WO2007102679A1 - Novel thienopyrimidine derivatives or pharmaceutically acceptable salts thereof, process for the preparation thereof and pharmaceutical composition comprising the same - Google Patents

Novel thienopyrimidine derivatives or pharmaceutically acceptable salts thereof, process for the preparation thereof and pharmaceutical composition comprising the same Download PDF

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Publication number
WO2007102679A1
WO2007102679A1 PCT/KR2007/001074 KR2007001074W WO2007102679A1 WO 2007102679 A1 WO2007102679 A1 WO 2007102679A1 KR 2007001074 W KR2007001074 W KR 2007001074W WO 2007102679 A1 WO2007102679 A1 WO 2007102679A1
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Prior art keywords
methyl
thieno
pyrimidin
thiophen
ylamino
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PCT/KR2007/001074
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French (fr)
Inventor
Myung-Hwa Kim
Chun-Ho Park
Kwangwoo Chun
Byung-Kyu Oh
Bo-Young Joe
Jong-Hee Choi
Hyuk-Man Kwon
Sun-Chul Huh
Ran Won
Kwang Hee Kim
Sun-Mee Kim
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Je Il Pharmaceutical Co., Ltd.
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Publication of WO2007102679A1 publication Critical patent/WO2007102679A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • 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

  • the present invention relates to a novel thienopyrimidine derivative or a pharmaceutically acceptable salt thereof, a process for the preparation thereof and a pharmaceutical composition comprising the same.
  • a thienopyrimidine derivative of the present invention inhibits the activity of IKB kinase- ⁇ (IKK ⁇ or IKK-2), whereby it inhibits the activity of nuclear factor KB (NF-KB). Accordingly, it can be used for prevention or treatment of NF- KB -related diseases, in particular, inflammatory diseases and cancers.
  • NF- ⁇ B Nuclear Factor kappa B
  • p50 subunit family p50, p52
  • p65 subunit family p65, c-Rel, ReIB
  • IKB protein I ⁇ B ⁇ , I ⁇ B ⁇ , I ⁇ B ⁇ , I ⁇ B ⁇ , I ⁇ B ⁇ and BcB
  • cytokines e.g., TNF- ⁇ , IL-I
  • bacterial or viral infections e.g., LPS, dsRNA
  • stress e.g., ROI, UV, adriamycin, radiation
  • oxidants activate IKB kinase complex composed of IKK ⁇ , IKK ⁇ , NEMO (IKK ⁇ ) or the like.
  • the activated IKB kinase complex phosphorylates at the two serine residues in the N- terminus of IKB proteins (I ⁇ B ⁇ phosphorylates at Ser32 and Ser36, I ⁇ B ⁇ phosphorylates at Serl9 and Ser23), wherein the phosphorylation of IKB proteins triggers IKB ubiquitination and degradation via the ubiquitin-proteosome pathway (VJ. Palombella et al., Cell, 78, 773-785, 1994; Ghosh S. et al, Cell. 109, 81-96, 2002).
  • NF- ⁇ B The free NF- ⁇ B from IKB translocates to the nucleus and binds to NF- ⁇ B binding site (consensus sequence: 5'-GGGPuNNPyPyCC-3') of target genes, thereby initiating the transcription of the genes coding the immune and inflammatory response related proteins (Barnes PJ. et al. N. Engl. J. Med. 336, 1066-1071, 1997).
  • Most of the genes regulated by NF- KB include proinflammatory mediators, cytokines, and cell adhesion molecules.
  • IKK ⁇ and IKK ⁇ have been elucidated concretely.
  • IKK- ⁇ is thought to be a pivotal target in NF- ⁇ B activation pathway as an anti-inflammatory and anti-cancer therapeutic agent.
  • the IKK ⁇ inhibition appears, therefore, as an attractive strategy to increase the anti-inflammatory and anti-cancer effect.
  • KB play key role in the normal physiological functions such as development and immune response
  • abnormal activation of NF- ⁇ B are associated with mutations in IKB protein, a translocation and amplification of NF- ⁇ B gene, and aberrant activation of IKK enzyme in inflammatory diseases such as arthritis, asthma (Yang L. et al., J. Exp. Med. 188, 1739-1750, 1998; Barnes P., et al, Trends Pharmacol, Therapeut.
  • NF-KB may be involved in the regulation of neural cell apoptosis. It has been found that NF-KB is activated and promotes cell death in focal cerebral ischemia (Schneider A. et al, Nature medicine Vol.5 No.5, 554-559, 1999). Accordingly, if the aberrant activation of NF- ⁇ B is regulated, it is possible to inhibit occurrence and progression of degenerative and rare diseases and to treat rare diseases caused by an aberrant apoptosis and inflammation.
  • Example thereof includes rheumatism, which is one of degenerative diseases.
  • Rheumatism is characterized by inflammation and hyperplasia, in which NF- KB is involved. It has been known that NF- ⁇ B in the synoviocyte of rheumatoid synovium is activated by various stimuli, and the activated NF- ⁇ B expresses proinflammatory mediators and inhibits synoviocyte apoptosis at the same time, thereby inducing inflammation and hyperplasia (Berenbaum F., Curr Opin Rheumatol. 2004 Sep; 16(5): 616-22; Liu H., et al., Curr Opin Pharmacol. 2003 Jun;3(3):317-22.).
  • a chemotherapeutic cure has been adopted by using various types of drugs that contain a steroid anti-inflammatory agent such as cortisone and other adrenocortical hormones, a non-steroid anti-inflammatory agent such as asprin, pyrroxicam and indomethacin, an auric agent such as orothiomalic acid, an anti-rheumatoid agent such as chloroquinone and D- phenisylamine, a gout inhibitor such as colchicin, and an immunosuppressant such as cyclophosphoamide, azathioprine, methotrexate and levamisol.
  • a steroid anti-inflammatory agent such as cortisone and other adrenocortical hormones
  • a non-steroid anti-inflammatory agent such as asprin, pyrroxicam and indomethacin
  • an auric agent such as orothiomalic acid
  • an anti-rheumatoid agent such as chloroquino
  • the above chemotherapeutic drugs cannot treat the disease fundamentally and produces a lot of side-effects due to the medicine in the case where steroid hormones known as an arthritis drug are administered for the treatment. Accordingly, there are difficulties in using the above chemotherapeutic drugs for the treatment.
  • the conventional chemotherapeutic drugs have problems such as a side-effect and a decreased effectiveness after being administered over a long period of time administration, a deficiency of anti-inflammation effect, a lack of efficacy toward already provoked arthritis and the like.
  • indomethacin, ibuprofen which can soothe pains effectively during the treatment of arthritis, and various kinds of nonsteroid antiphlogistic agents are only prepared for the administration. Disclosure of Invention Technical Problem
  • the present inventors have made an effort to develop a substance having an excellent inhibitory activity against IKK ⁇ , which is involved in inhibiting a transcriptional factor, NF- ⁇ B associated with inducing various immune and inflammatory diseases, and as a result, they have prepared a novel thienopyrimidine derivative. Further, they have found that the compound has an excellent inhibitory activity against IKK ⁇ , thereby completing the present invention.
  • Technical Solution
  • the present invention provides a novel thienopyrimidine derivative having an excellent anti-inflammatory and anti-cancer activity, or a pharmaceutically acceptable salt thereof, a process for the preparation thereof and a pharmaceutical composition comprising the same.
  • Fig. 1 illustrates that an amount of TNF- ⁇ in the blood of inflammation-induced mice, in the case where the compounds of the present invention (Examples 84 to 85) were orally administrated to inflammation-induced mice at concentrations of 30 and 100 D/D, respectively, and then lipopolysaccharide was abdominally administrated.
  • the present invention provides a novel thienopyrimidine derivative represented by the following Formula 1, which has an excellent anti-inflammatory and anti-cancer activity, a pharmaceutically acceptable salt thereof, or an isomer thereof.
  • X is O, S or NH
  • R is hydrogen; linear or branched C to C alkyl; -(CH )n -OR; -(CH )n -COOR; C to C heteroaryl substituted or unsubstituted with C to C alkyl or halogen, which comprise one or two heteroatom(s) selected from the group consisting of S, O and N; or
  • R is hydrogen; -(CH )n -Z; -(CH )n -OR; -(CH )n -COOR; -(CH )n -CONR'R"; -
  • R is hydrogen; linear or branched C to C alkyl; linear or branched C to C
  • C to C heterocyclic comprising one or two heteroatom(s) selected from the group consisting of N, O or S,
  • R is H, or linear or branched C to C alkyl
  • R is H, -OH, -NO , linear or branched C to C alkyl, -Y-C to C alkyl, -NR 1 R", -
  • CN -COOR, halogen, -Y-(CH )n -NR 1 R", -Y-(CH )n -OR, -Y-(CH )n -COOR, - Y-(CH )n -Z, -Y-(CH )n -M-R, -Y-(CH )n -M-(CH )n -NR 1 R", -Y-(CH )n -M-(CH )n -OR, -Y-(CH )n -M-(CH )n -COOR, -Y-(CH )n -M-(CH )n -CN or -Y-(CH )n -
  • R is H, linear or branched C to C alkyl, -OR, -NO , amine, mono- or di- alkylamine, -CN, -COOR, -0-(CH )n -NR 1 R", -0-(CH )n -OR, -0-(CH )n -COOR or - 0-(CH )n -Z,
  • R is H, linear or branched C to C alkyl, -OR, -NO , amine, mono- or di- alkylamine, -CN, -COOR, -(CH ⁇ -NR'R", -(CH ⁇ -OR, -(CH ⁇ -COR, -(CH ⁇ - COOR or -(CH 2 )n 2 -Z,
  • R and R are each independently hydrogen, linear or branched C to C alkyl, or halogen
  • R, R' and R" are each independently hydrogen, linear or branched C to C alkyl, or
  • M is O, S or -NR-
  • Y is O, S, NH, -NH-CO- or -CO-NH-,
  • Z is pyrrolidine; piperidine; piperazine; morpholine; thiomorpholine; 2- or
  • 3-oxo-pyrrolidine 2-, 3- or 4-oxo-piperidine; oxazole; triazole; pyridine; imidazole; imidazolidine; 2,5-dioxo-pyrrolidine; 2- or 3-oxo-piperazine;
  • n , n and n are each integer of 0 to 5.
  • X is O or S
  • R is hydrogen, methyl, -(CH )n -OR, -(CH )n -COOR, thiophenyl or
  • R is hydrogen, -(CH )n -Z, -(CH )n -OR, -(CH )n -COOR, -(CH )n -CONR'R", -
  • R is hydrogen, methyl, ethyl, propyl, isobutyl, t-butyl, 2-propenyl, cyclopropyl, -
  • R is H, -OH, -NO , methyl, -OCH , -NR 1 R", F, Cl, Br, I, -Y-(CH )n -NR 1 R", -
  • R is H
  • R is H, methyl, butyl, -(CH )n -NR 1 R", -(CH )n -OR or -(CH )n -COR,
  • R and R are each independently hydrogen
  • R, R' and R" are each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopentyl or -CH CF , [44] M is O or -NR-,
  • Y is O, -NH-CO- or -CO-NH-
  • Z is pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 2- or
  • n , n and n are each integer of 0 to 3.
  • Preferred examples of the thienopyrimidine derivative of Formula 1 of the present invention include the following compounds, but are not limited thereto:
  • the compounds of Formula 1 of the present invention can be prepared in the form of their pharmaceutically acceptable salts and solvates by a conventional method known in the art.
  • the acid addition salt formed by a pharmaceutically acceptable free acid thereof is useful.
  • the acid addition salt is prepared by a conventional method, for example, a method in which a compound is dissolved in an excessive amount of an acid solution, and then a salt is precipitated in a water miscible organic solvent, such as methanol, ethanol, acetone and acetonitrile.
  • Acid or alcohol for example, glycol monomethylether
  • the precipitated salt can be subjected to suction filtration.
  • an organic acid and inorganic acid can be used as a free acid.
  • Examples of the inorganic acid include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and tartaric acid
  • examples of the organic acid include methane- sulphonic acid, /?-toluenesulphonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, and hydroiodic acid, but not limited thereto.
  • a pharmaceutically acceptable metal salt can be prepared with a base.
  • An alkali metal or alkaline earth metal salt can be obtained by the method, for example, a method comprising dissolving a compound in an excessive amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering undissolved salts, evaporating the residue, and then drying the filtrate.
  • sodium, potassium or calcium salts are prepared as a metal salt, but not limited thereto.
  • the corresponding silver salts can be obtained by reacting alkali metal or alkaline earth metal salts with appropriate silver salts (e.g., silver nitrate).
  • compositions of the compound of Formula 1 contain an acidic or basic group in the compound of Formula 1.
  • the pharmaceutically acceptable salts include sodium, calcium, and potassium salts of a hydroxy group
  • other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulphonate(mesylate), /?-toluenesulphonate (tosylate), which can be prepared by the preparation method or process known in the art.
  • the compound of Formula 1 has an asymmetric center, it can be present in the form of the optically different enantiomers, and the scope of the invention comprises all of the optically active isomers and R or S type stereoisomers and the mixtures thereof.
  • the present invention comprises a racemic mixture, one or more enantiomer, one or more diastereo isomer or the mixture thereof, and the isolation and preparation method of isomer known in the art.
  • the present invention provides a process for preparing a thienopyrimidine derivative of Formula 1.
  • the thienopyrimidine derivative of Formula 1 is chemically prepared by the method described in the following Reaction Schemes, but not limited thereto. It will be understood that a thienopyrimidine derivative of Formula 1 of the present invention can be prepared by the various methods known in the art.
  • reaction schemes show the steps for preparing the representative compounds of the present invention, and other compounds may also be prepared by ⁇ Reaction Scheme 1> through ⁇ Reaction Scheme 9> with appropriate modifications of reagents, solvents and procedures.
  • Some compounds of the present invention were prepared by the methods, which are not described in ⁇ Reaction Scheme 1> through ⁇ Reaction Scheme 9>, and the methods thereof are described in detail in each Example.
  • R , R , R and R are as defined in Formula 1.
  • a ketone compound (I) is subjected to condensation reaction using a base such as malononitrile (II), acetate, ammonium acetate and benzylamine, or using an organic solvent such as benzene, toluene in the presence of 3-amino propionic acid to prepare a compound (III).
  • a base such as malononitrile (II), acetate, ammonium acetate and benzylamine
  • an organic solvent such as benzene, toluene in the presence of 3-amino propionic acid
  • the compound (III) prepared in the first step is reacted with sulfur(S) in the presence of a base such as pyridine, piperidine, triethylamine to prepare a thiazole compound (IV).
  • a base such as pyridine, piperidine, triethylamine
  • an organic solvent such as ethanol, butanol, dioxane, tetrahydrofuran and the mixture thereof can be used and the reaction is performed at room temperature or under heating, preferably under heating.
  • the compound (IV) prepared in the second step is reacted with a nitrile compound (V) and a hydrochloric solution in a sealed tube or replaced with hydrochloric acid gas to prepare a compound (VI).
  • the reaction is performed using dioxane, tetrahydrofuran or the like, as an organic solvent which does not adversely affect the reaction, under heating.
  • the amine compound (VI) prepared in the third step is converted to a chloro compound (VII), preferably which can be prepared by adding copper chloride in the presence of t-butylthionitrate, isoamyl nitrite or t-butyl nitrite or by adding sodium nitrite or potassium nitrite and then adding copper chloride in a hydrochloric solution.
  • a chloro compound (VII) preferably which can be prepared by adding copper chloride in the presence of t-butylthionitrate, isoamyl nitrite or t-butyl nitrite or by adding sodium nitrite or potassium nitrite and then adding copper chloride in a hydrochloric solution.
  • the reaction is performed using an aqueous solution, acetonitrile, dichloromethane, chloroform, dioxane, tetrahydrofuran or the like, as a sol vent which does not adversely affect the reaction. Further, the reaction is performed
  • the chloro compound (VII) prepared in the fourth step is dissolved in an organic solvent, and then hydrazine hydrate is slowly added thereto to prepare a hydrazine compound (VIII).
  • the reaction is performed using an aqueous solution, acetonitrile, tetrahydrofuran or the like, as a solvent which does not adversely affect the reaction. Further, the reaction is preferably performed, but not limited thereto, at room temperature or under heating.
  • the hydrazine compound (VIII) prepared in the fifth step is dissolved in an organic solvent, then reacted with citraconic anhydride to prepare a compound (X).
  • the reaction is performed using chloroform, dichloromethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, diethylether or the like, as an organic solvent which does not adversely affect the reaction. Further, the reaction is preferably performed, but not limited thereto, at room temperature or under heating.
  • the compound (X) prepared in the sixth step is dissolved in 1,4-dioxane or diethylether, then hydrochloric acid is added thereto to prepare a compound (XI). Further, the reaction is preferably performed, but not limited thereto, at cold or room temperature.
  • a ketone compound (I) is subjected to condensation reaction using a base such as ethyl cyanoacetate (XII), acetate, ammonium acetate and benzylamine, or using an organic solvent such as benzene, toluene in the presence of 3-amino propionic acid to prepare a compound (XIII).
  • a base such as ethyl cyanoacetate (XII), acetate, ammonium acetate and benzylamine, or using an organic solvent such as benzene, toluene in the presence of 3-amino propionic acid.
  • the reaction is preferably performed at room temperature or under heating.
  • the compound (XV) prepared in the third step is reacted in a phosphorous oxychloride solution to prepare a compound (VII).
  • pen- tachlorophosphine or phenyldiethylamine may be added thereto to perform the reaction.
  • the reaction can be performed without using any solvent or with a solvent, which does not adversely affect the reaction, such as dimethyl formamide. Further, the reaction is preferably performed, but not limited thereto, at room temperature or under heating.
  • a ketone compound (XVI) and ethyl cyanoacetate (XII) are dissolved in an organic solvent, sulfur(S) is added thereto, and reacted using a base such as diethylamine, morpholine and triethylamine, or under the condition of ethy- lammonium acetate and l-butyl-3-methylimidazoliumtetrabutylfluororate to prepare a compound (XVII).
  • the reaction can be performed using alcohol, dimethyl- formamide, 1,4-dioxane, benzene, 2-methylpropan-2-ol and the mixture thereof, as a solvent which does not adversely affect the reaction. Further, the reaction is preferably performed, but not limited thereto, at room temperature or under heating.
  • the next step is a step for preparing a compound (XIX) using the compound (XVII) prepared in the first step.
  • the reactions are carried out under the same condition as Reaction Scheme 2 for converting a compound (XIV) to a compound (XI).
  • a compound (XX) is dissolved in formamide (XXI) and heated to prepare a compound (XXII).
  • the reaction is performed under the same condition as Reaction Scheme 1 for converting a compound (VI) to a compound (XI), and in the case where R of the compound (XXII) is -OH, the reaction is preformed under the same condition as Reaction Scheme 2 for converting a compound (XV) to a compound (XI), to prepare a compound (XXIII).
  • a carboxylic acid compound (XXIV) is dissolved in tetrahydrofuran, and then reacted with N,N-dimethylformamide-dimethyl sulfonate complex (Dionisia Sanz, et al., J. Org. Chem, 67, 1462-1471, 2002) in the presence of lithium diisopropylamide (LDA) to prepare an enamine compound (XXV).
  • LDA lithium diisopropylamide
  • the reaction can be performed using diethylether in addition to tetrahydrofuran as a solvent. Further, the reaction is generally performed at cold or room temperature.
  • the compound (XXV) prepared in the first step is reacted with methyl cyanoacetate (XII) under the same condition as the first step of Reaction Scheme 2 to prepare a compound (XXVI).
  • the reaction is performed with a compound (XXVI) under the same condition as Reaction Scheme 1 for converting a compound (XIV) to a compound (XI), to prepare a compound (XXVIII).
  • the ketone compound (XXIX) is reacted under the general bromination condition to prepare a compound (XXX).
  • the bromination is preformed using bromine (Br ), tribromophosphine (PBr ), pyridinium tribromide, N- bromosuccinimide (NBS), copper (I) bromide, copper (II) bromide or the like and using an acid such as acetic acid, hydrobromic acid (HBr) or using triethylamine, ammonium acetate, urea or the like.
  • the reaction can be performed using alcohol, water, dimethyl formamide, tetrahydrofuran, diethylether, chloroform, tetra- chloromethane, benzene, ethylacetate or the like, as a solvent which does not adversely affect the reaction. Further, the reaction is performed, but not limited thereto, at cold or room temperature or under heating.
  • the compound (XXX) prepared in the first step is reacted with malononitrile (II) using a base such as diethylamine, triethylamine, pyridine to prepare a compound (XXXI).
  • a base such as diethylamine, triethylamine, pyridine
  • the reaction can be performed using dimethyl formamide, tetrahydrofuran, chloroform, benzene or the like, as a solvent which does not adversely affect the reaction. Further, the reaction is performed, but not limited thereto, at room temperature or under heating.
  • R , R , R and R are as defined in Formula 1.
  • a compound (XXX) is reacted with ethyl cyanoacetate (XII) under the same condition as the first step of Reaction Scheme 6 to prepare a compound (XXXIV).
  • the reaction is performed with a compound (XXXIV) under the same condition as Reaction Scheme 2 for converting a compound (XIV) to a compound (XI), to prepare a compound (XXXII).
  • a ketone compound (XXXVI) is reacted with malononitrile (II) or ethyl cyanoacetate (XII) using a base such as diethylamine, triethylamine, pyridine to prepare a compound (XXXVII) or a compound (XXXVIII).
  • a base such as diethylamine, triethylamine, pyridine
  • the reaction can be performed using methanol, ethanol or the like, as a solvent which does not adversely affect the reaction. Further, the reaction is performed, but not limited thereto, at room temperature or under heating.
  • Reaction Scheme 1 for converting a compound (IV) to a compound (XI), or a compound (XXXVIII) is reacted under the same condition as Reaction Scheme 2 for converting a compound (XIV) to a compound (XI), to prepare a compound (XXXIX).
  • R , R and R are as defined in Formula 1, and X is O or S.
  • Reaction Scheme 9> explains the process for preparing a compound (XLII) by reacting a compound (XL) with a compound (XLI). The reaction is preformed under the same condition as Reaction Scheme 1 for converting a compound (VIII) to a compound (X).
  • the present invention provides a pharmaceutical composition for preventing and treating inflammatory diseases and cancers comprising a thienopyrimidine derivative of Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof.
  • the inflammatory diseases include the pain caused by arthritis, for example, rheumatoid arthritis, spondyloarthopathies, gout, osteoarthritis, systemic lupus erythematosus and juvenile arthritis.
  • the inflammatory diseases or symptoms include, for example, myositis, gingivitis, synovitis, ankylosing spondylitis, burstitis, septic shock, burns, and injury.
  • a pharmaceutical composition comprising the compound according to the present invention as an active ingredient is useful in treating inflammatory symptoms accompanied by diseases such as inflammatory bowel disease, Crohn's disease, Type I diabetes, and psoriasis, and in treating various types of cancer.
  • the pharmaceutical composition comprising the compound of the present invention further includes suitable carriers, excipients or diluents according to the conventional methods.
  • Examples of carriers, excipients, and diluents contained in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • composition comprising the compound of the present invention can be formulated, according to the conventional method, in the form of composition for the oral administrations such as powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, medicines for external applications, suppository or injection solutions.
  • a formulation can be prepared, according to the conventional method, using a diluent or an excipient such as a filler, an extender, a binding agent, a wetting agent, a disintegrating agent, and a surfactant.
  • the solid preparation for oral administration includes tablet, pill, powder, granule, capsule, and can be prepared by mixing at least one of the excipient such as starch, calcium carbonate, sucrose, lactose, and gelatin.
  • lubricants can be used such as magnesium stearate, talc.
  • the liquid preparation for oral administration can include suspensions, liquid drugs, emulsions, and syrups, and include many excipients (e.g., wetting agent, sweetening agent, fragrant, preserving agent) other than commonly used simple diluents such as water, liquid paraffin.
  • the preparation for parenteral administration contains sterilized solutions, non-aqueous solvents, suspensions, emulsifiers, freeze-drying agents or suppositories.
  • the non-aqueous solvent or suspension solvent can include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyloleate.
  • the basic material of suppository includes witepsol, macrogol, Tween 61, cacao paper, laurin paper, or glycerogelatin.
  • the desirable dose of the compounds according to the present invention varies depending on the condition and the weight of the subject, severity, drug form, route and period of administration, and may be chosen by those skilled in the art. However, in order to obtain desirable effects, it is generally recommended to administer at the amount of 0.0001 to 500 mg/kg, preferably 0.01 to 300 mg/kg. The dose may be administered in single or several times per day. In terms of composition, the compounds having Formula 1 can be present 0.0001 to 50% by weight based on the total weight of the composition.
  • the compounds according to the present invention in pharmaceutical dosage forms may be used in the form of their pharmaceutically acceptable salts, and may also be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds.
  • the pharmaceutical composition of the present invention can be administered to a subject animal such as mammals (rat, mouse, domestic animals or human) through various routes. All modes of administration are contemplated, for example, administration can be made orally, rectally or by intravenous, intramuscular, subcutaneous, intrathecal, epidural or intracerebroventricular injection. Mode for the Invention
  • Example 8 (method 1) . l-(2,5-di-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride
  • Example 12 (2,5-di-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-hydrazine hydrochloride [411]
  • Example 13 3-methyl-l-(2-pyridin-4-yl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride [412]
  • Example 14 l-[2-(4-methoxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
  • Example 26 3-methyl-l-(2-thiophen-3-yl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride [470]
  • Example 27 3-methyl-l-(2-thiophen-2-yl-5-thiophen-3-yl-thieno[2,3-d] pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride [471]
  • Example 28 .
  • Step 1 Preparation of 4-chloro-2-[4-(2-piperidin-l-yl-ethoxy)-phenyl1 - 5-thiophen-2-yl-thieno[2.3-d1pyrimidine [724]
  • Step 4 Preparation of l-r6-(4-methoxy-phenylV5-methyl-2-thiophen-2-yl-thienor2.3-dlpyrimidin-4-ylaminol -3-methyl-pyrrole-2.5-dione hydrochloride
  • Example 58 l-[6-(4-hydroxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [857]
  • Example 59 l-[6-(4-hydroxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride

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Abstract

The present invention relates to a novel thienopyrimidine derivative having an excellent anti¬ inflammatory and anti-cancer activity, or a pharmaceutically acceptable salt thereof, a process for the preparation thereof and a pharmaceutical composition comprising the same. The compound according to the present invention strongly inhibits IKB kinase-β (IKK-β) involved in the activation of a transcriptional factor, NF-ϰB, which is associated with inducing various immune and inflammatory diseases, whereby a composition comprising the compound is a useful therapeutic agent against inflammatory diseases, in particular, arthritis and cancer.

Description

Description
NOVEL THIENOPYRIMIDINE DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, PROCESS
FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME Technical Field
[1] The present invention relates to a novel thienopyrimidine derivative or a pharmaceutically acceptable salt thereof, a process for the preparation thereof and a pharmaceutical composition comprising the same. A thienopyrimidine derivative of the present invention inhibits the activity of IKB kinase-β (IKKβ or IKK-2), whereby it inhibits the activity of nuclear factor KB (NF-KB). Accordingly, it can be used for prevention or treatment of NF- KB -related diseases, in particular, inflammatory diseases and cancers. Background Art
[2] NF-κB (Nuclear Factor kappa B) is a transcription factor composed of a family of five related proteins called p50 subunit family (p50, p52) and p65 subunit family (p65, c-Rel, ReIB), which may form homodimers or heterodimers. Under normal conditions, NF-κB transcription factors are present in the cytoplasm in an inactive form associated with their inhibitory proteins, IKB protein (IκBα, IκBβ, IκBγ, IκBε and BcB) (Ghosh, S., et al. Annu Rev. Immunol . 16, 225-260, 1998). However, various stimuli such as various cytokines (e.g., TNF-α, IL-I), bacterial or viral infections (e.g., LPS, dsRNA), stress (e.g., ROI, UV, adriamycin, radiation), and oxidants activate IKB kinase complex composed of IKKα, IKKβ, NEMO (IKKγ) or the like. Subsequently, the activated IKB kinase complex phosphorylates at the two serine residues in the N- terminus of IKB proteins (IκBα phosphorylates at Ser32 and Ser36, IκBβ phosphorylates at Serl9 and Ser23), wherein the phosphorylation of IKB proteins triggers IKB ubiquitination and degradation via the ubiquitin-proteosome pathway (VJ. Palombella et al., Cell, 78, 773-785, 1994; Ghosh S. et al, Cell. 109, 81-96, 2002). The free NF-κB from IKB translocates to the nucleus and binds to NF-κB binding site (consensus sequence: 5'-GGGPuNNPyPyCC-3') of target genes, thereby initiating the transcription of the genes coding the immune and inflammatory response related proteins (Barnes PJ. et al. N. Engl. J. Med. 336, 1066-1071, 1997). Most of the genes regulated by NF- KB include proinflammatory mediators, cytokines, and cell adhesion molecules.
[3] Recently, intracellular functions and protein structures of IKKα and IKKβ have been elucidated concretely. According to the recent report, IKK- β is thought to be a pivotal target in NF-κB activation pathway as an anti-inflammatory and anti-cancer therapeutic agent. The IKKβ inhibition appears, therefore, as an attractive strategy to increase the anti-inflammatory and anti-cancer effect.
[4] While the proteins, of which expressions are regulated by a transcription factor, NF-
KB, play key role in the normal physiological functions such as development and immune response, abnormal activation of NF-κB are associated with mutations in IKB protein, a translocation and amplification of NF-κB gene, and aberrant activation of IKK enzyme in inflammatory diseases such as arthritis, asthma (Yang L. et al., J. Exp. Med. 188, 1739-1750, 1998; Barnes P., et al, Trends Pharmacol, Therapeut. 18, 46-50, 1997), allergic rhinitis, atopic dermatitis, urticaria, systemic lupus erythematosus, psoriasis, ulcerative collitis, systemic inflammatory response, septic shock, polymyositis, polyarteritis nodosa, Alzheimer's disease (Keith T. Akama et al, Proc. Natl. Acad. ScL USA, 95, 5795-5800, 1998), as well as in various types of cancer such as skin cancer, solid tumors, blood cancer (Mercurio, F., et al., Oncogene, 18, 6163-6171, 1999; Rayet, B. et al., Oncogene, 18, 6938to6947, 1999). Further, NF- KB may be involved in the regulation of neural cell apoptosis. It has been found that NF-KB is activated and promotes cell death in focal cerebral ischemia (Schneider A. et al, Nature medicine Vol.5 No.5, 554-559, 1999). Accordingly, if the aberrant activation of NF-κB is regulated, it is possible to inhibit occurrence and progression of degenerative and rare diseases and to treat rare diseases caused by an aberrant apoptosis and inflammation.
[5] Example thereof includes rheumatism, which is one of degenerative diseases.
Rheumatism is characterized by inflammation and hyperplasia, in which NF- KB is involved. It has been known that NF-κB in the synoviocyte of rheumatoid synovium is activated by various stimuli, and the activated NF-κB expresses proinflammatory mediators and inhibits synoviocyte apoptosis at the same time, thereby inducing inflammation and hyperplasia (Berenbaum F., Curr Opin Rheumatol. 2004 Sep; 16(5): 616-22; Liu H., et al., Curr Opin Pharmacol. 2003 Jun;3(3):317-22.). It has been known that in an animal model of rheumatism, if the activation of NF- KB is inhibited by genetic manipulation or drugs, generation of proinflammatory mediators is reduced, and apoptosis increases, thus to significantly prevent both inflammation and hyperplasia.
[6] Conventionally, in order to treat such an arthritis, a chemotherapeutic cure has been adopted by using various types of drugs that contain a steroid anti-inflammatory agent such as cortisone and other adrenocortical hormones, a non-steroid anti-inflammatory agent such as asprin, pyrroxicam and indomethacin, an auric agent such as orothiomalic acid, an anti-rheumatoid agent such as chloroquinone and D- phenisylamine, a gout inhibitor such as colchicin, and an immunosuppressant such as cyclophosphoamide, azathioprine, methotrexate and levamisol.
