HK1211575B - Novel fused pyrimidine derivatives for inhibition of tyrosine kinase activity - Google Patents

Description

Fused pyrimidine derivatives for inhibition of tyrosine kinase activity

The application is a divisional application with the application number of 201180030338.6 and the name of 'novel condensed pyrimidine derivative for inhibiting tyrosine kinase activity', and the parent application is an application of PCT/KR2011/004482 submitted on the 20 th 6 th 2011 to the Chinese national stage.

Technical Field

The present invention relates to novel fused pyrimidine derivatives having inhibitory activity against tyrosine kinases, and pharmaceutical compositions containing the same as an active ingredient.

Background

There are many signal transduction systems in cells that are functionally linked to each other to control cell proliferation, growth, metabolism and apoptosis (williamg. kaelin jr., Nature Reviews Cancer5, 689, 2005). Disruption of intracellular control systems by genetic and environmental factors causes abnormal expansion or disruption of signal transduction systems, leading to tumor Cell production (Douglas Hanahan and Robert a. weinberg, Cell 100, 57, 2000).

Protein tyrosine kinases play an important role in this cellular regulation (Irena Melnikova and James golden, Nature Reviews Drug Discovery 3, 993, 2004), and abnormal expression or mutation thereof has been observed in cancer cells or autoimmune diseases. Protein tyrosine kinases are enzymes that catalyze the transport of phosphate groups from ATP to tyrosines located on protein substrates. Many growth factor receptor proteins function as tyrosine kinases to transmit cellular signals. The interaction between growth factors and their receptors generally controls cell growth, but aberrant signal transduction resulting from mutation or overexpression of any one of the receptors often induces a variety of cancers or autoimmune diseases (e.g., rheumatoid arthritis).

As for the effects of these tyrosine kinases, various growth factors and their receptors have been studied, and among them, Epidermal Growth Factor (EGF) and EGF receptor (EGFR) tyrosine kinases have been carefully studied (Nancy e.hynes and Heidi a.lane, Nature Reviews Cancer5, 341, 2005). EGFR tyrosine kinases are composed of receptors and tyrosine kinases that transport extracellular signals through the cell membrane to the nucleus. Various EGFR tyrosine kinases are classified into four subtypes according to their structural differences, namely, EGFR (Erb-B1), Erb-B2, Erb-B3 and Erb-B4, and EGFR activating mutations (e.g., a L858R point mutation in exon 21 and an in-frame deletion in exon 19 of the EGFR tyrosine kinase domain) are known to be important causes of non-small cell lung cancer.

Gefitinib (Gefitinib, AstraZeneca) was originally developed as a small molecule for inhibiting EGFR tyrosine kinase, which selectively and reversibly inhibits EGFR (Erb-B1). Erlotinib (Erlotinib, Roche) also has similar characteristics. These EGFR-targeted drugs are effective for non-small cell lung cancer (NSCLC) and provide therapeutic convenience to patients with EGFR activating mutations.

However, the development of resistance has been reported to reduce the activity of specific drugs used in EGFR-targeted therapies. It has been reported that about half of patients administered gefitinib or erlotinib exhibit drug resistance due to the secondary EGFR T790M mutation (William Pao et al, Public Library of Science Medicine, 2(3), 225, 2005, Cancer Res, 67(24), 11924, 2007). Furthermore, it has recently been found that irreversible inhibitors targeting EGFR are more beneficial in maintaining superior potency and overcoming resistance development than conventional reversible inhibitors (e.g., gefitinib and erlotinib) (Danan Li et al, Cancer Cell 12, 81, 2007; and Anja Michalczyk et al, Bioorganic & Medicinal Chemistry 16, 3482, 2008). Thus, irreversible inhibitors have been developed, such as BIBW-2992(Afatinib, BoeringerIngelheim) (C H Mom et al, British Journal of Cancer 98, 80, 2007), PF00299804(Dacomitinib, Pfizer) (Engelman JA et al, Cancer Res.67, 11924, 2007) and AV-412(AVEOpharmaceuticals) (Tsuyoshi et al, Cancer Sci.98(12), 1977, 2007), which are currently in clinical phase. These compounds are known to form a covalent bond with cysteine 773 (Cys773) located in the ATP domain of EGFR, thereby irreversibly blocking autophosphorylation of EGFR, which in turn effectively inhibits signal transduction of cancer cells (David w.fry et al, proc. natl.acad.sci.u.s.a.95, 12022, 1998); and it is known that these compounds exhibit higher inhibitory activity in vitro and in various in vivo models of cancer compared to commercially available reversible inhibitors (e.g. dual inhibitors of EGFR/HER-2 or pan-HER inhibitors) (Jeff b. small et al, j.med. chem.42, 1803, 1999). However, when these compounds are administered at a dose sufficient to overcome the resistance induced by the EGFR T790M mutation, they may cause severe side effects (such as skin rash, diarrhea, and weight loss) because of their high activity against EGFR WT (wild type) present in normal cells, thereby limiting their clinical applications (Martin l.sos et al, Cancer res.70, 868, 2010).

