[go: up one dir, main page]

WO2009030871A1 - Dérivés de pyrrolopyrimidine présentant une activité inhibitrice d'hsp90 - Google Patents

Dérivés de pyrrolopyrimidine présentant une activité inhibitrice d'hsp90 Download PDF

Info

Publication number
WO2009030871A1
WO2009030871A1 PCT/GB2007/003353 GB2007003353W WO2009030871A1 WO 2009030871 A1 WO2009030871 A1 WO 2009030871A1 GB 2007003353 W GB2007003353 W GB 2007003353W WO 2009030871 A1 WO2009030871 A1 WO 2009030871A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyano
chloro
phenyl
pyrrolo
methoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2007/003353
Other languages
English (en)
Inventor
Paul Brough
Martin Drysdale
Nicholas Davis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vernalis R&D Ltd
Original Assignee
Vernalis R&D Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vernalis R&D Ltd filed Critical Vernalis R&D Ltd
Priority to PCT/GB2007/003353 priority Critical patent/WO2009030871A1/fr
Publication of WO2009030871A1 publication Critical patent/WO2009030871A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to substituted bicyclic pyrrolopyrimidine compounds having HSP90 inhibitory activity, to the use of such compounds in medicine, in relation to diseases which are responsive to inhibition of HSP90 activity such as cancers, and to pharmaceutical compositions containing such compounds.
  • Molecular chaperones maintain the appropriate folding and conformation of proteins and are crucial in regulating the balance between protein synthesis and degradation. They have been shown to be important in regulating many important cellular functions, such as cell proliferation and apoptosis.
  • Hsps heat shock proteins
  • Hsps A number of multigene families of Hsps exist, with individual gene products varying in cellular expression, function and localization. They are classified according to molecular weight, e.g., Hsp70, Hsp90, and Hsp27.
  • diseases in humans can be acquired as a result of protein misfolding.
  • therapies which disrupt the molecular chaperone machinery may prove to be beneficial.
  • misfolded proteins can cause protein aggregation resulting in neurodegenerative disorders.
  • misfolded proteins may result in loss of wild type protein function, leading to deregulated molecular and physiological functions in the cell.
  • Hsps have also been implicated in cancer. For example, there is evidence of differential expression of Hsps which may relate to the stage of tumour progression. As a result of the involvement of Hsp90 in various critical oncogenic pathways and the discovery that certain natural products with anticancer activity are targeting this molecular chaperone suggests that inhibiting the function of Hsp90 may be useful in the treatment of cancer.
  • Hsp90 constitutes about 1-2% of total cellular protein. In cells, it forms dynamic multi-protein complexes with a wide variety of accessory proteins (referred to as co-chaperones) which appear responsible for regulating the chaperone function. It is essential for cell viability and it exhibits dual chaperone functions.
  • co-chaperones accessory proteins
  • Hsp90 forms a core component of the cellular stress response by interacting with many proteins after their native conformation has been altered.
  • Environmental stresses such as heat shock, heavy metals or alcohol, generate localised protein unfolding. Hsp90 (in concert with other chaperones) binds these unfolded proteins allowing adequate refolding and preventing nonspecific aggregation (Smith et al., 1998).
  • Hsp90 may also play a role in buffering against the effects of mutation, presumably by correcting the inappropriate folding of mutant proteins.
  • Hsp90 also has an important regulatory role.
  • Hsp90 plays a housekeeping role in the cell, maintaining the conformational stability and maturation of many client proteins.
  • steroid hormone receptors e.g. estrogen receptor, progesterone receptor
  • Ser/Thr or tyrosine kinases e.g. Her2, Raf-1 , CDK4, and Lck
  • a collection of apparently unrelated proteins e.g.
