WO2007075572A2 - Inhibiteurs a base de purine oralement actifs de la proteine de choc thermique 90 - Google Patents

Inhibiteurs a base de purine oralement actifs de la proteine de choc thermique 90 Download PDF

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WO2007075572A2
WO2007075572A2 PCT/US2006/048250 US2006048250W WO2007075572A2 WO 2007075572 A2 WO2007075572 A2 WO 2007075572A2 US 2006048250 W US2006048250 W US 2006048250W WO 2007075572 A2 WO2007075572 A2 WO 2007075572A2
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optionally substituted
purin
ylsulfanyl
ylamine
benzothiazol
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PCT/US2006/048250
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English (en)
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WO2007075572A3 (fr
Inventor
Srinivas R. Kasibhatla
Lin Zhang
Marcus F. Boehm
Junhua Fan
Kevin D. Hong
Marco Biamonte
Jiandong Shi
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Conforma Therapeutics Corporation
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Priority to AU2006331917A priority Critical patent/AU2006331917A1/en
Priority to CA002634723A priority patent/CA2634723A1/fr
Priority to EP06845721A priority patent/EP1962863A4/fr
Priority to JP2008547398A priority patent/JP2009521446A/ja
Publication of WO2007075572A2 publication Critical patent/WO2007075572A2/fr
Publication of WO2007075572A3 publication Critical patent/WO2007075572A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/36—Sulfur atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates in general to purine analogs and their use in inhibiting heat shock protein 90's (HSP90's) to thereby treat or prevent HSP90-dependent diseases, e.g., proliferative disorders such as breast cancer.
  • HSP90's heat shock protein 90's
  • Hsp90s Heat Shock Protein 90's
  • HSP90 chaperone proteins are associated with important signaling proteins, such as steroid hormone receptors and protein kinases, including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2 (Buchner, TIBS, 1999, 24, 136-141; Stepanova et. al., Genes Dev. 1996, 10, 1491-502; Dai et. al, J. Biol. Chem. 1996, 271, 22030-4).
  • steroid hormone receptors and protein kinases including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2 (Buchner, TIBS, 1999, 24, 136-141; Stepanova et. al., Genes Dev. 1996, 10, 1491-502; Dai et. al, J. Biol. Chem. 1996, 271, 22030-4).
  • Hsp70 ⁇ 60/Hop/Stil, Hip, Bagl, HSP40/Hdj2/Hsjl, immunophilins, p23, and p50
  • HSP40/Hdj2/Hsjl immunophilins
  • p23, and p50 may assist HSP90 in its function (see for example Caplan, Trends in Cell Biol., 1999, 9, 262-268).
  • Inhibition of Hsp90 causes these client proteins to adopt aberrant conformations, and these abnormally folded proteins are rapidly eliminated by the cell via ubiquitinylation and proteasome degradation.
  • the list of Hsp90 client proteins includes a series of notorious oncogenes.
  • HER-2/neu Herceptin ® (trastuzumab)
  • Bcr-Abl Gavec ® (imatinib mesylate)
  • the estrogen receptor tamoxifen
  • Casodex ® bonutamide
  • Some of the most sensitive Hsp90 clients are involved in growth signalling (Raf-1, Akt, cdk4, Src, Bcr-Abl, etc).
  • Hsp90 has an overall anti-proliferative effect.
  • some client proteins are involved in other fundamental .processes of tumorigenesis, namely apoptosis evasion (e.g. Apaf-1, RIP, Akt), immortality (e.g. hTert), angiogenesis (e.g. VEGFR, Flt-3, FAK, HDF-1), and metastasis (c-Met).
  • apoptosis evasion e.g. Apaf-1, RIP, Akt
  • immortality e.g. hTert
  • angiogenesis e.g. VEGFR, Flt-3, FAK, HDF-1
  • metastasis c-Met
  • the various client proteins are not equally responsive to Hsp90 inhibitors, and some undergo degradation at lower concentrations of the inhibitor, or with faster kinetics, depending on the cell line.
  • the more sensitive clients are usually those involved in growth signaling, but some mutated proteins found in tumor cells (mutant p53, Gleevec-resistant Bcr-Abl, see Gorre et. ah Blood, 2002, 700, 3041-3044) are particularly dependent on Hsp90 to preserve their conformation and function.
  • This unique feature sensitizes tumor cells to Hsp90 inhibitors, and when these factors converge, they confer on Hsp90 inhibitors notable anti-cancer properties in v itro and in vivo.
  • Hsp90 A remarkable advantage of targeting Hsp90 lies in the simultaneous depletion of multiple oncogenic proteins, thereby attacking several pathways necessary for cancer development, and reducing the likelihood of the tumor acquiring resistance to the Hsp90 inhibitor.
  • Another striking feature of Hsp90 is that it occurs in an activated form in cancer cells, and in a latent form in normal cells (Kamal et. ah Nature, 2003, 425, 407-410 and Workman et. ah Trends MoI. Med. 2004, JO, 47-51.) This provides an opportunity to specifically target cancer cells with inhibitors selective for the activated form. What distinguishes the activated and latent forms of Hsp90 at a molecular level is not well understood.
  • Hsp90 activity of Hsp90 is regulated by a highly sophisticated process involving at a minimum (1) Hsp90 dimerization, (2) formation of multi-protein complexes with numerous co-chaperones, and (3) ATP/ADP binding, ATP hydrolysis being essential for the chaperone cycle and function.
  • Hsp90 The chaperoning function of Hsp90 can be "switched off' by inhibiting its ATP-ase activity.
  • the nucleotides ADP and ATP can bind to two sites, one located close to the N-terminal, the other close to the C-terminal.
  • Geldanamycin isolated from the microorganism Streptomyces hygroscopicus, was originally identified for its antiprotozoal, herbicidal and antifungal activities.
  • Ansamycin antibiotics such as geldanamycin (GM), herbimycin A (HA), and 17-AAG are thought to exert their anticancerous effects by tight binding of the N-terminus pocket of HSP90, (while for example novobiocin binds to the C-terminal domain, see Yun et. ah Biochemistry, 2004, 43, 8217—8229), thereby destabilizing substrates that normally interact with HSP90 (Stebbins et a Cell, 1997, 89, 239-250).
  • This pocket is highly conserved and has weak homology to the ATP-binding site of DNA gyrase (Stebbins, C. et al., supra; Grenert, J.P.
  • HSP90 substrate destabilization occurs in tumor and non-transformed cells alike and has been shown to be especially effective on a subset of signaling regulators, e.g., Raf (Schulte, T. W. et al., 1997, Biochem. Biophys. Res. Commun. 239:655-9; Schulte, T. W., et al., 1995, J. Biol. Chem.
  • EGF receptor EGFR
  • Her2/Neu Hartmann, F., et al., 1997, Int. J. Cancer 70:221-9; Miller, P. et al., 1994, Cancer Res. 54:2724-2730; Mimnaugh, E. G., et al., 1996, J. Biol. Chem. 271:22796-801; Schnur, R. et al., 1995, J. Med. Chem.
  • HSP90 inhibitors have also been implicated in a wide variety of other utilities, including use as anti-inflammation agents, anti-infectious disease agents, agents for treating autoimmunity, agents for treating ischemia, and agents useful in promoting nerve regeneration ⁇ See, e.g., Rosen et al., WO 02/09696; PCT/USOl/23640; Degranco et al., WO 99/51223; PCT/US99/07242; Gold, U.S. Patent 6,210,974 Bl).
  • fibrogenetic disorders including but not limited to scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis, and pulmonary fibrosis may be treatable. (Strehlow, WO 02/02123; PCT/US01/20578).
  • Hsamycins and other HSP90 inhibitors thus hold great promise for the treatment and/or prevention of many types of disorders.
  • many of the natural-product derived Hsp90 inhibitors exhibit pharmaceutical deficiencies; their relative insolubility makes them difficult to formulate and administer, and they are not easily synthesized and currently must, at least in part, be generated through fermentation.
  • the dose limiting toxicity of ansamyins is hepatic.
  • the semi-synthetic inhibitor 17- allylamino,17-desmethoxy-geldanarnycin (17- AAG) is expensive to manufacture, difficult to formulate (the NCI clinical protocol consists of injecting a DMSO solution of 17- AAG) and at present administered only parenterally.
  • the 17-dimethylaminoethylamino analog is expensive to manufacture, difficult to formulate (the NCI clinical protocol consists of injecting a DMSO solution of 17- AAG) and at present administered only parenterally.
  • (17-DMAG) is more soluble, it exhibits all of the side effects of 17-AAG as well as gastrointestinal hemorrhaging in preclinical toxicity studies (Glaze et. al. Proc. Am. Assoc. Cancer. Res. 2003, 44, 162-162 and Eiseman et. al. Cancer Chemother. Pharmacol. 2005, 55, 21-32).
  • Radicicol (RC) another natural product Hsp90 inhibitor, is poorly water-soluble and is inactive in tumor xenograft models.
  • Semi-synthetic oxime derivatives of radicicol provide better solubility and substantially improved the pharmacological profile in murine models, but are still limited to intravenous administration (Ikuina et. al. J. Med. Chem.
  • the structures of these inhibitors were designed using the crystal structures of Hsp90 in complex with ATP, geldanamycin, or radicicol.
  • the 8-benzyladenines such as PU3 were designed to adopt the same C-shaped conformation as geldanamycin (Chiosis et. al. Current Cancer Drug Targets, 2003, 3, 371-376) with the adenine ring pointing to the adenine-binding site (hinge region), and the trimethoxybenzene ring emulating the H-bond accepting nature of the quinone ring of geldanamycin.
