WO2005007083A2 - Chemical compounds - Google Patents

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Publication number
WO2005007083A2
WO2005007083A2 PCT/US2004/019410 US2004019410W WO2005007083A2 WO 2005007083 A2 WO2005007083 A2 WO 2005007083A2 US 2004019410 W US2004019410 W US 2004019410W WO 2005007083 A2 WO2005007083 A2 WO 2005007083A2
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Prior art keywords
thieno
pyrimidin
ethynyl
amino
phenyl
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PCT/US2004/019410
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French (fr)
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WO2005007083A3 (en
Inventor
Scott Howard Dickerson
Holly Kathleen Emerson
Kevin Wayne Hinkle
Keith Robert Hornberger
Douglas Mccord Sammond
Stephon Smith
Kirk Lawrence Stevens
Robert Dale Hubbard
Kimberly Glennon Petrov
Michael John Reno
David Edward Uehling
Alex Gregory Waterson
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Smithkline Beecham Corporation
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Publication of WO2005007083A2 publication Critical patent/WO2005007083A2/en
Publication of WO2005007083A3 publication Critical patent/WO2005007083A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • R is NH 2 , C C 3 alkyl, or -OR';
  • R 1 is the group defined by -(Z)-(Z 1 ) m -(Z 2 ) n , wherein Z is heterocyclyl or heterocyclylene, Z 1 is OC(O), OC(S), or C(O), where m is 0 or 1 ,
  • Z 2 is heterocyclyl, aralkyl, N(H)R', C C 3 alkyl, -OR', halo, S(0) 2 R, C C 3 hydroxyalkyl, or C C 3 haloalkyl, where n is 0 or 1 ;
  • R' is -H, -(CH 2 ) q S(0) 2 R"', R""NR"R", C C 3 alkyl, -(CH 2 ) q OR", -C(0)R"', or - C(0)OR”'; q is O, 1 , 2, 3, or 4;
  • R" is
  • R 3 is the group defined by -(Q)-(Q 1 ) r -(Q 2 ) t , wherein Q is arylene, heteroarylene, aryl, or aralkyl, Q 1 is O, S(0) 2 , or S, where r is 0 or 1 , and Q 2 is aralkyl, heteroaryl, or aryl and t is 0 or 1.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a salt, solvate, or a physiologically functional derivative thereof and one or more of pharmaceutically acceptable carriers, diluents and exeipients.
  • a method of treating a disorder in a mammal comprising: administering to said mammal a therapeutically effective amount of a compound of formula (I) or a salt, solvate or a physiologically functional derivative thereof.
  • alkyl refers to a straight- or branched-chain hydrocarbon radical having from one to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of unsubstituted CrC 6 alkyl, C C 6 hydroxyalkyl, C r C 6 alkoxy, C C 6 alkylsulfanyl, C r C 6 alkylsulfenyl, C r C 6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aryl, aryloxy, heteroaryl, heterocyclyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halo, or C C 6 perfluoroalkyl, multiple degrees of substitution being allowed.
  • alkylene refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group which includes C r C 6 alkyl, C r C 6 alkoxy, C C 6 alkylsulfanyl, CrC 6 alkylsulfenyl, C C 6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aryl, heteroaryl, heterocyclyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halo, and C C 6 perfluoroalkyl, multiple degrees of substitution being allowed.
  • Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.
  • C 1 -C3 alkylene group is as defined above.
  • Exemplary "C 3 -C 7 cycloalkyl" groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Exemplary optional substituents include d.C 6 alkyl, C ⁇ .C 6 alkoxy, d.C 6 haloalkyl, C C 6 haloalkoxy, d.C 6 alkylsulfanyl, Ci.Ce alkylsulfenyl, Ci-ds alkylsulfonyl, C ⁇ -C 6 alkylsulfonylamino, arylsulfonoamino, alkylcarboxy, alkylcarboxyamide, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carboxamide, carbamoyl optionally substituted by alkyl, aminosulfonyl, acyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo, heteroaryl, hetero
  • heteroaryl refers to a monocyclic five to seven membered aromatic ring, or to a fused bicyclic or tricyclic aromatic ring system comprising two of such monocyclic five to seven membered aromatic rings.
  • alkylsulfanyl refers to the group R a S-, where R a is alkyl as defined above and the term "C ⁇ -C 6 alkylsulfanyl” refers to an alkylsulfanyl group as defined herein wherein the alkyl moiety contains at least 1 , and at most 6, carbon atoms.
  • haloalkylsulfanyl refers to the group R a S-, where
  • alkylsulfonyl refers to the group R a S(0) 2 -, where R a is alkyl as defined above and the term “C ⁇ -C 6 alkylsulfonyl” refers to an alkylsulfonyl group as defined herein wherein the alkyl moiety contains at least 1 , and at most 6, carbon atoms.
  • alkylsulfonylamino refers to the group -
  • mercapto refers to the group -SH.
  • carboxy refers to the group -C(0)OR a , wherein R a is H or alkyl as defined herein.
  • aroyl refers to the group R a C(O)- , where R a is aryl as defined herein.
  • aroylamino refers to the group R a C(0)NH- , where
  • R a is aryl as defined herein.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt or physiologically functional derivative thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
  • bonds represent either single or double bonds. As is understood by those skilled in the art and specifically illustrated in the working examples following (for instance see Examples 1 and 24) such bonds will each be independently a single or double bond depending on which of A 1 or A 2 is sulfur.
  • ⁇ valence are indicated by “ ", where it is understood that the unfilled valence is filled by attachment to the remainder of the molecule.
  • the appropriate attachments are further illustrated in the working examples recited below.
  • Z 1 is C(O)
  • Z 2 is -OH, or
  • Z 2 is halo, preferably -F, or Z 2 is C 1 -C3 hydroxyalkyl, preferably -CH 3 OH or In one embodiment, R 2 is -H. In another embodiment, R 2 is C C 3 alkyl.
  • R 4 is halo, preferably -Cl or -F, Q 1 is O and r is 1 , and Q 2 is selected from
  • Q 1 is S(0) 2 and r is 1
  • Q 2 is selected from
  • R 5 is halo, preferably -F.
  • Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N- methylglucamine, ox
  • compositions which include therapeutically effective amounts of compounds of the formula (I) and salts, solvates and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or exeipients.
  • the compounds of the formula (I) and salts, solvates and physiological functional derivatives thereof, are as described above.
  • magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • the compounds of formula (I), and salts, solvates and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of formula (I) and salts, solvates and physiological functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide -phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in ' the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurised aerosols, nebulizers or insufflators.
  • Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the human or other animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian.
  • an effective amount of a compound of formula (I) for the treatment of neoplastic growth, for example colon or breast carcinoma will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub- doses per day such that the total daily dose is the same.
  • An effective amount of a salt or solvate, or physiologically functional derivative thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above. 08
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and the use of at least one other cancer treatment method.
  • combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and at least one other pharmaceutically active agent, preferably an anti-neoplastic agent.
  • the compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the compounds of the Formula (I) or salts, solvates, or physiologically functional derivatives thereof and at least one additional cancer treatment therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination with such other anti-cancer therapies.
  • the other anti-cancer therapy is at least one additional chemotherapeutic therapy including administration of at least one anti-neoplastic agent.
  • the administration in combination of a compound of formula (I) or salts, solvates, or physiologically functional derivatives thereof with other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one anti-neoplastic agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms.
  • Anti-neoplastic agents useful in combination with the compounds and salts, solvates or physiologically functional derivatives thereof of formula I include, but are not limited to, the following:
  • cell cycle specific anti-neoplastic agents including, but not limited to, diterpenoids such as paclitaxel and its analog docetaxel; vinca alkaloids such as vinblastine, vincristine, vindesine, and vinorelbine; epipodophyllotoxins such as etoposide and teniposide; fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine ; antimetabolites such as allopuhnol, fludurabine, methotrexate, cladrabine, cytarabine, mercaptopurine and thioguanine; and camptothecins such as
  • cytotoxic chemotherapeutic agents including, but not limited to, alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine, and dacarbazine; anti-tumour antibiotics such as doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dacttino ycin and mithramycin; and platinum coordination complexes such as cisplatin, carboplatin, and oxaliplatin; and
  • anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene
  • progestrogens such as megestrol acetate
  • aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane
  • antiandrogens such as flutamide, nilutamide, bicalutamide, and cyproterone acetate
  • LHRH agonists and antagagonists such as goserelin acetate and luprolide, testosterone 5 ⁇ -dihydroreductase inhibitors such as finasteride
  • metalloproteinase inhibitors such as marimastat
  • antiprogestogens urokinase plasminogen activator receptor function inhibitors
  • cyclooxygenase type 2 (COX-2) inhibitors such as celecoxi
  • TIE-2 inhibitors include growth factor function inhibitors such as inhibitors of the functions of hepatocyte growth factor; platelet derived growth factor receptor (PDGFr), vascular endothelial growth factor receptor (VEGFR) and TIE-2; and other protein kinase inhibitors such as c-Raf, b-Raf, and cyclin dependent inhibitors such as CDK2 and CDK4 inhibitors.
  • growth factor function inhibitors such as inhibitors of the functions of hepatocyte growth factor
  • PDGFr platelet derived growth factor receptor
  • VEGFR vascular endothelial growth factor receptor
  • TIE-2 TIE-2
  • other protein kinase inhibitors such as c-Raf, b-Raf, and cyclin dependent inhibitors such as CDK2 and CDK4 inhibitors.
  • the compounds of formula (I) and salts, solvates and physiological functional derivatives thereof, are believed to have anticancer activity as a result of inhibition of one or more erbB family protein kinase and its effect on selected cell lines whose growth is dependent on erbB family protein kinase activity.
  • the present invention thus also provides compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof, or physiologically functional derivatives thereof, for use in medical therapy, and particularly in the treatment of disorders mediated by inappropriate activity of one or more erbB family kinase.
  • the inappropriate erbB family activity referred to herein is any erbB kinase activity that deviates from the normal erbB family kinase activity expected in a particular mammalian subject.
  • the inappropriate activity may arise from one or more of EGFR (erbB-1), erbB-2, or erbB-4.
  • Inappropriate erbB family kinase activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of erbB family kinase activity.
  • Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase or ligand leading to inappropriate or uncontrolled activation of the receptor.
  • erbB family kinase activity may reside in an abnormal source, such as a malignancy. That is, the level of erbB family activity does not have to be abnormal to be considered inappropriate, rather the activity derives from an abnormal source.
  • the present invention is directed to methods of regulating, modulating, or inhibiting one or more erbB family kinase for the prevention and/or treatment of disorders related to unregulated erbB family kinase activity.
  • the compounds of the present invention can also be used in the treatment of certain forms of cancer.
  • the compounds of the present invention can be used to provide additive or synergistic effects with certain existing cancer chemotherapies and radiation, and/or be used to restore effectiveness of certain existing cancer chemotherapies and radiation.
  • a further aspect of the invention provides a method of treatment of a mammal suffering from a disorder mediated by inappropriate one or more erbB family kinase activity, including susceptible malignancies, which includes administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or a physiologically functional derivative thereof.
  • the disorder is cancer.
  • a further aspect of the invention provides a method of treatment of a mammal suffering from cancer, which includes administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof.
  • a further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, in the preparation of a medicament for the treatment of a disorder characterized by inappropriate activity of one or more erbB family kinase.
  • the disorder is cancer.
  • the mammal requiring treatment with a compound of the present invention is typically a human being.
  • therapeutically effective amounts of the compounds of formula (I) or salts, solvates or physiologically derived derivatives thereof and agents which inhibit growth factor receptor function may be administered in combination to a mammal for treatment of a disorder mediated by inappropriate activity of one or more erbB family kinase, for instance in the treatment of cancer.
  • growth factor receptors include, for example, PDGFR, VEGFR, TIE-2, as well as erbB family kinase inhibitors other than those described herein. Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10(6):803-818 and in Shawver et al DDT Vol 2, No. 2 February 1997.
  • the compounds of the Formula (I) or salts, solvates, or physiologically functional derivatives thereof and the agent for inhibiting growth factor receptor function may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination.
  • the combination may be employed in combination in accordance with the invention by administration concomitantly in (1 ) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the Working Examples. Compounds of general formulae (II) and (III) may be prepared by methods known to those of skill in the art. The following synthetic schemes are meant to represent examples only and are not meant to limit the invention in any way. In all of the schemes described below, it is understood that protecting groups may be employed where necessary in accordance with general principles known to those of skill in the art, for example, see T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis. John Wiley & Sons.
  • a palladium catalyst bis(triphenylphosphine)palladium dichloride for example, a copper catalyst, copper(l) iodide for example, a base, triethylamine for example, a solvent, tetrahydrofuran (THF) for example, and at a temperature from 25 °C to 175 °C, preferably 50 °C to 60 °C.
  • a palladium catalyst bis(triphenylphosphine)palladium dichloride for example, a copper catalyst, copper(l) iodide for example, a base, triethylamine for example, a solvent, tetrahydrofuran (THF) for example, and at a temperature from 25 °C to 175 °C, preferably 50 °C to 60 °C.
  • THF tetrahydrofuran
  • the intermediate dihalogenated thieno[2,3-d]pyrimidines can then be converted to compounds of the general structure (I") by the two synthetic routes depicted as C and D in Scheme 2.
  • an appropriate dihalogenated thieno[2,3-d]pyrimidine is allowed to react with reagents capable of selectively introducing an acetylenyl group into the 6-position.
  • steps C and D in Scheme 2 may be carried out in reverse order using similar conditions as described above to afford the desired products.
  • the acetylenyl reagents wherein R 1 is a heterocyclic ring incorporating a nitrogen in the ring, may be prepared by the general route shown in Scheme 3.
  • a heterocycle bearing a suitably protected carboxylic acid is subjected to appropriate reducing conditions to obtain the aldehyde reagent V.
  • Suitable reducing conditions may, for example, consist of diisobutylaluminum hydride or other hydride reducing agents.
  • An alternative method involves reduction of the carboxylic acid functionality to the corresponding primary alcohol, followed by oxidation to the corresponding aldehyde.
  • the aldehyde derivative V is then subjected to a one-carbon homologation procedure to yield intermediate VI.
  • a reagent particularly useful for the transformation to acetylenic derivative VI is dimethyl 1-diazo-2- oxopropylphosphonate.
  • Suitable protecting groups (P) for the nitrogen of intermediates IV through VI include, for example, fert-butyl carbamate.
  • a suitable protecting group for the carboxylic acid functionality of intermediates IV through VI is methyl such that the carboxylate functionality is a methyl ester.
  • R which reprsents Z 1 and/or Z 2 defined above, (see schemes and examples below)
  • X represents a suitable heteroatom such as O, S, or N and n represents an integer from 0 to 3 in all schemes depicted herein.
  • intermediate VI is acetylenic reagent in the Pd-mediated coupling reactions
  • R 1 in schemes 1 and 2 are heterocyclic compounds bearing nitrogen in the ring as represented by intermediates VII and IX below.
  • Intermediates VII and IX may be treated with a suitable agent to remove the protecting group P of the secondary nitrogen that is part of the heterocyclic ring (Schemes 4 and 5).
  • P is ferf-butoxycarbonyl
  • deprotection conditions may include, but are not limited to, trifluoroacetic acid or HCl in a suitable solvent such as dichloromethane or chloroform.
  • the hydroxyl group may be converted into the corresponding fluoride in intermediate XIV by treatment with, for example, diethylaminosulfurtrifluoride (DAST).
  • DAST diethylaminosulfurtrifluoride
  • Activation of the alcohol group by treatment with tosyl chloride in the presence of an appropriate base yields the corresponding tosylate intermediate, which may be converted into the corresponding cyanide or azide by treatment with sodium cyanide or sodium azide respectively.
  • Suitable reducing reagents include, but are not limited to, triphenylphosphine.
  • Amine derivatives may also be obtained by treatment with the ketone or aldehyde derived by oxidation of the alcohol, followed by reductive amination in the presence of a reducing agent such as sodium cyanoborohydride.
  • a reducing agent such as sodium cyanoborohydride.
  • the cyanide derivatives XV may be transformed into a variety of additional intermediates according to methods known by those skilled in the art.
  • Treatment of the amine with an acyl halide yields the corresponding amide derivatives XIX, while treatment with a sulfonyl chloride RS0 2 CI gives the sulfonamide derivatives XX.
  • Treatment of the amine with an aldehyde or ketone in the presence of a reducing agent such as sodium cyanoborohydride supplies the alkylated secondary or tertiary amine intermediate XXI.
  • Targets that are substituted at the nitrogen atom that is part of the heteroaryl ring may be prepared from structures XXIII and XXV by treatment of these intermediates with the appropriate nitrogen derivatizing reagent.
  • treatment of the amine with an isocyanate affords the corresponding urea derivative XXIX.
  • Treatment of XXIII or XXV with an alkylating agent affords XXVI.
  • Suitable alkylating agents include alkylhalides or alkyl aldehydes or ketones in the presence of a reducing agent such as sodium cyanoborohydride.
  • Reported HPLC retention times were obtained on a Waters 2795 instrument attached to a Waters 996 diode array detector reading 210-500 nm.
  • the column used was a Synergi Max-RP (50 x 2 mm) model #00B-4337-B0.
  • Solvent gradient was 15% methanol:water to 100% methanol (0.1% formic acid) over 4 or 6 min.
  • Flow rate was 0.8 mL/min.
  • Injection volume was 3 microliters.
  • Chiral HPLC used for resolution in Example 29 was performed on a Novasep
  • 6-Bromo-4-chlorothieno[3,2-c ]pyrimidine M.J. Munchhof and S.B. Sobolov- Jaynes, Preparation of thienopyrimidines and thienopyridines as anticancer agents.
  • PCT Int. Appl. (1999), WO9924440) (1.05 g, 4 mmol) and 3-chloro-4-[(3- fluorobenzyl)oxy]aniline (G.S. Cockerill and K.E. Lackey, Preparation of anilinoquinazolines as protein tyrosine kinase inhibitors.
  • the reaction was filtered over a pad of Celite, washing the pad the CH 2 CI 2 (3 x 200 mL).
  • the organics were reduced in vacuo, refiltered over a pad of Celite, reduction in vacuo generated a viscous colorless oil that solidified upon standing.
  • the material was carried on without further purification.
  • the crude silyl ether (39 g, 80.5 mmol, based on starting material) was dissolved into THF (250 mL) and cooled to -78 °C for 30 min.
  • An addition funnel was charged with diisobutylaluminum hydride (201 mL, 201 mmol) and added to the reaction over 45 min.
  • the reaction was warmed to 0 °C, and stirred for 1 h.
  • the reaction was cooled to -78 °C and began addition of an aqueous solution of Rochelle's salt. After completion of addition, the reaction mixture was warmed to rt and stirred at rt until the layers became homogenous (about 2 h). The mixture was partitioned with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 400 mL). The organics were pooled, washed with brine (1 x 500 mL), dried over Na 2 S0 , filtered, and concentrated in vacuo. Purified via ISCO chromatography (hexanes:EtOAc) to afford the 27 g (75%, 2 steps) of the title compound as a colorless oil.
  • Step D tert-butyl (2S,4R)-4- ⁇ [tert-butyl(diphenyl)silyl]oxy ⁇ -2-ethynylpyrrolidine-1- carboxylate
  • Step F (3R,5S)-1-(tert-butoxycarbonyl)-5-ethynylpyrrolidin-3-yl morpholine-4- carboxylate
  • Step G (3R,5S)-1-(te ⁇ i-butoxycarbonyl)-5- ⁇ [4-( ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]phenyl ⁇ amino)thieno[3,2-d]pyrimidin-6-yl]ethynyl ⁇ pyrrolidin-3-yl morpholine-4-carboxylate
  • Step H (3R, 5S) -5- ⁇ [4-( ⁇ 3-chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ amino) thieno[3, 2-d]py midin- 6-yl]ethynyl ⁇ pyrrolidin-3-yl morpholine-4-carboxylate
  • the reaction was diluted with CH 2 CI 2 (200 mL), and carefully queched with saturated aqueous NaHC0 3 (50 mL), or until the pH>7.
  • the layers were separated, the organics were washed with saturated aqueous NaHC03 (1 x 50 mL).
  • the aqueous layers were pooled, back-extracted with CH 2 CI 2 , and the resulting organics were combined, dried over MgS0 4 , filtered and absorbed onto silica.
  • Step A tert-butyl (2S,4R)-4- ⁇ [(ethylamino)carbonyl]oxy ⁇ -2-ethynylpyrrolidine-1- carboxylate
  • Step B tert-butyl (2S,4R)-2- ⁇ [4-( ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]phenyl ⁇ amino)thieno[3,2-d]pyrimidin-6-yl]ethynyl ⁇ -4- ⁇ [(ethylamino)carbonyl]oxy ⁇ pyrrolidine-1 -carboxylate
  • Step C (3R,5S)-5- ⁇ [4-( ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ amino)thieno[3,2- t ⁇ ]pyrimidin-6-yl]ethynyl ⁇ pyrrolidin-3-yl ethylcarbamate
  • Step B tert-butyl (2S)-2-ethynyl-(4R,S)-4-morpholin-4-ylpyrrolidine-1-carboxylate
  • the reaction was diluted with 30 mL of EtOAc, and 10 mL of water. The layers were separated, and the organic phase was washed with 20 mL of saturated aqueous NaHCO 3 . The aqueous layers were combined and back-extracted with EtOAc. The organics were pooled, dried over Na 2 S0 4 , filtered and reduced in vacuo to afford a yellow oil.
  • Step C N- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6- ⁇ [(2S,4S)-4-morpholin-4- ylpyrrolidin-2-yl]ethynyl ⁇ thieno[3,2-d]pyrimidin-4-amine
  • Step B tert-butyl (2R,3S)-2-ethynyl-3-morpholin-4-ylpyrrolidine-1-carboxylate
  • Step C N- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6- ⁇ [(2R,3S)-3-morpholin-4- ylpyrrolidin-2-yl]ethynyl ⁇ thieno[3,2-d]pyrimidin-4-amine
  • the title compound was prepared from tet ⁇ -butyl (2R,3S)-2-ethynyl-3- morpholin-4-ylpyrrolidine-1 -carboxylate and 6-bromo-A/- ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]phenyl ⁇ thieno[3,2-c7]pyrimidin-4-amine by a procedure analogous to Example 1 , Steps G and H.
  • Step A tert-butyl (2S)-2-formyl-1 -pyrrolidinecarboxylate
  • the title compound was prepared from known (2S)-2-(hydroxymethyl)-1- pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step C.
  • 1 H NMR 400 MHz, CDCI 3 ): ⁇ 9.55-9.45 (m, 1 H), 4.22-4.02 (m, 1 H), 3.57-3.43 (m, 2H), 2.18- 1.84 (m, 4H), 1.47-1.42 (m, 9H).
  • Step E tert-butyl (2R)-2- ⁇ [4-( ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]phenyl ⁇ amino)thieno[3,2-t7]pyrimidin-6-yl]ethynyl ⁇ pyrrolidine-1- carboxylate
  • Step F N- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6-[(2R)-pyrrolidin-2-ylethynyl] thieno[3,2-d]pyrimidin-4-amine
  • the title compound was prepared from tert-butyl (2R)-2- ⁇ [4-( ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]phenyl ⁇ amino)thieno[3,2-t ⁇ ]pyrimidin-6-yl]ethynyl ⁇ pyrrolidine-1- carboxylate by a procedure analogous to Example 1 , Step H.
  • Step B tert-butyl 3-[(4- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]anilino ⁇ thieno[3,2- d]pyrimidin-6-yl)ethynyl]-1 -pyrrolidinecarboxylate
  • the title compound was prepared from tert-butyl 3-ethynyl-1- pyrrolidinecarboxylate and 6-bromo- ⁇ /- ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]phenyl ⁇ thieno[3,2-c ⁇ ]pyrimidin-4-amine by a procedure analogous to Example 1 , Step G.
  • Step C N- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6-(3- pyrrolidinylethynyl)thieno[3,2-d]pyrimidin-4-amine
  • the title compound was prepared from tert-butyl 3-[(4- ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]anilino ⁇ thieno[3,2-c/]pyrimidin-6-yl)ethynyl]-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step H.
  • Step B (3R,5S)-5-[(4- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]anilino ⁇ thieno[3,2-d]pyrimidin- 6-yl) ethynyl]-3-pyrrolidinol
  • the title compound was prepared from tert-butyl (2S,4R)-2-[(4- ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]anilino ⁇ thieno[3,2-t]pyrimidin-6-yl)ethynyl]-4-hydroxy-1- pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step H. 1 H NMR
  • Step B tert-butyl (2R,4R)-4- ⁇ [te ⁇ i-butyl(diphenyl)silyl]oxy ⁇ -2-ethynyl-1- pyrrolidinecarboxylate
  • Step D tert-butyl (2R,4R)-2-[(4- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]anilino ⁇ thieno[3,2- d]py ⁇ midin-6-yl)ethynyl]-4-hydroxy-1 -pyrrolidinecarboxylate
  • Step E (3R,5R)-5-[(4- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]anilino ⁇ thieno[3,2-d]pyrimidin- 6-yl) ethynyl]-3-pyrrolidinol
  • the title compound was prepared from tert-butyl (2R,4R)-2-[(4- ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]anilino ⁇ thieno[3,2-c7]pyrimidin-6-yl)ethynyl]-4-hydroxy-1- pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step H.
  • Step B tert-butyl (2S,4R)-2-[(4- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]anilino ⁇ thieno[3,2- d]pyrimidin-6-yl)ethynyl]-4-methoxy-1 -pyrrolidinecarboxylate
  • Step C N- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6- ⁇ [(2S,4R)-4- methoxypyrrolidinyl]ethynyl ⁇ thieno[3,2-d]pyrimidin-4-amine trifluoroacetate
  • the title compound was prepared as the trifluoroacetate salt from tert-butyl
  • Step B tert-butyl (2S,4S)-2-[(4- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]anilino ⁇ thieno[3,2- d]pyrimidin-6-yl) ethynyl]-4-fluoro- 1 -pyrrolidinecarboxylate
  • the title compound was prepared from tert-butyl (2S,4S)-2-ethynyl-4-fluoro-1- pyrrolidinecarboxylate and 6-bromo- ⁇ /- ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]phenyl ⁇ thieno[3,2-c ⁇ ]pyrimidin-4-amine by a procedure analogous to Example 1 , Step G.
  • Step C N- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6- ⁇ [(2S,4S)-4-fluoropyrrolidinyl] ethynyl ⁇ thieno[3,2-d]pyrimidin-4-amine
  • the title compound was prepared from tert-butyl (2S,4S)-2-[(4- ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]anilino ⁇ thieno[3,2-t]pyrimidin-6-yl)ethynyl]-4-fluoro-1- pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step H.
  • Step B tert-butyl (1S)-1-ethyl-4-hydroxy-5-hexynylcarbamate
  • tert-butyl (5S)-5-( ⁇ [tert-butyl(diphenyl)silyl]oxy ⁇ methyl)-2-ethynyl-2- hydroxy-1 -pyrrolidinecarboxylate 340 mg, 0.71 mmol
  • MeOH 8 mL
  • CeCI 3 heptahydrate 317 mg, 0.85 mmol
  • the slurry was cooled in a -45 °C bath and NaBH 4 (13 mg, 0.35 mmol) was added.
  • the reaction mixture was stirred for 30 minutes while keeping the cold bath temperature at -45 °C.
  • Step F ⁇ (2S)-5-[(4- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]anilino ⁇ thieno[3,2-d]pyrimidin-6- yl)ethynyl]pyrrolidinyl ⁇ methanol
  • the title compound was prepared as the trifluoroacetate salt from known 1 ,1- dimethylethyl 2-ethynyl-1 -piperidinecarboxylate and 6-bromo- ⁇ /-(3-chloro-4- ⁇ [(3- fluorophenyl)methyl]oxy ⁇ phenyl)thieno[3,2-c/]pyrimidin-4-amine hydrochloride by a procedure analogous to Example 1 , Steps G and H.
  • Step B [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-piperidin-3-ylethynyl-thieno[3,2- d]pyrimidin-4-yl)-amine trifluoroacetate
  • the title compound was prepared as the trifluoroacetate salt from 1 ,1- dimethylethyl 3-ethynyl-1 -piperidinecarboxylate and 6-bromo-/V-(3-chloro-4- ⁇ [(3- fluorophenyl)methyl]oxy ⁇ phenyl)thieno[3,2-c ]pyrimidin-4-amine hydrochloride by a procedure analogous to Example 1 , Steps G and H.
  • the reaction warmed to room temperature and stirred for 4 h.
  • the reaction was partitioned between ethyl acetate and distilled water and the organic layer was dried over sodium sulfate.
  • the solvent was removed under vacuum leaving a yellow oil.
  • the crude oil was purified by silica gel chromatography (gradient: 20-70% ethyl acetate/hexanes). Purification resulted in 633 mg (54%) of the title compound as a white powder.
  • Step F tert-butyl 3- ⁇ [4-( ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl ⁇ morpholine-4-carboxylate
  • Step A 6-bromo-N- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ thieno[2,3-d]pyrimidin-4- amine hydrochloride
  • Step B tert-butyl (2R)-2- ⁇ [4-( ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]phenyl ⁇ amino)thieno[2,3-d]pyrimidin-6-yl]ethynyl ⁇ pyrrolidine-1- carboxylate
  • Step C N- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6-[(2R)-pyrrolidin-2- ylethynyl]thieno[2,3-d]pyrimidin-4-amine
  • the title compound was prepared from tert-butyl (2R)-2- ⁇ [4-( ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]phenyl ⁇ amino)thieno[2,3-c/]pyrimidin-6-yl]ethynyl ⁇ pyrrolidine-1- carboxylate by a procedure analogous to Example 1 , Step H.
  • Step B tert-butyl (2R)-2-[(4-chlorothieno[3,2-d]pyrimidin-6-yl)ethynyl]-1- pyrrolidinecarboxylate
  • the title compound was prepared from tert-butyl (2R)-2-ethynyl-1- pyrrolidinecarboxylate and 6-bromo-4-chlorothieno[3,2-c/]pyrimidine by a procedure analogous to Example 1, Step G.
  • Step D tert-butyl (2R)-2-[(4- ⁇ [3-chloro-4-(2-pyridinyloxy)phenyl]amino ⁇ thieno[3,2-
  • Step E N-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine
  • Step B [3-chloro-4-(1-naphthalenyloxy)phenyl]amine
  • Step C 6-bromo-N-[3-chloro-4-(1-naphthalenyloxy)phenyl]thieno[3,2-d]pyrimidin-4- amine hydrochloride
  • the title compound was prepared as the trifluoroacetate salt from 6-bromo-/V- [3-chloro-4-(1 -naphthalenyloxy)phenyl]thieno[3,2-c/]pyrimidin-4-amine_and tert-butyl (2R)-2-ethynyl-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Steps G and H.
  • Step C N-[5-(2-pyridinyloxy) ⁇ 2-naphthalenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine trifluoroacetate
  • the title compound was prepared as the trifluoroacetate salt from 6-bromo-/V- [5-(2-pyridinyloxy)-2-naphthalenyl]thieno[3,2-c/]pyrimidin-4-amine and tert-butyl (2R)- 2-ethynyl-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Steps G and H.
  • Step D N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3, 2-d]pyrimidin-4-amine trifluoroacetate
  • the title compound was prepared as the trifluoroacetate salt from 6-bromo-/V- ⁇ 1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl ⁇ thieno[3,2-c/]pyrimidin-4-amine hydrochloride and tert-butyl (2R)-2-ethynyl-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Steps G and H.
  • Step B N-[1-(phenylmethyl)-1H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine trifluoroacetate
  • the title compound was prepared as the trifluoroacetate salt from 4-chloro-6- [(2R)-2-pyrrolidinylethynyl]thieno[2,3-c/]pyrimidine and known 5-amino-1- benzylindazole (G. S. Cockerill, K. E. Lackey, Preparation of quinazolinylamines and analogs as protein tyrosine kinase inhibitors. PCT Appl.
  • Step B 1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-amine
  • Step C 6-[(2R)-2-pyrrolidinylethynyl]-N-[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5- yl]thieno[3, 2-d]pyrimidin-4-amine trifluoroacetate
  • Step C N- ⁇ 3-chloro-4-[(1,3-thiazol-4-ylmethyl)oxy]phenyl ⁇ -6-[(2R)-2- pyrrolidinylethynyl]thieno[3, 2-d]pyrimidin-4-amine trifluoroacetate
  • Step A (3R,5S)-1-(tert-butoxycarbonyl)-5-[(4-chlorothieno[3,2-d]pyrimidin-6- yl)ethynyl]pyrrolidin-3-yl morpholine-4-carboxylate
  • Step B (3R,5S)-5-( ⁇ 4-[(1-benzyl-1H-indazol-5-yl)amino]thieno[3,2-d]pyrimidin-6- yl ⁇ ethynyl)pyrrolidin-3-yl morpholine-4-carboxylate hydrochloride
  • the title compound was prepared as the hydrochloride salt from 1-benzyl-1/- - indazol-5-amine and (3R,5S)-1 -(tert-butoxycarbonyl)-5-[(4-chlorothieno[3,2- c/]pyrimidin-6-yl)ethynyl]pyrrolidin-3-yl morpholine-4-carboxylate by a procedure analogous to Example 1 , Steps A and H.
  • Step B 3-chloro-4-[1-(3-fluorophenyl)ethoxy]aniline
  • Step C N-(3-chloro-4- ⁇ [(1R)1-(3-fluorophenyl)ethyl]oxy ⁇ phenyl)-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3, 2-d]pyrimidin-4-amine trifluoroacetate
  • the title compound was prepared as the trifluoroacetate salt from 3-chloro-4-[1-(3- fluorophenyl)ethoxy]aniline and tert-butyl (2R)-2-[(4-chlorothieno[3,2-d
  • the mixture of diastereomers obtained by this procedure was resolved at the Boc-protected stage by chiral supercritical fluid chromatography (SFC).
  • the title compound was prepared as the trifluoroacetate salt from tert-butyl (2R)-2-[(4-chlorothieno[3,2-djpyrimidin-6-yl)ethynyl]-1 -pyrrolidinecarboxylate and known 4-(phenylsulfonyl)aniline (Alfred Courtin, Syntheses of some alkyl-, cycloalkyl- and aryl-(4-aminophenyl) sulfones. Helvetica Chimica Acta (1983), 66(4), 1046-52) by a procedure analogous to Example 1 , Steps A and H.
  • Step B N-[3-chloro-4-(1,3-thiazol-2-ylthio)phenyl]-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3,2-d]pyrimidin-4-amine
  • the title compound was prepared as the trifluoroacetate salt from tert-butyl
  • Step C - tert-butyl (2R)-2-[(4- ⁇ [3-chloro-4-(pyridin-2- ylmethoxy)phenyl]amino ⁇ thieno[3,2-d]pyrimidin-6-yl)ethynyl]pyrrolidine-1-carboxylate
  • Step D N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3, 2-d]pyrimidin-4-amine hydrochloride
  • the title compound was prepared as the hydrochloride salt from tert-butyl (2R)-2-[(4- ⁇ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino ⁇ thieno[3,2-d]pyrimidin-6- yl)ethynyl]pyrrolidine-1-carboxylate by a procedure analogous to Example 1 , Step H.
  • Step B 1 -(2, 5-difluorobenzyl) - 1 H-indol-5-amine
  • Step C N-[1-(2,5-difluorobenzyl)-1H-indol-5-yl]-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3, 2 d]pyrimidin-4-amine trifluoroacetate
  • Step B 1-[(3-fluorophenyl)sulfonyl]-1H-indol-5-amine

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Abstract

The present invention discloses thienopyrimidine derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such thienopyrimidine derivatives are useful in the treatment of diseases associated with inappropriate ErbB family kinase activity.

Description

CHEMICAL COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to thienopyrimidine derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such thienopyrimidine derivatives are useful in the treatment of diseases associated with inappropriate ErbB family kinase activity.
BACKGROUND OF THE INVENTION An important large family of enzymes is the protein kinase enzyme family.
Currently, there are about 500 different known protein kinases. Protein kinases serve to catalyze the phosphorylation of an amino acid side chain in various proteins by the transfer of the γ-phosphate of the ATP-Mg2+ complex to said amino acid side chain. These enzymes control the majority of the signaling processes inside cells, thereby governing cell function, growth, differentiation and destruction (apoptosis) through reversible phosphorylation of the hydroxyl groups of serine, threonine and tyrosine residues in proteins. Studies have shown that protein kinases are key regulators of many cell functions, including signal transduction, transcriptional regulation, cell motility, and cell division. Several oncogenes have also been shown to encode protein kinases, suggesting that kinases play a role in oncogenesis. These processes are highly regulated, often by complex intermeshed pathways where each kinase will itself be regulated by one or more kinases. Consequently, aberrant or inappropriate protein kinase activity can contribute to the rise of disease states associated with such aberrant kinase activity. Due to their physiological relevance, variety and ubiquitousness, protein kinases have become one of the most important and widely studied family of enzymes in biochemical and medical research.
One type of protein kinases is protein tyrosine kinases (PTK). Aberrant PTK activity has been implicated in a variety of disorders including psoriasis, rheumatoid arthritis, bronchitis, as well as cancer. Development of effective treatments for such disorders is a constant and ongoing enterprise in the medical field. The ErbB family of PTKs, which includes c-ErbB-2, EGFR, and ErbB-4, is one group of PTKs that has attracted interest as a therapeutic target. Currently, of special interest, is the role of ErbB family PTKs in hyperproliferative disorders, particularly human malignancies. Elevated EGFR activity has, for example, been implicated in non-small cell lung, bladder, and head and neck cancers. Furthermore, increased c-ErbB-2 activity has been implicated in breast, ovarian, gastric and pancreatic cancers. Consequently, inhibition of ErbB family PTKs should provide a treatment for disorders characterized by aberrant ErbB family PTK activity. The biological role of ErbB family PTKs and their implication in various disease states is discussed, for instance in U.S. patent 5,773,476; International Patent Application WO 99/35146; M.C. Hung et al, Seminars in Oncology, 26: 4, Suppl. 12 (August) 1999, 51-59; Ullrich et al, Cell, 61 : 203-212, April 20, 1990; Modjtahedi et al, Int'l. J. of Oncology, 13: 335-342,1998; and J.R. Woodbum, Pharmacol. Ther., 82: 2-3, 241-250, 1999.
The present inventors have discovered novel thienopyrimidine compounds, which are inhibitors of erbB family kinase activity. Such derivatives are useful in the treatment of disorders associated with inappropriate erbB family kinase activity.
SUMMARY OF THE INVENTION
In a first aspect of the present invention, there is provided a compound of Formula (I):
(I) or a salt, solvate, or physiologically functional derivative thereof: wherein:
one of A1 and A2 is S and the other is CH, where ^ indicate a single or double bond; R is NH2, CrC3 alkyl, or -OR'; R1 is the group defined by -(Z)-(Z1)m-(Z2)n, wherein Z is heterocyclyl, or heterocyclylene, Z1 is OC(O), OC(S), or C(O), where m is 0 or 1 , Z2 is heterocyclyl, aralkyl, N(H)R', C C3 alkyl, -OR', halo, S(O)2R, d- C3 hydroxyalkyl, or C C3 haloalkyl, where n is 0 or 1 ; R' is -H, -(CH2)qS(0)2R"\ R""NR"R", CrC3 alkyl, -(CH2)qOR", -C(0)R"', or - C(0)OR"; q is 0, 1, 2, 3, or 4; R" is C C3 alkyl; R'" is C1-C3 alkyl or N(H)R"; R"" is C C6 alkyl; R2 is -H, C C3 alkyl, or C(0)R";
R3 is the group defined by -(Q)-(Q1)r-(Q2)t, wherein Q is arylene, heteroarylene, aryl, or aralkyl, Q1 is O, S(0)2, or S, where r is 0 or 1, and Q2 is aralkyl, heteroaryl, or aryl and t is 0 or 1.
In a second aspect of the present invention, there is provided a compound of Formula (I'):
Figure imgf000004_0001
(I') or a salt, solvate, or physiologically functional derivative thereof: wherein:
R is NH2, C C3 alkyl, or -OR'; R1 is the group defined by -(Z)-(Z1)m-(Z2)n, wherein Z is heterocyclyl or heterocyclylene, Z1 is OC(O), OC(S), or C(O), where m is 0 or 1 , Z2 is heterocyclyl, aralkyl, N(H)R', C C3 alkyl, -OR', halo, S(0)2R, C C3 hydroxyalkyl, or C C3 haloalkyl, where n is 0 or 1 ; R' is -H, -(CH2)qS(0)2R"', R""NR"R", C C3 alkyl, -(CH2)qOR", -C(0)R"', or - C(0)OR"'; q is O, 1 , 2, 3, or 4; R" is C C3 alkyl; R'" is C1-C3 alkyl or N(H)R"; R"" is C C6 alkyl; R2 is -H, CrC3 alkyl, or C(0)R";
R3 is the group defined by -(Q)-(Q1)r-(Q2)t, wherein Q is arylene, heteroarylene, aryl, or aralkyl, Q1 is O, S(0)2, or S, where r is 0 or 1 , and Q2 is aralkyl, heteroaryl, or aryl and t is 0 or 1.
In a third aspect of the present invention, there is provided a compound of Formula (I"):
Figure imgf000005_0001
(I") or a salt, solvate, or physiologically functional derivative thereof: wherein:
R is NH2, CrC3 alkyl, or -OR'; R1 is the group defined by -(Z)-(Z1)m-(Z2)n, wherein Z is heterocyclyl or heterocyclylene, Z1 is OC(O), OC(S), or C(O), where m is 0 or 1 , Z2 is heterocyclyl, aralkyl, N(H)R', CrC3 alkyl, -OR', halo, S(0)2R, C C3 hydroxyalkyl, or C1-C3 haloalkyl, where n is 0 or 1 ; R' is -H, -(CH2)qS(0)2R'", -R""NR"R", CrC3 alkyl, -(CH2)qOR", -C(0)R"', or - C(0)OR'"; q is O, 1 , 2, 3, or 4; R" is C C3 alkyl;
R'" is C1-C3 alkyl or N(H)R";
R"" is C C6 alkyl;
R2 is -H, C C-3 alkyl, or C(0)R";
R3 is the group defined by -(Q)-(Q1)r-(Q2)tι wherein Q is arylene, heteroarylene, aryl, or aralkyl, Q1 is O, S(0)2, or S, where r is 0 or 1 , and Q2 is aralkyl, heteroaryl, or aryl and t is 0 or 1.
In a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a salt, solvate, or a physiologically functional derivative thereof and one or more of pharmaceutically acceptable carriers, diluents and exeipients.
In a fifth aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being mediated by inappropriate activity of at least one erbB family kinase, comprising: administering to said mammal a therapeutically effective amount of a compound of formula (I) or a salt, solvate or a physiologically functional derivative thereof.
In a sixth aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being mediated by inappropriate activity of at least two erbB family kinases, comprising: administering to said mammal a therapeutically effective amount of a compound of formula (I) or a salt, solvate or a physiologically functional derivative thereof.
In a seventh aspect of the present invention, there is provided a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof for use in therapy.
In an eighth aspect of the present invention, there is provided the use of a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof in the preparation of a medicament for use in the treatment of a disorder mediated by inappropriate activity of at least one erbB family kinase. In a ninth aspect of the present invention, there is provided the use of a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof in the preparation of a medicament for use in the treatment of a disorder mediated by inappropriate activity of at least two erbB family kinases.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
As used herein the term "erbB family kinase" includes within its scope EGFR or erbB-1 , erbB-2, and erbB-4.
As used herein the term "alkyl" refers to a straight- or branched-chain hydrocarbon radical having from one to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of unsubstituted CrC6 alkyl, C C6 hydroxyalkyl, CrC6 alkoxy, C C6 alkylsulfanyl, CrC6 alkylsulfenyl, CrC6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aryl, aryloxy, heteroaryl, heterocyclyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halo, or C C6 perfluoroalkyl, multiple degrees of substitution being allowed. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like. As used herein, the terms "C1.C3 alkyl" and "CrC6 alkyl" refer to an alkyl group, as defined above, containing at least 1 , and at most 3 or 6 carbon atoms respectively. Examples of such branched or straight-chained alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.