  • Hsp90 is responsible for stabilising and activating mutated kinases where the wild type kinase is not an Hsp90 client (for an example see the B-Raf story published in da Rocha Dias et al., 2005). All of these proteins play key regulatory roles in many physiological and biochemical processes in the cell. New client proteins of Hsp90 are being constantly identified; see http://www.picard.ch/downloads/Hsp90interactors.pdf for the most up to date list.
  • Hsp90 The highly conserved Hsp90 family in humans consists of four genes, namely the cytosolic Hsp90 ⁇ and Hsp90 ⁇ isoforms, GRP94 in the endoplasmic reticulum and Hsp75/TRAP1 in the mitochondrial matrix. Apart from the differences in sub-cellular localisation, very little is known about the differences in function between Hsp90 ⁇ / ⁇ , GRP94 and TRAP1.
  • Hsp90 participates in a series of complex interactions with a range of client and regulatory proteins. Although the precise molecular details remain to be elucidated, biochemical and X-ray crystallographic studies carried out over the last few years have provided increasingly detailed insights into the chaperone function of Hsp90.
  • Hsp90 is an ATP-dependent molecular chaperone, with dimerisation of the nucleotide binding domains being essential for ATP hydrolysis, which is in turn essential for chaperone function. Binding of ATP results in the formation of a toroidal dimer structure in which the N terminal domains are brought into closer contact with each other resulting in a conformational switch known as the 'clamp mechanism'. This conformational switching is, in part, regulated by the various co-chaperones associated with Hsp90.
  • geldanamycin The predominant mechanism of action of geldanamycin, 17AAG, and radicicol involves binding to Hsp90 at the ATP binding site located in the N-terminal domain of the protein, leading to inhibition of the intrinsic ATPase activity of Hsp90.
  • Hsp90 ATPase activity by 17AAG induces the loss of p23 from the chaperone-client protein complex interrupting the chaperone cycle. This leads to the formation of a Hsp90-client protein complex that targets these client proteins for degradation via the ubiquitin proteasome pathway.
  • Treatment with Hsp90 inhibitors leads to selective degradation of important proteins (for example Her2, Akt, estrogen receptor and CDK4) involved in cell proliferation, cell cycle regulation and apoptosis, processes which are fundamentally important in cancer.
  • important proteins for example Her2, Akt, estrogen receptor and CDK4
  • Hsp90 function has been shown to cause selective degradation of important signalling proteins involved in cell proliferation, cell cycle regulation and apoptosis, processes which are fundamentally important and which are commonly deregulated in cancer.
  • An attractive rationale for developing drugs against this target for use in the clinic is that by simultaneously depleting proteins associated with the transformed phenotype, one may obtain a strong antitumour effect and achieve a therapeutic advantage against cancer versus normal cells. These events downstream of Hsp90 inhibition are believed to be responsible for the antitumour activity of Hsp90 inhibitors in cell culture and animal models.
  • Hsp90 inhibitors therefore resensitise strains which have become resistant to, for example, azole antifungal agents (e.g. fluconazole) as well as newer agents such as echinocandins.
  • azole antifungal agents e.g. fluconazole
  • PCT/GB2007/000831 is concerned with a class of cyano pyrrolopyrimidines which inhibit HSP90 activity. This invention relates to a subset of compounds within the PCT/GB2007/000831 class, but which are not specifically disclosed therein.
  • R is cyano or methoxy
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted C 1 -C 3 alkyl, and optionally substituted C 3 -C 6 cycloalkyl; or R 1 and R 2 taken together with the nitrogen to which they are attached form a 3- to 7-membered ring optionally substituted by chloro, bromo, cyano, C 1 -C 3 alkyl in which one or more hydrogens are optionally replaced by fluorine, or hydroxy(C 1 -C 3 alkyl)- in which one or more hydrogens in the alkyl part are optionally replaced by fluorine;