  • the benzene ring of PU3 was not designed to have exactly the same orientation as the quinone ring of geldanamycin.
  • PU24FC1 was formulated in DMSO/EtOH/phosphate- buffered saline 1:1:1 and administered intraperitoneally to mice bearing MCF-7 xenograft tumors, it induced at 100—300 mg/kg down-regulation of HER-2 and Raf-1, a pharmacodynamic response consistent with Hsp90 inhibition, and at 200 mg/kg it significantly repressed tumor growth.
  • the present invention provides water-soluble, orally bioavailable purine analogs, and their use in inhibiting heat shock protein 90's to thereby treat or prevent Hsp90-dependent diseases as demonstrated by their oral efficacy in tumor xenograft models.
  • the invention provides a compound of Formula I:
  • R s is independently selected from H and F; each R a , R b , R c , and R d is independently selected from H, halo, lower alkyl, OR 3 , SR 3 , C(O)N(R 4 ) 2 , NR 4 R 4 , C(O)R 2 , and -C(O)OR 4 ;
  • R x is independently selected from optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl and optionally substituted C 2 -C 6 alkynyl;
  • R y is independently selected from O, NR 1 and a bond
  • R z is independently selected from H, C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -P(O)(OR 4 ) 2 and C(O)R 2 ;
  • R 1 is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, C(O)R 2 , -C(O)OR 2 , C(O)NR 4 27 C(S)OR 2 , C(S)NR 4 2 , P(O)(OR 4 ) 2 , and SO 2 R 2 ;
  • R 2 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted
  • R 3 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, C(O)NR 4 2 , C(O)R 2 , and -C(O)OR 2 ; and
  • R 4 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, and optionally substituted heterocyclyl.
  • the invention also provides the following embodiments: -compounds of Formula I wherein R", R b , R c , and R d are independently selected from halo and OR 3 ;
  • R x is optionally substituted C 2 -C 3 alkyl, optionally substituted C 2 -C 3 alkenyl or optionally substituted C 2 -C 3 alkynyl, R y is NR 1 ; and R 2 is Ci-C 6 alkyl; -compounds of Formula I wherein R x is optionally substituted C 2 -C 3 alkyl, optionally substituted C 2 -C 3 alkenyl or optionally substituted C 2 -C 3 alkynyl; R y is a bond; and R z is H;
  • R x is optionally substituted C 2 -C 3 alkyl, optionally substituted C 2 -C 3 alkenyl or optionally substituted C 2 -C 3 alkynyl;
  • R y is NR 1 ; and
  • R z is C(O)R 2 .
  • R x is optionally substituted C 2 -C 3 alkyl, optionally substituted C 2 -C 3 alkenyl or optionally substituted C 2 -C 3 alkynyl;
  • R y is NH; and
  • R z is H.
  • R* is optionally substituted C 2 -C 3 alkyl, optionally substituted C 2 -C 3 alkenyl or optionally substituted C 2 -C 3 alkynyl
  • R y is NH
  • R z is C r Cg alkyl
  • the invention provides a compound of formula II:
  • R s is independently selected from H and F; each R ⁇ , R b , R c , and R d is independently selected from H, halo, lower alkyl, OR 3 , SR 3 , C(O)N(R 4 ) 2 , NR 4 R 4 ,
  • R x is independently selected from optionally substituted C 2 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl and optionally substituted C 2 -C 6 alkynyl;
  • R y is independently selected from O, NR 1 or a bond
  • R z is independently selected from H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -P(O)(OR 4 ) 2 and C(O)R 2 ;
  • R 1 is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, C(O)R 2 , -C(O)OR 2 , C(O)NR 4 2 , C(S)OR 2 , C(S)NR 4 2) P(O)(OR 4 ) 2 , and SO 2 R 2 ;
  • R 2 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
  • R 3 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, C(O)NR 4 2 , C(O)R 2 , and -C(O)OR 2 ; and
  • R 4 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, and optionally substituted heterocyclyl.
  • the invention also provides the following embodiments:
  • R a , R b , R c , and R d are halo;
  • R" is optionally substituted C 2 - C 3 alkyl;
  • R y is a bond; and
  • R z is H;
  • R a , R b , R c , and R d are halo;
  • R" is optionally substituted C 2 - C 3 alkyl;
  • R y is NR 1 ; and
  • R 2 is H;
  • R a , R b , R c , and R d are halo;
  • R x is optionally substituted C 2 - C 3 alkyl;
  • R y is NR 1 ;
  • R z is C 1 -C 6 alkyl;
  • R a , R b , R c , and R d are halo;
  • R x is optionally substituted C 2 - C 3 alkyl;
  • R y is a bond; and
  • R z is -P(O)(OR 4 ) 2 ;
  • R* is optionally substituted C 2 -C 3 alkyl;
  • R y is a bond; and
  • R z is H.
  • the invention provides a compound of formula III:
  • R s is independently selected from H and F; each R a , R c and R d is independently selected from H, halo, lower alkyl, OR 3 , SR 3 , C(O)N(R 4 ) 2 , NR 4 R 4 , C(O)R 2 , and -C(O)OR 4 ; R* is independently selected from optionally substituted C 2 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl and optionally substituted C 2 -C 4 alkynyl; R y is independently selected from O, NR 1 and a bond; and
  • R 2 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -P(O)(OR 4 ) 2 and C(O)R 2 ;
  • R 1 is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, C(O)R 2 , -C(O)OR 2 , C(O)NR 4 2> C(S)OR 2 , C(S)NR 4 2 , P(O)(OR 4 ) 2 , and SO 2 R 2 ;
  • R 2 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
  • R 3 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, C(O)NR 4 2 , C(O)R 2 , and -C(O)OR 2 ; and
  • R 4 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, and optionally substituted heterocyclyl.
  • the invention also provides the following embodiments: -compounds of Formula III wherein at least one of R a , R c , and R d is halo; R x is optionally substituted C 2 -C 3 alkyl; R y is a bond; and R z is H;
  • R a , R c , and R d are halo;
  • R* is optionally substituted C 2 -Cj alkyl;
  • R y is NR 1 ; and
  • R z is H;
  • R a , R c , and R d are halo;
  • R" is optionally substituted C 2 -C 3 alkyl;
  • R y is a bond; and
  • R z is C r C 6 alkyl;
  • X is independently selected from H, halo, CN, N 3 , N(R*) 2 , NR 1 S(O) 2 R 2 , OR 3 , SR 3 , lower alkyl, C(O)N(R 4 ) 2 , perhaloalkyl, C(O)R 2 , and -C(O)OR 4 ;
  • Y is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted araalkyl, optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl, optionally substituted heterocyclyl, optionally substituted alkylaminoalkyl (-(CH 2 ) O -NHR 2 ), optionally substituted alkylaminodialkyl (-(CH 2 ) n -NR 2 R 2 ), optionally substituted alkylcarbonylamino
  • R 2 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
  • R 3 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, C(O)NR 4 2 , C(O)R 2 , and -C(O)OR 2 ;
  • R 4 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, and optionally substituted heterocyclyl; and n is from 1 to 3.
  • the invention provides a compound of formula V:
  • X is independently selected from H, halo, CN, N 3 , N(R ] ) 2 , NR 1 S(O) 2 R 2 , OR 3 , SR 3 , lower alkyl, C(O)N(R 4 ) 2 , perhaloaLkyl, C(O)R 2 , and -C(O)OR 4 ;
  • Y is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted araalkyl, optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl, optionally substituted heterocyclyl, optionally substituted alkylaminoalkyl (-(CH 2 ) B -NHR 2 ), optionally substituted alkylaminodialkyl (-(CH 2 ) n -NR 2 R 2 ), optionally substituted alkylcarbony
  • Z is independently selected from H and halogen
  • R 1 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, C(O)R 2 , - C(O)OR 2 , C(O)NR 4 2 , C(S)OR 2 , C(S)NR 4 2 , P(O)(OR 4 ) 2 , and SO 2 R 2 ;
  • R 2 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
  • R 3 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, C(O)NR 4 2 , C(O)R 2 , and -C(O)OR 2 ;
  • R 4 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, and optionally substituted heterocyclyl; and n is from 1 to 3.
  • the invention provides a compound of formula VI:
  • X is independently selected from H, halo, CN, N 3 , N(R 1 )* NR 1 S(O) 2 R 2 , OR 3 , SR 3 , lower alkyl, C(O)N(R 4 ) 2 , perhaloalkyl, C(O)R 2 , and -C(O)OR 4 ;
  • Y is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted araalkyl, optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl, optionally substituted heterocyclyl, optionally substituted alkylaminoalkyl (-(CH 2 ) H -NHR 2 ), optionally substituted alkylaminodialkyl (-(CH 2 ) n -NR 2 R 2 ), optionally substituted alkylcarbonylaminoal
  • R 1 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, C(O)R 2 , - C(O)OR 2 , C(O)NR 4 2 , C(S)OR 2 , C(S)NR 4 2 , P(O)(OR 4 ) 2 , and SO 2 R 2 ;
  • R 2 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
  • R 3 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, C(O)NR 4 2 , C(O)R 2 , and -C(O)OR 2 ;
  • R 4 is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, and optionally substituted heterocyclyl; and n is from 1 to 3.