As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group which includes CrC6 alkyl, Cr C6 alkoxy, C C6 alkylsulfanyl, CrC6 alkylsulfenyl, C C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aryl, heteroaryl, heterocyclyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halo, and C C6 perfluoroalkyl, multiple degrees of substitution being allowed. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.
As used herein, the term "Cι_C3 alkylene" refers to an alkylene group, as defined above, which contains at least 1 , and at most 3, carbon atoms respectively. Examples of "C1-C3 alkylene" groups useful in the present invention include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, and the like.
As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) and the term "halo" refers to the halogen radicals: fluoro (-
F), chloro (-CI), bromo(-Br), and iodo(-l).
As used herein, the terms "C1-C3 haloalkyl" and "Cι.C6 haloalkyl" refer to an alkyl group as defined above containing at least 1 , and at most 3 or 6 carbon atoms respectively substituted with at least one halo group, halo being as defined herein.
Examples of such branched or straight chained haloalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more halos, e.g., fluoro, chloro, bromo and iodo.
As used herein, the term "C^Cs hydroxyoalkyl" refers to an alkyl group as defined above containing at least 1 , and at most 3 carbon atoms substituted with at least one hydroxy group, hydroxy being as defined herein. Examples of such branched or straight chained C1.C3 hydroxyloalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, and isopropyl substituted independently with one or more hydroxy groups, e.g., -OH.
As used herein, the term "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring containing from 3 to 10 carbon atoms and which optionally includes a C^C-3 alkylene linker through which it may be attached. In a like manner the term "C3.C7 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from three to seven carbon atoms optionally substituted with substituents selected from the group which includes Cι.C6 alkyl, Cι_C6 alkoxy,
Figure imgf000009_0001
alkylsulfanyl, Cι-C6 alkylsulfenyl, Ci.C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halo, Cι.C6 perfluoroalkyl, multiple degrees of substitution being allowed and which optionally includes a C1.C3 alkylene linker through which it may be attached. The C1-C3 alkylene group is as defined above. Exemplary "C3-C7 cycloalkyl" groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. As used herein, the term "C3.C cycloalkylene" refers to a non-aromatic alicyclic divalent hydrocarbon radical having from three to seven carbon atoms, optionally substituted with substituents selected from the group which includes Cι.C6 alkyl,
Figure imgf000009_0003
alkylsulfanyl, Cι_C6 alkylsulfenyl,
Figure imgf000009_0002
alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halo, C^ perfluoroalkyl, multiple degrees of substitution being allowed. Examples of "cycloalkylene" as used herein include, but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1 ,2-diyl, cyclobutyl-1 ,2-diyl, cyclopentyl-1 ,3-diyl, cyclohexyl-1 ,4-diyl, cycloheptyl-1 ,4-diyl, or cyclooctyl-1 ,5-diyl, and the like.
As used herein, the term "heterocyclic" or the term "heterocyclyl" refers to a three to twelve-membered non-aromatic heterocyclic ring, being saturated or having one or more degrees of unsaturation, containing one or more heteroatom substitutions selected from S, S(O), S(0)2, O, or N, optionally substituted with substituents selected from the group consisting of Cι.C6 alkyl, Cι-C6 alkoxy, Cι-C6 alkylsulfanyl, Cι.C6 alkylsulfenyl, Cι.C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, alkylcarboxyamide, carboxyamide, aminosulfonyl optionally substituted by alkyl, ureido, arylurea, arylthiourea, alkylurea, cycloalkylurea, sulfonylurea, nitro, cyano, halo, aryl, aralkyl, heteroaryl, or Cι.C6 perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more other "heterocyclic" ring(s) or cycloalkyl ring(s). Examples of "heterocyclic" moieties include, but are not limited to, tetrahydrofuranyl, pyranyl, 1 ,4-dioxanyl, 1 ,3-dioxanyl, piperidinyl, piperazinyl, 2,4-piperazinedionyl, pyrrolidinyl, pyrrolidinon-2-yl, pyrrolidinon-3-yl, pyrrolidinon-4-yl, pyrrolidinon-5-yl, imidazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, tetrahydrothiopyranyl tetrahydrothiophenyl, and the like.
As used herein, the term "heterocyclylene" refers to a non-aromatic three to twelve-membered heterocyclic ring diradical being unsaturated or having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO2, O, or N, optionally substituted with substituents selected from the group which includes C-|.C6 alkyl, C-i_C6 alkoxy, Cι.C6 alkylsulfanyl, d.C6 alkylsulfenyl, d- -6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, alkylcarboxyamide, carboxyamide, aminosulfonyl optionally substituted by alkyl, ureido, arylurea, arylthiourea, alkylurea, cycloalkylurea, sulfonylurea, nitro, cyano, halo and d-C6 perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more benzene rings or to one or more of another "heterocyclic" rings or cycloalkyl rings. Examples of "heterocyclylene" include, but are not limited to, tetrahydrofuran- 2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl, 1 ,4-dioxane-2,3-diyl, 1 ,3-dioxane-2,4- diyl, piperidine-2,4-diyl, piperidine-1 ,4-diyl, pyrrolidine-1 ,3-diyl, pyrrolidinon-2,3-yl, pyrrolidinon-2,4-yl, pyrrolidinon-2,5-yl, pyrrolidinon-3,4-yl, pyrrolidinon-3,5-yl, pyrrolidinon-4,5-yl, morpholine-2,4-diyl, and the like.
As used herein, the term "aryl" refers to an optionally substituted benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings or fused to one or more cycloalkyl ring(s) to form, for example, anthracene, phenanthrene, napthalene, indan ring systems. Exemplary optional substituents include d.C6 alkyl, Cι.C6 alkoxy, d.C6 haloalkyl, C C6 haloalkoxy, d.C6 alkylsulfanyl, Ci.Ce alkylsulfenyl, Ci-ds alkylsulfonyl, Cι-C6 alkylsulfonylamino, arylsulfonoamino, alkylcarboxy, alkylcarboxyamide, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carboxamide, carbamoyl optionally substituted by alkyl, aminosulfonyl, acyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo, heteroaryl, heterocyclyl, aryl, ureido, arylurea, alkylurea, cycloalkylurea, alkylthiourea, aryloxy, or aralkoxy, multiple degrees of substitution being allowed. Examples of "aryl" groups include, but are not limited to, indanyl, phenyl, 2-naphthyl, 1 -naphthyl, biphenyl, as well as substituted derivatives thereof.
As used herein, the term "arylene" refers to a benzene ring diradical or to a benzene ring system diradical fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group which includes Cι-C6 alkyl, d.C6 alkoxy, aryloxy, heteroaryloxy, Cι.C6 alkylsulfanyl, Cι-C6 alkylsulfenyl, Ci.Ce alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo, d.C6 perfluoroalkyl, heterocyclyl, heterocyclic spiro ring system, heteroaryl and aryl, multiple degrees of substitution being allowed. Examples of "arylene" include, but are not limited to, benzene-1 ,4-diyl, naphthalene-1 ,8-diyl, anthracene-1 ,4-diyl, and the like.
As used herein, the term "aralkyl" refers to an aryl or heteroaryl group, as defined herein, attached through a d_C3 alkylene linker, wherein the Cι_C3 alkylene is as defined herein. Examples of "aralkyl" include, but are not limited to, benzyl, phenylpropyl, 2-pyτidylmethyl, 3-isoxazolylmethyl, 5-methyl-3-isoxazolylmethyl, and
2-imidazolyl ethyl.
As used herein, the term "heteroaryl" refers to a monocyclic five to seven membered aromatic ring, or to a fused bicyclic or tricyclic aromatic ring system comprising two of such monocyclic five to seven membered aromatic rings. These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen heteroatoms, where N-oxides and sulfur oxides and dioxides are permissible heteroatom substitutions and may be optionally substituted with up to three members selected from a group consisting of d.C6 alkyl, Ci.Ce alkoxy, Cι.C6 haloalkyl, C C6 haloalkoxy, d.C6 alkylsulfanyl, Cι.C6 alkylsulfenyl, Ci.Ce alkylsulfonyl, Cι-C6 alkylsulfonylamino, arylsulfonoamino, alkylcarboxy, alkylcarboxyamide, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carboxamide, carbamoyl optionally substituted by alkyl, aminosulfonyl, acyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo, heteroaryl, heterocyclyl, aryl, ureido, arylurea, alkylurea, cycloalkylurea, alkylthiourea, aryloxy, or aralkoxy, multiple degrees of substitution being allowed. Examples of "heteroaryl" groups used herein include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinazolinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzimidazolyl, benzothiophenyl, indolyl, indazolyl, and substituted versions thereof.
As used herein, the term "heteroarylene" refers to a five - to seven - membered aromatic ring diradical, or to a polycyclic heterocyclic aromatic ring diradical, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N- oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of: Cι.C6 alkyl, d.C6 alkoxy, aryloxy, heteroaryloxy, Cι.C6 alkylsulfanyl, Ci- C6 alkylsulfenyl, Cι.C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo, Ci.Ce perfluoroalkyl, heterocyclyl, heterocyclic spiro ring system, heteroaryl, or aryl, multiple degrees of substitution being allowed. For polycyclic aromatic ring system diradicals, one or more of the rings may contain one or more heteroatoms. Examples of "heteroarylene" used herein are furan-2,5-diyl, thiophene-2,4-diyl, 1 ,3,4-oxadiazole- 2,5-diyl, 1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl, 1 ,3-thiazole-2,5-diyl, pyridine- 2,4-diyl, pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the like.
As used herein, the term "alkoxy" refers to the group RaO-, where Ra is alkyl as defined above and the terms "C1.C3 alkoxy" and "Ci.Ce alkoxy" refer to an alkoxy group as defined herein wherein the alkyl moiety contains at least 1 , and at most 3 or 6, carbon atoms. Exemplary "C1.C3 alkoxy" and "Ci.Ce alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.
As used herein, the term "hydroxy" refers to the group -OH.
As used herein, the term "amino" refers to the group -NH2.
As used herein the term "alkylamino" refers to the group -NHRa wherein Ra is alkyl as defined above.
As used herein the term "arylamino" refers to the group -NHRa wherein Ra is aryl as defined above.
As used herein the term "aralkylamino" refers to the group -NHRa wherein Ra is an aralkyl group as defined above.
As used herein the term "aralkoxy" refers to the group RbRaO-, where Ra is alkylene and Rb is aryl or heteroaryl all as defined above. As used herein the term "aryloxy" refers to the group RaO-, where Ra is aryl or heteroaryl both as defined above.
As used herein the term "ureido" refers to the group -NHC(0)NH2 As used herein, the term "arylurea" refers to the group -NHC(0)NHRaRb wherein Ra is aryl or heteroaryl and Rb is -H, alkyl, or aryl as defined above.
As used herein, the term "arylthiourea" refers to the group -NHC(S)NHRa wherein Ra is aryl as defined above.
As used herein, the term "alkylurea" refers to the group -NHC(0)NRaRb wherein Ra is alkyl and R is -H or alkyl as defined above.
As used herein, the term "cycloalkylurea" refers to the group -NHC(O)NHRa wherein Ra is cycloalkyl as defined above. As used herein, the term "sulfonylurea" refers to the group -N(H)S(O)2N(H)-.
As used herein, the term "haloalkoxy" refers to the group RaO-, where Ra is haloalkyl as defined above and the term "d.C6 haloalkoxy" refers to a haloalkoxy group as defined herein wherein the haloalkyl moiety contains at least 1 , and at most
6, carbon atoms. Exemplary d.C6 haloalkoxy groups useful in the present invention include, but is not limited to, trifluoromethoxy. As used herein, the term "alkylsulfanyl" refers to the group RaS-, where Ra is alkyl as defined above and the term "Cι-C6 alkylsulfanyl" refers to an alkylsulfanyl group as defined herein wherein the alkyl moiety contains at least 1 , and at most 6, carbon atoms. As used herein, the term "haloalkylsulfanyl" refers to the group RaS-, where
Ra is haloalkyl as defined above and the term "Cι.C6 haloalkylsulfanyl" refers to a haloalkylsulfanyl group as defined herein wherein the alkyl moiety contains at least 1 , and at most 6, carbon atoms. As used herein, the term "alkylsulfenyl" refers to the group RaS(0)-, where Ra is alkyl as defined above and the term "d.C6 alkylsulfenyl" refers to an alkylsulfenyl group as defined herein wherein the alkyl moiety contains at least 1 , and at most 6, carbon atoms. As used herein, the term "alkylsulfonyl" refers to the group RaS(0)2-, where Ra is alkyl as defined above and the term "Cι-C6 alkylsulfonyl" refers to an alkylsulfonyl group as defined herein wherein the alkyl moiety contains at least 1 , and at most 6, carbon atoms. As used herein, the term "alkylsulfonylamino" refers to the group -
NR S(0)2Ra wherein Ra is alkyl and Rb is -H or d.C6 alkyl as defined above, and the term "Ci.Ce alkylsulfonylamino" refers to an alkylsulfonylamino group as defined herein wherein the alkyl moiety contains at least 1 , and at most 6, carbon atoms. As used herein, the term "arylsulfonylamino" refers to the group -NRbS(0)2Ra wherein Ra is aryl or heteroaryl and R is -H or d.C6 alkyl as defined above.
As used herein, the term "alkylcarboxyamide" refers to the group -NHC(0)Ra wherein Ra is alkyl, amino, or amino substituted with alkyl, aryl or heteroaryl as described above.
As used herein the term "alkylcarboxy" refers to the group -C(0)Ra wherein Ra is alkyl as described above.
As used herein, the term "oxo" refers to the group =0.
As used herein, the term "mercapto" refers to the group -SH. As used herein, the term "carboxy" refers to the group -C(0)ORa, wherein Ra is H or alkyl as defined herein.
As used herein, the term "cyano" refers to the group -CN. As used herein the term "cyanoalkyl" refers to the group -RaCN wherein Ra is alkyl as defined above. Exemplary "cyanoalkyl" groups useful in the present invention include, but are not limited to, cyanomethyl, cyanoethyl, and cyanoisopropyl.
As used herein, the term "aminosulfonyl" refers to the group -S(O)2RaRb wherein Ra and Rb are independently H, C C6alkyl, aryl, aralkyl, or heteroaryl.
As used herein, the term "carbamoyl" refers to the group -OC(0)NHRa. where Ra is hydrogen or alkyl as defined herein. As used herein, the term "carboxamide" refers to the group -C(O)NRaRb wherein Ra and Rb are independently H, C C6alkyl, aryl, aralkyl, or heteroaryl.
As used herein, the term "sulfanyl" shall refer to the group -S-. As used herein, the term "sulfenyl" shall refer to the group -S(O)-. As used herein, the term "sulfonyl" shall refer to the group -S(O)2- or -S02-.
As used herein, the term "acyl" refers to the group RaC(0)-, where Ra is alkyl, cycloalkyl, or heterocyclyl as defined herein.
As used herein, the term "aroyl" refers to the group RaC(O)- , where Ra is aryl as defined herein. As used herein, the term "aroylamino" refers to the group RaC(0)NH- , where
Ra is aryl as defined herein.
As used herein, the term "heteroaroyl" refers to the group RaC(0)- , where Ra is heteroaryl as defined herein.
As used herein, the term "alkoxycarbonyl" refers to the group RaOC(0)-, where Ra is alkyl as defined herein.
As used herein, the term "acyloxy" refers to the group RaC(0)O- , where Ra is alkyl, cycloalkyl, or heterocyclyl as defined herein.
As used herein, the term "aroyloxy" refers to the group RaC(0)0- , where Ra is aryl as defined herein. As used herein, the term "heteroaroyloxy" refers to the group RaC(0)0- , where Ra is heteroaryl as defined herein.
As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.
As used herein, the term "physiologically functional derivative" refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1 : Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives.
As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt or physiologically functional derivative thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
As used herein, the term "substituted" refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated. Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. The compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I) above as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, it is understood that any tautomers and mixtures of tautomers of the compounds of formula (I) are included within the scope of the compounds of formula (I).
It is to be understood that reference to compounds of formula (I), (I'), or (I") above, following herein, refers to compounds within the scope of formula I, I', or I" as defined above with respect to A1, A2, m, n, q, r, R', R", R'", R"", R1, R2, R3, Z, Z1, Z2, Q, Q1, and Q2 unless specifically limited otherwise. In one embodiment, A1 is S and A2 is CH. In another embodiment, A1 is CH and A2 is S.
It is understood that the bonds of Formula (I) between A1 and A2 each (see arrows in partial formula (I) following)
Figure imgf000018_0001
represent either single or double bonds. As is understood by those skilled in the art and specifically illustrated in the working examples following (for instance see Examples 1 and 24) such bonds will each be independently a single or double bond depending on which of A1 or A2 is sulfur.
It is also understood that substituent bonding locations having an unfilled
, ^ valence are indicated by " ", where it is understood that the unfilled valence is filled by attachment to the remainder of the molecule. The appropriate attachments are further illustrated in the working examples recited below.
As recited above, R1 is the group defined by -(Z)-(Z1)m-(Z2)n. In one embodiment, Z is hetercyclyl and m and n are each 0. In another embodiment, Z is heterocyclyl and m is 0 and n is 0, where the heteroclyclyl group is selected from
Figure imgf000018_0002
In an alternative embodiment, Z is heterocyclylene, Z1 is OC(O) and m is 1 , n is 1 and Z2 is heterocyclyl. In another alternative embodiment, Z is
Figure imgf000018_0003
Z1 is OC(O), and
Z2 is
Figure imgf000019_0001
Z2 is N(H)R', wherein R' is C1-C3 alkyl.
In another alternative embodiment, Z is heterocyclylene, Z1 is C(O) and m is 1 , n is 1 and Z2 is C1-C3 haloalkyl. In an alternative embodiment, Z is
Figure imgf000019_0002
Z1 is C(O), and
Z 72 is C C3 haloalkyl, preferably -CF3.
In another embodiment, Z is heterocyclylene, m is 0, n is 1 and Z2 is heterocyclyl. In one embodiment, Z is
Figure imgf000019_0003
m is 0, and Z2 is
Figure imgf000019_0004
Z2 is C1-C3 alkyl, or
Z2 is -OH, or
Z2 is - OR' where R' is C C3 alkyl, preferably -CH3, or
Z2 is halo, preferably -F, or Z2 is C1-C3 hydroxyalkyl, preferably -CH3OH or In one embodiment, R2 is -H. In another embodiment, R2 is C C3 alkyl.
As recited above, R3 is the group defined by -(Q)-(Q1)r-(Q2)t. In one embodiment, Q is arylene, Q1 is O and r is 1 , and Q2 is aralkyl, aryl, or heteroaryl. In another embodiment, Q is
Figure imgf000020_0001
wherein R4 is halo, preferably -Cl or -F, Q1 is O and r is 1 , and Q2 is selected from
Figure imgf000020_0002
wherein each R5 is independently halo, preferably -F, -Cl, or -Br.
In one embodiment, Q is arylene or heteroarylene, Q1 is S and r is 1 , and Q2 is aryl. In one embodiment, Q is
Figure imgf000020_0003
wherein R4 is halo, preferably -Cl or -F, Q1 is S and r is 1 , Q2 is
Figure imgf000021_0001
In one embodiment, Q is arylene or heteroarylene, Q1 is S(O)2 and r is 1 , and Q2is aryl or heteroaryl. In one embodiment, Q is
Figure imgf000021_0002
Q1 is S(0)2 and r is 1 , and Q2 is selected from
Figure imgf000021_0003
where R5 is halo, preferably -F.
In an alternative embodiment, Q is arylene or heteroarylene, r is 0, and Q2 is aralkyl. In one embodiment, Q is selected from
Figure imgf000021_0004
r is 0, and Q is selected from
Figure imgf000022_0002
preferably
Figure imgf000022_0001
Figure imgf000022_0003
where R is halo, preferably -F Specific examples of compounds of the present invention include the following:
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}pyrrolidin-3-yl morpholine-4-carboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}pyrrolidin-3-yl ethylcarbamate; -{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2S,4S)-4-morpholin-4-ylpyrrolidin-2- yl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2R,3S)-3-morpholin-4-ylpyrrolidin-2- yl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[(2S)-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
A/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[(2S)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2R)-1-methylpyrrolidinyl] ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(3-pyrrolidinylethynyl)thieno[3,2- d]pyrimidin-4-amine;
(3R,5S)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinol;
(3R,5R)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinol; Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2S,4R)-4-methoxypyrrolidinyl] ethynyl}thieno[3,2-d]pyrimidin-4-amine;
A/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2S,4S)-4-fluoropyrrolidinyl] ethynyl}thieno[3,2-d]pyrimidin-4-amine;
{(2S)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]pyrrolidinyl}methanol;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-(2-piperidinylethynyl)thieno[3,2- d]pyrimidin-4-amine;
[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-piperidin-3-ylethynyl-thieno[3,2- d]pyrimidin-4-yl)-amine;
6-[(2S)-2-azetidinylethynyl]-N-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-d]pyrimidin-4-amine;
Λ/-(3-Chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(trifluoroacetyl)-2- pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(morpholin-3-ylethynyl)thieno[3,2- d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[2,3- d]pyrimidin-4-amine;
A/-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[3-chloro-4-(1-naphthyloxy)phenyl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[5-(2-pyridinyloxy)-2-naphthalenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
A/-[1-(3-fluorobenzyl)-1 H-indazol-5-yl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[1-(phenylmethyl)-1 H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
6-[(2R)-2-pyrrolidinylethynyl]-Λ/-[1-(1 ,3-thiazol-4-ylmethyl)-1 H-indazol-5-yl]thieno[3,2- d]pyrimidin-4-amine; Λ/-{3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}-6-[(2R)-2-pyrrolidinylethynyl] thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(1-benzyl-1 H-indazol-5-yl)amino]thieno[3,2-d]pyrimidin-6- yl}ethynyl)pyrrolidin-3-yl morpholine-4-carboxylate;
Λ/-[2-(3-fluorobenzyl)-1 H-benzimidazol-5-yl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine; Λ/-(3-chloro-4-{[(1 R)1 -(3-fluorophenyl)ethyl]oxy}phenyl)-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-[4-(phenylsulfonyl)phenyl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2-d]pyrimidin-4- amine;
Λ/-[3-chloro-4-(1 ,3-thiazol-2-ylthio)phenyl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine;
A/-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[1-(2,5-difluorobenzyl)-1H-indol-5-yl]-6-[(2R)-pyrrolidin-2-ylethynyl] thieno[3,2d]pyrimidin-4-amine;
Λ/-{1-[(3-fluorophenyl)sulfonyl]-1H-indol-5-yl}-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine; and
/V-(4-benzylphenyl)-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2-d]pyrimidin-4-amine;
or a salt, solvate, or physiologically functional derivative thereof.
Additional specific examples of compounds of the present invention include the following: Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(1-methyl-2- piperidinyl)ethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-(3-pyrrolidinylethynyl)thieno[2,3- d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-(3-piperidinylethynyl)thieno[2,3- d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2S)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine; (3R,5S)-5-[(4-{[1-methyl-2-(phenylmethyl)-1H-benzimidazol-5-yl]amino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinol;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-(2-piperidinylethynyl)thieno[2,3- d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(2,5-difluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(4S)-1 ,3-thiazolidin-4- ylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-[2-(phenylmethyl)-1H-benzimidazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[3-chloro-4-(phenyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin- 4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[((2S,4R)-4-{[2-(4- morpholinyl)ethyl]oxy}-2-pyrrolidinyl)ethynyl]thieno[3,2-d]pyrimidin-4-amine;
A/-{1-[(3-fluorophenyl)methyl]-1 H-indol-5-yl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine; Λ/-[1 -(phenylmethyl)-l H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
(3S,5S)-5-[(4-{[3-chloro-4-(1-naphthalenyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinol;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinol;
Λ/-[1 -(2-pyridinylmethyl)-1 H-benzimidazol-5-yl]-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinol; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2S)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinol;
Λ/-(3-fluoro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3-chloro-4-{[(3-fluorophenyl)methyl]amino}phenyl){6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-yl}amine; Λ/-[1-(phenylsulfonyl)-1 H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[1-(phenylmethyl)-1H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-{1-[(3,5-difluorophenyl)methyl]-1H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine; Λ/-[1-(2-pyridinylmethyl)-1 H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-{1-[(2-methyl-1,3-thiazol-4-yl)methyl]-1H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyi]thieno[3,2-d]pyrimidin-4-amine;
0-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl] [3-(4-morpholinyl)propyl]thiocarbamate;
4-(2,3-dihydro-1 H-indol-1-yl)-6-(2-pyrrolidinylethynyl)thieno[3,2-d]pyrimidine;
Λ/-(4-{[(2,5-difluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[2-(phenylmethyl)-1 ,3-benzothiazol-6-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[2-(phenylmethyl)-1,3-benzothiazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine; A/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(4-methyl-3- morpholinyl)ethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-{1-[1-(3-fluorophenyl)ethyl]-1H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
A/-(3-chloro-4-{[(2-methyl-1,3-thiazol-4-yl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine; phenyl[4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- yl}amino)phenyl]methanone;
Λ/-(3-chloro-4-{[(1 S)-1 -(3-fluorophenyl)ethyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine; Λ/-{3-chloro-4-[(6-fluoro-4-quinolinyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-{2-[(2,5-difluorophenyl)methyl]-1 H-benzimidazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-(1-methyl-1H-indazol-5-yl)-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- amine; _-b
Λ/-{3-chloro-4-[(3-fluorophenyl)oxy]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1-piperidinecarboxylate;
Λ/-[2-(phenylmethyl)-2H-indazol-6-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[1-(phenylmethyl)-1 H-indazol-6-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1-pyrrolidinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl methyl(phenyl)carbamate; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{4-[(methylsulfonyl)methyl]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyhmidin-4-amine;
6-[(2R)-2-pyrrolidinylethynyl]-N-[1-(2-thienylsulfonyl)-1 H-indol-5-yl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[1-(methylsulfonyl)-1 H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(6-methyl-2-pyridinyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine; Λ/2-(4-fluorophenyl)-Λ/°-{6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-yl}-1H- benzimidazole-2,5-diamine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-djpyrimidin-4-amine;
Λ/-[1-(cyclohexylmethyl)-1 H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-(2-phenyl-1 H-benzimidazol-5-yl)-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[(2,3-dichlorophenyl)methyl]-6-(2-pyrrolidinylethynyl)thieno[3,2-d]pyrimidin-4- amine; Λ/-[1 -(phenylsulfonyl)-2,3-dihydro-1 H-indol-5-yl]-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl diethylcarbamate;
Λ/-[4-(phenylmethyl)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4- amine; Λ/-[1 -(phenylmethyl)-2,3-dihydro-1 H-indol-5-yl]-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2R)-2-pyrrolidinylethynyl]-N-[1-(2-thienylsulfonyl)-2,3-dihydro-1 H-indol-5- yl]thieno[3,2-d]pyrimidin-4-amine;
4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-yl}amino)-N-1 ,3-thiazol-2- ylbenzenesulfonamide;
Λ/-{1-[(2-fluorophenyl)sulfonyl]-2,3-dihydro-1H-indol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-pyridinylmethyl)oxy]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyhmidin-4-amine; 3-({[2-chloro-4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- yl}amino)phenyl]oxy}methyl)-1 l5-pyridin-1-ol;
Λ/-{1-[(2-fluorophenyl)methyl]-2,3-dihydro-1 H-indol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-[1-(phenylmethyl)-4-piperidinyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin- 4-amine;
Λ/-{1 -[(5-chloro-1 ,2,3-thiadiazol-4-yl)methyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(5-chloro-1 ,2,3-thiadiazol-4-yl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine; Λ/-(3-fluoro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
1-phenyl-2-[4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- yl}amino)phenyl]ethanone;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1-[2-(methyloxy)ethyl]-2- pyrrolidinyl}ethynyl)thieno[3,2-d]pyrimidin-4-amine;
6-{[(2R)-1-acetyl-2-pyrrolidinyl]ethynyl}-N-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-d]pyrimidin-4-amine; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(methylsulfonyl)-2- pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
6-[(2R)-2-pyrrolidinylethynyl]-N-[1 -(1 ,3-thiazol-4-ylmethyl)-1 H-indazol-5-yl]thieno[2,3- d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine; methyl (2R)-2-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-1-pyrrolidinecarboxylate;
A/-[(3-chlorophenyl)methyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- amine;
Λ/-{3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-fluorophenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-bromophenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyl 4-morpholinecarboxylate; (2R)-2-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-1-pyrrolidinecarbaldehyde;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(cyclopropylmethyl)-2- pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-[4-(1-piperidinylsulfonyl)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin- 4-amine;
Λ/-[4-chloro-2-(phenylmethyl)-1 H-benzimidazol-6-yl]-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1 -[(1 -methyl-1 H-pyrrol-2- yl)methyl]-2-pyrrolidinyl}ethynyl)thieno[3,2-d]pyrimidin-4-amine; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1-[3-(dimethylamino)-2,2- dimethylpropyl]-2-pyrrolidinyl}ethynyl)thieno[3,2-d]pyrimidin-4-amine;
Λ/-[2-chloro-4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- yl}amino)phenyl]-3-fluorobenzenesulfonamide;
/V-{1-[(phenylmethyl)sulfonyl]-2,3-dihydro-1 H-indol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
2-{[5-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-yl}amino)-2,3-dihydro- 1 H-indol-1 -yl]sulfonyl}benzonitrile; 6-[(2R)-2-pyrrolidinylethynyl]-N-[1-(2-thienylsulfonyl)-1 H-indol-5-yl]thieno[2,3- d]pyrimidin-4-amine;
(3R,5S)-5-{[4-({3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{1-[1-(3-fluorophenyl)ethyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-aminee; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1 -[(1 - methylethyl)sulfonyl]-2-pyrrolidinyl}ethynyl)thieno[3,2-d]pyrimidin-4-amine;
2-(methyloxy)ethyl (2R)-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-1- pyrrolidinecarboxylate;
/V-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(2,2,3,3,3- pentafluoropropanoyl)-2-pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[((2R)-1 -{[5-chloro-1 -methyl-3- (trifluoromethyl)-1 H-pyrazol-4-yl]methyl}-2-pyrrolidinyl)ethynyl]thieno[3,2-d]pyrimidin- 4-amine;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl (3,5-dimethyl-4-isoxazolyl)carbamate; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(3,3,3-trifluoropropyl)-2- pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl (l-methylethyl)carbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1-[2- (methylsulfonyl)ethyl]-2-pyrrolidinyi}ethynyl)thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-fluoro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate; 2-fluoroethyi (2R)-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-1- pyrrolidinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-thienylsulfonyl)amino]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; Λ/-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[2-chloro-4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4- yl}amino)phenyl]-3-fluorobenzenesulfonamide;
Λ/-[1-(2-phenylethyl)-1 H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine; Λ/-[1 -(cyclohexylmethyl)-l H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
6-[(2R)-2-pyrrolidinylethynyl]-N-(4-{[3-(trifluoromethyl)phenyl]thio}phenyl)thieno[3,2- d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl [2-(methylsulfonyl)ethyl]carbamate;
Λ/-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
Λ/-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-methyl-1-piperazinecarboxylate;
Λ/-{[2,3-bis(methyloxy)phenyl]methyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[(2-chlorophenyl)methyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- amine;
Λ/-{[3-(methyloxy)phenyl]methyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin- 4-amine;
Λ/-[(2-fluorophenyl)methyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- amine; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
Λ/-[3-chloro-4-(phenylthio)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin- 4-amine;
(3R,5S)-5-[(4-{[1-(2-phenylethyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-[(4-{[1-(cyclohexylmethyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{1 -[(2-fluorophenyl)methyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine; 6-{[(2S,4S)-4-fluoro-2-pyrrolidinyl]ethynyl}-N-[1 -(phenylmethyl)-l H-indazol-5- yl]thieno[2,3-d]pyrimidin-4-amine;
(3R,5S)-5-[(4-{[1-(2-thienylsulfonyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
N-(3-chloro-4-{[(6-methyl-2-pyridinyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-{[4-({1-[(2-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; Λ/-{1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[1 -(1 ,3-thiazol-4-ylmethyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin- 6-yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[3-fluoro-1-(phenylmethyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin- 6-yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-[1-(phenylmethyl)-1 H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine; (3R,5S)-5-[(4-{[1 -(phenylmethyl)-l H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl [2-(4-morpholinyl)ethyl]carbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl [2-(1 -piperidinyl)ethyl]carbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl [2-(1-piperidinyl)ethyl]carbamate;
Λ/-[3-chloro-4-(1 ,3-thiazol-2-ylthio)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine; Λ/-[3-fluoro-1-(phenylmethyl)-1 H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
/V-[3-chloro-4-(phenylthio)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-d]pyrimidin- 4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl carbamate; Λ/-[4-(2-pyridinylthio)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4- amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl methylcarbamate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-{[4-({3-chloro-4-[(phenylthio)methyl]phenyl}amino)thieno[3,2-d]pyrimidin-6- yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(6-{[(3-fluorophenyl)methyl]oxy}-3-pyridinyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-{[4-({3-chloro-4-[(phenylsulfonyl)methyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
6-[(2R)-2-pyrrolidinylethynyl]-N-[1-(1 ,3-thiazol-4-ylmethyl)-1 H-indol-5-yl]thieno[2,3- d]pyrimidin-4-amine;
Λ/-[(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]methanesulfonamide;
Λ/-(3-chloro-4-{[(2-chloro-3-pyridinyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine; (3R,5S)-5-[(4-{[3-chloro-4-(phenylthio)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{1 -[(3-fluorophenyl)sulfonyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
(3R,5S)-5-{[4-({3-chloro-4-[(1 ,3-thiazol-2-ylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)sulfonyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; Λ/-{3-chloro-4-[(1 ,3-thiazol-2-ylmethyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinecarbonitrile;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate; Λ/-{3-chloro-4-[(phenylthio)methyl]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(phenylsulfonyl)methyl]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
A/-(6-{[(3-fluorophenyl)methyl]oxy}-3-pyridinyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[3-(methyloxy)phenyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2,3-difluorophenyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-[(4-{[5-(2-pyridinyloxy)-2-naphthalenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(6-fluoro-4-quinolinyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-(6-{[(2,5-difluorophenyl)methyl]oxy}-3-pyridinyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinecarbonitrile;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4S)-4-fluoro-2- pyrrolidinyl]ethynyl}thieno[2,3-d]pyrimidin-4-amine; (3S,5R)-5-{[4-({3,3-difluoro-1 -[(2-fluorophenyl)methyl]-2-oxo-2,3-dihydro-1 H-indol-5- yl}amino)thieno[3,2-d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-(6-{[(2-fluorophenyl)methyl]oxy}-3-pyridinyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinol; ethyl (2S,4S)-2-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-4-{[(ethyloxy)carbonyl]amino}-1-pyrrolidinecarboxylate; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethyl carbonate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 2-(methyloxy)ethyl carbonate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 3-(methylsulfonyl)propanoate; ethyl [(3S,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate; methyl [(3S,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl methanesulfonate;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4R)-4-(ethyloxy)-2- pyrrolidinyl]ethynyl}thieno[2,3-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 3-(methylthio)propanoate;
Λ/-(3-chloro-4-{[(4-chloro-2-pyridinyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl methanesulfonate;
6-{[(2S,4S)-4-azido-2-pyrrolidinyl]ethynyl}-N-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-d]pyrimidin-4-amine;
Λ/-[(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-4-morpholinecarboxamide;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinol;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4R)-4-(ethyloxy)-2- pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine; (3R,5S)-5-[(4-{[1 -(phenylmethyl)-l H-indazol-5-ylJamino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1-pyrrolidinecarboxylate;
(5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinone; (5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-2-pyrrolidinone;
(5S)-5-{[4-({3-chloro-4-[(1,3-thiazol-4-ylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-2-pyrrolidinone;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl methanesulfonate;
(3R,5S)-5-[(4-{[1 -(1 ,3-thiazol-4-ylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(3,5-difluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(2-methyl-1 ,3-thiazol-4- yl)methyi]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4- morpholinecarboxylate;
(3R,5S)-5-{[4-({1 -[(5-chloro-1 ,2,3-thiadiazol-4-yl)methyl]-1 H-indazol-5- yl}amino)thieno[3,2-d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1 -[1 -(3-fluorophenyl)ethyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[4-(2-pyridinylthio)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-3- pyrrolidinyl 4-morpholinecarboxylate; Λ/-{3-chloro-4-[(3-fluorophenyl)thio]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)thio]phenyl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate; (3R,5S)-5-{[4-({3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{3-chloro-4-[(3-methylphenyl)thio]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl propanoate; (3R,5S)-5-{[4-({3-chloro-4-[(3-methylphenyl)thio]phenyl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate; (3R,5R)-5-[(4-{[1 -(phenylmethyl)-l H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate; (3R,5R)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate; ύf
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl )ethynyl]-3-pyrrol id i nyl ethylcarbamate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate; (3R,5S)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyhmidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate; (3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-'pyrrolidinyl 4-thiomorpholinecarboxylate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate; (3S,5S)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate; (3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate; (3R,5R)-5-[(4-{[1 -(phenylmethyl)-l H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyhmidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate; (3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate; (3S,5R)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-({4-[(3-chIoro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-[(4-{[4-(phenylmethyl)phenyl]amino}thieno[3,2-dj|pyrimidin-6-yl)ethynyl]-3- pyrrolidinyl 4-morpholinecarboxylate;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4S)-4-(4- morpholinylmethyl)-2-pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4S)-4-(4- morpholinylmethyl)-2-pyrrolidinyl]ethynyl}thieno[2,3-d]pyrimidin-4-amine;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate; (3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate; (3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-djpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate; (3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate; (3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -piperidinecarboxylate;
(3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate; (3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate; (3S,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate; (3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate; (3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate; (3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1-piperazinecarboxylate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -piperazinecarboxylate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyi 4-thiomorpholinecarboxylate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyhmidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; Λ/-{[3-(phenyloxy)phenyl]methyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-d]pyrimidin- 4-amine;
(3R,5S)-5-{[4-({[3-(phenyloxy)phenyl]methyl}amino)thieno[3,2-d]pyrimidin-6- yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-thiomorpholinecarboxylate 1 ,1 -dioxide;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -piperidinecarboxylate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; (3S,5R)-5-{[4-({1 -[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate;
(5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2-d]pyrimidin-6- yl]ethynyl}-2-pyrrolidinone;
(5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-2-pyrrolidinone; (3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate; and
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; or a salt, solvate, or physiologically functional derivative thereof.
Still further specific examples of compounds of the present invention include the following: '
(3S,5R)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]pyrrolidinyl dimethylcarbamate; {(2R,5R)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]pyrrolidinyl}methyl ethylcarbamate;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2R,5R)-5-(4- morpholinylmethyl)pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2R,5R)-5-(4- morpholinyimethyl)pyrrolidinyl]ethynyl}thieno[3,2-d]pyhmidin-4-amine;
A/-((3S,5R)-5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}pyrrolidin-3-yl)propanamide;
Λ/-{(3R,5S)-5-[(4-{[1-(2,5-difluorobenzyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]pyrrolidin-3-yl}ethanesulfonamide; (3S,5S)-5-({4-[(1 -benzyl-1 H-indazol-5-yl)amino]thieno[2,3-d]pyrimidin-6- yl}ethynyl)pyrrolidin-3-yl pyrrolidine-1 -carboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yI]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate; (3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-2-pyrrolidinone; (5S)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-2-pyrrolidinone;
(5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-2-pyrrolidinone;
(5S)-5-({4-[(6-{[(2,5-difluorophenyl)methyl]oxy}-3-pyridinyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinone;
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate; (3R,5S)-5-{[4-({1 -[(2,5-difluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3R,5R)-5-[(4-{[1 -(phenylmethyl)-l H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate; 4b
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethyl(methyl)carbamate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3S,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3S,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1-[1-(3-fluorophenyl)ethyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[1-(3-fluorophenyl)ethyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-[(4-{[4-(phenylsulfonyl)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-3- pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[3-chloro-4-(phenylsulfonyl)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinone; (5R)-5-[(4-{[1 -(phenylmethyl)-l H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-2-pyrrolidinone;
(5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2-d]pyrimidin- 6-yljethynyl}-2-pyrrolidinone;
(5R)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yi]ethynyl}-2-pyrrolidinone;
(5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2-d]pyrimidin-6- yl]ethynyl}-2-pyrrolidinone;
(3R,5S)-5-{[4-({3-fluoro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; ethyl [(3S,5R)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
Λ/-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide;
Λ/-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide; Λ/-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-A/'-ethylurea;
[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl ethylcarbamate;
A/-ethyl-tV-((3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5- yl}amino)thieno[3,2-d]pyrimidin-6-yi]ethynyl}-3-pyrrolidinyl)urea;
Ay-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-/V-ethylurea;
/V-((3R,5S)-5-{[4-({3-chloro-4-[(3-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- dJpyrimidin-e-yljethynylJ-S-pyrrolidiny -tV-ethylurea; (3R,5S)-5-{[4-({1 -[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate; Λ/-ethyl-/V-{(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinyl}urea;
Λ/-((3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)-/V-ethylurea; ethyl [(3R,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
Λ/-((3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)ethanesulfonamide;
A/-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
1-{[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl}-2,5-pyrrolidinedione; (3R,5S)-5-({4-[(3-chloro-4-{[(1-methylethyl)oxy]methyl}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(5-methyl-3-isoxazolyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[3-(trifluoromethyl)phenyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl}ethanesulfonamide; ethyl ((3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate; ethyl ((3R,5S)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate;
(3S,5R)-5-{[4-({3-chloro-4-[(5-methyl-3-isoxazolyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)oxy]methyl}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; (3S,5R)-5-{[4-({1 -[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate; [(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl dimethylcarbamate; ethyl ((3 5S)-5-{[4-({1 -[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate;
[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methanol; (5f?Jf?)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)tetrahydro-1 H-pyrrolo[1 ,2-c][1 ,3]oxazol-3-one;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R,5R)-5-(4- morpholinylmethyl)-2-pyrroIidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide;
Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-/V-ethylurea; ethyl [(3R,5R)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
Λ/-((3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)propanamide;
Λ/-((3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)propanamide; (3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyhdinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate;
(5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3-d]pyrimidin- 6-yl]ethynyl}-2-pyrrolidinone;
(5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[2,3-d]pyrimidin- 6-yl]ethynyl}-2-pyrrolidinone; (3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3f?,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl )ethynyl]-3-pyrrol id inyl 1 -pyrrolidinecarboxylate; (3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; ,
(3 5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5f?)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3 ?,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyhdinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5f?)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3S,5R)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5f?)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
A/-[(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide; ethyl [(3S,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyl]carbamate;
Λ/-[(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
^^^-^ -((SR.SSJ-S-^-^l-^S-fluoropheny methy -I H-indazol-S- yl}amino)thieno[2,3-d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)urea;
Λ/-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-N'-ethylurea; Λ/-((3R,5S)-5-{[4-({3-chloro-4-[(3-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)-Λ/'-ethylurea;
A/-ethyl-A -{(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinyl}urea; ethyl [(3R,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate; Λ/-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide; ethyl ((3R,5S)-5-{[4-({3-chloro-4-[(2-pyhdinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate; ethyl ((3R,5S)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate;
A/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yI}ethynyl)-3-pyrrolidinyl]propanamide;
Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-/V-ethylurea; Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide;
[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl ethylcarbamate;
[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl dimethylcarbamate; ethyl [(3S,5R)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
Λ/-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide; ethyl [(3R,5R)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyhmidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methanol;
Λ/-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-/V-ethylurea; ethyl ((3R,5S)-5-{[4-({1 -[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate; A/-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
(5RJR)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)tetrahydro-1 H-pyrrolo[1 ,2-c][1 ,3]oxazol-3-one;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R,5R)-5-(4- morpholinylmethyl)-2-pyrrolidinyl]ethynyl}thieno[2,3-d]pyrimidin-4-amine;
(4S)-4-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-2-azetidinone;
(4S)-4-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-2-azetidinone; (4S)-4-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-azetidinone; and
(4S)-4-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indol-5-yl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-2-azetidinone;
or a salt, solvate, or physiologically functional derivative thereof. Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen on a substituent in the compound of formula (I). Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N- methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium and valerate. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these form a further aspect of the invention. While it is possible that, for use in therapy, therapeutically effective amounts of a compound of formula (I), as well as salts, solvates and physiological functional derivatives thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions, which include therapeutically effective amounts of compounds of the formula (I) and salts, solvates and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or exeipients. The compounds of the formula (I) and salts, solvates and physiological functional derivatives thereof, are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I), or salts, solvates and physiological functional derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or exeipients. Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5mg to 1g, preferably 1mg to 700mg, more preferably 5mg to 100mg of a compound of the formula (I), depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, b4
magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. bo
Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
The compounds of formula (I), and salts, solvates and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds of formula (I) and salts, solvates and physiological functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide -phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For treatments of the eye or other external tissues, for example mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
Pharmaceutical formulations adapted for topical administration in' the mouth include lozenges, pastilles and mouth washes.
Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurised aerosols, nebulizers or insufflators. Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the human or other animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of a compound of formula (I) for the treatment of neoplastic growth, for example colon or breast carcinoma, will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70kg adult mammal, the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub- doses per day such that the total daily dose is the same. An effective amount of a salt or solvate, or physiologically functional derivative thereof, may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above. 08
The compounds of the present invention and their salts and solvates, and physiologically functional derivatives thereof, may be employed alone or in combination with other therapeutic agents for the treatment of the above-mentioned conditions. In particular, in anti-cancer therapy, combination with other chemotherapeutic, hormonal or antibody agents is envisaged as well as combination with surgical therapy and radiotherapy. Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and the use of at least one other cancer treatment method. Preferably, combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and at least one other pharmaceutically active agent, preferably an anti-neoplastic agent. The compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
The compounds of the Formula (I) or salts, solvates, or physiologically functional derivatives thereof and at least one additional cancer treatment therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination with such other anti-cancer therapies. In one embodiment, the other anti-cancer therapy is at least one additional chemotherapeutic therapy including administration of at least one anti-neoplastic agent. The administration in combination of a compound of formula (I) or salts, solvates, or physiologically functional derivatives thereof with other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one anti-neoplastic agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time. Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms.
Anti-neoplastic agents useful in combination with the compounds and salts, solvates or physiologically functional derivatives thereof of formula I include, but are not limited to, the following:
(1) cell cycle specific anti-neoplastic agents including, but not limited to, diterpenoids such as paclitaxel and its analog docetaxel; vinca alkaloids such as vinblastine, vincristine, vindesine, and vinorelbine; epipodophyllotoxins such as etoposide and teniposide; fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine ; antimetabolites such as allopuhnol, fludurabine, methotrexate, cladrabine, cytarabine, mercaptopurine and thioguanine; and camptothecins such as
9-amino camptothecin, irinotecan, CPT-11 and the various optical forms of 7-(4- methylpiperazino-methylene)-10,11 -ethylenedioxy-20-camptothecin; (2) cytotoxic chemotherapeutic agents including, but not limited to, alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine, and dacarbazine; anti-tumour antibiotics such as doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dacttino ycin and mithramycin; and platinum coordination complexes such as cisplatin, carboplatin, and oxaliplatin; and
(3) other chemotherapeutic agents including, but not limited to, anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene; progestrogens such as megestrol acetate; aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane; antiandrogens such as flutamide, nilutamide, bicalutamide, and cyproterone acetate; LHRH agonists and antagagonists such as goserelin acetate and luprolide, testosterone 5α-dihydroreductase inhibitors such as finasteride; metalloproteinase inhibitors such as marimastat; antiprogestogens; urokinase plasminogen activator receptor function inhibitors; cyclooxygenase type 2 (COX-2) inhibitors such as celecoxib; angiogenic inhibiting agents such as VEGFR ou
inhibitors and TIE-2 inhibitors; growth factor function inhibitors such as inhibitors of the functions of hepatocyte growth factor; platelet derived growth factor receptor (PDGFr), vascular endothelial growth factor receptor (VEGFR) and TIE-2; and other protein kinase inhibitors such as c-Raf, b-Raf, and cyclin dependent inhibitors such as CDK2 and CDK4 inhibitors.
The compounds of formula (I) and salts, solvates and physiological functional derivatives thereof, are believed to have anticancer activity as a result of inhibition of one or more erbB family protein kinase and its effect on selected cell lines whose growth is dependent on erbB family protein kinase activity.
The present invention thus also provides compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof, or physiologically functional derivatives thereof, for use in medical therapy, and particularly in the treatment of disorders mediated by inappropriate activity of one or more erbB family kinase.
The inappropriate erbB family activity referred to herein is any erbB kinase activity that deviates from the normal erbB family kinase activity expected in a particular mammalian subject. The inappropriate activity may arise from one or more of EGFR (erbB-1), erbB-2, or erbB-4. Inappropriate erbB family kinase activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of erbB family kinase activity. Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase or ligand leading to inappropriate or uncontrolled activation of the receptor. Furthermore, it is also understood that unwanted erbB family kinase activity may reside in an abnormal source, such as a malignancy. That is, the level of erbB family activity does not have to be abnormal to be considered inappropriate, rather the activity derives from an abnormal source. The present invention is directed to methods of regulating, modulating, or inhibiting one or more erbB family kinase for the prevention and/or treatment of disorders related to unregulated erbB family kinase activity. In particular, the compounds of the present invention can also be used in the treatment of certain forms of cancer. Furthermore, the compounds of the present invention can be used to provide additive or synergistic effects with certain existing cancer chemotherapies and radiation, and/or be used to restore effectiveness of certain existing cancer chemotherapies and radiation.
A further aspect of the invention provides a method of treatment of a mammal suffering from a disorder mediated by inappropriate one or more erbB family kinase activity, including susceptible malignancies, which includes administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or a physiologically functional derivative thereof. In a preferred embodiment, the disorder is cancer.
A further aspect of the invention provides a method of treatment of a mammal suffering from cancer, which includes administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof.
A further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, in the preparation of a medicament for the treatment of a disorder characterized by inappropriate activity of one or more erbB family kinase. In a preferred embodiment, the disorder is cancer.
A further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, in the preparation of a medicament for the treatment of cancer and malignant tumours.
The mammal requiring treatment with a compound of the present invention is typically a human being. In another embodiment, therapeutically effective amounts of the compounds of formula (I) or salts, solvates or physiologically derived derivatives thereof and agents which inhibit growth factor receptor function may be administered in combination to a mammal for treatment of a disorder mediated by inappropriate activity of one or more erbB family kinase, for instance in the treatment of cancer. Such growth factor receptors include, for example, PDGFR, VEGFR, TIE-2, as well as erbB family kinase inhibitors other than those described herein. Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10(6):803-818 and in Shawver et al DDT Vol 2, No. 2 February 1997.
The compounds of the Formula (I) or salts, solvates, or physiologically functional derivatives thereof and the agent for inhibiting growth factor receptor function may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination. The combination may be employed in combination in accordance with the invention by administration concomitantly in (1 ) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the Working Examples. Compounds of general formulae (II) and (III) may be prepared by methods known to those of skill in the art. The following synthetic schemes are meant to represent examples only and are not meant to limit the invention in any way. In all of the schemes described below, it is understood that protecting groups may be employed where necessary in accordance with general principles known to those of skill in the art, for example, see T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis. John Wiley & Sons. These groups may be removed at a convenient stage of the compound synthesis using methods known to those of skill in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formulae (II) and (III). Those of skill in the art will recognize that if a stereocenter exists in compounds of Formulas (II) and (III), the present invention is meant to include both enantiomers, mixtures of such enantiomers and the individual enantiomers substantially free of the opposite enantiomer. In addition, when a compound contains more than one stereocenter, one of skill in the art will recognize that the present invention is meant to include mixtures of diastereomeric compounds, mixtures of enantiomers and the individual enantiomers substantially free of the opposite enantiomer.
Scheme I
Figure imgf000064_0001
ArNr-L B ArNH,
Figure imgf000064_0002
The compounds of formula (I'), wherein R1, R2 and R3 are defined as above, may be prepared from the appropriate halogen-substituted thienopyrimidine by the general synthetic routes depicted as A and B shown above in Scheme (I). In step 1 of route A , the halogen-substituted thienopyrimidine is coupled with a terminal acetylenic compound. These reactions are generally performed in the presence of a palladium catalyst, bis(triphenylphosphine)palladium dichloride for example, a copper catalyst, copper(l) iodide for example, a base, triethylamine for example, a solvent, tetrahydrofuran (THF) for example, and at a temperature from 25 °C to 175 °C, preferably 50 °C to 60 °C. The resulting product may then be allowed to react with an arylamine to displace the 6-chloro substituent on the pyrimidine moiety. These displacement reactions are typically performed in a solvent, isopropanol for example, and at a temperature from 25 °C to 175 °C , preferably 50 °C to 80 °C. Alternatively, the compounds of formula (I') may be prepared by carrying out the displacement and coupling steps described above in reverse order using similar conditions. The appropriate halogen-substituted thienopyrimidines are either commercially available or may be prepared using methods known to those of skill in the art. For example, 6-bromo-4-chlorothieno[3,2-d]pyrimidine may be prepared by the procedure described in published PCT application number WO 99/24440. The arylamines are either commercially available or can be prepared by methods known to those skilled in the art. For example, see the methods described in United States Patents 6,174, 883 and 6,207,669, which are hereby incorporated by reference to the extent that they teach methods for the preparation of arylamines useful in the preparation of compounds of the present invention.
The compounds of the general structure (I") wherein R1, R2 and R3 are defined as above may be prepared by the procedure shown below in Scheme (2). In the first step, commercially available (Maybridge Chemical Co.) thieno[2,3-d]pyrimid- 4(1 H)-one is allowed to react with a brominating agent to afford 6-bromo-thieno[2,3- d]pyrimid-4(1H)-one. These reactions are generally performed in the presence of a brominating reagent such as N-bromosuccinimide (NBS), a solvent, DMF for example, and at a temperature from 25 °C to 175 °C, preferably room temperature.
Next, a substituent capable of acting as a leaving group, such as chlorine, is introduced into the pyrimidine portion of the 6-thienopyrmidine intermediate. The leaving group may be introduced using a reagent capable of reacting selectively with the pyrimidine portion of the molecule, phosphorous oxychloride for example, to afford an appropriately substituted product, These reactions are generally performed at a temperature from 25 °C to 175 °C, preferably 80 °C to 106 °C. For example, 6- bromo-thieno[2,3-d]pyrimid-4(1H)-one was allowed to react with phosphorus oxychloride at 106 °C to afford 6-bromo-4-chlorothieno[2,3-d]pyrimidine. bb
Scheme 2
Bromination
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000066_0003
R- R — ≡— H Pd catalyst Pd catalyst
Figure imgf000066_0004
(I")
The intermediate dihalogenated thieno[2,3-d]pyrimidines can then be converted to compounds of the general structure (I") by the two synthetic routes depicted as C and D in Scheme 2. In the first step of route C, an appropriate dihalogenated thieno[2,3-d]pyrimidine is allowed to react with reagents capable of selectively introducing an acetylenyl group into the 6-position. These reactions are generally performed in the presence of a palladium catalyst, bis(triphenylphosphine)palladium dichloride for example, a copper catalyst, copper(l) iodide for example, a base, triethylamine for example, a solvent, tetrahydrofuran (THF) for example, and at a temperature from 25 °C to 175 °C, preferably 50 °C to 60 °C. Lastly, the resulting alkyne is allowed to react with an arylamine to displace the 6-chloro substituent on the pyrimidine moiety as described above for step 2 of Scheme 1. These reactions are generally performed in a solvent, isopropanol for example, and at a temperature from 25 °C to 175 °C , preferably 50 °C to 80 °C.
The arylamines are either commercially available or can be prepared by methods known to those skilled in the art. For example, see the methods described in United States Patents 6,174, 883 and 6,207,669, which are hereby incorporated by reference as indicated above.
Alternatively, steps C and D in Scheme 2 may be carried out in reverse order using similar conditions as described above to afford the desired products.
The acetylenyl reagents, wherein R1 is a heterocyclic ring incorporating a nitrogen in the ring, may be prepared by the general route shown in Scheme 3. A heterocycle bearing a suitably protected carboxylic acid is subjected to appropriate reducing conditions to obtain the aldehyde reagent V. Suitable reducing conditions may, for example, consist of diisobutylaluminum hydride or other hydride reducing agents. An alternative method involves reduction of the carboxylic acid functionality to the corresponding primary alcohol, followed by oxidation to the corresponding aldehyde. The aldehyde derivative V is then subjected to a one-carbon homologation procedure to yield intermediate VI. A reagent particularly useful for the transformation to acetylenic derivative VI is dimethyl 1-diazo-2- oxopropylphosphonate. Suitable protecting groups (P) for the nitrogen of intermediates IV through VI include, for example, fert-butyl carbamate. A suitable protecting group for the carboxylic acid functionality of intermediates IV through VI is methyl such that the carboxylate functionality is a methyl ester. In instances where the pyrrolidine ring contains certain substituents R, which reprsents Z1 and/or Z2 defined above, (see schemes and examples below), it may be necessary to protect these substituents during the synthetic steps that convert the carboxylic acid derivative IV to the corresponding alkyne VI. X represents a suitable heteroatom such as O, S, or N and n represents an integer from 0 to 3 in all schemes depicted herein. Scheme 3
Figure imgf000068_0001
VI
Use of intermediate VI as the acetylenic reagent in the Pd-mediated coupling reactions will afford compounds wherein R1 in schemes 1 and 2 are heterocyclic compounds bearing nitrogen in the ring as represented by intermediates VII and IX below. Intermediates VII and IX may be treated with a suitable agent to remove the protecting group P of the secondary nitrogen that is part of the heterocyclic ring (Schemes 4 and 5). When P is ferf-butoxycarbonyl, such deprotection conditions may include, but are not limited to, trifluoroacetic acid or HCl in a suitable solvent such as dichloromethane or chloroform.
Scheme 4
Figure imgf000069_0001
VII VIII
Figure imgf000069_0002
IX X n=0-3 When the heterocyclic ring of intermediate IV, VII or IX in Schemes 3, 4 and 5 are substituted such that R is hydroxyl or hydroxyalkyl, a variety of additional analogs may be prepared by methods described below and in the examples. For example, as shown in Scheme 5, when VI contains a hydroxyl substituent this intermediate may be transformed into carbamate XI, ester XII, ether XIII, fluoride XIV, cyanide XV, or amine XVI. Suitable conditions for formation of the carbamate XI include, but are not limited to, addition of a caramoyl chloride and a base such as sodium hydride (NaH). The hydroxyl group may be converted into the corresponding fluoride in intermediate XIV by treatment with, for example, diethylaminosulfurtrifluoride (DAST). Activation of the alcohol group by treatment with tosyl chloride in the presence of an appropriate base yields the corresponding tosylate intermediate, which may be converted into the corresponding cyanide or azide by treatment with sodium cyanide or sodium azide respectively. The azide may in turn be converted into the corresponding primary amine XVI where Rn and Rn+ι = H through treatment with a reducing reagent. Suitable reducing reagents include, but are not limited to, triphenylphosphine. Amine derivatives may also be obtained by treatment with the ketone or aldehyde derived by oxidation of the alcohol, followed by reductive amination in the presence of a reducing agent such as sodium cyanoborohydride. The cyanide derivatives XV may be transformed into a variety of additional intermediates according to methods known by those skilled in the art.
Scheme 5
Figure imgf000070_0001
VI XI: Y = OCNRnR, XII: Y = OCORn XIII: Y = ORn XIV: : Y = F XV: Y = = CN XVI: : Y = = NRnRn+1 Intermediate XVI, where either or both Rn and Rn+ι are hydrogen may in turn be transformed into a variety of amino pyrrolidine intermediates as shown in Scheme 6. For example, treatment of the amine with an alkyl or aryl isocyanate affords the corresponding urea derivative XVII. Treatment of the primary amine with an alkyl choroformate reagent RCOCI gives the carbamate XVIII. Treatment of the amine with an acyl halide yields the corresponding amide derivatives XIX, while treatment with a sulfonyl chloride RS02CI gives the sulfonamide derivatives XX. Treatment of the amine with an aldehyde or ketone in the presence of a reducing agent such as sodium cyanoborohydride supplies the alkylated secondary or tertiary amine intermediate XXI.
Scheme 6
Figure imgf000071_0001
χv| XVII: Y = NRnCONRnRn+1 XVIII: Y = NRnCO2Rn XIX: Y = NRnCORn XX: Y = NRnSO2Rn XXI: Y = NRnRn+1
As a specific embodiment of the transformations represented in Scheme 3, when mono-substituted alkyne intermediates VI XI-XXI are employed in the Pd- mediated thienopyrimidine coupling reactions, intermediates XXII and XXIV may be obtained as shown in Scheme 7 below. Removal of the heterocyclic nitrogen protecting group affords targets XXIII and XXV, wherein Y is defined according to structures XI-XXI above (Scheme 7). As an alternative method to supply target compounds XXIII and XXV, chemical transformations used to provide acetylenic agents XI-XXI from their acetylenic hydroxyl or amino precursors VI may also be applied to XXII and XXIV, to give other intermediates where Y is defined according to structures XI-XXI. It will be understood by those skilled in the art that many of the transformations applied to intermediates XXII and XXIV of Scheme 7 are particularly effective when both R2 and R3 are a group other than hydrogen. An especially useful method of obtaining final targets where R1 is aryl and R2 is H involves blocking the aniline nitrogen atom at the 1 -position of the thienopyrimidine ring as a terf-Boc carbamate prior to the Pd- mediated Sonogashira reaction of Schemes 1 and 2. (Renzo Rossi, Adriano Carpita, and Fabio Bellina, "Palladium- and/or Copper-Mediated Cross-Coupling Reactions Between 1-Alkynes and Vinyl, Aryl, 1-Alkynyl, 1 ,2-Propadienyl, Propargyl and Allylic Halides or Related Compounds. A Review" Organic Preparations and Procedures International, 27(2), 127-160 (1995)). Scheme 7
Figure imgf000072_0001
XII) (XXIII)
Figure imgf000072_0002
Targets that are substituted at the nitrogen atom that is part of the heteroaryl ring may be prepared from structures XXIII and XXV by treatment of these intermediates with the appropriate nitrogen derivatizing reagent. For example, treatment of the amine with an isocyanate affords the corresponding urea derivative XXIX. Treatment of XXIII or XXV with an alkylating agent affords XXVI. Suitable alkylating agents include alkylhalides or alkyl aldehydes or ketones in the presence of a reducing agent such as sodium cyanoborohydride. Treatment of XXIII or XXV with an acyl halide yields the corresponding amide derivatives XXVII or XXXI, while treatment of cyclic amines XXIII or XXV with an alkylchoroformate reagent RnCOCI gives carbamates XXIX or XXXIII. Treating the cyclic amines XXIII or XXV with sulfonyl chlorides RnS02CI give the sulfonamide derivatives XXVIII or XXXII. Treatment of XXIII or XXV with alkyl or aryl isocyanates affords urea derivatives XXXIV or XXXV. Scheme 7
Figure imgf000073_0001
XXVII: Z = CORn XXVIII: Z = SO2Rn XXIX: Z = COORn XXXIV: Z = CONRnRn+1
Figure imgf000073_0002
XXXII: Z = SO2Rn XXXIII: Z = COORn XXXV: Z = CONRnRn+1
It will be understood by those skilled in the art that all target compounds and intermediates in the above schemes that contain one or more chiral centers may be obtained as single enantiomers and diastereomers by choice of the appropriate chiral starting materials or by chiral separation. Illustrations of stereospecific syntheses are contained in the examples below.
Certain embodiments of the present invention will now be illustrated by way of example only. The physical data obtained for the compounds exemplified is consistent with the assigned structure of those compounds.
EXAMPLES As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal (ά
of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L- configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); L (liters); mL (milliliters); μL (microliters); psi (pounds per square inch); M (molar); mM (millimolar); i. v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles); rt (room temperature); min (minutes); h (hours); mp (melting point); TLC (thin layer chromatography); Tr (retention time); RP (reverse phase); MeOH (methanol); /-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO (dimethylsulfoxide); EtOAc (ethyl acetate); DME (1 ,2-dimethoxyethane); DCM (dichloromethane); DCE (dichloroethane); DMF (Λ/,/V-dimethylformamide); DMPU (Λ/,Λ/'-dimethylpropyleneurea); (CDI (1 ,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid); HOSu (Λ/-hydroxysuccinimide); HOBT (l-hydroxybenzotriazole); mCPBA (meta-chloroperbenzoic acid; EDC (ethylcarbodiimide hydrochloride); BOC or Boc (fe/τ-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm (atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP (4-dimethylaminopyridine); BSA (bovine serum albumin) ATP (adenosine triphosphate); HRP (horseradish peroxidase); DMEM (Dulbecco's modified Eagle medium); t4
HPLC (high pressure liquid chromatography); BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF (tetra-n-butylammonium fluoride); HBTU (0-Benzotriazole-1-yl-N,N,N',N'- tetramethyluronium hexafluorophosphate); Red Al (sodium bis(2-methoxyethoxy)aluminum hydride; HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid); DPPA (diphenylphosphoryl azide); PCC (pyridinium chlorochromate); fHN03 (fumed HN03); EDTA (ethylenediaminetetraacetic acid); Dess-Martin periodinane or Dess-Martin reagent ( 1 ,1 ,1 -tris(acetoxy)- 1 ,1- dihydro-1 ,2-benziodoxol-3-(1H)-one); and Seyferth-Gilbert reagent or Gilbert-Seyferth reagent (dimethyl 1-diazo-2- oxopropylphosphonate). All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCI. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted. 1H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, a
Varian Unity-400 instrument, or a General Electric QE-300. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiple.), br (broad).
Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA, JOEL SX-102, or a SCIEX-APIiii spectrometer; high resolution MS were obtained using a JOEL SX-102A spectrometer. All mass spectra were taken under electrospray ionization (ESI), chemical ionization (Cl), atmospheric pressure chemical ionization (APCI), electron impact (El) or by fast atom bombardment (FAB) methods. Infrared (IR) spectra were obtained on a Nicolet 510 FT-IR spectrometer using a 1,-mm NaCI cell. All reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution. Column to
chromatography was performed on silica gel (230-400 mesh, Merck) or on an ISCO Sg100c chromatography instrument.
Reported HPLC retention times (rt) were obtained on a Waters 2795 instrument attached to a Waters 996 diode array detector reading 210-500 nm. The column used was a Synergi Max-RP (50 x 2 mm) model #00B-4337-B0. Solvent gradient was 15% methanol:water to 100% methanol (0.1% formic acid) over 4 or 6 min. Flow rate was 0.8 mL/min. Injection volume was 3 microliters. Chiral HPLC used for resolution in Example 29 was performed on a Novasep
Supersep 20/30 SFC instrument. The column used was a Diacel ChiralCel OJ-H (3 x 25 cm). Eluting solvent was 15% methanol:85% CO2 at 105 bar and 40 °C over 13.3 min. Flow rate was 100 g/min. Injection volume was 9 mL.
Example 1
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}pyrrolidin-3-yl morpholine-4-carboxylate
Figure imgf000076_0001
Step A - 6-bromo-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}thieno[3,2-d]pyrimidin-4- amine hydrochloride
Figure imgf000076_0002
6-Bromo-4-chlorothieno[3,2-c ]pyrimidine (M.J. Munchhof and S.B. Sobolov- Jaynes, Preparation of thienopyrimidines and thienopyridines as anticancer agents. PCT Int. Appl. (1999), WO9924440) (1.05 g, 4 mmol) and 3-chloro-4-[(3- fluorobenzyl)oxy]aniline (G.S. Cockerill and K.E. Lackey, Preparation of anilinoquinazolines as protein tyrosine kinase inhibitors. PCT Int. Appl. (2001 ), WO0104111) (986 mg, 3.9 mmol) were heated at 60 °C for 3 h in isopropanol (30 mL). The mixture was concentrated and the resulting material was triturated with ethyl ether and collected by suction filtration to yield the title compound (1.7 g) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.28 (br s, 1 H), 8.62 (s, 1 H), 7.88 (d, 1 H), 7.70 (s, 1 H), 7.58 (dd, 1 H), 7.49-7.42 (m, 1 H), 7.33-7.24 (m, 3H), 7.17(ddd, 1 H), 5.26 (s, 2H). The free base could be obtained by using a variety of standard conditions including but not limited to treatment of the title compound with saturated sodium bicarbonate in isopropanol for 3-12 h followed by filtration of solids which were then washed with water and dried under vacuum.
Step B - tert-butyl (2S,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-
(hydroxymethyl)pyrrolidine-l -carboxylate
TBDPS
Figure imgf000077_0001
Commercial /V-Boc-frans-4-hydroxy-L-proline methyl ester (19.88 g, 80.9 mmol) was dissolved into 162 mL of CH2CI2, and cooled to 0 °C for 20 min. Imidazole (6.10 g, 89.7 mmol), 4-(dimethylamino)pyridine (99 mg, 0.82 mmol) and terf-butylchlorodiphenylsilane (22.99 mL, 88.99 mmol) were added to the reaction. The reaction was allowed to slowly warm to rt overnight, during which time the reaction generated a thick white precipitate. The reaction was filtered over a pad of Celite, washing the pad the CH2CI2 (3 x 200 mL). The organics were reduced in vacuo, refiltered over a pad of Celite, reduction in vacuo generated a viscous colorless oil that solidified upon standing. The material was carried on without further purification. The crude silyl ether (39 g, 80.5 mmol, based on starting material) was dissolved into THF (250 mL) and cooled to -78 °C for 30 min. An addition funnel was charged with diisobutylaluminum hydride (201 mL, 201 mmol) and added to the reaction over 45 min. The reaction was warmed to 0 °C, and stirred for 1 h. The reaction was cooled to -78 °C and began addition of an aqueous solution of Rochelle's salt. After completion of addition, the reaction mixture was warmed to rt and stirred at rt until the layers became homogenous (about 2 h). The mixture was partitioned with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 400 mL). The organics were pooled, washed with brine (1 x 500 mL), dried over Na2S0 , filtered, and concentrated in vacuo. Purified via ISCO chromatography (hexanes:EtOAc) to afford the 27 g (75%, 2 steps) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCI3): δ 7.64-7.63 (m, 2H), 7.62- 7.61 (m, 2H), 7.46-7.42 (m, 2H), 7.42-7.36 (m, 4H), 4.30-4.25 (m, 1 H), 4.25-4.18 (m, 1 H), 3.65 (dd, 1 H), 3.53-3.46 (m, 2H), 3.15 (dd, 1 H), 2.46 (br s, 1 H), 2.03-2.00 (m, 1H), 1.52-1.49 (m, 1H), 1.47 (s, 9H), 1.05 (s, 9H).
Step C - tert-butyl (2S,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-formylpyrrolidine-1- carboxylate
TBDPSO
Figure imgf000078_0001
fetf-Butyl (2S,4R)-4-{[tetτ-butyl(diphenyl)silyl]oxy}-2- (hydroxymethyl)pyrrolidine-l -carboxylate (15 g, 33 mmol) was dissolved into 225 mL of CH2CI2 and cooled to 0 °C for 30 min. The following reagents were added sequentially to the reaction: NaHC03 (6.91 g, 82.3 mmol), H20 (0.59 mL, 32 mmol), and Dess-Martin periodinane (20.9 g, 49.4 mmol). The resulting white slurry was stirred for 30 min at rt, then warmed to rt and stirred for 1.5 h. Thin layer chromatography indicated that starting material remained; addition of another charge of Dess-Martin periodinane (6.98 g, 16 mmol) and stirring for an additional 30 min at rt caused the starting material to be fully consumed. The reaction was cooled to 0 °C for 15 min, carefully added 200 mL of a 50:50 (v:v) aqueous solution of
NaHC03:aqueous solution of Na2S203. The reaction was stirred for 1 h at rt, after which, the reaction was partitioned with CH2CI2 (200 mL). The aqueous layer was extracted with CH2CI2 (200 mL) and the resulting organic layers were pooled, dried over Na2S04, filtered and concentrated in vacuo. The resulting material was filtered tb
over Celite and purified via ISCO chromatography (hexanes:EtOAc) to afford 11.2 g (75%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCI3): δ 9.49 (d, 0.4H), 9.37 (d, 0.6H), 7.63-7.59 (m, 4H), 7.46-7.37 (m, 6H), 4.44-4.27 (m, 2H), 3.60 (br d, 1 H), 3.45-3.29 (m, 1 H), 2.06 (m, 1 H), 1.82-1.74 (m, 1 H), 1.47-1.45 (m, 9H), 1.05 (s, 9H).
Step D - tert-butyl (2S,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-ethynylpyrrolidine-1- carboxylate
TBDPSO
Figure imgf000079_0001
terf-Butyl (2S,4/z?)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-formylpyrrolidine-1- carboxylate (11.2 g, 24J mmol) was dissolved into 100 mL of MeOH, and cooled to
0°C for 5 min. K2C03 (8.54 g, 61.8 mmol) was added and the mixture was allowed to stir at 0 °C for an additional 25 min. Slowly added the Seyferth-Gilbert reagent (Susumu Ohira, Methanolysis of dimethyl (1-diazo-2-oxopropyl)phosphonate: generation of dimethyl (diazomethyl)phosphonate and reaction with carbonyl compounds. Synthetic Communications (1989), 19(3-4), 561-564.) (9.49 g, 49.4 mmol) dropwise via a syringe (slight gas evolution ocurred during addition). After addition was complete, the reaction was allowed to slowly warm to rt, and stirred at rt for 1 h. The reaction was quenched with 200 mL of water and diluted with 200 mL of EtOAc. The layers were separated, and the aqueous layer was extracted with 200 mL of EtOAc. The organics were pooled, dried over Na2S04, filtered and reduced in vacuo to afford a yellow oil. Purification of the crude material via ISCO chromatography (hexanes:EtOAc) yielded 8.3 g (75%) of the title compound as a colorless oil. MS (ESI): 472 (M+Na)+.
Step E - tert-butyl (2S,4R)-2-ethynyl-4-hydroxypyrrolidine-1-carboxylate
Figure imgf000080_0001
tetf-Butyl (2S,4R)-4-{[terf-butyl(diphenyl)silyl]oxy}-2-ethynylpyrrolidine-1- carboxylate (7.38 g, 16.4 mmol) was dissolved into 120 mL of THF, and cooled to 0° for 20 min. A solution of TBAF (18.08 mL, 18.08 mmol, 1.0 M in THF) was added dropwise via a syringe; the reaction became brown-red upon stirring. After stirring at 0 °C for 1 h, the reaction was diluted with water, and partitioned with EtOAc. The layers were separated, the aqueous phase was back-extracted with EtOAc, and the organic phases were pooled. The organics were washed with brine, dried over MgS0 , filtered and concentrated in vacuo to afford a dark oil. The crude material was purified via ISCO chromatography (hexanes:EtOAc) to afford 3.25 g (94%) of the title compound as a light tan oil, that solidified upon standing. 1H NMR (400 MHz, CDCI3): δ 4.52 (br s, 2H), 3.57 (dd, 1H), 3.43 (br s, 1H), 2.32-2.20 (m, 3H), 1.92 (br s, 1 H), 1.48 (s, 9H).
Step F - (3R,5S)-1-(tert-butoxycarbonyl)-5-ethynylpyrrolidin-3-yl morpholine-4- carboxylate
Figure imgf000080_0002
tert-Butyl (2S,4/:?)-2-ethynyl-4-hydroxypyrrolidine-1-carboxylate (1.94 g, 9.18 mmol) was dissolved into 20 mL of DMF, and cooled to 0 °C for 30 min. NaH (1.10 g, 27.5 mmol, 60% dispersion in mineral oil) was added in one portion to the reaction mixture. The reaction darkened upon addition, and was stirred for 15 min at 0 °C. After warming to rt for 15 min, 4-morpholinecarbonyl chloride (2.06 g, 13.8 mmol) was added and vigorous gas evolution occurred. The reaction stirred at rt for 1 h, then was warmed to 60 °C for 1 h, after which time the reaction was cooled to 0 °C and quenched by dropwise addition of water. The reaction was diluted with EtOAc, and the layers were separated. The aqueous phase was back-extracted with EtOAc, the organic phases were pooled, dried over MgS04, filtered and reduced in vacuo to afford a re-orange residue. Purification of the residue via ISCO chromatography (hexanes: EtOAc) yielded 2.33 g (72%) of the title compound as a pale yellow oil. 1H NMR (400 MHz, CDCI3): ζ 5.28-5.25 (m, 1 H), 4.52 (m, 1 H), 3.64 (br s, 6H), 3.42 (br s, 4H), 2.38-2.30 (m, 3H), 1.48 (s, 9H).
Step G - (3R,5S)-1-(teιi-butoxycarbonyl)-5-{[4-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)thieno[3,2-d]pyrimidin-6-yl]ethynyl}pyrrolidin-3-yl morpholine-4-carboxylate
Figure imgf000081_0001
In a 3-neck round bottom flask with an addition funnel and a condenser, 6- bromo-Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}thieno[3,2-c ]pyrimidin-4-amine (3.73 g, 7.45 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.54 g, 0.78 mmol), and copper (I) iodide (0.20 g, 1.06 mmol) were slurried in THF (100 mL) for 10 min at rt. To the resulting slurry, added Et3N (2.49 mL, 17.75 mmol) dropwise via a syringe and allowed the red-colored solution to stir at rt for 10 min. The reaction was warmed to 60°C (alternatively the reaction also works if the reaction is heated to 50°C) and stirred for 5 min. A solution of the (3f?,5S)-1-(tetf-butoxycarbonyl)-5- ethynylpyrrolidin-3-yl morpholine-4-carboxylate (2.3 g, 7.10 mmol) in THF (20 mL) was added to the addition funnel. The alkyne was added to the reaction mixture over 1 h. After addition had finished, the reaction was allowed to stir at 60 °C for an additional 3 h. The reaction was cooled to rt, and partitioned with EtOAc and brine. The layers were separated, followed by back-extraction of the aqueous layer with EtOAc, which was pooled with the previous organic layers. The combined organics were dried over Na S0 , filtered and reduced in vacuo onto silica. Purification via ISCO chromatography (hexanes: EtOAc) afforded 2.45 g of the title compound as a light yellow solid. HRMS (ESI): (M+H)+ calculated 708.2059, found 708.2056.
Step H (3R, 5S) -5-{[4-({3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}amino) thieno[3, 2-d]py midin- 6-yl]ethynyl}pyrrolidin-3-yl morpholine-4-carboxylate
(3R,5S)-1-(fe/τ-butoxycarbonyl)-5-{[4-({3-chloro-4-[(3-fluorobenzyl) oxy] phenyl}amino)thieno[3,2-t]pyrimidin-6-yl]ethynyl}pyrrolidin-3-yl morpholine-4- carboxylate (2.3 g, 3.3 mmol) was dissolved into 34 mL of CH2CI2 at 0 °C for 15 min. Trifluroroacetic acid (6 mL, 77 mmol) was added dropwise via a syringe. Reaction stirred at 0 °C for 1hr, then was quickly warmed to rt, stirred at rt for 3 h. The reaction was diluted with CH2CI2 (200 mL), and carefully queched with saturated aqueous NaHC03 (50 mL), or until the pH>7. The layers were separated, the organics were washed with saturated aqueous NaHC03 (1 x 50 mL). The aqueous layers were pooled, back-extracted with CH2CI2, and the resulting organics were combined, dried over MgS04, filtered and absorbed onto silica. Purification of the residue via ISCO chromatography (EtOAc:MeOH) afforded 1.48 g (74%) of the title compound as a light-yellow colored solid. 1H NMR (400 MHz, CD3OD): δ 8.50 (s, 1 H), 7.79 (d, 1 H), 7.50 (dd, 1 H), 7.43-7.38 (m, 2H), 7.31 (d, 1 H), 7.26 (d, 1 H), 7.15 (br d, 1 H), 7.08-7.03 (m, 1 H), 5.27-5.24 (m, 1 H), 5.22 (s, 2H), 4.32 (t, 1 H), 3.63 (br s, 4H), 3.45 (br s, 4H), 3.35-3.32 (m, 1 H), 3.01 (d, 1 H), 2.39-2.33 (m, 1 H), 2.26-2.19 (m, 1 H); HRMS (ESI): (M+H)+ calculated 608.1535, found 608.1511.
Example 2
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}pyrrolidin-3-yl ethylcarbamate
Figure imgf000082_0001
Step A - tert-butyl (2S,4R)-4-{[(ethylamino)carbonyl]oxy}-2-ethynylpyrrolidine-1- carboxylate
Figure imgf000083_0001
terτ-Butyl (2S,4f?)-2-ethynyl-4-hydroxypyrrolidine-1 -carboxylate (0.42 g, 2.0 mmol) was dissolved into DMF (20 mL) at rt. To this solution was added 4- (dimethylamino)pyridine (0.24 g, 2.0 mmol) and ethyl isocyanate (0.31 mL, 4.0 mmol) and the reaction mixture was heated to 50 °C. The reaction was stirred for 18 h, and TLC indicated that starting material remained. Added an additional charge of isocyante (0.31 mL, 4.0 mmol) and stirred for an additional 4 h at 50 °C. The reaction was cooled to rt, partitioned between EtOAc (100 mL) and water (200 mL). The layers were separated, and the organics were washed with water (2 x 100 mL), brine (100 mL), dried over Na2S04, filtered and adsorbed onto silica. Purification via ISCO chromatography (hexanes:EtOAc) afforded 0.35 g (63%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCI3): δ 5.23 (br s, 1 H), 4.65-4.45 (m, 2H), 3.60 (br s, 2H), 3.24-3.19 (m, 2H), 2.39-2.24 (br m, 2H), 1.48 (s, 9H), 1.13 (t, 3H).
Step B - tert-butyl (2S,4R)-2-{[4-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)thieno[3,2-d]pyrimidin-6-yl]ethynyl}-4- {[(ethylamino)carbonyl]oxy}pyrrolidine-1 -carboxylate
Figure imgf000084_0001
The title compound was prepared from tert-butyl (2S,4R)-4- {[(ethylamino)carbonyl]oxy}-2-ethynylpyrrolidine-1 -carboxylate and 6-bromo-Λ/-{3- chloro-4-[(3-fluorobenzyl)oxy]phenyl}thieno[3,2- /]pyrimidin-4-amine hydrochloride by a procedure analogous to Example 1 , Step G. MS (ESI) 666 (M)+.
Step C - (3R,5S)-5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)thieno[3,2- tτ]pyrimidin-6-yl]ethynyl}pyrrolidin-3-yl ethylcarbamate
The title compound was prepared from tert-butyl (2S,4R)-2-{[4-({3-chloro-4- [(3-fluorobenzyl)oxy]phenyl}amino)thieno[3,2-d]pyrimidin-6-yl]ethynyl}-4- {[(ethylamino)carbonyl]oxy}pyrrolidine-1 -carboxylate by a procedure analogous to Example 1 , Step H. 1H-NMR (400 MHz, CD3OD): δ 8.50 (s, 1 H), 779 (d, 1 H), 7.50 (dd, 1H), 7.43-7.38 (m, 2H), 7.31 (d, 1 H), 7.25 (d, 1H), 7.15 (br d, 1H), 7.08-7.03 (m, 1 H), 5.22 (br s, 3H), 4.29-4.25 (m, 1 H), 3.12 (q, 2H), 2.96 (d, 1 H), 2.34-2.28 (m, 1 H), 2.22-2.17 (m, 1 H), 1.10 (t, 3H); HRMS (ESI): (M+H)+ calculated 566.1429, found 566.1425.
Example 3
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2S,4S)-4-morpholin-4-ylpyrrolidin-2- yl]ethynyl}thieno[3,2-d]pyrimidin-4-amine
Figure imgf000085_0001
Step A - tert-butyl (2S)-2-ethynyl-4-oxopyrrolidine-1-carboxylate
Figure imgf000085_0002
To a solution of tert-butyl (2S,4R)-2-ethynyl-4-hydroxypyrrolidine-1- carboxylate (0.252 g, 1.2 mmol) in 10mL of CH2CI2, the following items were added sequentially at rt: NaHC03 (0.50 g, 6.0 mmol), Dess-Martin periodinane (1.01g, 2.38 mmol), and water (21 μL, 1.2 mmol). The resulting white-slurry was allowed to stir for 1 h at rt. The reaction was quenched by addition of 20 ml of a 50:50 (v:v) saturated aqueous solution of NaHC03: Na S203, the mixture was allowed to stir at rt for 1.5 h. The layers were separated, and the organic phase was extracted with saturated aqueous NaHC03 and brine. The resulting organic phase was dried over MgS04, filtered, and reduced in vacuo to afford a yellow solid. Purification of the material via column chromatography (hexanes: EtOAc) afforded the title compound as an off- white solid, 98% yield. 1H NMR (400 MHz, CDCI3): δ 4.99 (br s, 1 H), 3.90 (d, 1H), 373 (d, 1H), 2.89 (dd, 1 H), 2.63 (d, 1 H), 2.34 (d, 1 H), 1.50 (s, 9H).
Step B - tert-butyl (2S)-2-ethynyl-(4R,S)-4-morpholin-4-ylpyrrolidine-1-carboxylate
Figure imgf000086_0001
To a solution tert-butyl (2S)-2-ethynyl-4-oxopyrrolidine-1 -carboxylate (0.16 g, 0.764 mmol) in 2.2 mL of CH2CI2 added morpholine (0.2 mL, 2.29 mmol), triethylamine (0.212 mL, 1.528 mmol), and acetic acid (94 μL, 1.60 mmol) at rt. After stirring the orange-colored reaction for 15min, NaBH(OAc)3 (0.647 g, 1.528 mmol) was added in one portion. The resulting slurry stirred overnight at rt. The reaction was diluted with 30 mL of EtOAc, and 10 mL of water. The layers were separated, and the organic phase was washed with 20 mL of saturated aqueous NaHCO3. The aqueous layers were combined and back-extracted with EtOAc. The organics were pooled, dried over Na2S04, filtered and reduced in vacuo to afford a yellow oil.
Purification of the residue via ISCO chromatography with hexanes:EtOAc yielded 100 mg (47%) of the title compound as a yellow solid, as a 2:1 mixture of diastereomers. 1H NMR (400 MHz, CDCI3): δ 4.50-4.30 (br m, 1 H), 3.90-3.80 (br m, 0.5 H, from the minor diastereomer), 3.71 (t, 4H); 3.14 (t, 1 H), 2.67 (m, 1 H), 2.53-2.41 (m, 5H), 2.35-
2.23 (m, 1H), 2.00 (q, 1H), 1.68 (br m, 0.5H from the minor diastereomer), 1.47 (s,
9H).
Step C - N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2S,4S)-4-morpholin-4- ylpyrrolidin-2-yl]ethynyl}thieno[3,2-d]pyrimidin-4-amine
The title compound was prepared from tert-butyl (2S)-2-ethynyl-(4R,S)-4- morpholin-4-ylpyrrolidine-1 -carboxylate and 6-bromo-N-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}thieno[3,2-d]pyrimidin-4-amine by a procedure analogous to Example 1 , Steps G and H. 1H NMR (400 MHz, CD3OD): δ 8.50 (s, 1 H); 7.80 (d, 1H); 7.50 (dd, 1 H); 7.43-7.38 (m, 2H); 7.31 (br d, 1H); 7.26 (br d, 1 H); 7.15 (d, 1H); 7.05 (td, 1 H); 5.22 (s, 2H); 4.22 (t, 1 H); 3.70 (t, 4 H); 3.15 (dd, 1 H); 2.95-2.84 (m, 2H); 2.57-2.45 (m, 5H); 1.90-1.83 (m, 1 H); HRMS (ESI): (M+H)+ calculated 564.1636, found 564.1633.