[7] However, the above chemotherapeutic drugs cannot treat the disease fundamentally and produces a lot of side-effects due to the medicine in the case where steroid hormones known as an arthritis drug are administered for the treatment. Accordingly, there are difficulties in using the above chemotherapeutic drugs for the treatment. The conventional chemotherapeutic drugs have problems such as a side-effect and a decreased effectiveness after being administered over a long period of time administration, a deficiency of anti-inflammation effect, a lack of efficacy toward already provoked arthritis and the like. At the present time, indomethacin, ibuprofen, which can soothe pains effectively during the treatment of arthritis, and various kinds of nonsteroid antiphlogistic agents are only prepared for the administration. Disclosure of Invention Technical Problem
[8] Therefore, it is necessary to solve these problems and to develop a new therapeutic agent for arthritis, which alleviates acute inflammation symptom and pain sufficiently. A drug without side-effect is strongly needed, since most drugs presently used have some sort of side-effect although the side-effect varies depending on their severities and individual differences, and it is usually administered over a long period of time in order to treat especially rheumatoid arthritis.
[9] The present inventors have made an effort to develop a substance having an excellent inhibitory activity against IKKβ, which is involved in inhibiting a transcriptional factor, NF-κB associated with inducing various immune and inflammatory diseases, and as a result, they have prepared a novel thienopyrimidine derivative. Further, they have found that the compound has an excellent inhibitory activity against IKKβ, thereby completing the present invention. Technical Solution
[10] The present invention provides a novel thienopyrimidine derivative having an excellent anti-inflammatory and anti-cancer activity, or a pharmaceutically acceptable salt thereof, a process for the preparation thereof and a pharmaceutical composition comprising the same. Brief Description of the Drawings
[11] Fig. 1 illustrates that an amount of TNF-α in the blood of inflammation-induced mice, in the case where the compounds of the present invention (Examples 84 to 85) were orally administrated to inflammation-induced mice at concentrations of 30 and 100 D/D, respectively, and then lipopolysaccharide was abdominally administrated. Best Mode for Carrying Out the Invention [12] The present invention provides a novel thienopyrimidine derivative represented by the following Formula 1, which has an excellent anti-inflammatory and anti-cancer activity, a pharmaceutically acceptable salt thereof, or an isomer thereof.
[13] [Formula 1]
[14]
Figure imgf000006_0001
[15] wherein
[16] X is O, S or NH,
[17] R is hydrogen; linear or branched C to C alkyl; -(CH )n -OR; -(CH )n -COOR; C to C heteroaryl substituted or unsubstituted with C to C alkyl or halogen, which comprise one or two heteroatom(s) selected from the group consisting of S, O and N; or
Figure imgf000006_0002
[18] R is hydrogen; -(CH )n -Z; -(CH )n -OR; -(CH )n -COOR; -(CH )n -CONR'R"; -
Y-(CH 2 )n 1 -NR1R"; -Y-(CH 2 )n 1 -OR; -Y-(CH2 )n 1 -COOR; C 5 to C 20 heteroary Jl substituted or unsubstituted with C to C alkyl or halogen, which comprise one or two heteroatom(s) selected from the group consisting of S, O and N; or
Figure imgf000006_0003
[19] R is hydrogen; linear or branched C to C alkyl; linear or branched C to C
3 J to 1 10 J 2 10 alkenyl; C to C cycloalkyl; -CH -C to C cycloalkyl; -NR1R"; C to C heteroaryl or -CH -C to C heteroaryl substituted or unsubstituted with C to C alkyl or halogen, which comprise one or two heteroatom(s) selected from the group consisting of S, O and N,; or
^y-(CH2Jn1 [20] R and R are each independently H; =CH ; linear or branched C to C alkyl; halogen; -OR; or connected to each other to form C to C aryl, C to C cycloalkyl, or
6 20 5 7
C to C heterocyclic comprising one or two heteroatom(s) selected from the group consisting of N, O or S,
[21] R is H, or linear or branched C to C alkyl,
[22] R is H, -OH, -NO , linear or branched C to C alkyl, -Y-C to C alkyl, -NR1R", -
7 2 1 5 1 5
CN, -COOR, halogen, -Y-(CH )n -NR1R", -Y-(CH )n -OR, -Y-(CH )n -COOR, - Y-(CH )n -Z, -Y-(CH )n -M-R, -Y-(CH )n -M-(CH )n -NR1R", -Y-(CH )n -M-(CH )n -OR, -Y-(CH )n -M-(CH )n -COOR, -Y-(CH )n -M-(CH )n -CN or -Y-(CH )n -
2 2 2 3 2 2 2 3 2 2
M-(CH )n -Z, [23] R is H, linear or branched C to C alkyl, -OR, -NO , amine, mono- or di- alkylamine, -CN, -COOR, -0-(CH )n -NR1R", -0-(CH )n -OR, -0-(CH )n -COOR or - 0-(CH )n -Z,
2 2
[24] R is H, linear or branched C to C alkyl, -OR, -NO , amine, mono- or di- alkylamine, -CN, -COOR, -(CH^-NR'R", -(CH^-OR, -(CH^-COR, -(CH^ - COOR or -(CH 2 )n 2 -Z,
[25] R and R are each independently hydrogen, linear or branched C to C alkyl, or halogen, [26] R, R' and R" are each independently hydrogen, linear or branched C to C alkyl, or
-CH 2 CF 3 ;
[27] M is O, S or -NR-,
[28] Y is O, S, NH, -NH-CO- or -CO-NH-,
[29] Z is pyrrolidine; piperidine; piperazine; morpholine; thiomorpholine; 2- or
3-oxo-pyrrolidine; 2-, 3- or 4-oxo-piperidine; oxazole; triazole; pyridine; imidazole; imidazolidine; 2,5-dioxo-pyrrolidine; 2- or 3-oxo-piperazine;
2,5-dioxo-2,5-dihydro-pyrrole; 2-oxo-imidazolidine; 4,4-ethylenedioxy-piperidine; 2- or 3-thienyl; 2- or 3-furyl;
Figure imgf000007_0001
— N N-R0 or
Figure imgf000007_0002
, and [30] n , n and n are each integer of 0 to 5.
[31]
[32] Preferably, in Formula 1,
[33] X is O or S,
[34] R is hydrogen, methyl, -(CH )n -OR, -(CH )n -COOR, thiophenyl or
^-(CH2Jn1
[35] R is hydrogen, -(CH )n -Z, -(CH )n -OR, -(CH )n -COOR, -(CH )n -CONR'R", -
Y-(CH )n -NR1R", thiophenyl or
Figure imgf000008_0001
[36] R is hydrogen, methyl, ethyl, propyl, isobutyl, t-butyl, 2-propenyl, cyclopropyl, -
CH -cyclopropyl, amine, 2-methylthiophenyl, -CH -thiophenyl, furanyl, pyridinyl or
^-(CH2Jn1
[37] R and R are each independently H, =CH methyl, F, Cl, Br, I, or connected to each other to form phenyl or pyridine, [38] R is H or methyl,
[39] R is H, -OH, -NO , methyl, -OCH , -NR1R", F, Cl, Br, I, -Y-(CH )n -NR1R", -
Y-(CH )n -OR, -Y-(CH )n -Z, -Y-(CH )n -M-(CH )n -NR1R", -Y-(CH )n -M-(CH )n -
2 2 2 2 2 2 2 3 2 2 2 3
OR, -Y-(CH )n -M-(CH )n -COOR, -Y-(CH )n -M-(CH )n -CN or -Y-(CH )n -M-(CH
2)n3-Z,
[40] R is H,
[41] R is H, methyl, butyl, -(CH )n -NR1R", -(CH )n -OR or -(CH )n -COR,
[42] R and R are each independently hydrogen,
[43] R, R' and R" are each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopentyl or -CH CF , [44] M is O or -NR-,
[45] Y is O, -NH-CO- or -CO-NH-,
[46] Z is pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 2- or
3-oxo-pyrrolidine, 2,5-dioxo-pyrrolidine, 2- or 3-oxo-piperazine, 2-oxo-imidazolidine,
4,4-ethylenedioxy -piperidine,
Figure imgf000009_0001
— N N-R9 or
Figure imgf000009_0002
, and [47] n , n and n are each integer of 0 to 3.
1 2 3
[48]
[49] Preferred examples of the thienopyrimidine derivative of Formula 1 of the present invention include the following compounds, but are not limited thereto:
[50] 1) 3-methyl-l-(5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione,
[51] 2) 3,4-dichloro-l-(5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride,
[52] 3) 2-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-isoindole-l,3-dione hydrochloride,
[53] 4) 2-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrolo[3,4-c] pyridine-
1,3-dione hydrochloride,
[54] 5) 3-methyl-l-(5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride,
[55] 6) l-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride,
[56] 7) l-(2,6-di-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride,
[57] 8) l-(2,5-di-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride,
[58] 9) 3-methyl-l-[2-(5-methyl-thiophen-2-yl)-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino]-pyrrole-2,5-dione hydrochloride,
[59] 10) l-[5-(4-methoxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride,
[60] 11) l-[5-(4-hydroxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride,
[61] 12) (2,5-di-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-hydrazine hydrochloride, [62] 13) 3-methyl-l-(2-pyridin-4-yl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride, [63] 14) l-[2-(4-methoxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [64] 15) 3-methyl-l-(5-thiophen-2-yl-2-p-tolyl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride, [65] 16) 3-methyl-l-(5-thiophen-2-yl-2-thiophen-2-ylmethyl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride, [66] 17) 3-methyl-l-(2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride,
[67] 18) 3-methyl-l-(5-methyl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride, [68] 19) l-(2-benzyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride, [69] 20) 3-methyl-l-(5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride, [70] 21) 3-methyl-l-(2-phenyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione, [71] 22) 3-methyl-l-(2-phenyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride, [72] 23) l-[2-(4-hydroxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [73] 24) l-[2-(4-fluoro-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [74] 25) l-[2-(3-fluoro-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [75] 26) 3-methyl-l-(2-thiophen-3-yl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride, [76] 27) 3-methyl-l-(2-thiophen-2-yl-5-thiophen-3-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride, [77] 28) 3-methyl-l-(5-thiophen-2-yl-2-thiophen-3-ylmethyl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride, [78] 29) 3-methyl-l-(5-phenyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride, [79] 30) 3-methyl-l-(2-thiophen-2-yl-5-p-tolyl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride, [80] 31) l-[2-(4-methoxy-benzyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [81] 32) l-[2-(4-diethylaminophenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino
] -3-methyl-pyrrole-2,5-dione hydrochloride, [82] 33) l-[2-(3-hydroxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [83] 34) l-[2-(4-methoxy-phenyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [84] 35) l-[2-(3-methoxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [85] 36) l-[2-(3-methoxy-phenyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [86] 37) l-[2-(3-fluoro-phenyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [87] 38) l-[2-(3-methoxy-benzyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [88] 39)
4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2-yl-thieno[2,3-d]p yrimidine-5-carboxylic acid ethyl ester hydrochloride, [89] 40) l-[5-(3-hydroxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [90] 41) l-[5-(3-methoxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [91] 42) l-[2-(4-dimethylamino-phenyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [92] 43) l-[2-(4-amino-phenyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [93] 44) l-(2-furan-2-yl-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [94] 45) 3-methyl-l-(2-methyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride, [95] 46) l-[2-(4-amino-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [96] 47) l-(2-amino-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride, [97] 48) l-(2-cyclopropyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione, [98] 49)
[4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-5-yl] -acetic acid methyl ester hydrochloride, [99] 50) l-(5-hydroxymethyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride, [100] 51) l-(5-methoxymethyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride, [101] 52) 3-methyl-l-{2-[4-(2-piperidin-l-yl-ethoxy)-phenyl] -
5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride, [102] 53) 3-methyl-l-{2-[3-(2-piperidin-l-yl-ethoxy)-phenyl] -
5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride, [103] 54) l-[6-(4-hydroxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [104] 55) l-[6-(4-methoxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [105] 56) l-{6-[4-(2-dimethylamino-ethoxy)phenyl]-5-methyl-2-thiophen-2-yl-furo[2,3-d
]pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride, [106] 57) l-[6-(4-methoxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino]-3-methyl-pyrrole-2,5-dione hydrochloride, [107] 58) l-[6-(4-hydroxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino]-3-methyl-pyrrole-2,5-dione hydrochloride, [108] 59) [5-methyl-4-(3-methyl-2,5-dioxo -
2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-6-yl] -acetic acid methyl ester hydrochloride, [109] 60) l-[6-(3-hydroxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino]-3-methyl-pyrrole-2,5-dione, [110] 61)
5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2-yl-thien o[2,3-d]pyrimidine-6-carboxylic acid amide hydrochloride, [111] 62) l-[6-(3-methoxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino]-3-methyl-pyrrole-2,5-dione, [112] 63)
5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2-yl-thien o[2,3-d]pyrimidine-6-carboxylic acid methyl ester hydrochloride, [113] 64) l-(6-methoxy-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [114] 65) l-[6-(4-methoxy-benzyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino]-pyrrole-2,5-dione hydrochloride, [115] 66) l-[6-(4-hydroxy-benzyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino]-pyrrole-2,5-dione hydrochloride, [116] 67) 3-methyl-l-[5-methyl-6-(4-nitrophenyl)-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino] -pyrrole-2,5-dione hydrochloride, [117] 68) 3-methyl-l-(6-phenyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride, [118] 69)
3-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2-yl-th ieno[2,3-d]pyrimidin-6-yl]-propionic acid ethyl ester, [119] 70) l-(6-hydroxymethyl-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride, [120] 71) l-(6-methoxymethyl-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride, [121] 72) l-[6-(3-methoxybenzyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino]-3-methyl-pyrrole-2,5-dione hydrochloride, [122] 73) l-[6-(3-hydroxy-benzyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -
3-methyl-pyrrole-2,5-dione hydrochloride, [123] 74) l-{6-[3-(2-dimethylamino-ethoxy)-benzyl]-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride, [124] 75)
5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2-yl-thien o[2,3-d]pyrimidine-6-carboxylic acid-(2-dimethylamino-ethyl)-amide hydrochloride, [125] 76) 3-methyl-l-{5-[4-(2-piperidin-l-yl-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride, [126] 77) 3-methyl-l-{5-[3-(2-piperidin-l-yl-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride, [127] 78) l-{5-[3-(2-dimethylamino-ethoxy)-phenyl]-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride, [128] 79) l-{5-[3-(3-dimethylamino-propoxy)-phenyl]-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride, [129] 80) 3-methyl-l-{5-[3-(2-morpholin-4-yl-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride, [130] 81) 3-methyl-l-{5-[3-(2-piperazin-l-yl-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione dihydrochloride, [131] 82)
3-methyl-l-[5-methyl-6-(4-methyl-piperazin-l-ylmethyl)-2-thiophen-2-yl-thieno[2,3-d
]pyrimidin-4-ylamino] -pyrrole-2,5-dione dihydrochloride, [132] 83) 3-methyl-l-(5-{3-[2-(4-methyl-piperazin-l-yl)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione dihydrochloride, [133] 84) l-{6-[4-(2-dimethylamino-ethoxy)phenyl] - 5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-di one hydrochloride, [134] 85) 3-methyl-l-{5-methyl-6-[4-(2-piperidin-l-yl-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride, [135] 86) l-{6-[4-(2-methoxy-ethoxy)-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride, [136] 87) l-{6-[3-(2-methoxy-ethoxy)-phenyl]-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione, [137] 88) 3-methyl-l-{5-methyl-6-[4-(2-morpholin-4-yl-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride, [138] 89) l-{2-t-butyl-6-[4-(2-dimethylamino-ethoxy)-phenyl]-5-methyl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride, [139] 90) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl]-2-isobutyl-5-methyl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride, [140] 91) l-{2-allyl-6-[4-(2-dimethylamino-ethoxy)-phenyl]-5-methyl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride, [141] 92) 3-methyl-l-{5-methyl-6-[4-(2-piperazin-l-yl-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride, [142] 93) l-{6-[4-(3-dimethylamino-propoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-di one hydrochloride, [143] 94) l-{6-[4-(2-amino-ethoxy)-phenyl]-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride, [144] 95) l-{6-[4-(2-diethylamino-ethoxy)-phenyl]-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride, [145] 96) 3-methyl-l-{5-methyl-6-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride, [146] 97) 3-methyl-l-{5-methyl-6-[4-(2-(4-methyl piperazin-l-yl)-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride, [147] 98) l-(6-{4-[2-(ethyl-methyl-amino)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-pyrrol e-2,5-dione hydrochloride, [148] 99) 3-methyl-l-(5-methyl-6-{4-[2-(methyl-propyl-amino)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride, [149] 100) 3-methyl-l-(5-methyl-6-{4-[2-(2-oxo-pyrrolidin-l-yl)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride, [150] 101) l-(6-{4-[2-(isopropyl-methyl-amino)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-pyrrol e-2,5-dione hydrochloride, [151] 102) 3-methyl-l-(5-methyl-6-{4-(2-thiomorpholin-4-yl-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride, [152] 103) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl]-2,5-dimethyl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride, [153] 104) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl]-5-methyl-2-propyl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride, [154] 105) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-cyclopropyl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dion e hydrochloride, [155] 106) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl]-5-methyl-2-ethyl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride, [156] 107) l-{2-cyclopropylmethyl-6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dione hydrochloride [157] 108) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride, [158] 109) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3,4-dimethyl-pyrrole-2,5
-dione hydrochloride, [159] 110) 3,4-dichloro-l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride, [160] 111) l-[6-(4-{2-[4-(2-amino-ethyl)-piperazin-l-yl] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3-meth yl-pyrrole-2,5-dione hydrochloride, [161] 112) l-[6-(4-{2-[2-amino-ethyl)-methyl-amino] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3-meth yl-pyrrole-2,5-dione hydrochloride, [162] 113) l-[6-(4-{2-[(2-dimethylamino-ethyl)-methyl-amino] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3-meth yl-pyrrole-2,5-dione hydrochloride, [163] 114) l-[6-(4-{2-[4-(2-dimethylamino-ethyl)-piperazin-l-yl] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3-meth yl-pyrrole-2,5-dione hydrochloride, [164] 115) l-[6-(4-{2-[4-(2-methoxy-ethyl)-piperazin-l-yl] - ethoxy } -phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-meth yl-pyrrole-2,5-dione hydrochloride, [165] 116) 3-methyl-l-(5-methyl-6-{4-[2-(2-piperazin-l-yl-ethoxy)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride, [166] 117) l-(6-{4-[2-(4-acetyl-piperazin-l-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-pyrrol e-2,5-dione hydrochloride, [167] 118) l-(6-{4-[2-(2,5-dioxo-pyrrolidin-l-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-pyrrol e-2,5-dione, [168] 119) l-[6-(4-{2-[4-(2-hydroxy-ethyl)-piperazin-l-yl] - ethoxy }-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-meth yl-pyrrole-2,5-dione hydrochloride, [169] 120) 3-methyl-l-(5-methyl-6-{4-[2-(3-oxo-piperazin-l-yl)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride, [170] 121) l-[6-(4-{2-[(2-hydroxy-ethyl)-methyl-amino] - ethoxy }-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-meth yl-pyrrole-2,5-dione hydrochloride, [171] 122) l-[6-(4-{2-[(2-methoxy-ethyl)-methyl-amino] - ethoxy }-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-meth yl-pyrrole-2,5-dione hydrochloride, [172] 123) l-(6-{4-[2-(l,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-pyrrol e-2,5-dione hydrochloride [173] 124) l-(6-{4-[2-(2,5-dioxo-2,5-dihydro-pyrrole-l-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-pyrrol e-2,5-dione, [174] 125) 3-methyl-l-(5-methyl-6-{4-[2-(2-oxo-imidazolidin-l-yl)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione, [175] 126) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-ethyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dion e hydrochloride, [176] 127) l-(6-{4-[2-(4-butyl-piperazin-l-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-pyrrol e-2,5-dione dihydrochloride, [177] 128) l-({6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl}-methyl-amino)-3-methyl-pyrro le-2,5-dione hydrochloride,
[178] 129) methyl-
(2-{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen-2-yl -thieno[2,3-d]pyrimidin-6-yl]-phenoxy}-ethyl)-carbamic acid ?-butyl ester,
[179] 130) 3-methyl-l-{5-methyl-6-[4-(2-methylamino-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
[180] 131) l-[6-(4-methoxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino]-3-methylene-pyrrolidine-2,5-dione,
[181] 132) 3-methylene-l-{5-methyl-6-[4-(2-methylamino-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrolidine-2,5-dione hydrochloride,
[182] 133) l-{6-[4-(2-butylamino-ethoxy)-phenyl]-5-methyl-2-thiophen-2-yl-thieno[2,3-d
]pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride,
[183] 134) l-[(6-{4-[2-(2-methoxy-ethylamino)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-methyl-amino]-3-meth yl-pyrrole-2,5-dione hydrochloride,
[184] 135) l-[(6-{4-[2-(2-hydroxy-ethylamino)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-methyl-amino]-3-meth yl-pyrrole-2,5-dione hydrochloride,
[185] 136) 3-methyl-l-(5-methyl-6-{4-[2-(3-methyl-butylamino)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride,
[186] 137)
3-methyl-l-(5-methyl-2-thiophen-2-yl-6-{4-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-ph enyl}-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride,
[187] 138) 3-dimethylamino-JV -
{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen-2-yl-th ieno[2,3-d]pyrimidin-6-yl]-phenyl}-propionamide hydrochloride,
[188] 139)
3-[methyl-(2-{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thi ophen-2-yl-thieno[2,3-d]pyrimidin-6-yl]-phenoxy}-ethyl)-amino] -propionic acid,
[189] 140) isopropyl-
(2-{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen-2-yl -thieno[2,3-d]pyrimidin-6-yl]-phenoxy}-ethyl)-carbamic acid ?-butyl ester,
[190] 141) l-{6-[4-(2-isopropylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-di one hydrochloride,
[191] 142) 3-methyl-l-{5-methyl-6-[4-(piperidin-4-yloxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
[192] 143) l-{6-[4-(2-benzylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-di one hydrochloride, and
[193] 144)
3-(2-{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen-2- yl-thieno[2,3-d]pyrimidin-6-yl] -phenoxy } -ethylamino)-propionitrile hydrochloride.
[194]
[195] The compounds of Formula 1 of the present invention can be prepared in the form of their pharmaceutically acceptable salts and solvates by a conventional method known in the art.
[196] The acid addition salt formed by a pharmaceutically acceptable free acid thereof is useful. The acid addition salt is prepared by a conventional method, for example, a method in which a compound is dissolved in an excessive amount of an acid solution, and then a salt is precipitated in a water miscible organic solvent, such as methanol, ethanol, acetone and acetonitrile. Acid or alcohol (for example, glycol monomethylether) in the same molar amount of compound and water is heated and the mixture is evaporated and dried, or the precipitated salt can be subjected to suction filtration.
[197] At this time, as a free acid, an organic acid and inorganic acid can be used.
Examples of the inorganic acid include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and tartaric acid, and examples of the organic acid include methane- sulphonic acid, /?-toluenesulphonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, and hydroiodic acid, but not limited thereto.
[198] Further, a pharmaceutically acceptable metal salt can be prepared with a base. An alkali metal or alkaline earth metal salt can be obtained by the method, for example, a method comprising dissolving a compound in an excessive amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering undissolved salts, evaporating the residue, and then drying the filtrate. At this time, it is pharmaceutically acceptable that sodium, potassium or calcium salts are prepared as a metal salt, but not limited thereto. Further, the corresponding silver salts can be obtained by reacting alkali metal or alkaline earth metal salts with appropriate silver salts (e.g., silver nitrate). [199] Pharmaceutically acceptable salts of the compound of Formula 1, if it is not indicated specifically herein, contain an acidic or basic group in the compound of Formula 1. For example, the pharmaceutically acceptable salts include sodium, calcium, and potassium salts of a hydroxy group, and other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulphonate(mesylate), /?-toluenesulphonate (tosylate), which can be prepared by the preparation method or process known in the art.
[200] Further, since the compound of Formula 1 has an asymmetric center, it can be present in the form of the optically different enantiomers, and the scope of the invention comprises all of the optically active isomers and R or S type stereoisomers and the mixtures thereof. The present invention comprises a racemic mixture, one or more enantiomer, one or more diastereo isomer or the mixture thereof, and the isolation and preparation method of isomer known in the art.
[201]
[202] Further, the present invention provides a process for preparing a thienopyrimidine derivative of Formula 1. The thienopyrimidine derivative of Formula 1 is chemically prepared by the method described in the following Reaction Schemes, but not limited thereto. It will be understood that a thienopyrimidine derivative of Formula 1 of the present invention can be prepared by the various methods known in the art.
[203] The reaction schemes show the steps for preparing the representative compounds of the present invention, and other compounds may also be prepared by <Reaction Scheme 1> through <Reaction Scheme 9> with appropriate modifications of reagents, solvents and procedures. Some compounds of the present invention were prepared by the methods, which are not described in <Reaction Scheme 1> through <Reaction Scheme 9>, and the methods thereof are described in detail in each Example.
[204] [Reaction Scheme 1]
[205]
Figure imgf000020_0001
IV
Figure imgf000020_0002
VII
Figure imgf000020_0003
ViIi x xi
[206] wherein R , R , R and R are as defined in Formula 1.
1 3 4 5
[207] <Reaction Scheme 1> explains the process for preparing a compound (XI) consisting of seven steps using a ketone compound (I), which is commercially available or prepared by a method known in the art, as a starting material.
[208] At the first step, a ketone compound (I) is subjected to condensation reaction using a base such as malononitrile (II), acetate, ammonium acetate and benzylamine, or using an organic solvent such as benzene, toluene in the presence of 3-amino propionic acid to prepare a compound (III). In this step, the reaction is preferably carried out under heating.
[209] At the second step, the compound (III) prepared in the first step is reacted with sulfur(S) in the presence of a base such as pyridine, piperidine, triethylamine to prepare a thiazole compound (IV). At this time, as an organic solvent, an alcohol solvent such as ethanol, butanol, dioxane, tetrahydrofuran and the mixture thereof can be used and the reaction is performed at room temperature or under heating, preferably under heating.
[210] At the third step, the compound (IV) prepared in the second step is reacted with a nitrile compound (V) and a hydrochloric solution in a sealed tube or replaced with hydrochloric acid gas to prepare a compound (VI). At this time, the reaction is performed using dioxane, tetrahydrofuran or the like, as an organic solvent which does not adversely affect the reaction, under heating.
[211] At the fourth step, the amine compound (VI) prepared in the third step is converted to a chloro compound (VII), preferably which can be prepared by adding copper chloride in the presence of t-butylthionitrate, isoamyl nitrite or t-butyl nitrite or by adding sodium nitrite or potassium nitrite and then adding copper chloride in a hydrochloric solution. At this time, the reaction is performed using an aqueous solution, acetonitrile, dichloromethane, chloroform, dioxane, tetrahydrofuran or the like, as a sol vent which does not adversely affect the reaction. Further, the reaction is performed, but not limited thereto, under heating.
[212] At the fifth step, the chloro compound (VII) prepared in the fourth step is dissolved in an organic solvent, and then hydrazine hydrate is slowly added thereto to prepare a hydrazine compound (VIII). At this time, the reaction is performed using an aqueous solution, acetonitrile, tetrahydrofuran or the like, as a solvent which does not adversely affect the reaction. Further, the reaction is preferably performed, but not limited thereto, at room temperature or under heating.
[213] At the sixth step, the hydrazine compound (VIII) prepared in the fifth step is dissolved in an organic solvent, then reacted with citraconic anhydride to prepare a compound (X). At this time, the reaction is performed using chloroform, dichloromethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, diethylether or the like, as an organic solvent which does not adversely affect the reaction. Further, the reaction is preferably performed, but not limited thereto, at room temperature or under heating.
[214] In the seventh step, the compound (X) prepared in the sixth step is dissolved in 1,4-dioxane or diethylether, then hydrochloric acid is added thereto to prepare a compound (XI). Further, the reaction is preferably performed, but not limited thereto, at cold or room temperature.
[215] [Reaction Scheme 2] [216]
0 EtOOC^CN R1 n JL + NC-^-COOEt if
Q- NH2
XIV
Figure imgf000021_0001
XV VII
Figure imgf000021_0002
[217] wherein R , R , R and R are as defined in Formula 1.
1 3 4 5
[218] <Reaction Scheme 2> explains the process for preparing a compound (XI) consisting of 7 steps using a ketone compound (I), which is commercially available or prepared by the method known in the art, as a starting material.
[219] At the first step, a ketone compound (I) is subjected to condensation reaction using a base such as ethyl cyanoacetate (XII), acetate, ammonium acetate and benzylamine, or using an organic solvent such as benzene, toluene in the presence of 3-amino propionic acid to prepare a compound (XIII). In this time, the reaction is preferably performed at room temperature or under heating.
[220] At the next step, the compound (XIII) prepared in the first step is reacted under the same conditions as the second and third step of Reaction Scheme 1 to prepare a compound (XV).
[221] At the fourth step, the compound (XV) prepared in the third step is reacted in a phosphorous oxychloride solution to prepare a compound (VII). At this time, pen- tachlorophosphine or phenyldiethylamine may be added thereto to perform the reaction. The reaction can be performed without using any solvent or with a solvent, which does not adversely affect the reaction, such as dimethyl formamide. Further, the reaction is preferably performed, but not limited thereto, at room temperature or under heating.
[222] At the fifth, sixth and seventh step, the compound (VII) prepared in the fourth step is reacted under the same conditions as the fifth, sixth and seventh of Reaction Scheme 1 to prepare a compound (XI).
[223] [Reaction Scheme 3]
[224]
Figure imgf000022_0001
XVIII XIX
[225] wherein R , R , R and R are as defined in Formula 1.
2 3 4 5
[226] <Reaction Scheme 3> explains the process for preparing a compound (XIX) using a ketone compound (XVI), which is commercially available or prepared by the method known in the art, as a starting material.
[227] At the first step, a ketone compound (XVI) and ethyl cyanoacetate (XII) are dissolved in an organic solvent, sulfur(S) is added thereto, and reacted using a base such as diethylamine, morpholine and triethylamine, or under the condition of ethy- lammonium acetate and l-butyl-3-methylimidazoliumtetrabutylfluororate to prepare a compound (XVII). At this time, the reaction can be performed using alcohol, dimethyl- formamide, 1,4-dioxane, benzene, 2-methylpropan-2-ol and the mixture thereof, as a solvent which does not adversely affect the reaction. Further, the reaction is preferably performed, but not limited thereto, at room temperature or under heating.
[228] The next step is a step for preparing a compound (XIX) using the compound (XVII) prepared in the first step. The reactions are carried out under the same condition as Reaction Scheme 2 for converting a compound (XIV) to a compound (XI).
[229] [Reaction Scheme 4] [230]
Figure imgf000023_0001
(R8= CN, COOR) (R7= NH2, OH)
[231] wherein R 1 , R2 , R 4 and R 5 are as defined in Formula 1. [232] <Reaction Scheme 4> explains the process for preparing a compound (XXIII) using a compound (XX), which can be commercially available or prepared by the methods of Reaction Schemes 1, 2 and 3.
[233] At the first step, a compound (XX) is dissolved in formamide (XXI) and heated to prepare a compound (XXII). At the next step, in the case where R of the compound (XXII) is -NH , the reaction is performed under the same condition as Reaction Scheme 1 for converting a compound (VI) to a compound (XI), and in the case where R of the compound (XXII) is -OH, the reaction is preformed under the same condition as Reaction Scheme 2 for converting a compound (XV) to a compound (XI), to prepare a compound (XXIII).
[234] [Reaction Scheme 5] [235]
Figure imgf000023_0002
XXVII
[236] wherein R 2 , R 3 , R 4 and R 5 are as defined in Formula 1. [237] <Reaction Scheme 5> explains the process for preparing a compound (XXVIII) using a compound (XXIV), which is commercially available or prepared by the method known in the art.