  • R 3 and R 4 are independently selected from hydrogen, C 1 -C 3 alkyl in which one or more hydrogens are optionally replaced by fluorine, and cyclopropyl; or R 2 and R 3 taken together with the carbon to which they are attached form a 3- to 6-membered ring cycloalkyl ring;
  • n 1, 2 or 3;
  • R 5 and R 6 are independently selected from hydrogen, C 1 -C 3 alkyl, and C 3 -C 6 cycloalkyl; or R 5 and R 6 taken together with the nitrogen to which they are attached form a 3- to 7-membered ring optionally substituted by chloro, bromo, cyano, C 1 -C 3 alkyl in which one or more hydrogens are optionally replaced by fluorine, or hydroxy(C 1 -C 3 alkyl)- in which one or more hydrogens in the alkyl part are optionally replaced by fluorine; or (ii) Ci-C 3 alkoxy in which one or more hydrogens in the alkyl part are optionally replaced by fluorine.
  • the nitrogens in the fused pyrimidine ring present in the compounds of the invention may be oxidesed to form N-oxides.
  • Such N-oxides substantially retain the HSP90 inhibitory activity of the parent compounds, and are thus form part of the invention.
  • Any unqualified reference herein to a compound which falls within formula (I) (“compounds of the invention") is to be construed as a reference to that compound, irrespective of whether it is or is not in the form of an N-oxide.
  • compounds of the invention which may exist in one or more stereoisomeric form, because of the presence of asymmetric atoms or rotational restrictions, can exist as a number of stereoisomers with R or S stereochemistry at each chiral centre or as atropisomeres with R or S stereochemistry at each chiral axis.
  • the invention includes all such enantiomers and diastereoisomers and mixtures thereof. Any unqualified reference herein to a compound which falls within formula (I) ("compounds of the invention”) is to be construed as a reference to that compound, irrespective of whether it is or is not in the form of a pure stereoisomer or a mixture of stereoisomers.
  • the invention provides the use of a compound of compound of the invention in the preparation of a composition for inhibition of HSP90 activity in vitro or in vivo.
  • the invention also provides a method of treatment of diseases which are responsive to inhibition of HSP90 activity in mammals, which method comprises administering to the mammal an amount of a compound of the invention effective to inhibit said HSP90 activity.
  • the in vivo use, and method, of the invention is applicable to the treatment of diseases in which HSP90 activity is implicated, including use for immunosuppression or the treatment of viral disease, drug resistant fungal infection (since HSP90 inhibitors are able to resensitise strains which have become resistant to, for example, azole antifungal agents (e.g.
  • fluconazole as well as newer agents such as echinocandins
  • protozoal infections inflammatory diseases such as rheumatoid arthritis, asthma, multiple sclerosis, Type I diabetes, lupus, psoriasis and inflammatory bowel disease; cystic fibrosis angiogenesis-related disease such as diabetic retinopathy, haemangiomas, and endometriosis; or for protection of normal cells against chemotherapy-induced toxicity; or diseases where failure to undergo apoptosis is an underlying factor; or protection from hypoxia-ischemic injury due to elevation of Hsp70 in the heart and brain; scrapie/CJD, Huntingdon's or Alzheimer's disease. Use for the treatment of cancer is especially indicated.
  • substituted as applied to any moiety herein means substituted with at least one substituent, for example selected from (CVC ⁇ Jalkyl, (C 1 -C 6 JaIkOXy (including methylenedioxy and ethylenedioxy substitution on adjacent carbon atoms of a carbocyclic or heterocyclic ring), hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, mercapto(C 1 -C 6 )alkyl, (CrCeJalkylthio, monocyclic carbocyclic of 3-6 ring carbon atoms, monocyclic heterocyclic of 5 or 6 ring atoms, halo (including fluoro and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile
  • the optional substituent contains an alkyl radical
  • that alkyl radical may be substituted by a monocyclic carbocyclic group of 3-6 ring carbon atoms, or a monocyclic heterocyclic group of 5 or 6 ring atoms.