Example 4
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2R,3S)-3-morpholin-4-ylpyrrolidin-2- yl]ethynyl}thieno[3,2-d]pyrimidin-4-amine
Figure imgf000087_0001
Step A - 1 ert-butyl (2S,3S)-2-(hydroxymethyl)-3-morpholin-4~ylpyrrolidine-1-carboxylate
Figure imgf000087_0002
(3R,7S)-3-phenyl-1 ,7a-dihydro-5H-pyrrolo[1 ,2-c][1 ,3]oxazol-5-one (Rui
Zhang, Ahmed Mamai, and Jose S. Madalengoitia, Cyclopropanation Reactions of Pyroglutamic Acid-Derived Synthons with Akylidene Transfer Reagents. Journal of Organic Chemistry (1999), 64(2), 547-555, and references therein) (0.40 g, 2.0 mmol) was ground into a fine powder using a mortar and pestle. The material was transferred to a reaction vessel, diluted with water (0.2 mL) and treated with morpholine (0.35 g, 4.0 mmol) at rt. The reaction to stirred at rt for 3 h. The reaction was partitioned between EtOAc and water, the layers were separated, and the organic layer was washed with brine (20 mL). The organics were dried over Na2S04, filtered and reduced in vacuo, to afford a yellow-colored foam, carried on without further purification. The crude amine (0.45 g, 1.56 mmol) was dissolved into THF (20 mL) and solid LAH (0.27 g, 7.02 mmol) was added (vigorous gas evolution occurred). The resulting slurry stirred for 1 h at rt, then was heated to 70 °C. The reaction was allowed to proceed at reflux for 18 h, after which the contents were cooled to rt, then to 0 °C for 30 min. The reaction was carefully quenched with saturated aqueous Na2S03, a white precipitate formed immediately. The slurry was filtered over Celite and eluted with EtOAc. The filtrate was dried over Na2S04, filtered and reduced in vacuo to afford a yellow-orange solid. The material was carried on without further purification. The crude alcohol (0.40 g, 1.5 mmol) was dissolved into EtOAc (10 mL) at rt, and treated with di-te/τ-butyl dicarbonate (0.66 g, 3.0 mmol), 10 wt% palladium on activated carbon (0.055 mg, 0.052 mmol). The contents were placed onto a Parr hydrogenation apparatus, evacuated with N2 (x5), then H2 (x2) and pressurized with H2 (>60 psi) at rt. Stirred for 6 days. The contents were removed from the Parr apartus, filtered over Celite, washing the pad with EtOAc (5 x 15 mL). The organics were reduced in vacuo to afford a yellow oil, purified via ISCO chromatography to afford 0.32 g (57%, 3 steps) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCI3): δ 3.95-3.55 (m, 9H), 3.27-3.20 (m, 1 H), 275-2.47 (m, 5H), 1.95-1.83 (m, 2H), 1.46 (s, 9H).
Step B - tert-butyl (2R,3S)-2-ethynyl-3-morpholin-4-ylpyrrolidine-1-carboxylate
Figure imgf000088_0001
The title compound was prepared from tert-butyl (2S,3S)-2-(hydroxymethyl)- 3-morpholin-4-ylpyrrolidine-1 -carboxylate by a procedure analogous to Example 1 , Steps C and D. 1H NMR (400 MHz, CDCI3): δ 4.45-4.30 (m, 1 H), 372-3.66 (m, 4H), 3.37-3.31 (m, 1 H), 3.10 (br s, 1 H), 2.60-2.50 (m, 4H), 2.29 (br s, 1 H), 2.14-2.10 (m, 1 H), 1.85 (br s, 1 H), 1.66-1.58 (m, 1 H), 1.47 (s, 9H).
Step C - N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2R,3S)-3-morpholin-4- ylpyrrolidin-2-yl]ethynyl}thieno[3,2-d]pyrimidin-4-amine
The title compound was prepared from tetτ-butyl (2R,3S)-2-ethynyl-3- morpholin-4-ylpyrrolidine-1 -carboxylate and 6-bromo-A/-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}thieno[3,2-c7]pyrimidin-4-amine by a procedure analogous to Example 1 , Steps G and H. 1H NMR (400 MHz, CD3OD): δ 8.50 (s, 1 H), 7.80 (d, 1 H), 7.50 (dd, 1 H), 7.43-7.38 (m, 2H), 7.30 (br d, 1 H), 7.25 (br d, 1 H); 7.14 (d, 1 H), 7.08-7.03 (m, 1 H), 5.21 (s, 2H), 4.02 (d, 1H), 3.71 (m, 4H), 3.11-2.99 (m, 3H), 2.70- 2.59 (m, 4H), 2.16-2.08 (m, 1 H), 1.84-175 (m, 1 H); HRMS (ESI): (M+H)+ calculated 564.1636, found 566.1634.
Example 5
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[(2S)-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine
Figure imgf000089_0001
Step A - tert-butyl (2S)-2-formyl-1 -pyrrolidinecarboxylate
Figure imgf000090_0001
The title compound was prepared from known (2S)-2-(hydroxymethyl)-1- pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step C. 1H NMR (400 MHz, CDCI3): δ 9.55-9.45 (m, 1 H), 4.22-4.02 (m, 1 H), 3.57-3.43 (m, 2H), 2.18- 1.84 (m, 4H), 1.47-1.42 (m, 9H).
Step B - tert-butyl (2S)-2-ethynyl-1-pyrrolidinecarboxylate
Figure imgf000090_0002
The title compound was prepared from tetf-butyl (2S)-2-formyl-1- pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step D. 1H NMR (400 MHz, CDCI3): δ 4.53-4.40 (br m, 1 H), 3.48-3.32 (br m, 2H), 2.20-1.90 (m, 5H), 1.47 (s, 9H).
Step C - tert-butyl (2S)-2-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2- d]pyrimidin-6-yl) ethynyl]- 1 -pyrrolidinecarboxylate
Figure imgf000090_0003
The title compound was prepared from 6-bromo-Λ/-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}thieno[3,2- yrimidin-4-amine and tert-butyl (2S)-2-ethynyl- 1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step G. MS (ESI): 579 (M+H)+. Step D - Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[(2S)- pyrrolidinylethynyl]thieno[3,2-o pyrimidin-4-amine
The title compound was prepared from tetf-butyl (2S)-2-[(4-{3-chloro-4-[(3- fluorobenzyl)oxy]anilino}thieno[3,2-t]pyrimidin-6-yl)ethynyl]-1-pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step H. 1H NMR (400 MHz, DMSO-cfe): δ 9.71 (s, 1 H), 8.57 (s, 1 H), 7.92 (d, 1 H), 7.61 (dd, 1 H), 7.54 (s, 1 H), 7.50-7.45 (m, 1 H), 7.34-7.30 (m, 2H), 7.25 (d, 1 H), 7.19 (dt, 1 H), 5.26 (s, 2H), 4.06 (dd, 1 H), 2.93-278 (m, 2H), 2.10-2.03 (m, 1 H), 1.82-1.66 (m, 3H); HRMS (ESI): (M+H)+ calculated 479.1109, found 479.1122.
Example 6
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[(2S)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine
Figure imgf000091_0001
Step A - 1-(tert-butoxy carbonyl) -D-proline
Figure imgf000091_0002
To a solution containing 20.0 g (0.173 mol) of D-proline and 200mL of THF at 0 °C was added 39.8 g (0.182 mol) of di-tet -butyldicarbonate followed, by 25 mL (0.182 mol) of triethylamine. The reaction mixture was allowed to warm to rt and stirred overnight. The THF was removed under reduced pressure and the residue was dissolved in ether and washed with saturated aqueous NaHC03, saturateed aqueous NH CI, and brine. The organic layer was dried over MgS04 and the solvent was removed under reduced pressure to give 36.2 g (97%) of the title compound as a white solid. 1H-NMR (300 MHz, DMSO-c/e): δ 1.33 (s, 9H), 1.79 (m, 3H), 2.16 (m, 1H), 3.31 (m, 2H), 4.05 (m, 1 H).
Step B - tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate
Figure imgf000092_0001
To a stirred solution containing 9.0g (41.8 mmol) of 1-(fert-butoxycarbonyl)-D- proline and 70 mL of THF at 0 °C was added 5.4 mL (54.4 mmol) of borane dimethyl sulfide complex dropwise. When the evolution of hydrogen had ceased, the reaction mixture was heated at reflux for 1.5 h, then cooled to rt and quenched by the careful addition of excess methanol. The solvents were removed under reduced pressure. The residue was taken up in excess methanol and concentrated to dryness to give the title compound, which was used without further purification. 1H-NMR (300MHz, CDCI3): δ 1.47 (s, 9H), 1.82 (m, 2H), 2.00 (m, 2H), 3.33 (m, 1 H), 3.96 (br s, 1 H), 4.8 (br s, 1H).
Step C - tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate
Figure imgf000092_0002
To a stirred solution containing crude tert-butyl (2R)-2- (hydraxymethyl)pyrrolidine-l -carboxylate and 200 mL of dichloromethane at 0 °C was added 13.3 g (61.9 mmol) of PCC, followed by 58 g of 4 A molecular sieves, and 3.7 mL (64.8 mmol) of acetic acid. The reaction mixture was allowed to warm slowly to rt and stirred for 8 h. The dark reaction mixture was filtered through a short plug of celite, eluting with dichloromethane, and the solvents were removed under reduced pressure. The residue was taken up in a small amount of dichloromethane and passed over a short plug of silica gel, eluting with 2:1 hexanes:ethyl acetate. The solvents were removed under reduced pressure to give 7.12g (85%) of the title compound as a clear oil which was used without further purification. 1H-NMR (300 MHz, CDCI3): δ 1.42 (s, 5H), 1.45 (s, 4H), 1.82-2.16 (m, 4H), 3.49 (m, 2H), 4.04 (m, 0.5H), 4.19 (m, 0.5H), 9.44 (d, 0.5H), and 9.55 (s, 0.5H).
Step D - tert-butyl (2R)-2-ethynylpyrrolidine-1-carboxylate
Figure imgf000093_0001
The title compound was prepared from tert-butyl (2R)-2-formylpyrrolidine-1- carboxylate by a procedure analogous to Example 1 , Step D. 1H-NMR (300 MHz, CDCI3): δ 1.48 (s, 9H), 1.88 (m, 1 H), 2.05 (br m, 2H), 2.22 (br m, 1 H), 3.30 (br m, 1 H), 3.45 (br m, 1 H), 4.42-4.52 (br m, 1 H).
Step E - tert-butyl (2R)-2-{[4-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)thieno[3,2-t7]pyrimidin-6-yl]ethynyl}pyrrolidine-1- carboxylate
Figure imgf000093_0002
The title compound was prepared from tert-butyl (2R)-2-ethynyl-1- pyrrolidinecarboxylate and 6-bromo-/V-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}thieno[3,2-c7]pyrimidin-4-amine by a procedure analogous to Example 1 , Step G. 1H NMR (CDCI3, 300 MHz): δ 1.47 (s, 9H), 1.88-2.18 (m, 4H), 3.32-3.42 (m, 1 H), 3.47-3.55 (m, 1 H), 4.61-479 (m, 1 H), 5.18 (m, 2H), 6.75 (brs, 1 H), 6.98 (d, 1 H), 7.03 (ddd, 1 H), 7.19-7.24 (m, 2H), 7.23-7.40 (m, 3H), 7.60 (s, 1 H), 8.64 (s, 1 H); MS (ESI): 578.9 (M+H)+.
Step F - N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[(2R)-pyrrolidin-2-ylethynyl] thieno[3,2-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R)-2-{[4-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)thieno[3,2-tτ]pyrimidin-6-yl]ethynyl}pyrrolidine-1- carboxylate by a procedure analogous to Example 1 , Step H. 1H-NMR (300 MHz, DMSO-de): δ 1.64-1.83 (m, 3H), 2.01-2.10 (m, 2H), 277-2.84 (m, 1 H), 2.87-2.95 (m, 1 H), 4.06 (dd, 1H), 5.24 (s, 2H), 7.18 (ddd, 1H), 7.25 (d, 1H), 7.28-7.33 (m, 2H), 7.46 (ddd, 1 H), 7.54 (s, 1 H), 7.59 (dd, 1 H), 7.90 (d, 1 H), 8.56 (s, 1 H), 9.70 (br s, 1H); HRMS (ESI): (M+H)+ calculated 479.1109, found: 479.1119.
Example 7
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2R)-1-methylpyrrolidinyl] ethynyl}thieno[3,2-d]pyrimidin-4-amine
Figure imgf000094_0001
To Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3,2-c]pyrimidin-4-amine (46 mg, 0.1 mmol) in DMF (0.5 mL) was added cesium carbonate (38 mg, 0.1 mmol) followed by methyl iodide (7 μL, 0.1 mmol). The mixture was stirred for 12 h at rt and then additional Cesium Carbonate (19 mg) and Mel (4 μL) were added. The mixture was stirred for an additional 2 h and then diluted with CH2CI2 (100 mL) and H20 (30 mL). The organic layer was separated, dried over MgS0 , filtered, and concentrated in vacuo. The residue was triturated (EtOAc/Hexanes) and collected via filtration to provide 18 mg (32%) of the title compound as a cream powder. 1H-NMR (400 MHz, CDCI3): δ 8.63 (s, 1 H), 7.61 (d, 1H), 7.41 (s, 1H), 7.40-7.32 (m, 2H), 7.26-7.18 (m, 3H), 7.03 (dt, 1H), 6.98 (d, 1 H), 5.19 (s, 2H), 3.35 (t, 1 H), 2.98-2.93 (m, 1 H), 2.47 (s, 3H), 2.45-2.40 (m, 1 H), 2.27-2.18 (m, 1 H), 2.08- 1.90 (m, 2H), 1.89-177 (m, 1 H); HRMS (ESI): (M+H)+ calculated 493.1265, found 493.1255.
Example 8
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(3-pyrrolidinylethynyl)thieno[3,2- d]pyrimidin-4-amine
Figure imgf000095_0001
Step A - tert-butyl 3-ethynyl-1 -pyrrolidinecarboxylate
Figure imgf000095_0002
The title compound was prepared from known tert-butyl 3-formylpyrrolidine-1- carboxylate by a procedure analogous to Example 1 , Step D. 1H-NMR (400 MHz, CDCI3): δ 3.64-3.60 (m, 1 H), 3.50 (br m, 1 H), 3.35-3.27 (m, 2H), 2.95-2.92 (m, 1 H), 2.18-2.12 (m, 1 H), 2.11 (d, 1 H), 1.99-1.89 (m, 1 H), 1.46 (s, 9H).
Step B - tert-butyl 3-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-1 -pyrrolidinecarboxylate
Figure imgf000096_0001
The title compound was prepared from tert-butyl 3-ethynyl-1- pyrrolidinecarboxylate and 6-bromo-Λ/-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}thieno[3,2-cτ]pyrimidin-4-amine by a procedure analogous to Example 1 , Step G. MS (ESI): 579 (M+H)+.
Step C - N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(3- pyrrolidinylethynyl)thieno[3,2-d]pyrimidin-4-amine The title compound was prepared from tert-butyl 3-[(4-{3-chloro-4-[(3- fluorobenzyl)oxy]anilino}thieno[3,2-c/]pyrimidin-6-yl)ethynyl]-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step H. 1 H-NMR (400 MHz, DMSO-d6): δ 9.69 (br s, 1H), 8.57 (s, 1H), 7.91 (d, 1H), 7.60 (dd, 1H), 7.53 (s, 1H), 7.50-7.45 (m,
1 H), 7.34-7.30 (m, 2H), 7.26 (d, 1 H), 7.19 (dt, 1 H), 5.26 (s, 2H), 3.24-3.07 (m, 3H), 2.96-2.83 (m, 2H), 279-274 (m, 1 H), 2.18-2.08 (m, 1 H), 1.82-173 (m, 1 H); HRMS (ESI): (M+H)+ calculated 479.1109, found 479.1116.
Example 9
(3R,5S)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinol
Figure imgf000096_0002
Step A - tert-butyl (2S,4R)-2-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-4-hydroxy-1 -pyrrolidinecarboxylate
Figure imgf000097_0001
The title compound was prepared from tert-butyl (2S,4R)-2-ethynyl-4- hydroxypyrrolidine-1 -carboxylate and 6-bromo-Λ/-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}thieno[3,2-c7]pyrimidin-4-amine by a procedure analogous to Example 1 , Step G. MS (ESI): 595 (M+H)+.
Step B - (3R,5S)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin- 6-yl) ethynyl]-3-pyrrolidinol The title compound was prepared from tert-butyl (2S,4R)-2-[(4-{3-chloro-4-[(3- fluorobenzyl)oxy]anilino}thieno[3,2-t]pyrimidin-6-yl)ethynyl]-4-hydroxy-1- pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step H. 1H NMR
(400 MHz, DMSO-de): δ 9.76 (s, 1H), 8.57 (s, 1H), 7.91 (d, 1H), 7.61 (dd, 1H), 7.58
(s, 1 H), 7.50-7.44 (m, 1 H), 7.34-7.30 (m, 2H), 7.25 (d, 1 H), 7.19 (dt, 1 H), 5.26 (s,
2H), 4.94 (s, 1 H), 4.36-4.32 (m, 2H), 4.11 (bs, 1 H), 3.10 (dd, 1 H), 2.76 (d, 1 H), 2.11-
2.06 (m, 1H), 1.98-1.91 (m, 1H); HRMS (ESI): (M+H)+ calculated 495.1058, found
495.1086.
Example 10
(3R,5R)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinol yt
Figure imgf000098_0001
Step A - tert-butyl (2R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-formyl-1- pyrrolidinecarboxylate
Figure imgf000098_0002
The title compound was prepared from known tert-butyl (2R,4R)-4-{[tert- butyl(diphenyl)silyl]oxy}-2-(hydroxymethyl)-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step C. MS (ESI): 476 (M+Na)+.
Step B - tert-butyl (2R,4R)-4-{[teιi-butyl(diphenyl)silyl]oxy}-2-ethynyl-1- pyrrolidinecarboxylate
Figure imgf000098_0003
The title compound was prepared from tert-butyl (2R,4R)-4-{[tert- butyl(diphenyl)silyl]oxy}-2-formyl-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step D. MS (ESI): 472 (M+Na)+.
Step C - tert-butyl (2R,4R)-2-ethynyl-4-hydroxy-1-pyrrolidinecarboxylate
Figure imgf000099_0001
The title compound was prepared from tert-butyl (2R,4R)-4-{[tert- butyl(diphenyl)silyl]oxy}-2-ethynyl-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step E. 1H-NMR (400 MHz, CDCI3): δ 4.63-4.54 (br m, 1 H), 4.45 (br s, 1 H), 3.55 (br s, 2H), 2.39-2.17 (m, 4H), 1.49 (s, 9H).
Step D - tert-butyl (2R,4R)-2-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2- d]pyήmidin-6-yl)ethynyl]-4-hydroxy-1 -pyrrolidinecarboxylate
Figure imgf000099_0002
The title compound was prepared from tert-butyl (2R,4R)-2-ethynyl-4- hydroxy-1 -pyrrolidinecarboxylate and 6-bromo-Λ/-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}thieno[3,2-c]pyrimidin-4-amine by a procedure analogous to Example 1 , Step G. MS (ESI): 595 (M+H)+.
Step E - (3R,5R)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin- 6-yl) ethynyl]-3-pyrrolidinol The title compound was prepared from tert-butyl (2R,4R)-2-[(4-{3-chloro-4-[(3- fluorobenzyl)oxy]anilino}thieno[3,2-c7]pyrimidin-6-yl)ethynyl]-4-hydroxy-1- pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step H. 1H NMR (400 MHz, DMSO-ce) δ 9.72 (s, 1H), 8.57 (s, 1H), 7.92 (d, 1H), 7.60 (dd, 1H), 7.56 (s, 1 H), 7.50-7.45 (m, 1 H), 7.34-7.30 (m, 2H), 7.25 (d, 1 H), 7.19 (dt, 1 H), 5.26 (s, 2H), 4.85 (d, 1 H), 4.23-4.18 (m, 1 H), 4.05-4.01 (m, 1 H), 2.87-274 (m, 2H), 2.40-2.33 (m, 1 H), 172-1.67 (m, 1 H); HRMS (ESI): (M+H)+ calculated 495.1058, found 495.1049.
Example 11
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2S,4R)-4-methoxypyrrolidinyl] ethynyl}thieno[3,2-d]pyrimidin-4-amine
Figure imgf000100_0001
Step A - tert-butyl (2S,4R)-2-ethynyl-4-methoxy-1-pyrrolidinecarboxylate
Me
Figure imgf000100_0002
To tert-butyl (2S,4R)-2-ethynyl-4-hydroxypyrrolidine-1 -carboxylate (380 mg, 1.8 mmol) in DMF (4 mL) was added CsC03 (1.2 g, 3.7 mmol) followed by Mel (224 μL, 3.6 mmol). The reaction was stirred for 2 days while three additional aliquots of Mel (50 μL, 0.8 mmol) were added. The reaction mixture was poured into EtOAc (200 mL) and saturated aqueous NaHC03 (50 mL). The organic layer was separated, washed with brine (50 mL), dried over MgS04, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (25% EtOAc/Hexanes) to provide 331 mg (82%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCI3): δ 4.53-4.47 (br m, 1 H), 4.08 (br s, 1 H), 3.79 (s, 1 H), 3.52 (br m, 2H), 3.32 (s, 3H), 2.26 (br m, 2H), 1.47 (s, 9H).
Step B - tert-butyl (2S,4R)-2-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-4-methoxy-1 -pyrrolidinecarboxylate
Figure imgf000101_0001
The title compound was prepared from tert-butyl (2S,4R)-2-ethynyl-4- methoxy-1 -pyrrolidinecarboxylate and 6-bromo-Λ/-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}thieno[3,2-c/]pyrimidin-4-amine by a procedure analogous to Example 1 , Step G. MS (ESI) 609 (M+H)+.
Step C - N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2S,4R)-4- methoxypyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine trifluoroacetate The title compound was prepared as the trifluoroacetate salt from tert-butyl
(2S,4R)-2-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-t7]pyrimidin-6- yl)ethynyl]-4-methoxy-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step H. 1H-NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1 H), 8.57 (s, 1 H), 7.91 (d, 1 H), 7.60 (dd, 1 H), 7.56 (s, 1 H), 7.50-7.44 (m, 1 H), 7.34-7.30 (m, 2H), 7.25 (d, 1 H), 7.19 (dt, 1 H), 5.26 (s, 2H), 4.16 (t, 1 H), 3.98-3.95 (m, 1 H), 3.05 (dd, 1 H), 2.83 (dd, 1 H), 2.21-2.16 (m, 1 H), 1.94-1.87 (m, 1 H); MS (ESI) 509 (M+H)+.
Example 12
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2S,4S)-4-fluoropyrrolidinyl] ethynyl}thieno[3,2-d]pyrimidin-4-amine
Figure imgf000102_0001
Step A - tert-butyl (2S,4S)-2-ethynyl-4-fluoro-1-pyrrolidinecarboxylate
Figure imgf000102_0002
tert-Butyl (2S,4R)-2-ethynyl-4-hydroxypyrrolidine-1 -carboxylate (90 mg, 0.43 mmol) was dissolved in CH2CI2 and cooled in a -78 °C bath. DAST (84 μL, 0.64 mmol) was added dropwise and the solution was stirred for 15 min at -78 °C. Solid K2C03 (100 mg, 0.72 mmol) was added to the reaction and the cold bath was removed. Upon reaching rt, the mixture was diluted with EtOAc (100 mL) and saturated aqueous NaHC03 (50 mL). The organic layer was separated, washed with brine (50 mL), dried over MgS04, filtered and concentrated in vacuo. The yellow oil was purified via silica gel chromatography (30% EtOAc/Hexanes) to provide 87 mg (96%) of the title compound as a clear oil. 1H-NMR (400 MHz, CDCI3): δ 5.25 (dt, 1 H), 474-4.48 (m, 1 H), 378-3.53 (m, 2H), 3.21 (m, 1 H), 2.44-2.22 (m, 2H), 1.48 (d, 9H).
Step B - tert-butyl (2S,4S)-2-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2- d]pyrimidin-6-yl) ethynyl]-4-fluoro- 1 -pyrrolidinecarboxylate
Figure imgf000103_0001
The title compound was prepared from tert-butyl (2S,4S)-2-ethynyl-4-fluoro-1- pyrrolidinecarboxylate and 6-bromo-Λ/-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}thieno[3,2-cτ]pyrimidin-4-amine by a procedure analogous to Example 1 , Step G. MS (ESI): 597 (M+H)+.
Step C - N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2S,4S)-4-fluoropyrrolidinyl] ethynyl}thieno[3,2-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2S,4S)-2-[(4-{3-chloro-4-[(3- fluorobenzyl)oxy]anilino}thieno[3,2-t]pyrimidin-6-yl)ethynyl]-4-fluoro-1- pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step H. 1H-NMR (400 MHz, DMSO-c/e): δ 9.73 (s, 1 H), 8.58 (s, 1 H), 7.92 (d, 1 H), 7.61 (dd, 1 H), 7.57 (s, 1 H), 7.50-7.45 (m, 1 H), 7.34-7.30 (m, 2H), 7.26 (d, 1 H), 7.19 (dt, 1 H), 5.27 (dt, 1 H), 5.26 (s, 2H), 4.15-4.11 (m, 1 H), 3.19-3.10 (m, 1 H), 3.02-2.90 (m, 1 H), 2.48-2.38 (m, 1 H), 2.11-2.02 (m, 1 H); MS (ESI) 497 (M+H)+.
Example 13
{(2S)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]pyrrolidinyl}methanol
Figure imgf000104_0001
Step A - tert-butyl (5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-ethynyl-2-hydroxy- 1 -pyrrolidinecarboxylate
Figure imgf000104_0002
TMS acetylene (72 mg, 0.7 mmol) in THF (3 mL) was cooled in a -78 °C bath. nBuLi (2.5M in hexanes, 270 μL, 0.68 mmol) was added dropwise and the mixture was stirred for 10 min. at -78 °C. Known tert-butyl (2S)-2-(hydroxymethyl)-5- oxopyrrolidine-1 -carboxylate (277 mg, 0.6 mmol) in THF (2 mL) was then added dropwise to the cold intermediate anion. The cold bath was removed and the reaction was allowed to warm to rt. The reaction was cooled in an ice bath and carefully quenched with EtOAc followed by H20. The mixture was diluted with EtOAc (150 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was separated, washed with brine (50 mL), dried over MgS04, filtered and concentrated in vacuo. The brown oil was purified via ISCO chromatography (10% to 30% EtOAc/Hexanes) to provide 194 mg (66%) of the title compound as a yellow oil as a mixture of two diastereomers. MS (ESI): 502 (M+Na)+.
Step B - tert-butyl (1S)-1-ethyl-4-hydroxy-5-hexynylcarbamate
Figure imgf000105_0001
To tert-butyl (5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-ethynyl-2- hydroxy-1 -pyrrolidinecarboxylate (340 mg, 0.71 mmol) in MeOH (8 mL) at rt was added CeCI3 heptahydrate (317 mg, 0.85 mmol). The slurry was cooled in a -45 °C bath and NaBH4 (13 mg, 0.35 mmol) was added. The reaction mixture was stirred for 30 minutes while keeping the cold bath temperature at -45 °C. Additional NaBH4 (13 mg, 0.35 mmol) was added and the reaction mixture was stirred for 30 minutes while keeping the cold bath temperature at -45 °C. The mixture was quenched through addition of EtOAc (5 mL) and then saturated aqueous NaHC03 (5 mL) followed by removal of the cold bath. The mixture was diluted with EtOAc (200 mL) and saturated aqueous NaHC03 (50 mL). The organic layer was separated, washed with brine (50 mL), dried over MgS04, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (EtOAc/Hexanes) to provide 297 mg (87%) of the title compound as a yellow oil as a mixture of two diastereomers. MS (ESI): 504 (M+Na)+.
Step C - tert-butyl (2S)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-ethynyl-1- pyrrolidinecarboxylate
Figure imgf000105_0002
tert-Butyl (1 S)-1-ethyl-4-hydroxy-5-hexynylcarbamate (169 mg, 0.35 mmol) in CH2CI2 (2 mL) was cooled in a -78 °C bath. DAST (51 μL, 0.39 mmol) was added dropwise and the solution was stirred for 15 min. at -78 °C. Solid K2C03 (73 mg, 0.53 mmol) was added to the reaction flask in a single portion and the cold bath was removed. Upon reaching rt, the mixture was diluted with EtOAc (200 mL) and saturated aqueous NaHC03 (50 mL). The organic layer was separated, washed with brine (50 mL), dried over MgS04, filtered and concentrated in vacuo. The yellow oil was purified via silica gel chromatography (5% EtOAc/Hexanes) to provide 137 mg (84%) of the title compound as a clear oil as a mixture of two diastereomers. MS (ESI): 486 (M+Na)+.
Step D - tert-butyl (5S)-2-ethynyl-5-(hydroxymethyl)-1-pyrrolidinecarboxylate
Figure imgf000106_0001
The title compound was prepared from tert-butyl (2S)-2-({[tert- butyl(diphenyl)silyl]oxy}methyl)-5-ethynyl-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step E. 1H NMR (300 MHz, CDCI3): δ 4.65-4.44 (m, 2H), 4.13-3.60 (m, 3H), 2.37-1.92 (m, 5H), 1.49 (s, 9H).
Step E - tert-butyl (5S)-2-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-5-(hydroxymethyl)-1 -pyrrolidinecarboxylate
Figure imgf000106_0002
The title compound was prepared from tert-butyl (5S)-2-ethyny|-5- (hydroxymethyl)-l -pyrrolidinecarboxylate and 6-bromo-Λ/-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}thieno[3,2-c |pyrimidin-4-amine by a procedure analogous to Example 1 , Step G. MS (ESI): 609 (M+H)+.
Step F - {(2S)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]pyrrolidinyl}methanol
The title compound was prepared from tert-butyl (5S)-2-[(4-{3-chloro-4-[(3- fluorobenzyl)oxy]anilino}thieno[3,2-rjpyrimidin-6-yl)ethynyl]-5-(hydroxymethyl)-1- pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step H. 1H NMR (400 MHz, DMSO-c/e): δ 9.72 (s, 1 H), 8.57 (s, 1 H), 7.92 (d, 1 H), 7.61 (dd, 1 H), 7.56 (s, 1 H), 7.51-7.44 (m, 1 H), 7.34-7.30 (m, 2H), 7.25 (d, 1 H), 7.19 (dt, 1 H), 5.26 (s, 2H), 4.62 (bs, 1 H), 4.18 (dt, 1 H), 3.50-3.15 (m, 1 H), 2.17-1.91 (m, 2H), 1.87-179 (m, 1 H), 1.60-1.47 (m, 1 H), 1.24 (br m, 2H); MS (ESI): 509 (M+H)+.
Example 14
N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-(2-piperidinylethynyl)thieno[3,2- d]pyrimidin-4-amine trifluoroacetate
Figure imgf000107_0001
The title compound was prepared as the trifluoroacetate salt from known 1 ,1- dimethylethyl 2-ethynyl-1 -piperidinecarboxylate and 6-bromo-Λ/-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-c/]pyrimidin-4-amine hydrochloride by a procedure analogous to Example 1 , Steps G and H. 1H NMR (300 MHz, DMSO-c/6): δ 9.64 (s, 1 H), 9.33 (br s, 1 H), 9.22 (br s, 1 H), 8.64 (s, 1 H), 7.90 (d, 1 H), 7.76 (s, 1 H), 7.60 (dd, 1 H), 7.51-7.43 (m, 1 H), 7.33-7.15 (m, 4H), 5.26 (s, 2H), 4.61 (br s, 1 H), 3.29-3.26 (m,1 H), 3.05 (br s, 1 H), 2.11-2.07 (m, 2H), 1.89-1.59 (m, 5H); HRMS (ESI):
(M+H)+ calculated 493.1265, found 493.1272.
Example 15 [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-pipeήdin-3-ylethynyl-thieno[3,2- d]pyrimidin-4-yl)-amine 10/
Figure imgf000108_0001
Step A - 1 ,1-dimethylethyl 3-ethynyl-1 -piperidinecarboxylate
Figure imgf000108_0002
The title compound was prepared from known 1 ,1-dimethylethyl 3-formyl-1- piperidinecarboxylate by a procedure analogous to Example 1 , Step D. 1H NMR (300
MHz, CDCI3): δ 3.92 (m, 1 H), 3.74 (dt, 1 H), 3.03 - 2.96 (m, 2H), 2.48-2.41 (m, 1 H), 2.07 (d, 1 H), 2.02 -1.96 (m, 1 H), 175-170 (m, 1 H), 1.61-1.55 (m, 1 H), 1.47 (s, 9H),
1.45-1.40 (m, 1 H).
Step B - [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-piperidin-3-ylethynyl-thieno[3,2- d]pyrimidin-4-yl)-amine trifluoroacetate
The title compound was prepared as the trifluoroacetate salt from 1 ,1- dimethylethyl 3-ethynyl-1 -piperidinecarboxylate and 6-bromo-/V-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-c ]pyrimidin-4-amine hydrochloride by a procedure analogous to Example 1 , Steps G and H. 1H NMR (300 MHz, DMSO-c/e): δ 9.94 (s, 1 H), 8.74 (br s, 1 H), 8.64 (br s, 1 H), 7.89 (s, 1 H), 7.62-7.58 (m, 2H), 7.51- 7.44 (m, 1 H), 7.34-7.16 (m, 4H), 5.26 (s, 2H), 3.47-3.44 (m, 1 H), 3.17 (m, 3H), 3.08- 2.96 (m, 1 H), 2.04 (m, 1 H), 1.87-1.68 (m, 3H); MS (ESI): 494 (M+H)+.
Example 16 6-[(2S)-2-azetidinylethynyl]-N-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-d]pyrimidin-4-amine
Figure imgf000109_0001
Step A - 1, 1-dimethylethyl (2S)-2-ethynyl-1-azetidinecarboxylate
Figure imgf000109_0002
The title compound was prepared from known 1 ,1-dimethylethyl (2S)-2- formyl-1-azetidinecarboxylate by a procedure analogous to Example 1 , Step D. 1H NMR (300 MHz, CDCI3): δ 476-470 (m, 1 H), 3.99-3.81 (m, 2H), 2.57-2.45 (m, 2H), 2.33-2.24 (m, 1 H), 1.46 (s, 9H).
Step B - 6-[(2S)-2-azetidinylethynyl]-N-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-d]pyrimidin-4-amine trifluoroacetate
The title compound was prepared as the trifluoroacetate salt from 1 ,1- dimethylethyl (2S)-2-ethynyl-1-azetidinecarboxylate and 6-bromo-Λ/-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-c/]pyrimidin-4-amine hydrochloride by a procedure analogous to Example 1 , Steps G and H. 1H NMR (300 MHz, DMSO-c/e): δ 10.00 (s, 1 H), 9.79 (br s, 1 H), 9.14 (br s, 1 H), 8.64 (s, 1 H), 7.89 (d, 1 H), 7.77 (s, 1 H), 7.59 (dd, 1 H), 7.51-7.43 (m, 1 H), 7.33-7.25 (m, 2H), 7.21-7.16 (m, 1 H), 5.85 (br s, 1 H), 5.52 (m, 1 H), 5.26 (s, 2H), 4.03-3.97 (m, 1 H), 3.84 (br s, 1 H), 2.80-2.69 (m,
2H); HRMS (ESI): (M+H)+ calculated 465.0952, found 465.0970.
Example 17
N-(3-Chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(trifluoroacetyl)-2- pyrrolidinyl]ethynyl}thieno[3, 2-d]pyrimidin-4-amine
Figure imgf000110_0001
To a suspension of /V-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6- [(2R)-2-pyrrolidinylethynyl]thieno[3,2-c]pyrimidin-4-amine (50 mg, 0.10 mmol) in 2 mL CH2CI2 cooled to 0 °C was added trifluoroacetic anhydride (0.06 mL, 0.40 mmol). When the starting material disappeared by TLC, the reaction was allowed to warm to rt and diluted with methanol. The mixture was diluted further with methylene chloride. The organic phase was washed with saturated aqueous NaHC03, water and brine. The organic layer was dried over MgS04 and concentrated. The crude material was purified via column chromatography to afford the title compound as a yellow solid (30 mg, 53%). 1H NMR (300 MHz, DMSO-e/6): δ 9.75 (s, 1 H), 8.56 (s, 1 H), 7.91 (s, 1 H), 7.59 (m, 2H), 7.44 (m, 1 H), 7.31-7.14 (M, 4H), 5.23 (s, 2H), 5.06 (m, 1 H), 3.79 (m, 1 H), 3.65 (m, 1 H), 2.26-2.22 (m, 1 H), 2.10-2.09 (m, 3H); HRMS
(ESI): (M+H)+ calculated 575.0932, found 575.0941.
Example 18
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(morpholin-3-ylethynyl)thieno[3,2- d]pyrimidin-4-amine
Figure imgf000110_0002
Step A - (3S)-4-benzyl-5-oxomorpholine-3-carboxylic acid
Figure imgf000110_0003
Chloroacetyl chloride (2.26 mL, 28.2 mmol) was added to a 0 °C stirred suspension of Λ/-benzyl-L-serine (5.00 g, 25.6 mmol) and sodium hydroxide (1.23 g, 30.8 mmol) in distilled water (25 mL). The reaction stirred for 30 min and 10 mL of sodium hydroxide (30% w/w) was added. The reaction was heated to 32 °C and stirred for 2 h. The reaction was then cooled to 0 °C and concentrated HCl was added until the mixture reached pH 1. The suspension was filtered and resulted in 2.5 g (41 %) of the title compound as a white powder. 1H NMR (400 MHz, DMSO-c/6): 9.47 (d, 1H), 7.52 (m, 2H), 7.40 (m, 3H), 4.26 (s, 2H), 4.20 (s, 2H), 4.00-3.82 (m, 3H).
Step B - [(3R)-4-benzylmorpholin-3-yl]methanol
Figure imgf000111_0001
Red Al (20 mL, 53.2 mmol, 65% w/w in toluene) was added slowly to a stirred suspension of (3S)-4-benzyl-5-oxomorpholine-3-carboxylic acid (2.5 g, 10.6 mmol) in toluene (30 mL). The reaction stirred at room temperature for 15 h. The reaction was cooled to 0 °C and ethanol was added drop-wise until gas evolution stopped. The mixture was treated with 2/V sodium hydroxide (100 mL) and the toluene layer was separated. The toluene was washed with 2/V HCl and the aqueous layer was separated and treated with 2/V sodium hydroxide until alkaline. The alkaline solution was extracted with ethyl acetate. The solvent was removed under vacuum and the resulting oil was dissolved in ethanol. The hydrochloride salt was formed by adding 1M HCI/diethyl ether. Filtration yielded 1.3 g (59%) of a dark pink hydrochloride salt. MS (ESI): 208 (M+H)+.
[(3R)-4-Benzylmorpholin-3-yl]methanol hydrochloride (1.3 g, 5.3 mmol) was stirred vigorously with ammonium formate (989 mg, 15.7 mmol), palladium (650 mg, 10% on carbon), methanol (13 mL) and distilled water (1 mL) at 60 °C for 15 h. The reaction mixture was filtered and the filtrate concentrated to an oil. The resulting (3R)-morpholin-3-ylmethanol was mixed with THF (15 mL), triethylamine (2.9 mL, 21.3 mmol) and di(tert-butyl) dicarbonate (3.5 g, 16 mmol) at 0°C. The reaction warmed to room temperature and stirred for 4 h. The reaction was partitioned between ethyl acetate and distilled water and the organic layer was dried over sodium sulfate. The solvent was removed under vacuum leaving a yellow oil. The crude oil was purified by silica gel chromatography (gradient: 20-70% ethyl acetate/hexanes). Purification resulted in 633 mg (54%) of the title compound as a white powder. 1H NMR (400 MHz, CDCI3): δ 4.02 (br s, 1 H), 3.96-3.80 (4H), 3.75 (d, 1 H), 3.58 (dd, 1 H), 3.47 (dt, 1 H), 3.18 (t, 1 H), 1.47 (s, 9H).
Step D - tert-butyl 3-formylmorpholine-4-carboxylate
Figure imgf000112_0001
The title compound was prepared from tert-butyl (3R)-3- (hydroxymethyl)morpholine-4-carboxylate by a procedure analogous to Example 1 , Step C. 1H NMR (400 MHz, CDCI3): δ 9.65 (s, 1H), 4.54-4.24 (m, 1H), 3.97-3.60 (m, 2H), 3.69 (dd, 1 H), 3.58-3.38 (m, 1 H), 3.46 (d, 1 H), 3.32-3.00 (m, 1 H), 1.47 (s, 9H).
Step E - tert-butyl 3-ethynylmorpholine-4-carboxylate
Figure imgf000112_0002
The title compound was prepared from tert-butyl 3-formylmorpholine-4- carboxylate by a procedure analogous to Example 1 , Step D. 1H NMR (400 MHz, CDCIs): 4.74 (br s, 1 H), 3.99-3.86 (m, 2H), 3.71 (d, 2H), 3.60 (dd, 1 H), 3.47 (dd, 1 H), 3.39-3.24 (m, 1 H), 2.31 (s, 1H), 1.48 (s, 9H).
Step F - tert-butyl 3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}morpholine-4-carboxylate
Figure imgf000112_0003
The title compound was prepared from tert-butyl 3-ethynylmorpholine-4- carboxylate and 6-bromo-/V-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}thieno[3,2- c ]pyrimidin-4-amine hydrochloride by a procedure analogous to Example 1 , Step G. 1H NMR (400 MHz, CDCI3): δ 8.66 (s, 1 H), 7.60 (s, 1 H), 7.47 (s, 1 H), 7.39-7.35 (m, 2H), 7.24 (m, 1 H), 7.12 (br s, 1 H). 7.03 (m, 1 H), 6.98 (d, 1 H), 5.19 (s, 2H), 4.99 (br s, 1 H), 4.02 (d, 1 H), 3.93 (d, 1 H), 3.75 (d, 1 H), 3.67 (dd, 1 H), 3.50 (t, 1 H), 3.33 (t, 1 H), 3.14 (dd, 1 H), 1.48 (s, 9H). MS (ESI): 595 (M+H)+.
Step G - N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(morpholin-3- ylethynyl)thieno[3,2-d]pyrimidin-4-amine The title compound was prepared from tert-butyl 3-{[4-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)thieno[3,2-c/]pyrimidin-6-yl]ethynyl}morpholine-4- carboxylate by a procedure analogous to Example 1 , Step H. 1H NMR (400 MHz, CDCI3): δ 8.64 (s, 1 H), 7.60 (s, 1 H), 7.43 (s, 1 H), 7.42-7.28 (m, 2H), 7.27-7.20 (m, 2H), 7.07-6.91 (m, 3H), 5.20 (s, 2H), 3.95 (m, 2H), 3.76 (m, 1 H), 3.67 (m, 2H), 3.08 (m, 1 H), 2.90 (m, 1 H). MS (ESI): 495 (M+H)+. The free base was dissolved in THF (2 mL) and treated with 1 M HCl in diethyl ether (100 μL) to form the hydrochloride salt. The solvent was removed and a brown powder was collected. MS (ESI): 495 (M+H)+.
Example 19
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[2,3- d]pyrimidin-4-amine
Figure imgf000113_0001
Step A - 6-bromo-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}thieno[2,3-d]pyrimidin-4- amine hydrochloride
Figure imgf000114_0001
The title compound was prepared from 6-bromo-4-chlorothieno[2,3- c/]pyrimidine and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline by a procedure analogous to Example 1 , Step 1. 1H-NMR (400 MHz, DMSO-c/6): δ 5.23 (s, 2H), 7.17 (ddd, 1 H), 7.25 (d, 1 H), 7.28-7.32 (m, 2H), 7.45 (ddd, 1 H), 7.66 (dd, 1 H), 8.01 (d, 1 H), 8.08 (s, 1 H), 8.48 (s, 1 H), 9.75 (br s, 1 H); MS (Cl): 463.9 (M+H)+.
Step B - tert-butyl (2R)-2-{[4-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)thieno[2,3-d]pyrimidin-6-yl]ethynyl}pyrrolidine-1- carboxylate
Figure imgf000114_0002
The title compound was prepared from 6-bromo-Λ/-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}thieno[2,3-c/]pyrimidin-4-amine and tert-butyl (2R)-2- ethynylpyrrolidine-1-carboxylate by a procedure analogous to Example 1 , Step G. 1H NMR (400 MHz, DMSO-c/6): δ 1.43 (s, 9H), 1.87-2.03 (m, 2H), 2.13-2.25 (m, 1 H), 3.25-3.38 (m, 3H), 4.66-475 (m, 1 H), 5.23 (s, 2H), 7.17 (dd, 1 H), 7.25-7.32 (m, 3H), 7.43-7.49 (m, 1 H), 7.64 (d, 1 H), 7.98-8.03 (m, 2H), 8.52 (s, 1 H), and 9.65 (s, 1 H); MS (APCI): 579.2 (M+H)+. Step C - N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[2,3-d]pyrimidin-4-amine The title compound was prepared from tert-butyl (2R)-2-{[4-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)thieno[2,3-c/]pyrimidin-6-yl]ethynyl}pyrrolidine-1- carboxylate by a procedure analogous to Example 1 , Step H. 1H NMR (400 MHz, DMSO-c/e): δ 1.67-7.84 (m, 3H), 2.02-2.09 (m, 1 H), 279-2.85 (m, 1 H), 2.90-2.96 (m, 1 H), 4.07 (dd, 1 H), 5.23 (s, 2H), 7.17 (ddd, 1 H), 7.26 (d, 1 H), 7.28-7.33 (m, 2H), 7.46 (ddd, 1 H), 7.64 (dd, 1 H), 7.96 (s, 1 H), 8.01 (d, 1 H), 8.51 (s, 1 H), and 9.64 (br s, 1 H); HRMS (ESI): (M+H)+ calculated 479.1109, found 479.1118.