Clinical trials of irreversible inhibitors in non-small cell lung cancer demonstrated that these compounds exhibit improved activity compared to conventional reversible inhibitors, but the therapeutic effect in the development of resistance in cancer patients remains weak. Therefore, there is still a need to develop novel drugs that are effective against drug-resistant cancers and that do not have adverse side effects.

At the same time, there is a lot of evidence that B cells (B lymphocytes) and T cells (T lymphocytes) play a key role in inflammatory diseases, autoimmune diseases and/or immune-mediated diseases.

For example, aberrant signaling can induce dysregulated B-cell proliferation and differentiation, leading to all kinds of lymphomas, including various acute or chronic lymphoid leukemias; and may result in the formation of autoantibodies, thereby causing inflammatory, autoimmune and/or immune-mediated diseases.

Bruton's Tyrosine Kinase (BTK) is a member of the TEC family of tyrosine kinases and plays an important role in B cell activation and cell conductance. BTK plays an essential role in B cell signaling pathways that link B Cell Receptor (BCR) stimuli on the surface of B cells with responders in downstream cells. Furthermore, BTK is known to be a key regulator of B cell formation and of mature B cell activation and survival (Khan et al, Immunity 3, 283, 1995; Ellmeier et al, J.Exp.Med.192, 1611, 2000; Kurosaki, Current Opinion in Immunology12, 276, 2000; Schaeffer and Schwartzberg, Current Opinion in Immunology12, 282, 2000). Thus, inhibition of BTK may be a therapeutic approach to block B cell mediated disease processes.

For example, BTK deficient mice are known to be resistant to collagen-induced arthritis, and BTK inhibitors have been shown to have dose-dependent efficacy in mouse models of arthritis (Jansson and Holmdahl, Clin. exp. Immunol.94, 459, 1993; Pan et al, chem. Med chem.2, 58, 2007). Thus, potent BTK inhibitors are useful in the treatment of rheumatoid arthritis.

In addition, cells other than B cells that may be involved in the disease process (i.e., myeloid-derived mast cells) also express BTK. Antigen-induced degranulation has been reported to be inhibited in BTK-deficient myeloid-derived mast cells (Iwaki et al, j.biol.chem.280, 40261, 2005). This suggests that BTK can be used to treat pathological mast cell responses, such as allergy and asthma.

Furthermore, monocytes without BTK activity show a decrease in TNF-. alpha.production after stimulation (Horwood et al JExp Med.197, 1603, 2003). Thus, TNF- α mediated inflammation can be modulated by BTK inhibitors.

Furthermore, BTK has been reported to play a role in apoptosis as some modulators (Islam and Smith, immunol. rev.178, 49, 2000). Therefore, BTK inhibitors would be useful in the treatment of certain B cell lymphomas and leukemias (Feldhahn et al, j.exp.med.201, 1837, 2005).

Meanwhile, T cells play a role in transmitting signals, which are transmitted from antigen presenting cells to downstream effectors through T Cell Receptors (TCRs) on the cell surface, by activating various intercellular kinases, such as janus kinase. At this time, they secrete various Interleukins (IL) or interferon- γ to activate various leukocytes as well as B cells. Protein kinases involved in T cell signal transduction are Janus kinases (JAKs) (e.g., JAK1, JAK2, JAK3, and TYK2), IL-2 inducible T cell kinases (ITKs), and TEC family kinases (e.g., Resting Lymphocyte Kinase (RLK)).