  • the invention provides a compound selected from the group consisting of:
  • Figure 1 (a) represents levels of Hsp90 clients, Hsp70, and PI-3K p85 in murine A549 tumor xenografts following a single oral administration of 89'H 3 PO 4 at 200 mg/kg, and (b) Levels of Hsp90 clients and PI- 3K in murine N87 tumor xenografts 24 h after a three-day course of 17- AAG (intraperitoneally, 1 x 90 mg/kg/day) or 126-H 3 PO 4 (orally, 2 x 200 or 2 x 100 mg/kg/day).
  • Figure 3 represents a pharmacokinetic study of 264 delivered at 100 mg/kg via oral gavage
  • Figure 4 represents a tumor growth inhibition study of 264 in the N87 xenograft model
  • a "pharmaceutically acceptable salt” may be prepared for any compound of the invention having a functionality capable of forming a salt, for example an acid or base functionality.
  • Pharmaceutically acceptable salts may be. derived from organic or inorganic acids and bases.
  • Compounds of the invention that contain one or more basic functional groups, e.g., amino or alkylamino, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable organic and inorganic acids.
  • These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • acids examples include hydrochloric, hydrobrornic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, gluconic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, 1,2 ethanesulfonic acid (edisylate), galactosyl- d-gluconic acid, and the like.
  • compositions of the present invention that contain one or more acidic functional groups are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Illustrative examples of some of the bases that can be used include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. See, for example, Berge et al., supra. [0026] "Prodrugs" are derivative compounds derivatized by the addition of a group that endows greater solubility to the compound desired to be delivered.
  • prodrug is typically acted upon by an enzyme, e.g., an esterase, amidase, or phosphatase, to generate the active compound.
  • an enzyme e.g., an esterase, amidase, or phosphatase.
  • Suitable positions for derivatization of the compounds of the invention to create "prodrugs" include but are not limited to the Y group, the phenyl ring of the purines, and the Q group. Those of ordinary skill in the art have the knowledge and means to accomplish this without undue experimentation. Examples of prodrugs of contenplated by the present application, without limitation, include:
  • R alkyl, aryl, or heteroaryl
  • X u — C(R 1 XR 11 JNH 2
  • R', R" are independently selected from hydrogen, alkyl, aryl, or heteroaryl.
  • R hydrogen, alkyl, aryl, or heteroaryl
  • X alkyl, aryl or heteroaryl
  • Tautomers are compounds whose structures differ in arrangements of atoms, but which exist in • equilibrium.
  • T is in equilibrium with a second tautomeric form designated T'.
  • the predominance of one tautomer versus another is controlled by factors which include but are not limited to the nature of the solvent, temperature, pressure, the presence or absence of other molecules, and the nature of substituents on the molecule having tautomeric forms.
  • alkyl refers to an optionally substituted straight-chain, optionally substituted branched-chain, or optionally substituted cyclic alkyl radical having from 1 to about 30 carbons, more preferably 1 to 12 carbons.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like.
  • cycloalkyl embraces cyclic configurations, is subsumed within the definition of alkyl and specifically refers to a monocyclic, bicyclic, tricyclic, and higher multicyclic alkyl radicals wherein each cyclic moiety has from 3 to about 8 carbon atoms.
  • cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • a “lower alkyl” is a shorter alkyl, e.g., one containing from 1 to about 6 carbon atoms.
  • alkenyl refers to an optionally substituted straight-chain, optionally substituted branched-chain, or optionally substituted cyclic alkenyl hydrocarbon radical having one or more carbon- carbon double-bonds and having from 2 to about 30 carbon atoms, more preferably 2 to about 18 carbons.
  • alkenyl radicals include ethenyl, propenyl, butenyl, 1,4-butadienyl and the like.
  • the term can also embrace cyclic alkenyl structures.
  • a "lower akenyl” refers to an alkenyl having from 2 to about 6 carbons.
  • alkynyl refers to an optionally substituted straight-chain, optionally substituted branched-chain, or cyclic alkynyl hydrocarbon radical having one or more carbon-carbon triple-bonds and having from 2 to about 30 carbon atoms, more preferably 2 to about 12 carbon atoms.
  • the term also includes optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon radicals having one or more carbon-carbon triple bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms.
  • alkynyl radicals include ethynyl, propynyL butynyl and the like.
  • heteroalkyl, heteroalkenyl and heteroalkynyl include optionally substituted alkyl, alkenyl and alkynyl structures, as described above, and which have one or more skeletal chain atoms selected from an atom other that carbon, e.g., oxygen, nitrogen, sulfur, phosphorous or combinations thereof.
  • carbon chain may embrace any alkyl, alkenyl, alkynyl, or heteroalkyl, heteroalkenyl, or heteroalkynyl group, and may be linear, cyclic, or any combination thereof.
  • the "chain” only includes those carbon atoms that compose the bottom or top of a given ring and not both, and where the top and bottom of the ring(s) are not equivalent in length, the shorter distance shall be used in determining chain length. If the chain contains heteroatoms as part of the backbone, those atoms are not calculated as part of the carbon chain length.
  • alkoxy refers to an alkyl ether radical, alkyl-O-, wherein the term alkyl is defined as above.
  • alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
  • aryloxy alone or in combination, refers to an aryl ether radical wherein the term aryl is defined as below. Examples of aryloxy radicals include phenoxy, benzyloxy and the like.
  • alkylthio refers to an alkyl thio radical, alkyl-S-., wherein the term alkyl is defined as above.
  • arylthio alone or in combination, refers to an aryl thio radical, aryl-S-, wherein the term aryl is defined as below.
  • aryl refers to an optionally substituted aromatic ring system.
  • aryl includes monocyclic aromatic rings, polyaromatic rings and polycyclic aromatic ring systems containing from six to about twenty carbon atoms.
  • aryl also includes monocyclic aromatic rings, polyaromatic rings and polycyclic ring systems containing from 6 to about 12 carbon atoms, as well as those containing from 6 to about 10 carbon atoms.
  • the polyaromatic and polycyclic aromatic rings systems may contain from two to four rings. Examples of aryl groups include, without limitation, phenyl, biphenyl, naphthyl and anthryl ring systems.
  • heteroaryl refers to optionally substituted aromatic ring systems containing from about five to about 20 skeletal ring atoms and having one or more heteroatoms such as, for example, oxygen, nitrogen, sulfur, and phosphorus.
  • heteroaryl also includes optionally substituted aromatic ring systems having from 5 to about 12 skeletal ring atoms, as well as those having from 5 to about 10 skeletal ring atoms.
  • heteroaryl may include five- or six-membered heterocyclic rings, polycyclic heteroaromatic ring systems and polyheteroaromatic ring systems where the ring system has two, three or four rings.
  • heterocyclic, polycyclic heteroaromatic and polyheteroaromatic include ring systems containing optionally substituted heteroaromatic rings having more than one heteroatom as described above (e.g., a six membered ring with two nitrogens), including polyheterocyclic ring systems of from two to four rings.
  • heteroaryl includes ring systems such as, for example, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl, indolyl, quinolinyl, N-alkyl pyrrolyl, pyridyl-N-oxide, pyrimidoyl, pyrazinyl, imida ⁇ olyl, pyrazolyl, oxazolyl, benzothiophenyl, purinyl, indolizinyl, thienyl and the like.
  • ring systems such as, for example, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl, indolyl, quinolinyl, N-alkyl pyrrolyl, pyridyl-N-oxide, pyrimidoyl, pyrazinyl, imida ⁇ olyl, pyrazolyl, oxazolyl, benzothi
  • heteroarylalkyl refers to a C1-C4 alkyl group containing a heteroaryl group, each of which may be optionally substituted.
  • heteroarylthio refers to the group -S-heteroaryl.
  • acyloxy refers to the ester group -OC(O)-R, where R is H, alkyl, alkenyl, alkynyl, aryl, or arylalkyl, wherein the alkyl, alkenyl, alkynyl and arylalkyl groups may be optionally substituted.
  • carboxy esters refers to -C(O)OR where R is alkyl, aryl or arylalkyl, wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.
  • carbboxamido refers to
  • R-C-N- R' where each of R and R' are independently selected from the group consisting of H, alkyl, aryl and arylalkyl, wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.
  • arylalkyl refers to an alkyl radical as defined above in which one H atom is replaced by an aryl radical as defined above, such as, for example, benzyl, 2-phenylethyl and the like.
  • alkylaryl alone or in combination, refers to an aryl radical as defined above in which one H atom is replaced by an alkyl radical as defined above, such as, for example, tolyl, xylyl and the like.
  • haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy include alkyl, alkenyl, alkynyl and alkoxy structures, as described above, that are substituted with one or more fluorines, chlorines, bromines or iodines, or with combinations thereof.
  • cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl include optionally substituted cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl groups.
  • the term “carbocycle” includes optionally substituted, saturated or unsaturated, three- to eight-membered cyclic structures in which all of the skeletal atoms are carbon.
  • the term “heterocycle” includes optionally substituted, saturated or unsaturated, three- to eight-membered cyclic structures in which one or more skeletal atoms is oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • Illustrative examples include pyridine, pyran, thiophan, pyrrole, furan, thiophen, pentatomic and hexatomic lactam rings, and the like.
  • membered ring can embrace any cyclic structure, including carbocycles and heterocycles as described above.
  • membered is meant to denote the number of skeletal atoms that constitute the ring.
  • pyridine, pyran, and thiophan are 6 membered rings and pyrrole, furan, and thiophen are 5 membered rings.