Example 20
N-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine
Figure imgf000115_0001
The title compound was prepared from 6-bromo-4-chlorothieno[3,2- rJpyrimidine and tert-butyl (2R)-2-ethynylpyrrolidine-1 -carboxylate alkyne by a procedure analogous to Example 1 , Step G. 1H NMR (300 MHz, CDCI3): δ 8.96 (s, 1 H), 7.95 (s, 1 H), 4.82-4.69 (m, 1 H), 3.54-3.39 (m, 3H), 2.23-1.98 (m, 3H), 1.50 (s, 9H). Step B - tert-butyl (2R)-2-[(4-chlorothieno[3,2-d]pyrimidin-6-yl)ethynyl]-1- pyrrolidinecarboxylate The title compound was prepared from tert-butyl (2R)-2-ethynyl-1- pyrrolidinecarboxylate and 6-bromo-4-chlorothieno[3,2-c/]pyrimidine by a procedure analogous to Example 1, Step G.
Step C - [3-chloro-4-(2-pyridinyloxy)phenyl]amine
Figure imgf000116_0001
4-amino-2-chlorophenol (0.5 g, 3.5 mmol) was combined with 2-fluoropyridine (0.34 g, 3.5 mmol), DMSO (10 mL) and potassium carbonate (0.96 g, 6.97 mmol). The reaction mixture was stirred at 100 °C for 5 h then at 130 °C for 3 h. By LC/MS reaction was incomplete; excess 2-fluoropyridine (0.34 g, 3.5 mmol) was added and then the reaction was heated to 140 °C for 2 h then 100 °C overnight. The reaction was cooled to room temperature then partitioned between ethyl acetate (150 mL) and water (150 mL), the organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude mixture of product and starting materials. This mixture was purified by silica gel chromatography to give 0.3 g (39%) of the title compound. MS (APCI): 221(M+H)+.
Step D - tert-butyl (2R)-2-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-
Figure imgf000116_0002
The title compound was prepared from tert-butyl (2R)-2-[(4-chlorothieno[3,2- c/]pyrimidin-6-yl)ethynyl]-1 -pyrrolidinecarboxylate and [3-chloro-4-(2- pyridinyloxy)phenyl]amine by a procedure analogous to Example 1 , Step A. MS (ESI): 548 (M+H)+.
Step E - N-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine
The title compound was prepared from tert-butyl (2R)-2-[(4-{[3-chloro-4-(2- pyridinyloxy)phenyl]amino}thieno[3,2-c/]pyrimidin-6-yl)ethynyl]-1- pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step H. 1H NMR (400 MHz, DMSO-c/e): δ 9.87 (s, 1 H), 8.63 (s, 1 H), 8.13-8.07 (m, 2H), 7.87 (ddd, 1 H), 7.73 (dd, 1 H), 7.58 (s, 1 H), 7.31 (d, 1 H), 7.16-7.08 (m, 2H), 4.10-4.04 (m, 1 H), 2.97- 2.87 (m, 1 H), 2.87-277 (m, 1 H), 2.13-2.01 (m, 1 H), 1.85-1.63 (m, 3H); HRMS (ESI): (M+H)+ found 448.1015.
Example 21
N-[3-chloro-4-(1-naphthyloxy)phenyl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine
Figure imgf000117_0001
Step A - 1-[(2-chloro-4-nitrophenyl)oxy]naphthalene
Figure imgf000117_0002
Commercially available 1-bromo-2-chloro-4-nitrobenzene (10.0 g, 42 mmol) and commercially available 1-naphthalenol (6.7 g, 46 mmol) were combined in acetonitrile (100 mL). Cesium carbonate (34.4g, 106 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. Water (150 mL) was added to the reaction mixture which was then extracted with ethyl acetate (150 mL), washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in 11 /
vacuo. The resulting crude compound was dissolved in diethyl ether (20 mL) and hexanes were added until solids precipitated from solution. The solids were filtered and collected to afford 6.2 g (49%) of the title compound. 1H-NMR (400 MHz, DMSO- c/e): δ 8.52 (d, 1 H), 8.10 (dd, 1 H), 8.06 (d, 1 H), 7.92 (d, 1 H), 7.84 (d, 1 H), 7.65-7.55 (m, 3H), 7.32 (d, 1 H), 6.88 (d, 1 H).
Step B - [3-chloro-4-(1-naphthalenyloxy)phenyl]amine
Figure imgf000118_0001
1-[(2-chloro-4-nitrophenyl)oxy]naphthalene (1.0 g, 23.3 mmol) and dichlorostannane dihydrate (3.76 g, 137mmol) were dissolved in ethyl acetate (30 mL) and heated at 70 °C for 16 h. The reaction was cooled to room temperature, ethyl acetate (150 mL) and saturated sodium bicarbonate (100 mL) were added, followed by filtration of the resulting organic/aqueous mixture through Celite. The filtrate was partitioned and the organic layer was then washed with brine, dried over sodium sulfate and concentrated to obtain a semi-solid which was then sonicated in ethyl acetate/ethyl ether and filtered to give 0.79 g (87%) of the title compound. MS (ESI): 269 (M)+.
Step C - 6-bromo-N-[3-chloro-4-(1-naphthalenyloxy)phenyl]thieno[3,2-d]pyrimidin-4- amine hydrochloride
Figure imgf000118_0002
The title compound was prepared as the hydrochloride salt from [3-chloro-4- (1-naphthalenyloxy)phenyl]amine and 6-bromo-4-chlorothieno[3,2-c/]pyrimidine by a procedure analogous to Example 1 , Step A. MS (APCI): 482 (M)+ Step D - N-[3-chloro-4-(1-naphthyloxy)phenyl]-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3,2-d]pyrimidin-4-amine
The title compound was prepared as the trifluoroacetate salt from 6-bromo-/V- [3-chloro-4-(1 -naphthalenyloxy)phenyl]thieno[3,2-c/]pyrimidin-4-amine_and tert-butyl (2R)-2-ethynyl-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Steps G and H. 1H-NMR (400 MHz, DMSO-c/6): δ 10.06 (s, 1 H); 9.49 (br s, 1 H); 9.42 (br s, 1 H); 8.68 (s, 1 H); 8.21-8.15 (m, 2H); 8.02-7.98 (m, 1 H); 7.79 (s, 1 H); 7.72 (s, 1 H); 771-7.69 (m, 1 H); 7.64-7.58 (m, 2H); 7.45 (t, 1 H); 7.18 (d, 1 H); 6.80 (d, 1 H); 478-471 (m, 1 H); 3.36-3.22 (m, 2H); 2.43-2.35 (m, 1 H); 2.12-1.93 (m, 3H); HRMS: (M+H)+ found 497.1209.
Example 22
N-[5-(2-pyridinyloxy)-2-naphthalenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine trifluoroacetate
Figure imgf000119_0001
Step A - [5-(2-pyridinyloxy)-2-naphthalenyl]amine
Figure imgf000119_0002
The title compound was prepared from 6-amino-1-naphthalenol and 2- fluoropyridine by a procedure analogous to Example 20, Step B. MS (ESI): 237 (M+H)+. Step B - 6-bromo-N-[5-(2-pyridinyloxy)-2-naphthalenyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride
Figure imgf000120_0001
The title compound was prepared as the hydochloride salt from [5-(2- pyridinyloxy)-2-naphthalenyl]amine and 6-bromo-4-chlorothieno[3,2-c/]pyrimidine by a procedure analogous to Example 1 , Step 1. MS (ESI): 449 (M)+
Step C - N-[5-(2-pyridinyloxy)~2-naphthalenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine trifluoroacetate
The title compound was prepared as the trifluoroacetate salt from 6-bromo-/V- [5-(2-pyridinyloxy)-2-naphthalenyl]thieno[3,2-c/]pyrimidin-4-amine and tert-butyl (2R)- 2-ethynyl-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Steps G and H. 1H-NMR (400MHz, DMSO-d6): δ 10.23 (s, 1 H), 9.46 (br s, 2H), 8.69 (s, 1 H), 8.41 (s, 1H), 8.09 (s, 1H), 7.93-775 (m, 3H), 7.53 (t, 1H), 7.22-7.10 (m, 3H), 4.73 (br s, 1 H), 3.35-3.19 (m, 2H), 2.42-2.33 (m, 1 H), 2.10-1.94 (m, 3H); HRMS (ESI): (M+H)+ found 464.153.
Example 23
N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine trifluoroacetate
Figure imgf000120_0002
Step A - 1-[(3-fluorophenyl)methyl]-5-nitro-1H-indazole
Figure imgf000121_0001
To a solution of 0.489 g (3.0 mmol) of 5-nitroindazole in 25 mL of 90% acetone/water was added 0.828 g (6.0 mmol) of K2C03, 0.0567 g (4.5 mmol) of m- fluorobenzyl bromine, and 0.025 g (0.17mmol) of Nal. The resulting mixture was stirred at 55 °C for 18 h. The reaction was then cooled and the acetone was evaporated in vacuo. The aqueous residue was extracted with ethyl acetate, and the organic layer was washed with distilled water and dried over MgS04. The crude product was purified by silica gel chromatography (10% ethyl acetate/chloroform) to afford 0.333 g of 1-[(3-fluorophenyl)methyl]-5-nitro-1H-indazole.; 1H NMR (400 MHz, CDCI3) δ 7.85 (s, 1 H), 7.24 (d, 1 H), 7.13 (d, 1 H), 6.95 (m, 2H), 6.93 (s, 1 H), 6.84 (d, 1 H), 6.81 (d, 1H), 5.52 (s, 2H); MS (ESI): 272 (M+H)+.
Step B - 1-[(3-fluorophenyl)methyl]-1H-indazol-5-amine
Figure imgf000121_0002
To a solution of 0.333 g (1.22 mmol) of 5-nitro-1-(3-fluorobenzyl)-indazole in 10 mL of 75% methanol/water was added 0.342 g (6.12 mmol) of iron powder and 0.558 g (10.4 mmol) of ammonium chloride. The resulting mixture is stirred at 65 °C for 18 h. The reaction was then cooled, diluted with 100 mL of ethyl acetate, filtered and evaporated in vacuo. The aqueous residue was extracted with ethyl acetate, and the organic layer was washed with distilled water and dried over MgS04 to afford 0.189 g of 1-[(3-fluorophenyl)methyl]-1H-indazol-5-amine. 1H NMR (400 MHz, DMSO-c/e) δ 7.77 (s, 1 H), 7.35 (m, 2H), 7.07 (t, 1 H), 6.96 (m, 2H), 6.77 (m, 2H), 5.54 (s, 2H), 4.83 (br s, 2H); MS(ESI): 241 (M+H)+. < Step C - 6-bromo-N-{1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}thieno[3,2- d]pyrimidin-4-amine hydrochloride
Figure imgf000122_0001
The title compound was prepared from 1-[(3-fluorophenyl)methyl]-1H-indazol-
5-amine and 6-bromo-4-chlorothieno[3,2-c |pyrimidine by a procedure analogous to Example 1 , Step A. MS (APCI): 454 (M+H)+.
Step D - N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3, 2-d]pyrimidin-4-amine trifluoroacetate
The title compound was prepared as the trifluoroacetate salt from 6-bromo-/V- {1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}thieno[3,2-c/]pyrimidin-4-amine hydrochloride and tert-butyl (2R)-2-ethynyl-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Steps G and H. 1H NMR (400 MHz, DMSO-c/6): δ 10.13(br s, 1 H), 9.44 (br s, 2H), 8.63 (s, 1 H), 8.18 (s, 1 H) 8.07 (s, 1 H), 7.77 (t, 2H), 7.59 (d, 1 H), 7.39 (q, 1H), 7.12 (t, 1 H), 7.06 (d, 1 H), 5.72 (s, 2H), 4.72 (br s, 1 H), 3.28 (m, 2H), 2.36 (m, 2H), 2.03 (m, 3H); MS (ESI): 469 (M+H)+.
Example 24
N-[1-(phenylmethyl)-1H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine trifluoroacetate
Figure imgf000122_0002
1Z_.
Step A - tert-butyl (2S)-2-[(4-chlorothieno[2,3-d]pyrimidin-6-yl)ethynyl]pyrrolidine-1- carboxylate
Figure imgf000123_0001
The title compound was prepared from 6-bromo-4-chlorothieno[2,3- c/jpyrimidine and tert-butyl (2R)-2-ethynylpyrrolidine-1 -carboxylate by a procedure analogous to Example 1 , Step G. 1H-NMR (400 MHz, CDCI3): δ 1.50 (s, 9H), 1.93- 2.23 (m, 4H), 3.33-3.58 (m, 2H), 4.65-4.84 (m, 1 H), 7.42 (s, 1 H), 8.84 (s, 1 H); MS (ESI): 363.0 (M-CI+0)+.
Step B - N-[1-(phenylmethyl)-1H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine trifluoroacetate The title compound was prepared as the trifluoroacetate salt from 4-chloro-6- [(2R)-2-pyrrolidinylethynyl]thieno[2,3-c/]pyrimidine and known 5-amino-1- benzylindazole (G. S. Cockerill, K. E. Lackey, Preparation of quinazolinylamines and analogs as protein tyrosine kinase inhibitors. PCT Appl. 1999, WO9935132) by a procedure analogous to Example 1 , Steps A and H. 1H NMR (CD3OD): δ 8.42 (s, 1 H), 8.12 (s, 1H), 8.08 (s, 1 H), 7.92 (s, 1H), 7.58 (s, 2H), 7.28 (m, 3H). 7.22 (d. 2H), 5.66 (s. 2H), 4.72 (t, 1 H), 3.39 (m, 2H), 2.49 (m, 1 H), 2.20 (m, 3H); MS (ESI): 451 (M+H)+.
Example 25
6-[(2R)-2-pyrrolidinylethynyl]-N-[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]thM^ d]pyrimidin-4-amine trifluoroacetate 1Z3
Figure imgf000124_0001
Step A - 5-nitro-1-(1 ,3-thiazol-4-ylmethyl)-1 H-indazole
Figure imgf000124_0002
The title compound was prepared from 5-nitroindazole and 4-
(chloromethyl)thiazole hydrochloride by a procedure analogous to Example 23, Step A. 1H NMR (400 MHz, CDCI3): δ 879(s, 1 H), 8.74 (s, 1 H), 8.27 (d, 1 H), 8.25 (s, 1 H), 7.64 (d, 1H), 7.16 (s, 1H), 5.81 (s, 2H); MS (ESI): 261 (M+H)+.
Step B - 1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-amine
Figure imgf000124_0003
The title compound was prepared from 5-nitro-1-(1 ,3-thiazol-4-ylmethyl)-1H- indazole by a procedure analogous to Example 23, Step B. 1H NMR (400 MHz, CDCI3): δ 877(s, 1 H), 7.85 (s, 1 H), 7.30 (d, 1 H), 6.94 (s, 1 H), 6.91 (s, 1 H), 6.87 (d, 1 H), 5.72 (s, 2H), 3.61 (br s, 2H); MS (APCI): 231 (M+H)+.
Step C - 6-[(2R)-2-pyrrolidinylethynyl]-N-[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5- yl]thieno[3, 2-d]pyrimidin-4-amine trifluoroacetate
The title compound was prepared as the trifluoroacetate salt from tert-butyl (2R)-2-[(4-chlorothieno[3,2-c/]pyrimidin-6-yl)ethynyl]-1 -pyrrolidinecarboxylate and 1 - (1 ,3-thiazol-4-ylmethyl)-1H-indazol-5-amine by a procedure analogous to Example 1 , Steps A and H. 1H NMR (400 MHz, CD3OD): δ 8.97 (s, 1H), 8.68 (s, 1H), 8.14 (s, 1H), 8.03 (s, 1 H). 7.76 (d, 1 H), 7.57 (m, 2H), 7.43 (s, 1H), 5.84 (s, 2H), 4.70 (t, 1H), 3.39 (m, 2H), 2.46 (m, 1 H), 2.17 (m, 3H); MS (APCI): 458 (M+H)+.
Example 26
N-{3-chloro-4-[(1,3-thiazol-4-ylmethyl)oxy]phenyl}-6-[(2R)-2-pyrrolidinylethynyl] thieno[3, 2-d]pyrimidin-4-amine trifluoroacetate
Figure imgf000125_0001
Step A - 4-{[(2-chloro-4-nitrophenyl)oxy]methyl}-1,3-thiazole
Figure imgf000125_0002
The title compound was prepared from commercially available 2-chloro-4- nitrophenol and 4-(chloromethyl)thiazole hydrochloride by a procedure analogous to Example 23, Step A. 1H NMR (400 MHz, CDCI3): δ 8.86 (s, 1 H), 8.33 (s, 1 H), 8.15 (d, 1H), 7.51 (s, 1H), 7.18 (d, 1H), 5.46 (s, 2H); MS(ESI): 271 (M+H)+.
Step B - {3-chloro-4-[(1,3-thiazol-4-ylmethyl)oxy]phenyl}amine
Figure imgf000125_0003
The title compound was prepared from 4-{[(2-chloro-4- nitrophenyl)oxy]methyl}-1,3-thiazole by a procedure analogous to Example 23, Step B. 1H NMR (400 MHz, CDCI3): δ 8.82(s, 1H), 7.46 (s, 1H), 6.86 (d, 1H), 6.75 (s, 1H), 6.53 (d, 1 H), 5.24 (s, 2H), 3.51 (br s, 2H); MS (ESI): 241 (M+H)+.
Step C - N-{3-chloro-4-[(1,3-thiazol-4-ylmethyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3, 2-d]pyrimidin-4-amine trifluoroacetate
The title compound was prepared from tert-butyl (2R)-2-[(4-chlorothieno[3,2- c/]pyrimidin-6-yl)ethynyl]-1 -pyrrolidinecarboxylate and {3-chloro-4-[(1 ,3-thiazol-4- ylmethyl)oxy]phenyl}amine by a procedure analogous to Example 1 , Steps A and H. 1H NMR (400 MHz, CD3OD): δ 9.07 (s, 1 H), 8.72 (s, 1H), 7.74 (d, 2H), 7.63 (s, 1H), 7.51 (d, 1 H), 7.33 (d, 1 H), 5.37 (s. 2H), 4.74 (t, 1 H), 3.42 (m, 2H), 2.49 (m, 1 H), 2.21 (m, 3H); MS (APCI): 468 (M+H)+.
Example 27 (3R,5S)-5-({4-[(1-benzyl-1H-indazol-5-yl)amino]thieno[3,2-d]pyrimidin-6- yl}ethynyl)pyrrolidin-3-yl morpholine-4-carboxylate hydrochloride
Figure imgf000126_0001
Step A - (3R,5S)-1-(tert-butoxycarbonyl)-5-[(4-chlorothieno[3,2-d]pyrimidin-6- yl)ethynyl]pyrrolidin-3-yl morpholine-4-carboxylate
Figure imgf000126_0002
The title compound was prepared from (3R,5S)-1-(tert-butoxycarbonyl)-5- ethynylpyrrolidin-3-yl morpholine-4-carboxylate and 6-bromo-4-chlorothieno[2,3- cTJpyrimidine by a procedure analogous to Example 1 , Step G. 1H-NMR (400 MHz, CDCI3): δ 8.97 (s, 1 H), 7.57 (s, 1 H), 5.34-5.31 (m, 1 H), 373-3.63 (br m, 7H), 3.50- 3.40 (br s, 5H), 2.53-2.43 (m, 1 H), 1.51 (s, 9H); MS (ESI): 515 (M+Na)+.
Step B - (3R,5S)-5-({4-[(1-benzyl-1H-indazol-5-yl)amino]thieno[3,2-d]pyrimidin-6- yl}ethynyl)pyrrolidin-3-yl morpholine-4-carboxylate hydrochloride
The title compound was prepared as the hydrochloride salt from 1-benzyl-1/- - indazol-5-amine and (3R,5S)-1 -(tert-butoxycarbonyl)-5-[(4-chlorothieno[3,2- c/]pyrimidin-6-yl)ethynyl]pyrrolidin-3-yl morpholine-4-carboxylate by a procedure analogous to Example 1 , Steps A and H. 1H NMR (400 MHz, DMSO-c/6): 10.15 (br s, 1H), 9.85 (br s, 1H), 8.59 (s, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 779-7.68 (m, 2H), 7.57-7.50 (m, 1 H), 7.35-7.20 (m, 5H), 5.67 (s, 2H), 5.27 (s, 1 H), 4.93-4.82 (m, 2H), 3.66-3.47 (m, 4H), 3.47-3.24 (m, 4H), 2.40-2.23 (m, 2H), 1.73 (s, 1 H), 1.33 (s, 1 H); MS (ESI): 580 (M+H)+.
Example 28
N-[2-(3-fluorobenzyl)-1H-benzimidazol-5-yl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine trifluoroacetate
Figure imgf000127_0001
Step A - 2-(3-fluorobenzyl)-5-nitro-1H-benzimidazole
Figure imgf000127_0002
A solution of commercially available 4-nitrobenzene-1 ,2-diamine (1.91 g, 12.5 mmol) and (3-fluorophenyl)acetic acid (2.89 g, 18.8 mmol) in aqueous 4 M HCl (17 mL) was heated to 100 °C for 21 h. The resultant mixture was poured into 200 mL aqueous 3 M NaOH and extracted with 30% /-PrOH/CHCI3 (5 x 100 mL). The combined organic fractions were dried over MgS04 and concentrated to afford 3.39 g (100%) of the title compound. MS (APCI): 272.1 (M+H)+.
Step B - 2-(3-fluorobenzyl)-1H-benzimidazol-5-amine
Figure imgf000128_0001
The title compound was prepared from 2-(3-fluorobenzyl)-5-nitro-1H- benzimidazole by a procedure analogous to Example 23, Step B. MS (ESI): 242.0 (M+H)+.
Step C - N-[2-(3-fluorobenzyl)-1 H-benzimidazol-5-yl]-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate The title compound was prepared as the trifluoroacetate salt from 2-(3- fluorobenzyl)-1H-benzimidazol-5-amine and tert-butyl (2R)-2-[(4-chlorothieno[3,2- c/]pyrimidin-6-yl)ethynyl]-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Steps A and H. 1H NMR (400 MHz, DMSO-d6): δ 10.28 (br s, 1 H), 9.58
(br s, 2H), 8.66 (s, 1 H), 8.34 (s, 1 H), 7.78 (s, 1 H), 7.76 (d, 1 H), 7.49-7.43 (m, 1 H),
7.35-7.17 (m, 3H), 477-471 (m, 1 H), 4.54 (s, 2H), 3.37-3.20 (m, 2H), 2.41-2.34 (m,
1 H), 2.13-1.91 (m, 3H); HRMS (ESI): (M+H)+ calculated 469.1611 , found 469.1625.
Example 29
N-(3-chloro-4-{[(1R)1-(3-fluorophenyl)ethyl]oxy}phenyl)-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate
Figure imgf000128_0002
Step A - 2-chloro-1-[1-(3-fluorophenyl)ethoxy]-4-nitrobenzene
Figure imgf000129_0001
NaH (60% suspension in mineral oil, 214 mg, 5.35 mmol) was added to a solution of commercially available 1 -(3-fluorophenyl)ethanol (500 mg, 3.57 mmol) in DMSO (3.6 mL) and stirred at rt for 30 min (gas evolution observed). Commercially available 2-chloro-1-fluoro-4-nitrobenzene (627 mg, 3.57 mmol) was then added and the reaction stirred a further 20 h at rt. The reaction mixture was then poured into water (75 mL) and extracted with diethyl ether (3 x 25 mL). The combined organic fractions were washed with brine (1 x 50 mL), dried over MgS04, filtered, and concentrated. Purification by silica gel chromatography (5 to 8% EtOAc:hexanes) afforded 623 mg (59%) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-de) δ 8.30 (d, 1 H), 8.12 (dd, 1 H), 7.45-7.40 (m, 1 H), 7.29-7.24 (m, 3H), 7.15-7.10 (m, 1 H), 5.88 (q, 1 H), 1.63 (d, 3H).
Step B - 3-chloro-4-[1-(3-fluorophenyl)ethoxy]aniline
Figure imgf000129_0002
The title compound was prepared from 2-chloro-1-[1-(3-fluorophenyl)ethoxy]- 4-nitrobenzene by a procedure analogous to Example 23, Step B. MS (APCI): 266.1 (M+H)+.
Step C - N-(3-chloro-4-{[(1R)1-(3-fluorophenyl)ethyl]oxy}phenyl)-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3, 2-d]pyrimidin-4-amine trifluoroacetate
The title compound was prepared as the trifluoroacetate salt from 3-chloro-4-[1-(3- fluorophenyl)ethoxy]aniline and tert-butyl (2R)-2-[(4-chlorothieno[3,2-d|pyrimidin-6- yl)ethynyl]-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Steps A and H. The mixture of diastereomers obtained by this procedure was resolved at the Boc-protected stage by chiral supercritical fluid chromatography (SFC). 1H NMR (DMSO-d6): δ 9.87 (br s, 1 H), 9.44 (br s, 2H), 8.60 (s, 1 H), 7.83 (d, 1 H), 7.73 (s, 1 H), 7.48-7.38 (m, 2H), 7.29-7.23 (m, 2H), 7.13-7.08 (m, 2H), 5.68-5.63 (m, 1 H), 4.75- 4.68 (m, 1 H), 3.34-3.23 (m, 2H), 2.41-2.33 (m, 1 H), 2.09-1.94 (m, 3H), 1.59 (d, 3H); HRMS: (M+H)+ calculated 493.1265, found 493.1287.
Example 30
N-[4-(phenylsulfonyl)phenyl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2-d]pyrimidin-4- amine
Figure imgf000130_0001
The title compound was prepared as the trifluoroacetate salt from tert-butyl (2R)-2-[(4-chlorothieno[3,2-djpyrimidin-6-yl)ethynyl]-1 -pyrrolidinecarboxylate and known 4-(phenylsulfonyl)aniline (Alfred Courtin, Syntheses of some alkyl-, cycloalkyl- and aryl-(4-aminophenyl) sulfones. Helvetica Chimica Acta (1983), 66(4), 1046-52) by a procedure analogous to Example 1 , Steps A and H. 1H NMR (DMSO-d6): δ 10.30 (br s, 1 H), 9.48 (br s, 2H), 8.71 (s, 1 H), 8.10-8.05 (m, 2H), 7.98-7.92 (m, 4H), 7.81 (s, 1 H), 770-7.59 (m, 3H), 4.75 (t, 1 H), 3.36-3.21 (m, 2H), 2.44-2.31 (m, 1 H), 2.13-1.95 (m, 3H); HRMS: (M+H)+ calculated 461.1106, found 461.1098.
Example 31
N-[3-chloro-4-(1,3-thiazol-2-ylthio)phenyl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine
Figure imgf000131_0001
Step A - 3-chloro-4-(1,3-thiazol-2-ylthio)aniline
Figure imgf000131_0002
The title compound was prepared from 2-[(2-chloro-4-nitrophenyl)thio]-1 ,3- thiazole (prepared by methods known to those skilled in the art) by a procedure analogous to Example 23, Step B. MS (APCI): 242.98 (M+H)+.
Step B - N-[3-chloro-4-(1,3-thiazol-2-ylthio)phenyl]-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3,2-d]pyrimidin-4-amine The title compound was prepared as the trifluoroacetate salt from tert-butyl
(2R)-2-[(4-chlorothieno[3,2-c/]pyrimidin-6-yl)ethynyl]-1 -pyrrolidinecarboxylate and 3- chloro-4-(1 ,3-thiazol-2-ylthio)aniline by a procedure analogous to Example 1 , Steps A and H. 1H NMR (DMSO-d6): δ 10.21 (br s, 1 H), 9.51 (br s, 2H), 8.76 (s, 1 H), 8.32 (s, 1 H), 7.93 (s, 1 H), 7.89 (s, 1 H), 7.72 (m, 5H), 4.75 (t, 1 H, J = 5.2 Hz), 3.29 (m, 2H), 2.38 (m, 1 H), 2.06 (m, 3H); HRMS: (M+H)+ calculated 470.0335, found 470.0337.
Example 32
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine hydrochloride
Figure imgf000132_0001
Step A - 2-[(2-chloro-4-nitrophenoxy)methyl]pyridine
Figure imgf000132_0002
To a solution containing 2.0 g (11.4 mmol) of 2-chloro-1-fluoro-4-nitrobenzene and 10mL of DMF was added 173 g (12.5 mmol) of potassium carbonate followed by 1.1mL (11.4 mmol) of pyridin-2-ylmethanol. The reaction mixture was heated to 100 °C for 16 h, then cooled to rt, poured into water, and filtered. The filtrate was washed with water and ether, then collected to provide 2.4 g (80%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 5.46 (s, 2H), 7.38 (dd, 1 H), 7.47 (d, 1 H, J = 9.6 Hz), 7.56 (d, 1 H), 7.88 (ddd, 1 H), 8.23 (dd, 1 H), 8.36 (d, 1 H), 8.59 (d, 1 H); MS (ESI): 265.0 (M+H)+.
Step B - 3-chloro-4-(pyridin-2-ylmethoxy)aniline hydrochloride
Figure imgf000133_0001
The title compound was prepared as the hydrochloride salt by a procedure analogous to Example 23, Step B. 1H NMR (400 MHz, DMSO-d6): δ 5.44 (s, 2H), 7.35 (s, 2H), 7.54 (s, 1 H), 7.64 (dd, 1H), 7.79 (d, 1 H), 8.18 (ddd, 1H), 8.74 (d, 1H); MS (ESI): 235.0 (M+H)+.
Step C - tert-butyl (2R)-2-[(4-{[3-chloro-4-(pyridin-2- ylmethoxy)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]pyrrolidine-1-carboxylate
Figure imgf000133_0002
The title compound was prepared from 3-chloro-4-(pyridin-2-ylmethoxy)aniline hydrochloride and tert-butyl (2R)-2-[(4-chlorothieno[3,2-djpyrimidin-6- yl)ethynyl]pyrrolidine-1 -carboxylate by a procedure analogous to Example 1 , Step A. 1HNMR (400 MHz, CDCI3): δ 1.46 (s, 9H), 1.93-2.14 (m, 4H), 3.33-3.55 (m, 2H), 4.62-470 (m, 1 H), 5.32 (s, 2H), 7.03 (d, 1 H), 7.24-7.28 (m, 2H), 7.33 (dd, 1 H), 7.41 (br s, 1 H), 7.61 (d, 1 H), 7.67 (d, 1 H), 7.78 (ddd, 1 H), 8.60 (d, 1 H), and 8.63 (s, 1 H); MS (APCI): 562.0 (M+H)+.
Step D - N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3, 2-d]pyrimidin-4-amine hydrochloride The title compound was prepared as the hydrochloride salt from tert-butyl (2R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]pyrrolidine-1-carboxylate by a procedure analogous to Example 1 , Step H. 1H NMR (400 MHz, CD3OD): δ 1.97-2.14 (m, 3H), 2.35-2.43 (m, 1 H), 3.23-3.29 (m, 1 H), 3.31-3.36 (m, 1 H), 4.65 (dd, 1 H), 5.51 (s, 2H), 7.27 (d, 1 H), 7.52 (dd, 1 H), 7.62 (s, 1H), 7.76 (br s, 1H), 7.93 (ddd, 1H), 8.13 (d, 1H), 8.53 (ddd, 1H), 8.70 (s, 1H), 8.78 (d, 1 H); HRMS: (M+H)+ calculated 462.1155, found 462.1164.
Example 33
N-[1-(2,5-difluorobenzyl)-1H-indol-5-yl]-6-[(2R)-pyrrolidin-2-ylethynyl] thieno[3, 2d]pyrimidin-4-amine trifluoroacetate
Figure imgf000134_0001
Step A - 1-(2,5-difluorobenzyl)-5-nitro-1H-indole
Figure imgf000134_0002
To a solution of 5-nitroindole (2.0 g, 12.3 mmol) in 40 mL DMF was added 3.4 g (24.6 mmol) K2C03 and 3.81 g (18.4 mmol) 2,5-difluorobenzylbromide. The mixture was warmed to 60 °C and stirred overnight. When all the starting material was reacted, the mixture was diluted with water and the organic extracted with ethyl acetate. The organic phase was dried over Na2S0 and the solvent was removed to afford the title compound. 1H NMR (300 MHz, (CD3)2CO): δ 8.57 (d, 1 H), 8.04 (d, 1 H), 7.72 (d, 1 H), 7.71 (d, 1 H), 7.32-7.26 (m, 1 H), 7.21-7.17 (m, 1 H), 6.99-6.94 (m, 1 H), 6.80 (d, 1 H), 5.57 (s, 2H).
Step B - 1 -(2, 5-difluorobenzyl) - 1 H-indol-5-amine
Figure imgf000135_0001
1-(2,5-Difluorobenzyl)-5-nitro-1H-indole (3.5g, 12.1 mmol) was dissolved in 60 mL glacial acetic acid, 3.5 g (61 mmol) iron was added, and the mixture stirred at 60 °C overnight. When all the starting material was reacted, the mixture was filtered through Celite, neutralized with 6 M NaOH and the organic layer was extracted with ethyl acetate. The organic phase was dried over Na2S04 and the solvent was removed to afford the title compound. 1H NMR (400 MHz, (CD3)2CO): δ 7.27-7.26 (m, 2H), 7.15-7.12 (m, 2H), 6.70 (m, 2H), 6.50 (d, 1H), 6.21 (d, 1H), 5.33 (s, 2H), 4.54 (s, 2H).
Step C - N-[1-(2,5-difluorobenzyl)-1H-indol-5-yl]-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3, 2 d]pyrimidin-4-amine trifluoroacetate
The title compound was prepared as the trifluoroacetate salt from 1-(2,5- difluorobenzyl)-1H-indol-5-amine and tert-butyl (2R)-2-[(4-chlorothieno[3,2- djpyrimidin-6-yl)ethynyl]pyrrolidine-1 -carboxylate by a procedure analogous to Example 1, Steps A and H. 1H NMR (400 MHz, (CD3)2CO): $ 10.09 (br s, 1 H), 9.37 130
(br s, 1 H), 8.52 (s, 1 H), 7.74 (s, 1 H), 7.64 (s, 1 H), 7.54-7.52 (m, 2H), 7.32-7.19 (m, 3H), 6.84 (s, 1 H), 6.55 (d, 1 H), 5.50 (s, 2H), 4.65 (s, 1 H), 3.46-3.25 (m, 2H), 2.35- 2.33 (m, 1 H), 2.02-1.94 (m, 3H). MS (ESI): 486 (M+H)+.
Example 34
N-{1-[(3-fluorophenyl)sulfonyl]-1H-indol-5-yl}-6-[(2R)-pyrrolidin-2-ylethyny^ d]pyrimidin-4-amine
Figure imgf000136_0001
Step A - 1-[(3-fluorophenyl)sulfonyl]-5-nitro-1H-indole
Figure imgf000136_0002
A flask was charged with 1.0 g (7.4 mmol) 5-nitroindole, 50 mL THF, and the mixture was cooled to 0 °C. NaH (271 mg, 11.3 mmol, 60% in mineral oil) was added and the mixture stirred at 0 °C for 30 minutes. Then, 1.4 g (7.4 mmol) 3- fluorobenzenesulfonyl chloride was added dropwise, and the reaction mixture warmed to react at rt. When all the staritng material had reacted, the mixture was quenched with 10% HCl solution, diluted with ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Mg2S04, the solvent was removed, and the crude title compound (2.23 g) was used 130
in the next step without further purification. 1H NMR (300 MHz, (CD3)2CO): δ 8.59 (s, 1 H), 8.21-8.20 (m, 2H), 8.12 (d, 1 H), 8.03 (d, 1 H), 7.92 (d, 1 H), 772-7.60 (m, 2H), 7.11 (d, 1 H).
Step B - 1-[(3-fluorophenyl)sulfonyl]-1H-indol-5-amine
Figure imgf000137_0001
The title compound was prepared from 1-[(3-fluorophenyl)sulfonyl]-5-nitro-1H- indole by a procedure analogous to Example 33, Step B. MS (APCI): 290 (M+H)+.
Step C - N-{1-[(3-fluorophenyl)sulfonyl]-1H-indol-5-yl}-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate The title compound was prepared as the trifluoroacetate salt from 1-[(3- fluorophenyl)sulfonyl]-1H-indol-5-amine and tert-butyl (2R)-2-[(4-chlorothieno[3,2- d]pyrimidin-6-yl)ethynyl]pyrrolidine-1 -carboxylate by a procedure analogous to Example 1 , Steps A and H. 1H NMR (400 MHz, (CD3)2CO): δ 10.0 (br s, 1 H), 9.41 (br s, 1H), 8.60 (s, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 7.96-7.92 (d, 1H), 7.89-7.86 (m, 2H), 7.74 (s, 1 H), 771-7.58 (m, 3H), 6.93 (d, 1 H), 4.73 (m, 1 H), 3.27 (m, 2H), 2.45- 2.30 (m, 1 H), 2.09-1.96 (m, 3H); MS (ESI): 516 (M-H)+.
Example 35
N-(4-benzylphenyl)-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2-d]pyrimidin-4-amine
Figure imgf000137_0002
The title compound was prepared from tert-butyl (2R)-2-[(4-chlorothieno[3,2- djpyrimidin-6-yl)ethynyl]pyrrolidine-1 -carboxylate and commercially available 4- benzylaniline by a procedure analogous to Example 1 , Steps A and H. 1H NMR (DMSO-d6): δ 9.83 (s, 1 H), 8.60 (s, 1 H), 8.17 (s, 1 H), 7.77 (s, 1 H), 7.63 (d, 2H), 7.36- 7.20 (m, 7H), 477-474 (m, 1 H), 3.98 (s, 2H), 3.41-3.29 (m, 2H), 2.45-2.38 (m, 2H), 2.12-2.00 (m, 2H); MS (APCI): 411.1 (M+H)+.
Example 36 (3S,5R)-5-[(4-{[1-(Phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate
Figure imgf000138_0001
thylethyl (2R,4S)-2-ethynyl-4-hydroxy-1-pyrrolidinecarboxylate
Figure imgf000138_0002
To a solution containing 2.6 g (12.3 mmol) of 1 ,1-dimethylethyl (2R,4R)-2- ethynyl-4-hydroxy-1 -pyrrolidinecarboxylate, 2.89 g (27.0 mmol) of 4-nitrobenzoic acid, and 40 mL of toluene at 0°C was added 8.1 g (30.8 mmol) of triphenyl phosphine, followed by 5.4 g (30.8 mmol) of DEAD in portions. The reaction mixture was allowed to stir for 2h, then quenched by the addition of water and extracted with ethyl acetate. The organic layers were dried over MgS0 and the solvent was removed under reduced pressure. The residue was subjected to silica gel chromatography to give 3.9 g (88%) of 1 ,1-dimethylethyl (2R,4S)-2-ethynyl-4-{[(4- nitrophenyl)carbonyl]oxy}-1 -pyrrolidinecarboxylate as a yellow solid: 1H-NMR (CDCI3, 400MHz) δ 8.29 (d, 2H, J = 8.8 Hz), 8.17 (d, 2H, J = 8.8 Hz), 5.56-5.59 (m, 1H), 4.60- 4.74 (m, 1 H), 3.69-3.80 (m, 2H), 2.44-2.56 (m, 2H), 2.34 (brs, 1 H), 1.50 (s, 9H). To a solution containing 3.9 g (10.9 mmol) of 1 ,1-dimethylethyl (2R,4S)-2- ethynyl-4-{[(4-nitrophenyl)carbonyl]oxy}-1 -pyrrolidinecarboxylate and 30 mL of methanol was added 3.0 g (21.8 mmol) of potassium carbonate. The reaction mixture was allowed to stir for 30 min, then diluted with water and extracted with ethyl acetate. The organic layers were dried over MgS04 and the solvent was removed under reduced pressure. The residue was subjected to silica gel chromatography to give 1.75 g (76 %) of the title compound as a clear oil. 1H-NMR (CDCI3, 400MHz) δ 4.09-4.18 (m, 2H), 3.58 (dd, 1 H, J = 11.5 and 4.8 Hz), 3.35-3.50 (m, 1 H), 2.21-2.27 (m, 4H), 1.49 (s, 9H).
Step B- 1,1-dimethylethyl (2R,4S)-4-{[(ethylamino)carbonyl]oxy}-2-ethynyl-1- pyrrolidinecarboxylate
Figure imgf000139_0001
To a solution containing 1.75 g (8.3 mmol) of 1 ,1-dimethylethyl (2R,4S)-2- ethynyl-4-hydroxy-1 -pyrrolidinecarboxylate and 35 mL of THF at 0 °C was added 0.7 mL (5.7 mmol) of trichloroacetyl chloride. The reaction was allowed to stir at this temperature for 30 min and 35 mL (70.6 mmol) of a 2.0 M solution of ethylamine in THF was added. The reaction mixture was allowed to stir for an additional 1 h, then partitioned between ethyl acetate and water. The organic layers were washed with brine and dried over MgS04. The solvents were removed under reduced pressure and the residue was subjected to silica gel chromatography to give 1.44 g of the title compound as a clear oil: 1H NMR (CDCI3, 400 MHz) δ 5.23 (brs, 1 H), 4.63 (brs, 1 H), 4.48-4.55 (m, 1 H), 3.45-3.62 (m, 2H), 3.19-3.35 (m, 2H), 2.29-2.36 (m, 3H), 1.48 (s, 9H), 1.13 (t, 3H, = 7.1 Hz).
Step C- 6-Bromo-N-[1-(phenylmethyl)-1H-indazol-5-yl]thieno[3,2-d]pyrimidin-4-amine
Figure imgf000140_0001
A solution containing 12.0 g (53.7 mmol) of 1-(phenylmethyl)-1H-indazol-5- amine, 13.4 g (53.7 mmol) of 6-bromo-4-chlorothieno[3,2-d]pyrimidine, and 50 mL of isopropanol was heated at 60°C for 13 h. The reaction mixture was filtered and the filter cake was washed with isopropanol and ether to give 24.1 g (95%) of hydrochloride salt of the title compound as a yellow solid: 1H NMR (d6-DMSO, 400MHz) δ 10.56 (brs, 1H), 8.67 (brs, 1H), 8.20 (s, 1H), 8.07 (s, 1 H), 7.81 (d, 1H, J = 8.9 Hz), 7.72 (s, 1 H), 7.57 (dd, 1 H, J = 8.9 and 1.9 Hz), 7.25-7.39 (m, 5H), 5.74 (s, 2H). ESIMS: 436.0 and 438.0 (M+H+).
Step D- 1, 1 -Dimethylethyl (2R,4S)-4-{[(ethylamino)carbonyl]oxy}-2-[(4-{[1-
(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-1- pyrrolidinecarboxylate
Figure imgf000140_0002
In a procedure analogous to Example 1 , Step G, 2.24 g of the title compound was prepared from 2.13 g (4.5 mmol) of the hydrochloride salt of 6-bromo-/V-[1 - (phenylmethyl)-1H-indazol-5-yl]thieno[3,2-djpyrimidin-4-amine and 1.44 g (4.95 mmol) of 1 ,1-dimethylethyl (2R,4S)-4-{[(ethylamino)carbonyl]oxy}-2-ethynyl-1- pyrrolidinecarboxylate as a white solid: 1H NMR (CDCI3, 400MHz) δ 8.64 (s, 1H), 8.08 (s, 1 H), 7.88 (s, 1 H), 7.28-7.40 (m, 5H), 7.20-2.25 (m, 2H), 6.99 (brs, 1 H), 5.64 (s, 2H), 5.25 (brs, 1 H), 4.64 (brs, 2H), 3.63 (brs, 2H), 3.20 (m, 2H), 2.30-2.49 (m, 3H), 1.55 (s, 9H), 1.14 (t, 3H, J = 7.1 Hz).