[238] At the first step, a carboxylic acid compound (XXIV) is dissolved in tetrahydrofuran, and then reacted with N,N-dimethylformamide-dimethyl sulfonate complex (Dionisia Sanz, et al., J. Org. Chem, 67, 1462-1471, 2002) in the presence of lithium diisopropylamide (LDA) to prepare an enamine compound (XXV). At this time, the reaction can be performed using diethylether in addition to tetrahydrofuran as a solvent. Further, the reaction is generally performed at cold or room temperature.
[239] In the second step, the compound (XXV) prepared in the first step is reacted with methyl cyanoacetate (XII) under the same condition as the first step of Reaction Scheme 2 to prepare a compound (XXVI). At the next step, the reaction is performed with a compound (XXVI) under the same condition as Reaction Scheme 1 for converting a compound (XIV) to a compound (XI), to prepare a compound (XXVIII).
[240] [Reaction Scheme 6]
[241]
Figure imgf000024_0001
XXXIl
[242] wherein R , R , R , R and R are as defined in Formula 1.
1 2 3 4 5
[243] <Reaction Scheme 6> explains the process for preparing a compound (XXXIII) using a ketone compound (XXIX), which is commercially available or prepared by the method known in the art.
[244] At the first step, the ketone compound (XXIX) is reacted under the general bromination condition to prepare a compound (XXX). At this time, the bromination is preformed using bromine (Br ), tribromophosphine (PBr ), pyridinium tribromide, N- bromosuccinimide (NBS), copper (I) bromide, copper (II) bromide or the like and using an acid such as acetic acid, hydrobromic acid (HBr) or using triethylamine, ammonium acetate, urea or the like. At this time, the reaction can be performed using alcohol, water, dimethyl formamide, tetrahydrofuran, diethylether, chloroform, tetra- chloromethane, benzene, ethylacetate or the like, as a solvent which does not adversely affect the reaction. Further, the reaction is performed, but not limited thereto, at cold or room temperature or under heating.
[245] In the second step, the compound (XXX) prepared in the first step is reacted with malononitrile (II) using a base such as diethylamine, triethylamine, pyridine to prepare a compound (XXXI). At this time, the reaction can be performed using dimethyl formamide, tetrahydrofuran, chloroform, benzene or the like, as a solvent which does not adversely affect the reaction. Further, the reaction is performed, but not limited thereto, at room temperature or under heating. [246] At the next step, the reaction is performed with a compound (XXXI) under the same condition as Reaction Scheme 1 for converting a compound (IV) to a compound (XI), to prepare a compound (XXXIII). [247] [Reaction Scheme 7]
[248]
Figure imgf000025_0001
xxx x XxXxXiIvV xxxv
Figure imgf000025_0002
[249] wherein R , R , R , R and R are as defined in Formula 1.
1 2 3 4 5
[250] <Reaction Scheme 7> explains the process for preparing a compound (XXXII) using the compound (XXX) prepared in the first step of Reaction Scheme 6.
[251] At the first step, a compound (XXX) is reacted with ethyl cyanoacetate (XII) under the same condition as the first step of Reaction Scheme 6 to prepare a compound (XXXIV). At the next step, the reaction is performed with a compound (XXXIV) under the same condition as Reaction Scheme 2 for converting a compound (XIV) to a compound (XI), to prepare a compound (XXXII).
[252] [Reaction Scheme 8]
[253]
R A ° /OH — J
XXXVI XIl
Figure imgf000025_0003
XXXVIII
[254] wherein R , R , R and R are as defined in Formula 1.
1 3 4 5
[255] <Reaction Scheme 8> explains the process for preparing a compound (XXXIX) using a ketone compound (XXXVI), which is commercially available or prepared by the method known in the art.
[256] At the first step, a ketone compound (XXXVI) is reacted with malononitrile (II) or ethyl cyanoacetate (XII) using a base such as diethylamine, triethylamine, pyridine to prepare a compound (XXXVII) or a compound (XXXVIII). At this time, the reaction can be performed using methanol, ethanol or the like, as a solvent which does not adversely affect the reaction. Further, the reaction is performed, but not limited thereto, at room temperature or under heating.
[257] At the next step, a compound (XXXVII) is reacted under the same condition as
Reaction Scheme 1 for converting a compound (IV) to a compound (XI), or a compound (XXXVIII) is reacted under the same condition as Reaction Scheme 2 for converting a compound (XIV) to a compound (XI), to prepare a compound (XXXIX).
[258] [Reaction Scheme 9]
[259]
Figure imgf000026_0001
XL XLII
[260] wherein R , R and R are as defined in Formula 1, and X is O or S.
[261] <Reaction Scheme 9> explains the process for preparing a compound (XLII) by reacting a compound (XL) with a compound (XLI). The reaction is preformed under the same condition as Reaction Scheme 1 for converting a compound (VIII) to a compound (X).
[262]
[263] Further, the present invention provides a pharmaceutical composition for preventing and treating inflammatory diseases and cancers comprising a thienopyrimidine derivative of Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof.
[264] The inflammatory diseases include the pain caused by arthritis, for example, rheumatoid arthritis, spondyloarthopathies, gout, osteoarthritis, systemic lupus erythematosus and juvenile arthritis.
[265] The inflammatory diseases or symptoms include, for example, myositis, gingivitis, synovitis, ankylosing spondylitis, burstitis, septic shock, burns, and injury.
[266] In a specific embodiment, a pharmaceutical composition comprising the compound according to the present invention as an active ingredient is useful in treating inflammatory symptoms accompanied by diseases such as inflammatory bowel disease, Crohn's disease, Type I diabetes, and psoriasis, and in treating various types of cancer.
[267] In a preferred embodiment, the pharmaceutical composition comprising the compound of the present invention further includes suitable carriers, excipients or diluents according to the conventional methods.
[268] Examples of carriers, excipients, and diluents contained in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
[269] The composition comprising the compound of the present invention can be formulated, according to the conventional method, in the form of composition for the oral administrations such as powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, medicines for external applications, suppository or injection solutions.
[270] Specifically, a formulation can be prepared, according to the conventional method, using a diluent or an excipient such as a filler, an extender, a binding agent, a wetting agent, a disintegrating agent, and a surfactant. The solid preparation for oral administration includes tablet, pill, powder, granule, capsule, and can be prepared by mixing at least one of the excipient such as starch, calcium carbonate, sucrose, lactose, and gelatin. Further, in addition to a simple excipient, lubricants can be used such as magnesium stearate, talc. The liquid preparation for oral administration can include suspensions, liquid drugs, emulsions, and syrups, and include many excipients (e.g., wetting agent, sweetening agent, fragrant, preserving agent) other than commonly used simple diluents such as water, liquid paraffin. The preparation for parenteral administration contains sterilized solutions, non-aqueous solvents, suspensions, emulsifiers, freeze-drying agents or suppositories. The non-aqueous solvent or suspension solvent can include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyloleate. The basic material of suppository includes witepsol, macrogol, Tween 61, cacao paper, laurin paper, or glycerogelatin.
[271] The desirable dose of the compounds according to the present invention varies depending on the condition and the weight of the subject, severity, drug form, route and period of administration, and may be chosen by those skilled in the art. However, in order to obtain desirable effects, it is generally recommended to administer at the amount of 0.0001 to 500 mg/kg, preferably 0.01 to 300 mg/kg. The dose may be administered in single or several times per day. In terms of composition, the compounds having Formula 1 can be present 0.0001 to 50% by weight based on the total weight of the composition.
[272] Further, the compounds according to the present invention in pharmaceutical dosage forms may be used in the form of their pharmaceutically acceptable salts, and may also be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds. [273] The pharmaceutical composition of the present invention can be administered to a subject animal such as mammals (rat, mouse, domestic animals or human) through various routes. All modes of administration are contemplated, for example, administration can be made orally, rectally or by intravenous, intramuscular, subcutaneous, intrathecal, epidural or intracerebroventricular injection. Mode for the Invention
[274] Herein, the present invention will be described in more detail with reference to
Examples. Examples are provided only for the purpose of illustrating the present invention, and accordingly it is not intended that the present invention is limited thereto.
[275] Example 1 . 3-Methyl-l-(5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione
[276] Step 1. Preparation of 2-(l-thiophen-2-yl-ethylidene)-malononitrile
[277]
Figure imgf000028_0001
[278] 2-Acetylthiophene (500mg, 3.96mmol), malononitrile (300mg, 4.75mmol), ammonium acetate (915mg, 12mmol) and acetic acid (0.7ml, 12mmol) were dissolved in toluene (20ml). The reaction mixture was refluxed for 16 hours. After reaction, reaction mixture was poured into ethyl acetate, and washed with water and IM HCl aquous solution. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 5:1) to give 350mg (yield: 51%, brown oil) of the target compound.
[279] 1U NMR(400D, CDCI); δ 8.05(d, J=4.0Hz, IH), 7.80(d, J=4.8Hz, IH), 7.80(t, J
=4.4Hz, IH), 2.71 (s, 3H).
[280]
[281] Step 2. Preparation of 5'-amino-[2.3'1bithiophenlv-4'-carbonitrile
[282]
Figure imgf000028_0002
[283] The compound (300mg, 1.72mmol) prepared in the step 1 and sulfur (66mg,
2.06mmol) were dissolved in ethanol (20ml). Therein, piperidine (0.2mL, 2.06mmol) was added, and the reaction mixture was stirred at 8O0C for 5 hours. After reaction, reaction mixture was poured into ethyl acetate, and washed with water and saturated ammonium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 5:1) to give 230mg (yield: 65%, yellow oil) of the target compound.
[284] 1U NMR(400D, CDCI); δ 7.45(d, J=3.6Hz, IH), 7.26(d, J=4.4Hz, 2H), 7.05(dd, J
=3.6Hz, J=4.8Hz, IH), 4.92(s, 2H).
[285]
[286] Step 3. Preparation of 5-thiophen-2-yl-thieno[2.3-dlpyrimidin-4-ylamine
[287]
Figure imgf000029_0001
[288] The compound (lOOmg, 0.48mmol) prepared in the step 2 was dissolved in formamide (3ml). The reaction mixture was stirred at 18O0C for 18 hours. After reaction, the reaction mixture was poured into ethyl acetate, and washed with water and saturated sodium hydrogen carbonate aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 1:2) to give 40mg (yield: 35%, white solid) of the target compound.
[289] 1U NMR(400D, CDCI); δ 8.44(s, IH), 7.43(t, J=3.6Hz, IH), 7.26(s, IH), 7.15(d, J
=3.2Hz, 2H), 5.77(br, 2H).
[290]
[291] Step 4. Preparation of 4-chloro-5-thiophen-2-yl-thienor2.3-dlpyrimidine
[292]
Figure imgf000029_0002
[293] Copper chloride (69mg, 0.51mmol) and ?-butyl nitrite (76D, 0.64mmol) were dissolved in acetonitrile (5ml). The reaction mixture was stirred at 7O0C for 30 minutes. Therein, the compound (lOOmg, 0.43mmol) prepared in the step 3 which was dissolved in THF (2ml) was slowly added, and the reaction mixture was stirred at the same temperature for 2 hours. Thereafter, the reaction mixture was cooled at room temperature, and poured into ethyl acetate(lθml) and washed with water and sodium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 51:1) to give 62mg (yield: 57%, white solid) of the target compound. [294] 1U NMR(400D, CDCI); δ 8.88(s, IH), 7.62(s, IH), 7.43(d, IH, J=4.8Hz), 7.15(d, J
=4.0Hz, IH), 7.12(dd, J=3.2Hz, J=5.2Hz, IH). [295] [296] Step 5. Preparation of 3-methyl-l-(5-thiophen-2-yl-thieno[2.3-d1 pyrimidin-
4-ylaminos)-pyrrole-2.5-dione [297]
Figure imgf000030_0001
[298] The compound (70mg, 0.28mmol) prepared in the step 4 was dissolved in THF
(5ml). Therein, hydrazine monohydrate (27D, 0.56mmol) was slowly added, and the reaction mixture was stirred at 8O0C for 4 hours. After reaction, the solvent was removed under reduced pressure, and dried in vacuum drier. The residue was dissolved in chloroform, therein citraconic anhydride (75D, 0.84mmol) was slowly added, and the reaction mixture was stirred at 8O0C for 20 hours. The reaction mixture was washed with water and saturated sodium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 1:1) to give 51mg (yield: 54%, white solid) of the target compound.
[299] 1U NMR(400D, CDCI); δ 8.50(s, IH), 7.43(d, J=4.8Hz, IH), 7.38(s, IH), 7.34(d, J
=4.0Hz, IH), 7.14(m, 2H), 6.49(s, IH), 2.16(d, J=1.6Hz, 3H).
[300]
[301] Example 2 . 3,4-dichloro-l-(5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride
[302]
Figure imgf000030_0002
[303] Step 1. Preparation of 3.4-dichloro-l-(5-thiophen-2-yl-thieno[2.3-d1 pyrimidin-
4-ylaminos)-pyrrole-2-5-dione
[304] According to the similar procedure in the step 5 of example 1 by using the compound prepared in the step 4 of example 1 and 3,4-dichlorofuran-2-5-dione, 27mg (yield for 2 steps: 34%, yellow solid) of the target compound was obtained. [305] 1U NMR(400D, CDCI); δ 8.54(s, IH), 7.47(d, J=5.2Hz, IH), 7.43(s, IH), 7.33(d, J
=3.2Hz, IH), 7.20-7.18(m, 2H). [306] [307] Step 2. Preparation of 3.4-dichloro-l-(5-thiophen-2-yl-thieno[2.3-dl pyrimidin-
4- ylamino)-pyrrole-2-5-dione hydrochloride [308] The compound (27mg, 0.068mmol) prepared in the step 1 was dissolved in 4N HCl
1,4-dioxane solution, and the reaction mixture was stirred at room temperature for 18 hours. After reaction, the reaction mixture was filtered to give 12mg (yield: 41%, yellow solid) of the target compound. [309] 1U NMR(400D, DMSO-d): δ 8.45(s, IH), 8.32(s, IH), 7.84(s, IH), 7.67-7.66(m,
IH), 7.34-7.33(m, IH), 7.18-7.16(m, IH). [310] [311] Compounds listed below were prepared by the similar procedure in above Example
1 and Example 2. [312] Example 3 . 2-(5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-isoindole-l,3-dione hydrochloride [313] Example 4 . 2-(5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrolo[3,4-c]pyridine-l,3-dione hydrochloride [314] Example 5 . 3-methyl-l-(5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2-5-dione hydrochloride [315] Example 6 . l-(5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride [316] [Table 1]
[317]
Figure imgf000032_0001
[318] [319] Example 7 . l-(2,6-di-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride
[320] Step 1. Preparation of dimethyl-(2-thiophen-2-yl-vinviy amine [321]
0
//
OH
[322] 2-thiopheneacetic acid (500mg, 3.51mmol) w cas dissolvedN i'n THF (20ml). Thereafter, the temperature was lowered into O0C. Therein, 1.8M lithium diisopro pylamide (LDA) in heptane solution was slowly added over 30 minutes, and the reaction mixture was stirred at O0C for 1 hour. After reaction, the solvent was removed under reduced pressure. The residue was dissolved in THF (20ml) and the temperature was lowered into -7O0C, therein N,N-dimethylformamide-dimethylsulfonate complex (2.41ml, 14.0mmol: Dionisia Sanz, et al. J. Org. Chem. 2002, 67, 1462-1471) was slowly added, and the reaction mixture was stirred at room temperature for 1 hour. After reaction, the solvent was concentrated under reduced pressure to give 344mg (yield: 64%, colorless oil) of the target compound.
[323] 1U NMR(400D, CDCD; δ 6.84(m, 2H), 6.65(d, J=14.0Hz, IH), 6.61(d, J=2.8Hz, IH), 5.35(d, J=14.0Hz, IH), 2.76(s, 6H).
[324] [325] Step 2. Preparation of 5-amino-r2.2'lbithiophenlv-4-carboxylic acid methyl ester [326]
Figure imgf000033_0001
[327] The compound (300mg, 1.95mmol) prepared in the step 1, methyl cyanoacetate
(0.19ml, 2.14mmol) and sulfur (66mg, 2.06mmol) were dissolved in ethanol (20ml). Therein, morpholine (57D, 0.58mmol) was slowly added, and the reaction mixture was stirred at 8O0C for 5 hours. After reaction, the reaction mixture was poured into ethyl acetate, and washed with water and saturated ammonium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 5:1) to give 230mg (yield: 65%, yellow solid) of the target compound.
[328] 1U NMR(400D, CDCI); δ 8.50(m, 2H), 7.49(s, IH), 7.28(m, 2H), 6.24(s, 2H),
3.85(s, 3H).
[329]
[330] Step 3. Preparation of 2.6-di-thiophen-2-yl-thienor2.3-dlpyrimidin-4-ol
[331]
Figure imgf000033_0002
[332] The compound (lOOmg, 0.48mmol) prepared in the step 2 and 2-thiophene car- bonitrile (0.058ml, 0.62mmol) were dissolved in 3.6M HCl 1,4-dioxane solution(6ml). The reaction mixture was stirred at 11O0C for 36 hours. After reaction, reaction mixture was poured into ethyl acetate, and washed with water and saturated sodium hydrogen carbonate aqueous solution. Combined organic layer was concentrated under reduced pressure to give 67mg (yield: 51%, brown solid) of the target compound.
[333] 1U NMR(400D, CDCI) δ 8.23(d, J=2.8Hz, IH), 7.80(d, J=4.8Hz, IH), 7.62(d, J
=4.8Hz), IH, 7.53(s, IH), 7.46(d, J=3.6Hz, IH), 7.23(dd, J=4.0Hz, J=4.8Hz, IH), 7.23(dd, J=3.6Hz, J=5.2Hz, IH).
[334]
[335] Step 4. Preparation of 4-chloro-2.6-di-thiophen-2-yl-thoeno[2.3-dlpyrimidine
[336]
Figure imgf000033_0003
[337] The compound (67mg, 0.21mmol) prepared in the step 3 was dissolved in phospho- rousoxy chloride (POCl , 3ml). Thereafter, the reaction mixture was stirred at 1000C for 2 hours. After reaction, the reaction mixture was poured into ice water and ethyl acetate was added. The organic layer was washed with water and saturated sodium hydrogen carbonate aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 2:1) to give 55mg (yield: 80%, white solid) of the target compound.
[338] 1U NMR(400D, CDCI) δ 7.99(d, J=3.6Hz, IH), 7.85(d, J=4.8Hz, IH), 7.78(d, J
=4.8Hz, IH), 7.68(d, J=3.6Hz, IH), 7.64(s, IH), 7.23(m, 2H).
[339]
[340] Step 5. Preparation of l-(2.6-di-thiophen-2-yl-thienor2.3-dl pyrimidin-
4-ylaminoV3-methyl-pyrrole-2.5-dione
[341]
Figure imgf000034_0001
[342] The compound (55mg, 0. lβmmol) prepared in the step 4 was dissolved in THF
(5ml). Therein, hydrazine monohydrate (23D, 0.48mmol) was slowly added, and the reaction mixture was stirred at 8O0C for 10 hours. After reaction, the solvent was removed under reduced pressure, and dried in vacuum drier. The residue was dissolved in chloroform(5ml), therein citraconic anhydride (43D, 0.48mmol) was slowly added, and the reaction mixture was stirred at 8O0C for 20 hours. The reaction mixture was washed with water and saturated sodium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 1:1) to give 37mg (yield: 54%, white solid) of the target compound.
[343] 1U NMR(400D, CDCI); δ 10.73(s, IH), 7.81(s, IH), 7.70(s, IH), 7.70(d, J=4.0Hz,
2H), 7.46(dd, J=LlBz, J=3.6Hz, IH), 7.20(dd, J=4.0Hz, J=5.2Hz, IH), 7.14(t, J =4.4Hz, IH), 7.02(d, J=2.0Hz, IH), 2.07(s, 3H).
[344]
[345] Step 6. Preparation of l-(2.6-di-thiophen-2-yl-thieno[2.3-dl pyrimidin-
4- ylamino)-3-methyl-pyrrole-2.5-dione hydrochloride
[346]
Figure imgf000035_0001
[347] The compound (37mg, 0.087mmol) prepared in the step 5 was dissolved in 4N HCl 1,4-dioxane (0.5ml) and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered to give 35mg (yield: 88%, white solid) of the target compound.
[348] 1U NMR(400D, DMSO-d); δ 10.80(s, IH), 7.86(s, IH), 7.70(s, IH), 7.70(d, J =4.4Hz, 2H), 7.46(dd, J=1.2Hz, J=3.6Hz, IH), 7.18(dd, J=4.0Hz, J=5.2Hz, IH), 7.14(t, J=4.4Hz, IH), 7.00(d, J=2.0Hz, IH), 2.17(s, 3H).
[349] [350] Example 8 (method 1) . l-(2,5-di-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride
[351] Step 1. Preparation of 2- (l-thophen-2-yl-ethylidene)-malononitrile [352]
Figure imgf000035_0002
[353] 2-Acetylthiophene (2Og, O.lβmol), malononitrile (12.6g, 0.19mol), ammonium acetate (36.6g, 0.48mol) and acetic acid (27.2ml, 0.48mol) were dissolved in toluene (120ml). The reaction mixture was refluxed for 18 hours. After reaction, the reaction mixture was poured into ethyl acetate, and washed with water and IN HCl aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 3:1) to give 20.8g (yield: 75%, brown solid) of the target compound.
[354] 1U NMR(400D, CDCI); δ 8.05(d, J=4.0Hz, IH), 7.80(d, J=4.8Hz, IH), 7.80(t, J =4.4Hz, IH), 2.71 (s, 3H).
[355] [356] Step 2. Preparation of 5'-amino-[2.3'1bithiophenlv-4'-carbonitrile [357]
Figure imgf000035_0003
[358] The compound (20.8g, 0.12mol) prepared in the step 1 and sulfur (4.6g, 0.14mol) were dissolved in ethanol (60ml). Therein, piperidine (14.1ml, 0.146mol) was slowly added, and the reaction mixture was stirred at 8O0C for 16 hours. After reaction, reaction mixture was poured into ethyl acetate, and washed with water and saturated ammonium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 5:1) to give 14.4g (yield: 60%, yellow oil) of the target compound.
[359] 1U NMR(400D, CDCI); δ 7.45(d, J=3.6Hz, IH), 7.26(d, J=4.4Hz, 2H), 7.05(dd, J
=3.6Hz, J=4.8Hz, IH), 4.92(br, 2H).
[360]
[361] Step 3. Preparation of 2.5-di-thiophen-2-yl-thienor2.3-dlpyrimidin-4-ylamine
[362]
Figure imgf000036_0001
[363] The compound (300mg, 1.45mmol) prepared in the step 2 and 2-thiophene car- bonitrile (162D, 1.75mmol) were dissolved in 4N HCl 1,4-dioxane solution (6ml). The reaction mixture was stirred at 11O0C for 24 hours. After reaction, reaction mixture was poured into ethyl acetate, and washed with water and saturated sodium hydrogen carbonate aqueous solution. Combined organic layer was concentrated under reduced pressure to give 256mg (yield: 56%, brown solid) of the target compound.
[364] 1H NMR(400D, CDCI); δ 7.95(s, IH), 7.41(t, J=3.6Hz, IH), 7.13(m, 4H), 5.49(br,
2H).
[365]
[366] Step 4. Preparation of 4-chloro-2.5-di-thiophen-2-yl-thienor2.3-dlpyrimidine
[367]
Figure imgf000036_0002
[368] Copper chloride (CuCl, 174mg, 1.29mmol) and t-butyl nitrite (192D, 1.624mmol) were dissolved in acetonitrile (5ml). The reaction mixture was stirred at 7O0C for 30 minutes. Therein, the compound (340mg, 1.08mmol) prepared in the step 3 which was dissolved in THF (2ml) was slowly added, and the reaction mixture was stirred at the same temperature for 3 hours. Thereafter, the reaction mixture was cooled at room temperature, and poured into ethyl acetate, and washed with water and brine. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 3:1) to give 75mg (yield: 21%, white oil) of the target compound. [369] 1U NMR(400D, CDCI); δ 8.06(d, J=4.0Hz, IH), 7.50(d, J=5.6Hz, IH), 7.46(s, IH),
7.40(d, J=5.6Hz, IH), 7.16(m, 2H), 7.12(dd, IH, J=3.2Hz, J=5.2Hz). [370] [371] Step 5. Preparation of l-(2.5-di-thiophen-2-yl-thieno[2.3-dl pyrimidin-
4-ylamino)-3-methyl-pyrrole-2.5-dione [372]
Figure imgf000037_0001
[373] The compound (75mg, 0.22mmol) prepared in the step 4 was dissolved in THF (3ml). Therein, hydrazine monohydrate (33D, 0.67mmol) was slowly added, and the reaction mixture was stirred at 8O0C for 4 hours. After reaction, the solvent was removed under reduced pressure, and dried in vacuum drier. The residue was dissolved in chloroform, therein, citraconic anhydride (65D, 0.67mmol) was slowly added, and the reaction mixture was stirred at 8O0C for 18 hours. The reaction mixture was washed with water and saturated sodium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 2:1) to give 46mg (yield: 48%, yellow solid) of the target compound.
[374] 1U NMR(400D, CDCD; δ 7.80(d, J=4.0Hz, IH), 7.45(d, J=4.8Hz, IH), 7.38(m, 2H), 7.30(s, IH), 7.18(m, IH), 7.14(br, 12H), 7.07 (dd, J=4.0Hz, J=5.2Hz, IH), 6.59(d, J=1.6Hz, IH), 2.23(s, IH).
[375] [376] Step 6. Preparation of l-(2.5-di-thiophen-2-yl-thieno[2.3-dl pyrimidin- 4- ylamino)-3-methyl-pyrrole-2.5-dione hydrochloride
[377]
l
Figure imgf000037_0002
[378] The compound (30mg, 0.071mmol) prepared in the step 5 was dissolved in 4N HCl 1,4-dioxane solution and the reaction mixture was stirred at room temperature for 18 hours. The resulting solid in the reaction mixture was filtered to give 29mg (yield: 89%, yellow solid) of the target compound. [379] 1H NMR(400D, DMSO-d); δ 8.68(s, IH), 7.75(s, IH), 7.69(m, 3H), 7.30(d, J
=3.6Hz, IH), 7.20(t, J=4.0Hz, IH), 7.14(t, J=4.8Hz, IH), 6.93(s, IH), 2.12(s, 3H). [380] [381] Example 8 (method 2) . l-(2,5-di-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride
[382] Step 1. Preparation of 2-cvano-3-thiophen-2-yl-but-2-enoic acid methyl ester
[383]
Figure imgf000038_0001
[384] 2-Acetylthiophene (Ig, 7.92mmol), methyl cyanoacetate (0.836ml, 9.51mmol), ammonium acetate (1.8g, 23.77mmol) and acetic acid (1.36ml, 23.77mmol) were dissolved in toluene (20ml). The reaction mixture was refluxed for 16 hours. After reaction, the reaction mixture was poured into ethyl acetate, and washed with water and IN HCl aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 5:1) to give 812mg (yield: 53%, yellow oil) of the target compound.
[385] 1U NMR(400D, CDCI); δ 8.03(d, J=4.0Hz, IH), 7.80(d, J=4.8Hz, IH), 7.78(t, J
=4.4Hz, IH), 3.88(s, 3H) 2.71(s, 3H).
[386]
[387] Step 2. Preparation of 5'-amino-r2.3'lbithiophenly-4'-carboxylic acid methyl ester
[388]
Figure imgf000038_0002
[389] The compound (250mg, 1.21mmol) prepared in the step 1 and sulfur (46.4mg,
1.45mmol) were dissolved in ethanol (10ml). Therein, piperidine (143D, 1.45mmol) was added, and the reaction mixture was stirred at 8O0C for 18 hours. After reaction, the reaction mixture was poured into ethyl acetate, and washed with water and saturated ammonium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 5:1) to give 88mg (yield: 31%, yellow solid) of the target compound.
[390] 1U NMR(400D, CDCI); δ 7.25(d, J=3.6Hz, IH), 7.01 (m, 2H), 6.22(s, IH), 6.1 l(s,
2H), 3.67(s, 3H). [391]
[392] Step 3. Preparation of 2.5-di-thiophen-2-yl-thienor2.3-dlpyrimidin-4-ol
[393]
Figure imgf000039_0001
[394] The compound (lOOmg, 0.48mmol) prepared in the step 2 and 2-thiophene car- bonitrile (58D, 0.62mmol) were dissolved in 3.6M HCl 1,4-dioxane solution (6ml). The reaction mixture was stirred at 11O0C for 36 hours. After reaction, the reaction mixture was poured into ethyl acetate, and washed with water and saturated sodium hydrogen- carbonate aqueous solution. Combined organic layer was concentrated under reduced pressure to give 67mg (yield: 51%, brown solid) of the target compound.
[395] 1U NMR(400D, DMSO-d); δ 8.19(d, J=4.4Hz, IH), 7.84(d, J=5.2Hz, IH), 7.7 l(d, J
=3.6Hz, IH), 7.51(m, 2H), 7.22(m, IH), 7.10(m, IH).
[396]
[397] Step 4. Preparation of 4-chloro-2.5-di-thiophen-2-yl-thienor2.3-dlpyrimidine
[398]
Figure imgf000039_0002
[399] The compound (272mg, 0.861mmol) prepared in the step 3 was dissolved in phos- phorousoxychloride (3ml). Thereafter, the reaction mixture was stirred at 1000C for 2 hours. After reaction, the reaction mixture was poured into ice water and ethyl acetate, and washed with water and saturated sodium hydrogen carbonate aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 2:1) to give 234mg (yield: 81%, yellow solid) of the target compound.
[400] 1U NMR(400D, CDCI); δ 8.06(d, J=4.0Hz, IH), 7.50(d, J=5.6Hz, IH), 7.46(s, IH),
7.40(d, J=5.6Hz, IH), 7.16(m, 2H), 7.12(dd, J=3.2Hz, J=5.2Hz, IH).
[401]
[402] Step 5. Preparation of l-(2.5-di-thiophen-2-yl-thienor2.3-dl pyrimidin-
4-ylaminoV3-methyl-pyrrole-2.5-dione hydrochloride
[403]
Figure imgf000040_0001
[404] According to the similar procedure in the step 5 and step 6 of example 8 (method 1) by using the compound prepared in the step 4, the target compound was obtained. [405] [406] Compounds listed below were prepared by the similar procedure in above Example
8 (method 1) [407] Example 9 .
3-methyl-l-[2-(5-methyl-thiophen-2-yl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4- ylamino] -pyrrole-2,5-dione hydrochloride [408] Example 10 . l-[5-(4-methoxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [409] Example 11 . l-[5-(4-hydroxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride
[410] Example 12 . (2,5-di-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-hydrazine hydrochloride [411] Example 13 . 3-methyl-l-(2-pyridin-4-yl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride [412] Example 14 . l-[2-(4-methoxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [413] Example 15 . 3-methyl-l-(5-thiophen-2-yl-2-p-tolyl-thieno[2,3-d] pyrimidine-
4-ylamino)-pyrrole-2,5-dione hydrochloride [414] Example 16 . 3-methyl-l-(5-thiophen-2-yl-2-thiophen-2-ylmethyl-thieno[2,3-d] pyrimidine-4-ylamino)-pyrrole-2,5-dione hydrochloride [415] [Table 2]
[416]
Figure imgf000041_0001
[417] [418] Intermediate (!) : Preparation of 4-chloro-2-(5-methyl-thiophen-2-yl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidine
[419] Step 1. Preparation of 2-(5-methyl-thiophen-2-ylV5-thiophen-2-v1-thienor2.3-dl Dyrimidin-4-ylamine [420]
Figure imgf000042_0001
[421] According to the similar procedure in the step 3 of example 8 (method 1) by using the 5'-amino-[2,3']bithiophenyl-4'-carbonitrile (490mg, 2.4mmol) prepared in the step 2 of example 8(method 1) and 5-methyl-thiophen-2-carbonitrile (402mg, 2.8mmol), 505mg (yield: 65%, yellow solid) of the target compound was obtained.