  • the optional substituent is or comprises a monocyclic carbocyclic group of 3-6 ring carbon atoms, or a monocyclic heterocyclic group of 5 or 6 ring atoms, that ring may itself be substituted by any of the non-cyclic optional substituents listed above.
  • An "optional substituenf may be one of the substituent groups encompassed in the above description.
  • salt includes base addition, acid addition and quaternary salts.
  • Compounds of the invention which are acidic can form salts, including pharmaceutically or veterinarily acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-ethyl piperidine, dibenzylamine and the like.
  • bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-ethyl piperidine, dibenzylamine and the like.
  • Those compounds (I) which are basic can form salts, including pharmaceutically or veterinarily acceptable salts with inorganic acids, e.g.
  • hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
  • organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic and p-toluene sulphonic acids and the like.
  • variable substituents in compounds of the invention is cyano or methoxy. Currently methoxy is preferred.
  • Ri and R 2 are independently selected from hydrogen; optionally substituted Ci-C 3 alkyl i.e. methyl, ethyl, n- or iso-propyl; and optionally substituted C 3 -C 6 cycloalkyl i.e.
  • Ri and R 2 may be selected from, for example, halo, amino, mono- or di- (Ci-C 3 alkyl)amino, hydroxyl, methoxy, or cyano.
  • R 1 and R 2 are independently selected from hydrogen, methyl, trifluoromethyl, ethyl, 2-trifluoroethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, hydroxymethyl and hydroxyethyl.
  • Ri and R 2 taken together with the nitrogen to which they are attached form a, 3-, 4-, 5- or 6-membered ring optionally substituted by fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, ethyl, hydroxymethyl, hydroxy, or hydroxyethyl.
  • the ring formed by R 1 and R 2 and the nitrogen to which they are attached may be, for example, a piperidine, homopiperidine, piperazine, or morpholine ring.
  • R 3 and R 4 are independently selected from hydrogen, C 1 -C 3 alkyl ie methyl, ethyl or n- or iso- propyl, in which one or more hydrogens are optionally replaced by fluorine, and cyclopropyl; or R 2 and R 3 taken together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl ring i.e. a cylopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
  • R 3 and R 4 are each hydrogen, or one of R 3 and R 4 is hydrogen and the other is methyl.
  • n 1 , 2 or 3.
  • Z is (i) -NR 5 R 6 wherein R 5 and R 6 are independently selected from hydrogen, Ci-C 3 alkyl i.e. methyl, ethyl, or n- or iso-propyl, and C 3 -C 6 cycloalkyl i.e.
  • Z may be -NR 5 R 6 wherein R 5 and R 6 are independently selected from hydrogen, methyl, trifluoromethyl, ethyl, and cyclopropyl; or R 5 and R 6 taken together with the nitrogen to which they are attached form a 5- or 6-membered ring such as a piperidine, piperazine, or morpholine ring, optionally substituted by chloro, bromo, cyano, methyl, trifluoromethyl, hydroxymethyl or hydroxyethyl.
  • Z is methoxy, trifluoromethoxy, or ethoxy.
  • the compounds of the invention are inhibitors of HSP90 and are useful in the treatment of diseases which are responsive to inhibition of HSP90 activity, as referred to above.
  • diseases include cancers; viral diseases such as Hepatitis C (HCV) (Waxman, 2002); Immunosuppression such as in transplantation (Bijlmakers, 2000 and Yorgin, 2000); Antiinflammatory diseases (Bucci, 2000) such as Rheumatoid arthritis, Asthma, MS, Type I Diabetes, Lupus, Psoriasis and Inflammatory Bowel Disease; Cystic fibrosis (Fuller, 2000); Angiogenesis-related diseases (Hur, 2002 and Kurebayashi, 2001 ): diabetic retinopathy, haemangiomas, psoriasis, endometriosis and tumour angiogenesis.
  • an Hsp90 inhibitor of the invention may protect normal cells against chemotherapy-induced toxicity and be useful in diseases where failure to undergo apoptosis is an underlying factor.