Step E- (3S,5R)-5-[(4-{[1-(Phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinyl ethylcarbamate
In a procedure analogous to Example 1 , Step H, 1.4 g of the title compound was prepared from 1 ,1-dimethylethyl (2R,4S)-4-{[(ethylamino)carbonyl]oxy}-2-[(4-{[1- (phenylmethyl)-l H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-1 - pyrrolidinecarboxylate as a white solid: 1H NMR (CD3OD, 400 MHz) δ 8.46 (s, 1 H),
8.09 (s, 1 H), 8.02 (s, 1 H), 7.52-7.59 (m, 3H), 7.39 (s, 1 H), 7.27-7.31 (m, 4H), 7.21- 7.26 (m, 2H), 5.68 (s, 2H), 5.19 (brs, 1 H), 4.25 (t, 1 H, J = 8.1 Hz), 3.12 (q, 2H, J = 7.3 Hz), 2.95 (d, 1 H, J = 12.5 Hz), 2.24-2.54 (m, 2H), 2.13-2.20 (m, 2H), 1.10 (t, 3H, J = 7.3 Hz). HRMS calcd for C29H27N702s: 538.2039; found: 538.2025.
Example 37
(3S,5R)-5-{[4-({1-[(3-Fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate
Figure imgf000141_0001
Step A- 1, 1-dimethylethyl (2R,4S)-2-ethynyl-4-[(1-pyrrolidinylcarbonyl)oxy]-1- pyrrolidinecarboxylate
Figure imgf000141_0002
To a solution of 1 ,1-dimethylethyl (2R,4S)-2-ethynyl-4-hydroxy-1- pyrrolidinecarboxylate (1.16 g, 5.5 mmol) in DMF (30 mL) at 0 °C under nitrogen was added a 60% dispersion of sodium hydride (0.66 g, 16.5 mmol). The reaction was stirred for 10 min at 0 °C after which time the mixture was allowed to warm to rt for 30 min. 1-pyrrolidinecarbonyl chloride (1.2 mL, 10.9 mmol) was then added via syringe and the mixture allowed to stir for 15 min after which time the mixture was stirred at 65 °C for 2 h. The reaction was allowed to cool to rt, was diluted with EtOAc, was cooled to 0 °C and was quenched with water. The organic phase was washed with water and brine, dried over Na2S04, filtered and reduced in vacuo and purified via silica gel chromatography (3:1 hexane:ethyl acetate to 1 :1 hexane:ethyl acetate) to afford 1.68 g of the title compound as a colorless oil. 1H NMR (400 MHz, CDCI3): δ 5.25 (m, 1 H), 4.55 (br d, 1 H), 3.63 (m, 2H), 3.37 (t, 2H), 3.27 (t, 2H), 2.36 (m, 3H), 1.85 (br t, 4H), 1.48 (s, 9H). Step B- 1, 1-dimethylethyl (2R,4S)-2-[(4-chlorothieno[2,3-d]pyrimidin-6- yl)ethynyl]-4-[(1-pyrrolidinylcarbonyl)oxy]-1 -pyrrolidinecarboxylate
Figure imgf000142_0001
Nitrogen was bubbled through a mixture of 6-bromo-4-chlorothieno[2,3- djpyrimidine (0.62 g, 2.5 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.070 g, 0.10 mmol), copper (I) iodide (0.047 g, 0.25 mmol) and triethylamine (0.69 mL, 5.00 mmol) in THF (10 mL) for 10 min while stirring at rt. To the mixture was added a solution of 1 ,1-dimethylethyl (2R,4S)-2-ethynyl-4-[(1-pyrrolidinylcarbonyl)oxy]-1- pyrrolidinecarboxylate (0.84 g, 2.74 mmol) in THF (10 mL) dropwise via a syringe and the mixture allowed to stir at 65 °C for 3 h. The reaction was cooled to rt, absorbed onto silica in vacuo, and purified via silica gel chromatography (hexanes:EtOAc) to afford 0.82 g of the title compound as a yellow solid. 1H NMR (400 MHz, CDCI3): δ 8.85 (s, 1 H), 7.45 (br s, 1 H) 5.32 (m, 2H), 4.85 (br d, 1 H), 3.69 (m, 2H), 3.39 (t, 2H), 3.30 (t, 2H), 2.44 (m, 3H), 1.87 (br m, 4H), 1.50 (s, 9H). LC-MS (ES+) (M+ + Na+) 499.
Step C- (3S, 5R)-5-{[4-({1-[(3-Fluorophenyl)methyl]-1H-indazol-5- yl}amino)thieno[2,3-d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate 1 ,1 -Dimethylethyl (2R,4S)-2-[(4-chlorothieno[2,3-d]pyrimidin-6-yl)ethynyl]-4- [(1-pyrrolidinylcarbonyl)oxy]-1 -pyrrolidinecarboxylate (0.10 g, 0.21 mmol) and 1-[(3- fluorophenyl)methyl]-1H-indazol-5-amine (.053 g, 0.22 mmol) were combined in isopropanol (1 mL) in a teflon-capped vial and were heated with stirring at 85 °C for 1.5 h after which time the reaction was allowed to cool to rt and stirred 12 h. The reaction mixture was diluted with CH2CI2 and NEt3 (1 mL), absorbed onto silica gel in vacuo, and purified via silica gel C (5:95 MeOH/ CH2CI2). The residue was treated with trifluoroacetic acid/ CH2CI2 (2 mL/2 mL) and the mixture concentrated to dryness in vacuo. Redissolved residue in 5:95 MeOH/ CH2CI2 (2 mL) and stirred with 500 mg MS-carbonate overnight, filtered, and removed solvent in vacuo to afford 72 mg of the title compound as a yellow solid. 1H NMR (400 MHz, CDCI3): δ 8.55 (s, 1H), 8.07 (s, 1 H), 8.02 (d, 1 H), 7.47 (m, 1 H), 7.27 (m, 5H), 6.98 (m, 2H), 6.86 (br d, 1 H), 5.60 (s, 2H), 5.30 (m, 1H), 4.32 (t, 1 H), 3.38 (m, 5H), 3.12 (d, 1 H), 2.26 (m, 2H), 1.86 (br m, 4H). HRMS (ESI): (M+H)+ calculated 582.2087, found 582.2079.
Example 38
(5R)-5-[(4-{[1-(Phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl) ethynyl]-2-pyrrolidinone
Figure imgf000143_0001
Step A- (5R)-5-Ethynyl-2-pyrrolidinone
Figure imgf000143_0002
To a -78 °C solution of ethyl R - pyrrolidinone (5.0 g, 31.8 mmol) in anhydrous CH2CI2 (150 mL) was added a solution of 1.0 M DIBAL-H in hexanes (32 mL, 32.0 mmol). After 1 h, additional DIBAL-H in hexanes (48 mL, 48.0 mmol) was added. After 2 h the reaction was quenched at -78 °C with MeOH and allowed to warm to room temperature. The reaction mixture was further diluted with MeOH (total 160 mL) and K2C03 (13.1 g, 95 mmol). The mixture was then treated with Seyferth-Gilbert reagent (7.5 g, 38.2 mmol) according to the procedure given in Example 1 , step D to afford, after workup and purification, the title compound. 1H NMR (300 MHz, CD3OD) δ 4.47 (m, 1 H), 3.36 (d, 1 H, J = 1.2 Hz), 2.88 (m, 1 H), 2.1- 2.6 (m, 4H).
Step B- (5R)-5-[(4-chlorothieno[3,2-d]pyrimidin-6-yl)ethynyl]-2-pyrrolidinone
Figure imgf000144_0001
A mixture of 6-bromo-4-chlorothieno[3,2-djpyrimidine (1.3 g, 52.2 mmol), (5R)-5-ethynyl-2-pyrrolidinone (0.50 g, 45.9 mmol), Pd(Ph3)2CI2 (0.123 g, 0.1 mmol), Cu(l)l, (0.07 g, 0.05 mmol), triethylamine (1.5 mL, 10.8 mmol) and THF were combined and the mixture was heated under N2 to 60 °C. The reaction was monitored by TLC until complete, and worked up as described in earlier examples to give, after purification by chromatography the title compound judged to be 95% ee by chiral analytical chromatography. 1H NMR (300 MHz, CD3OD) δ 9.02 (s, 1 H), 7.77 (s, 1 H), 4.82-4.87 (dd, 1 H, J = 9, 5 Hz,), 2.33-272 (m, 5H).
Step C- (5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl) ethynyl]-2-pyrrolidinone A mixture of 1-(phenylmethyl)-1 H-indazol-5-amine (0.067 g, 0.029 mmol),
(5R)-5-[(4-chlorothieno[3,2-dJpyrimidin-6-yl)ethynyl]-2-pyrrolidinone (0.08 g, 0.027 mmol) and isopropanol (20 mL) were combined and the mixture was heated at reflux for 8 h. The mixture was cooled and poured into diethyl ether to give a precipitate that was filtered to afford the title compound hydrochoride salt (100 mg, 55%) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.81 (s, 1 H), 8.25 (s, 1 H), 8.10 (s, 1 H), 7.7 (d, 1 H, J = 9 Hz), 7.57-7.61 (m, 2H), 7.39 (dd, 1 H), J = 15, 9 Hz), 7.03-7.13 (m, 2H), 6.99 (d, 1 H), J = 9.6 Hz), 4.78 (m, 1 H), 2.29-2.65 (m, 5H). MS (AP)+ = 501.2.
Example 39
(3S,5R)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]pyrrolidinyl dimethylcarbamate
Figure imgf000145_0001
Step A- le -Butyl (2R,4S)-4-{[(dimethylamino)carbonyl]oxy}-2-ethynyl-1- pyrrolidinecarboxylate
Figure imgf000145_0002
tert-Butyl (2R,4S)-2-ethynyl-4-hydroxy-1 -pyrrolidinecarboxylate (2.5 g, 11.8 mmol) was dissolved into 100 mL of DMF and cooled to 0°C for 10 min. NaH (1.42 g, 35.5 mmol, 60% dispersion in mineral oil) was added in one portion to the reaction mixture. The mixture was allowed to stir for 10 min. at 0°C and was then allowed to warm to ambient temperature for 20 min. Dimethylcarbamyl chloride (2.54 g, 23.66 mmol) was added and vigorous gas evolution occurred. The reaction stirred at RT for 1.5 hr, then was warmed to 60°C for 1 hr. The reaction was cooled to 0°C and quenched via dropwise addition of water. The reaction was diluted with EtOAc, and the layers were separated. The aqueous phase was back-extracted with EtOAc, the organic phases were pooled, dried over MgS04, filtered and reduced in vacuo. Purification of the residue via ISCO chromatography (hexanes:EtOAc) yielded a colorless oil, 3.1 g, 93% yield. 1H NMR (400 MHz, CDCI3) δ 5.23 (m, 1 H), 4.54 (bd, 1 H), 3.58 (m, 2H), 2.84 (s, 3H), 2.90 (s, 3H), 2.41-2.29 (m, 3H), 1.48 (s, 9H),.
Step B- teή-Butyl (2R,4S)-2-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[2,3- d]pyrimidin-6-yl)ethynyl]-4-{[(dimethylamino)carbonyl]oxy}-1 -pyrrolidinecarboxylate
Figure imgf000146_0001
To Λ/-(6-bromothieno[2,3-c Ipyrimidin-4-yl)-/\/-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amine (4.27 g, 9.22 mmol), tert-butyl (2R,4S)-4- {[(dimethylamino)carbonyl]oxy}-2-ethynyl-1 -pyrrolidinecarboxylate (3.0 g, 10.60 mmol), dichlorobis(triphenylphosphine)palladium(ll) (711 mg, 1.014 mmol) and copper(l) iodide (263 mg, 1.38 mmol) in THF (45 mL) was added Et3N (3.23 mL, 23 mmol). The mixture was heated at 60°C for 2.5 h. The mixture was cooled, filtered, and pre-absorbed onto silica gel. The crude material was purified via silica gel chromatography (EtOAc/Hexanes) to provide 4.4 g (72%) of the desired product as a golden yellow solid. MS (ES+, m/z) 666 (M+H)+.
Step C- (3S, 5R)-5-[(4-{3-Chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[2,3-d]pyrimidin- 6-yl)ethynyl]pyrrolidinyl dimethylcarbamate
Figure imgf000146_0002
To tert-butyl (2R,4S)-2-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[2,3- djpyrimidin-6-yl)ethynyl]-4-{[(dimethylamino)carbonyl]oxy}-1-pyrrolidinecarboxylate (78 mg, 0.12 mmol) in CH2CI2 (2 mL) at RT was added TFA (0.5 mL). The solution was stirred for 3 h and concentrated in vacuo. The residue was dissoved in 2% MeOH/CH2CI2 (100 mL) and washed with saturated aqueous NaHC03 (20 mL). The organic layer was separated, dried over MgS04, filtered and concentrated in vacuo. The solid was triturated (EtOAc/Hexanes) and collected via filtration to provide 40 mg (60%) of the desired product as a solid. 1H NMR (400 MHz, DMSO-d6). δ 9.64 (s, 1 H), 8.51 (s, 1 H), 8.00 (d, J=2.6 Hz, 1 H), 7.96 (s, 1 H), 7.64 (dd, J=9.0, 2.6 Hz, 1 H), 7.45 (m, 1 H), 7.31-7.24 (m, 3H), 7.17 (dt, J=87, 2.4 Hz, 1 H), 5.23 (s, 2H), 5.06 (m, 1 H), 4.20 (t, J=7.3 Hz, 1 H), 3.49-3.38 (m, 2H), 3.17 (dd, J=12.0, 5.3 Hz, 1 H), 2.80 (m, 6H), 2.16-2.03 (m, 2H). MS (ES+, m/z) 566 (M+H)+.
Example 40 {(2R, 5R)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3, 2-d]pyrimidin-6- yl)ethynyl]pyrrolidinyl}methyl ethylcarbamate
Figure imgf000147_0001
Step A- (2R)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3, 4-dihydro-2H-pyrrole
Figure imgf000147_0002
(5R)-5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2-pyrrolidinone (8.04 g, 22.7 mmol) was dissolved in THF (100 mL) and cooled in a -30 °C bath for 20 min. Cp2ZrHCI (9.4g, 36.4 mmol) was added in 5 portions over 10 min. There was little observable reaction. The slurry was stirred for 30 min. at -30°C and then allowed to warm to RT. Upon reaching RT, the mixture was concentrated in vacuo. The residue was suspended in 1/1 Hexanes/EtOAc (50 mL) and passed through a silica packed filter frit, eluting with 1/1 Hexanes/EtOAc. Volatile organics were removed in vacuo to yield 5.34 g (70 %) of product. LRMS (ES+, m/z) 338 (M+H)+.
Step B- (2R,5R)-2-({lleύ-butyl(diphenyl)silyl]oxy}methyl)~5-ethynylpyrrolidine
Figure imgf000147_0003
TMS acetylene (4.92 mL, 34.8 mmol) in THF (60 mL) was cooled in a -78°C bath for 15 min. A solution of ti-BuLi (2.5M in hexanes, 12.7 mL, 31.8 mmol) was added dropwise and the solution was allowed to stir at -78 °C for 30 minutes. Boron trifluoride diethyl etherate (3.97 mL, 31.8 mmol) was added dropwise and the solution was allowed to stir at -78 °C for 15 minutes. (2R)-2-({[ført- butyl(diphenyl)silyl]oxy}methyl)-3,4-dihydro-2H-pyrrole (5.34g, 15.8 mmol) in 20 mL THF was added dropwise. The solution was stirred for 1 h at -78°C and the cold bath was removed. The solution was allowed to warm to RT and was then cooled again in a -78°C bath. The solution was carefully quenched with MeOH and then diluted with EtOAc and then H20. The cold bath was removed and the mixture was allowed to warm. The reaction was further diluted with EtOAc (200 mL) and washed with water (100 mL). The organics were dried (MgS04), filtered and concentrated to a dark oil. This residue was taken up in MeOH (80 mL) and treated with K2C03 (4.4g, 31.8 mmol). The reaction was stirred for 3h at RT and then diluted with EtOAc (500 L) and H20 (200 mL). The organic phase was dried (MgS04), filtered, and concentrated to a dark oil which was purified via flash chromatography (hexanes/EtOAc) to give 2.57g of product (45%) as a brown oil. LRMS (ES+, m/z) 364 (M+H)+.
Step C- tart-Butyl (2R,5R)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-ethynyl-1- pyrrolidinecarboxylate
Figure imgf000148_0001
(2R,5R)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-ethynylpyrrolidine (2.56 g, 7.0 mmol) was dissolved in CH2CI2 (50 mL). Boc20 (2.43g, 11.0 mmol), 'PrEtN (3.7 mL, 22.0 mmol), and DMAP (43 mg, 0.35 mmol) were added and the mixture was allowed to stir at RT overnight. The solution was further diluted with CH2CI2 (200 ml) and was washed with saturated aqueous NaHC03 (3 x 100 mL). The organic phase was dried (MgS0 ), filtered and concentrated in vacuo. The crude residue was purified via flash chromatography (hexanes/EtOAc) to afford 27g of product (83%) as an oil. LRMS (ES+, m/z) 486 (M+Na)+.
Step D- tert-Butyl (2R,5R)-2-ethynyl-δ-(hydroxymethyl)-1-pyrrolidinecarboxylate
Figure imgf000149_0001
tert-Butyl (2R,5R)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-ethynyl-1- pyrrolidinecarboxylate (2.64g, 5.7 mmol) was dissolved in THF (20 mL) and treated with TBAF (1.0 M in THF, 11.4 ml, 11.4 mmol). The solution was stirred for 2h and then diluted with EtOAc (250 mL) and washed with H20 (2 x 50 mL). The organic phase was dried (MgS0 ), filtered and concentrated in vacuo. The resulting crude residue was purified via flash chromatography (hexanes/EtOAc) to afford 1.14g of product (89%). 1H NMR (400 MHz, CDCI3) δ. 4.46 (m, 1 H), 4.09 (bs, 1 H), 3.61 (d, J=5.8 Hz, 2H), 2.30 (m, 1H), 2.21 (s, 1H), 2.10 (m, 1H), 1.97 (m, 1H), 1.70 (m, 1H).
Figure imgf000149_0002
Step E- tert-Butyl 6-bromothieno[3,2-d]pyrimidin-4-yl{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}carbamate To A/-(6-bromothieno[3,2-d|pyrimidin-4-yl)-Λ/-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amine HCl (3 g, 6.0 mmol) in CH2CI2 (50 mL) was added 'PrEtN (4.2 mL, 24 mmol), Boc20 (1.96 g, 9.0 mmol), and DMAP (37 mg, 0.3 mmol). The reaction was heated in a 50°C oil bath overnight and was then allowed to cool. The reaction was diluted with EtOAc (300 mL) and washed with saturated aqueous NaHC03 (100 mL) and then brine (100 mL). The organic phase was dried (MgS0 ), filtered and concentrated in vacuo. The residue was purified via flash chromatography (EtOAc/hexanes) to provide the product (2.6g, 71 %) as a cream foam. LRMS (APCI+, m/z) 565 (M+H)+.
Figure imgf000150_0001
Step F- tert-Butyl (2R,5R)-2-[(4-{(tert-butoxycarbonyl)-3-chloro-4-[(3- fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-5-(hydroxymethyl)-1- pyrrolidinecarboxylate tert-Butyl 6-bromothieno[3,2-c/]pyrimidin-4-yl{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}carbamate (1.3 g, 2.3 mmol), PdCI2(PPh3)2 (81 mg, 0.12 mmol), Cul (44 mg, 0.23 mmol), and Et3N (1.0 mL, 7.2 mmol) in THF (12 mL) were heated in a 60°C oil bath. tert-Butyl (2R,5R)-2-ethynyl-5-(hydroxymethyl)-1- pyrrolidinecarboxylate (570 mg, 2.5 mmol) in THF (10 mL) was added dropwise over a period of 45 min. The reaction was heated for an additional 2.5h at 60°C and was then allowed to cool. The reaction mixture was diluted with EtOAc (250 mL) and washed with brine (100 mL). The organic phase was dried (MgS04), filtered and concentrated in vacuo. The residue was purified via flash chromatography (hexanes/EtOAc) to afford 1.30g product (80%) as a cream foam. LRMS (ES+, m/z) 709 (M+H)+.
Step G- tert-Butyl (2R,5R)-2-[(4-{(tert-butoxycarbonyl)-3-chloro-4-[(3- fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-5- ({[(ethylamino)carbonyl]oxy}methyl)-1-pyrrolidinecarboxylate
Figure imgf000150_0002
To tert-butyl (2R,5R)-2-[(4-{(tert-butoxycarbonyl)-3-chloro-4-[(3- fluorobenzyl)oxy]anilino}thieno[3,2-dJpyrimidin-6-yl)ethynyl]-5-(hydroxymethyl)-1- pyrrolidinecarboxylate (200 mg, 0.28 mmol) in THF (2 mL) was added trichloromethyl chloroformate (20 μL, 0.17 mmol) followed immediately by Et3N (59 μL, 0.42 mmol). Immediately a white precipitate formed. The slurry was allowed to stir for 15 min. at RT. Ethylamine (2.0 M in THF, 0.70 mL, 1.4 mmol) was added and the reaction was stirred for 30 min. The mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHC03 (50 mL) and then brine (50 mL). The organic phase was dried (MgS0 ), filtered and concentrated in vacuo. The residue was purified via flash chromatography (hexanes/EtOAc) affording 135 mg product (61 %) as a white foam. LRMS (ES+, m/z) 780 (M+H)+.
Step H- {(2R,5R)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]pyrrolidinyl}methyl ethylcarbamate To tert-butyl (2R,5R)-2-[(4-{(tert-butoxycarbonyl)-3-chloro-4-[(3- fluorobenzyl)oxy]anilino}thieno[3,2-riJpyrimidin-6-yl)ethynyl]-5- ({[(ethylamino)carbonyl]oxy}methyl)-1 -pyrrolidinecarboxylate (131 mg, 0.17 mmol) in CHCI3 (4 mL) was added Trifluoroacetic acid (1 mL) and the reaction was allowed to stir for 5h at RT. The solution was concentrated in vacuo and the residue was diluted in 2% MeOH/CH2CI2 (70 mL) and washed with saturated aqueous NaHC03 (15 mL). The organic phase was dried (MgS0 ), filtered and concentrated in vacuo to yield 69.7 mg product (72%) as a light yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1 H), 8.57 (s, 1 H), 7.91 (d, J=2.2 Hz, 1H), 7.60 (dd, J=9.0, 2.4 Hz, 1H), 7.55 (s, 1 H), 7.46 (m, 1 H), 7.33-7.24 (m, 3H), 7.18 (m, 1 H), 7.09 (m, 1 H), 5.25 (s, 2H), 4.18 (m, 1 H), 3.87-377 (m, 2H), 3.43 (m, 1 H), 2.99 (m, 2H), 2.89 (bs, 1 H), 2.11 (m, 1 H), 1.95 (m, 1 H), 1.82 (m, 1 H), 1.47 (m, 1 H), 1.00 (t, =7.2 Hz, 3H). LRMS (ES+, m/z) 580 (M+H)+.
Example 41
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2R,5R)-5-(4- morpholinylmethyl)pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine
Figure imgf000152_0001
Step A- tert-Butyl (2R,5R)-2-[(4-{(tert-butoxycarbonyl)-3-chloro-4-[(3- fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-5-(4-morpholinylmethyl)- 1 -pyrrolidinecarboxylate
Figure imgf000152_0002
To tert-butyl (2R,5R)-2-[(4-{(tert-butoxycarbonyl)-3-chloro-4-[(3- fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-5-(hydroxymethyl)-1- pyrrolidinecarboxylate (120 mg, 0.17 mmol) in CH2CI (2 mL) was added Dess-Martin periodinane (79 mg, 0.19 mmol) at RT. The slurry was stirred for 3h and then diluted with CH2CI2 (50 mL) and saturated aqueous sodium potassium tartrate. The biphasic solution was stirred vigorously for 2h and then the organic phase was dried (MgS04), filtered and concentrated in vacuo. The residue was taken up in CH2CI2 (2 mL) and was charged with morpholine (74 μL, 0.85 mmol) and AcOH (20 μL, 0.34 mmol). The mixture was stirred for 30 min. and then NaBH(OAc)3 (71 mg, 0.34 mmol) was added and the reaction was allowed to stir overnight. The reaction was diluted with EtOAc (70 mL) and washed with H20 (2 x 30 mL). The organic phase was dried (MgS0 ), filtered and concentrated in vacuo. The residue was purified via flash chromatography (hexanes/EtOAc) to afford 100 mg of product (76 %). LRMS (ES+, m/z) 778 (M+H)+.
Figure imgf000153_0001
Step B- N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2R,5R)-5-(4- morpholinylmethyl)pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine To tert-butyl (2R,5R)-2-[(4-{(tert-butoxycarbonyl)-3-chloro-4-[(3- fluorobenzyl)oxy]aniIino}thieno[3,2-c/]pyrimidin-6-yl)ethynyl]-5-(4-morpholinylmethyl)-
1 -pyrrolidinecarboxylate (100 mg, 0.13 mmol) in CHCI3 (3 mL) was added trifluoroacetic acid (1 mL) and the reaction was allowed to stir for 5h at RT. The solution was concentrated in vacuo and the residue was diluted in 2% MeOH/CH2CI2 (70 mL) and washed with saturated aqueous NaHC03 (15 mL). The organic phase was dried (MgS0 ), filtered and concentrated in vacuo. The residue was triturated (EtOAc) and filtered to yield 32.0 mg product (43%). 1H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1 H), 8.55 (s, 1 H), 7.89 (d, J=2.3 Hz, 1 H), 7.58 (dd, J= 8.9, 2.7 Hz, 1 H), 7.52 (s, 1 H), 7.44 (m, 1 H), 7.30 (m, 2H), 7.23 (d, =8.9 Hz, 1 H), 7.17 (dt, =8.7, 2.4 Hz, 1 H), 5.24 (s, 2H), 4.17 (m, 1 H), 3.55 (m, 4H), 3.39 (m, 1 H), 2.48 (m, 4H), 1.37 (m, 1 H), 2.38-2.17 (m, 2H), 2.10 (m, 1H), 1.96 (m, 1 H), 1.79 (m, 1 H). LRMS (ES+, m/z) 578 (M+H)+.
Example 42
N-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide
Figure imgf000153_0002
4S)-2-ethynyl-4-[(trifluoroacetyl)amino]-1-
Figure imgf000154_0001
A solution of 1 ,1-dimethylethyl (2R,4R)-2-ethynyl-4-hydroxy-1- pyrrolidinecarboxylate (1.0 g, 47mmol) in THF (47 mL) was cooled to 0C for 10 min. To the solution was added Et3N (1.3 mL, 9.4 mmol) followed by methanesulfonyl chloride (0.53 mL, 7.1 mmol), and the resulting reaction was stirred for 1hr at OC. The reaction was diluted with Et20, quenched with water. The layers were separated, and the aqueous layer was extracted with Et20. The resulting organic extracts were combined, dried over MgS04, filtered, and reduced in vacuo. The crude mesylate was used without further purification. The mesylate was dissolved into DMF (10mL), added NaN3 (0.47 g, 7.8 mmol) and heated the reaction to 60 °C for 18 h. The reaction was quenched by addition of water, and extracted with Et 0. The layers were separated and the aqueous layer was extracted with Et20. The resulting organic extracts were combined, dried over MgSO , filtered, and reduced in vacuo. The crude azide was used without further purification. The crude residue was dissolved in THF (20 mL), treated with PPh3 (1.2 g, 4.7 mmol) and water (1 mL), allowed to stir for 18 h at RT. The reaction was partitioned between water and Et20. The layers were separated and the aqueous layer was extracted with Et20. The resulting organic extracts were combined, dried over MgS0 , filtered, and reduced in vacuo. The crude amine was dissolved into CH CI2 (20 mL) and cooled to 0C for 15 min. To the reaction was added the following, Et3N (1.7 mL, 14.1 mmol), and trifluoroacetic anhydride (0.99 mL, 7.1 mmol), the reaction was allowed to stir for 15 min at 0C, then warmed to RT and stirred at RT for 1 h. The reaction was quenched with water, diluted with CH2CI2. The layers were separated and the aqueous layer was extracted with CH2CI2. The resulting organic extracts were combined, dried over MgS0 , filtered, and reduced in vacuo directly onto silica. Purification via ISCO chromatography (hexanes:EtOAc) afforded the desired product 1.0 g, 71% yield 1H NMR (400 MHz, CD3OD) δ 4.62-4.58 (m, 2H), 372-3.68 (m, 1 H), 3.30-3.25 (m, 1H), 2.75 (bs, 1H), 2.30-2.26 (bm, 2H), 1.47 (s, 9H).
Step B- 1,1 -Dimethylethyl (2R,4S)-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-4- [(trifluoroacetyl)amino]-1 -pyrrolidinecarboxylate
Figure imgf000155_0001
To a mixture of 6-bromo-Λ/-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-dJpyrimidin-4-amine (0.72 g, 1.5 mmol) (Ph3P)2PdCI2 (0.12 g, 0.17 mmol), Cul (42 mg, 0.22 mmol) was added THF (7.5mL) and the mixture was allowed to stir at RT for 10 min. Added Et3N (0.37 g, 3.67 mmol) to the reaction mixture and stirred for an additional 5 min at RT, then, warmed to 60 °C for 5 min. Charged an addition funnel with 1 ,1-dimethylethyl (2R,4S)-2-ethynyl-4- [(trifluoroacetyl)amino]-1-pyrrolidinecarboxylate (0.45 g, 1.47 mmol) in THF (7.5mL), added to the reaction over 20 min. The reaction was allowed to stir an additional 3 h at 60 °C. The reaction was cooled to RT, filtered, and the crude reaction mixture was absorbed directly onto silica. Purification via ISCO (hexanes:EtOAc) yielded an orange solid, 0.76 g, 76% yield. LCMS: m/z 690 (M+).
Step C- 1,1 -Dimethylethyl (2R,4S)-4-amino-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-1- pyrrolidinecarboxylate
Figure imgf000156_0001
1 ,1 -Dimethylethyl (2R,4S)-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-4- [(trifluoroacetyl)amino]-1 -pyrrolidinecarboxylate (1.2 g, 1.80mmol) was dissolved into a mixture of THF/H20 12 mL/1 mL. Added 2.3 mL of 1 M LiOH, and stirred at RT. After 24 h, the reaction was diluted with EtOAc/ H20. The layers were separated, extracted with EtOAc (2x20 mL). The organic layers were pooled, dried over MgS04, filtered, and reduced in vacuo onto silica. Purification via ISCO chromatography (EtOAc/ MeOH) afforded a yellow solid, 0.82 g, 79% yield. LCMS: m/z 594 (M+). 1 ,1 -Dimethylethyl (2R,4S)-4-amino-2-({4-[(3-chloro-4-{[(3-fluorophenyl) methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-1 -pyrrolidinecarboxylate (0.16 g, 0.27 mmol) was dissolved into CH2CI2 (2 mL), added Et3N (82 mg, 0.81 mmol) and cooled to 0 °C for 10 min. Added appropriate activated chloride, for this example, ethaneslufonyl chloride (38 mg, 0.3 mmol) was added at 0 °C. Stirred for 1 h, then the reaction was quenched with sat. aq. NaHC03, diluted with CH2CI2. The layers were separated, the organics were extracted with CH2CI2 (3x3mL). The organic extracts were pooled, dried over MgS04, filtered, reduced in vacuo onto silica. Purification via ISCO chromatography (hexanes: EtOAc) yielded a yellow solid, that was used directly in the next step. The residue was dissolved into CH2CI2 (4 mL) at RT. Added trifluoroacetic acid (1.4 g, 13 mmol) and stirred for 1hr at RT. The reaction was diluted with CH2CI2, quenched with sat aq NaHC03. The layers were separated, the organics were extracted with CH2CI2 (3x3 mL). The organic extracts were pooled, dried over MgS0 , filtered, reduced in vacuo onto silica. Purification via ISCO chromatography (EtOAc/MeOH) to afford a yellow solid, 63mg, 45% yield over 2 steps. 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 7.79 (d, J = 2Hz, 1 H), 7.50 (dd, J = 2, 6Hz, 1 H), 7.43-7.38 (m, 2H), 7.30 (bd, J = 7Hz, 1 H), 7.25 (bd, J = 10Hz, 1 H), 7.15 (d, J = 7Hz, 2H), 7.07-7.03 (m, 1 H), 5.22 (s, 2H), 4.26 (t, J = 7 Hz, l ob
1 H), 4.07-4.04 (m, 1 H), 3.36-3.36 (m, 1 H), 3.08 (q, J = 7Hz, 2H), 2.82-278 (m, 1 H), 2.30-2.21 (m, 1 H), 2.21-2.18 (m, 1 H), 1.33 (t, J = 7 Hz, 3H). HRMS calculated C27H25CIFN503S2 [M]+ 586.1150, found 586.1146.
Example 43
Ethyl [(3S, 5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl) methyljoxy} phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]carbamate
Figure imgf000157_0001
1,1 -Dimethylethyl (2R, 4S)-4-amino-2-({4-[(3-chloro-4-{[(3-fluorophenyl) methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-1 -pyrrolidinecarboxylate (0.16 g, 0.26 mmol) was dissolved into CH2CI2 (2 mL), added Et3N (82 mg, 0.81 mmol) and cooled to 0 °C for 10 min. Added ethyl cloroformate (31 mg, 0.29mmol) was added at 0 °C. Stirred for 1 h, then the reaction was quenched with sat. aq. NaHC03, diluted with CH2CI2. The layers were separated, the organics were extracted with CH2CI2 (3x3 mL). The organic extracts were pooled, dried over MgS04, filtered, reduced in vacuo onto silica. Purification via ISCO chromatography (hexanes: EtOAc) yielded a yellow solid, that was used directly in the next step. The residue was dissolved into CH2CI2 (4 mL) at RT. Added trifluoroacetic acid (1.4 g, 13 mmol) and stirred for 1h at RT. The reaction was diluted with CH2CI2, quenched with sat aq NaHC03. The layers were separated, the organics were extracted with CH2CI2 (3x3 mL). The organic extracts were pooled, dried over MgS04, filtered, reduced in vacuo onto silica. Purification via ISCO chromatography (EtOAc/MeOH) to afford a yellow solid, 48 mg, 43% yield over 2 steps. 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1 H), 7.79 (d, J = 2Hz, 1H), 7.50 (dd, J = 3, 9Hz, 1 H), 7.43-7.38 (m, 2H), 7.30 (bd, J = 7Hz, 1 H), 7.25 (bd, J = 10Hz, 1 H), 7.14 (d, 9Hz, 1 H), 7.08-7.04 (m, 1H), 5.22 (s, 2H), 4.26-4.21 (m, 2H), 4.10-4.05 (m, 2H), 278-274 (m, 1 H), 2.26-2.19 (m, 1 H), 2.15-2.09 (m, 1 H), 1.23 (t, J = 7Hz, 3H). HRMS calculated CzsHssCI sOsS [M]+ 566.1429, found 566.14252.
Example 44 N-((3S,5R)-5-{[4-({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}pyrrolidin-3-yl)propanamide:
Figure imgf000158_0001
1 ,1 -Dimethylethyl (2R, 4S)-4-amino-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-1- pyrrolidinecarboxylate (0.15 g, 0.25 mmol) was dissolved into CH2CI2 (2 mL), added
Et3N (75mg, 075mmol), DMAP (3mg, 0.02mmol) and cooled to 0C for 10 min.
Added propionyl chloride (25 mg, 0.28 mmol) at OC. Stirred for 1 h, then the reaction was quenched with sat. aq. NaHC03, diluted with CH2CI2. The layers were separated, the organics were extracted with CH2CI2 (3x3 mL). The organic extracts were pooled, dried over MgS0 , filtered, reduced in vacuo onto silica. Purification via radial chromatography (hexanes: EtOAc) yielded a yellow solid, that was used directly in the next step. The residue was dissolved into CH2CI2 (4mL) at RT. Added trifluoroacetic acid (1.4 g, 13 mmol) and stirred for 1hr at RT. The reaction was diluted with CH2CI2, quenched with sat aq NaHC03. The layers were separated, the organics were extracted with CH2CI2 (3x3mL). The organic extracts were pooled, dried over MgS04, filtered, reduced in vacuo onto silica. Purification via radial chromatography (EtOAc/MeOH) to afford a yellow solid, 63 mg, 45% yield over 2 steps. 1H NMR (400 MHz, d6-DMSO) δ 9.72 (s, 1 H), 8.57 (s, 1 H), 7.92-7.88 (m, 2H), 7.62-7.58 (m, 2H), 7.50-7.45 (m, 1 H), 7.34-7.24 (m, 3H), 7.21-7.17 (m, 1 H), 5.26 (s, 2H), 4.26-4.22 (m, 2H), 3.18-3.14 (m, 1 H), 2.64-2.60 (m.1 H), 2.10-1.97 (m, 4H), 0.99 (t, J = 7.9 Hz, 3H). HRMS calculated C28H25CIFN5θ2S [M+H]+ 550.1480 found 550.1480.
Example 45
H-((3S,5R)-5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}pyrrolidin-3-yl)-N'-ethylurea
Figure imgf000159_0001
1 ,1 -Dimethylethyl (2R,4S)-4-amino-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-1- pyrrolidinecarboxylate (0.15 g, 0.25 mmol) was dissolved into CH2CI2 (2 mL), added Et3N (75 mg, 0.75 mmol), and cooled to 0 °C for 10 min. Added ethyl isocyanate (25 mg, 0.28 mmol) at 0 °C. Stirred for 1 h, then the reaction was quenched with sat. aq. NaHC03, diluted with CH2CI2. The layers were separated, the organics were extracted with CH2CI2 (3x3mL). The organic extracts were pooled, dried over MgS0 , filtered, reduced in vacuo onto silica. Purification via radial chromatography (hexanes: EtOAc) yielded a yellow solid, that was used directly in the next step. The residue was dissolved into CH2CI2 (4mL) at RT. Added trifluoroacetic acid (1.4g, 13mmol) and stirred for 1 hr at RT. The reaction was diluted with CH2CI2, quenched with sat aq NaHC03. The layers were separated, the organics were extracted with CH2CI2 (3x3mL). The organic extracts were pooled, dried over MgS04, filtered, reduced in vacuo onto silica. Purification via radial chromatography (EtOAc/MeOH) to afford a yellow solid, 38mg, 26% yield over 2 steps. 1H NMR (400 MHz, d6- DMSO) δ 9.72 (s, 1 H), 8.56 (s, 1 H), 7.91 (m, 1 H), 7.61-7.59 (m, 1 H), 7.55 (s, 1 H), 7.50-7.44 (m, 1 H), 7.34-7.30 (m, 2H), 7.25 (d, J = 9.2 Hz,1 H), 7.21-7.16 (m, 1 H), 6.00-5.98 (m, 1 H), 576-573 (m, 1 H), 5.25 (s, 2H), 4.19-4.11 (m, 2H), 3.14-3.10 (m, 1 H), 3.03-2.98 (m, 2H), 2.96 (s, 1 H), 2.56-2.53 (m, 1 H), 2.09-2.02 (m, 1 H), 1.92-1.87 (m, 1 H), 0.98 (t, J = 7.2 Hz, 3H). HRMS calculated C28H26CIFN602S [M+H]+ 565.1589 found 565.1592.
Example 46 N-Ethyl-N'-{(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinyl}urea trifluoroacetate 159
Figure imgf000160_0001
Step A - 1, 1-dimethylethyl (2S,4S)-2-ethynyl-4-{[(4-methylphenyl)sulfonyl]oxy}-1- pyrrolidinecarboxylate
Figure imgf000160_0002
tert-Butyl (2S,4R)-2-ethynyl-4-hydroxypyrrolidine-1 -carboxylate (6.89 g, 33.0 mmol), 4-methylbenzenesulfonic acid (12.46 g, 49.6 mmol), and triphenyl phosphine (17.34 g, 66.1 mmol) was dissolved into THF (165 mL) at rt. To this solution was added diethyl 1 ,2-diazenedicarboxylate (10.9 ml, 66.1 mmol) and the reaction mixture stirred at rt. The reaction was stirred for 22 h, and TLC indicated that starting material remained. The reaction was partitioned between EtOAc (500 mL) and water (200 mL). The layers were separated, and the organics were washed with water (1 x 300 mL), brine (300 mL), dried over MgS04, filtered and adsorbed onto silica. Purification via ISCO chromatography (hexanes:EtOAc) afforded 6.1 g (51%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCI3): δ 7.83 (d, 2H), 7.36 (d, 2H), 5.07 (br s, 1 H), 4.55 (br s, 1 H), 3.60 (br s, 2H), 2.35 (br s, 2H), 2.27 (s, 1 H), 1.45 (s, 9H).
Step B - 1 ,1-dimethylethyl (2S,4R)-4-azido-2-ethynyl-1-pyrrolidinecarboxylate
Figure imgf000161_0001
1 ,1 -Dimethylethyl (2S,4S)-2-ethynyl-4-{[(4-methylphenyl)sulfonyl]oxy}-1- pyrrolidinecarboxylate (6.14 g, 16.8(mmol), and sodium azide (3.27 g, 50 mmol), was dissolved into DMF (40 mL) and the reaction mixture was heated to 50 °C. The reaction was stirred for 22 h, and TLC indicated that starting material was consumed. The reaction was partitioned between diethyl ether (300 mL) and water (200 mL). The layers were separated, and the organics were washed with water (2 x 100 mL), dried over MgS04, filtered and adsorbed onto silica. Purification via 50 g silica gel plug (chloroform) afforded 3 g (76%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCI3): δ 4.65-4.45 (br d, 1 H), 4.22 (br s, 1 H), 3.64 (m, 1 H), 3.52-3.35 (br d, 1 H), 2.28 (br s, 3H), 1.48 (s, 9H).
Step C - 1 ,1 -Dimethylethyl (2S,4R)-4-{[(ethylamino)carbonyl]amino}-2-ethynyl-1- pyrrolidinecarboxylate
Figure imgf000161_0002
1 ,1 -Dimethylethyl (2S,4R)-4-azido-2-ethynyl-1-pyrrolidinecarboxylate (0.7 g, 3 mmol), PPh3 (0.94 g, 3.5 mmol), and 2 ml of water was dissolved into THF (20 mL) at rt. The reaction was stirred for 22 h, and TLC indicated that starting material was consumed. The reaction was diluted with ethyl acetate (50 mL) and dried over MgS04, and filtered. To this solution was added ethyl isocyanate (0.32 g, 4.4 mmol) and the reaction mixture was heated to 50 °C. The reaction was stirred for 3 h, and TLC indicated that starting material was consumed. The crude mixture was adsorbed onto silica. Purification via ISCO chromatography (hexanes:EtOAc) afforded 0.74 g (88%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCI3): δ 4.97- 4.63 (br m, 2H), 4.49 (br s, 2H), 3.69 (br s, 1H), 3.18 (m, 3H), 2.28 ( br s, 1H), 2.17- 2.00 (br d, 1 H), 1.47 (s, 9H), 1.11 (t, 3H).
Step D 1 ,1-dimethylethyl (2S,4R)-2-[(4-chlorothieno[3,2-djpyrimidin-6-yl)ethynyl]-4- {[(ethylamino)carbonyl]amino}-1 -pyrrolidinecarboxylate
Figure imgf000162_0001
To a solution of of 6-bromo-4-chlorothieno[3,2-dJpyrimidine (0.280 g, 1.12 mmol) in 15 mL of THF was combined with 1 ,1-dimethylethyl (2S,4R)-4- {[(ethylamino)carbonyl]amino}-2-ethynyl-1-pyrrolidine-carboxylate (0.363 g, 1.12 mmol), dichlorobis(triphenylphosphine) palladium (II) (0.04 g, 0.056 mmol), copper (I) iodide (0.042 g, 0.224 mmol), and triethylamine (0.47 mL, 3.37 mmol). The reaction mixture was heated to 60 °C for 2 h, then cooled to room temperature and filtered through Celite. Silica gel was added to the filtrate and the solvent was removed in vacuo. The resulting solid was loaded on to a column of silica gel and eluted with 0- 4% methanol in chloroform gradient to give 0.3 g (60%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCI3): δ 8.97 (s, 1 H); 7.57 (s, 1 H); 4.89-4.26 (br m, 4H); 3.81 (br s, 1 H); 3.24 (m, 3H); 2.46 (br s, 1 H); 2.33-2.11 (br d, 1 H); 1.50 (s, 9H); 1.14 (m, 3H).