[422] 1U NMR(400D, CDCI): δ 7.71(d, J=4.8Hz, IH), 7.66(d, J=3.2Hz, IH), 7.55(s, IH),
7.26(d, J=3.2Hz, IH), 7.22(m, IH), 6.85(d, J=3.6Hz, IH), 2.47(s, 3H).
[423]
[424] Step 2. Preparation of
4-chloro-2-(5-methyl-thiophen-2-yl)-5-thiophen-2-yl-theno[2.3-dlpyrimidine
[425]
Figure imgf000042_0002
[426] According to the similar procedure in the step 4 of example 8 (method 1) by using the compound (500mg, 4.52mmol) prepared in the step 1, 200mg (yield: 39%, yellow solid) of the target compound was obtained. [427] 1U NMR(400D, CDCI): δ 7.89(d, J=4.0Hz, IH), 7.44(s, IH), 7.42(m, IH), 7.16(m,
IH), 7.12(dd, IH, J=3.6Hz, J=5.2Hz), 6.83(m, IH), 3.80(s, 3H). [428] [429] Intermediate (D : Preparation of
4-chloro-5-(4-methoxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidine [430]
Figure imgf000042_0003
[431] According to the similar procedure in the step 1 to step 4 of example 8 (method 1) by using 4-methoxy acetophenone, 700mg (yield for final step: 53%, brown solid) of the target compound was obtained. [432] 1U NMR(400D, CDCI): δ 8.09(m, IH), 7.51(m, IH), 7.35(d, J=8.8Hz, 2H), 7.29(s,
IH), 7.16(m, IH), 6.97 (d, J=8.8Hz, 2H), 3.87(s, 3H). [433] [434] Intermediate (3) : Preparation of 4-(4-chloro-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-5-yl)-phenol [435]
Figure imgf000043_0001
[436] 4-chloro-5-(4-methoxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidine(590mg,
1.32mmol) prepared in intermediate (2) was dissolved in dichloromethane (10ml). Therein IM boron tribromide dichloromethane solution (8ml) was slowly added, and the reaction mixture was stirred at room temperature for 2 hours. After reaction, the reaction mixture was poured into ethyl acetate, and washed with water and saturated sodium hydrogen carbonate aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 2:1) to give 483mg (yield: 73 %, brown solid) of the target compound.
[437] 1U NMR(400D, CDCI): δ 8.02(m, IH), 7.51(m, IH), 7.33(d, J=8.0Hz, 2H), 7.29(s,
IH), 7.21(m, IH), 6.88(d, J=8.8Hz, 2H).
[438]
[439] Intermediate (4) : Preparation of
4-chloro-2-pyridin-4-yl-5-thiophen-2-yl-thieno[2,3-d]pyrimidine
[440]
Figure imgf000043_0002
[441] According to the similar procedure in the step 3 and 4 of example 8 (method 1) by using the compound prepared in the step 2 of example 8 (method 1) and 4-cyanopyridine, 21mg (yield: 16%, yellow solid) of the target compound was obtained.
[442] 1U NMR(400D, CDCI): δ 8.08(br s, 2H), 8.38~8.34(m, 2H), 7.67(s, IH),
7.47~7.45(m, IH), 7.21-7.19(m, IH), 7.16~7.14(m, IH).
[443]
[444] Intermediate (5) : Preparation of 4-chloro-2,5-di-thiophen-2-yl-thieno[2,3-d] pyrimidine
[445]
Figure imgf000044_0001
[446] According to the similar procedure in the step 3 and 4 of example 8 (method 1) by using 5'-amino-[2,3']bithiophenyl-4'-carbonitrile prepared in the step 2 of example 8 (method 1) and 4-methoxybenzonitrlie, 130mg (yield: 17%, dark brown solid) of the target compound was obtained.
[447] 1U NMR(400D, CDCI); δ 8.48(d, J=8.8Hz, 2H), 7.49(s, IH), 7.43(d, J=5.2Hz, IH),
7.18(d, J=5.2Hz, IH), 7.13(dd, J=2.8Hz, 5.2Hz, IH) 7.01(d, J=8.8Hz, 2H), 3.90(s, 3H).
[448]
[449] Intermediate (6) : Preparation of
4-chloro-5-thiophen-2-yl-2-p-tolyl-thieno[2,3-d]-pyrimidine
[450]
Figure imgf000044_0002
[451] According to the similar procedure in the step 3 and 4 of example 8 (method 1) by using the compound prepared in the step 2 of example 8 (method 1) and 4-tolunitrile, 45mg (yield for 2 steps: 7%, white solid) of the target compound was obtained.
[452] 1U NMR(400D, CDCI); δ 8.21(d, J=8.0Hz, 2H), 7.45(dd, J=1.2Hz, J=4.8Hz, IH),
7.28(d, J=8.0Hz, 2H), 7.23(s, IH), 7.16(m, 2H), 2.41(s, 3H).
[453]
[454] Intermediate (7) : Preparation of
4-chloro-5-thiophen-2-yl-2-thiophen-2-ylmethyl-thieno[2,3-d]-pyrimidine
[455]
Figure imgf000044_0003
[456] According to the similar procedure in the step 3 and 4 of example 8(method 1) by using the 5'-amino-[2,3']bithiophenyl-4'-carbonitrile prepared in the step 2 of example 8 (method 1) and 2-thiophenacetonitrile, 50mg (yield for 2 steps: 10%, brown oil) of the target compound was obtained.
[457] 1U NMR(400D, CDCI); δ 7.53(s, IH), 7.41(d, J=5.2Hz, IH), 7.19(d, J=5.2Hz, IH), 7.14-7.09(m, 2H), 7.03(d, J=3.2Hz, IH), 6.95(t, J=4.0Hz, IH), 4.55(s, 2H). [458] [459] Compounds listed below were prepared by the similar procedure in above Example
8 (method 2). [460] Example 17 . 3-methyl-l-(2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride [461] Example 18 . 3-methyl-l-(5-methyl-thieno[2,3-d] pyrimidin-
4-ylamino)pyrrole-2,5-dione hydrochloride [462] Example 19 . l-(2-benzyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride [463] Example 20 . 3-methyl-l-(5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride [464] Example 21 . 3-methyl-l-(2-phenyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione [465] Example 22 . 3-methyl-l-(2-phenyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride [466] Example 23 . l-[2-(4-hydroxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [467] Example 24 . l-[2-(-4-fluoro-phenyl)-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [468] Example 25 . l-[2-(3-fluoro-phenyl)-5-thiophen-2-yl-theno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [469] Example 26 . 3-methyl-l-(2-thiophen-3-yl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride [470] Example 27 . 3-methyl-l-(2-thiophen-2-yl-5-thiophen-3-yl-thieno[2,3-d] pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride [471] Example 28 . 3-methyl-l-(5-thiophen-2-yl-2-thiophen-3-ylmethyl-thieno[2,3-d] pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride [472] Example 29 . 3-methyl-l-(5-phenyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride [473] Example 30 . 3-methyl-l-(2-thiophen-2-yl-5-p-tolyl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride [474] Example 31 . l-[2-(4-methoxy-benzyl)-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino]3-methyl-pyrrole-2,5-dione hydrochloride [475] Example 32 . l-[2-(4-diethylaminophenyl)-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride
[476] Example 33 . l-[2-(3-hydroxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [477] Example 34 . l-[2-(4-methoxy-phenyl)-5-phenyl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [478] Example 35 . l-[2-(3-methoxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [479] Example 36 . l-[2-(3-methoxy-phenyl)-5-phenyl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [480] Example 37 . l-[2-(3-fluoro-phenyl)-5-phenyl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [481] Example 38 . l-[2-(3-methoxy-benzyl)-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [482] Example 39 .
4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen-2-yl-thieno[2,3-d
]pyrimidine-5-carboxylic acid ethyl ester hydrochloride [483] Example 40 . l-[5-(3-hydroxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [484] Example 41 . l-[5-(3-methoxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [485] Example 42 . l-[2-(4-dimethylamino-phenyl)-5-phenyl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [486] Example 43 . l-[2-(4-amino-phenyl)-5-phenyl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [487] Example 44 . l-(2-furan-2-yl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride [488] Example 45 . 3-methyl-l-(2-methyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)pyrrole-2,5-dione hydrochloride [489] Example 46 . l-[2-(4-amino-phenyl)-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [490] Example 47 . l-(2-amino-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride [491] Example 48 . l-(2-cyclopropyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-l,5-dione [492] Example 49 .
[4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen-2-yl-thieno[2,3- d]pyrimidin-5-yl]-acetic acid methyl ester hydrochloride [493] Example 50 . l-(5-hydroxymethyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride [494] Example 51 . l-(5-methoxymethyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride [495] [Table 3] [496]
Figure imgf000047_0001
[497]
Figure imgf000048_0001
[498]
Figure imgf000049_0001
[499]
Figure imgf000050_0001
[500]
[501] Intermediate (H) : Preparation of 4-chloro-2-thiophen-2-yl-thieno[2,3-d] pyrimidine
[502]
Figure imgf000050_0002
[503] According to the similar procedure in the step 3 and 4 of example 8(method 2) by using methyl^-aminothiophen-S-carboxylate (315mg, 2.0mmol), 347 mg (yield for final step: 96%, brown solid) of the target compound was obtained.
[504] 1U NMR(400D, DMSO-d): δ 8.03 (m, 2H), 7.86 (m, IH), 7.55 (t, J=4.4Hz, IH),
7.24(m, IH).
[505]
[506] Intermediate (9) : Preparation of 4-chloro-5-methyl-thieno[2,3-d]pyrimidine
[507] Step 1. Preparation of 5-methyl-thieno[2.3-dlpyrimidin-4-ol
[508]
Figure imgf000051_0001
[509] 2-amino-4-methyl-thiophen-3-carboxylic acid ethyl ester (2g, 10.6mmol) was dissolved in formamide (10ml). The reaction mixture was stirred at 18O0C for 12 hours. After reaction, the reaction mixture was poured into ethyl acetate, and washed with water and saturated sodium hydrogen chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.4g (yield: 79%, pale yellow solid) of the target compound.
[510]
[511] Step 2. Preparation of 4-chloro-5-methyl-thienor2.3-dlpyrimidine
[512]
Figure imgf000051_0002
[513] The compound, 5-methyl-thieno[2,3-d]pyrimidin-4-ol, (1.4g, 8.42mmol) prepared in the step 1 was dissolved in phosphorusoxy chloride (5ml). Thereafter, the reaction mixture was stirred at 11O0C for 1 hour. After reaction, the reaction mixture was poured into ice water and chloroform, and washed with water and saturated sodium hydrogen carbonate aqueous solution. Combined organic layer was concentrated under reduced pressure. The residue was purified by recrystallization (n-hexane and ethyl acetate) to give 590mg (yield: 39%, yellow solid) of the target compound.
[514] 1U NMR(400D, CDCI): δ 8.81 (s, IH), 7.24 (s, IH), 2.70 (s, 3H).
[515]
[516] Intermediate (10) : Preparation of l-benzvM-chloro-S-thiophen-l-yl-thienori.S-dlpyrimidine
[517] Step 1. Preparation of 5'-amino-[2.3'lbithiophenyl-4'-carboxylic acid methyl ester
[518] e
Figure imgf000052_0001
[519] The compound (lOOmg, 0.48mmol) prepared in the step 2 of example 8(method 2) was refluxed in catalyst amount of cone, sulfuric acid and methanol (5ml) to give
21mg (yield: 46%, colorless solid) of the target compound. [520] 1U NMR(400D, CDCI); δ 7.25(d, J=3.6Hz, IH), 7.01 (m, 2H), 6.22(s, IH), 6.1 l(s,
2H), 3.67(s, 3H). [521]
[522] Step 2. Preparation of 2-benzyl-4-chloro-5-thiophen-2-yl-thieno[2.3-dlpyrimidine
[523]
Figure imgf000052_0002
[524] According to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the compound prepared in the step 1 and benzyl cyanide (0.14ml, 1.25mmol), 26mg (yield for final step: 23%, yellow oil) of the target compound was obtained.
[525] 1H-NMR^OOD, CDCI) δ 7.50(s, IH), 7.44~7.40(m, 3H), 7.33~7.21(m, 3H),
7.13~7.08(m, 2H), 4.36(s, 2H)
[526]
[527] Intermediate (11) : Preparation of
4-chloro-2-phenyl-5-thiophen-2-yl-thieno[2,3-d]pyrimidine
[528]
Figure imgf000052_0003
[529] According to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the compound, 5'-amino-[2,3']bithiophenyl-4'-carboxylic acid methyl ester, (190mg, 0.79mmol), prepared in the step 2 of example 8 and benzonitrile (240D, 2.38mmol), 140mg (yield for 2 steps: 55%, light yellow solid) of the target compound was obtained.
[530] 1U NMR(400D, CDCI); δ 8.54-8.52(m, 2H), 7.56(s, IH), 7.53-7.51(m, 3H), 7.44(d,
J=5.2Hz, IH), 7.19(d, J=3.6Hz, IH), 7.14(t, J=4.4Hz, IH).
[531]
[532] Intermediate (12) : Preparation of 4-(4-chloro-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-2-yl)-phenol
[533]
Figure imgf000053_0001
[534] According to the similar procedure in the step 3 and 4 of example 8(method 2) by using the compound, 5'-amino-[2,3']bithiophenyl-4'-carboxylic acid methyl ester, (200mg, 0.84mmol), prepared in the step 2 of example 8 (method 2) and 4-cyanophenol (200mg, 1.67mmol), 115mg (yield for 2 steps: 40%, white solid) of the target compound was obtained.
[535] 1U NMR(400D, OMSOd ); δ 10.23(s, IH), 8.27(d, J=8.8Hz, 2H), 8.03(s, IH),
7.70(d, J=5.2Hz, IH), 7.28(d, J=2.4Hz, IH), 7.18(t, J=5.2Hz, IH) 6.92(d, J=8.8Hz, 2H).
[536]
[537] Intermediate (13) : Preparation of l-[2-(4-fluoro-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3-meth yl-pyrrole-2,5-dione hydrochloride
[538] Step 1. Preparation of 2-(4-fluoro-phenylV5-thiophen-2-yl-thienor2.3-dl pyrimidin-
4-ol
[539]
Figure imgf000053_0002
[540] According to the similar procedure in the step 3 of example 8 (method 2) by using the compound (213.9mg, 0.89mmol) prepared in the step 2 of example 8(method 2) and 4-fluorobenzonitrile, 171mg (yield: 58%, yellow solid) of the target compound was obtained.
[541] 1U NMR(400D, OMSOd ); δ 12.77(s, IH), 8.24(dd, J=8.8, 5.4Hz, 2H), 7.70(d, J
=3.9Hz, IH), 7.66(s, IH), 7.56(d, J=4.9Hz, IH), 7.45(d, /=8.8, 2H), 7.13(dd, /=4.9, 3.9Hz, IH).
[542]
[543] Step 2. Preparation of 4-chloro-2-(4-fluoro-phenylV5-thiophen-2-yl-thienor2.3-dl pyrimidine
[544]
Figure imgf000054_0001
[545] According to the similar procedure in the step 4 of example 8(method 2) by using the compound (168mg, 0.51mmol) prepared in the step 1, 149mg (yield: 84%, yellow solid) of the target compound was obtained. [546] 1U NMR(400D, CDCI); δ 8.53(m, 2H), 7.54(s, IH), 7.43(d, J=4.9Hz, IH),
7.20-7.12(m, 4H). [547] [548] Intermediate (14) : Preparation of l-[2-(3-fluoro-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3-meth yl-pyrrole-2,5-dione hydrochloride [549] Step 1. Preparation of 2-G-fluoro-phenylV5-thiophen-2-yl-thienor2.3-dl pyrimidin-
4-ol [550]
Figure imgf000054_0002
[551] According to the similar procedure in the step 3 of example 8(method 2) by using the compound prepared in the step 2 of example 8(method 2) and 3-fluorobenzonitrile, 203mg (yield: 65%, yellow solid) of the target compound was obtained.
[552] 1U NMR(400D, DMSO-d); δ 12.78(s, IH), 8.04(d, /=7.8, IH), 8.00(d, /=10.2Hz,
IH), 7.71(d, /=3.9Hz, IH), 7.67(s, IH), 7.60(m, IH), 7.55(d, /=4.9, IH), 7.45(m, IH), 7.12(dd, /=4.9, 3.9Hz, IH).
[553]
[554] Step 2. Preparation of 4-chloro-2-G-fluoro-phenylV5-thiophen-2-yl-thienor2.3-dl pyrimidine
[555]
Figure imgf000054_0003
[556] According to the similar procedure in the step 4 of example 8(method 2) by using the compound (203mg, 0.62mmol) prepared in the step 1, 206mg (yield: 96%, yellow solid) of the target compound was obtained.
[557] 1U NMR(400D, CDCI); δ 8.32(d, /=7.8Hz, 2H), 7.57(s, IH), 7.49-7.43(m, 2H),
7.22-7.12(m, 3H).
[558] [559] Intermediate (15) : Preparation of 4-chloro-2-thiophen-3-yl-5-thieno[2,3-d] pyrimidine
[560]
Figure imgf000055_0001
[561] 5'-amino-[2,3']bithiophenyl-4'-carboxylic acid methyl ester (200mg, 0.835mmol) obtained according to the similar procedure in the step 1 and 2 of example 8 (method 2) by using 2-acetylthiophene (Ig, 7.92mmol) was dissolved in 1,-dioxane (5ml). Therein, 3-thiophenecarbonitrile (273mg, 2.5mmol) and 3.2M HCl solution was added, and the reaction mixture was stirred at 1000C for 24 hours to give 2-thiophen-3-yl-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ol (192mg, yield: 72%). Thereafter, according to the similar procedure in the step 4 of example 8(method 2), 180mg (yield: 86%, yellow solid) of the target compound was obtained.
[562] 1U NMR (400D, CDCI): δ 8.39-8.38(m, IH), 7.96-7.95(m, IH), 7.51(s, IH),
7.44-7.38(m, 2H), 7.18-7.12(m, 2H).
[563]
[564] Intermediate (16) : Preparation of
4-chloro-2-thiophen-2-yl-5-thiophen-3-yl-thieno[2,3-d]pyrimidine
[565]
Figure imgf000055_0002
[566] According to the similar procedure in the step 1 to 4 of example 8(method 2) by using the 3-acetylthiophene (Ig, 7.92mmol), 52mg (yield for final step: 98%, yellow oil) of the target compound was obtained. [567] 1H-NMR (400D, CDCI) δ 8.27(d, J=2.5Hz, IH), 8.04(d, J=IAUz, IH), 7.9 l(d, J
=4.7Hz, IH), 7.63(s, IH), 7.56~7.54(m, IH), 7.51(d, J=4.7Hz, IH), 7.24(t, J=4.3Hz,
IH). [568] [569] Intermediate (17) : Preparation of
4-chloro-5-thiophen-2-yl-2-thiophen-3-ylmethyl-thieno[2,3-d]pyrimidine [570]
Figure imgf000056_0001
[571] According to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the compound, 5'-amino-[2,3']bithiophenyl-4'-carboxylic acid methyl ester, prepared in the step 2 of example 8(method 2) and 3-thiophenacetonitrile, 250mg (yield for 2 steps: 86%, yellow oil) of the target compound was obtained.
[572] 1U NMR(400D, CDCI); δ 7.51(s, IH), 7.41(d, J=4.8Hz, IH), 7.26(dd, J=2.6Hz,
5.4Hz, IH), 7.21(s, IH), 7.16-7.09(m, 3H), 4.38(s, 2H).
[573]
[574] Intermediate (18) : Preparation of
4-chloro-5-phenyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidine
[575]
Figure imgf000056_0002
[576] According to the similar procedure in the step 1 to 4 of example 8(method 2) by using the acetophenone, 160mg (overall yield: 5%, white solid) of the target compound was obtained.
[577] 1U NMR(400D, DMSO d-6 ); δ 8.26(d, J=3.6Hz, IH), 7.90(d, J=3.6Hz, IH), 7.56(d, J
=6.4Hz, 2H), 7.48(s, IH), 7.38(m, 3H), 7.24(t, J=4.4Hz, IH). [578] [579] Intermediate (19) : Preparation of
4-chloro-2-thiophen-2-yl-5-p-tolyl-thieno[2,3-d]pyrimidine
[580]
Figure imgf000056_0003
[581] According to the similar procedure in the step 1 to 4 of example 8 (method 2) by using the 4-methyl acetophenone, 200mg (overall yield: 6%, white solid) of the target compound was obtained.
[582] 1U NMR(400D, DMSO d-6 ); δ 8.20(d, J=3.6Hz, IH), 7.85(d, J=3.6Hz, IH), 7.45(d, J
=8.0Hz, 2H), 7.36(s, IH), 7.21(m, 3H), 2.34(s, IH). [583] [584] Intermediate (20) : Preparation of
4-chloro-2-(4-methoxy-benzyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidine
[585]
Figure imgf000057_0001
[586] According to the similar procedure in the step 3 and 4 of example 8(method 2) by using the compound prepared in the step 2 of example 8 (method 2) and (4-methoxyphenyl)acetonitrile, 238mg (yield for final step: 84%, yellow oil) of the target compound was obtained.
[587] 1U NMR(400D, CDCI): δ 7.63(d, J=3.6Hz, IH), 7.54(s, IH), 7.52(d, J=5. IHz, IH),
7.30(d, J=8.4Hz, 2H), 7.09~7.07(m, IH), 6.90(d, J=8.7Hz, 2H), 3.88(s, 2H), 3.71(s, 3H).
[588]
[589] Intermediate (21) : Preparation of [4-(4-chloro-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-2-yl)-phenyl]-dimethylamine
[590]
Figure imgf000057_0002
[591] According to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the compound prepared in the step 2 of example 8 (method 2) and 4-(dimethylamino)-benzonitrile, 68mg (yield for 2 steps: 81%, yellow solid) of the target compound was obtained.
[592] 1U NMR(400D, CDCI); δ 8.40 (m, 2H), 7.41 (m, IH), 7.40 (s, IH), 7.17 (m, IH)
7.11 (m, IH), 6.77 (m, 2H),3.06 (s, 6H).
[593]
[594] Intermediate (22) : Preparation of 3-(4-chloro-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-2-yl)-phenol
[595]
Figure imgf000057_0003
[596] According to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the compound, 5'-amino-[2,3']bithiophenyl-4'-carboxylic acid methyl ester, prepared in the step 2 of example 8(method 2) and 3-hydroxybenzonitrile, 82mg (yield for final step: 39%, colorless solid) of the target compound was obtained. [597] 1U NMR(400D, CDCI): δ 9.64-9.52(br, IH), 8.10-7.98(m, 2H), 7.79(s, IH), 7.45-
7.36(m, 2H), 7.16-7.09(m, 2H), 7.31-6.92(m, IH). [598] [599] Intermediate (23) : Preparation of 4-chloro-2-(-4-methoxy-phenyl)-5-pheny 1- thieno[2,3-d]pyrimidine [600]
Figure imgf000058_0001
[601] According to the similar procedure in the step 1 and 2 of example 8 (method 2) by using the 1-pheny-ethanon, intermediate compound was obtained. Thereafter, according to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the intermediate compound and 4-methoxybenzonitrile, 188mg (yield for final step: 92%, yellow oil) of the target compound was obtained.
[602] 1U NMR(400D, CDCI): δ 8.18(d, J=8.8Hz, 2H), 7.72(s, IH), 7.67~7.61(m, 2H),
7.41~7.33(m, 3H), 6.99(d, J=8.8Hz, 2H), 3.88(s, 3H).
[603]
[604] Intermediate (24) : Preparation of
4-chloro-2-(3-methoxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidine
[605]
Figure imgf000058_0002
[606] According to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the compound, 5'-amino-[2,3']bithiophenyl-4'-carboxylic acid methyl ester, prepared in the step 2 of example 8(method 2) and 3-methoxybenzonitrile, 51mg (yield for final step: 81%, colorless solid) of the target compound was obtained.
[607] 1U NMR(400D, CDCI): δ 8.14-8.07 (m, 2H), 7.55(s, IH), 7.44- 7.40(m, 2H),
7.19-7.12(m, 2H), 7.08-7.05(m, IH), 3.94(s, 3H).
[608]
[609] Intermediate (25) : Preparation of
4-chloro-2-(-3-methoxy-phenyl)-5-phenyl-thieno[2,3-d]pyrimidine
[610]
Figure imgf000059_0001
[611] According to the similar procedure in the step 1 and 2 of example 8 (method 2) by using the compound, 1-pheny-ethanon, intermediate compound was obtained. Thereafter, according to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the intermediate compound and 3-methoxybenzonitrile, 251mg (yield for final step: 92%, yellow oil) of the target compound was obtained.
[612] 1U NMR(400D, CDCI):δ 7.78~7.73(m, 2H), 7.59(d, J=8.0Hz, 2H), 7.53(s, IH),
7.48~7.36(m, 3H), 7.16~7.14(m, IH), 3.86(s, 3H).
[613]
[614] Intermediate (26) : Preparation of
4-chloro-2-(-3-fluoro-phenyl)-5-phenyl-thieno[2,3-d]pyrimidine
[615]
Figure imgf000059_0002
[616] According to the similar procedure in the step 1 and 2 of example 8 (method 2) by using the 1-pheny-ethanon, intermediate compound was obtained. Thereafter, according to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the intermediate compound and 3-fluorobenzonitrile, 251mg (yield for final step: 93%, yellow solid) of the target compound was obtained.
[617] 1U NMR(400D, CDCI): δ 8.04~8.01(m, 2H), 7.61~7.56(m, 4H), 7.47~7.36(m, 4H).
[618]
[619] Intermediate (27) : Preparation of
4-chloro-2-(3-methoxy-benzyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidine
[620]
Figure imgf000059_0003
[621] According to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the compound prepared in the step 2 of example 8 (method 2) and (3-methoxyphenyl)acetonitrile, 148mg (yield for final step: 71%, yellow oil) of the target compound was obtained.
[622] 1U NMR(400D, CDCI): δ 7.68~7.62(m, IH), 7.56(s, IH), 7.52~7.51(m, IH), 7.24(t, J=7.8Hz, IH), 7.10-7.07 (m, IH), 6.96(s, IH), 6.93(d, J=7.7Hz, IH), 6.84(d, J=8.0Hz,
IH), 3.96(s, 2H), 3.73(s, 3H). [623] [624] Intermediate (28) : Preparation of 4-chloro-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-5-carboxylic acid ethyl ester [625]
Figure imgf000060_0001
[626] According to the similar procedure in the step 1 to 4 of example 8 (method 2) by using the compound, ethyl pyruvate, 25mg (overall yield: 1%, white solid) of the target compound was obtained. [627] 1U NMR(400D, DMSO-d): δ 8.26(d, J=3.6Hz, IH), 8.02(s, IH), 7.91(d, J=3.6Hz,
IH), 7.24(t, J=4.0Hz, IH), 4.29(q, J=3.2Hz, 2H), 1.17(t, J=7.2Hz, 3H). [628] [629] Intermediate (29) : Preparation of
4-chloro-5-(3-methoxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidine [630]
Figure imgf000060_0002
[631] According to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the compound, 2-amino-4-(3-methoxy-phenyl)-thiophen-3-carboxylic acid methyl ester, prepared in the step 1 and 2 of example 8 (method 2) and l-(3-methoxy-phenyl)-ethanone, 1.17g (yield for 2 steps: 18%, yellow solid) of the target compound was obtained.
[632] 1U NMR(400D, CDCI): δ 8.10(m, IH), 7.53-7.51(m, IH), 7.35-7.17(m, 2H),
6.99-6.89(m, 3H).
[633]
[634] Intermediate (30) : Preparation of 3-(4-chloro-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-5-yl)-phenol
[635]
Figure imgf000060_0003
[636] IM boron tribromide dichloromethane solution was slowly added to the solution of 4-chloro-5-(3-methoxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidine (86mg, 0.24mmol) in dichloromethane (5ml) at O0C. Then the reaction mixture was stirred at 250C for 8 hours. After reaction, the reaction mixture was poured into dichloromethane, and washed with water. Combined organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 4:1) to give 63mg (yield: 71%, yellow solid) of the target compound.
[637] 1U NMR(400D, CDCI): δ 8.09-8.08(m, IH), 7.53-7.51(m, IH), 7.35-7.26(m, 2H),
7.17-7.15(m, IH), 6.99(m, 3H).
[638]
[639] Intermediate (31) : Preparation of [4-(4-chloro-5-phenyl-thieno[2,3-d] pyrimidin-2-yl)-phenyl-dimethyl-amine
[640]
Figure imgf000061_0001
[641] According to the similar procedure in the step 1 and 2 of example 8 (method 2) by using the acetophenone (200mg, 1.66mmol), intermediate compound, 2-amino-4-phenyl-thiophen-3-carboxylic acid methyl ester was obtained. Thereafter, according to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the intermediate compound(217mg, 0.93mmol, 54%) and
4-(dimethylamino)-benzonitrile (270mg, 1.86mmol), 215mg (yield for 2 steps: 64%, old gold solid) of the target compound was obtained.
[642] 1U NMR(400D, CDCI); δ 8.40(d, J=9.2Hz, 2H), 7.45-7.43(m, 5H), 7.25(s, IH),
6.78(d, J=8.8Hz, 2H), 3.07(s, 6H).
[643]
[644] Intermediate (32) : Preparation of 4-(4-chloro-5-phenyl-thieno[2,3-d] pyrimidin-2-yl)-phenylamine
[645] Step 1. Preparation of 4-chloro2-(4-nitro-phenylV5-phenyl-thienor2.3-dlpyrimidine
[646]
Figure imgf000061_0002
[647] According to the similar procedure in the step 1 and 2 of example 8(method 2) by using the acetophenone (200mg, 1.66mmol), intermediate compound, 2-amino-4-phenyl-thiophen-3-carboxylic acid methyl ester was obtained. Thereafter, according to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the intermediate compound (217mg, 0.93mmol) and 4-nitro-benzonitrile (275mg, 1.86mmol), 217mg (yield for 2 steps: 63%, yellow solid) of the target compound was obtained.
[648] 1U NMR(400D, CDCI); δ 8.74(d, J=8.0Hz, 2H), 8.36(d, J=8.0Hz, 2H), 7.52(s, IH),
7.48-7.46(m, 5H).
[649]
[650] Step 2. Preparation of 4-(4-chloro-5-phenyl-thieno[2.3-dl pyrimidin-
2-yl)-phenylamine
[651]
Figure imgf000062_0001
[652] The compound (215mg, 0.58mmol) prepared in the step 1 was dissolved in ethanol
(20ml). Therein, iron (290mg, 5.17mmol) and cone. HCl aqueous solution (0.2mL, 0. ImL/ 10OmL starting) were added stepwise, and then the reaction mixture was stirred at room temperature for 3 hours. After reaction, reaction mixture was filtered and neutralized with 2N NaOH aqueous solution, and aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 3:1) to give 170mg (yield: 86%, white solid) of the target compound.
[653] 1U NMR(400D, CDCI); δ 8.35(d, J=8.8Hz, 2H), 7.49-7.39(m, 5H), 7.28(s, IH),
6.76(d, J=8.4Hz, 2H), 4.01(brs, 2H).
[654]
[655] Intermediate (33) : Preparation of
4-chloro-2-furan-2-yl-5-thiophen-2-yl-thieno[2,3-d]pyrimidine
[656]
Figure imgf000062_0002
[657] According to the similar procedure in the step 3 and 4 of example 8(method 2) by using the 5'-amino-[2,3']bithiophenyl-4'-carboxylic acid methyl ester prepared in the step 2 of example 8(method 2) and 2-cyanofurane, 137mg (yield for final step: 72%, colorless solid) of the target compound was obtained. [658] 1H-NMR^OOD, CDCI): δ 7.67(dd, /=1.6, 1.2Hz, IH), 7.53(s, IH), 7.44- 7.42(m,
2H), 7.17(dd, /=3.8, 1.2Hz, IH), 7.13-7.11(m, IH), 6.61(dd, /=3.6, 1.2Hz, IH).