  • acyl includes alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl substituents attached to a compound via a carbonyl functionality (e.g., -CO-alkyl, -CO-aryl, -CO-arylalkyl or -CO-heteroarylalkyl, etc.).
  • "Optionally substituted” groups may be substituted or unsubstituted.
  • substituents of an "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or designated subsets thereof: alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylthio, arylthio, heteroarylthio, oxo, carboxyesters (C(O)OR 5 ), carboxamido (C(O)NR y 2 ), acyloxy, H; halo, CN, NO 2 , N 3 , OH, C(O)R y , pyridinyl, thiophenyl, furanyl, indolyl, indazoly
  • An optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), monosubstiruted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and monosubstututed (e.g., -CH 2 CF 3 ).
  • halogen includes F, Cl, Br and I.
  • sulfide refers to a sulfur atom covalently linked to two atoms; the formal oxidation state of said sulfur is (II).
  • thioether may used interchangebly with the term "sulfide”.
  • sulfoxide refers to a sulfur atom covalently linked to three atoms, at least one of which is an oxygen atom; the formal oxidation state of said sulfur atom is (IV).
  • sulfone refers to a sulfur atom covalently linked to four atoms, at least two of which are oxygen atoms; the formal oxidation state of said sulfur atom is (VI).
  • Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms.
  • the scope of the present invention is intended to cover all isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well. Further, it is possible using well known techniques to separate the various forms, and some embodiments of the invention may feature purified or enriched species of a given enantiomer or diasteriomer.
  • a "pharmacological composition” refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, with other chemical components, such as pharmaceutically acceptable carriers and/or excipients. The purpose of a pharmacological composition is to facilitate administration of a compound to an organism.
  • pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically- acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and e
  • excipient refers to an inert substance added to a pharmacological composition to further facilitate administration of a compound.
  • excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • HSP90 competitive binding assays and functional assays can be performed as known in the art substituting in the compounds of the invention. Chiosis et al., Chemistry & Biology 8:289-299 (2001), describe some of the known ways in which this can be done. For example, competition binding assays using, e.g., geldanamycin or 17-
  • AAG as a competitive binding inhibitor of HSP90 can be used to determine relative HSP90 affinity of the compounds of the invention by immobilizing the compound of interest or other competitive inhibitor on a gel or solid matrix, preincubating HSP90 with the other inhibitor, passing the preincubated mix over the gel or matrix, and then measuring the amount of HSP90 that sticks or does not stick to the gel or matrix.
  • Downstream effects can also be evaluated based on the known effect of HSP90 inhibition on function and stability of various steroid receptors and signaling proteins including, e.g., Rafl and Her2.
  • Compounds of the present invention induce dose-dependent degradation of these molecules, which can be measured using standard techniques.
  • Inhibition of HSP90 also results in up-regulation of HSP90 and related chaperone proteins that can similarly be measured.
  • Antiproliferative activity on various cancer cell lines can also be measured, as can morphological and functional differentiation related to HSP90 inhibition. For example, the
  • PCR polymerase chain reaction
  • HER-2 expression in breast cancer cells can be determined with the use of an immunohistochemical assay, such as the Dako HercepTM test (Dako Corp., Carpinteria, CA).
  • the HercepTM test is an antibody staining assay designed to detect HER-2 overexpression in tumor tissue specimens. This particular assay grades HER-2 expression into four levels: 0, 1, 2, and 3, with level 3 representing the highest level of HER-2 expression.
  • Accurate quantitation can be enhanced by employing an Automated Cellular Imaging System (ACIS) as described, e.g., by Press, M, et al, (2000), Modem Pathology 13:225A.
  • ACIS Automated Cellular Imaging System
  • Antibodies, polyclonal or monoclonal can be purchased from a variety of commercial suppliers, or may be manufactured using well-known methods, e.g., as described in Harlow et al., Antibodies: A Laboratory Manual, 2nd Ed; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y. (1988).
  • HER-2 overexpression can also be determined at the nucleic acid level since there is a reported high correlation between overexpression of the HER-2 protein and amplification of the gene that codes for it.
  • One way to test this is by using RT-PCR.
  • the genomic and cDNA sequences for HER-2 are known.
  • Specific DNA primers can be generated using standard, well-known techniques, and can then be used to amplify template already present in the cell. An example of this is described in Kurokawa, H et al, Cancer Res. 60: 5887-5894 (2000).
  • PCR can be standardized such that quantitative differences are observed as between normal and abnormal cells, e.g., cancerous and noncancerous cells.
  • Well known methods employing, e.g., densitometry can be used to quantitate and/or compare nucleic acid levels amplified using PCR.
  • FISH fluorescent in situ hybridization
  • other assays can be used, e.g., Northern and/or Southern blotting.
  • FISH fluorescent in situ hybridization
  • this nucleic acid probe can be conjugated to a fluorescent molecule, e.g., fluorescein and/or rhodamine, that preferably does not interfere with hybridization, and which fluorescence can later be measured following hybridization.
  • Immuno and nucleic acid detection can also be directed against proteins other than HSP90 and Her-2, which proteins are nevertheless affected in response to HSP90 inhibition.
  • the 8-substituted purine analogs of formula 5 or 2 can be prepared from 4,5- diaminopyrimidines and the carboxylates or their derivatives, such as amides, esters, nitriles, orthoesters, imidates etc (see, e.g.,Townsend Chemistry of Nucleosides and Nucleotides, Vol. 1; Plenum Press, New York and London, page 148-158; Tetrahedron Lett. 36, 4249, 1995).
  • Substituted 4,5-diaminopyrimidines can be obtained commercially or from substituted 2-chIoro-3-amino pyrimidi ⁇ e or 2-chloro-3-nitropyrimidines as known in the art. See, e.g., Tetrahedron, 40, 1433 (1984); J. Am. Chem. Soc, 118, 135 (1975); Synthesis 135 (1975); J. Med. Chem. 39, 4099 (1996).
  • Compounds of formula 5 can be converted to compounds of formula 2 by simple alkylation with alkylhalides, alkyltosylates, mesolates or triflates in polar solvents like THF, DMF or DMSO using bases like NaH, Cs 2 CO 3 or K 2 CO 3 , or by the well-known Mitsunobu alkylation method.
  • Compounds of formula 2 can be further modified to give compounds of formula 1 or the intermediates to prepare compounds of formula 1, e.g., substitution of 6-chloro ⁇ urine by ammonia or alkylamines.
  • C-2 substitution of purines, e.g., halogenation with F, Cl or Br can be introduced via 2-aminopurines as described by Eaton et al., J. Org. Chem. 34(3), 747-8 (1969) or by nucleophilic substitution as described, e.g., in. J. Med. Chem. 36, 2938 (1993) and Heterocycles, 30, 435, (1990).
  • These C-2 substitutions also can be introduced via metalation as described, e.g., in J. Org. Chem. 62(20), 6833 (1997), followed by addition of desired electrophile.
  • General purine substitution can be accomplished as described in J. Med. Chem. 42, 2064 (1999).
  • intermediates of formula 2 can be prepared from chloroaminopyrimidines such as formula 6 by the following two steps: (1) treatment of the compounds of formula 6 with corresponding amine (Y-NH2), e.g., butylamine, in presence of base such as triethyl amine or N,N-diisopropyl amine in polar solvents such as n-BuOH to give the substituted diamine compounds of formula 4; (2) treatment of the compounds of formula 4 using the same methods as described earlier going from formula 7 to formula 5. Similar methods as described earlier can be used to introduce the C-2 substitution (point at which Z or G moiety attaches).
  • Compounds of formula 1 where A is other than NH 2 can be prepared starting with the corresponding substituent in place (if it can withstand the transformations), or, for halogen or substituted amines, these can be prepared from the 6-amine.
  • the compounds of formula 1 can also be prepared from formula 3, where L is halogen, using Negishi-type couplings (e.g., as described in J. Org. Chem. 2001, 66, 7522; J. Org. Chem. 1991, 56, 1445).
  • substituted adenines or purines of formula 8 can be treated with halogenating agents such as bromine or iodine, followed by alkylation at N-9 to give compounds of formula 10, wherein M is halogen such as bromine or iodine (Dang et.al. PCT, WO 98/39344).
  • Compounds of formula 16 can be prepared from trihalopyrimidines such as those of formula 12 by nitration to give compounds of formula 13. Subsequent displacement of the halogen with amine (YNH 2 ) and reduction of the nitrogroup gives the diamines of formula 15. Alternatively, reduction of the nitrogroup may precede halogen displacement.
  • Diamines of formula 15 can be readily cyclized to the imidazole ring of the compounds of formula 16, wherein L is H, SH, OH or NH 2 (Org. Syn. Collective Vol. 2, 65; Org. Syn. Collective Vol. 4, 569).
  • the compounds of formula 1 can also be synthesized from the compounds of formula 16, wherein L is SH, OH, or NH 2 , by reacting with aromatic halides, boronic acids, triflates, or their equivalents in presence of a catalyst such as palladium or copper (Buchwald, S. L. et. al. J. Am. Chem. Soc, 1998, 120, 213-214; Buchwald, S. L. et. al. Ace. Chem. Res. 1998, 31, 805; Buchwald, S. L. et. al Org. Lett., 2002, 4, 3517-3520).
  • a catalyst such as palladium or copper
  • Z-groups of formula 1 can be introduced by modifying existing 2-substiruents such as G.
  • Other substitutions such as S-alkyl or aryl, O-alkyl can be made from nucleophilic substitution reactions; metal-catalysed reactions, etc. (see, e.g., Aerschot et. al., J. Med. Chem. 55:2938 (1993); Buchwald, S. L. et. al., Heterocycles, 30: 435 (1990).