Step E Λ/-ethyl-Λ/,-{(3R,5S)-5-[(4-{[1 -(phenylmethyl)-l H-indazol-5-yl]amino}thieno[3,2- dJpyrimidin-6-yl)ethynyl]-3-pyrrolidinyl}urea trifluoroacetate
Figure imgf000163_0001
To a solution of of 1 ,1-dimethylethyl (2S,4R)-2-[(4-chlorothieno[3,2- dJpyrimidin-6-yl)ethynyl]-4-{[(ethylamino)carbonyl]amino}-1-pyrrolidine-carboxylate (0.6 g, 0.135 mmol) in isopropanol was added of 1-(phenylmethyl)-1H-indazol-5- amine (0.5 g, 0.223 mmol). The resulting mixture was stirred at 65 °C for 18 h. The reaction was then cooled and the crude mixture was adsorbed onto silica. Purification via ISCO chromatography (methano chloroform). The product was dissolved in 2.5 ml of chloroform and 2.5 ml of trifluoroacetic acid was added. The mixture stirred for 3 h. The solvent was removed to afford 80 mg (91%) of the title compound as an orange solid. 1H NMR (400 MHz, CD3OD): δ 8.72 (s, 1H); 8.16 (s, 1 H); 8.03 (s, 1 H) 7.67 (d, 1 H); 7.63 (s, 1 H); 7.54 (d, 1 H); 7.33-7.23 (m, 5H); 5.7 (s, 2H); 4.96 (m, 1 H); 4.43 (m, 1 H); 3.65 (m, 1 H); 3.3 (m, 1 H); 3.15 (q, 2H); 2.45 (m, 2H); 1.09 (t, 3H); MS (ESI): 537 (M+H)+.
Example 47 -{(3R,5S)-5-[(4-{[1-(2,5-Difluorobenzyl)-1H-indol-5-yl]amino}thieno[3,2-d]pyrimidin- 6-yl)ethynyl]pyrrolidin-3-yl}ethanesulfonamide trifluoroacetate
Figure imgf000163_0002
teή-Butyl (2S,4R)-4-[(ethylsulfonyl)amino]-2-ethynylpyrrolidine- 1 -
Figure imgf000164_0001
Figure imgf000164_0002
The title compound was prepared from 1 ,1-dimethylethyl (2S,4R)-4-azido-2- ethynyl-1 -pyrrolidinecarboxylate and ethylsulfonylchloride by a procedure analogous to Example 1 , Step C. 1H NMR (300 MHz, CDCI3): δ 4.57 (brs, 1 H), 4.41 (m, 1 H), 4.26 (m, 1 H), 3.83 (m, 1 H), 3.27 (brs, 1 H), 3.13 (q, J = 6.0 Hz, 2H), 3.41 (m, 1 H), 2.35 (s, 1 H), 1.64 (s, 1 H), 1.52 (m, 9H), 1.43 (t, J = 7.5 Hz, 3H).
Step B - tert-Butyl (2S,4R)-2-[(4-chlorothieno[3,2-d]pyrimidin-6-yl)ethynyl]-4-[(ethyl sulfonyl)amino]pyrrolidine-1 -carboxylate
Figure imgf000164_0003
The title compound was prepared from tert-butyl (2S,4R)-4-[(ethylsulfonyl)amino]-2- ethynylpyrrolidine-1 -carboxylate and 6-bromo-4-chlorothieno[3,2-dJpyrimidine by a procedure analogous to Example 1 , Step D. MS (ESI): 471 (M)+
Step C - -{(3R,5S)-5-[(4-{[1-(2,5-Difluorobenzyl)-1H-indol-5-yl]amino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]pyrrolidin-3-yl}ethanesulfonamide trifluoroacetate
Figure imgf000165_0001
The title compound was prepared as the trifluoroacetate salt from tert-butyl (2S,4R)-2-[(4-chlorothieno[3,2-djpyrimidin-6-yl)ethynyl]-4-
[(ethylsulfonyl)amino]pyrrolidine-1 -carboxylate and 1-(2,5-difluorobenzyl)-1H-indol-5- amine by a procedure analogous to Example 1 , Step E. 1H NMR (400 MHz, DMSO- d6) δ 10.21 (s, 1 H), 9.71 (s, 1 H), 8.60 (s, 1 H), 7.76 (s, 1 H), 7.68 (s, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.57 (m, 2H), 7.30 (m, 3H), 6.84 (m, 1 H), 6.57 (d, J = 4Hz, 1 H), 5.53 (s, 2H), 4.83 (m, 1 H), 4.16 (m, 1 H), 3.59 (m, 1 H), 3.11 (m, 3.11 (m, 3H), 2.35 (m, 2H), 1.20 (t, J = 6.0 Hz, 3H) MS (ESI): 593 (M)+
Example 48
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate
Figure imgf000165_0002
Step A-1, 1-Dimethylethyl(2R,4R)-2-ethynyl-4-[(1-pyrrolidinylcarbonyl)oxy]-1- pyrrolidinecarboxylate o N
The title compound was prepared from 1-pyrrolidinecarbonyl chloride and 1 ,1- dimethylethyl (2R,4R)-2-ethynyl-4-hydroxy-1 -pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step F. 1H-NMR (400 MHz, CDCI3): δ 5.26 (br s, 1 H), 4.73- 4.52 (br d, 1 H), 3.68-3.52 (m, 2H), 3.40 (br s, 4H), 2.40-2.20 (m, 3H), 1.87 (br m, 4H), 1.49 (s, 9H).
Step B-1, 1 -dimethylethyl (2R,4R)-2-[(4-chlorothieno[3,2-d]pyrimidin-6-yl)ethynyl]-4- 1(1 -pyrrolidinylcarbonyl)oxy]-1 -pyrrolidinecarboxylate
Figure imgf000166_0001
A mixture of 6-bromo-4-chlorothieno[3,2-d]pyrimidine (0.472 g, 1.89 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.106 g, 0.151 mmol), and copper (I) iodide (0.014 g, 0.075 mmol) were combined in a 100 mL round bottom flask which was then placed under N2 with stirring. THF (13 mL) and triethylamine (1.05 mL, 7.92 mmol) were then added to the stirring reagents and the resulting mixture was placed in a preheated oil bath of 65 °C. Next 1 ,1-dimethylethyl (2R,4R)-2-ethynyl-4-[(1- pyrrolidinylcarbonyl)oxy]-1 -pyrrolidinecarboxylate (0.640, 2.08 mmol) was dissolved in 5ml of THF. This solution was added dropwise via syringe to the heated reaction mixture. The resulting reaction was heated for 4.5 h, cooled to room temperature then reduced in vacuo onto silica. Purification via ISCO column chromatography (Ethyl acetate: Hexanes) afforded 0.623 g of the title compound. MS (ESI): 499 (M+Na)+. Step C-1, 1 -dimethylethyl (2R,4R)-2-[(4-{[1-(phenylmethyl)-1H-indazol-5- yl]amino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-4-[(1-pyrrolidinylcarbonyl)oxy]-1- pyrrolidinecarboxylate
Figure imgf000167_0001
The title compound was prepared from 1,1-dimethylethyl (2R,4R)-2-[(4- chlorothieno[3,2-djpyrimidin-6-yl)ethynyl]-4-[(1-pyrrolidinylcarbonyl)oxy]-1- pyrrolidinecarboxylate(0.075g, 0.157mmol) and known 1-(phenylmethyl)-1H-indazol- 5-amine(0.039g, 0.173mmol) by a procedure analogous to Example 1 , Step A. MS (ESI): 664 (M+H)+.
Step D- (3R,5R)-5-[(4-{[1-(Phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate The title compound was prepared from 1 -dimethylethyl (2R,4R)-2-[(4-{[1- (phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-4-[(1- pyrrolidinylcarbonyl)oxy]-1-pyrrolidinecarboxylate by a procedure analogous to Example 1 , Step H. 1H NMR (300 MHz, DMSO-d6): δ 9.77 (s, 1H), 8.50 (s, 1H), 8.11 (s, 1H), 8.04 (s, 1 H), 7.70 (d, 1 H), 7.53 (d, 1 H), 7.47 (s, 1 H), 7.34-7.18 (m, 6H), 5.66 (s, 2H), 5.01 (s, 1 H), 4.12 (m, 1 H), 3.21 (m, 5H), 3.05 (m, 1H), 2.90 (d, 1 H), 2.35 (m, 1H), 1.87 (br d, 1 H), 1.71 (br s, 5H). MS (ESI): 564 (M+H)+.
Example 49
(3S,5S)-5-({4-[(1-benzyl-1H-indazol-5-yl)amino]thieno[2,3-d]pyrimidin-6- yl}ethynyl)pyrrolidin-3-yl pyrrolidine-1 -carboxylate
Figure imgf000167_0002
Step A- tert-Butyl (2S,4S)-2-ethynyl-4-[(pyrrolidin-1-ylcarbonyl)oxy]pyrrolidine-1- carboxylate
Figure imgf000168_0001
To a solution of tert-butyl (2S,4S)-2-ethynyl-4-hydroxypyrrolidine-1- carboxylate (1.0g, 4.73 mmol) in THF (50 mL) under N2 at 0 °C, triethylamine (3.3 mL, 23.7 mmol) was added dropwise followed by diphosgene (0.40 mL, 3.31 mmol) with evolution of gas from the reaction mixture. The solution was allowed to stir at 0 °C for 30 minutes. Pyrrolidine (1.98 mL, 23.7 mmol) was then added and the reaction mixture was allowed to stir at 0 °C for 2 hours. Upon consumption of the starting alcohol by TLC (Rf alcohol = 0.4, Rf carbamate = 0.5; 50% EtOAc in hexanes) the solution was diluted with EtOAc (30 mL) and washed with 5% aq. NaHS04 (50 mL). The aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organics were dried (MgS04), filtered and concentrated in vacuo. The residue was chromatographed (0-50% gradient of EtOAc in hexanes) to yield the title compound (1.27 g, 87%) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ 5.18 (t, J = 4 Hz, 1 H), 4.58 (d, J = 9 Hz, 1 H), 3.59 (s, 1 H), 3.40 (m, 5H), 2.68 (s, 1 H), 2.41 (s, 1 H), 2.23 (d, J = 14 Hz, 1 H), 1.88 (m, 4H), 1.48 (s, 9H).
Figure imgf000168_0002
Step B- tert-Butyl (2S,4S)-2-[(4-chlorothieno[2,3-d]pyrimidin-6-yl)ethynyl]-4- [(pyrrolidin-1-ylcarbonyl)oxy]pyrrolidine-1 -carboxylate To a solution of tert-butyl (2S,4S)-2-ethynyl-4-[(pyrrolidin-1- ylcarbonyl)oxy]pyrrolidine-1 -carboxylate (136 mL, 0.44 mmol) and 6-bromo-4- chlorothieno[2,3-d]pyrimidine (100 mg, 0.40 mmol) in THF (7 mL) under N2, triethylamine (0.15 mL, 1.0 mmol) was added followed by the addition of Pd(PPh3)2CI2 (15 mg, 0.02 mmol) and Cul (15 mg, 0.08 mmol). The reaction mixture was stirred overnight at 65 °C. The reaction mixture was diluted with EtOAc, filtered through celite and rinsed with EtOAc (5 mL) and MeOH (5 mL). The filtrate was evaporated onto silica gel and chromatographed (20-100% gradient of EtOAC in hexanes) to yield the title compound (103 mg, 54%) as a yellow oil. ESIMS (M+H)+ = 477.
Figure imgf000169_0001
Step C- tert-Butyl (2S,4S)-2-({4-[(1-benzyl-1 H-indazol-5-yl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-4-[(pyrrolidin-1-ylcarbonyl)oxy]pyrrolidine-1-carboxylate
To a solution of tert-butyl (2S,4S)-2-[(4-chlorothieno[2,3-d]pyrimidin-6- yl)ethynyl]-4-[(pyrrolidin-1-ylcarbonyl)oxy]pyrrolidine-1 -carboxylate (125 mg, 0.262 mmol) in isopropanol (2 mL), 1-benzyl-1 H-indazol-5-amine was added and the solution was heated to 65 °C overnight. The reaction mixture was diluted with EtOAc, evaporated onto silica gel and chromatographed (20-80% gradient of EtOAc in hexanes) to yield the title compound (90 mg, 52%) as a yellow solid. 1H NMR (400 MHz, CDCI3) δ 8.53 (s, 1 H), 8.04 (s, 1 H), 7.98 (s, 1 H), 7.27 (m, 9H), 5.60 (s, 2H), 5.27 (s, 1 H), 4.89 (s, 1 H), 4.77 (s), 3.64 (m, 2H), 3.37 (m, 4H), 2.36 (m, 2H), 1.79 (m, 4H), 1.47 (s, 9H). ESIMS (M+H)+ = 664.
Step D- (3S,5S)-5-({4-[(1-Benzyl-1H-indazol-5-yl)amino]thieno[2,3-d]pyrimidin-6- yl}ethynyl)pyrrolidin-3-yl pyrrolidine-1 -carboxylate To a solution of tert-butyl (2S,4S)-2-({4-[(1-benzyl-1 H-indazol-5-yl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-4-[(pyrrolidin-1 -ylcarbonyl)oxy]pyrrolidine-1 -carboxylate (90 mg, 0.136 mmol) in CH2CI2 (2 mL) was added trifluoroacetic acid (0.3 mL, 3.9 mmol). After stirring overnight at room temperature, the reaction was partitioned between CH2CI2 (5 mL) and aqueous NaHC03 (5 mL). The aqueous layer was extracted with CH2CI2 (2 x 5 mL). The combined organics were dried (MgS04), filtered and concentrated in vacuo to yield the title compound (40 mg, 52%) as a yellow-tan solid. 1H NMR (400 MHz, CDCI3) δ 8.55 (s, 1 H), 8.06 (s, 1 H), 7.98 (d, J = 4 Hz, 1 H), 7.40 (m, 2H), 7.30 (m, 3H), 7.21 (m, 2H), 7.10 (s, 1H), 7.04 (s, 1H), 5.62 (s, 2H), 5.22 (m, 1 H), 4.10 (dd, J = 8, 4 Hz, 1 H), 3.37 (m, 4H), 3.24 (d, J = 12 Hz, 1 H), 3.11 (dd, J = 12, 8 Hz, 1 H), 2.49 (m, 1 H),'2.10 (m, 1 H), 1.84 (m, 4H). ESIMS (M+H)+ = 564.
Example 50
Ethyl ((3R,5R)-5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}pyrrolidin-3-yl) carbamate
Figure imgf000170_0001
Step A - Tert-butyl (2R,4R)-2-ethynyl-4-[(trifluoroacetyl)amino]pyrrolidine-1- carboxylate
Figure imgf000170_0002
To a solution of tert-butyl (2R,4S)-2-ethynyl-4-hydroxypyrrolidine-1- carboxylate (1.15 g, 5.4 mmol) in CH2CI2 cooled to 0 °C was added methane sulfonyl chloride (0.63 ml, 8.1 mmol) and triethylamine (1.5 ml, 10.8 mmol). After the starting material was consumed by TLC, the reaction was quenched with the addition of water and warmed to rt. The organic layer was separated, dried over MgS04, and concentrated to an oil. The oil was dissolved in DMF and sodium azide (527 mg, 8.1 mmol) added. The mixture was heated to 70 °C for 16 h. The mixture was cooled to rt and diluted with water. The aqueous mixture was extracted with EtOAc. The combined organics were washed with water and brine, dried over MgS04 and concentrated to an oil. A mixture of this oil and PPh3 (2.12 g, 8.1 mmol) in water (0.68 ml, 37.8 mmol) and 35 ml THF was stirred at rt for 16 h. The reaction was concentrated to a yellow oil. To a solution of this oil in 50 ml CH2CI2, cooled to 0 °C, was added triethylamine (2.3 ml, 16.2 mmol) and trifluoroacetic anhydride (1.14 ml, 8.1 mmol). After the addition was complete, the ice bath was removed and the reaction was stirred at rt for an hour. The reaction was diluted with water and extracted with CH2CI2. The organic layer was washed with sat'd NaHC03 and brine, dried over MgS0 and concentrated. The crude material was purified through silica to give the title compound as a white solid (1.041 g, 63% over all steps). 1H NMR (400 MHz, d6-DMSO) δ 9.60 (m, 1 H), 4.42 (m, 1 H), 4.23 (m, 1 H), 3.60 (m, 1 H), 3.34 (m, 1H), 3.22 (s, 1H), 2.44 (m, 1 H), 2.08 (m, 1 H), 1.41 (s, 9H) ppm.
Step B - 1, 1 -Dimethylethyl (2R, 4R)-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-4- l(trifluoroacetyl)amino]-1 -pyrrolidinecarboxylate
Figure imgf000171_0001
The title compound was prepared from 6-bromo-Λ/-(3-chloro-4-{[(3- fluorophenyl)-methyl]oxy}phenyl)thieno[2,3-dJpyrimidin-4-amine and tert-butyl (2R,4R)-2-ethynyl-4-[(trifluoroacetyl)amino]pyrrolidine-1 -carboxylate by a procedure analogous to example 1 , step G. MS (ESI) m/z = 690 [M+H]+. Step C - 1,1 -Dimethylethyl (2R,4R)-4-amino-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2, 3-d]pyrimidin-6-yl}ethynyl)-1 - pyrrolidinecarboxylate
Figure imgf000172_0001
To a solution of 1 ,1-dimethylethyl (2R,4R)-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-4- [(trifluoroacetyl)amino]-1 -pyrrolidinecarboxylate (525 mg, 0.76 mmol) in 9 ml THF was added a 1 M solution of lithium hydroxide (1.14 ml, 1.14 mmol). After 16 h, the reaction was diluted with water and extracted with methylene chloride. The combined organic phases were dried over MgS0 and purified through silica (90:0.5:0.5 CH2CI2:MeOH:EtOAc) to give the title compound as a yellow foam. 1H NMR (400 MHz, d6-DMSO) δ 9.67 (s, 1H), 8.53 (s, 1 H), 8.01-7.98 (m, 2H), 7.65 (d, J = 8.4 Hz, 1H), 7.50-7.44 (m, 1H), 7.33-7.26 (m, 3H), 7.21-7.16 (m, 1H), 5.24 (s, 2H), 4.66-4.65 (m, 1H), 3.51 (m, 1 H), 3.39 (m, 1H), 2.99 (m, 1 H), 2.46-2.43 (m, 1 H), 1.80 (m, 3H), 1.44 (s, 9H).
Step D - 1,1 -Dimethylethyl (2R,4R)-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-4- {[(ethyloxy)carbonyl]amino}-1 -pyrrolidinecarboxylate
Figure imgf000172_0002
To a solution of 1 ,1-dimethylethyl (2R,4R)-4-amino-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-1- pyrrolidinecarboxylate (197 mg, 0.33 mmol) in CH2CI2 cooled to 0 °C was added triethylamine (0.14 ml, 0.99 mmol) and ethyl chloroformate (34 μl, 0.36 mmol). The reaction was diluted with CH2CI2 and washed with sat'd NaHC03, water and brine. The organic phase was dried over MgS04 and purified through silica (5% MeOH/CH2CI2) to give the title compound. MS (ESI) m/z = 666 [M+H]+.
Step E - ethyl [(3R,5R)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2, 3-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate 1 , 1 -Dimethylethyl (2R,4R)-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-4- {[(ethyloxy)carbonyl]amino}-1 -pyrrolidinecarboxylate was deprotected by a procedure analogous to Example 1 , Step H. 1H NMR (400 MHz, d6-DMSO) δ 9.66 (s, 1 H), 8.52 (s,1 H), 8.02-7.98 (m, 2H), 7.67-7.64 (m, 1 H), 7.50-7.44 (m, 1 H), 7.33-7.25 (m, 3H), 7.21-7.16 (m, 1 H), 5.24 (s, 2H), 4.08-4.04 (m, 1 H), 4.01-3.91 (m, 3H), 2.99-2.95 (m, 1 H), 272-2.67 (m, 1 H), 2.47-2.40 (m, 1 H), 173-1.67 (m, 1 H), 1.17-1.14 (m, 3H). HRMS calculated C28H25CIFN5O3S [M+H]+ 566.1429 found 566.1428.
Additional compounds of formula (I), (I') and (I") were prepared according to the procedures of Schemes 1 to 7 and Examples 1 to 50 and were characterized as being the following:
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(1-methyl-2- piperidinyl)ethynyl]thieno[3,2-c/]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-(3-pyrrolidinylethynyl)thieno[2,3- dJpyrimidin-4-amine; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-(3-piperidinylethynyl)thieno[2,3- dJpyrimidin-4-amine trifluoroacetate;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2S)-2- pyrrolidinylethynyl]thieno[2,3-φyrimidin-4-amine; (3R,5S)-5-[(4-{[1-methyl-2-(phenylmethyl)-1H-benzimidazol-5-yl]amino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinol hydrochloride;
A/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-(2-piperidinylethynyl)thieno[2,3- c/]pyrimidin-4-amine trifluoroacetate;
A/-(3-chloro-4-{[(2,5-difluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(4S)-1 ,3-thiazolidin-4- ylethynyl]thieno[3,2-dJpyrimidin-4-amine trifluoroacetate;
Λ/-[2-(phenylmethyl)-1H-benzimidazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- dJpyrimidin-4-amine trifluoroacetate;
/V-[3-chloro-4-(phenyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-dJpyrimidin- 4-amine trifluoroacetate;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[((2S,4R)-4-{[2-(4- morpholinyl)ethyl]oxy}-2-pyrrolidinyl)ethynyl]thieno[3,2-dJpyrimidin-4-amine;
Λ/-{1-[(3-fluorophenyl)methyl]-1H-indol-5-yl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- dJpyrimidin-4-amine trifluoroacetate; Λ/-[1 -(phenylmethyl)-l H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- dJpyrimidin-4-amine trifluoroacetate;
(3S,5S)-5-[(4-{[3-chloro-4-(1-naphthalenyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinol;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- c |pyrimidin-6-yl}ethynyl)-3-pyrrolidinol;
Λ/-[1 -(2-pyridinylmethyl)-1 H-benzimidazol-5-yl]-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-c/]pyrimidin-4-amine hydrochloride;
(3R,5S)-5-({4-f(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinol hydrochloride; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2S)-2- pyrrolidinylethynyl]thieno[3,2-djpyrimidin-4-amine hydrochloride;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinol hydrochloride;
/V-(3-fluoro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4-amine trifluoroacetate;
(3-chloro-4-{[(3-fluorophenyl)methyl]amino}phenyl){6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-djpyrimidin-4-yl}amine trifluoroacetate; Λ/-[1-(phenylsulfonyl)-1H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine trifluoroacetate;
Λ/-[1-(phenylmethyl)-1H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- djpyrimidin-4-amine trifluoroacetate;
Λ/-{1-[(3,5-difluorophenyl)methyl]-1H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; Λ/-[1 -(2-pyridinylmethyl)-1 H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine trifluoroacetate;
Λ/-{1 -[(2-methyl-1 ,3-thiazol-4-yl)methyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate;
0-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- c/]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl] [3-(4-morpholinyl)propyl]thiocarbamate;
4-(2,3-dihydro-1H-indol-1-yl)-6-(2-pyrrolidinylethynyl)thieno[3,2-djpyrimidine;
Λ/-(4-{[(2,5-difluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- dJpyrimidin-4-amine hydrochloride;
Λ/-[2-(phenylmethyl)-1 ,3-benzothiazol-6-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine formate;
Λ/-[2-(phenylmethyl)-1 ,3-benzothiazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- dJpyrimidin-4-amine trifluoroacetate; Λ-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(4-methyl-3- morpholinyl)ethynyl]thieno[3,2-c/]pyrimidin-4-amine hydrochloride;
Λ/-{1 -[1 -(3-fluorophenyl)ethyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-c/]pyrimidin-4-amine trifluoroacetate;
Λ/-(3-chloro-4-{[(2-methyl-1 ,3-thiazol-4-yl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4-amine trifluoroacetate; phenyl[4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4- yl}amino)phenyl]methanone trifluoroacetate;
Λ/-(3-chloro-4-{[(1 S)-1-(3-fluorophenyl)ethyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; Λ/-{3-chloro-4-[(6-fluoro-4-quinolinyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-djpyrimidin-4-amine;
A-{2-[(2,5-difluorophenyl)methyl]-1H-benzimidazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-djpyrimidin-4-amine trifluoroacetate;
A-(1-methyl-1H-indazol-5-yl)-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4- amine trifluoroacetate; Λ/-{3-chloro-4-[(3-fluorophenyl)oxy]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- dJpyrimidin-4-amine trifluoroacetate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -piperidinecarboxylate;
Λ/-[2-(phenylmethyl)-2H-indazol-6-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- djpyrimidin-4-amine trifluoroacetate;
Λ-[1-(phenylmethyl)-1H-indazol-6-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine trifluoroacetate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl methyl(phenyl)carbamate; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{4-[(methylsulfonyl)methyl]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- dJpyrimidin-4-amine;
6-[(2R)-2-pyrrolidinylethynyl]-Λ/-[1-(2-thienylsulfonyl)-1H-indol-5-yl]thieno[3,2- d]pyrimidin-4-amine trifluoroacetate;
Λ/-[1-(methylsulfonyl)-1H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- djpyrimidin-4-amine trifluoroacetate;
Λ/-{3-chloro-4-[(6-methyl-2-pyridinyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-c/]pyrimidin-4-amine trifluoroacetate; /V2-(4-fluorophenyl)-Λ/5-{6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4-yl}-1H- benzimidazole-2,5-diamine trifluoroacetate;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-c/]pyrimidin-4-amine trifluoroacetate;
Λ/-[1-(cyclohexylmethyl)-1H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- dJpyrimidin-4-amine trifluoroacetate;
A/-(2-phenyl-1H-benzimidazol-5-yl)-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine trifluoroacetate;
Λ/-[(2,3-dichlorophenyl)methyl]-6-(2-pyrrolidinylethynyl)thieno[3,2-dJpyrimidin-4-amine trifluoroacetate; Λ/-[1-(phenylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4-amine formate; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl diethylcarbamate;
Λ/-[4-(phenylmethyl)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-djpyrimidin-4- amine formate; A-[1 -(phenylmethyl)-2,3-dihydro-1 H-indol-5-yl]-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-c/]pyrimidin-4-amine formate;
6-[(2R)-2-pyrrolidinylethynyl]-Λ/-[1-(2-thienylsulfonyl)-2,3-dihydro-1H-indol-5- yl]thieno[3,2-dJpyrimidin-4-amine formate;
4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4-yl}amino)-/V-1 ,3-thiazol-2- ylbenzenesulfonamide trifluoroacetate;
/V-{1-[(2-fluorophenyl)sulfonyl]-2,3-dihydro-1H-indol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-djpyramidin-4-amine formate;
/V-{3-chloro-4-[(3-pyridinylmethyl)oxy]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- djpyrimidin-4-amine trifluoroacetate; 3-({[2-chloro-4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-djpyrimidin-4- yl}amino)phenyl]oxy}methyl)-1 λ5-pyridin-1 -ol trifluoroacetate;
Λ/-{1-[(2-fluorophenyl)methyl]-2,3-dihydro-1H-indol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-c/]pyrimidin-4-amine formate;
Λ/-[1-(phenylmethyl)-4-piperidinyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-djpyrimidin- 4-amine trifluoroacetate;
A-{1 -[(5-chloro-1 ,2,3-thiadiazol-4-yl)methyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate;
Λ/-(3-chloro-4-{[(5-chloro-1 ,2,3-thiadiazol-4-yl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4-amine trifluoroacetate; Λ/-(3-fluoro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-c ]pyrimidin-4-amine hydrochloride;
1-phenyl-2-[4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4- yl}amino)phenyl]ethanone trifluoroacetate;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1-[2-(methyloxy)ethyl]-2- pyrrolidinyl}ethynyl)thieno[3,2-djpyrimidin-4-amine hydrochloride;
6-{[(2R)-1-acetyl-2-pyrrolidinyl]ethynyl}-Λ/-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-d]pyrimidin-4-amine hydrochloride; A-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(methylsulfonyl)-2- pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
6-[(2R)-2-pyrrolidinylethynyl]-Λ/-[1-(1 ,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]thieno[2,3- djpyrimidin-4-amine trifluoroacetate;
Λ/-{3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-c ]pyrimidin-4-amine hydrochloride; methyl (2R)-2-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-1 -pyrrolidinecarboxylate;
/V-[(3-chlorophenyl)methyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-c/]pyrimidin-4- amine hydrochloride;
Λ-{3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-c/]pyrimidin-4-amine trifluoroacetate;
(3R,5S)-5-({4-[(3-chloro-4-fluorophenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-bromophenyl)amino]thieno[3,2-dJpyrimidin-6-yl}ethynyl)-3- pyrrolidinyl 4-morpholinecarboxylate; (2R)-2-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- c/]pyrimidin-6-yl}ethynyl)-1-pyrrolidinecarbaldehyde;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(cyclopropylmethyl)-2- pyrrolidinyl]ethynyl}thieno[3,2-c7]pyrimidin-4-amine;
A-[4-(1-piperidinylsulfonyl)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin- 4-amine hydrochloride;
Λ/-[4-chloro-2-(phenylmethyl)-1H-benzimidazol-6-yl]-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-c/]pyrimidin-4-amine trifluoroacetate;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1 -[(1 -methyl-1 H-pyrrol-2- yl)methyl]-2-pyrrolidinyl}ethynyl)thieno[3,2-dJpyrimidin-4-amine; Λ-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1-[3-(dimethylamino)-2,2- dimethylpropyl]-2-pyrrolidinyl}ethynyl)thieno[3,2-d]pyrimidin-4-amine;
Λ/-[2-chloro-4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4- yl}amino)phenyl]-3-fluorobenzenesulfonamide trifluoroacetate;
Λ/-{1-[(phenylmethyl)sulfonyl]-2,3-dihydro-1H-indol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4-amine formate;
2-{[5-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-yl}amino)-2,3-dihydro- 1 H-indol-1 -yl]sulfonyl}benzonitrile formate; 6-[(2R)-2-pyrrolidinylethynyl]-Λ/-[1-(2-thienylsulfonyl)-1H-indol-5-yl]thieno[2,3- dJpyrimidin-4-amine;
(3R,5S)-5-{[4-({3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}amino)thieno[3,2- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
Λ/-{1 -[1 -(3-fluorophenyl)ethyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-c]pyrimidin-4-amine trifluoroacetate; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1 -[(1 - methylethyl)sulfonyl]-2-pyrrolidinyl}ethynyl)thieno[3,2-djpyrimidin-4-amine;
2-(methyloxy)ethyl (2R)-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-c/]pyrimidin-6-yl}ethynyl)-1- pyrrolidinecarboxylate;
N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(2,2,3,3,3- pentafluoropropanoyl)-2-pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[((2R)-1-{[5-chloro-1-methyl-3- (trifluoromethyl)-1/-/-pyrazol-4-yl]methyl}-2-pyrrolidinyl)ethynyl]thieno[3,2-d]pyrimidin- 4-amine;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl (3,5-dimethyl-4-isoxazolyl)carbamate; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(3,3,3-trifluoropropyl)-2- pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl (l-methylethyl)carbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indol-5-yl]amino}thieno[3,2-c/]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate hydrochloride;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1-[2- (methylsulfonyl)ethyl]-2-pyrrolidinyl}ethynyl)thieno[3,2-djpyrimidin-4-amine;
(3R,5S)-5-({4-[(3-fluoro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate hydrochloride; 2-fluoroethyl (2R)-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-dJpyrimidin-6-yl}ethynyl)-1- pyrrolidinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-thienylsulfonyl)amino]phenyl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate; Λ/-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- c/]pyrimidin-4-amine;
A/-[2-chloro-4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-rilpyrimidin-4- yl}amino)phenyl]-3-fluorobenzenesulfonamide trifluoroacetate;
Λ/-[1-(2-phenylethyl)-1H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- djpyrimidin-4-amine trifluoroacetate; Λ -[1 -(cyclohexylmethyl)-l H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine trifluoroacetate;
6-[(2R)-2-pyrrolidinylethynyl]-Λ/-(4-{[3-(trifluoromethyl)phenyl]thio}phenyl)thieno[3,2- djpyrimidin-4-amine trifluoroacetate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- c/]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl [2-(methylsulfonyl)ethyl]carbamate;
Λ/-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
Λ/-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine trifluoroacetate; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-methyl-1-piperazinecarboxylate;
Λ/-{[2,3-bis(methyloxy)phenyl]methyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- dJpyrimidin-4-amine trifluoroacetate;
/V-[(2-chlorophenyl)methyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- amine trifluoroacetate;
/V-{[3-(methyloxy)phenyl]methyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-dJpyrimidin- 4-amine trifluoroacetate;
Λ/-[(2-fluorophenyl)methyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4- amine trifluoroacetate; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- c]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d|pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
Λ/-[3-chloro-4-(phenylthio)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-c/]pyrimidin- 4-amine trifluoroacetate;
(3R,5S)-5-[(4-{[1-(2-phenylethyl)-1H-indol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate formate; (3R,5S)-5-[(4-{[1-(cyclohexylmethyl)-1H-indol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate formate;
A-{1 -[(2-fluorophenyl)methyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-dJpyrimidin-4-amine trifluoroacetate;
Λ/-{3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- djpyrimidin-4-amine; 6-{[(2S,4S)-4-fluoro-2-pyrrolidinyl]ethynyl}-Λ/-[1-(phenylmethyl)-1H-indazol-5- yl]thieno[2,3-d]pyrimidin-4-amine;
(3R,5S)-5-[(4-{[1-(2-thienylsulfonyl)-1H-indol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate hydrochloride;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate hydrochloride; tV-(3-chloro-4-{[(6-methyl-2-pyridinyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-c/]pyrimidin-4-amine trifluoroacetate;
(3R,5S)-5-{[4-({1-[(2-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate; Λ/-{1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-djpyrimidin-4-amine trifluoroacetate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-[(4-{[1 -(1 ,3-thiazol-4-ylmethyl)-1 H-indol-5-yl]amino}thieno[3,2-dlpyrimidin- 6-yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate hydrochloride;
(3R,5S)-5-[(4-{[3-fluoro-1-(phenylmethyl)-1H-indol-5-yl]amino}thieno[3,2-d]pyrimidin- 6-yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
A/-[1-(phenylmethyl)-1H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- djpyrimidin-4-amine formate; (3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl [2-(4-morpholinyl)ethyl]carbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1r-/-indazol-5-yl]amino}thieno[3,2-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl [2-(1 -piperidinyl)ethyl]carbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl [2-(1-piperidinyl)ethyl]carbamate;
A/-[3-chloro-4-(1 ,3-thiazol-2-ylthio)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine hydrochloride; Λ/-[3-fluoro-1-(phenylmethyl)-1H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine hydrochloride;
A/-[3-chloro-4-(phenylthio)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-d]pyrimidin- 4-amine hydrochloride;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl carbamate; Λ/-[4-(2-pyridinylthio)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-dJpyrimidin-4- amine hydrochloride;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl methylcarbamate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- c]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-{[4-({3-chloro-4-[(phenylthio)methyl]phenyl}amino)thieno[3,2-c/]pyrimidin-6- yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate formate;
(3R,5S)-5-({4-[(6-{[(3-fluorophenyl)methyl]oxy}-3-pyridinyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-{[4-({3-chloro-4-[(phenylsulfonyl)methyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate formate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
6-[(2R)-2-pyrrolidinylethynyl]-Λ/-[1 -(1 ,3-thiazol-4-ylmethyl)-1 H-indol-5-yl]thieno[2,3- d]pyrimidin-4-amine formate;
Λ/-[(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]methanesulfonamide;
Λ/-(3-chloro-4-{[(2-chloro-3-pyridinyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-djpyrimidin-4-amine trifluoroacetate; (3R,5S)-5-[(4-{[3-chloro-4-(phenylthio)phenyl]amino}thieno[3,2-djpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
Λ/-{1-[(3-fluorophenyl)sulfonyl]-1H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine trifluoroacetate;
(3R,5S)-5-{[4-({3-chloro-4-[(1,3-thiazol-2-ylmethyl)oxy]phenyl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)sulfonyl]-1H-indazol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate; Λ/-{3-chloro-4-[(1 ,3-thiazol-2-ylmethyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine trifluoroacetate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- c/]pyrimidin-6-yl}ethynyl)-3-pyrrolidinecarbonitrile;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate; Λ/-{3-chloro-4-[(phenylthio)methyl]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- ]pyrimidin-4-amine;
Λ -{3-chloro-4-[(phenylsulfonyl)methyl]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- c/]pyrimidin-4-amine;
Λ/-(6-{[(3-fluorophenyl)methyl]oxy}-3-pyridinyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[3-(methyloxy)phenyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-{[4-({3-chloro-4-[(2,3-difluorophenyl)oxy]phenyl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate; (3R,5S)-5-[(4-{[5-(2-pyridinyloxy)-2-naphthalenyl]amino}thieno[3,2-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(6-fluoro-4-quinolinyl)oxy]phenyl}amino)thieno[3,2- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
Λ/-(6-{[(2,5-difluorophenyl)methyl]oxy}-3-pyridinyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-djpyrimidin-4-amine hydrochloride;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinecarbonitrile;
A-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4S)-4-fluoro-2- pyrrolidinyl]ethynyl}thieno[2,3-djpyrimidin-4-amine; (3S,5R)-5-{[4-({3,3-difluoro-1 -[(2-fluorophenyl)methyl]-2-oxo-2,3-dihydro-1 H-indol-5- yl}amino)thieno[3,2-d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate hydrochloride;
Λ/-(6-{[(2-fluorophenyl)methyl]oxy}-3-pyridinyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-dJpyrimidin-4-amine hydrochloride;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinol trifluoroacetate; ethyl (2S,4S)-2-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-4-{[(ethyloxy)carbonyl]amino}-1-pyrrolidinecarboxylate; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethyl carbonate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 2-(methyloxy)ethyl carbonate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 3-(methylsulfonyl)propanoate; ethyl [(3S,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-djpyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate; methyl [(3S,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-dJpyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl methanesulfonate trifluoroacetate;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4R)-4-(ethyloxy)-2- pyrrolidinyl]ethynyl}thieno[2,3-dJpyrimidin-4-amine trifluoroacetate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d|pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 3-(methylthio)propanoate formate;
Λ/-(3-chloro-4-{[(4-chloro-2-pyridinyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-dJpyrimidin-4-amine; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl methanesulfonate;
6-{[(2S,4S)-4-azido-2-pyrrolidinyl]ethynyl}-Λ/-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-d]pyrimidin-4-amine;
Λ/-[(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-4-morpholinecarboxamide;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinol trifluoroacetate;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4R)-4-(ethyloxy)-2- pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine; (3R,5S)-5-[(4-{[1 -(phenylmethyl)-l H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate trifluoroacetate;
(5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-2-pyrrolidinone hydrochloride; (5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-c/]pyrimidin-6- yl)ethynyl]-2-pyrrolidinone hydrochloride; (5S)-5-{[4-({3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}amino)thieno[3,2- c/]pyrimidin-6-yl]ethynyl}-2-pyrrolidinone hydrochloride;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl methanesulfonate trifluoroacetate;
(3R,5S)-5-[(4-{[1 -(1 ,3-thiazol-4-ylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-{[4-({1-[(3,5-difluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-({4-[(3-chloro-4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)amino]thieno[3,2-dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4- morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-{[4-({1 -[(5-chloro-1 ,2,3-thiadiazol-4-yl)methyl]-1 H-indazol-5- yl}amino)thieno[3,2-dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate; (3R,5S)-5-{[4-({1 -[1 -(3-fluorophenyl)ethyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-[(4-{[4-(2-pyridinylthio)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-3- pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{3-chloro-4-[(3-fluorophenyl)thio]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- dJpyrimidin-4-amine hydrochloride;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)thio]phenyl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate formate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate trifluoroacetate; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- c/]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-djpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3R,5S)-5-{[4-({3-chloro-4-[(1,3-thiazol-4-ylmethyl)oxy]phenyl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{3-chloro-4-[(3-methylphenyl)thio]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- dJpyrimidin-4-amine formate; 135
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl propanoate;
(3R,5S)-5-{[4-({3-chloro-4-[(3-methylphenyl)thio]phenyl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate; (3R,5S)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1b/-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate; (3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-{[4-({3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}amino)thieno[2,3- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate formate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-c/]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate; (3R,5R)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate trifluoroacetate; (3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate formate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-c/]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate trifluoroacetate; (3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate formate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate hydrochloride;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-c lpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate trifluoroacetate; (3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-c ]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-thiomorpholinecarboxylate trifluoroacetate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- c/]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate trifluoroacetate; (3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate formate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate hydrochloride;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate hydrochloride;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate hydrochloride; (3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- c]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate hydrochloride; (3R,5R)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d|pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate hydrochloride;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate hydrochloride;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate trifluoroacetate; (3S,5S)-5-[(4-{[1 -(phenylmethyl)-l rV-indazol-5-yl]amino}thieno[2,3-djpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate hydrochloride;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate hydrochloride;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate trifluoroacetate; (3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-djpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate; (3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-c/]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate; (3R,5R)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-djpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate; (3S,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-dJpyrimidin-6- yl)ethynyl]-3-pyrroIidinyl dimethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate trifluoroacetate; (3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-[(4-{[4-(phenylmethyl)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-3- pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
/V-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4S)-4-(4- morpholinylmethyl)-2-pyrrolidinyl]ethynyl}thieno[3,2-dJpyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4S)-4-(4- morpholinylmethyl)-2-pyrrolidinyl]ethynyl}thieno[2,3-dJpyrimidin-4-amine; (3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- c/]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate; (3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate trifluoroacetate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate; (3S,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate trifluoroacetate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-c/]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate trifluoroacetate; (3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-c/]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -piperidinecarboxylate trifluoroacetate;
(3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate trifluoroacetate;
(3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate trifluoroacetate; (3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d|pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3S,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate; (3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3S,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate; (3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-dlpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate; (3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-c/]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate; (3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate trifluoroacetate; (3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[2,3- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate trifluoroacetate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -piperazinecarboxylate trifluoroacetate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1r7-indazol-5-yl]amino}thieno[3,2-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -piperazinecarboxylate trifluoroacetate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-thiomorpholinecarboxylate trifluoroacetate; (3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{[3-(phenyloxy)phenyl]methyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-dJpyrimidin- 4-amine;
(3R,5S)-5-{[4-({[3-(phenyloxy)phenyl]methyl}amino)thieno[3,2-d]pyrimidin-6- yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-thiomorpholinecarboxylate 1 ,1-dioxide trifluoroacetate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)et y nyl]-3-py rrol id i ny 1 1 -piperidinecarboxylate trifluoroacetate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- cV]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate hydrochloride;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate hydrochloride; (5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2-c/]pyrimidin-6- yl]ethynyl}-2-pyrrolidinone hydrochloride; (5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-cτ]pyrimidin-6- yl)ethynyl]-2-pyrrolidinone hydrochloride;
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate hydrochloride;
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate trifluoroacetate; (3R,5S)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-c/|pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-2-pyrrolidinone;
(5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3)2-c/]pyrimidin- 6-yl]ethynyl}-2-pyrrolidinone;
(5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indol-5-yl}amino)thieno[3,2-dJpyrimidin- 6-yl]ethynyl}-2-pyrrolidinone;
(5S)-5-({4-[(6-{[(2,5-difluorophenyl)methyl]oxy}-3-pyridinyl)amino]thieno[3,2- c/]pyrimidin-6-yl}ethynyl)-2-pyrrolidinone; (3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-c/]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- c Jpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethyl(methyl)carbamate; (3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3S,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1 -[1 -(3-fluorophenyl)ethyl]-1 H-indazol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[1-(3-fluorophenyl)ethyl]-1H-indazol-5-yl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[4-(phenylsulfonyl)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-3- pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[3-chloro-4-(phenylsulfonyl)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate; (3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-2-pyrrolidinone;
(5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-2-pyrrolidinone; (5R)-5-{[4-({1 -[(2,5-difluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-2-pyrrolidinone;
(5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2-djpyrimidin-6- yl]ethynyl}-2-pyrrolidinone;
(3R,5S)-5-{[4-({3-fluoro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
Λ/-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-/V-ethylurea; [(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl ethylcarbamate;
Λ-ethyl-/V-((3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5- yl}amino)thieno[3,2-c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)urea;
A/-((3R,5S)-5-{[4-({3-chloro-4-[(3-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)-/V-ethylurea;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate; Λ/-((3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)-/V-ethylurea; ethyl [(3R,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-dJpyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
A-((3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indol-5-yl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)ethanesulfonamide;
Λ/-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
1-{[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl}-2,5-pyrrolidinedione;
(3R,5S)-5-({4-[(3-chloro-4-{[(1-methylethyl)oxy]methyl}phenyl)amino]thieno[3,2- c/|pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-{[4-({3-chloro-4-[(5-methyl-3-isoxazolyl)oxy]phenyl}amino)thieno[3,2- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[3-(trifluoromethyl)phenyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl}ethanesulfonamide; ethyl ((3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate; ethyl ((3R,5S)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate; (3S,5R)-5-{[4-({3-chloro-4-[(5-methyl-3-isoxazolyl)oxy]phenyl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)oxy]methyl}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indol-5-yl}amino)thieno[3,2- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate; [(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl dimethylcarbamate; ethyl ((3R,5S)-5-{[4-({1 -[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate;
[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- djpyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methanol;
(5R,7aR)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)tetrahydro-1 H-pyrrolo[1 ,2-c][1 ,3]oxazol-3-one; Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R,5R)-5-(4- morpholinylmethyl)-2-pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide;
Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-Λ/,-ethylurea; ethyl [(3R,5R)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-djpyrimidin-6-yl}ethynyl)-3- pyrrolidinyl]carbamate;
Λ-((3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)propanamide;
Λ-((3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- dJpyrimidin-6-yl]etnynyl}-3-pyrrolidinyl)propanamide;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; (3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate;
(5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3-d]pyrimidin- 6-yl]ethynyl}-2-pyrrolidinone;
(5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indol-5-yl}amino)thieno[2,3-d]pyrimidin- 6-yl]ethynyl}-2-pyrrolidinone;
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3R,5R)-5-({4-[(3-chloro-4-{[(3-fiuorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- c/]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-c/]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- d|pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-djpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- djpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- jpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-dJpyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[2,3- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
Λ/-[(3S,5S)-5-({4-[(3-chloro-4-{[(3-fiuorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide; ethyl [(3S,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-dJpyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
Λ/-[(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
A-ethyl-Λ/'-((3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5- yl}amino)thieno[2,3-c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)urea;
Λ/-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-/V-ethylurea;
Λ/-((3R,5S)-5-{[4-({3-chloro-4-[(3-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)-/V-ethylurea;
A/-ethyl-/V-{(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinyl}urea; ethyl [(3R,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
Λ/-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide; ethyl ((3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate; ethyl ((3R,5S)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- dJpyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate;
A/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide; -[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-/V-ethylurea;
Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide;
[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl ethylcarbamate; [(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl dimethylcarbamate; ethyl [(3S,5R)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-djpyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate; Λ/-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methanol; Λ/-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- djpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-/V-ethylurea; ethyl ((3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indol-5-yl}amino)thieno[2,3- c/]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate;
A-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
(5R,7R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- dJpyrimidin-6-yl}ethynyl)tetrahydro-1 H-pyrrolo[1 ,2-c][1 ,3]oxazol-3-one;
A-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R,5R)-5-(4- morpholinylmethyl)-2-pyrrolidinyl]ethynyl}thieno[2,3-c lpyrimidin-4-amine; (4S)-4-{[4-({1 -[(3-fluorophenyl)methyl]-1 ry-indazol-5-yl}amino)thieno[3,2-c Ipyrimidin- 6-yl]ethynyl}-2-azetidinone;
(4S)-4-[(4-{[1-(phenylmethyl)-1rτ'-indazol-5-yl]amino}thieno[3,2--/]pyrimidin-6- yl)ethynyl]-2-azetidinone;
(4S)-4-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- dJpyrimidin-6-yl}ethynyl)-2-azetidinone; and
(4S)-4-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indol-5-yl}amino)thieno[3,2-dJpyrimidin- 6-yl]ethynyl}-2-azetidinone.