  • Such an Hsp90 inhibitor may also be useful in diseases where the induction of a cell stress or heat shock protein response could be beneficial, for example, protection from hypoxia-ischemic injury due to elevation of Hsp70 in the heart (Hutter, 1996 and Trost, 1998) and brain (Plumier, 1997 and Rajder, 2000).
  • Hsp90 inhibitor - induced increase in Hsp70 levels could also be useful in diseases where protein misfolding or aggregation is a major causal factor, for example, neurogenerative disorders such as scrapie/CJD, Huntingdon's and Alzheimer's (Sittler, 2001 ; Trazelt, 1995 and Winklhofer, 2001)". Accordingly, the invention also includes:
  • a pharmaceutical or veterinary composition comprising a compound of the invention, together with a pharmaceutically or veterinarily acceptable carrier.
  • a method of treatment of diseases or conditions which are responsive to inhibition of HSP90 activity in mammals which method comprises administering to the mammal an amount of a compound of the invention effective to inhibit said HSP90 activity.
  • a suitable dose for orally administrable formulations will usually be in the range of 0.1 to 3000 mg, once, twice or three times per day, or the equivalent daily amount administered by infusion or other routes.
  • optimum dose levels and frequency of dosing will be determined by clinical trials as is conventional in the art.
  • the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
  • the orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • almond oil fractionated coconut oil
  • oily esters such as glycerine, propy
  • the drug may be made up into a cream, lotion or ointment.
  • Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
  • the active ingredient may also be administered parenterally in a sterile medium.
  • the drug can either be suspended or dissolved in the vehicle.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • Compounds of the invention may be administered together with other classes opf pharmaceutically active drugs.
  • combination therapy with two or more different classes of anticancer agent is a recognised and widespread practice.
  • the present compounds may be used in such combination therapy, particularly where the other drug(s) have a mode of action different from HSP90 inhibition.
  • Flash chromatography was performed with pre-packed silica gel cartridges (Strata SI-1; 61 A, Phenomenex, Cheshire UK or 1ST Flash II, 54A, Argonaut, Hengoed, UK). Thin layer chromatography was conducted with 5 x 10 cm plates coated with Merck Type 60 F 254 silica gel.
  • LC/MS Method A
  • LC/MS Method A
  • column Phenomenex Luna 3u C18(2) 30 x 4.6 mm
  • Buffer A prepared by dissolving 1.93g ammonium acetate in 2.5 L HPLC grade H 2 O and adding 2 mL formic acid.
  • Buffer B prepared by adding 132 mL buffer A to 2.5 L of HPLC grade acetonitrile and adding 2 mL formic acid; elution gradient 95:5 to 5:95 buffer A : buffer.B over 3.75 minutes.
  • Flow rate 2.0 ml_/min) Retention Times (RT) are reported in minutes, lonisation is positive unless otherwise stated.
  • Some compounds of the invention were purified by preparative HPLC. Preparative HPLC purifications were performed on a Waters FractionLynx MS Autopurification system with a Gemini ® 5 ⁇ M C18(2), 100 mm * 20 mm i.d. column from Phenomenex, running at a flow rate of 20 mL min '1 with UV diode array detection (210 - 400 nm) and mass-directed collection. Various gradients (1 to 4) were used and these are shown in table 1. The pH of the eluant and the solvent gradient depends on the characteristics of the compound being purified.
  • Solvent B 95% v/v HPLC grade acetonitrile + 5% v/v Solvent A + 0.08% v/v formic acid.
  • Solvent A HPLC grade Water + 10 mM ammonium acetate + 0.08% v/v ammonia solution.
  • Solvent B 95% v/v HPLC grade acetonitrile + 5% v/v Solvent A + 0.08% v/v ammonia solution.
  • the mass spectrometer was a Waters Micromass ZQ2000 spectrometer operating in positive or negative ion electrospray ionisation modes, with a molecular weight scan range of 150 to 1000.
  • Step 1 ⁇ chloro ⁇ -methylsulfanyl-Z ⁇ -trimethylsilanyl-ethoxymethyO-ZH-pyrrolo ⁇ .S-dJpyrimidine
  • Ethyl thioglycolate (0.31 ml_, 2.78 mmol) was added to a mixture of NaH (46 mg, 1.15 mmol, 60% dispersion in mineral oil) in THF (10 ml.) at O 0 C under N 2 .