  • the E component (aromatic or heteroaromatic or alkyl) of the compounds of formula 11 can be further modified as needed using well known procedures including, e.g., nucleophilic additions, electrophilic additions, halogenations, etc. to give Q (see, e.g., Advanced Organic Chemistry, March. J. Wiley Interscience).
  • these sulfone compounds can be made by coupling of sulfonyl salts such as Li, Na, K (ArS(O) 2 Li) and compounds of formulae 10 or 16 (wherein M or L is halogen such as Br or I) in polar solvents such as DMF. (Cbem. Abstr. 1952, 4549). With controlled reduction of these sulfones, one can make compounds of formula 1 where X is S(O) and S(O) 2 .
  • 8-Haloadenines can be coupled to thiophenols under basic conditions.
  • a wide array of bases is available, as for instance, LiOH, NaOH, tf-BuONa, K 2 CO 3 , KOH, J-BuOK, Cs 2 CO 3 , or CsOH.
  • the thiophenol can already carry all the substituents necessary for biological activity or can be modified after coupling (Scheme C). Preparation of thiophenol, then coupling
  • the thiophenol is first prepared using one of the many known methods. These methods have been extensively reviewed (Wardell, J.L. Preparation of Thiols. In The Chemistry of the Thio Group,
  • the second route of scheme C entails coupling of 8-haloadenine to a thiophenol, and subsequent treatment with an electrophilic species (Cl + , Br + , I + , NO + etc.) using standard reagents for electrophilic aromatic substitutions.
  • 8-(Ary!sulfanyl)adenines can be prepared from 8-mercaptoadenines with electrophilic species, as illustrated in scheme D.
  • the mercaptoadenine is reacted with a diazonium salt, in a polar solvent such as DMF or DMSO, in the presence or absence of base (Biamonte, M. A., J. Org. Chem., 2005, 70, 717), or a radical cation is generated with PhI(OCOCFj) 2 and is trapped with a 8-mercaptoadenine (Kita, Y., J. Org. Chem., 1995, 60, 7144). Coupling of a 8-mercapt ⁇ adenine with a diazonium salt
  • Substituted benzothiazole-2-thiols and benzoxazole-2-thiols were prepared from the condensation O- ethylxanthic acid, potassium salt or any suitable salts and 2-haloanilines or 2-hydroxyanilines respectively, scheme F. These compounds can also be prepared from 2-aminobenzothiazoles (ref. Kasibhatla et. al. US Patent 6,489,476 Bl) by diazotization followed by displacement with SH using thiourea or O-ethylxanthic acid, potassium salt (see ref. The Chemistry of the Thio Group, Part 1, Patai S. Ed. John Wiley & Sons. London, 1974, pp 163-263 and Ma, C J. Org. Chem. 2001, 66, 4525. ).
  • the 8-benzyladenines were synthesized by either of the two methods illustrated in Scheme H.
  • the first method followed a sequence closely related to the one described by Drysdale et al., and started from commercial 4,6-dicUoro-5-aminopyrirnidine, which was treated with butylamine, acylated with the appropriate phenacyl chloride, and cyclized to afford the desired 9-butyl-8-(2,5-dimethoxybenzyl)-9H-purin-6-ylamine.
  • the second method was similar to the one of Chiosis et al.
  • the published method involves acylation of 4,5,6-triaminopyrimidine hemisulfate in aqueous solution (4,5,6-triaminopyrimidine is soluble only in water at pH > 7), and required, in our hands, several equivalents of the appropriate acyl fluoride to compensate for the accompanying hydrolysis of the reagent.
  • 4,5,6-triaminopyrimidine is soluble only in water at pH > 7
  • the free base of 4,5,6- triaminopyrimidine was readily isolated as needles by neutralizing and cooling to 0-5 0 C an aqueous solution of the commercial hemisulfate.
  • the free base proved to be soluble in N-methyl-2-pyrrolidone (NMP), and could be efficiently acylated in this solvent with a single equivalent of acyl chloride to give the amide.
  • NMP N-methyl-2-pyrrolidone
  • Synthetic scheme H Preparation of 8-benzyladenines. Reagents and conditions: (a) BuNH 2 , Et 3 N, H-BUOH, 90 0 C, 16 h (83%); (b) 2,5-dirnethoxyphenylacetic acid, TsCl, Et 3 N, DCE, 40 0 C, 16 h (71%); (c) NH 3 , MeOH, 120 0 C, 3 d (80%); (d) NaOH, H 2 O, 0-5 0 C (67%);
  • Synthetic scheme I Preparation of 8-(arylsulfanyl)adenine Reagents and conditions: (a) BuI, Cs 2 CO 3 , DMF 3 rt, 16 h (62%); (b) 2,5-dimethoxybenzenethiol, 150 0 C, 4 h (69%).
  • 8- bromoadenine could be alkylated with 5-chloro-l-pentyne to give 8-Bromo-9-pent-4-ynyl-9//-purin-6-ylamine, and coupled to the thiophenolate to provide the pentyne analog 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9//- purin-6-ylamine.
  • 2-Fluoro-8-(2-iodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9i/-purin-6-ylamine was prepared by a conceptually similar route starting from 2,6-diamino-8-bromo ⁇ urine, using a Balz-Schiemann reaction (wo-AmONO/HBF 4 ) to replace the 2-NH 2 group with a fluorine.
  • OAc or Cl-(CH 2 ) 3 -OAc were selected as as alkylating agents, in which the masked hydroxyl group provided a handle for further functionalization. Unlike the unsubstituted adenine, the alkylated product was easily brominated at C(8). The bromine atom was then displaced with the potassium thiophenolate, and the acetyl protecting group cleaved in situ to give the 8-sulfanyladenine. The hydroxy group was riiesylated and displaced with amines to give the corresponding N-alkylamines of generic structure A (Scheme K).
  • Hsp90 inhibitor analogs could also be prepared using the three-step general procedure outlined in Scheme L.
  • Adenine alkylation with the appropriate alkyl hahde in the presence of Cs 2 CO 3 in DMF gave predominantly the N-9 substituted isomers.
  • Bromination of the purines followed by coupling with substituted benzothiazole-2-thiols in the presence of t-BuOK in DMF at elevated temperature provided the final products.
  • Adenine alkylation to give the N-9 regiosisomer was unambiguously assigned by preparing a representative compound via a different synthetic route (Scheme M). Following the described synthesis (Howson et al. J.Med. Chem. 1988, 23, 433-439), 5-arnmo-4,6-dichloropyrirnidine was treated with aminopropylalcohol to give the diaminosubstituted pyrimidine. Cyclization with triethylorthoformate in acetic anhydride gave the 6-chloropurine derivative which was further reacted with ammonia in MeOH to give, without purification, the 9-substituted adenine.
  • Benzothiazole-2-thiols were obtained by four different synthetic approaches as depicted in Schemes N, O, P, Q.
  • the key reaction in all four routes involved the condensation of 2-haloanilines with the potassium salt of ethylxanthic acid to give benzothiazole-2-thiols.
  • the substituted 2-haloanilines were prepared via three different routes: 1) Reduction of 2-nitrobromobenzene with Fe in EtOH to give the substituted 2-haloaniIine, 2) bromination of 2-nitroaniline through Sandmeyer reaction followed by reduction with Fe in EtOH (Scheme O) and, 3) nitrolation of 1,2-dibromobenzene with HNO 3 in H 2 SO 4 (Scheme P) to give a mixture of the 3- and 4- NO 2 regioisomers, followed by reduction of the desired 3-NO 2 regioisomer with Fe in EtOH to give 2,3-dibromoaniline.
  • Reagents and conditions (a) Br 2 or Cl 2 gas, 50% acetic acid; (b) POCl 3 , DMF, 12O 0 C 3 0.5h; (c) SnCl 2 -H 2 O, HCl, rt, 4h; (d) EtOCSSK, DMF, 16O 0 C, 4h
  • Step 2 To a solution of 2,5-dimethoxyphenylacetic acid (1 mmol) and Et 3 N (1 mmol) in CHjCl 2 was added p-toluenesulfonyl chloride (1 mmol) at rt. After 1 h, the mixture was treated with a solution of the product of step 1, 6-chloro-5-amino-4-butyl pyrimidine (1 mmol in CH 2 Cl 2 ), followed by addition of Et 3 N (2 mmol). The resultant mixture was refluxed for 20 h. Solvent was removed and the residue dissolved into EtOAc, the organic layer washed with water and dried.
  • 8-(2,5-dimethoxybenzyl)-9-butyl adenine can also be prepared from N-(4-butylamino-6-chloro- ⁇ yrimidin-5-yl)-2-(2,5-dimethoxyphenyl) acetamide according to the following procedure: A solution of N-(4- butylamino-6-chloro-pyrimidin-5-yl)-2-(2,5-dimethoxyphenyl) acetamide (1 mmol) is taken into 7M NH 3 in MeOH (70 mmol) and the mixture heated at 120 C in a steel bomb for 72 h. Solvent is removed by azeotrope distillation with toluene.