[659]
[660] Intermediate (34) : Preparation of 4-chloro-2- methyl-
5-thiophen-2-yl-thieno[2,3-d]pyrimidine
[661]
Figure imgf000063_0001
[662] According to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the compound, 5'-amino-[2,3']bithiophenyl-4'-carboxylic acid methyl ester prepared in the step 2 of example 8(method 2) and acetonitrile, 436mg (yield for 2 steps: 90%, yellow solid) of the target compound was obtained.
[663] 1U NMR(400D, CDCI): δ 7.73 (m, IH), 7.59 (m, IH), 7.46 (s, IH), 7.17 (m, IH),
2.37(s, 3H).
[664]
[665] Intermediate (35) : Preparation of 4-(4-chloro-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-2-yl)-phenylamine
[666] Step 1. Preparation of 4-chloro-2-(4-nitrophenylV5-thiophen-2-yl-thienor2.3-dl pyrimidine
[667]
Figure imgf000063_0002
[668] According to the similar procedure in the step 3 and 4 of example 8(method 2) by using the 5'-amino-[2,3']bithiophenyl-4'-carboxylic acid methyl ester prepared in the step 2 of example 8(method 2) and 4-nitrobenzonitrile, 230mg (yield for 2 steps: 77%, yellow solid) of the target compound was obtained.
[669] 1U NMR(400D, CDCI): δ 8.72 (m, 2H), 8.35 (m, 2H), 7.66 (s, IH), 7.47 (m, IH)
7.19 (m, IH), 7.15 (m, IH).
[670]
[671 ] Step 2. Preparation of 4-(4-chloro-5-thiophen-2-yl-thienor2.3-dl pyrimidin-
2-ylVphenylamine
[672]
Figure imgf000064_0001
[673] The compound (50mg, 0.13mmol) prepared in the step 1 was dissolved in ethanol
(3ml). Therein, iron (Fe, 75mg, 1.34mmol), 12N HCl aqueous solution (0.0ImL) and water (0.2ml) were added, and the reaction mixture was stirred at 9O0C for 4 hours. After reaction, the reaction mixture was filtered and filtrate was concentrated. Therein, water was added and extracted with ethyl acetate (10ml). Combined organic layer was washed with brine(5ml) twice and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:n-hexane = 1:1) to give 32mg (yield: 69%, yellow solid) of the target compound.
[674] 1U NMR(400D, CDCI): δ 7.99(d, J=4.0Hz, IH), 7.84(d, J=5.2Hz, IH), 7.27 -
7.25(m, 3H), 6.70(d, J=8.4Hz, 2H), 5.65(s, IH), 2.56(s, 2H).
[675]
[676] Intermediate (36) : Preparation of 4-chloro-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-2-yl-amine
[677]
Figure imgf000064_0002
[678] According to the similar procedure in the step 3 and 4 of example 8(method 2) by using the compound (500mg, 2.1mmol) prepared in the step 2 of example 8 (method 2) and cyanamide, 130mg (yield for 2 steps: 23%, white solid) of the target compound was obtained.
[679] 1U NMR(400D, DMSO-d): δ 7.63(d, J=3.6Hz, IH), 7.45(d, J=5.2Hz, IH), 7.05(m,
2H), 6.62(br, 2H).
[680]
[681] Intermediate (37) : Preparation of
4-chloro-2-cyclopropyl-5-thiophen-2-yl-thieno[2,3-d]pyrimidine
[682]
Figure imgf000064_0003
[683] According to the similar procedure in the step 3 and 4 of example 8(method 2) by using the 5'-amino-[2,3']bithiophenyl-4'-carboxylic acid methyl ester prepared in the step 2 of example 8(method 2) and 4-cyclopropylnitrile, 366mg (yield for 2 steps:
72%, yellow solid) of the target compound was obtained. [684] 1U NMR(400D, CDCI): δ 7.98 (s, IH), 7.68 (m, IH), 7.24 (m, IH), 7.16 (m, IH)
2.29 (m, IH), 1.60 (m, 2H), 1.10 (m, 2H). [685] [686] Intermediate (38) : Preparation of (4-chloro-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-5-yl)-acetic acid ethyl ester
[687] Step 1. Preparation of 4-bromo-3-oxo-butyric acid ethyl ester
[688]
Figure imgf000065_0001
[689] Ethyl acetoacetate (ImI, 7.84mmol) was dissolved in chloroform, therein, bromine
(0.6ml, 11.76mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. Sodium sulfite solution was added to quench the reaction, and ethyl acetate was added. Organic layer was washed with water and IN HCl aqueous solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 4:1) to give 800mg (yield: 49%, colorless oil) of the target compound.
[690] 1U NMR(400D, CDCI); δ 4.20(q, J=4.0Hz, 2H), 4.04(s, 2H), 3.69(s, 2H), 1.28(t, J
=8.0Hz, 3H).
[691]
[692] Step 2. Preparation of 2-amino-4-ethoxycarbonylmethyl-thiophen-3-carboxylic acid ethyl ester
[693]
Figure imgf000065_0002
[694] The compound (800mg, 3.83mmol) prepared in the step 1, ethyl cyanoacetate
(0.45mL, 4.0mmol) and sodium sulfide 9 hydrate (Na S-9H O, lOOOmg, 4.0mmol) were dissolved in ethanol (15ml). Therein, triethylamine (0.6mL, 4.0mmol) was slowly added, and the reaction mixture was stirred at 4O0C for 36 hours. After reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 4: 1) to give 70mg (yield: 8%, pale yellow solid) of the target compound. [695] 1H-NMR^OOD, CDCI) δ 6.18(br, 2H), 6.00(s, IH), 4.19(m, 4H), 3.68(s, 2H),
1.27(m, 6H). [696] [697] Step 3. Preparation of (4-chloro-2-thiophen-2-yl-thieno[2.3-dl pyrimidin-
5-yl)-acetic acid ethyl ester [698]
Figure imgf000066_0001
[699] According to the similar procedure in the step 3 and 4 of example 8 (method 2) by using the compound (700mg, 1.62mmol) prepared in the step 2, 60mg (yield for 2 steps: 9%, white solid) of the target compound was obtained. [700] 1U NMR(400D, CDCI): δ 8.07(dd, J=LlBz, J=3.6Hz, IH), 7.50(dd, J=LlBz, J
=4.8Hz, IH), 7.33(s, IH), 7.15(m, 2H), 4.24(q, J=6.8Hz, 2H), 4.07(s, 2H), 1.27 (t, J
=6.8Hz, 3H). [701] [702] Intermediate (39) : Preparation of 4-chloro-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-5-carboxylic acid ethyl ester [703] Step 1. Preparation of 4-(N'- 1 -bu- toxycarbonyl-hydrazinoV2-thiophen-2-yl-thienor2.3-dlpyrimidin-5-carboxylic acid ethyl ester [704]
Figure imgf000066_0002
[705] 4-Chloro-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-5-carboxylic acid ethyl ester
(80mg, 0.25mmol), prepared in the intermediate step (28) was dissolved in THF (5ml). Therein, ?-butyl carbazate (98mg, 0.74mmol) was added, and the reaction mixture was refluxed for 12 hours. After reaction, the solvent was removed under reduced pressure then the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 4:1) to give lOOmg (yield: 95%, white solid) of the target compound.
[706] 1U NMR(400D, CDCI): δ 10.77(s, IH), 8.22(s, IH), 7.99(d, J=3.6Hz, IH), 7.45(d,
J=4.8Hz, IH), 7.12(t, J=4.4Hz, IH), 4.42(qt, J=7.2Hz, 2H), 1.58(s, 9H), 1.43(t, J =7.0Hz, 3H). [707]
[708] Step 2. Preparation of N'-f5-hvdroxymethyl-2-thiophen-2-yl-thienor2.3-dl pyrimidin-4-yls)hvdrazine carboxylic acid t -butyl ester [709]
Figure imgf000067_0001
[710] The compound (lOOmg, 0.23mmol) prepared in the step 1 was dissolved in THF
(5ml), therein, 2N lithium borohydride in THF solution (0.32OmL, 0.65mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. Cold IN HCl aqueous solution was added to quench the reaction, and aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 30:1) to give 85mg (yield: 96%, white solid) of the target compound.
[711] 1U NMR(400D, CDCI): δ 9.34(s, IH), 7.98(d, J=3.6Hz, IH), 7.44(d, J=4.8Hz, IH),
7.30(t, J=4.4Hz, IH), 6.79(s, IH), 4.77(d, J=4.8Hz, 2H), 3.37(s, 3H), 1.53(s, 9H).
[712]
[713] Step 3. Preparation of N'-(5-methoxymethyl-2-thiophen-2-yl-thieno[2.3-dl pyrimidin-4-yl)hvdrazine carboxylic acid t -butyl ester
[714]
Figure imgf000067_0002
[715] The compound (1 lOmg, 0.29mmol) prepared in the step 2 was dissolved in dried
THF (10ml). Thereafter, the temperature was lowered into O0C, and therein, sodium hydride (12mg, 0.31mmol) was added, and the reaction mixture was stirred at O0C for 1 hour. Iodomethane (36D, 0.58mmol) was added, then the reaction mixture was warmed up to room temperature slowly and stirred at that temperature for 2 days. Ice water was added to quench the reaction, and aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 30:1) to give 34mg (yield: 30%, white solid) of the target compound.
[716] 1U NMR(400D, CDCI): δ 7.95(d, J=3.6Hz, IH), 7.90(s, IH), 7.54(d, J=4.0Hz, IH),
7.43(s, IH), 7.14(t, J=4.8Hz, IH), 4.86(s, 2H), 3.36(s, 3H), 1.43(s, 9H). [717] [718] Step 4. Preparation of (5-methoxymethyl-2-thiophen-2-yl-thieno[2.3-d1 pyrimidin- 4-yls)hvdrazine
[719]
Figure imgf000068_0001
[720] The compound (34mg, 0.09mmol) prepared in the step 3 was dissolved in 1,4-dioxane (5ml) and chloroform (2ml). Therein, 3.6M HCl in 1,4-dioxane solution (2ml) was added, and the reaction mixture was stirred at room temperature for 2 days. The cold saturated sodium hydrogen carbonate aqueous solution was added and the reaction mixture was stirred for 1 hour, and the aqueous layer was extracted with chloroform, and the organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 20mg (yield: 79%, bright brown oil) of the target compound.
[721] [722] Example 52 . 3-methyl-l-{2-[4-(2-piperidin-l-yl-ethoxy)-phenyl] - 5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride
[723] Step 1. Preparation of 4-chloro-2-[4-(2-piperidin-l-yl-ethoxy)-phenyl1 - 5-thiophen-2-yl-thieno[2.3-d1pyrimidine [724]
Figure imgf000068_0002
[725] The intermedial (12), 4-(4-chloro-5-thiophen-2-yl-thieno[2,3-d] pyrimidin- 2-yl)-phenol (lOOmg, 0.29mmol), prepared by the procedure in step 1 to step 4 of example 8 (method 2), triphenylphosphine (99mg, 0.38mmol) and 1-piperidinethanol (42D, 0.32mmol) were dissolved in THF (10ml). Thereafter, the temperature was lowered into O0C, and therein diisopropylazodicarboxylate (DIAD, 63D, 0.32mmol) was added slowly, and the reaction mixture was stirred at room temperature for overnight. Solvent was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10:1) to give 50mg (yield: 38%, colorless oil) of the target compound.
[726] 1U NMR(400D, DMSC^ ); δ 8.46(d, J=8.8Hz, 2H), 7.48(s, IH), 7.43(d, J=3.6Hz, IH), 7.18(d, J=3.6Hz, IH), 7.13(t, J=4.2Hz, IH), 7.01(d, J=8.8Hz, 2H), 4.20(t, J =6.0Hz, 2H), 2.82(t, J=6.0Hz, 2H), 2.54(br, 4H), 1.65-1.60(m, 4H), 1.47-146(m, 2H). [727] [728] Step 2. Preparation of 3-methyl-l-(2-[4-(2-piperidin-l-yl-ethoxy)-phenyl1 -
5-thiophen-2-yl-thieno[2.3-dlpyrimidin-4-ylamino ) -pyrrole-2.5-dione hydrochloride [729]
Figure imgf000069_0001
[730] According to the similar procedure in the step 5 and step 6 of example 8(method 1) by using the compound (50mg, 0.1 lmmol) prepared in the step 1, 53mg (yield for 2 steps: 82%, yellow solid) of the target compound was obtained.
[731] 1U NMR(400D, DMSO-d): δ 10.78(s, IH), 8.62(s, IH), 8.13(d, J=8.8Hz, 2H),
IJl(S, IH), 7.69(d, J=5.2Hz, IH), 7.32(d, J=3.2Hz, IH), 7.21(t, J=4.4Hz, IH), 7.08(d, J=8.8Hz, 2H), 6.96(s, IH), 4.52-3.47(m, 2H), 3.52-3.41(m, 4H), 2.99-2.97(m, 2H), 2.14(s, 3H), 1.90- 1.79(m, 4H), 1.70-1.67 (m, 2H).
[732]
[733] Example 53 . 3-methyl-l-{2-[3-(2-piperidin-l-yl-ethoxy)-phenyl] -
5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride
[734] Step 1. Preparation of 4-chloro-2-[3-(2-piperidin-l-yl-ethoxy)-phenyl1 -
5-thiophen-2-yl-thieno[2.3-d1pyrimidine
[735]
Figure imgf000069_0002
[736] According to the similar procedure in the step 1 example 52 by using the intermediate (22), 3-(4-chloro-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-2-yl)-phenol, prepared by the procedure in the step 1 to step 4 of example 8 (method 2), 34mg (yield: 23%, colorless solid) of the target compound was obtained.
[737] 1U NMR(400D, CDCI): δ 8.14-8.09(m, 2H), 7.69-7.64(m,lH), 7.55(s, IH),
7.46-7.39(m, 2H), 7.19-7.05(m, 2H), 4.26(t, J=6.0Hz, 2H), 2.86(t, J=6.0Hz, 2H), 2.61-2.57 (m, 4H), 1.68-1.47(m, 6H).
[738]
[739] Step 2. Preparation of 3-methyl-l-(2-r3-(2-piperidin-l-yl-ethoxyVphenyll -
5-thiophen-2-yl-thienor2.3-dlpyrimidin-4-ylamino)-pyrrole-2.5-dione hydrochloride [740]
Figure imgf000070_0001
[741] According to the similar procedure in the step 5 and step 6 of example 8 (method 1) by using the compound (34mg, 0.07 mmol) prepared in the step 1, 27 mg (yield for final step: 50%, yellow solid) of the target compound was obtained.
[742] 1U NMR(400D, DMSO-d): δ 10.47(br, IH), 8.73(s, IH), 7.85-7.70(m, 4H), 7.43(t, J=8.0Hz, IH), 7.33(d, J=2.8Hz, IH), 7.23(t, J=4.0Hz, IH), 7.13(d, J=8.0Hz, IH), 7.07(s, IH), 4.43(br, 2H), 3.51(br, 4H), 3.03(br, 2H), 2.17(s, 3H), 1.81-1.69(m, 4H), 1.40(m, 2H).
[743] [744] Example 54 . l-[6-(4-hydroxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride
[745] Step 1. Preparation of (4-methoxy-phenyl)-acetyl chloride [746]
OH
0
"C ^0XXf1
[747] (4-methoxy-phenyl)-acetic acid (5g, 30mmol) and oxalyl chloride (5.25ml, 60mmol) were dissolved in benzene (15ml). The reaction mixture was stirred at room temperature for 3.5 hours. After reaction, reaction mixture was concentrated under reduced pressure. The residue was used to next step.
[748] [749] Step 2. Preparation of (4-methoxy-phenyl)-acetaldehvde [750]
Cl H
0 0
[751] The temperature of DMF (35ml) was lowered into O0C. Therein, cadmium chloride (1Og, 54.5mmol) was slowly added, and stirred 30 minutes. The reaction mixture was filtered and washed with carbon tetrachloride to give CdCl Dl.5DMF. CdCEl.5DMF
& 2 2
(20.5g, 21 mmol) and sodium borohydride (NaBH , 1.14g, 30mmol) were added to ace-
4 tonitrile (150ml) and HMPA (7.5ml) at -50C, and stirred 5 minutes. Thereafter, solvent of the compound (5.05g, 27.3mmol) prepared in the step 1 in acetonitrile was added to the mixture and then stirred for 5minutes. The reaction mixture was diluted with water, acidified with 10% HCl aqueous solution to pH 3, and extracted with ethyl acetate. Combined organic layer was dried over anhydrous magnesium sulfate and con- centrated under reduced pressure to give 2.16g (yield for 2 steps: 48%, colorless oil) of the target compound. [752] 1U NMR(400D, CDCI): δ 9.62(s, IH), 7.06(d, J=8.4Hz, 2H), 6.85(d, J=8.4Hz, 2H),
3.71(s, 3H), 3.53(s, 2H). [753] [754] Step 3. Preparation of 2-amino-5-(4-methoxy-phenyl)-thiophen-3-carboxyric acid ethyl ester [755]
„ xj 6 ;Λ
[756] The compound (498mg, 3.316mmol) prepared in the step 2, ethyl cyanoacetate
(0.353ml, 3.316mmol) and sulfur (106mg, 3.316mmol) were dissolved in N,N-dimethylformamide (3ml). Therein, triethylamine (0.254ml, 1.824mmol) was added slowly, and the reaction mixture was stirred at 5O0C for 28 hours. After reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 10:1) to give 550mg (yield: 60%, pale yellow solid) of the target compound.
[757] 1U NMR(400D, CDCI): δ 7.37(d, J=8.8Hz, 2H), 7.01(s, IH), 6.87(d, J=8.8Hz, 2H),
5.95(br, 2H), 4.29(q, J=6.8Hz, 2H), 3.81(s, 3H), 1.37(t, J=6.8Hz, 3H)
[758]
[759] Step 4. Preparation of 6-C4-methoxy-phenylV2-thiophen-2-yl-thienor2.3-dl pyrimidin-4-ol
[760]
Figure imgf000071_0001
[761] According to the similar procedure in the step 3 of example 8 (method 2) by using the compound prepared in the step 3, 410mg (yield: 61%, yellow solid) of the target compound was obtained. [762] 1H-NMR (400D, DMSC^ ): δ 8.23(d, J=8.0Hz, IH), 7.90(d, J=5.2Hz, IH), 7.70(d,
J=8.4Hz, 2H), 7.68(s, IH), 7.25(t, J=4.0Hz, IH), 7.01(d, J=8.4Hz, 2H), 3.80(s, 3H) [763] [764] Step 5. Preparation of 4-chloro-6-(4-methoxy-phenyl)-2-thiophen-2-yl-thieno[2.3-d lpyrimidine [765]
Figure imgf000072_0001
[766] According to the similar procedure in the step 4 of example 8(method 2) by using the compound prepared in the step 4, 400mg (yield: 92%, yellow solid) of the target compound was obtained. [767] 1U NMR(400D, CDCI): δ 8.06(dd, /=3.6, 1.2Hz, IH), 7.65(d, /=8.8Hz, 2H),
7.50(dd, /=5.2, 1.2Hz, IH), 7.41(s, IH), 7.16(dd, /=5.2, 3.6Hz, IH), 6.98(d, /=8.8Hz,
2H), 3.87(s, 3H) [768] [769] Step 6. Preparation of 4-(4-chloro-2-thiophen-2-yl-thieno[2.3-dl pyrimidin-
6-yl)-phenol
[770]
Figure imgf000072_0002
[771] According to the similar procedure in the step 1 of intermediate 3 by using the compound prepared in the step 5, 400mg (yield: 92%, yellow solid) of the target compound was obtained. [772] 1U NMR(400D, DMSO-d): δ 10.1(br, IH), 7.99(dd, /=3.6, 1.2Hz, IH), 7.79(dd, /
=4.8, 1.2Hz, IH), 7.75(dd, /=8.8, 2.0Hz, 2H), 7.24(dd, /=4.8, 3.6Hz, IH), 6.91(dd, /
=8.8, 2.0Hz, 2H) [773] [774] Step 7. Preparation of l-[6-(4-hvdroxy-phenyl)-2-thiophen-2-yl-thieno[2.3-dl pyrimidin-4-ylaminol-3-methyl-pyrrole-2.5-dione [775]
Figure imgf000072_0003
[776] According to the similar procedure in the step 5 of example 1 by using the compound prepared in the step 6, lOOmg (yield: 76%, yellow solid) of the target compound was obtained. [777] 1H-NMR (400D, CDCI) δ 10.67(br, IH), 9.98(br, IH), 7.79(s, IH), 7.69-7.67(m,
2H), 7.56(dd, /=8.8, 2.0Hz, 2H), 7.14(t, /=4.4Hz, IH), 7.01 (d, /=2.0Hz, IH), 6.92(dd,
/=8.8, 2.0Hz, 2H), 2.18(d, /=2.0Hz, 3H) [778] [779] Step 8. Preparation of l-[6-(4-hvdroxy-phenyl)-2-thiophen-2-yl-thieno[2.3-dl nvrimidin-4-v1aminol-3-methvl-pyrrole-2.5-dione hydrochloride
[780]
Figure imgf000073_0001
[781] According to the similar procedure in the step 2 of example 2 by using the compound prepared in the step 8, 70mg (yield: 65%, yellow solid) of the target compound was obtained.
[782] 1H NMR(400D, DMSO-d): δ 10.73(br, IH), 7.84(s, IH), 7.69-7.67(m, 2H), 7.56(dd, /=8.8, 2.0Hz, 2H), 7.16-7.12(m, IH), 7.01(d, /=2.0Hz, IH), 6.93(dd, /=8.8, 2.0Hz, 2H), 2.18(d, /=2.0Hz, 3H)
[783] [784] Compounds listed below were prepared by the similar procedure in above Example 54.
[785] Example 55 . l-[6-(4-methoxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride
[786] [Table 4] [787]
Figure imgf000073_0003
[788] [789] Example 56 . l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-furo[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-d ione hydrochloride
[790] Steo 1. Preparation of 2-bromo- l-(4-methoxv-phenvlVproDan- 1-one [791]
Figure imgf000073_0002
[792] 4'-methoxypropiophenone (10.7ml, 70mmol) and CuBr (31.2g, 140mmol) were added to 1,4-dioxane (200ml). The reaction mixture was refluxed for 6 hours. After cooling to room temprature, the reaction mixture was diluted with water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 15:1) to give 13. Ig (yield: 76%, pale yellow solid) of the target compound. [793] 1U NMR(400D, CDCI): δ 8.03(d, J = 8.8 Hz, 2H), 7.08(d, J = 8.8 Hz, 2H), 5.79(q,
J = 6.4 Hz, IH), 3.87(s, 3H), 1.77(d, J= 6.4 Hz, 3H) [794] [795] Step 2. Preparation of
2-amino-5-(4-methoxy-phenyl)-4-methyl-furan-3-carbonitrile [796]
Figure imgf000074_0001
[797] The compound (2.43g, lOmmol) prepared in the step 1 and malononitrile (1.Og,
15mmol) were dissolved in dried N,N-dimethylformamide (10ml). Thereafter, the temperature was lowered into O0C. Therein, diethylamine (3.1ml, 30mmol) was added slowly with maintaining a temperature of the mixture below 4O0C, and the reaction mixture was stirred for 3 hours. The reaction mixture was poured into water (60ml) and filtered, washed with water and n-hexane. The residue was purified by recrys- tallization with ethanol to give 1.42g (yield: 68%, yellowish brown solid) of the target compound.
[798] 1U NMR(400D, CDCI): δ 7.45(br, 2H), 7.36(d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz,
2H), 3.77(s, 3H), 2.11(s, 3H)
[799]
[800] Step 3. Preparation of 6-(4-methoxy-phenyl)-5-methyl-2-thiophene-2-yl-furo[2.3-d lpyrimidin-4-ylamine
[801]
Figure imgf000074_0002
[802] The compound (910mg, 4mmol) prepared in the step 2 was dissolved in saturated
HCl in 1,4-dioxane solution (15ml) and 2-thiophenecarbonitrile (1.11ml, 12mmol) was added. The reaction mixture was stirred for 12 hours. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over dried over anhydrous magnesium sulfate. The residue was filtered with acetone and diethyl ether and washed with water and n-hexane to give 511mg (yield: 38%, brown solid) of the target compound.
[803] 1H-NMR (400D, DMSC^ ): δ 8.26(d, J=3.6Hz, IH), 7.89(d, J=4.4Hz, IH), 7.66(d,
J=8.8Hz, 2H), 7.25-7.23(m, IH), 7.09(d, J=8.8Hz, 2H), 3.82(s, 3H), 2.50(s, 3H)
[804] [805] Step 4. Preparation of
4-chloro-6-(4-methoxy-phenyls)-5-methyl-2-thiophen-2-yl-furor2.3-dlpyrirnidine [806]
Figure imgf000075_0001
[807] The compound (500mg, 1.5mmol) prepared in the step 3 and isoamylnitrite
(0.42ml, 3.2mmol) were dissolved in carbon tetrachloride (50ml). The reaction mixture was refluxed for 14 hours. Thereafter, the reaction mixture was cooled at room temper ature, and removed solvent under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 12:1) to give 37mg (yield: 7%, yellow solid) of the target compound.
[808] 1U NMR(400D, CDCI): δ 8.06(dd, /=3.8, 1.2Hz, IH), 7.76(d, /=8.8Hz, 2H),
7.50-7.49(m, IH), 7.16-7.14(m, IH), 7.04(d, /=8.8Hz, 2H), 3.89(s, 3H), 2.63(s, 3H)
[809]
[810] Step 5. Preparation of 4-(4-chloro-5-methyl-2-thiophene-2-yl-furor2.3-dl pyrimidin-6-yl)-phenol
[811]
Figure imgf000075_0002
[812] The compound (35mg, O.lmmol) prepared in the step 4 was dissolved in dichloromethane (20ml). Therein, IM boron tribromide(BBr ) in dichloromethane solution (0.25ml, 0.25mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. After reaction, the reaction mixture was poured into ethyl acetate, and washed with water and saturated sodium hydrogen carbonate aqueous solution. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 6:1) to give 31mg (yield: 91 %, yellow solid) of the target compound.
[813] 1H-NMR (400D, CDCI) δ 8.07-8.05(m, IH), 7.70(d, /=8.8, 2H), 7.50- 7.48(m, IH),
7.16-7.14(m, IH), 6.97 (d, /=8.8, 2H), 2.57(s, 3H)
[814]
[815] Step 6. Preparation of (2-r4-(4-chloro-5-methyl-2-thiophene-2-yl-furor2.3-dl pyrimidin-6-yl)-phenoxyl-ethyl)-dimethyl-amine
[816]
Figure imgf000076_0001
[817] The compound (31mg, 0.09mmol) prepared in the step 5,
N,N-dimethylethanolamine (0.085ml, 0.18mmol) and triphenylphosphine (PPh , 47 mg, 0.18mmol) were diluted with in THF (ImI). Therein diidopropylazodicarboxylate (0.035ml, 0.18mmol) was added. The reaction mixture was stirred for 36 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography (chloroform:methanol = 9:1) to give 15mg (yield: 40%, yellow solid) of the target compound.
[818] 1U NMR(400D, CDCD: δ 8.10-8.09(m, IH), 7.93(d, /=8.8, 2H), 7.50- 7.48(m, IH), 7.18-7.16(m, IH), 7.23(d, /=8.8, 2H), 4.18-4.15(m, 2H), 2.83-2.81(m, 2H), 2.67(s, 3H), 2.40(s, 6H)
[819] [820] Step 7. Preparation of (244-(4-hydrazino-5-methyl-2-thiophene-2-yl-furor2.3-dl pyrimidin-6-yl)-phenoxyl-ethyl)-dimethyl-amine
[821]
Figure imgf000076_0002
[822] The compound (15mg, 0.036mmol) prepared in the step 6 and hydrazine monohydrate (5D, O.lmmol) were dissolved in THF (3ml). The reaction mixture was refluxed for 5 hours. After reaction, reaction mixture was concentrated under reduced pressure. The residue was used to the next step without further purification.
[823] [824] Step 8. Preparation of l-(6-[4-(2-dimethylamino-ethoxy)-phenyll - 5-methyl-2-thiophene-2-yl-furo[2.3-dlpyrimidin-4-ylamino)-3-methyl-pyrrole-2.5-dio ne
[825]
Figure imgf000076_0003
[826] The compound prepared in the step 7 was dissolved in chloroform (3ml). Therein, citraconic anyhdride (89D, O.lmmol) was added. The reaction mixture was refluxed for 12 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 7:1) to give 12mg (yield: 66%, yellow solid) of the target compound.
[827] 1U NMR(400D, CDCD: δ 7.77(dd, /=3.6, 1.2Hz, IH), 7.63(d, /=8.8Hz, 2H), 7.35(dd, /=5.0, 1.2Hz, IH), 7.06(dd, /=5.0, 4.0Hz, IH), 7.02(d, /=8.8Hz, 2H), 6.63(q, /=1.6Hz, IH), 4.20(t, /=5.6Hz, 2H), 2.89(t, /=5.2Hz, 2H), 2.52(s, 3H), 2.44(s, 6H), 2.27(d, /=1.6Hz, 3H)
[828] [829] Step 9. Preparation of l-(6-[4-(2-dimethylamino-ethoxy)-phenyll - 5-methyl-2-thiophene-2-yl-furo[2.3-dlpyrimidin-4-ylamino)-3-methyl-pyrrole-2.5-dio ne hydrochloride
[830]
Figure imgf000077_0001
[831] The compound (12mg, 0.036mmol) prepared in the step 8 was dissolved in 1,4-dioxane (ImI). Therein, 4N HCl 1,4-dioxane solution(0.10ml, 0.4mmol) was added, and the reaction mixture was stirred for 1 hour. The resulting solid was filtered and washed with 1,4-dioxane and ethyl acetate to give 12mg (yield: 93%, yellow solid) of the target compound.
[832] 1U NMR(400D, DMSO-d): δ 10.23(br, IH), 9.59(s, IH), 7.77(d, J=SABz, 2H), 7.71-7.67(m, 2H), 7.20(d, J=SABz, IH), 7.15-7.13(m, 2H), 7.01(s, IH), 4.44(br, 2H), 3.55(br, 2H), 2.87(d, /=4.4Hz, 6H), 2.59(s, 3H), 2.18(s, 3H)
[833] [834] Example 57 . l-[6-(4-methoxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride
[835] Step 1. Preparation of 2-amino-5-(4-methoxy-phenylV4-methyl-thiophen-3-carboxylic acid ethyl ester [836]
Figure imgf000077_0002
[837] l-(4-methoxy-phenyl)-propan-2-one (3.08ml, 20mmol), ethyl cyanoacetate (2.13ml, 22mmol) and sulfur (704mg, 20mmol) were dissolved in ethanol (15ml). Therein, di- ethylamine (2.07ml, 20mmol) was added slowly, and the reaction mixture was stirred at room temperature for 36 hours. After reaction, the reaction mixture was poured into ethyl acetate, and washed with water. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 10:1) to give 3.79g
(yield: 65%, pale yellow solid) of the target compound. [838] 1U NMR(400D, CDCI): δ 7.39(br, 2H), 7.23(d, J=8.8Hz, 2H), 6.96(d, J=8.8Hz,
2H), 4.19(q, J=6.8Hz, 2H), 3.76(s, 3H), 2.19(s, 3H), 1.26(t, J=6.8Hz, 3H) [839] [840] Step 2. Preparation of
6-(4-methoxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2.3-dlpyrimidin-4-ol [841]
Figure imgf000078_0001
[842] The compound (874mg, 3mmol) prepared in the step 1 was dissolved in saturated
HCl in 1,4-dioxane solution (10ml). Therein, 2-thiophencarbonitrile (0.419ml, 4.5mmol) was added, and the reaction mixture was stirred for 12 hours. After reaction, the reaction mixture was poured into saturated sodium bicarbonate aqueous solution. The resulting solid was filtered and washed with water and ethyl acetate to give 948mg (yield: 93%, yellow solid) of the target compound.