  • 4-(2-Chloro-4-methoxy-5- methoxymethoxy-phenyl)-2-methanesulfonyl-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3- d]pyrimidine-5-carbonitrile (1.28 g, 2.32 mmol) dissolved in THF (10 mL) was then added dropwise.
  • reaction mixture After stirring at ambient temperature for 5 minutes, the reaction mixture was cooled with an ice-water bath and diisopropyldiazodicarboxylate (55 ⁇ L, 0.281 mmol) was added and reaction mixture allowed to warm to ambient temperature and stir for 1.5 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and saturated aqueous ammonium chloride solution (20 ml_).
  • the title compound was made by way of method of example 22 step 3 (diazotization and quench with aqueous Iodine / sodium iodide solution).
  • the title compound was prepared by way of the method of example 26 step 1 (boronic acid formation and subsequent cross coupling).
  • Step 5 4-(2-Chloro-4-cyano-5-methoxy-phenyl)-2-methanesulfonyl-7-(2-trimethylsilanyl- ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile
  • the title compound was prepared by way of the method of example 1 step 10 (oxidation with mcpba).
  • the binding affinity for HSP90 of the compounds of the invention can be measured using a Fluorescence Polarization Assay.
  • Fluorescence polarization also known as fluorescence an i sot ropy ⁇ measures the rotation of a fluorescing species in solution, where the larger molecule the more polarized the fluorescence emission.
  • fluorophore When the fluorophore is excited with polarized light, the emitted light is also polarized.
  • the molecular size is proportional to the polarization of the fluorescence emission.
  • Test compound is added to the assay plate, left to equilibrate and the anisotropy measured again. Any change in anisotropy is due to competitive binding of compound to HSP90, thereby releasing probe.
  • Chemicals are of the highest purity commercially available and all aqueous solutions are made up in AR water.
  • BSA bovine serum albumen
  • the Z' factor is calculated from zero controls and positive wells. It typically gives a value of 0.7 - 0.9.
  • Control wells are at either side of the 96 well plates, where 40 ⁇ l of medium is added.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I) qui sont des inhibiteurs d'HSP90 et qui sont utiles entre autres pour le traitement de cancers. Dans la formule, R représente cyano ou méthoxy; R1 et R2 sont choisis indépendamment parmi l'hydrogène, alkyle C1-C3 éventuellement substitué et cycloalkyle C3-C6 éventuellement substitué; ou bien R1 et R2 forment, avec l'azote auquel ils sont attachés, un cycle ayant de 3 à 7 éléments éventuellement substitué par chloro, bromo, cyano, alkyle C1-C3 dans lequel un ou plusieurs hydrogènes sont éventuellement remplacés par du fluor ou hydroxy(alkyle C1-C3 )- dans lequel un ou plusieurs hydrogènes dans la partie alkyle sont éventuellement remplacés par du fluor; R3 et R4 sont choisis indépendamment parmi l'hydrogène, alkyle C1-C3 dans lequel un ou plusieurs hydrogènes sont éventuellement remplacés par du fluor et cyclopropyle; ou bien R2 et R3 forment, avec le carbone auquel ils sont attachés, un cycle cycloalkyle ayant de 3 à 6 éléments; n représente 1, 2 ou 3; et Z représente (i) -NR5R6, R5 et R6 étant choisis indépendamment parmi l'hydrogène, alkyle C1-C3 et cycloalkyle C3-C6; ou bien R5 et R6 forment, avec l'azote auquel ils sont attachés, un cycle ayant de 3 à 7 éléments éventuellement substitué par chloro, bromo, cyano, alkyle C1-C3 dans lequel un ou plusieurs hydrogènes sont éventuellement remplacés par du fluor ou hydroxy(alkyle C1-C3 )- dans lequel un ou plusieurs hydrogènes dans la partie alkyle sont éventuellement remplacés par du fluor; ou (ii) alcoxy C1-C3 dans lequel un ou plusieurs hydrogènes dans la partie alkyle sont éventuellement remplacés par du fluor.
PCT/GB2007/003353 2007-09-07 2007-09-07 Dérivés de pyrrolopyrimidine présentant une activité inhibitrice d'hsp90 Ceased WO2009030871A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/GB2007/003353 WO2009030871A1 (fr) 2007-09-07 2007-09-07 Dérivés de pyrrolopyrimidine présentant une activité inhibitrice d'hsp90