  • Step 1 2-(2,5-Dimethoxy-phenyl)-N-(2,5,6-triamino-pyrimidin-4-yl)-acetamide, HCl
  • Step 3 8-(2,5-Dimethoxy-benzyl)-9- ⁇ ent-4-ynyl-9H-purine-2,6-diamine
  • Step 4 8-(2,5-Dimethoxy-benzyl)-2-fluoro-9-pent-4-ynyl-9H-purin-6-ylamine
  • a solution of the above purine-2,6-diamine (11.8 g, 32.2 mmol) in 48% aq. HBF 4 (250 ml) was treated at -10 °C with iso-amyl nitrite (5.20 ml, 38.8 mmol), and warmed to r.t over 2.5 h.
  • the reaction mixture was diluted with MeOH (400 ml) and CH 2 Cl 2 (1500 ml), and carefully neutralized with a solution Of K 2 CO 3 (125 g) in water (500 ml). Caution: vigorous gas evolution.
  • HPLC method Agilent Zorbax 300 SB C 18, 4.6 X 150 mm, 5 ⁇ m; Column Temperature: Ambient; Flow Rate: 1.0 ml/min, Gradient: 10% acetonitrile (0.05% TFA) in water (0.1% TFA) to 100% acetonitrile (0.05% TFA) in 10 minutes, hold at 100 % for 1 minutes); Retention times are measured in minutes.
  • the alkylatkra was' done with l-bromo-4-chlorobutane followed by treatment with ethylamine to give the 4- ethylaminobutyl isolated as solid.
  • Example 16 8-(2 5 5-Dimethoxy-benzyl)-9-[2-(dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)-ethyl]-9H- ⁇ urin-6- ylamine (16) isolated as solid.
  • Example 18 8-(2,5-Dimethoxy-benzyl)-9-(3,3,3-trifluoro-propyl)-9H-purin-6-ylamine (19) isolated as solid
  • NIS N- iodo-succinamide
  • the resulting aniline can be further monoalkylated (Acetylchloride; CH 2 Cl 2 ) or reductively alkylated (RCHO, NaBH(OAc) 3 , 1 ,2-dichloroethane, r.t.)
  • Standard procedures can give the corresponding alcohol (NaBH 4 , MeOH, r.t.), tosyl hydrazone (TsNHNH 2 , EtOH, reflux), oximes (RONH 2 'HC1, DMF, 60 0 C), amines (R 1 R 2 NH, NaBH(OAc) 3 , C1-(CH 2 ) 2 -C1 r.t.), homoallylic alcohol (AJlSiMe 3 , TiCl 4 ), CH 2 Cl 2 , -78 0 C), or alkenes.
  • Negishi couplings A mixture of 3,4-dichlorobenzyl bromide (0.47 g, 1.96 mmol) and Rieke Zinc (3.0 ml, 5g/100 ml THF, 2.35 mmol) was stirred overnight at r.t. in a flame-dried Schlenk tube and decanted to provide a 0.65M stock solution of 3,4- dichlorobenzyl zinc bromide.
  • Step 1 Adenine (47 g, 0.35 mole) was suspended in 200 ml of CHC13 before adding bromine (180 ml, 3.5 mole) in one portion. The suspension was left stirring at room temperature for 72 hours in a closed system that was vented by a 2OG needle. The reaction was worked up by adding shaved ice into the suspension before slowly neutralizing with aqueous ammonia to pH 8-9, followed by precipitation of the desired product with acetic acid. The crude product was dried under reduced pressure for 2 days to give 8-Bromoadenine as a light brown powder (45 g, 60% yield).
  • Step 2 8-Bromopurine (2.2g, lOmmole) was dissolved in 50 ml of DMF before adding 1-bromo-butane (2.2 ml, 20 mmol) and cesium carbonate (6.7g, 20 mmol) into the solution. The reaction mixture was left stirring at room temperature for 16 hours before quenching with water and extracting with EtOAc. The organic layer was washed with water and dried with MgSO4 before removing solvent under reduced pressure. A white powder (0.9g,
  • Step 3 To a mixture of sodium hydride (96 mg, 4 mmol) in DMF (4ml) was added 3-methoxy- benzenethiol (1.12 g, 8 mmol). After 30 min, a solution of 8-bromo-9-butyl-9H- ⁇ urin-6-ylamine (0.54 g, 2 mmol) in DMF (6 ml) was added and stirred for 12 h at 70 0 C.
  • Step 4 To a solution of 9-butyl-8-(3-methoxy-phenylsulfanyl)-9H-puiin-6-ylamine (0.26g, 0.73 mmol) in
  • Example S3 8-(2,5-dimethoxy- ⁇ henylsulfanyl)-2-amino-9(4-methyl-pent-3-enyl)-9H-purin-6-ylamine (53)
  • N9 alkylation was done as a final step after the bromine displacement of 8-bromo ⁇ urine with 2,5-dimethoxy thiophenol.
  • Example 60 8-(2,5-dimethoxy-phenylsulfanyl)-9(4-acetyloxybutyl)-9H-purin-6-ylamine (60) 1 H NMR (DMSOd 6 ) ⁇ 1.70(m, 2H 5 CH 2 ), 1.90(m, 2H, CH 2 ), 2.02(s ?
  • Step 2 A solution of the above thione (30.8 mg, 0.138 mmol) and t-BuOK (15.5 mg, 0.138 mmol) in
  • Step 2 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purine-2,6-diamine
  • Example 71 9-(3-chloro- ⁇ ropyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamrne (71)
  • the title compound was obtained by reacting 8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine with 1- bromo-3-chloro-propane as in Example 15 Step 1.
  • Rt 7.93 min (5-100-12).
  • Example 73 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-[3-(4-methyl-pi ⁇ erazin-l-yl)-propyl]-9H-purin-6-ylarnine ' (73)
  • Example 74 9-(3-Dimethylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (74)
  • 1 H NMR (CDCl 3 ) ⁇ 8.34 (s, IH), 7.71, (d, IH), 6.71 (d, IH), 6.56 (dd, IH), 5.83
  • Example 81 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(2-piperidin-l-yl-ethyl)-9H-purin-6-ylamine (81)
  • Example 82 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(2-propylammo-emyl)-9H-purin-6-ylamine (82)
  • Example 83 8-(2,5-Dimethoxy-phe ⁇ ylsulfanyl)-9-(3-dimethylamino-propyl)-9H-purin-6-ylamine (83)
  • Example 84 8-(2-Iodo-5-rnethoxy-phenylsulfanyl)-9-(2-iso ⁇ ropylarnino-ethyl)-9H- ⁇ urin-6-ylarnine (84)
  • Example 95 9-(3-tert-Butylarnmo-propyl)-8-(2-iodo-5-methoxy- ⁇ henylsulfanyl)-9H-purin-6-ylamine (95)
  • Step 1 Methanesulfonic acid 3-[6-amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-propyl ester was reacted with tert-butylamine according to the general procedure A.
  • the crude reaction product was extracted into aq. HCl, and the aqueous solution was washed ten times with CHCI 3 .
  • Rt 6.05 min (5-100-12).
  • 1 H NMR (CDCl 3 ) ⁇ 8.34 (s, IH), 7.70 (d, IH), 6.71 (d, IH), 6.58 (dd, IH), 5.85 (br. s, 2H), 4.38 (t, 2H), 3.65 (s, 3H), 3.03 (quint, 2H),
  • Example 100 9-[2-(Cyclopropylmethyl-amino)-ethyl]-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6- ylamine (100)
  • Example 104 9-(2-Cyclopropylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (104)
  • Example 105 9-(2-Allylamino-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (105)
  • the title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxy- ⁇ henylsulfanyl)-9H-purin-6- ylamine with allylamine according to the general procedure A.
  • Rt 5.62min.
  • Example 106 8-(24odo-5-methoxy-phenylsulfanyl)-9-(2-mo ⁇ holin-4-yl-ethyl)-9H-purin-6-ylamine (106)
  • the title compound was obtained by reacting 9-(2-cMoro-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6- ylamine with morpholine according to the general procedure A.
  • Rt 5.33 min.
  • Example 108 9-[3-( 1 -Elhyl-propylamino)-propyl]-8-(2-iodo-5-ineUioxy ⁇ henylsulfanyl)-9H ⁇ urin-6-ylarnine (108)
  • Example 110 9-(3-Heprylamino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H- ⁇ urin-6-ylarnine (110)
  • Example 111 9-(3-Cyclopentylamino-pro ⁇ yl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H- ⁇ urin-6-ylamine (111)
  • Example 113 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(3-isobutylamino-pro ⁇ yl)-9H-purin-6-ylamine (113)
  • Example 120 9-(3-Cyclobutylarnino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (120)
  • the title compound was obtained by reacting 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6- ylamine with cyclobutylamine according to the general procedure A.
  • Rt 5.785min.
  • 1 H NMR (CDCl 3 ) ⁇ 8.37 (s, IH), 7.72 (d, IH) 3 6.67(d, IH), 6.56 (dd, IH), 6.02 (br.
  • Example 121 9-(3-Arnino-propyl)-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (121) Step 1 ⁇ 3-[6-Amirio-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-propyl ⁇ -carbamic acid tert-butyl ester A mixture of 8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine (260 mg), BocNH-(CH 2 ) 3 -Cl, and Cs 2 CO 3 (1.29 g) in DMF (3mL) was heated to 50 0 C for 16 h.
  • Step 2 9-(3-An ⁇ ino-propyl)-8-(2-iodo-5-niethoxy-phenylsulfanyl)-9H-purin-6-ylamine
  • a solution of ⁇ 3-[6-amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-propyl ⁇ -carbamic acid tert-butyl ester (54 mg) in DCM (3 mL) was treated with TFA (0.5 mL) for 30 min and evaporated.