[843] 1U NMR(400D, DMSO-d): δ 8.25(d, J=3.6Hz, IH), 7.89(d, J=4.8Hz, IH), 7.46(d, J
=8.8Hz, 2H), 7.25(t, J=4.8Hz, IH), 7.07(d, J=8.8Hz, 2H), 3.81(s, 3H), 2.54(s, 3H)
[844]
[845] Step 3. Preparation of
4-chloro-6-(4-methoxy-phenylV5-methyl-2-thiophen-2-yl-thienor2.3-dlpyrimidine
[846]
Figure imgf000078_0002
[847] The compound (948mg, 2.79mmol) prepared in the step 2 was dissolved in phos- phrousoxy chloride (POCl , 5ml). Thereafter, the reaction mixture was refluxed for 3 hours. After reaction, the reaction mixture was poured into saturated sodium bicarbonate aqueous solution. The resulting solid was filtered and washed with water and n-hexane to give 948mg (yield: 91%, yellow solid) of the target compound.
[848] 1U NMR(400D, CDCI): δ 8.07(d, J=3.6Hz, IH), 7.51(d, J=4.8Hz, IH), 7.44(d, J
=8.8Hz, 2H), 7.16(t, J=4.8Hz, IH), 7.02(d, J=8.8Hz, 2H), 3.88(s, 3H), 2.65(s, 3H)
[849]
[850] Step 4. Preparation of l-r6-(4-methoxy-phenylV5-methyl-2-thiophen-2-yl-thienor2.3-dlpyrimidin-4-ylaminol -3-methyl-pyrrole-2.5-dione hydrochloride
[851]
Figure imgf000079_0001
[852] According to the similar procedure in the step 5 and 6 of example 8(method 1) by using the compound prepared in the step 3, 150mg (yield for final step: 78%, yellow solid) of the target compound was obtained. [853] 1U NMR(400D, DMSO-d): δ 9.66(s, IH), 7.70-7.68(m, 2H), 7.49(d, J=8.8Hz, 2H),
7.16-7.09(m, 3H), 7.01(d, J=2.0Hz, IH), 3.82(s, 3H), 2.62(s, 3H), 2.18(d, J=2.0Hz,
3H) [854] [855] Compounds listed below were prepared by the similar procedure in above Example
57. [856] Example 58 . l-[6-(4-hydroxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride [857] Example 59 .
[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen-2-yl-t hieno[2,3-d]pyrimidin-6-yl]-acetic acid methyl ester hydrochloride [858] Example 60 . l-[6-(3-hydroxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino]-3-methyl-pyrrole-2,5-dione [859] Example 61 .
5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen-2-yl-thi eno[2,3-d]pyrimidin-6-carboxylic acid amide hydrochloride [860] Example 62 . l-[6-(3-methoxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino]-3-methyl-pyrrole-2,5-dione [861] Example 63 .
5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen-2-yl-thi eno[2,3-d]pyrimidin-6-carboxylic acid methyl ester hydrochloride [862] Example 64 . l-(6-methoxy-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride [863] Example 65 . l-[6-(4-methoxy-benzyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino] -pyrrole-2,5-dione hydrochloride [864] Example 66 . l-[6-(4-hydroxy-benzyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino] -pyrrole-2,5-dione hydrochloride [865] Example 67 .
3-methyl-l-[5-methyl-6-(4-nitrophenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4- ylamino] -pyrrole-2,5-dione hydrochloride [866] Example 68 . 3-methyl-l-(6-phenyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino)-pyrrole-2,5-dione hydrochloride [867] Example 69 .
3-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen-2-yl- thieno[2,3-d]pyrimidin-6-yl]-propionic acid ethyl ester [868] Example 70 . l-(6-hydroxymethyl-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride [869] Example 71 . l-(6-methoxymethyl-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride [870] [Table 5]
[871]
Figure imgf000081_0001
[872]
Figure imgf000082_0002
[873] [874] Intermediate (40) : Preparation of
(4-chloro-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-6-yl)-acetic acid methyl ester
[875] Step 1. Preparation of 4-oxo-pentanoic acid methyl ester [876]
0
OH cone H2 SO4 O Me
0 M eOH1 reflux, 1 8hr 0
[877] 4-oxo-pentanoic acid (Ig, 8.61mmol) and catalyst amount of sulfuric acid were dissolved in methanol (10ml). The reaction mixture was refluxed to give 740mg (yield: 66%, colorless oil) of the target compound.
[878] [879] Step 2. Preparation of (4-chloro-5-methyl-2-thiophen-2-yl-thienor2.3-dl pyrimidin- 6-ylVacetic acid methyl ester
[880]
Figure imgf000082_0001
[881] According to the similar procedure in the step 1 to 3 of example 57 by using the compound prepared in the step 1, 181mg (yield for final step: 85%, yellow oil) of the target compound was obtained.
[882] 1U NMR(400D, CDCD: δ 8.22(d, J=3.6Hz, IH), 7.87(d, J=5.1Hz, IH), 7.22(t, J=4.3Hz, IH), 3.94(s, 2H), 3.65(s, 3H), 2.41(s, 3H)
[883] [884] Intermediate (41) : Preparation of 4-chloro-6-(3-methoxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidine
[885]
Figure imgf000083_0001
[886] According to the similar procedure in the step 1 to 3 of example 57 by using l-(2-methoxy-phenyl)-propan-2-one, 330mg (yield for final step: 89%, yellow solid) of the target compound was obtained.
[887] 1U NMR(400D, CDCI): δ 8.09(dd, J=3.6Hz, IH), 7.52(dd, J=4.8Hz, IH), 7.41(t,J
=8Hz, IH), 7.17(dd, J=5.2Hz, IH), 7.07 (d, J=6.8Hz, IH), 7.03-6.97 (m, 2H), 3.87(s, 3H), 2.67(s, 3H)
[888] [889] Intermediate (42) : Preparation of 4-chloro-6-(3-hydroxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidine
[890]
Figure imgf000083_0002
[891] The intermediate (41) (250mg, 0.67mmol) was dissolved in IM boron tribromide dichloromethane solution (0.28ml, 1.67mmol) slowly, and the reaction mixture was stirred at room temprature for 12 hours. After reaction, the reaction mixture was poured into saturated sodium hydrogen carbonate aqueous solution. The resulting solid was filtered and washed with water and ethyl acetate to give 1 lOmg (yield: 55%, yellow solid) of the target compound.
[892] 1U NMR(400D, CDCD: δ 9.88(br, IH), 8.01(t, IH), 7.85(d, J=5.2Hz, IH), 7.36(t, J =8.0Hz, IH), 7.25(t, J=4.0Hz, IH), 7.00-6.90(m, 3H), 2.62(s, 3H)
[893] [894] Intermediate (43) : Preparation of
4-chloro-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-6-carboxylic acid methyl ester
[895]
Figure imgf000084_0001
[896] According to the similar procedure in the step 1 to 3 of example 57 by using methyl acetoacetate, 330mg (yield for 3 steps: 14%, white solid) of the target compound was obtained. [897] 1U NMR(400D, DMSO-d): δ 7.93(br, IH), 7.68(br, IH), 7.14(br, IH), 3,78(s, 3H),
2.84(s, 3H) [898] [899] Intermediate (44) : Preparation of
4-chloro-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-6-carboxylic amide [900]
Figure imgf000084_0002
[901] According to the similar procedure in the step 1 to 3 of example 57 by using ace- toacetamide, 80mg (yield for 3 steps: 5%, yellow solid) of the target compound was obtained. [902] 1U NMR(400D, DMSO-d); δ 7.99(d, J=3.6Hz, IH), 7.70(d, J=4.8Hz, IH), 7.49(br,
2H), 7.15(t, J=4.0Hz, IH), 2.75(s, 3H) [903] [904] Intermediate (45) : Preparation of
4-chloro-6-methoxy-5-methyl-2-thiophen-2-yl-thienor2.3-dlpyrimidine [905]
Figure imgf000084_0003
[906] According to the similar procedure in the step 1 to 3 of example 57 by using the compound, methoxy acetone, the target compound (yield for final step: 32%, yellow solid) was obtained. [907] 1U NMR(400D, CDCI): δ 7.98(dd, /=4.0, 1.2Hz, IH), 7.45(dd, /=5.2, 1.2Hz, IH),
7.13(dd, /=5.2, 4.0Hz, IH), 4.03(s, 3H), 2.44(s, 3H) [908] [909] Intermediate (46) : Preparation of
4-chloro-6-(4-methoxy-benzyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidine [910]
Figure imgf000085_0001
[911] According to the similar procedure in the step 1 to 3 of example 57 by using the compound, 4-(4-methoxyphenyl)-2-butanone, 260mg (yield for final step: 52%, yellow solid) of the target compound was obtained. [912] 1U NMR(400D, CDCI): δ 8.02(dd, J=LlBz, IH), 7.47(dd, J=LlBz, IH),
7.15-7.12(m, 3H), 6.86(d, J=8.8Hz, 2H), 4.13(s, 2H), 3.79(s, 3H), 2.61(s, 3H) [913] [914] Intermediate (47) : Preparation of
4-(4-chloro-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-phenol
[915]
Figure imgf000085_0002
[916] The intermediate (46) (280mg, 0.7mmol) was dissolved in dichloromethane.
Therein, IM boron tribromide dichloromethane solution (0.58ml, 3.5mmol) was added solwly, and the reaction mixture was stirred at room temprature for 12 hours. After reaction, the reaction mixture was poured into saturated sodium hydrogen carbonate aqueous solution. The resulting solid was filtered and washed with water and ethyl acetate to give 60mg (yield for final step: 23%, yellow solid) of the target compound.
[917] 1U NMR(400D, CDCI): δ 9.42(br, IH), 7.96(d, IH), 7.80(d, J=4.4Hz, IH), 7.22(t, J
=4.0Hz, IH), 7.08(d, J=7.6Hz, 2H), 6.72(d, J=7.2Hz, 2H), 4.16(s, 2H), 2.60(s, 3H)
[918]
[919] Intermediate (48) : Preparation of
4-chloro-5-methyl-6-(4-nitrophenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidine
[920] Step 1. Preparation of pentan-2.4-dione sodium salt
[921]
0 0 0 0
A-X. ΛΛ θ Naφ
[922] Pentan-2,4-dione (4.85g, 48.4mmol) was dissolved in ethanol (15ml). Thereafter, the reaction mixture was stirred at room temperature for 48 hours. The resulting solid was filtered and washed with n-hexane and diethyl ether to give 2.53g (yield: 44%, white solid) of the target compound. [923]
[924] Step 2. Preparation of l-(4-nitrophenyls)-propan-2-one
[925]
- O N-O S
N a
[926] The compound (88Omg, 7.21mmol) prepared in the step 1 was dissolved in
N,N-dimethylformamide (4.3ml). 4-bromonitrobenzene (292mg, 1.44mmol) and copper iodide (CuI, 274mg, 1.44mmol) were added to the solution. The reaction mixture was stirred at 11O0C for 2 hours under nitrogen atmosphere. After cooling the room temprature, IN sodium hydroxide aqueous solution (5ml) was added to the mixture, and stirred at room temperature for 3 hours. After reaction, the reaction mixture was poured into ethyl acetate, and washed with saturated sodium chloride aqueous solution twice. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 1:4) to give 78mg (yield: 30%, yellow oil) of the target compound.
[927] 1U NMR(400D, CDCI): δ 8.07(d, /=4.2, 2H), 7.63(d, /=4.8, 2H), 3.71(s, 2H),
2.08(s, 3H).
[928]
[929] Step 3. Preparation of 2-amino-4-methyl-5-(4-nitrophenylVthiophen-3-carboxylic acid methyl ester
[930]
Figure imgf000086_0001
[931] The compound (78mg, 0.43mmol) prepared in the step 2 was dissolved in ethanol
(0.5ml). Ethyl cyanoacetate (48mg, 0.43mmol), sulfur (13mg, 0.39mmol) and di- ethylamine (0.04ml, 0.39mmol) were added, and the reaction mixture was stirred at room temprature for 48 hours. After reaction, the reaction mixture was poured into ethyl acetate, and washed with brine and water twice. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 3:1) to give 24mg (yield: 20%, red solid) of the target compound.
[932] 1H NMR(400D, CDCI): δ 8.23(d, /=8.4, 2H), 7.48(d, /=8.4, 2H), 6.30(brs, 2H),
4.30(q, /=7.2Hz,2H), 2.40(s, 3H), 1.39(t, /=6.8Hz, 3H).
[933]
[934] Step 4. Preparation of 4-chloro-5-methyl-6-(4-nitrophenyls)-2-thiophen-2-yl-thienor2.3-dlpyrimidine [935]
Figure imgf000087_0001
[936] According to the similar procedure in the step 2 and 3 of example 57 by using the compound prepared in the step 3, 400mg (yield for 2 steps: 88%, yellow solid) of the target compound was obtained. [937] 1U NMR(400D, CDCI): δ 2.70 (s, 3H), 7.17 (dd, IH), 7.26 (S, IH, 6-H), 7.54 (dd,
IH), 7.69 (d, 2H) 8.10 (dd, IH), 8.37 (d, 2H) [938] [939] Intermediate (49) : Preparation of
3-(4-chloro-5-methyl-2-thiophen-2-yl-thienor2.3-dlpyrimidin-6-vπ-propionic acid methyl ester [940]
Figure imgf000087_0002
[941] According to the similar procedure in the step 1 to 3 of example 57 by using ethyl
4-acetobutyrate, 243mg (yield for final step: 77%, yellow oil) of the target compound was obtained. [942] 1U NMR(400D, CDCI): δ 8.04~8.03(m, IH), 7.49~7.48(m, IH), 7.16~7.13(m, IH),
4.16(q, /=7.3, 6.9Hz, 2H), 3.21(t, /=7.5Hz, 2H), 2.69(t, /=7.5Hz, 2H), 2.58(s, 3H),
1.27(s, /=7.1Hz, 3H) [943] [944] Intermediate (50) : Preparation of
(4-chloro-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-6-yl)-methanol [945]
Figure imgf000087_0003
[946] The intermediate 43, 4-chloro-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
6-carboxylic acid methyl ester (120mg, 0.35mmol) was dissolved in THF (5ml). Thereafter, the temperature was lowered into O0C. Therein, lithium aluminum hydride (14mg, 0.35mmol) was slowly added, and the reaction mixture was stirred at room temperature for 30 minutes. Water (0.014ml) was added to quench the reaction. Ethyl acetate was added and the reaction mixture was washed with water and saturated ammonium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 32mg (yield: 31%, white solid) of the target compound. [947] 1U NMR(400D, CDCI): δ 8.04(m, IH), 7.50(m, IH), 7.15(m, IH), 4.91(s, 2H),
2.55(s, 3H) [948] [949] Intermediate (51) : Preparation of
4-chloro-6-methoxymethyl-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidine [950]
Figure imgf000088_0001
[951] The intermediate 50, (4-chloro-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
6-yl)-methanol (50mg, 0.13mmol) was dissolved in dried THF (5ml). Thereafter, the temperature was lowered into O0C. Therein, 60% sodium hydride (5.6mg, 0.14mmol) was added, and the reaction mixture was stirred at O0C for 30minutes. Iodomethane (0.008ml, 0.13mmol) was added, and stirred at room temperature for 2 hours. Ethyl acetate was added to the mixture and washed with water and saturated ammonium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 3:1) to give 28mg (yield: 51%, yellow oil) of the target compound.
[952] 1U NMR(400D, CDCI): δ 8.05(d, J=3.6Hz, IH), 7.50(d, J=4.4Hz, IH), 7.16(m,
IH), 4.92(s, 2H), 3.82(s, 3H), 2.49(s, 3H)
[953]
[954] Example 72 . l-[6-(3-methoxybenzyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride
[955] Step 1. Preparation of 4-(3-methoxyphenyl)-3-buten-2-one
[956]
Figure imgf000088_0002
[957] meta-Anisaldehyde (5g, 36.72mmol) was dissolved in acetone (30ml). Thereafter, the solution of sodium hydroxide (2.05g, 51.41mmol) in water (30ml) was added slowly, and the reaction mixture was stirred at room temperature for 2 hours. After reaction, solvent was concentrated. The residue was diluted with ethyl acetate and washed with water. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 3:2) to give 4.3g (yield: 66%, yellow oil) of the target compound. [958] 1U NMR(400D, CDCI): δ7.50(d, /=16. IHz, IH), 7.32(t, J=UUz, IH), 7.15(d, /
=6.6Hz, IH), 7.06(s, IH), 6.97~6.94(m, IH), 6.72(d, /=16.1Hz, IH), 6.84(s, 3H),
2.39(s, 3H) [959]
[960] Step 2. Preparation of 4-(3-methoxyphenyl)-3-butan-2-one
[961]
Figure imgf000089_0001
[962] The compound (4.43g, 24.40mmol) prepared in the step 1 was dissolved in ethanol
(25ml). Catalyst amount of acetic acid and Palladium 10wt.% on activated carbon were added to the mixture. The reaction mixture was stirred on hydrogen atmosphere at room temperature. The reaction mixture was filtered through the cellite pad. The filtrate was concentrated under reduced pressure to give 3.87g (yield: 89%, colorless oil) of the target compound.
[963] 1U NMR(400D, CDCI): δ7.20(t, /=8.0Hz, IH), 6.78~6.75(m, 2H), 6.73(s, IH),
3.79(s, 3H), 2.89~2.85(m, 2H), 2.78~2.74(m, 2H), 2.15(s, 3H)
[964]
[965] Step 3. Preparation of
4-chloro-6-(3-methoxybenzyl)-5-methyl-2-thiophen-2-yl-thieno[2.3-dlpyrimidine
[966]
Figure imgf000089_0002
[967] According to the similar procedure in the step 1 and 3 of example 57 by using the compound (3.87g, 21.71mmol) prepared in the step 2, 783mg (yield for final step:
75%, yellow oil) of the target compound was obtained. [968] 1U NMR(400D, CDCI): δ7.96~7.95(m, IH), 7.82~7.81(m, IH), 7.27~7.21(m, 2H),
6.87~6.82(m, 3H), 4.27(s, 2H), 3.73(s, 3H), 2.59(s, 3H) [969] [970] Step 4. Preparation of l-[6-(3-methoxybenzyl)-5-methyl-2-thiophen-2-yl-thieno[2.3-dlpyrimidin-4-ylaminol-
3-methyl-pyrrole-2.5-dione hydrochloride [971]
Figure imgf000090_0001
[972] According to the similar procedure in the step 5 and 6 of example 8 (method 1) by using the compound (86mg, 0.22mmol) prepared in the step 3, 20mg (yield for final step: 40%, yellow solid) of the target compound was obtained. [973] 1H-NMR^OOD, DMSC^ ): δ9.56(s, IH), 7.66~7.63(m, 2H), 7.24(t, J=7.8Hz, IH),
7.13~7.10(m, IH), 7.00(s, IH), 6.85~6.80(m, 3H), 4.21(s, 2H), 3.73(s, 3H), 2.60(s,
3H), 2.17(s, 3H)
[974] [975] Example 73 . l-tø-CS-hydroxy-benzyO-l-thiophen-l-yl-thienol^β-d] pyrimidin- 4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride
[976] Step 1. Preparation of 3-(4-chloro-5-methyl-2-thiophen-2-yl-thieno[2.3-d1 pyrimidin-6-ylmethvl)-phenol [977]
Figure imgf000090_0002
[978] According to the similar procedure in the intermediate 47 by using the compound (400mg, 1.03mmol) prepared in the step 3 of example 72, 320mg (yield: 83%, yellow solid) of the target compound was obtained.
[979] 1H-NMR^OOD, DMSC^ ): δ9.35(s, IH), 8.21 (d, J=4.3Hz, IH), 7.85(d, J=5.1Hz, IH), 7.24~7.20(m, IH), 7.13~7.04(m, IH), 6.67 (d, J=7.7Hz, IH), 6.61(s, IH), 4.04(s, 2H), 2.47(s, 3H)
[980] [981] Step 2. Preparation of l-[6-(3-hvdroxy-benzyl)-2-thiophen-2-yl-thieno[2.3-d1 pyrimidin-4-ylamino1 -3-methyl-pyrrole-2.5-dione hydrochloride
[982]
Figure imgf000090_0003
[983] According to the similar procedure in the step 5 and 6 of example 8 (method 1) by using the compound (lOOmg, 0.26mmol) prepared in the step 1, 2mg (yield for final step: 22%, yellow solid) of the target compound was obtained.
[984] 1H-NMR^OOD, DMSC^ ): δ8.21(d, J=3.6Hz, IH), 7.85(d, J=4.7Hz, IH), 7.68~7.63(m, IH), 7.21~7.20(m, IH), 7.10(t, J=8.0Hz, IH), 6.67 (d, J=7.3Hz, IH),
6.61~6.60(m, 2H), 4.04(s, 2H), 3.56(s, 3H), 2.20(s, 3H) [985] [986] Example 74 . l-{6-[3-(2-dimethylamino-ethoxy)-benzyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dione hydrochloride [987] Step 1. Preparation of (2-r3-f4-chloro-5-methyl-2-thiophen-2-yl-thienor2.3-dl pyrimidin-6-ylmethyl)-phenoxy1-ethyl)-dimethyl-amine [988]
Figure imgf000091_0001
[989] According to the similar procedure in the step 6 of example 56 by using the compound (lOOmg, 0.22mmol) prepared in the step 1 of example 73, 38mg (yield: 31%) of the target compound was obtained.
[990] 1H-NMR^OOD, OMSOd ): δ9.37(s, IH), 7.94~7.93(m, IH), 7.74~7.73(m, IH),
7.20~7.18(m, IH), 7.10(t, J=7.7Hz, IH), 6.69(d, J=7.7Hz, IH), 6.62(s, IH), 4.67(t, J =5.7Hz, 2H), 4.12(s, 2H)
[991]
[992] Step 2. Preparation of l-(6-r3-(2-dimethylamino-ethoxy)-benzyl1 -
2-thiophen-2-yl-thienor2.3-d1pyrimidin-4-ylamino)-3-methyl-pyrrole-2.5-dione hydrochloride
[993]
Figure imgf000091_0002
[994] According to the similar procedure in the step 5 and 6 of example 8 (method 1) by using the compound (50mg, 0.1 lmmol) prepared in the step 1, 22mg (yield for final step: 88%, yellow solid) of the target compound was obtained.
[995] 1H-NMR^OOD, OMSOd ): δlθ.78(br s, IH), 7.99~7.98(m, IH), 7.77(d, J=5.1Hz,
IH), 7.22~7.20(m, IH), 7.12(t, J=7.7Hz, IH), 6.69~6.62(m, 3H), 4.98~4.96(m, 2H), 4.14(s, 2H), 3.66~3.65(m, 2H), 2.88(s, 3H), 2.87(s, 3H), 2.52(s, 3H), 2.20(s, 3H)
[996]
[997] Example 75 .
5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen-2-yl-thi eno[2,3-d]pyrimidin-6-carboxylic acid-(2-dimethylamino-ethyl)-amide hy- drochloride
[998] Step 1. Preparation of 4-hvdroxy-5-methyl-2-thiophen-2-yl-thienor2.3-dl pyrimidin-6-carboxylic acid ethyl ester
[999]
Figure imgf000092_0001
[1000] According to the similar procedure in the step 1 and 2 of example 57 by using the compound, ethyl acetoacetate, 1.5g (yield: 61%, yellow solid) of the target compound was obtained. [1001] 1U NMR(400D, DMSO-d): δ 8.27(d, J=3.6Hz, IH), 7.94(d, J=5.2Hz, IH), 7.25(t, J
=4.4Hz, IH), 4.30(q, J=7.2Hz, 2H), 2.83(s, 3H), 1.3 l(t, J=6.8Hz, 3H) [1002] [1003] Step 2. Preparation of 4-hvdroxy-5-methyl-2-thiophen-2-yl-thienor2.3-dl pyrimidin-6-carboxylic acid [1004]
Figure imgf000092_0002
[1005] The compound (480mg, 1.5mmol) prepared in the step 1 was added to 2N sodium hydroxide aqueous solution (30ml). Thereafter, the reaction mixture was refluxed for 14 hours. After reaction, the reaction mixture was extracted with ethyl acetate. The aqueous layer was acidified with 6N HCl aqueous solution, and the solid was filtered. Thereafter, the resulting solid was washed with water and n-hexane to give 410mg (yield: 94%, white solid) of the target compound.
[1006] 1U NMR(400D, DMSO-d): δ 8.28(d, J=4.0Hz, IH), 7.94(d, J=4.87Hz, IH),
7.26-7.24(m, IH), 2.82(s, 3H)
[1007]
[1008] Step 3. Preparation of 4-chloro-5-methyl-2-thiophen-2-yl-thieno[2.3-dl pvrimidin-
6-carboxylic acid
[1009]
Figure imgf000092_0003
[1010] According to the similar procedure in the step 4 of example 8 (method 1) by using the compound prepared in the step 2, 320mg (yield: 52%, yellow solid) of the target compound was obtained.
[1011] 11UU NNMMRR((440000DD,, CCDDCCII)): δ 9.70(br, IH), 8.08(dd, /=3.8, 1.2Hz, IH), 7.57(dd, /=5.2, 0.8Hz, IH), 7.18(dd, /=5.2, 4.0Hz, IH), 3.03(s, 3H)
[1012]
[1013] Step 4. Preparation of 4-chloro-5-methyl-2-thiophen-2-yl-thieno[2.3-dl pyrimidin-
6-carboxylic acid-(2-dimethylamino-ethyl)-amide [1014]
Figure imgf000093_0001
[1015] To the compound (60mg, 0.20mmol) prepared in the step 3, were added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (48mg, 0.26mmol) and 1-hydroxybenzotriazole hydrate (2mg, 0.02mmol) with dichlorome thane (2ml). Therein, N,N-dimethylethyenediamine (24D, 0.22mmol) was added slowly. The reaction mixture was stirred for 2 hours. After reaction, the solvent was removed under reduced pressure. The residue was purified by column chromatography (chloroform:methanol = 9:1) to give 60mg (yield: 80%, yellow solid) of the target compound.
[1016] 1U NMR(400D, CDCI): δ 8.10(d, /=4.0Hz, IH), 7.55(d, /=4.8Hz, IH),
7.19-7.17(m, IH), 6.84(br, IH), 3.54(q, /=5.6Hz, 2H), 2.91(s, 3H), 2.55(t, /=5.6Hz, 2H), 2.29(s, 6H)
[1017]
[1018] Step 5. Preparation of
5-methyl-4-G-methyl-2.5-dioxo-2.5-dihydro-pyrrol-l-ylaminoV2-thiophen-2-yl-thieno r2.3-dlpyrimidin-6-carboxylic acid-(2-dimethylamino-ethylVamide hydrochloride
[1019]
Figure imgf000093_0002
[1020] According to the similar procedure in the step 5 to 6 of example 8 (method 1) by using the compound prepared in the step 4, 35mg (yield for final step: 54%, yellow solid) of the target compound was obtained.
[1021] 1U NMR(400D, DMSO-d): δ 11.34(br, IH), 9.55(br, IH), 8.78(t, /=5.6Hz, IH),
7.84(d, /=3.6Hz, IH), 7.47(d, /=4.8Hz, IH), 7.10(t, /=3.6Hz, IH), 6.69(d, J=LlBz, IH), 3.86-3.82(m, 2H), 3.43-3.39(m, 2H), 2.97(s, 3H), 2.94(d, /=4.8Hz, 6H), 2.24(d, / = 1.2Hz, 3H) [1022]
[1023] Example 76 . 3-methyl-l-{5-[4-(2-piperidin-l-yl-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride
[1024]
Figure imgf000094_0001
[1025] According to the similar procedure in the step 6 of example 56 and in the step 5 and 6 of example 8(method 1) by using 4-(4-chloro-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-5-yl)-phenol prepared in example 11, 8mg (yield for final step: 38%, yellow solid) of the target compound was obtained.
[1026] 1U NMR (400D, DMSO-d): δ 10.43(s, IH), 9.52(s, IH), 8.76(d, J=5.2Hz, IH),
7.54(d, J=8.0Hz, 2H), 7.15(m, 3H), 7.02(s, IH), 4.52(s, 2H), 3.01(m, 2H), 2.14(s, 3H), 1.81-1.69(m, 5H), 1.20(m, IH)
[1027]
[1028] Compounds listed below were prepared by the similar procedure in above Example 76.
[1029] Example 77 . 3-methyl-l-{5-[3-(2-piperidin-l-yl-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride
[1030] Example 78 . l-{5-[3-(2-dimethylamino-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dione hydrochloride
[1031] Example 79 . l-{5-[3-(3-dimethylamino-propoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dione hydrochloride
[1032] Example 80 . 3-methyl-l-{5-[3-(2-morpholin-4-yl-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride
[1033] Example 81 . 3-methyl-l-{5-[3-(2-piperazin-l-yl-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione dihy- drochloride
[1034] Example 82 .
3-methyl-l-[5-methyl-6-(4-methyl-piperazin-l-ylmethyl)-2-thiophen-2-yl-thieno[2, 3-d]pyrimidin-4-ylamino] -pyrrole-2,5-dione dihydrochloride
[1035] Example 83 . 3-methyl-l-(5-{3-[2-(4-methyl-piperazin-l-yl)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione dihydrochloride
[1036] [Table 6] [1037]
Figure imgf000095_0001
[1038]
[1039] Example 84 . l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5
-dione hydrochloride
[1040] Step 1. Preparation of 4-(4-chloro-5-methyl-2-thiophen-2-yl-thienor2.3-dl pyrimidin-6-ylVphenol [1041]
Figure imgf000096_0001
[1042] The compound (559mg, 1.5mmol) prepared in the step 3 of example 57 was dissolved in dichloromethane. Therein, IM boron tribromide in dichloromethane solution (3.75ml, 3.75mmol) was added slowly, and the reaction mixture was stirred at room temperature for 12 hours. After reaction, the reaction mixture was poured into saturated sodium hydrogen carbonate aqueous solution. The resulting solid was filtered and washed with water and ethyl acetate to give 435mg (yield: 81 %, yellow solid) of the target compound.
[1043] 1H-NMR (400D, DMSO-d): δ 10.0(s, IH), 7.98(dd, /=4.0, 1.2Hz, IH), 7.84(dd, / =5.2, 1.2Hz, IH), 7.40(dd, /=8.8, 2.0Hz, 2H), 7.23(dd, /=5.2, 4.0Hz, IH), 7.98(dd, / =8.8, 2.0Hz, 2H), 2.57(s, 3H)
[1044] [1045] Step 2. Preparation of (2-r4-(4-chloro-5-methyl-2-thiophen-2-yl-thienor2.3-dl pyrimidin-6-ylVphenoxyl-ethyl)-dimethyl-amine
[1046]
Figure imgf000096_0002
[1047] The compound (151mg, 0.42mmol) prepared in the step 1, triphenylphosphine (PPh , 220mg, 0.84mmol) and N,N-dimethylethanolamine (85D, 0.42mmol) were diluted with in THF (ImI). Therein, diisopropylazodicarboxylate (DIAD, 170D, 0.84mmol) was added slowly, and the reaction mixture was stirred at room temperature for 36 hours. Solvent was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:methanol = 20:1) to give 83mg (yield: 46%, white solid) of the target compound.
[1048] 1H-NMR (400D, CDCD: δ 8.05(dd, /=4.0, 1.2Hz, IH), 7.48(dd, /=5.2, 1.2Hz, IH), 7.41(dd, /=8.8, 2.0Hz, 2H), 7.16(dd, /=5.2, 4.0Hz, IH), 7.02(dd, /=8.8, 2.0Hz, 2H), 4.13(t, /=5.6Hz, 2H), 2.79(t, /=5.6Hz, 2H), 2.62(s, 3H), 2.37(s, 6H)
[1049] [1050] Step 3. Preparation of (2-r4-(4-hydrazino-5-methyl-2-thiophen-2-yl-thienor2.3-dl pyrimidin-6-ylVphenoxyl-ethyl)-dimethyl-amine
[1051]
Figure imgf000096_0003
[1052] The compound (83mg, 0.193mmol) prepared in the step 2 and hydrazine monohydrate (H NNH -H O, 2OD, 0.425mmol) were dissolved in THF (3ml). The reaction mixture was refluxed for 5 hours. After reaction, the reaction mixture was concentrated under reduced pressure. The residue was used to the next step without further purification.