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/GB2007/003353 WO2009030871A1 (fr) 2007-09-07 2007-09-07 Dérivés de pyrrolopyrimidine présentant une activité inhibitrice d'hsp90

Publications (1)

Publication Number Publication Date
WO2009030871A1 true WO2009030871A1 (fr) 2009-03-12

Family

ID=39409806

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2007/003353 Ceased WO2009030871A1 (fr) 2007-09-07 2007-09-07 Dérivés de pyrrolopyrimidine présentant une activité inhibitrice d'hsp90

Country Status (1)

Country Link
WO (1) WO2009030871A1 (fr)

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011027081A2 (fr) 2009-09-03 2011-03-10 Sanofi-Aventis Nouveaux derives de 5,6,7,8-tetrahydroindolizine inhibiteurs d'hsp90, compositions les contenant et utilisation
JP2015134797A (ja) * 2008-12-10 2015-07-27 ウィスタ ラボラトリーズ リミテッド ３，６−二置換キサンチリウム塩
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9533954B2 (en) 2010-12-22 2017-01-03 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US9533984B2 (en) 2013-04-19 2017-01-03 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US9708318B2 (en) 2015-02-20 2017-07-18 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9890156B2 (en) 2015-02-20 2018-02-13 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
CN114259564A (zh) * 2021-11-30 2022-04-01 清华大学 Hsp90抑制剂阻碍stat3线粒体转运和治疗哮喘的新应用
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12428420B2 (en) 2021-06-09 2025-09-30 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6635762B1 (en) * 1998-06-19 2003-10-21 Pfizer Inc. Monocyclic-7H-pyrrolo[2,3-d]pyrimidine compounds, compositions, and methods of use
WO2006105372A2 (fr) * 2005-03-30 2006-10-05 Conforma Therapeutics Corporation Alkynyle pyrrolopyrimidines et analogues associes en tant qu'inhibiteurs de hsp90
WO2007104944A1 (fr) * 2006-03-11 2007-09-20 Vernalis (R & D) Ltd. Dérivés de pyrrolopyrimidine en tant qu'inhibiteurs de hsp90

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6635762B1 (en) * 1998-06-19 2003-10-21 Pfizer Inc. Monocyclic-7H-pyrrolo[2,3-d]pyrimidine compounds, compositions, and methods of use
WO2006105372A2 (fr) * 2005-03-30 2006-10-05 Conforma Therapeutics Corporation Alkynyle pyrrolopyrimidines et analogues associes en tant qu'inhibiteurs de hsp90
WO2007104944A1 (fr) * 2006-03-11 2007-09-20 Vernalis (R & D) Ltd. Dérivés de pyrrolopyrimidine en tant qu'inhibiteurs de hsp90

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015134797A (ja) * 2008-12-10 2015-07-27 ウィスタ ラボラトリーズ リミテッド ３，６−二置換キサンチリウム塩
US10399955B2 (en) 2008-12-10 2019-09-03 Wista Laboratories Ltd. 3,6-disubstituted xanthylium salts
US9549933B2 (en) 2008-12-10 2017-01-24 Wista Laboratories Ltd. 3,6-disubstituted xanthylium salts
WO2011027081A2 (fr) 2009-09-03 2011-03-10 Sanofi-Aventis Nouveaux derives de 5,6,7,8-tetrahydroindolizine inhibiteurs d'hsp90, compositions les contenant et utilisation
US10813930B2 (en) 2010-12-22 2020-10-27 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US9533954B2 (en) 2010-12-22 2017-01-03 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US10213427B2 (en) 2010-12-22 2019-02-26 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US11053246B2 (en) 2012-06-13 2021-07-06 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US11840534B2 (en) 2012-06-13 2023-12-12 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US10131667B2 (en) 2012-06-13 2018-11-20 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US9745311B2 (en) 2012-08-10 2017-08-29 Incyte Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
US10450313B2 (en) 2013-04-19 2019-10-22 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10947230B2 (en) 2013-04-19 2021-03-16 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US10040790B2 (en) 2013-04-19 2018-08-07 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US11530214B2 (en) 2013-04-19 2022-12-20 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US9533984B2 (en) 2013-04-19 2017-01-03 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9890156B2 (en) 2015-02-20 2018-02-13 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11173162B2 (en) 2015-02-20 2021-11-16 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10632126B2 (en) 2015-02-20 2020-04-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10738048B2 (en) 2015-02-20 2020-08-11 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10251892B2 (en) 2015-02-20 2019-04-09 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10214528B2 (en) 2015-02-20 2019-02-26 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10016438B2 (en) 2015-02-20 2018-07-10 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11014923B2 (en) 2015-02-20 2021-05-25 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9801889B2 (en) 2015-02-20 2017-10-31 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11667635B2 (en) 2015-02-20 2023-06-06 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9708318B2 (en) 2015-02-20 2017-07-18 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11472801B2 (en) 2017-05-26 2022-10-18 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US12024517B2 (en) 2018-05-04 2024-07-02 Incyte Corporation Salts of an FGFR inhibitor
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US12473286B2 (en) 2018-05-04 2025-11-18 Incyte Corporation Salts of an FGFR inhibitor
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12083124B2 (en) 2019-10-14 2024-09-10 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US12168660B2 (en) 2019-12-04 2024-12-17 Incyte Corporation Derivatives of an FGFR inhibitor
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12428420B2 (en) 2021-06-09 2025-09-30 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
CN114259564B (zh) * 2021-11-30 2023-03-14 清华大学 Hsp90抑制剂阻碍stat3线粒体转运和治疗哮喘的新应用
CN114259564A (zh) * 2021-11-30 2022-04-01 清华大学 Hsp90抑制剂阻碍stat3线粒体转运和治疗哮喘的新应用