  • Step 2 ⁇ 2-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-ethyl ⁇ -carbarnic acid tert-butyl ester
  • Step 1 3-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-propan-l-ol
  • Step 3 8-(24odo-5-memoxy ⁇ henylsulfanyl)-9-(3-isopropylaniino-propyl)-9H-purin-6-ylarnine Methanesulfonic acid 3-[6-amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-propyl ester was reacted with isopropylamine according to the general procedure A. The crude reaction product was extracted into aq. HCl, and the aqueous solution was washed ten times with CHCl 3 . Neutralization (NaHCO 3 ) and back-extraction into CHCl 3 gave the title compound as a crude oil.
  • Step 4 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(3-iso ⁇ ro ⁇ yIamino-propyl)-9H-purin-6-ylamine, H 3 PO 4 salt.
  • a solution of 8-(2-iodo-5-niethoxy-phenylsulfanyl)-9-(3-isopropylarriino ⁇ ropyl)-9H-purin-6-ylamine (1.03 g) in refluxing EtOH (30 mL) was treated with a 0.84 M solution OfH 3 PO 4 in EtOH (2.1 mL). The phosphate salt precipitated immediately, and was collected by filtration, and washed with EtOH.
  • Step 5 9-[2-(2,2-Dimethyl-propylamino)-ethyl]-8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6- ylamine, H 3 PO 4 salt.
  • Example 134 9-(2-Diemylamino-ethyl)-8-(2-iodo-5-methoxy- ⁇ henylsulfanyl)-9H-purin-6-ylamine (134)
  • Example 135 8-(2-Iodo-5-methoxy-phenylsulfanyI)-9-(2-pyi ⁇ olidi ⁇ -l-yl-ethyl)-9H-purin-6-ylainine (135)
  • the title compound was obtained by reacting 8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine with (2- chloro-ethoxy)-ethene according to the general procedure C.
  • the title compound was obtained by reacting 8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine with 2-(2- chloro-ethoxy) -propane according to the general procedure C.
  • Example 138 ⁇ 3-[6-Arnino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-propyl ⁇ -rnelhyl-carbamatic acid tert-butyl ester (138)
  • 1 H NMR (CDCl 3 ) ⁇ 8.28 (s, IH), 7.73 (d, IH), 6.74 (d, IH), 6.59 (dd,
  • Example 139 8-(2-Iodo-5-rnemoxy-phenylsulfanyl)-9-(3-pyrrol-l-yl-propyl)-9H-purin-6-ylamine (139)
  • the title compound was obtained by reacting 8-(2-iodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine with l-(3- bromo-propyl)-lH-pyrrole according to the general procedure C.
  • Rt 8.27 min (5-100-12).
  • Example 140 ⁇ 3-[6-Amino-8-(2-iodo-5-methoxy-phenylsulfanyl)-purin-9-yl]-propyl ⁇ -carbamic acid tert-butyl ester (140)
  • Step 3 ⁇ S-C ⁇ -Amino-S-CS-methoxy-l-methyl-buta-l ⁇ -dienylsulfany ⁇ -purin-P-ylj-propylj-methyl- carbamic acid tert-butyl ester
  • Example 141 8-(2-Iodo-5-trifluoromethoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine (141) Step 1 l-Iodo-2-nitro-4-triiluoromethoxy-benzene
  • Step 4 8-(2-Iodo-5-trifluoromethoxy-phenylsulfanyl)-9H-purin-6-ylamine
  • HBF 4 (1.5 mL) was cooled to -10 "C and treated dropwise with a solution OfNaNO 2 (0.17g) in water (1 mL).
  • the solid diazonium salt was collected by filtration, washed with diethyl ether, and air-dried to give the title compound (0.77g), which was used without further purification.
  • Step 3 8-(2,4-diiodo-5-methoxy-phenylsulfanyl)-9H-purin-6-ylamine
  • Example 144 8-(2,5-Dimethoxy-biphenyl-3-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine (144) Step 1 2,5-Dimethoxy-3-nitro-biphenyl A mixture of l-bromo-2,5-dimethoxy-3-rritro-benzene (1.35 g), PhB(OH) 2 (1.00 g), K 3 PO 4 (2.3 g), Pd(PPh 3 ) 4 (0.33 g) and toluene (20 mL) was heated to 108 0 C for 24 h.
  • Step 5 8-(2,5-Dimethoxy-biphenyl-3-ylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine
  • Step 4 8-(3-Bromo-2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine
  • the title compound was obtained by reacting 8-bromo-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine with 2- mercaptothiazole according to the general procedure B.
  • the title compound was obtained by reacting 8-bromo-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine with 2- mercaptobenzothiazole according to the general procedure B.
  • the title compound was obtained by reacting 8-bromo-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylami ⁇ .e with 2- mercaptobenzimidazole according to the general procedure B.
  • Example 152 8-( 1 -AUyI- lH-benzoirnidazol-2-ylsulfanyl)-9-(4-methyl- ⁇ ent-3-enyl)-9H-purin-6-ylamine (152)
  • Step 1 Acetic acid 3-[6-amino-8-(2,3-dihydro-benzo[ 1 ,4]dioxin-6-ylsulfanyl)-purin-9-yl]-propyl ester
  • Step 2 3-[6-Arnino-8-(2,3-dihydro-benzo[ 1 ,4]dioxin-6-ylsulfanyl)-purin-9-yl]-propan- 1 -ol
  • Example 171 8-(7-Bromo-beri2othiazol-2-ylsulfanyl)-9-buryl-P//-purine-6-ylamine (171)
  • Step 2 8-(7-Bromo-benzothiazol-2-ylsulfanyl)-9-butyl-9/7-purine-6-ylamine 8-(7-Bromo-benzott ⁇ azol-2-ylsulfanyl)-9-butyl-P//-piirine-6-ylarriine was prepared by the same method described in example 232 except that 7-bromo-benzothiazole-2-thiol was used instead of 7-chloro-benzothiazole-2-thiol.
  • Step 2 P-Butyl-S ⁇ -methyl-benzothiazol ⁇ -ylsulfanylJ-P/ir-purine- ⁇ -ylamine 9-Butyl-8-(7-methyl-benzodiiazol-2-ylsulfanyl)-P//- ⁇ urme-6-ylamine was prepared by the same method described in example 49.1 except that 7-methyl-benzothiazole-2-thiol was used instead of 7-chloro-benzothiazole-2 -thiol.
  • 9-Butyl-8-(7-memoxy-berizothiazol-2-ylsulfanyl)-P/r ⁇ urine-6-ylarnine was prepared by the same method described in example 232 except that 7-methoxy-benzothiazole-2-thiol was used instead of 7-chloro-benzothiazole-2-thioI.
  • 7-Ethoxy-benzothiazole-2 -thiol was prepared by the method described for 7-methoxy-benzothiazole-2-thiol (example 173, step 1) except that iodoethane was used instead of iodomethane. 7-Ethoxy-benzothiazole-2-thiol was obtained as a white powder.
  • Step 2 9-Butyl-8-(7-ethoxy-benzothiazol-2-ylsulfanyl)-P//-purine-6-ylarnine
  • 9-Butyl-8-(7-ethoxy-benzothiazol-2-ylsulfanyl)-PW- ⁇ urine-6-ylamine was prepared by the same method described example 232 except that 7-ethoxy-benzothiazole-2 -thiol was used instead of 7-chloro-benzothiazole-2 -thiol.
  • Step 2 9-Butyl-8-(7-trifluoromethyl-benzothiazol-2-ylsulfanyl)-P//-purine-6-ylamine
  • Example 177 9-Butyl-8-(7-chloro-thiazole[4,5-c]pyridin-2-ylsulfanyl)-P/f-purin-6-ylamine (177) 9-Butyl-8-(7-chloro-thiazole[4,5-c]pyridin-2-ylsulfanyl)-P//-purin-6-ylamine was prepared by the same method described in example 232 except that 7-chloro-thiazole [4,5-c] pyridine-2-thiol (see 206, step 1) was used instead of 7-chloro-benzothiazole-2-thiol.
  • 9-Bu1yl-8-(4-chloro-beiizomiazol-2-ylsulfanyl)-P// ⁇ urme-6-ylarnine was prepared by the same method described in example 232 except that 4-chloro-benzothiazole-2-thiol was used instead of 7-chloro-benzothiazole-2-thiol.
  • HPLC: RT 9.43 min(method:5-100-15).
  • Acetic acid 4-[6-arriino- ⁇ -(7-fluoro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-butyl ester was prepared by the same method described in example 232.
  • Example 189 Acetic acid 3-[6-amino-8-(6 > 7-dichloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propyl ester (189) Acetic acid 3-[6-amino-8-(6,7-dichloro-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propyl ester was prepared by the samej ⁇ ethod described in example 232.
  • Example 191 (7-Methoxy-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-P ⁇ r -purin-6-ylamine (191) 8-(7-Methoxy-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-9//-purin-6-ylamine was prepared by the same method described in example 232.
  • Example 192 8-(7-Methyl-ber_zothiazol-2-ylsulfanyl) ⁇ 9-pent-4-ynyl-P//-purin-6-ylamine (192) 8-(7-Methyl-ben2 ⁇ thiazol-2-ylsulfanyl)-9-pent-4-ynyl-P7/-purin-6-ylarairi ⁇ was prepared by the same method described in example 232 except that 7-methyl-benzothiazole-2-thiol was used instead of 7-chlorc ⁇ benzothiazole-2- thiol.