Biological Data: Compounds of the present invention were tested for ErbB family protein tyrosine kinase inhibitory activity in substrate phosphorylation assays and cell proliferation assays.
Enzyme Assays: Compounds of the present invention were tested for EGFR, ErbB-2, and ErbB-4 protein tyrosine kinase inhibitory activity in substrate phosphorylation assays using enzymes purified from a baculovirus expression system. Reagent production was conducted essentially as described (Brignola, P.S., et al, (2002) J. Biol. Chem. v. 277 2, 1576-1585). The method measures the ability of the isolated enzyme to catalyse the transfer of the -phosphate from ATP onto the tyrosine residue of a biotinylated synthetic peptide (biotin-Ahx-RAHEEIYHFFFAKKK-amide). The extent of tyrosine phosphorylation was measured using an anti-phosphotyrosine antibody, and quantified by homogenous time-resolved fluorescence (HTRF). The enzymes were first diluted from their concentrated stock solutions into buffer containing 100 mM MOPS (pH7.5); 0.01% Tween-20; 0.1 mg/mL bovine serum albumin (BSA); and 80 nM EGFR, 100 nM ErbB2, or 100nM ErbB4. The enzymes were incubated in this buffer for 30 minutes at room temperature before addition to the assay plates. Reactions were performed in black 384-well polystyrene flat-bottom plates in a final volume of 20 μL. Reaction mixtures contained 100 mM MOPS (pH 7.5), 2 mM MnCI2, 20 μ ATP, 0.01% Tween-20, 0.1 mg/mL (BSA), 0.8 μM peptide substrate, and 1mM dithiothreitol. Reactions were initiated by adding enzyme. 0.4 nM EGRF, 5 nM ErbB2, and 0.5 nM ErbB4 were the final enzyme concentrations. Reactions were allowed to proceed for 90 minutes and were then terminated by the addition of 20 μL 100 mM EDTA to each well. 40 μL /well of HTRF mix were then added to the assay plates for the detection of phosphorylated substrate. Final assay concentrations were: 100mM HEPES (pH7.5), 0.1 mg/mL BSA, 15nM streptavidin-labeled allophycocyanin (PerkinElmer), and 1nM europium-labeled anti- phosphotyrosine antibody (PerkinElmer). Assay plates were left unsealed and were counted in a Wallac Multilabel Counter 1420 (PerkinElmer). Compounds under analysis were dissolved in Me2SO to 1.0 mM and serially diluted 1 to 3 with Me2SO through twelve dilutions. 1 μL of each concentration was transferred to the corresponding well of an assay plate. This creates a final compound concentration range from 0.00027 to 47.6 μM. The data for dose responses were plotted as % Inhibition calculated with the data reduction formula 100*(1-(U1-C2)/(C1-C2)) versus concentration of compound where U is the unknown value, C1 is the average control value obtained for 4.76% DMSO, and C2 is the average control value obtained for 0.035 M EDTA. Data were fitted with a curve described by: y = ((Vmax * x) / ( K + x )) + Y2
where Vmax is the upper asymptote, Y2 is the Y intercept, and K is the IC50. The results for reach compound were recorded as plC50s, calculated as follows:
plC50 = -Log10(K)
All exemplified compounds were run with the recited assay and showed inhibitory activity versus erbB family kinases with a plC5o of 5.5 or greater.
Cellular assays: Methylene Blue Growth Inhibition Assay
Human breast (BT474), head and neck (HN5) and gastric tumor (N87) cell lines and human foreskin Fibroblasts (HFF) were cultured in low glucose DMEM (Life Technologies 12320-032) containing 10% fetal bovine serum (FBS) at 37oC in a humidified 10% C02, 90% air incubator. The SV40 transformed human mammary epithelial cell line HB4a was transfected with either human H-ras cDNA (HB4a r4.2) or the human c-ErbB2 cDNA (HB4a c5.2). The HB4a clones were cultured in RPMI containing 10% FBS, insulin (5 μg/ml), hydrocortisone (5 μg/ml), supplemented with the selection agent hygromycin B (50μg/ml). Cells were harvested using trypsin/EDTA, counted using a haemocytometer, and plated in 100 ml of the appropriate media, at the following densities, in a 96-well tissue culture plate (Falcon 3075): BT474 10,000 cells/well, HN5 3,000 cells/well, N87 10,000 ceils/well, HB4a c5.2 3,000 cells/well, HB4a r4.2 3,000 cells/well, HFF 2500 cells/well. The next day, compounds were diluted in DMEM containing 100 mg/ml gentamicin, at twice the final required concentration, from 10mM stock solutions in DMSO. 100ml/well of these dilutions were added to the 100ml of media currently on the cell plates. Medium containing 0.6% DMSO was added to control wells. Compounds diluted in DMEM were added to all cell lines, including the HB4a r4.2 and HB4a c5.2 cell lines. The final concentration of DMSO in all wells was 0.3%. Cells were incubated at 37 °C, 10% C02 for 3 days. Medium was removed by aspiration. Cell biomass was estimated by staining cells with 100μl per well methylene blue (Sigma M9140, 0.5% in 50:50 ethano water), and incubation at room temperature for at least 30 minutes. Stain was removed, and the plates rinsed under a gentle stream of water, and air- dried. To release stain from the cells 100μl of solubilization solution was added (1% N-lauroyl sarcosine, Sodium salt, Sigma L5125, in PBS), and plates were shaken gently for about 30 minutes. Optical density at 620 nM was measured on a microplate reader. Percent inhibition of cell growth was calculated relative to vehicle treated control wells. Concentration of compound that inhibits 50% of cell growth (IC50) was interpolated using nonlinear regression (Levenberg-Marquardt) and the equation, y = Vmax*(1-(x/(K+x))) + Y2, where "K" was equal to the IC50.
All exemplified compounds were run with the recited assay and showed inhibitory activity versus tumor cell lines with a plC50 of 5.5 or greater.

Claims

We claim:
1. A compound of Formula (I):
Figure imgf000204_0001
(I) or a salt, solvate, or physiologically functional derivative thereof: wherein:
one of A1 and A2 is S and the other is CH, where ^ indicate a single or double bond;
R is NH2, C1-C3 alkyl, or -OR';
R1 is the group defined by -(Z)-(Z1)m-(Z2)n, wherein Z is heterocyclyl, or heterocyclylene, Z1 is OC(O), OC(S), or C(O), where m is 0 or 1 , Z2 is heterocyclyl, aralkyl, N(H)R', CrC3 alkyl, -OR', halo, S(O)2R, C C3 hydroxyalkyl, or C C3 haloalkyl, where n is 0 or 1 ; R' is -H, -(CH2)qS(0)2R'", R""NR"R", CrC3 alkyl, -(CH2)qOR", -C(0)R"', or - C(0)OR"; q is O, 1 , 2, 3, or 4; R" is C1-C3 alkyl; R"' is C1-C3 alkyl or N(H)R"; R"" is C Ce alkyl; R2 is -H, Cι-C3 alkyl, or C(0)R";
R3 is the group defined by -(Q)-(Q1)r-(Q2)t, wherein Q is arylene, heteroarylene, aryl, or aralkyl, Q1 is O, S(0)2, or S, where r is 0 or 1, and Q2 is aralkyl, heteroaryl, or aryl and t is 0 or 1.
A compound of Formula (I'):
Figure imgf000205_0001
(I') or a salt, solvate, or physiologically functional derivative thereof: wherein:
R is NH2, C1-C3 alkyl, or -OR';
R1 is the group defined by -(Z)-(Z1)m-(Z2)n, wherein Z is heterocyclyl or heterocyclylene, Z is OC(O), OC(S), or C(O), where m is 0 or 1 , Z2 is heterocyclyl, aralkyl, N(H)R\ CrC3 alkyl, -OR', halo, S(0)2R, Cr C3 hydroxyalkyl, or C1-C3 haloalkyl, where n is 0 or 1; R' is -H, -(CH2)qS(0)2R"', R""NR"R", C C3 alkyl, -(CH2)qOR", -C(O)R'", or - C(0)OR'"; q is 0, 1 , 2, 3, or 4; R" is C1-C3 alkyl; R'" is C1-C3 alkyl or N(H)R"; R"" is CrCe alkyl; R2 is -H, C C3 alkyl, or C(0)R";
R3 is the group defined by -(Q)-(Q1)r-(Q2)t, wherein Q is arylene, heteroarylene, aryl, or aralkyl, Q1 is O, S(0)2, or S, where r is 0 or 1, and Q2 is aralkyl, heteroaryl, or aryl and t is 0 or 1.
3. A compound of Formula (I"): 205
Figure imgf000206_0001
(I") or a salt, solvate, or physiologically functional derivative thereof: wherein:
R is NH2, C1-C3 alkyl, or -OR';
R1 is the group defined by -(Z)-(Z1)m-(Z2)n, wherein Z is heterocyclyl or heterocyclylene, Z1 is OC(O), OC(S), or C(O), where m is 0 or 1 , Z2 is heterocyclyl, aralkyl, N(H)R', C C3 alkyl, -OR', halo, S(0)2R, C1 C3 hydroxyalkyl, or C C3 haloalkyl, where n is 0 or 1 ; R' is -H, -(CH2)qS(0)2R'", -R""NR"R", C C3 alkyl, -(CH2)qOR", -C(0)R"', or C(0)OR'"; q is 0, 1 , 2, 3, or 4; R" is C1-C3 alkyl; R'" is C C3 alkyl or N(H)R"; R"" is d-Ce alkyl; R2 is -H, C C3 alkyl, or C(0)R";
R3 is the group defined by -(Q)-(Q1)r-(Q2)t, wherein Q is arylene, heteroarylene, aryl, or aralkyl, Q1 is O, S(0)2, or S, where r is 0 or 1 , and Q2 is aralkyl, heteroaryl, or aryl and t is 0 or 1.
4. A compound as claimed in claim 1 , wherein A1 is S and A2 is CH.
5. A compound as claimed in claim 1 , wherein A1 is CH and A2 is S.
6. A compound as claimed in claim 1 , wherein Z is hetercyclyl and m and n are each 0. 206
7. A compound as claimed in claim 1 , wherein Z is heterocyclyl and m is 0 and n is 0, where the heteroclyclyl group is selected from
Figure imgf000207_0001
8. A compound as claimed in claim 1 , wherein Z is heterocyclylene, Z1 is OC(O) and m is. 1, n is 1 and Z2 is heterocyclyl.
A compound as claimed in claim 1, wherein, Z is
Figure imgf000207_0002
Z1 is OC(O), and
Figure imgf000207_0003
Z2£ is N(H)R', wherein R' is C C3 alkyl.
10. A compound as claimed in claim 1 , wherein Z is heterocyclylene, Z1 is C(O) and m is 1 , n is 1 and Z2 is CrC3 haloalkyl.
11. A compound as claimed in claim 1 , wherein Z is
Figure imgf000207_0004
Z1 is C(O), and
Z2 is CrC3 haloalkyl, preferably -CF3. 2005/007083 207
12. A compound as claimed in claim 1 , wherein Z is heterocyclylene, m is 0, n is 1 and Z2 is heterocyclyl.
13. A compound as claimed in claim 1 , wherein Z is
Figure imgf000208_0001
m is 0, and Z2 is
Figure imgf000208_0002
Z2 is C1-C3 alkyl, or Z2 is -OH, or
Z2 is - OR' where R' is CrC3 alkyl, preferably -CH3, or Z2 is halo, preferably -F, or Z2 is C1-C3 hydroxyalkyl, preferably -CH3OH or
14. A compound as claimed in claim 13, wherein Z2 is - OR' where R' is -CH3.
15. A compound as claimed in claim 13, wherein Z2 is -F.
16. A compound as claimed in claim 13, wherein Z2 is -CH3OH.
17. A compound as claimed in claim 1 , wherein R2 is -H.
18. A compound as claimed in claim 1 , wherein R2 is C C3 alkyl.
19. A compound as claimed in claim 1 , wherein Q is arylene, Q1 is O, r is 1 , and Q2 is aralkyl, aryl, or heteroaryl.
20. A compound as claimed in claim 1 , wherein Q is 2005/007083 208
Figure imgf000209_0001
wherein R4 is halo, preferably -Cl or -F, Q1 is O and r is 1 , and Q2 is selected from
Figure imgf000209_0002
wherein each R is independently halo, preferably -F, -Cl, or -Br,
21. A compound as claimed in claim 20, wherein R4 is -Cl or -F.
22. A compound as claimed in claim 20, wherein R5 is independently -F, -Cl, or - Br.
23. A compound as claimed in claim 1 , wherein Q is arylene or heteroarylene, Q1 is S and r is 1 , and Q2 is aryl.
24. A compound as claimed in claim 1 , wherein Q is
Figure imgf000209_0003
wherein R4 is halo, preferably -Cl or -F, Q1 is S and r is 1 , Q2 is 2005/007083 209
Figure imgf000210_0001
25. A compound as claimed in claim 24, wherein R4 is -Cl or -F.
26. A compound as claimed in claim 1 , wherein Q is arylene or heteroarylene, Q1 is S(0)2 and r is 1 , and Q2 is aryl or heteroaryl.
27. A compound as claimed in claim 1 , wherein Q is
Figure imgf000210_0002
Q1 is S(0)2 and r is 1 , and Q2 is selected from
Figure imgf000210_0003
where R5 is halo, preferably -F.
28. A compound as claimed in claim 27, wherein R5 is -F.
29. A compound as claimed in claim 1 , wherein Q is arylene or heteroarylene, r is 0, and Q2 is aralkyl.
30. A compound as claimed in claim 1, wherein Q is selected from
Figure imgf000211_0001
r is 0, and Q is selected from
Figure imgf000211_0003
preferably
Figure imgf000211_0002
Figure imgf000211_0004
where R5 is halo, preferably -F.
31. A compound as claimed in claim 30, wherein R5 is -F.
32. A compound selected from the group:
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}pyrrolidin-3-yl morpholine-4-carboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}pyrrolidin-3-yl ethylcarbamate;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2S,4S)-4-morpholin-4-ylpyrrolidin-2- yl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
/V-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2R,3S)-3-morpholin-4-ylpyrrolidin-2- yl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[(2S)-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[(2S)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2R)-1-methylpyrrolidinyl] ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(3-pyrrolidinylethynyl)thieno[3,2- d]pyrimidin-4-amine; (3R,5S)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinol;
(3R,5R)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinol;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2S,4R)-4-methoxypyrrolidinyl] ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2S,4S)-4-fluoropyrrolidinyl] ethynyl}thieno[3,2-d]pyrimidin-4-amine;
{(2S)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]pyrrolidinyI}methanol;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-(2-piperidinylethynyl)thieno[3,2- d]pyrimidin-4-amine;
[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-piperidin-3-ylethynyl-thieno[3,2- d]pyrimidin-4-yl)-amine;
6-[(2S)-2-azetidinylethynyl]-N-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-d]pyrimidin-4-amine;
Λ/-(3-Chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(trifluoroacetyl)-2- pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(morpholin-3-ylethynyl)thieno[3,2- d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[2,3- d]pyrimidin-4-amine;
Λ/-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[3-chloro-4-(1-naphthyloxy)phenyl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[5-(2-pyridinyloxy)-2-naphthalenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[1-(3-fluorobenzyl)-1 H-indazol-5-yl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[1-(phenylmethyl)-1 H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine; 6-[(2R)-2-pyrrolidinylethynyl]-Λ/-[1 -(1 ,3-thiazol-4-ylmethyl)-1 H-indazol-5-yl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}-6-[(2R)-2-pyrrolidinylethynyl] thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(1-benzyl-1 H-indazol-5-yl)amino]thieno[3,2-d]pyrimidin-6- yl}ethynyl)pyrrolidin-3-yl morpholine-4-carboxylate;
Λ/-[2-(3-fluorobenzyl)-1 H-benzimidazol-5-yl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(1 R)1-(3-fluorophenyl)ethyl]oxy}phenyl)-6-[(2R)-pyrrolidin-2- ylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-[4-(phenylsulfonyl)phenyl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2-d]pyrimidin-4- amine;
Λ/-[3-chloro-4-(1 ,3-thiazol-2-ylthio)phenyl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[1-(2,5-difluorobenzyl)-1H-indol-5-yl]-6-[(2R)-pyrrolidin-2-ylethynyl] thieno[3,2d]pyrimidin-4-amine;
Λ/-{1-[(3-fluorophenyl)sulfonyl]-1 H-indol-5-yl}-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2- d]pyrimidin-4-amine; and
Λ/-(4-benzylphenyl)-6-[(2R)-pyrrolidin-2-ylethynyl]thieno[3,2-d]pyrimidin-4-amine;
or a salt, solvate, or physiologically functional derivative thereof.
33. A compound selected from the group:
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(1-methyl-2- piperidinyl)ethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-(3-pyrrolidinylethynyl)thieno[2,3- d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-(3-piperidinylethynyl)thieno[2,3- d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2S)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine; (3R,5S)-5-[(4-{[1-methyl-2-(phenylmethyl)-1 H-benzimidazol-5-yl]amino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinol;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-(2-piperidinylethynyl)thieno[2,3- d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(2,5-difluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(4S)-1 ,3-thiazolidin-4- ylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-[2-(phenylmethyl)-1 H-benzimidazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[3-chloro-4-(phenyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin- 4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[((2S,4R)-4-{[2-(4- morpholinyl)ethyl]oxy}-2-pyrrolidinyl)ethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-{1-[(3-fluorophenyl)methyl]-1 H-indol-5-yl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[1-(phenylmethyl)-1 H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
(3S,5S)-5-[(4-{[3-chloro-4-(1-naphthalenyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinol;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinol; -[1 -(2-pyridinylmethyl)-1 H-benzimidazol-5-yl]-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinol;
Λ-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2S)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinol;
Λ/-(3-fluoro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3-chloro-4-{[(3-fluorophenyl)methyl]amino}phenyl){6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-yl}amine;
Λ/-[1-(phenylsulfonyl)-1 H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine; Λ/-[1-(phenylmethyl)-1 H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ-{1 -[(3,5-difluorophenyl)methyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-[1-(2-pyridinylmethyl)-1 H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-{1 -[(2-methyl-1 ,3-thiazol-4-yl)methyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
0-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl] [3-(4-morpholinyl)propyl]thiocarbamate;
4-(2,3-dihydro-1 H-indol-1-yl)-6-(2-pyrrolidinylethynyl)thieno[3,2-d]pyrimidine;
/V-(4-{[(2,5-difluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[2-(phenylmethyl)-1 ,3-benzothiazol-6-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[2-(phenylmethyl)-1 ,3-benzothiazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(4-methyl-3- morpholinyl)ethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-{1 -[1 -(3-fluorophenyl)ethyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(2-methyl-1 ,3-thiazol-4-yl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine; phenyl[4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- yl}amino)phenyl]methanone;
N-(3-chloro-4-{[(1S)-1-(3-fluorophenyl)ethyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(6-fluoro-4-quinolinyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-{2-[(2,5-difluorophenyl)methyl]-1 H-benzimidazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-(1-methyl-1 H-indazol-5-yl)-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- amine;
Λ/-{3-chloro-4-[(3-fluorophenyl)oxy]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -piperidinecarboxylate;
Λ/-[2-(phenylmethyl)-2H-indazol-6-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[1-(phenylmethyl)-1 H-indazol-6-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl methyl(phenyl)carbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{4-[(methylsulfonyl)methyl]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
6-[(2R)-2-pyrrolidinylethynyl]-N-[1-(2-thienylsulfonyl)-1 H-indol-5-yl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[1-(methylsulfonyl)-1 H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(6-methyl-2-pyridinyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
A/2-(4-fluorophenyl)-Λ/5-{6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-yl}-1 H- benzimidazole-2,5-diamine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
Λ/-[1-(cyclohexylmethyl)-1 H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ-(2-phenyl-1 H-benzimidazol-5-yl)-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[(2,3-dichlorophenyl)methyl]-6-(2-pyrrolidinylethynyl)thieno[3,2-d]pyrimidin-4- amine;
Λ/-[1 -(phenylsulfonyl)-2,3-dihydro-1 H-indol-5-yl]-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl diethylcarbamate; Λ/-[4-(phenylmethyl)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4- amine;
Λ/-[1 -(phenylmethyl)-2,3-dihydro-1 H-indol-5-yl]-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2R)-2-pyrroiidinylethynyl]-N-[1-(2-thienylsulfonyl)-2,3-dihydro-1 H-indol-5- yl]thieno[3,2-d]pyrimidin-4-amine;
4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-yl}amino)-N-1 ,3-thiazol-2- ylbenzenesulfonamide;
/V-{1-[(2-fluorophenyl)sulfonyl]-2,3-dihydro-1 H-indol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(3-pyridinylmethyl)oxy]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
3-({[2-chloro-4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- yl}amino)phenyl]oxy}methyl)-1y15-pyridin-1-ol; -{1-[(2-fluorophenyl)methyl]-2,3-dihydro-1 H-indol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-[1-(phenylmethyl)-4-piperidinyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin- 4-amine;
Λ/-{1 -[(5-chloro-1 ,2,3-thiadiazol-4-yl)methyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(5-chloro-1 ,2,3-thiadiazol-4-yl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
Λ/-(3-fluoro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
1-phenyl-2-[4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- yl}amino)phenyl]ethanone;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1-[2-(methyloxy)ethyl]-2- pyrrolidinyl}ethynyl)thieno[3,2-d]pyrimidin-4-amine;
6-{[(2R)-1-acetyl-2-pyrrolidinyl]ethynyl}-N-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-d]pyrimidin-4-amine;
A/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(methylsulfonyl)-2- pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
6-[(2R)-2-pyrrolidinylethynyl]-N-[1 -(1 ,3-thiazol-4-ylmethyl)-1 H-indazol-5-yl]thieno[2,3- d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine; methyl (2R)-2-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-1 -pyrrolidinecarboxylate;
Λ/-[(3-chlorophenyl)methyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- amine;
Λ/-{3-chloro-4-[(1,3-thiazol-4-ylmethyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-fluorophenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-bromophenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyl 4-morpholinecarboxylate;
(2R)-2-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-1-pyrrolidinecarbaldehyde;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(cyclopropylmethyl)-2- pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-[4-(1-piperidinylsulfonyl)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin- 4-amine;
Λ/-[4-chloro-2-(phenylmethyl)-1 H-benzimidazol-6-yl]-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
A/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1 -[(1 -methyl-1 H-pyrrol-2- yl)methyl]-2-pyrrolidinyl}ethynyl)thieno[3,2-d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1-[3-(dimethylamino)-2,2- dimethylpropyl]-2-pyrrolidinyl}ethynyl)thieno[3,2-d]pyrimidin-4-amine;
Λ/-[2-chloro-4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- yl}amino)phenyl]-3-fluorobenzenesulfonamide;
Λ/-{1-[(phenylmethyl)sulfonyl]-2,3-dihydro-1 H-indol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
2-{[5-({6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-yl}amino)-2,3-dihydro- 1 H-indol-1 -yl]sulfonyl}benzonitrile;
6-[(2R)-2-pyrrolidinylethynyl]-N-[1-(2-thienylsulfonyl)-1 H-indol-5-yl]thieno[2,3- d]pyrimidin-4-amine;
(3R,5S)-5-{[4-({3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{1 -[1 -(3-fluorophenyl)ethyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-aminee;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1-[(1- methylethyl)sulfonyl]-2-pyrrolidinyl}ethynyl)thieno[3,2-d]pyrimidin-4-amine; 2-(methyloxy)ethyl (2R)-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-1- pyrrolidinecarboxylate;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(2,2,3,3,3- pentafluoropropanoyl)-2-pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[((2R)-1-{[5-chloro-1-methyl-3-
(trifluoromethyl)-1 H-pyrazol-4-yl]methyl}-2-pyrrolidinyl)ethynyl]thieno[3,2-d]pyrimidin-
4-amine;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl (3,5-dimethyl-4-isoxazolyl)carbamate;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R)-1-(3,3,3-trifluoropropyl)-2- pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl (l-methylethyl)carbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
A/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-({(2R)-1-[2- (methylsulfonyl)ethyl]-2-pyrrolidinyl}ethynyl)thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-fluoro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
2-fluoroethyl (2R)-2-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-1- pyrrolidinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-thienylsulfonyl)amino]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[2-chloro-4-({6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4- yl}amino)phenyl]-3-fluorobenzenesulfonamide;
Λ/-[1-(2-phenylethyl)-1H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
Λ/-[1-(cyclohexylmethyl)-1 H-indazol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
6-[(2R)-2-pyrrolidinylethynyl]-N-(4-{[3-(trifluoromethyl)phenyl]thio}phenyl)thieno[3,2- d]pyrimidin-4-amine; (3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl [2-(methylsulfonyl)ethyl]carbamate;
Λ/-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
Λ/-[3-chloro-4-(2-pyridinyloxy)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-methyl-1 -piperazinecarboxylate;
Λ/-{[2,3-bis(methyloxy)phenyl]methyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2- d]pyrimidin-4-amine;
Λ/-[(2-chlorophenyl)methyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- amine;
Λ/-{[3-(methyloxy)phenyl]methyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin- 4-amine;
Λ/-[(2-fluorophenyl)methyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4- amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
Λ/-[3-chloro-4-(phenylthio)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[3,2-d]pyrimidin- 4-amine;
(3R,5S)-5-[(4-{[1-(2-phenylethyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[1-(cyclohexylmethyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
N-{1 -[(2-fluorophenyl)methyI]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
6-{[(2S,4S)-4-fluoro-2-pyrrolidinyl]ethynyl}-N-[1-(phenylmethyl)-1 H-indazol-5- yl]thieno[2,3-d]pyrimidin-4-amine;
(3R,5S)-5-[(4-{[1-(2-thienylsulfonyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; N-(3-chloro-4-{[(6-methyl-2-pyridinyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-{[4-({1-[(2-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[1 -(1 ,3-thiazol-4-ylmethyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin- 6-yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[3-fluoro-1-(phenylmethyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin- 6-yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-[1-(phenylmethyl)-1 H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl [2-(4-morpholinyl)ethyl]carbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl [2-(1 -piperidinyl)ethyl]carbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl [2-(1-piperidinyl)ethyl]carbamate;
A/-[3-chloro-4-(1 ,3-thiazol-2-ylthio)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
Λ/-[3-fluoro-1-(phenylmethyl)-1 H-indol-5-yl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
Λ/-[3-chloro-4-(phenylthio)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-d]pyrimidin- 4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl carbamate;
Λ/-[4-(2-pyridinylthio)phenyl]-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4- amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl methylcarbamate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-{[4-({3-chloro-4-[(phenylthio)methyl]phenyl}amino)thieno[3,2-d]pyrimidin-6- yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; i-21
(3R,5S)-5-({4-[(6-{[(3-fluorophenyl)methyl]oxy}-3-pyridinyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(phenylsulfonyl)methyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
6-[(2R)-2-pyrrolidinylethynyl]-N-[1 -(1 ,3-thiazol-4-ylmethyl)-1 H-indol-5-yl]thieno[2,3- d]pyrimidin-4-amine;
Λ/-[(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]methanesulfonamide;
Λ/-(3-chloro-4-{[(2-chloro-3-pyridinyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
(3R,5S)-5-[(4-{[3-chloro-4-(phenylthio)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{1 -[(3-fluorophenyl)sulfonyl]-1 H-indazol-5-yl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
(3R,5S)-5-{[4-({3-chloro-4-[(1 ,3-thiazol-2-ylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)sulfonyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{3-chloro-4-[(1 ,3-thiazol-2-ylmethyl)oxy]phenyl}-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinecarbonitrile;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate; tV-{3-chloro-4-[(phenylthio)methyl]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
Λ/-{3-chloro-4-[(phenylsulfonyl)methyl]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
Λ-(6-{[(3-fluorophenyl)methyl]oxy}-3-pyridinyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[3-(methyloxy)phenyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2,3-difluorophenyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-[(4-{[5-(2-pyridinyloxy)-2-naphthalenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(6-fluoro-4-quinolinyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-(6-{[(2,5-difluorophenyl)methyl]oxy}-3-pyridinyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinecarbonitrile;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4S)-4-fluoro-2- pyrrolidinyl]ethynyl}thieno[2,3-d]pyrimidin-4-amine;
(3S,5R)-5-{[4-({3,3-difluoro-1-[(2-fluorophenyl)methyl]-2-oxo-2,3-dihydro-1 H-indol-5- yl}amino)thieno[3,2-d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-(6-{[(2-fluorophenyl)methyl]oxy}-3-pyridinyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinol; ethyl (2S,4S)-2-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-4-{[(ethyloxy)carbonyl]amino}-1 -pyrrolidinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethyl carbonate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 2-(methyloxy)ethyl carbonate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 3-(methylsulfonyl)propanoate; ethyl [(3S,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate; methyl [(3S,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl methanesulfonate;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4R)-4-(ethyloxy)-2- pyrrolidinyl]ethynyl}thieno[2,3-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 3-(methylthio)propanoate; Λ/-(3-chloro-4-{[(4-chloro-2-pyridinyl)methyl]oxy}phenyl)-6-[(2R)-2- pyrrolidinylethynyl]thieno[2,3-d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl methanesulfonate;
6-{[(2S,4S)-4-azido-2-pyrrolidinyl]ethynyl}-N-(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)thieno[3,2-d]pyrimidin-4-amine;
Λ/-[(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-4-morpholinecarboxamide;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinol;
Λ/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4R)-4-(ethyloxy)-2- pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinone;
(5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-2-pyrrolidinone;
(5S)-5-{[4-({3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-2-pyrrolidinone;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl methanesulfonate;
(3R,5S)-5-[(4-{[1 -(1 ,3-thiazol-4-ylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(3,5-difluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyri mid in-6-yl]ethynyl}-3-pyrrol id inyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(2-methyl-1 ,3-thiazol-4- yl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4- morpholinecarboxylate;
(3R,5S)-5-{[4-({1 -[(5-chloro-1 ,2,3-thiadiazol-4-yl)methyl]-1 H-indazol-5- yl}amino)thieno[3,2-d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1 -[1 -(3-fluorophenyl)ethyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yI]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[4-(2-pyridinylthio)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-3- pyrrolidinyl 4-morpholinecarboxylate; 4
Λ/-{3-chloro-4-[(3-fluorophenyl)thio]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)thio]phenyl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{3-chloro-4-[(3-methylphenyl)thio]phenyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3- d]pyrimidin-4-amine;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl propanoate;
(3R,5S)-5-{[4-({3-chloro-4-[(3-methylphenyl)thio]phenyl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(1 ,3-thiazol-4-ylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate; (3R,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-[(4-{[1-(phenyImethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-thiomorpholinecarboxylate; (3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methylj-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate; -_ t
(3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyI]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate; (3R,5S)-5-[(4-{[4-(phenylmethyl)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-3- pyrrolidinyl 4-morpholinecarboxylate;
A/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4S)-4-(4- morpholinylmethyl)-2-pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2S,4S)-4-(4- morpholinylmethyl)-2-pyrrolidinyl]ethynyl}thieno[2,3-d]pyrimidin-4-amine;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -piperidinecarboxylate; (3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl dimethylcarbamate;
(3S,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3S,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate; (3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -piperazinecarboxylate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -piperazinecarboxylate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-thiomorpholinecarboxylate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{[3-(phenyloxy)phenyl]methyl}-6-[(2R)-2-pyrrolidinylethynyl]thieno[2,3-d]pyrimidin- 4-amine;
(3R,5S)-5-{[4-({[3-(phenyloxy)phenyl]methyl}amino)thieno[3,2-d]pyrimidin-6- yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-thiomorpholinecarboxylate 1 ,1 -dioxide;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -piperidinecarboxylate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate;
(5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2-d]pyrimidin-6- yl]ethynyl}-2-pyrrolidinone; (5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-2-pyrrolidinone;
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate; and
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; or a salt, solvate, or physiologically functional derivative thereof.
34. A compound selected from the group:
(3S,5R)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]pyrrolidinyl dimethylcarbamate;
{(2R,5R)-5-[(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]pyrrolidinyl}methyl ethylcarbamate;
Λ/-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2R,5R)-5-(4- morpholinylmethyl)pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
A-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-{[(2R,5R)-5-(4- morpholinylmethyl)pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-((3S,5R)-5-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}pyrrolidin-3-yl)propanamide;
Λ/-{(3R,5S)-5-[(4-{[1-(2,5-difluorobenzyl)-1 H-indol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]pyrrolidin-3-yl}ethanesulfonamide trifluoroacetate;
(3S,5S)-5-({4-[(1-benzyl-1H-indazol-5-yl)amino]thieno[2,3-d]pyrimidin-6- yl}ethynyl)pyrrolidin-3-yl pyrrolidine-1 -carboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; (3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-2-pyrrolidinone;
(5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-2-pyrrolidinone;
(5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-2-pyrrolidinone;
(5S)-5-({4-[(6-{[(2,5-difluorophenyl)methyl]oxy}-3-pyridinyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinone;
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; Zάό
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl ethyl(methyl)carbamate;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynylj-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5S)-5-{[4-({3-chloro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({1 -[1 -(3-fluorophenyl)ethyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({1 -[1 -(3-fluorophenyl)ethyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[4-(phenylsulfonyl)phenyl]amino}thieno[3,2-d]pyrimidin-6-yl)ethynyl]-3- pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-[(4-{[3-chloro-4-(phenylsulfonyl)phenyl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyi]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; (5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinone;
(5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-2-pyrrolidinone;
(5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-2-pyrrolidinone;
(5R)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-2-pyrrolidinone;
(5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2-d]pyrimidin-6- yl]ethynyl}-2-pyrrolidinone;
(3R,5S)-5-{[4-({3-fluoro-4-[(3-fluorophenyl)sulfonyl]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate; ethyl [(3S,5R)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
Λ-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide;
Λ/-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
Λ/-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-/V-ethylurea;
[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl ethylcarbamate;
A/-ethyl-/V-((3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5- yl}amino)thieno[3,2-d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)urea;
Λ/-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-/V-ethylurea;
Λ/-((3R,5S)-5-{[4-({3-chloro-4-[(3-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)-/V-ethylurea;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
Λ/-ethyl-Λ/'-{(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinyl}urea;
A/-((3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)-N'-ethylurea; ethyl [(3R,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyl]carbamate;
Λ/-((3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)ethanesulfonamide;
Λ/-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
1-{[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl}-2,5-pyrrolidinedione;
(3R,5S)-5-({4-[(3-chloro-4-{[(1-methylethyl)oxy]methyl}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-{[4-({3-chloro-4-[(5-methyl-3-isoxazolyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[3-(trifluoromethyl)phenyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-{(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl}ethanesulfonamide; ethyl ((3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate; ethyl ((3R,5S)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate;
(3S,5R)-5-{[4-({3-chloro-4-[(5-methyl-3-isoxazolyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)oxy]methyl}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 4-morpholinecarboxylate;
Λ/-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide;
(3R,5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl ethylcarbamate;
[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl dimethylcarbamate; ethyl ((3R,5S)-5-{[4-({1 -[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate;
[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methanol; (5R,7aR)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)tetrahydro-1 H-pyrrolo[1 ,2-c][1 ,3]oxazol-3-one;
A/-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R,5R)-5-(4- morpholinylmethyl)-2-pyrrolidinyl]ethynyl}thieno[3,2-d]pyrimidin-4-amine;
Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide;
Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-N'-ethylurea; ethyl [(3R,5R)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyl]carbamate;
Λ/-((3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)propanamide;
Λ/-((3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[3,2- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)propanamide;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate;
(3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -piperidinecarboxylate;
(5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3-d]pyrimidin- 6-yl]ethynyl}-2-pyrrolidinone;
(5S)-5-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[2,3-d]pyrimidin- 6-yl]ethynyl}-2-pyrrol idi none;
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 4-morpholinecarboxylate;
(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5S)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate; P (3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3R,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl dimethylcarbamate;
(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-[(4-{[3-chloro-4-(2-pyridinyloxy)phenyl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5R)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3-d]pyrimidin-6- yl)ethynyl]-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
(3S,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl 1 -pyrrolidinecarboxylate;
Λ/-[(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide; ethyl [(3S,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
Λ/-[(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide; Zόϋ
Λ/-ethyl-N'-((3R,5S)-5-{[4-({1-[(3-fluorophenyl)methyl]-1 H-indazol-5- yl}amino)thieno[2,3-d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)urea;
Λ/-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-N'-ethylurea;
Λ/-((3R,5S)-5-{[4-({3-chloro-4-[(3-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)-N'-ethylurea;
Λ/-ethyl-N'-{(3R,5S)-5-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[2,3- d]pyrimidin-6-yl)ethynyl]-3-pyrrolidinyl}urea; ethyl [(3R,5S)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
N-[(3R,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide; ethyl ((3R,5S)-5-{[4-({3-chloro-4-[(2-pyridinylmethyl)oxy]phenyl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate; ethyl ((3R,5S)-5-{[4-({1 -[(3-fluorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate;
Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
Λ/-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-N'-ethylurea;
Λ-[(3R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide;
[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl ethylcarbamate;
[(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methyl dimethylcarbamate; ethyl [(3S,5R)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
Λ/-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]ethanesulfonamide; ethyl [(3R,5R)-5-({4-[(3-chloro-4-{[(3- fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3-d]pyrimidin-6-yl}ethynyl)-3- pyrrolidinyljcarbamate;
(3S,5S)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl dimethylcarbamate; [(2R,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-2-pyrrolidinyl]methanol;
N-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]-N'-ethylurea; ethyl ((3R,5S)-5-{[4-({1 -[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[2,3- d]pyrimidin-6-yl]ethynyl}-3-pyrrolidinyl)carbamate;
N-[(3S,5R)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)-3-pyrrolidinyl]propanamide;
(5R,7aR)-5-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[2,3- d]pyrimidin-6-yl}ethynyl)tetrahydro-1 H-pyrrolo[1 ,2-c][1 ,3]oxazol-3-one;
N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-{[(2R,5R)-5-(4- morpholinylmethyl)-2-pyrrolidinyl]ethynyl}thieno[2,3-d]pyrimidin-4-amine;
(4S)-4-{[4-({1-[(3-fiuorophenyl)methyl]-1 H-indazol-5-yl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-2-azetidinone;
(4S)-4-[(4-{[1-(phenylmethyl)-1 H-indazol-5-yl]amino}thieno[3,2-d]pyrimidin-6- yl)ethynyl]-2-azetidinone;
(4S)-4-({4-[(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]thieno[3,2- d]pyrimidin-6-yl}ethynyl)-2-azetidinone; and
(4S)-4-{[4-({1-[(2,5-difluorophenyl)methyl]-1 H-indol-5-yl}amino)thieno[3,2-d]pyrimidin- 6-yl]ethynyl}-2-azetidinone;
or a salt, solvate, or physiologically functional derivative thereof.
35. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound as claimed in any one of claims 1 to 34, or a salt, solvate, or a physiologically functional derivative thereof and one or more of pharmaceutically acceptable carriers, diluents and exeipients.
36. A method of treating a disorder in a mammal, said disorder being mediated by inappropriate activity of at least one erbB family kinase, comprising: administering to said mammal a therapeutically effective amount of a compound as claimed in any one of claims 1 to 34, or a salt, solvate or a physiologically functional derivative thereof.
37. A method of treating a disorder in a mammal, said disorder being mediated by inappropriate activity of at least two erbB family kinases, comprising: administering to said mammal a therapeutically effective amount of a compound as claimed in any one of claims 1 to 34, or a salt, solvate or a physiologically functional derivative thereof.
38. A compound as claimed in any one of claims 1 to 34, or a salt, solvate, or a physiologically functional derivative thereof for use in therapy.
39. Use of a compound as claimed in any one of claims 1 to 34, or a salt, solvate, or a physiologically functional derivative thereof in the preparation of a medicament for use in the treatment of a disorder mediated by inappropriate activity of at least one erbB family kinase.
40. Use of a compound as claimed in any one of claims 1 to 34, or a salt, solvate, or a physiologically functional derivative thereof in the preparation of a medicament for use in the treatment of a disorder mediated by inappropriate activity of at least two erbB family kinases.
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