Similar Documents

Publication Publication Date Title
WO2009030871A1 (fr) Dérivés de pyrrolopyrimidine présentant une activité inhibitrice d'hsp90
CA2537135C (fr) Composes pyrimidothiophene
AU2014400628B2 (en) Aminopyridazinone compounds as protein kinase inhibitors
CN104470919B (zh) 作为pad4抑制剂的2-(氮杂吲哚-2-基)苯并咪唑
AU2017363257B2 (en) Degradation of protein kinases by conjugation of protein kinase inhibitors with E3 ligase ligand and methods of use
EP2651417B1 (fr) Dérivés pyrrolopyrimidine inhibant ask1
EP2920162B1 (fr) Inhibiteurs de la tyrosine kinase de bruton
AU2017315343A1 (en) Amino-pyrrolopyrimidinone compounds and methods of use thereof
CA3088025A1 (fr) Inhibiteurs de l'interaction proteine-proteine du domaine bcl6 btb et leurs utilisations
EP2007767B1 (fr) Derives de pyrrolopyrimidine en tant qu'inhibiteurs de hsp90
AU2002366801B8 (en) Pyrrolopyrimidine A2b selective antagonist compounds, their synthesis and use
JP2017039738A (ja) ベンゾジアゼピンブロモドメイン阻害剤
TWI826509B (zh) 作為vanin抑制劑之雜芳族化合物
JPH08507056A (ja) インターロイキン−１および腫瘍壊死因子阻害作用を有するピラゾリトリアジン
CA2723237A1 (fr) Amides substitues, leur methode de preparation et d'utilisation en tant qu'inhibiteurs de btk
CN104768946A (zh) 作为p97复合物的抑制剂的稠合嘧啶
CA2514287A1 (fr) 2-cyanopyrrolopyrimidines et utilisations pharmaceutiques de celles-ci
ZA200601715B (en) Pyrimidothiophene compounds
WO2008050078A1 (fr) Dérivés de ptéridine servant d'inhibiteurs de kinases plk (polo-like) utiles dans le traitement d'un cancer
WO2020114943A1 (fr) Composés hétéroaromatiques utilisés en tant qu'inhibiteurs de vanine
EP3080099B1 (fr) Inhibiteurs de la tyrosine kinase de bruton
US20220041592A1 (en) Heteroaromatic compounds as vanin inhibitors
EP2004648A1 (fr) Composés de purine en tant qu'inhibiteurs de la protéine hsp90 utilisés pour le traitement du cancer
EP2057155A1 (fr) Dérivés 1h-pyrrolo[2,3-b]pyridine utiles en tant qu'inhibiteurs d'hsp90
EP2313413B1 (fr) Dérivés de pyrazolo [1,5-a] pyrimidine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07823889

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07823889

Country of ref document: EP

Kind code of ref document: A1