[1053]
[1054] Step 4. Preparation of l-(6-[4-(2-dimethylamino-ethoxyy phenyl! -
5-methyl-2-thiophen-2-yl-thieno[2.3-dlpyrimidin-4-ylamino)-3-methyl-pyrrole-2.5-di one
[1055]
Figure imgf000097_0001
[1056] The compound prepared in the step 3 was dissolved in chloroform (3ml). Therein, citraconic anyhdride (26D, 0.29mmol) was added. The reaction mixture was refluxed for 4 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 1:1) to give 32mg (yield: 32%, pale yellow solid) of the target compound.
[1057] 1U NMR(400D, CDCI): δ 7.76(d, J=3.6Hz, IH), 7.70(s, IH), 7.38(d, J=4.4Hz, IH),
7.33(d, J=8.4Hz, 2H), 7.07(t, J=4.4Hz, IH), 6.95(d, J=8.4Hz, 2H), 6.63(d, J=1.6Hz, IH), 4.46(t, J=4.0Hz, 2H), 3.52(t, J=4.0Hz, 2H), 2.96(s, 6H), 2.55(s, 3H), 2.26(d, J = 1.6Hz, 3H)
[1058]
[1059] Step 5. Preparation of l-(6-[4-(2-dimethylamino-ethoxy)-phenyll -
5-methyl-2-thiophen-2-yl-thieno[2.3-dlpyrimidin-4-ylamino)-3-methyl-pyrrole-2.5-di one hydrochloride
[1060]
Figure imgf000097_0002
[1061] The compound (32mg, 0.062mmol) prepared in the step 4 was dissolved in
1,4-dioxane (3ml). Therein 4M HCl 1,4-dioxane solution (10OD, 0.4mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The resulting solid was filtered and washed with 1,4-dioxane and diethyl ether to give 14mg (yield: 42%, yellow solid) of the target compound.
[1062] 1U NMR(400D, DMSO-d): δ 10.3(br, IH), 9.68(s, IH), 7.72-7.66(m, 2H), 7.55(d, J =8.4Hz, 2H), 7.22-7.13(m, 3H), 7.02(d, J=2.0Hz, IH), 4.44(t, J=4.0Hz, 2H), 3.54(t, J =4.0Hz, 2H), 2.87(d, J=4.8Hz, 6H), 2.55(s, 3H), 2.19(d, J=2.0Hz, 3H)
[1063]
[1064] Compounds listed below were prepared by the similar procedure in above Example 84.
[1065] Example 85 . 3-methyl-l-{5-methyl-6-[4-(2-piperidin-l-yl-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride
[1066] Example 86 . l-{6-[4-(2-methoxy-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5 -dione hydrochloride
[1067] Example 87 . l-{6-[3-(2-methoxy-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5 -dione
[1068] Example 88 . 3-methyl-l-{5-methyl-6-[4-(2-morpholin-4-yl-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride
[1069] Example 89 . l-{2-t-butyl-6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dione hydrochloride
[1070] Example 90 . l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
2-isobutyl-5-methyl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dion e hydrochloride
[1071] Example 91 . l-{2-allyl-6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dione hydrochloride
[1072] Example 92 . 3-methyl-l-{5-methyl-6-[4-(2-piperazin-l-yl-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride
[1073] Example 93 . l-{6-[4-(3-dimethylamino-propoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5 -dione hydrochloride
[1074] Example 94 . l-{6-[4-(2-amino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5 -dione hydrochloride
[1075] Example 95 . l-{6-[4-(2-diethylamino-ethoxy)-phenyl] -
2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dione hydrochloride [1076] Example 96 . 3-methyl-l-{5-methyl-6-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride
[1077] Example 97 .
3-methyl-l-{5-methyl-6-[4-(2-(4-methyl-piperazin-l-yl)-ethoxy)-phenyl]-2-thiophe n-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride
[1078] Example 98 . l-(6-{4-[2-(ethyl-methyl-amino)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-py rrole-2,5-dione hydrochloride
[1079] Example 99 . 3-methyl-l-(5-methyl-6-{4-[2-(methyl-propyl-amino)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride
[1080] Example 100 . 3-methyl-l-(5-methyl-6-{4-[2-(2-oxo-pyrrolidin-l-yl)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride
[1081] Example 101 . l-(6-{4-[2-(isopropyl-methyl-amino)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl--thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-p yrrole-2,5-dione hydrochloride
[1082] Example 102 . 3-methyl-l-(5-methyl-6-{4-[2-(2-thiomolpholin-4-yl)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride
[1083] Example 103 . l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
2,5-dimethyl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dione hydrochloride
[1084] Example 104 . l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-propyl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dione hydrochloride
[1085] Example 105 . l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-cyclopropyl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5- dione hydrochloride
[1086] Example 106 . l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-ethyl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dione hydrochloride
[1087] Example 107 . l-{2-cyclopropylmethyl-6-[4-(2-dimethylamino-ethoxy)-phenyl] -5-methyl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dione hydrochloride
[1088] Example 108 . l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-thophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hy- drochloride [1089] Example 109 . l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3,4-dimethyl-pyrrole
-2,5-dione hydrochloride [1090] Example 110 . 3,4-dichloro-l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride [1091] Example 111 . l-[6-(4-{2-[4-(2-amino-ethyl)-piperazin-l-yl] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3-m ethyl-pyrrole-2,5-dione hydrochloride [1092] Example 112 . l-[6-(4-{2-[(2-amino-ethyl)-methyl-amino] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3-m ethyl-pyrrole-2,5-dione hydrochloride [1093] Example 113 . l-[6-(4-{2-[(2-dimethylamino-ethyl)-methyl-amino] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3-m ethyl-pyrrole-2,5-dione hydrochloride [1094] Example 114 . l-[6-(4-{2-[4-(2-dimethylamino-ethyl)-piperazin-l-yl] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3-m ethyl-pyrrole-2,5-dione hydrochloride [1095] Example 115 . l-[6-(4-{2-[4-(2-methoxy-ethyl)-piperazin-l-yl] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3-m ethyl-pyrrole-2,5-dione hydrochloride [1096] Example 116 . 3-methyl-l-(5-methyl-6-{4-[2-(2-piperazin-l-yl-ethoxy)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride [1097] Example 117 . l-(6-{4-[2-(4-acetyl-piperazin-l-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-py rrole-2,5-dione hydrochloride [1098] Example 118 . l-(6-{4-[2-(2,5-dioxo-pyrrolidin-l-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-py rrole-2,5-dione [1099] Example 119 . l-[6-(4-{2-[4-(2-hydroxy-ethyl)-piperazin-l-yl] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3-m ethyl-pyrrole-2,5-dione hydrochloride [1100] Example 120 . 3-methyl-l-(5-methyl-6-{4-[2-(3-oxo-piperazin-l-yl)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride [1101] Example 121 . l-[6-(4-{2-[(2-hydroxy-ethyl)-methyl-amino] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3-m ethyl-pyrrole-2,5-dione hydrochloride [1102] Example 122 . l-[6-(4-{2-[(2-methoxy-ethyl)-methyl-amino] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylainino]-3-in ethyl-pyrrole-2,5-dione hydrochloride [1103] Example 123 . l-(6-{4-[2-(l,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-py rrole-2,5-dione hydrochloride [1104] Example 124 . l-(6-{4-[2-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-py rrole-2,5-dione [1105] Example 125 . 3-methyl-l-(5-methyl-6-{4-[2-(2-oxo-imidazolidin-l-yl)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione [1106] [Table 7] [1107]
Figure imgf000102_0001
[1108]
Figure imgf000103_0001
[1109]
Figure imgf000104_0001
[1110]
Figure imgf000105_0001
[1111]
Figure imgf000106_0002
[1112]
[1113] Intermediate (52) : Preparation of
2-t-butyl-4-chloro-6-(4-methoxy-phenyl)-5-methyl-thieno[2,3-d]pyrimidine
[1114]
Figure imgf000106_0001
[1115] According to the similar procedure in the step 2 and 3 of example 57 by using the compound prepared in the step 1 of example 57 and pivalonitrile, 168mg (yield for final step: 73%, yellow solid) of the target compound was obtained.
[1116] 1U NMR(400D, CDCI) δ 7.40(d, J=8.0Hz, 2H), 6.99(d, J=8.4Hz, 2H), 3.85(s, 3H),
2.66(s, 3H), 1.36(s, 9H)
[1117] [1118] Intermediate (53) : Preparation of 4-chloro-2-isobutyl-6-(4-methoxy-phenyl)-5-methyl-thieno[2,3-d]pyrimidine
[1119]
Figure imgf000107_0001
[1120] According to the similar procedure in the step 2 and 3 of example 57 by using the compound prepared in the step 1 of example 57 and isovaleronitrile, 82mg (yield for final step: 76%, brown solid) of the target compound was obtained.
[1121] 1U NMR(400D, CDCI) δ 7.41(d, J=8.4Hz, 2H), 6.99(d, J=I 1.2Hz, 2H), 3.84(s,
3H), 2.87(d, J=7.2Hz, 2H), 2.62(s, 3H), 2.33(m, IH), 0.98(d, J=6.4Hz, 6H)
[1122]
[1123] Intermediate (54) : Preparation of
2-allyl-4-chloro-6-(4-methoxy-phenyl)-5-methyl-thieno[2,3-d]pyrimidine
[1124]
Figure imgf000107_0002
[1125] According to the similar procedure in the step 2 and 3 of example 57 by using the compound prepared in the step 1 of example 57 and allyl cyanide, 247mg (yield for final step: 70%, brown solid) of the target compound was obtained.
[1126] 1U NMR(400D, CDCI) δ 7.40(d, J=8.4Hz, 2H), 7.01(d, J=8.8Hz, 2H), 5.70(m, IH),
5.03(t, J=8.4Hz, 2H), 3.84(s, 3H), 2.62(s, 3H), 2.38(d, J=4.4Hz, 2H)
[1127]
[1128] Intermediate (55) : Preparation of
4-chloro-6-(4-methoxy-phenyl)-2,5-dimethyl-thieno[2,3-d]pyrimidine
[1129]
Figure imgf000107_0003
[1130] According to the similar procedure in the step 2 and 3 of example 57 by using the compound prepared in the step 1 of example 57 and acetonitrile, 142mg (yield for 2 steps: 67%, yellow solid) of the target compound was obtained.
[1131] 1U NMR(400D, CDCI); δ 7.42(d, 2H, /=8.8), 7.02(d, 2H, J=8.8Hz), 3.88(s, 3H),
2.80(s, 3H), 2.63(s, 3H).
[1132]
[1133] Intermediate (56) : Preparation of
4-chloro-6-(4-methoxy-phenyl)-5-methyl-2-propyl-thieno[2,3-d]pyrimidine [1134]
Figure imgf000108_0001
[1135] According to the similar procedure in the step 2 and 3 of example 57 by using the compound (500mg, 1.72mmol) prepared in the step 1 of example 57 and butyronitrile, 430mg (yield for 2 steps: 80%, purple solid) of the target compound was obtained.
[1136] 1U NMR(400D, CDCI) δ 7.39(d, J=8.8Hz, 2H), 7.02(d, J=8.8Hz, 2H), 4.12(t, J
=5.6Hz, 2H), 2.97(t, J=5.6Hz, 2H), 2.76(t, J=5.6Hz, 2H), 2.62(s, 3H), 2.35(s, 6H), 1.93-1.84(m, 2H), 1.01(t, J=7.2Hz, 3H).
[1137]
[1138] Intermediate (58) : Preparation of 2-(methyl-propyl-amino)-ethanol
[1139]
O ^ VJ
[1140] Pyrrolidine (0.835ml, lOmmol) and 2-bromoethanol (0.28ml, 4.0mmol) were dissolved in THF (10ml). The reaction mixture was refluxed for 36 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography (dichlorome thane: methanol = 10:1) to give 380mg (yield: 83%, brown oil) of the target compound.
[1141] 1U NMR(400D, CDCI): δ 3.64(t, J=5.6Hz, 2H), 2.65(t, J=5.6Hz, 2H), 2.56(m, 4H),
1.78(m, 4H)
[1142]
[ 1143] Intermediate (59) : Preparation of 2-pyrrolidin-l-yl-ethanol
[1144]
Figure imgf000108_0002
[1145] 1-methylaminoethanol (1.07ml, 13mmol) and 2-bromopropane (0.59ml, 6.5mmol) were dissolved in THF (10ml). The reaction mixture was refluxed for 36 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethan: methanol = 10:1) to give 180mg (yield: 24%, colorless oil) of the target compound.
[1146] 1U NMR(400D, CDCI): δ 3.58(t, J=5.6Hz, 2H), 2.52(t, J=5.6Hz, 2H), 2.37(m, 2H),
2.24(s, 3H), 0.90(t, J=7.2Hz, 3H)
[1147]
[1148] Intermediate (60) : Preparation of 4-chloro-6-(4-methoxy-phenyl)-5-methyl-2-cvclopropyl-thienor2.3-dlpyriinidine
[1149]
Figure imgf000109_0001
[1150] According to the similar procedure in the step 2 and 3 of example 57 by using the compound (868mg, 3mmol) prepared in the step 1 of example 57 and cyclopropyl cyanide, 486mg (yield for 2 steps: 49%, pale yellow solid) of the target compound was obtained.
[1151] 1U NMR(400D, CDCI) δ 7.40(d, J=8.8Hz, 2H), 7.00(d, J=8.8Hz, 2H), 3.87(s, 3H),
2.60(s, 3H), 2.33-2.26(m, IH), 1.93-1.84(m, 2H), 1.26-1.08(m, 4H)
[1152]
[1153] Intermediate (61) : Preparation of
4-chloro-6-(4-methoxy-phenyl)-5-methyl-2-ethyl-thieno[2,3-d]pyrimidine
[1154]
Figure imgf000109_0002
[1155] According to the similar procedure in the step 2 and 3 of example 57 by using the compound (868mg, 3mmol) prepared in the step 1 of example 57 and propionitrile, 794mg (yield for 2 steps: 83%, pale yellow solid) of the target compound was obtained.
[1156] 1U NMR(400D, CDCI) δ 7.41(d, J=8.8Hz, 2H), 7.01(d, J=8.8Hz, 2H), 3.87(s, 3H),
3.04(q, J=75.6Hz, 2H), 2.63(s, 3H), 1.41(t, J=7.6Hz, 3H)
[1157]
[1158] Intermediate (62) : Preparation of
4-chloro-2-cyclopropylmethyl-6-(4-methoxy-phenyl)-5-methyl-thieno[2,3-d]pyrim idine
[1159]
Figure imgf000109_0003
[1160] According to the similar procedure in the step 2 and 3 of example 57 by using the compound (400mg, 1.37mmol) prepared in the step 1 of example 57 and cyclopropy- lacetonitrile, 290mg (yield for 2 steps: 61%, yellow solid) of the target compound was obtained. [1161] 1U NMR(400D, CDCI) δ 7.42(d, J=8.8Hz, 2H), 7.02(d, J=8.8Hz, 2H), 3.88(s, 3H),
2.90(d, J=6.8Hz, 2H), 2.64(s, 3H), 1.32(m, IH), 0.54(m, 2H), 0.33(m, 2H)
[1162]
[1163] Intermediate (63) : Preparation of {2-[4-(2-hydroxy-ethyl)-piperazin-l-yl] - ethyl}-carbamic acid tert-butyl ester
[1164]
Figure imgf000110_0001
[1165] l-(2-hydroxyethyl)-piperazine (0.49Og, 3.80mmol),
2-(tert-butoxycarbonylamino)ethylbromide (0.936g, 4.18mmol), sodium hydrogen carbonate (1.00Og, 7.60mmol) and sodium iodide (0.056g, 0.38mmol) were dissolved in acetonitrile (10ml). The reaction mixture was refluxed for 6 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography (chloroform:methanol = 7:1) to give 780mg (yield: 76%, yellow oil) of the target compound.
[1166] 1U NMR(400D, CDCI); δ 5.00(br, IH), 3.61(t, J=5.6Hz, 2H), 3.23- 3.22(m, 2H),
2.63-2.44(m, 12H), 1.45(s, 9H)
[1167]
[1168] Intermediate (64) : Preparation of {2-[(2-hydroxy-ethyl)-methyl-amino] - ethyl}-carbamic acid tert-butyl ester
[1169]
M + Br-^^NiBoc Boc ^ N ^
[1170] 2-(methylamino)ethanol (0.30Og, 3.994mmol) and (2-bromo-ethyl)-carbamic acid t- butyl ester (0.985g, 4.39mmol) were dissolved in THF (15ml). The reaction mixture was refluxed for 16 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethan: methanol = 10:1) to give 431mg (yield: 50.4%, colorless oil) of the target compound.
[1171] 1H-NMR (400D, CDCI) δ 4.84(br, IH), 3.60(t, /=5.6, 2H), 3.224(m, 2H), 2.55(m,
4H), 2.27(s, 3H), 1.43(s, 9H)
[1172]
[1173] Intermediate (65) : Preparation of
[2-({2-[4-(4-chloro-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-6-yl)-phenox y]-ethyl}-methyl-amino)-ethyl]-carbamic acid t-butyl ester
[1174]
Figure imgf000111_0001
[1175] The compound (0.207g, 0.58mmol) prepared in the step 1 of example 84, the intermediate (64) (0.15 Ig, 0.69mmol) and triphenylphosphine (PPh , 0.227g, 0.87mmol) were dissolved in THF (5ml). Therein, DIAD (0.167ml, 0.87mmol) was added slowly, and the reaction mixture was stirred for 16 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane methanol = 10:1) to give 330mg (yield: 99%, yellow solid) of the target compound.
[1176] 1H-NMR (400D, CDCI) δ 7.75(m, IH), 7.33(m, 3H), 7.31(s, IH), 7.02(m, IH),
7.00(d, J=8.8Hz, 2H), 4.11(t, J=5.6Hz, 2H), 3.25(m, 2H), 2.86(br, 2H), 2.64(s, 3H), 2.61(br, 2H), 1.65(s, 3H), 1.45(s, 9H)
[1177]
[1178] Intermediate (66) : Preparation of 2-[4-(2-methoxy-ethyl)-piperazin-l-yl] - ethanol
[1179]
Figure imgf000111_0002
[1180] l-(2-hydroxyethyl)-piperazine (0.49Og, 3.80mmol), 2-bromo-ethyl-methyl-ether (0.580g, 4.18mmol), sodium hydrogen carbonate (1.0Og, 7.60mmol) and sodium iodide (0.056g, 0.38mmol) were dissolved in acetonitrile (10ml). The reaction mixture was refluxed for 14 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:methanol = 7:1) to give 500mg (yield: 71%, yellow oil) of the target compound.
[1181] 1U NMR(400D, CDCI); δ 3.64(t, J=5.6Hz, 2H), 3.36(s, 3H), 3.27- 3.24(m, 2H),
2.63-2.44(m, 12H)
[1182]
[1183] Intermediate (67) : Preparation of l-[4-(2-hydroxy-ethyl)-piperazin-l-yl] - ethanol
[1184]
Figure imgf000111_0003
[1185] 1-acetylpiperazine (Ig, 8mmol) and 2-bromoethanol (0.28ml, 4.0mmol) were dissolved in THF (10ml). The reaction mixture was refluxed for 36 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography (dichlorome thane: methanol = 10:1) to give 380mg (yield: 55.1%, brown oil) of the target compound.
[1186] 1H-NMR (400D, CDCI) δ 3.67 (m, 4H), 3.5 l(m, 2H), 2.59(t, J=5.6Hz, 2H), 2.56(m,
4H), 2.10(s, 3H)
[1187]
[1188] Intermediate (68) : Preparation of
2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperazin-l-yl}-ethanol
[1189]
Figure imgf000112_0001
[1190] According to the similar procedure in the intermediate 64 by using piperazine (500mg, 5.80mmol) and 2-bromoethanol (0.90ml, 12.76mmol) of the target intermediate was obtained. This intermediate and imidazole (300mg, 4.40mmol) were dissolved in DMF (10ml). Therein, tert-butyldimethylsilyl chloride (TBDMS-Cl, 664mg, 4.40mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was poured into ethyl acetate, and washed with water. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:methanol = 6:1) to give 675mg (yield for 2 steps: 63%, yellow oil) of the target compound.
[1191] 1U NMR(400D, CDCI) δ 3.75(t, J=6.4Hz, 2H), 3.60(t, J=5.5Hz, 2H), 2.55~2.52(m,
12H), 0.89(s, 9H), 0.059(s, 6H)
[1192]
[ 1193] Intermediate (69) : Preparation of 2-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl] -methyl-amino}-ethanol
[1194] Step 1. Preparation of (2-bromo-ethoxy)-t-butyl-dimethyl-silane
[1195]
B r ^_X,H _ B r^^OTB D M S
[1196] 2-bromoethanol (1.Og, 8.0mmol) was dissolved in DMF (5ml). Therein, tert- butyldimethylsilyl chloride (1.45g, 9.6mmol) and imidazole (1.36g, 20.0mmol) were added, and the reaction mixture was stirred at room temperature for 20 hours. Thereafter, the reaction mixture was poured into diethyl ether, and washed with water and saturated sodium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane=100%) to give 1.Og (yield: 53%, colorless oil) of the target compound.
[1197] 11HH--NNMMIR (CD3OD, 400D) δ 3.89(t/=6.6Hz, 2H), 3.40(t, J=6.6Hz, 2H), 0.90(s, 9H), 0.09(s, 6H)
[1198]
[1199] Step 2. Preparation of 2-(r2-ft-butyl-dimethyl-silanyloxyVethyll - methyl- amino ) -ethanol [1200]
Br^-OTBDMS + ^N^°H HO^^N^^OTBDMS
H I
[1201] The compound (1.Og, 4.18mmol) prepared in the step 1 and
2-(methylamino)ethanol (0.270ml, 3.34mmol) were dissolved in acetonitrile (10ml). Therein, potassium carbonate (700mg, 5.04mmol) and sodium iodide (50mg, 0.33mmol) were added, and the reaction mixture was refluxed for 10 hours. After cooling to room temperature, the resulting solid was filtered out and the flitrate was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:methanol = 10:1) to give 560mg (yield: 71%, colorless oil) of the target compound.
[1202] 1H-NMR (CD OD, 400D) δ 3.71(t/=5.8Hz, 2H), 3.57(t, J=5.2Hz, 2H),
2.62-2.58(m, 4H), 2.33(s, 3H), 0.89(s, 9H), 0.07(s, 6H).
[1203]
[1204] Intermediate (70) : Preparation of 2-[(2-methoxy-ethyl)-methyl-amino] - ethanol
[1205]
Figure imgf000113_0001
[1206] 2-bromoethylmethyl ether (1.53g, l lmmol) and 2-(methylamino)ethanol (750mg, lOmmol) were dissolved in acetonitrile (10ml). Therein, potassium carbonate (2.76g, 20mmol) and sodium iodide (150mg, lmmol) were added, and the reaction mixture was refluxed for 6 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography (chloroform:methanol = 20:1) to give 1.2g (yield: 92%, colorless oil) of the target compound.
[1207] 1U NMR(400D, CDCI) δ 3.59(t, J=5.6Hz, 2H), 3.48(t, J=5.6Hz, 2H), 3.36(s, 3H),
2.64(t, J=5.6Hz, 2H), 2.58(t, J=5.6Hz, 2H), 2.33(s, 3H)
[1208]
[1209] Intermediate (71) : Preparation of 2-(l,4-dioxa-8-azaspiro[4,5] dec- 8-yl)-ethanol [1210]
Figure imgf000114_0001
[1211] ,4-dioxa-8-azaspiro[4,5]dec caneP (0.45ml. 3.49mmol) and 2-bromoethanol (0.28ml, 4.0mmol) were dissolved in THF (10ml). The reaction mixture was refluxed for 36 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10:1) to give 340mg (yield: 52.1%, brown oil) of the target compound.
[1212] 1H-NMR (400D, CDCI) δ 3.96(s, 4H), 3.61(t, J=5.6Hz, 2H), 2.59(m, 4H), 2.56(t, J
=5.6Hz, 2H), 1.78(m, 4H)
[1213]
[1214] Example 126 . l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-ethyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-inethyl-pyrrole-2,5-d ione hydrochloride
[1215] Step 1. Preparation of (4-methoxy-phenylVacetaldehyde
[1216]
Figure imgf000114_0002
[1217] 4-methoxyphenethylalcohol (2g, 13.14mmol) and triethylamine (7.33ml,
52.56mmol) were dissolved in dichloromethane (50ml). Therein, the solution of pyridine sulfide complex (4.18g, 26.28mmol) in dimethylsulfoxide (10ml) was added, and the reaction mixture was stirred for 8 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 3:1) to give 1.29g (yield: 66.0%, yellow oil) of the target compound.
[1218] 1H-NMR (400D, CDCI) δ 10.03(t, IH, J=2.0Hz), 7.12(d, 2H, J=8.4Hz), 6.86(d, 2H,
J=6.4Hz), 3.79(s, 3H), 3.62(d, 2H, J=2.0Hz)
[1219]
[1220] Step 2. Preparation of l-(4-methoxy-phenylVbutan-2-ol
[1221]
Figure imgf000114_0003
[1222] The compound (1.29g, 7.15mmol) prepared in the step 1 was dissolved in THF
(20ml). Thereafter, the temperature was lowered into -1O0C and therein, l.OM ethyl- magnesiumbromide in THF (8ml, 8.0mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. Thereafter, the reaction mixture was poured into ammonium chloride solution to quench. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography
(n-hexane: ethyl acetate = 3:1) to give 1.02g (yield: 66%, yellow oil) of the target compound. [1223] 1U NMR(400D, CDCI); δ 7.12(d, 2H, J=8.4Hz), 6.86(d, 2H, J=6.4Hz), 3.79(s, 3H),
3.62(s, 2H), 3.40(m, IH), 2.47 (q, 2H, J=7.2Hz), 1.00(t, 3H, J=7.2Hz) [1224]
[1225] Step 3. Preparation of l-(4-methoxy-phenyl)-propan-l-one
[1226]
Figure imgf000115_0001
[1227] The compound (1.02g, 5.77mmol) prepared in the step 2 was dissolved in dichloromethane (20ml). Therein, Dess-Martin-periodinane (2.45g, 5.77mmol) was added, and the reaction mixture was stirred at room temperature for 30minutes. Thereafter, the reaction mixture was poured into sodium hydrogen carbonate solution to quench. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 7:1) to give 812mg (yield: 78.8%, yellow oil) of the target compound.
[1228] 1U NMR(400D, CDCI); δ 7.12(d, 2H, J=8.4Hz), 6.86(d, 2H, J=6.4Hz), 3.79(s, 3H),
3.62(s, 2H), 2.47 (q, 2H, J=7.2Hz), 1.00(t, 3H, J=7.2Hz)
[1229]
[1230] Step 4. Preparation of
2-amino-4-ethyl-5-(4-methoxy-phenylVthiophen-3-carboxylic acid ethyl ester
[1231]
Figure imgf000115_0002
[1232] The compound (lOOmg, 0.56mmol) prepared in the step 3, ethyl cyanoacetate
(0.071ml, 6.72mmol) and sulfur (18mg, 0.56mmol) were dissolved in ethanol (20ml). Therein, morpholine (57D, 0.58mmol) was added slowly, and the reaction mixture was stirred at 8O0C for 5 hours. After reaction, the reaction mixture was poured into ethyl acetate, and washed with water and saturated ammonium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 5:1) to give 80mg (yield: 46.8%, yellow solid) of the target compound. [1233] 1U NMR(400D, CDCI); δ 7.27(d, 2H, J=8.8Hz), 6.90(d, 2H, J=8.8Hz), 6.13(br, 2H), 4.3 l(q, 2H, J=7.6Hz), 3.79(s, 3H), 2.70(q, 2H, J=7.2Hz), 1.37(t, 3H, J=7.2Hz), 1.13(t, 3H, J=7.2Hz)
[1234] [1235] Step 5. Preparation of 5-ethyl-6-(4-methoxy-phenyl)-2-thiopnen-2-yl-thieno[2.3-dl pyrimidin-4-ol
[1236]
Figure imgf000116_0001
[1237] The compound (500mg, 1.64mmol) prepared in the step 4 and 2-thiophene car- bonitrile (0.23ml, 2.46mmol) were dissolved in 3.6M HCl in 1,4-dioxane solution (6ml). The reaction mixture was stirred at 11O0C for 36 hours. After reaction, reaction mixture was poured into ethyl acetate, and washed with water and saturated sodium hydrogen carbonate aqueous solution. Combined organic layer was concentrated under reduced pressure to give 480mg (yield: 79.4%, brown solid) of the target compound.
[1238] 1U NMR(400D, CDCD; δ 8.06(d, IH, J=3.6Hz), 7.49(d, IH, J=5.2Hz), 7.43(d, 2H, J=8.8Hz), 7.15(d, IH, J=3.6Hz), 7.00(d, 2H, J=8.8Hz), 3.87(s, 3H), 3.00(q, 2H, J =7.2Hz), 1.37(t, 3H, J=7.2Hz)
[1239] [1240] Step 6. Preparation of 4-chloro-5-ethyl-6-(4-methoxy-phenylV2-thiophen-2-yl-thienor2.3-dlpyrimidine
[1241]
Figure imgf000116_0002
[1242] The compound (480mg, 1.30mmol) prepared in the step 5 was dissolved in phosphorus oxychloride (8ml). Thereafter, the reaction mixture was stirred at 1000C for 6 hours. After reaction, the reaction mixture was poured into ice water and ethyl acetate, and washed with water and saturated sodium hydrogen carbonate aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 2:1) to give 160mg (yield: 31.7%, yellow solid) of the target compound.
[1243] 1U NMR(400D, CDCD; δ 8.06(d, IH, J=3.6Hz), 7.49(d, IH, J=5.2Hz), 7.43(d, 2H, J=8.8Hz), 7.15(d, IH, J=3.6Hz), 7.00(d, 2H, J=8.8Hz), 3.87(s, 3H), 3.00(q, 2H, J =7.2Hz), 1.37(t, 3H, J=7.2Hz)
[1244] [ 1245 ] Step 7. Preparation of 4-(4-chloro-5-ethyl-2-thiophen-2-yl-thieno[2.3-d1 pyrimidin- β-ylVphenol [1246]
Figure imgf000117_0001
[1247] According to the similar procedure in the step 1 of example 84 by using the compound (160mg, 0.41mmol) prepared in the step 6, lOOmg (yield: 65.8%, yellow solid) of the target compound was obtained. [1248] 1U NMR(400D, CDCI); δ 8.07(d, IH, J=3.6Hz), 7.51(d, IH, J=5.2Hz), 7.43(d, 2H,
J=8.8Hz), 7.15(d, IH, J=3.6Hz), 6.95(d, 2H, J=8.8Hz), 5.20(s, IH), 3.02(q, 2H, J
=7.2Hz), 1.31(t, 3H, J=7.2Hz) [1249] [1250] Step 8. Preparation of l-(6-[4-(2-dimethylamino-ethoxy)-phenyll -
5-ethyl-2-thiophen-2-yl-thieno[2.3-dlpyrimidin-4-ylamino)-3-methyl-pyrrole-2.5-dion e hydrochloride [1251]
Figure imgf000117_0002
[1252] According to the similar procedure in the step 2,3,4,5 of example 84 by using the compound (lOOmg, 0.27mmol) prepared in the step 7, 41.0mg (yield: 26.7%, yellow solid) of the target compound was obtained. [1253] 1H-NMR (400D, DMSO-d) δ 10.73(s, IH), 9.52(s, IH), 7.69(m, 2H), 7.49(d, J
=8.8Hz, 2H), 7.16(m, 3H), 7.02(d, J=2.0Hz, IH), 4.45(t, J=4.4Hz, 2H), 3.59(m, 2H),
3.02(m, 2H), 2.85(s, 3H), 2.84(s, 3H), 2.18(d, J=1.6Hz, 3H), 1.24(t, J=7.6Hz, 3H) [1254] [1255] Compounds listed below were prepared according to the above procedure (See table
8). [1256] Example 127 . l-(6-{4-[2-(4-butyl-piperazin-l-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-py rrole-2,5-dione dihydrochloride [1257] Example 128 . l-({6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl}-methyl-amino)-3-methyl-p yrrole-2,5-dione hydrochloride [1258] Example 129 . methyl-
(2-{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen- 2-yl-thieno[2,3-d]pyrimidin-6-yl]-phenoxy}-ethyl-carbamic acid t-butyl ester
[1259] Example 130 . 3-methyl-l-{5-methyl-6-[4-(2-methylamino-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride
[1260] Example 131 . l-[6-(4-methoxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino]-3-methylen-pyrrolidine-2,5-dione
[1261] Example 132 . 3-methylen-l-{5-methyl-6-[4-(2-methylamino-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrolidine-2,5-dione hydrochloride
[1262] Example 133 . l-{6-[4-(2-butylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5 -dione hydrochloride
[1263] Example 134 . l-[(6-{4-[2-(2-methoxy-ethylamino)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-methyl-amino]-3- methyl-pyrrole-2,5-dione hydrochloride
[1264] Example 135 . l-[(6-{4-[2-(2-hydroxy-ethylamino)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-methyl-amino]-3- methyl-pyrrole-2,5-dione hydrochloride
[1265] Example 136 . 3-methyl-l-(5-methyl-6-{4-[2-(3-methyl-butylamino)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride
[1266] Example 137 .
