 2009-05-28 2012-09-11 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
US9006249B2 (en) 2009-05-28 2015-04-14 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
US8394853B2 (en) 2009-05-28 2013-03-12 Novartis Ag Substituted aminopropionic derivatives as neprilysin inhibitors
CN102482298A (zh) * 2009-09-11 2012-05-30 亚当密茨凯维奇大学 新型(e)-苯乙烯基-炔基取代的硅化合物和获得(e)-苯乙烯基-炔基取代的硅化合物的方法
CN102482298B (zh) * 2009-09-11 2015-03-11 亚当密茨凯维奇大学 (e)-苯乙烯基-炔基取代的硅化合物和获得(e)-苯乙烯基-炔基取代的硅化合物的方法
US8877786B2 (en) 2009-11-20 2014-11-04 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8642635B2 (en) 2009-11-20 2014-02-04 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8377978B2 (en) 2009-11-20 2013-02-19 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8222286B2 (en) 2009-11-20 2012-07-17 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US9102635B2 (en) 2013-02-14 2015-08-11 Novartis Ag Substituted bisphenyl butanoic acid derivatives as NEP inhibitors with improved in vivo efficacy
US9163040B2 (en) 2013-02-14 2015-10-20 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
US9480693B2 (en) 2013-02-14 2016-11-01 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
US10112963B2 (en) 2013-02-14 2018-10-30 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
WO2017214491A1 (fr) * 2016-06-09 2017-12-14 Blinkbio, Inc. Charges utiles thérapeutiques à base de silanol

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