  • Example 193 8-(4-Ammo-7-fluorol-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-P//-pufin-6-ylamine (193) 8-(4-Arr ⁇ mo-7-fluorol-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-P/f-purin-6-ylamine was prepared by the same method described in example 232.
  • 1 H NMR (CDCl 3 ) ⁇ 2.04 (t, IH), 2.16 (m, 2H), 2.36(m, 2H), 4.43 (t, 2H), 5.58 (s, 2H), 7.03 (m, 2H), 8.41 (s, IH).
  • 8-(7-Ethoxy-benzothiazol-2-ylsulfanyl)-9-pent-4-ynyl-P7/-purin-6-ylamine was prepared by the same method described in example 232 except that 7-ethoxy-benzothiazole-2-thiol was used instead of 7-chloro-benzothiazole-2- thiol.
  • Acetic acid 2-[6-amino-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-purin-9-yl]-ethyl ester was prepared by the same method described in example 232.
  • 1 H NMR (CDCl 3 ) ⁇ 1.93 (s, 3H), 3.94(s, 3H), 4.45 (t, 2H), 4.62(t, 2H), 5.72 (bs, 2H), 6.81 (d, IH), 7.41 (t, IH), 7.55 (d, IH), 8.41 (s, IH).
  • HPLC: RT 5.36min (5-100-7).
  • Example 196 Acetic acid 3-[6-amino-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propyl ester (196) Acetic acid 3-[6-amino-8-(7-methoxy-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propyl ester was prepared by the same method described in example 232.
  • Example 197 Acetic acid 3-[6-amino-8-(7-methyl-benzothiazol-2-ylsulfanyl)- ⁇ urin-9-yl]- ⁇ ro ⁇ yl ester (197) Acetic acid 3-[6-amino-8-(7-methyl-benzothiazol-2-ylsulfanyl)-purin-9-yl]-propyl ester was prepared by the same method described in example 232.
  • Acetic acid 2-[6-amino-8-(7-bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-purin-9-yl]-ethyl ester was prepared by the same method described as in 232.
  • 1 H NMR (CDCl 3 ) ⁇ 1.98(s, 3H), 4.53 (t, 2H), 4.64 (t, 2H), 5.73 (s, 2H), 8.43 (s, IH), 8.72(s, IH), 9.2 (s, IH).
  • HPLC: RT 4.98min (method:5-100-7).
  • Example 200 Acetic acid 3-[6-amino-8-(7-bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-purin-9-yl]- ⁇ ropyl ester (200)
  • Acetic acid 3-[6-amino-8-(7-bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)-purin-9-yl]- ⁇ ro ⁇ yl ester was prepared by the same method described in 232.
  • Example 203 ⁇ 3-[6-Arnino-8-(7-bromo-thiazole[4,5-c]pyridin-2-ylsulfanyl)- ⁇ urin-9-yl]propyl ⁇ -phosphonic acid diethyl ester (203) ⁇ 3-[6-Amino-8-(7-bromo-thiazole[4,5-c]pyridi ⁇ -2-ylsulfanyl)-purin-9-yl]propyl ⁇ -phospho ⁇ ic acid diethyl ester was prepared by the same method described as in 232.
  • Acetic acid 2-[6-amirio-8-(7-bro ⁇ io-thiazole[4,5-c]pyridin-2-ylsulfanyl)-purin-9-yl]-ethyl ester was prepared by the same method described as in 232.
  • 1 H NMR (CDCl 3 ) ⁇ 2.02 (s, 3H), 4.47 (t, 2H), 4.64 (t, 2H), 5.71 (s, 2H) 5 8.45 (s, IH), 8.50(s, IH), 9.1 (s, IH).
  • HPLC: RT 4.90min (method:5-100-7).
  • Example 205 Acetic acid 3-[6-amino-8-(7-chloro-thiazolo[4,5-c]pyridin-2-ylsulfanyl)- ⁇ urin-9-yl]- ⁇ ropyl ester (205)
  • Acetic acid 3-[6-amino-8-(7-chloro-thiazolo[4,5-c]pyridin-2-ylsulfanyl)-purin-9-yl]-propyl ester was prepared by the same method described in 177.
  • HPLC: RT 5.06min (5-100-7).
  • Step 1 7-Chloro-thiazole [4,5-c] pyridine-2-thiol
  • 3-nitro- ⁇ yridin-4-ol 15g, 107mmol
  • Acetic acid 200ml
  • POCl 3 7.42ml, 79.8mmol
  • Step 2 ⁇ 2-[6-Aiiiino-8-(7-chloro-thiazolo[4,5-c]pyridinl-2-ylsulfanyl)-purin-9-yl]-ethyl ⁇ -phos ⁇ honic acid diethyl ester ⁇ 2-[6-Amino-8-(7-chloro-thiazolo[4,5-c]pyridinl-2-ylsulfanyl)-purin-9-yl]-ethyl ⁇ -phosphonic acid diethyl ester was prepared by the same method described in example 232 except that chloro-thiazole [4,5-c] pyridine-2-thiol was used instead of 7-chloro-benzothiazole-2-thiol.

Abstract

La présente invention concerne des composés de purine innovants, leurs tautomères et leurs sels pharmaceutiquement acceptables ainsi que les compositions pharmaceutiquement et les complexes qui les comprennent, par exemple les complexes de HSP90, et leurs procédés d'utilisation. Les procédés d'utilisation des composés de purine innovants de l'invention, de leurs tautomères et de leurs sels pharmaceutiquement acceptables incluent leur utilisation pour inhiber les protéines de choc thermique 90 (HSP90) afin de traiter ou de prévenir les maladies liées aux HSP90, par exemple les troubles prolifératifs tels que le cancer du sein.
PCT/US2006/048250 2005-12-22 2006-12-18 Inhibiteurs a base de purine oralement actifs de la proteine de choc thermique 90 WO2007075572A2 (fr)

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AU2006331917A AU2006331917A1 (en) 2005-12-22 2006-12-18 Orally active purine-based inhibitors of heat shock protein 90
CA002634723A CA2634723A1 (fr) 2005-12-22 2006-12-18 Inhibiteurs a base de purine oralement actifs de la proteine de choc thermique 90
EP06845721A EP1962863A4 (fr) 2005-12-22 2006-12-18 Inhibiteurs a base de purine oralement actifs de la proteine de choc thermique 90
JP2008547398A JP2009521446A (ja) 2005-12-22 2006-12-18 熱ショックタンパク質９０の経***性なプリンベースの阻害剤

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2038041A2 (fr) * 2006-05-12 2009-03-25 Myriad Genetics, Inc. Composés thérapeutiques et leur utilisation contre le cancer
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JP2011503206A (ja) * 2007-11-14 2011-01-27 ミレクシス， インコーポレイテッド 疾患および障害の治療における治療化合物およびその使用方法
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Publication number Priority date Publication date Assignee Title
EP2038041A2 (fr) * 2006-05-12 2009-03-25 Myriad Genetics, Inc. Composés thérapeutiques et leur utilisation contre le cancer
JP2009536960A (ja) * 2006-05-12 2009-10-22 ミリアド ジェネティクス， インコーポレイテッド 治療用化合物および癌におけるそれらの使用
EP2038041A4 (fr) * 2006-05-12 2010-02-17 Myriad Genetics Inc Composés thérapeutiques et leur utilisation contre le cancer
JP2010522184A (ja) * 2007-03-20 2010-07-01 キュリス，インコーポレイテッド Ｈｓｐ９０インヒビターとしての縮合アミノピリジン
US8324240B2 (en) 2007-03-20 2012-12-04 Curis, Inc. Fused amino pyridine as HSP90 inhibitors
JP2011503206A (ja) * 2007-11-14 2011-01-27 ミレクシス， インコーポレイテッド 疾患および障害の治療における治療化合物およびその使用方法
US8722703B2 (en) 2009-01-16 2014-05-13 Curis, Inc. Fused amino pyridines for the treatment of brain tumors
US9346808B2 (en) 2011-04-05 2016-05-24 Sloan-Kettering Institute For Cancer Research Hsp90 inhibitors
US9546170B2 (en) 2011-04-05 2017-01-17 Sloan-Kettering Institute For Cancer Research Hsp90 inhibitors
US9926321B2 (en) 2011-04-05 2018-03-27 Sloan-Kettering Institute For Cancer Research Hsp90 inhibitors
US10064867B2 (en) 2011-04-05 2018-09-04 Sloan-Kettering Institute For Cancer Research Hsp90 inhibitors
US9163021B2 (en) 2012-10-04 2015-10-20 Pfizer Limited Pyrrolo[3,2-c]pyridine tropomyosin-related kinase inhibitors
US10421758B2 (en) 2013-08-16 2019-09-24 Memorial Sloan-Kettering Cancer Center Selective Grp94 inhibitors and uses thereof
AU2019202669B2 (en) * 2013-08-16 2020-12-03 Memorial Sloan-Kettering Cancer Center Selective grp94 inhibitors and uses thereof
US11267816B2 (en) 2013-08-16 2022-03-08 Memorial Sloan-Kettering Cancer Center Selective Grp94 inhibitors and uses thereof
CN109721499A (zh) * 2018-12-19 2019-05-07 南京杰科丰环保技术装备研究院有限公司 一种硝基甲苯加氢制备甲基苯胺的制备方法

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AU2006331917A1 (en) 2007-07-05
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WO2007075572A3 (fr) 2009-05-07
EP1962863A2 (fr) 2008-09-03
CA2634723A1 (fr) 2007-07-05

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