3-methyl-l-(5-methyl-2-thophen-2-yl-6-{4-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]- phenyl}-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride
[1267] Example 138 . 3-dimethylamino- N -
{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen-2-y l-thieno[2,3-d]pyrimidin-6-yl]-phenyl}-propionamide hydrochloride
[1268] Example 139 .
3-[methyl-(2-{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2- thiophen-2-yl-thieno[2,3-d]pyrimidin-6-yl]-phenoxy}-ethyl)-amino]-propionic acid
[1269] Example 140 . isopropyl-
(2-{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen- 2-yl-thieno[2,3-d]pyrimidin-6-yl]-phenoxy}-ethyl)-amino]-carbamic acid t-butyl ester
[1270] Example 141 . l-{6-[4-(2-isopropylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5 -dione hydrochloride
[1271] Example 142 . 3-methyl-l-{5-methyl-6-[4-(piperidin-4-yloxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride
[1272] Example 143 . l-{6-[4-(2-benzylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5 -dione hydrochloride
[1273] Example 144 .
3-(2-{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophe n-2-yl-thieno[2,3-d]pyrimidin-6-yl]-phenoxy}-ethylamino)-propionitrile hydrochloride
[1274] [Table 8]
[1275]
Figure imgf000120_0001
[1276]
Figure imgf000121_0001
[1277] [1278] Experimental Example 1 : In vitro IKK enzyme assay
TM [1279] In vitro IKK assay was performed with IKK-β enzyme (PV3836) and Z' Lyte1 kinase assay kit-Ser/Thr 5 peptide (PV3178), purchased from Invitrogen. The kinase assay kit adopted the principle of FRET (Fluorescence-Resonance Energy Transfer) and the experiment was carried out according to the described protocol. [1280] 2.5 D of test compound dissolved in 4-fold concentrated water was aliquotted onto each well of a low volume non-binding surface 384-well plate (Cat. No. 3676. Corning) manufactured by Corning, 5 D of the mixture of IKK-β(4ng) and 4 μM Ser/ Thr 5 peptide was added thereto, and stirred well on a plate stirrer for 30 seconds. The plate was left at room temperature. 2.5 D of 20 μM ATP was added thereto, and mixed well for 30 seconds. Subsequently, the plate was left at room temperature for 1 hour. 5 D of a development solution was added to each reaction solution and incubated at room temperature for 1 hour to decompose unphosphorylated peptide substrates. 5 D of a stop solution was added to each well to terminate the reaction. Fluorescent signals were measured using PerkinElmer En Vision™. A general dual (BS50/BS50) was used as a mirror block, a Photometric 405 (8 nm band width) as an excitation filter, Um- belliferone 460 (25 nm band width) and FITC 535 (25 nm band width) as an emission filter. An emission ratio and percent phosphorylation were determined from the fluorescent signals by following the protocol, in which the IC value of the compound was calculated using a SigmaPlot SAV (SPSS Inc.).
[1281] The results are shown in Table 9 (herein, A means IC 5J0 s<5 μM, B means IC 5J0 s<10 μM, and C means IC 's>10 μM).
50
[1282] [Table 9] [1283]
Figure imgf000122_0001
[1284] As shown in Table 9, it was found that the compounds of the present invention have an excellent inhibitory activity against IKKβ enzyme. [1285] [1286] Experimental Example 2 : NF-κB reporter gene assay
[1287] A549/NF B-luc cells (Panomics, #RC0002) were cultured in the medium
[DMEM/HG + 10% FBS + 100 unit/D of penicillin, 100 D/D of streptomycin and 2 mM of L-glutamine (ATCC #30-2220) + 100 D/D of hygromycin B (Roche #10843555001)], and seeded to 96 well plate (1.4xlO5 to 1.5xlO5 cells per well) to culture in the hygromycin B -free medium for 20 hours. The compound of Example 1 was diluted with the hygromycin B- and FBS (fetal bovine serum)-free medium with various concentrations (0.1% DMSO final concentration), added to the cells, and the cells were pre-incubated. After 1 hour, the cells were treated with 50 ng/D of TNF-α (Peprotech #300-01A). After 6 hours, a luciferase test (Promega #E2610, Bright-Glo™ Luciferase assay kit) was carried out. Briefly, 100 D of Bright-GloM reagent was added to 100 D of the medium for cell lysis. After 2 minutes, fluorescent signals were measured using
PerkinElmer En Vision with a 700nm low pass luminescence filter (Perkinelmer, 2100 multilabel reader) (Reference: Moorthy S.S. etc, The design and synthesis of novel orally active inhibitors of AP- 1 and NF-κB Mediated transcriptional activation. SAR of in vitro and in vivo studies, Bioorganic & Medicinal Chemistry Letters, 13, 2003, P4077).
[1288] The results are shown in Table 10 (herein, A means IC 5J0 s<10 μM and B means IC 50 <20 μM).
[1289] [Table 10] [1290]
Figure imgf000123_0001
[1291] As shown in Table 10, it was found that the compounds of the present invention have an excellent inhibitory activity against NF-κB.
[1292] [1293] Experimental Example 3 : LPS-induced TNF-α production [1294] LPS-induced TNF-α production was evaluated by measuring the amount of TNF-α accumulated in the medium. Raw 264.7 cells (ATTC, USA), the mouse macrophage cell lines, were used in the assay.
[1295] Raw 264.7 cells were cultured in DMEM/HG medium containing 10% fetal bovine serum (FBS). For determination of TNF-α level, Raw 264.7 cells were seeded with an amount of 5xlO5 cells/D per 96 well plate and incubated for 24 hours at 37 0C in a numidified incubator with 5% CO The various concentrations of the compound (0.1 to 10 μM) was added thereto, and cells were activated with lipopoly saccharide (final concentration: 1D/D (Sigma, USA)). After a 24 hours incubation, the medium was collected. The amount of TNF-α in the collected medium was measured using ELISA assay kit (Biosource international, USA). [1296] The results are shown in Table 11 (herein, AA is IC 50 's<l μM, A is IC 50 's<5 μM, B is IC 's<10 μM and C is IC 's>10 μM).
50 50
[1297] [Table 11] [1298]
Figure imgf000124_0001
[1299] «• NT: Not tested
[1300]
[1301] As shown in Table 11, it was found that the compounds of the present invention have an excellent inhibitory activity against TNF-α production. [1302] [1303] Experimental Example 4 : Nitric oxide (NO) inhibition assay
[1304] Raw 264.7 cells were cultured in the medium (DMEM/HG, 10% FBS, 100 U/D of penicillin-streptomycin, 5% CO and 370C), and placed into 96 well plate in an amount of 5x10 to 1x10 cells per well, followed by culturing for 24 hours. The diluted compounds of Example 1 to 144 and LPS (1 D/D) were added to the medium. After 24 hours, 100 D was taken out from the medium to react with 100 D of a Griess solution for 10 minutes, and then the level of nitrite was determined at optical density (OD) 560 nm. The corresponding concentration of nitrite in the sample was determined from the standard curve of sodium nitrite (Reference: Schmidt, H.H., Determination of Nitric Oxide via measurement of nitrite and nitrate in culture media. Biochemica., 22, 1995).
[1305] The results are shown in Table 12 (herein, AA means IC 's<l μM, A means IC 's<
50 50
5 μM, B is IC 's<10 μM, and C means IC 's>10 μM). r 50 50
[1306] [Table 12] [1307]
Figure imgf000126_0001
[1308] •X NT: Not tested [1309] [1310] As shown in Table 12, it was found that the compounds of the present invention have an excellent inhibitory activity against NO production.
[1311] [1312] Experimental Example 5 : TNF -α inhibition assay in mouse [1313] An amount of TNF-α was measured from blood of 7 to 9 week old male BALB/c mice (Japan SLC, Inc.). The mice were abdominally administrated with lipopolysaccharide (10 D/mouse, sigma, L-2880) to induce inflammation. The mice were fasted for 24 hours before lipopolysaccharide administration. The compounds prepared in Example 84 and 85 were dissolved in distilled water, and then orally administrated with a concentration of 30 mg/kg and 100 mg/kg (amount of administration: 10 D/kg). After 1 hour, Lipopolysaccharide was administrated. After 90 minutes, blood was collected from the mouse heart, and then serum was separated. The amount of TNF-α in the collected serum was measured using ELISA assay kit (Biosource International, USA).
[1314] The results were given in Fig. 1 and Table 13. [1315] [Table 13] [1316]
Figure imgf000127_0001
[1317]
[1318] As shown in Fig. 1 and Table 13, it was found that the compounds of the present invention have an excellent inhibitory activity against TNF-α production.
Industrial Applicability
[1319] The thienopyrimidine derivative of the present invention was found to inhibit IKK- β, NF-κB, TNF-α and Nitric oxide strongly through in vitro assays such as an IKK assay, NF-κB reporter gene assay, LPS-induced TNF-α production and nitric oxide (NO) inhibition assay, and through TNF-α inhibition assay in a mouse, which are associated with a chance of developing a therapeutic agent for inflammatory diseases and cancer. Accordingly, the compounds can be used as a pharmaceutical composition useful for treating and preventing pains and inflammation caused by inflammatory diseases, in particular, arthritis and cancer.

Claims

Claims
[1] A thienopyrimidine derivative having the following Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof: <Formula 1>
Figure imgf000128_0001
wherein
X is O, S or NH,
R is hydrogen; linear or branched C to C alkyl; -(CH )n -OR; -(CH )n -
1 1 10 2 1 2 1
COOR; C to C heteroaryl substituted or unsubstituted with C to C alkyl or
5 20 J 1 3 J halogen, which comprise one or two heteroatom(s) selected from the group consisting of S, O and N; or
Figure imgf000128_0002
R2 is hydrogen; -(CH )n -Z; -(CH )n -OR; -(CH^n^COOR; -(CH^n^CONR'R"; -Y-(CH 2 )n 1 -NR1R"; -Y-(CH 2 )n 1 -OR; -Y-(CH2 )n 1 -COOR; C 5 to C 20 heteroaryl substituted or unsubstituted with C to C alkyl or halogen, which comprise one or two heteroatom(s) selected from the group consisting of S, O and N; or
R7\ /^=\
^-(CH2Jn1
R 3 is hy J drog °en; linear or branched C 1 to C 10 alkyl; linear or branched C 2 to C 10 alkeny Jl; ' C 3 to C ? cy Jcloalky Jl; -CH 2 -C3 to C ? cy Jcloalky Jl; -NR1R"; ' C 5 to C 20 heteroaryl or -CH -C to C heteroaryl substituted or unsubstituted with C to C
2 5 20 1 3 alkyl or halogen, which comprise one or two heteroatom(s) selected from the group consisting of S, O and N,; or
^HCH2)H1 R and R are each independently H; =CH ; linear or branched C to C alkyl; halogen; -OR; or connected to each other to form C to C aryl, C to C
6 20 5 7 cycloalkyl, or C to C heterocyclic comprising one or two heteroatom(s) selected from the group consisting of N, O or S,
R is H, or linear or branched C to C alkyl,
R is H, -OH, -NO , linear or branched C to C alkyl, -Y-C to C alkyl, -NR1R", -
7 2 1 5 1 5
CN, -COOR, halogen, -Y-(CH )n -NR1R", -Y-(CH )n -OR, -Y-(CH )n -COOR, -
2 2 2 2 2 2
Y-(CH )n -Z, -Y-(CH )n -M-R, -Y-(CH )n -M-(CH )n -NR1R", -Y-(CH )n - M-(CH )n -OR, -Y-(CH )n -M-(CH )n -COOR, -Y-(CH )n -M-(CH )n -CN or -
2 3 2 2 2 3 2 2 2 3
Y-(CH )n -M-(CH )n -Z,
R is H, linear or branched C to C alkyl, -OR, -NO , amine, mono- or di- alkylamine, -CN, -COOR, -0-(CH )n -NR1R", -0-(CH )n -OR, -0-(CH )n - COOR or -0-(CH )n -Z,
2 2
R 9 is H, linear or branched C 1 to C5 alkyl, -OR, -NO 2 , amine, mono- or di- alkylamine, -CN, -COOR, -(CH^-NR'R", -(CH^-OR, -(CH^-COR, -(CH2 )n 2 -COOR or -(CH 2 )n 2 -Z,
R and R are each independently hydrogen, linear or branched C to C alkyl, or halogen,
R, R' and R" are each independently hydrogen, linear or branched C to C alkyl, or -CH 2 CF 3 ;
M is O, S or -NR-,
Y is O, S, NH, -NH-CO- or -CO-NH-,
Z is pyrrolidine; piperidine; piperazine; morpholine; thiomorpholine; 2- or 3-oxo-pyrrolidine; 2-, 3- or 4-oxo-piperidine; oxazole; triazole; pyridine; imidazole; imidazolidine; 2,5-dioxo-pyrrolidine; 2- or 3-oxo-piperazine; 2,5-dioxo-2,5-dihydro-pyrrole; 2-oxo-imidazolidine; 4,4-ethylenedioxy-piperidine; 2- or 3-thienyl; 2- or 3-furyl;
Figure imgf000129_0001
— N N-R9 or
Figure imgf000129_0002
, and n , n and n are each integer of 0 to 5.
[2] The thienopyrimidine derivative, a pharmaceutically acceptable salt thereof, or an isomer thereof according to claim 1, wherein X is O or S, R is hydrogen, methyl, -(CH )n -OR, -(CH )n -COOR, thiophenyl or
^-(CH2Jn1
R is hydrogen, -(CH )n -Z, -(CH )n -OR, -(CH )n -COOR, -(CH )n -CONR'R",
-Y-(CH )n -NR1R", thiophenyl or
Figure imgf000130_0001
R is hydrogen, methyl, ethyl, propyl, isobutyl, t-butyl, 2-propenyl, cyclopropyl, -CH -cyclopropyl, amine, 2-methylthiophenyl, -CH -thiophenyl, furanyl, pyridinyl or
R7^ /=\
^H -(CH2)H1
R and R are each independently H, =CH methyl, F, Cl, Br, I, or connected to each other to form phenyl or pyridine,
R is H or methyl,
R is H, -OH, -NO , methyl, -OCH , -NR1R", F, Cl, Br, I, -Y-(CH )n -NR1R", -
Y-(CH )n -OR, -Y-(CH )n -Z, -Y-(CH )n -M-(CH )n -NR1R", -Y-(CH )n -
M-(CH )n -OR, -Y-(CH )n -M-(CH )n -COOR, -Y-(CH )n -M-(CH )n -CN or -
2 3 2 2 2 3 2 2 2 3
Y-(CH )n -M-(CH )n -Z,
R is H,
R is H, methyl, butyl, -(CH )n -NR1R", -(CH )n -OR or -(CH )n -COR,
R and R are each independently hydrogen,
R, R' and R" are each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isopentyl or -CH CF ,
M is O or -NR-,
Y is O, -NH-CO- or -CO-NH-,
Z is pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 2- or
3-oxo-pyrrolidine, 2,5-dioxo-pyrrolidine, 2- or 3-oxo-piperazine,
2-oxo-imidazolidine, 4,4-ethylenedioxy-piperidine,
Figure imgf000131_0001
— N N-R9 or
Figure imgf000131_0002
, and n , n and n are each integer of 0 to 3.
[3] The thienopyrimidine derivative, a pharmaceutically acceptable salt thereof, or an isomer thereof according to claim 1, wherein the compound is selected from the group consisting of
1) 3-methyl-l-(5-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione,
2) 3,4-dichloro-l-(5-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
3) 2-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-isoindole- 1 ,3-dione hydrochloride,
4) 2-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrolo[3,4-c] pyridine- 1,3-dione hydrochloride,
5) 3-methyl-l-(5-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
6) l-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride,
7) l-(2,6-di-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride,
8) l-(2,5-di-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride, 9) 3-methyl-l-[2-(5-methyl-thiophen-2-yl)-5-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino] -pyrrole-2,5-dione hydrochloride,
10) l-[5-(4-methoxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
11) l-[5-(4-hydroxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
12) (2,5-di-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-hydrazine hydrochloride, 13) 3-methyl- l-(2-pyridin-4-yl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
14) l-[2-(4-methoxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
15) 3-methyl- l-(5-thiophen-2-yl-2-p-tolyl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
16) 3-methyl- l-(5-thiophen-2-yl-2-thiophen-2-ylmethyl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
17) 3-methyl- l-(2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
18) 3-methyl- l-(5-methyl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride,
19) l-(2-benzyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride,
20) 3-methyl- l-(5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
21) 3-methyl- l-(2-phenyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione,
22) 3-methyl- l-(2-phenyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
23) l-[2-(4-hydroxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
24) l-[2-(4-fluoro-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] - 3-methyl-pyrrole-2,5-dione hydrochloride,
25) l-[2-(3-fluoro-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] - 3-methyl-pyrrole-2,5-dione hydrochloride,
26) 3-methyl- l-(2-thiophen-3-yl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
27) 3-methyl- l-(2-thiophen-2-yl-5-thiophen-3-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
28) 3-methyl- l-(5-thiophen-2-yl-2-thiophen-3-ylmethyl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
29) 3-methyl- l-(5-phenyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
30) 3-methyl- l-(2-thiophen-2-yl-5-p-tolyl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
31) l-[2-(4-methoxy-benzyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride, 32) l-[2-(4-diethylaminophenyl)-5-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino]-3-methyl-pyrrole-2,5-dione hydrochloride,
33) l-[2-(3-hydroxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
34) l-[2-(4-methoxy-phenyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino] - 3-methyl-pyrrole-2,5-dione hydrochloride,
35) l-[2-(3-methoxy-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
36) l-[2-(3-methoxy-phenyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino] - 3-methyl-pyrrole-2,5-dione hydrochloride,
37) l-[2-(3-fluoro-phenyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino] - 3-methyl-pyrrole-2,5-dione hydrochloride,
38) l-[2-(3-methoxy-benzyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
39)
4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2-yl-thieno[2, 3-d]pyrimidine-5-carboxylic acid ethyl ester hydrochloride,
40) l-[5-(3-hydroxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
41) l-[5-(3-methoxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
42) l-[2-(4-dimethylamino-phenyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
43) l-[2-(4-amino-phenyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino] - 3-methyl-pyrrole-2,5-dione hydrochloride,
44) l-(2-furan-2-yl-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] - 3-methyl-pyrrole-2,5-dione hydrochloride,
45) 3-methyl- l-(2-methyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-pyrrole-2,5-dione hydrochloride,
46) l-[2-(4-amino-phenyl)-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] - 3-methyl-pyrrole-2,5-dione hydrochloride,
47) l-(2-amino-5-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride,
48) l-(2-cyclopropyl-5-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-3-methyl-pyrrole-2,5-dione,
49)
[4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2-yl-thieno[2 ,3-d]pyrimidin-5-yl] -acetic acid methyl ester hydrochloride, 50) l-(5-hydroxymethyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride,
51) l-(5-methoxymethyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride,
52) 3-methyl-l-{2-[4-(2-piperidin-l-yl-ethoxy)-phenyl] - 5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
53) 3-methyl-l-{2-[3-(2-piperidin-l-yl-ethoxy)-phenyl] - 5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
54) l-[6-(4-hydroxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
55) l-[6-(4-methoxy-phenyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
56) l-{6-[4-(2-dimethylamino-ethoxy)phenyl] -
5-methyl-2-thiophen-2-yl-furo[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5 -dione hydrochloride,
57) l-[6-(4-methoxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino]-3-methyl-pyrrole-2,5-dione hydrochloride,
58) l-[6-(4-hydroxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino]-3-methyl-pyrrole-2,5-dione hydrochloride,
59)
[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2-y l-thieno[2,3-d]pyrimidin-6-yl] -acetic acid methyl ester hydrochloride,
60) l-[6-(3-hydroxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino]-3-methyl-pyrrole-2,5-dione,
61)
5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2-yl
-thieno[2,3-d]pyrimidine-6-carboxylic acid amide hydrochloride,
62) l-[6-(3-methoxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-
4-ylamino]-3-methyl-pyrrole-2,5-dione,
63)
5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2-yl
-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester hydrochloride,
64) l-(6-methoxy-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] - 3-methyl-pyrrole-2,5-dione hydrochloride,
65) l-[6-(4-methoxy-benzyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino]-pyrrole-2,5-dione hydrochloride, 66) l-[6-(4-hydroxy-benzyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino]-pyrrole-2,5-dione hydrochloride,
67) 3-methyl-l-[5-methyl-6-(4-nitrophenyl)-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino] -pyrrole-2,5-dione hydrochloride,
68) 3-methyl-l-(6-phenyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylam ino)-pyrrole-2,5-dione hydrochloride,
69)
3-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2 -yl-thieno[2,3-d]pyrimidin-6-yl]-propionic acid ethyl ester,
70) l-(6-hydroxymethyl-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride,
71) l-(6-methoxymethyl-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride,
72) l-[6-(3-methoxybenzyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino]-3-methyl-pyrrole-2,5-dione hydrochloride,
73) l-[6-(3-hydroxy-benzyl)-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
74) l-{6-[3-(2-dimethylamino-ethoxy)-benzyl]-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride,
75)
5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrole-l-ylamino)-2-thiophen-2-yl -thieno[2,3-d]pyrimidine-6-carboxylic acid-(2-dimethylamino-ethyl)-amide hydrochloride,
76) 3-methyl-l-{5-[4-(2-piperidin-l-yl-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
77) 3-methyl-l-{5-[3-(2-piperidin-l-yl-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
78) 1 - { 5 - [3 - (2-dimethylamino-ethoxy ) -phenyl] -2-thiophen-2-yl- thieno [2, 3 -d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride,
79) l-{5-[3-(3-dimethylamino-propoxy)-phenyl]-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride,
80) 3-methyl-l-{5-[3-(2-morpholin-4-yl-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
81) 3-methyl-l-{5-[3-(2-piperazin-l-yl-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione dihy- drochloride,
82)
3-methyl- 1 - [5-methyl-6-(4-methyl-piperazin- 1 -ylmethyl)-2-thiophen-2-yl-thieno
[2,3-d]pyrimidin-4-ylamino]-pyrrole-2,5-dione dihydrochloride,
83) 3-methyl-l-(5-{3-[2-(4-methyl-piperazin-l-yl)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione dihydrochloride ,
84) l-{6-[4-(2-dimethylamino-ethoxy)phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole- 2,5-dione hydrochloride,
85) 3-methyl- l-{5-methyl-6-[4-(2-piperidin-l-yl-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
86) l-{6-[4-(2-methoxy-ethoxy)-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino] -3-methyl-pyrrole-2,5-dione hydrochloride,
87) l-{6-[3-(2-methoxy-ethoxy)-phenyl]-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione,
88) 3-methyl-l-{5-methyl-6-[4-(2-morpholin-4-yl-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
89) l-{2-t-butyl-6-[4-(2-dimethylamino-ethoxy)-phenyl]-5-methyl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride,
90) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl]-2-isobutyl-5-methyl-thieno[2,3-d ]pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride,
91) l-{2-allyl-6-[4-(2-dimethylamino-ethoxy)-phenyl]-5-methyl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride,
92) 3-methyl- l-{5-methyl-6-[4-(2-piperazin-l-yl-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
93) l-{6-[4-(3-dimethylamino-propoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole- 2,5-dione hydrochloride,
94) l-{6-[4-(2-amino-ethoxy)-phenyl]-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride,
95) l-{6-[4-(2-diethylamino-ethoxy)-phenyl]-2-thiophen-2-yl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride,
96) 3-methyl- l-{5-methyl-6-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hy- drochloride,
97) 3-methyl-l-{5-methyl-6-[4-(2-(4-methyl piperazin-l-yl)-ethoxy) -phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
98) l-(6-{4-[2-(ethyl-methyl-amino)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl- pyrrole-2,5-dione hydrochloride,
99) 3-methyl- l-(5-methyl-6-{4-[2-(methyl-propyl-amino)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride,
100) 3-methyl- l-(5-methyl-6-{4-[2-(2-oxo-pyrrolidin- l-yl)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride,
101) l-(6-{4-[2-(isopropyl-methyl-amino)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl- pyrrole-2,5-dione hydrochloride,
102) 3-methyl- l-(5-methyl-6-{4-(2-thiomorpholin-4-yl-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride,
103) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl]-2,5-dimethyl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride,
104) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl]-5-methyl-2-propyl-thieno[2,3-d ]pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride,
105) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-cyclopropyl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2, 5-dione hydrochloride,
106) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl]-5-methyl-2-ethyl-thieno[2,3-d] pyrimidin-4-ylamino } -3-methyl-pyrrole-2,5-dione hydrochloride,
107) l-{2-cyclopropylmethyl-6-[4-(2-dimethylamino-ethoxy)-phenyl] - 5-methyl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2,5-dione hydrochloride
108) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
109) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3,4-dimethyl-pyrr ole-2,5-dione hydrochloride,
110) 3,4-dichloro-l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] - 5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
111) l-[6-(4-{2-[4-(2-amino-ethyl)-piperazin-l-yl] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3- methyl-pyrrole-2,5-dione hydrochloride,
112) l-[6-(4-{2-[2-amino-ethyl)-methyl-amino] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3- methyl-pyrrole-2,5-dione hydrochloride,
113) l-[6-(4-{2-[(2-dimethylamino-ethyl)-methyl-amino] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3- methyl-pyrrole-2,5-dione hydrochloride,
114) l-[6-(4-{2-[4-(2-dimethylamino-ethyl)-piperazin-l-yl] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3- methyl-pyrrole-2,5-dione hydrochloride,
115) l-[6-(4-{2-[4-(2-methoxy-ethyl)-piperazin-l-yl] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3- methyl-pyrrole-2,5-dione hydrochloride,
116) 3-methyl-l-(5-methyl-6-{4-[2-(2-piperazin-l-yl-ethoxy)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride,
117) 1 -(6- { 4- [2-(4-acetyl-piperazin- 1 -yl)-ethoxy] -phenyl } -5-methyl-2-thiophen- 2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-pyrrole-2,5-dione hydrochloride,
118) l-(6-{4-[2-(2,5-dioxo-pyrrolidin-l-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl- pyrrole-2,5-dione,
119) l-[6-(4-{2-[4-(2-hydroxy-ethyl)-piperazin-l-yl] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3- methyl-pyrrole-2,5-dione hydrochloride,
120) 3-methyl-l-(5-methyl-6-{4-[2-(3-oxo-piperazin-l-yl)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride,
121) l-[6-(4-{2-[(2-hydroxy-ethyl)-methyl-amino] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3- methyl-pyrrole-2,5-dione hydrochloride,
122) l-[6-(4-{2-[(2-methoxy-ethyl)-methyl-amino] - ethoxy}-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino]-3- methyl-pyrrole-2,5-dione hydrochloride, 123) l-(6-{4-[2-(l,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl- pyrrole-2,5-dione hydrochloride
124) l-(6-{4-[2-(2,5-dioxo-2,5-dihydro-pyrrole-l-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl- pyrrole-2,5-dione,
125) 3 -methyl- 1 - (5 -methyl- 6- { 4- [2- (2-oxo-imidazolidin- 1 -yl) -ethoxy ] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione,
126) l-{6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-ethyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole-2, 5-dione hydrochloride,
127) l-(6-{4-[2-(4-butyl-piperazin-l-yl)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl- pyrrole-2,5-dione dihydrochloride,
128) l-({6-[4-(2-dimethylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl}-methyl-amino)-3-methyl -pyrrole-2,5-dione hydrochloride,
129) methyl-
(2-{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophe n-2-yl-thieno[2,3-d]pyrimidin-6-yl]-phenoxy}-ethyl)-carbamic acid ?-butyl ester,
130) 3-methyl-l-{5-methyl-6-[4-(2-methylamino-ethoxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
131) l-[6-(4-methoxy-phenyl)-5-methyl-2-thiophen-2-yl-thieno[2,3-d] pyrimidin- 4-ylamino]-3-methylene-pyrrolidine-2,5-dione,
132) 3-methylene- 1 - { 5-methyl-6- [4- (2-methylamino-ethoxy) -phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrolidine-2,5-dione hydrochloride,
133) l-{6-[4-(2-butylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole- 2,5-dione hydrochloride,
134) l-[(6-{4-[2-(2-methoxy-ethylamino)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-methyl-amino]- 3-methyl-pyrrole-2,5-dione hydrochloride,
135) l-[(6-{4-[2-(2-hydroxy-ethylamino)-ethoxy] - phenyl}-5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-methyl-amino]- 3-methyl-pyrrole-2,5-dione hydrochloride,
136) 3-methyl- l-(5-methyl-6-{4-[2-(3-methyl-butylamino)-ethoxy] - phenyl}-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride, 137)
3-methyl-l-(5-methyl-2-thiophen-2-yl-6-{4-[2-(2,2,2-trifluoro-ethylamino)-etho xy]-phenyl}-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione hydrochloride,
138) 3-dimethylamino-Λf -
{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophen- 2-yl-thieno[2,3-d]pyrimidin-6-yl]-phenyl}-propionamide hydrochloride, 139)
3-[methyl-(2-{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino) -2-thiophen-2-yl-thieno[2,3-d]pyrimidin-6-yl]-phenoxy}-ethyl)-amino]-propioni c acid,
140) isopropyl-
(2-{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiophe n-2-yl-thieno[2,3-d]pyrimidin-6-yl]-phenoxy}-ethyl)-carbamic acid ?-butyl ester,
141) l-{6-[4-(2-isopropylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole- 2,5-dione hydrochloride,
142) 3-methyl-l-{5-methyl-6-[4-(piperidin-4-yloxy)-phenyl] - 2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-pyrrole-2,5-dione hydrochloride,
143) l-{6-[4-(2-benzylamino-ethoxy)-phenyl] -
5-methyl-2-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino}-3-methyl-pyrrole- 2,5-dione hydrochloride, and
144)
3-(2-{4-[5-methyl-4-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-ylamino)-2-thiop hen-2-yl-thieno[2,3-d]pyrimidin-6-yl]-phenoxy}-ethylamino)-propionitrile hydrochloride.
[4] A pharmaceutical composition for preventing and treating inflammatory diseases, comprising the compound, a pharmaceutically acceptable salt thereof or an isomer thereof according to any one of claims 1 to 3.
[5] The pharmaceutical composition according to claim 4, which the inflammatory disease is selected from the group consisting of rheumatoid arthritis, spondy- loarthopathies, gout, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis.
[6] The pharmaceutical composition according to claim 4, wherein the inflammatory disease is selected from the group consisting of myositis, gingivitis, synovitis, ankylosing spondylitis, burstitis, septic shock, burns, and injury. [7] The pharmaceutical composition according to claim 4, which is useful for treating inflammatory symptoms accompanied by inflammatory diseases selected from the group consisting of inflammatory bowel disease, Crohn's disease, Type
I diabetes, and psoriasis. [8] A pharmaceutical composition for preventing and treating cancer, comprising the compound, a pharmaceutically acceptable salt thereof or an isomer thereof according to any one of claims 1 to 3.
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