Extensive research has been conducted on Janus kinases (including JAK3) as targets for autoimmune and/or immune diseases. Among them, unlike JAK2 involved in hematopoiesis and erythrocytic homeostasis or JAK1 expressed in various tissues, JAK3 is expressed in lymphocytes and plays a very important role in signal transduction via various cytokines (i.e., IL-2, IL-4, IL-7, IL-9, and IL-15), which is more attractive (Flanagan et al, Journal of clinical chemistry, 53, 8468, 2010). According to animal studies, JAK3 plays a role in the maturation of B cells and T cells and in maintaining T cell function.

Thus, JAK3 inhibitors may be useful in the treatment of rheumatoid arthritis, psoriasis, allergic dermatitis, lupus, multiple sclerosis, type I diabetes and complications of diabetes, cancer, asthma, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other indications where immunosuppression is beneficial (e.g. organ transplantation or xenografts) (Pesu M, Laurence A, Kishore N, et al, Immunol Rev 223, 132, 2008.; Kawahara A, Minami Y, Miyazaki T, et al, Proc Natl Acad Sci USA 92, 8724, 1995; Nosaka T, van Deur JMA, Tripp RA, et al, Science 270, 800, 1995; Papageorgi Ac, Wikman LEK, et al, Trends Sci 25, Pharma 558, 2004).

Meanwhile, other TEC family kinases also play important roles in T cell activation (pamelal. schwartzberg, et al, Nature Reviews Immunology 5, 284, 2005). For example, deletion of ITK's that are characteristically expressed in mouse T cells results in reduced cell proliferation induced via T cell receptor stimulation and reduced secretion of various cytokines (e.g., IL-2, IL-4, IL-5, IL-10, and IFN-. gamma.) (Schaeffer et al, Science 284, 638, 1999; Fowell et al, Immunity 11, 399, 1999; Schafer et al, Nature Immunology2, 1183, 2001).

Furthermore, in ITK deficient mice, the immune symptoms of allergic asthma are reduced and lung inflammation, eosinophil infiltration and mucus production in response to allergen ovalbumin challenge are significantly reduced (Muller et al, Journal of immunology 170, 5056, 2003). This suggests that ITK inhibitors are useful in the treatment of asthma.

Furthermore, ITK is also associated with allergic dermatitis. It has been reported that this gene is more highly expressed in peripheral blood T cells of patients with severe allergic dermatitis than in controls or patients with mild allergic dermatitis (Matsumoto et al, International archives of Allergy and Immunology 129, 327, 2002).

Meanwhile, RLK functions to activate the secretion of IL-2, which is produced by signal transduction of T cell receptors of spleen cells. Thus, inhibition of RLK reduces multiple responses by T cells (Schaeffer et al, Nature Immunology2, 1183, 2001; Schaeffer et al, Science 284, 638, 1999).

Furthermore, bone marrow tyrosine kinases (BMX) are known to be involved in epithelial and endothelial cell migration (Pan et al, mol.cell.biol.2002, 22, 7512). Therefore, BMK inhibitors can be developed as anticancer drugs for inhibiting cancer cell metabolism and angiogenesis.

As above, since TEC family kinases (e.g., BTK, ITK, RLK, BMX, etc.) and Janus kinases (e.g., JAK3) play key roles in B cell and/or T cell activation associated with the pathogenesis of inflammatory, autoimmune, and immune-mediated diseases, compounds for effectively inhibiting the kinases are useful as therapeutic agents for a variety of inflammatory, autoimmune, and immune-mediated diseases.

In addition, compounds for inhibiting BTK involved in inducing B cell activation of B cell lymphoma and BMX involved in cancer cell metabolism can be used as anticancer or antitumor agents.

Therefore, the development of compounds that inhibit the above kinases and selectively inhibit variant EGFR (e.g., the secondary T790M mutation and the L858R point mutation at exon 21 or the in-frame deletion at exon 19) is one of the most important challenges.

Although it has been shown that EGFR irreversible inhibitors, which form covalent bonds with cysteine (Cys773) located at position 773 of the ATP domain of EGFR, can exhibit inhibitory effects on TEC family kinases (e.g., BTK, ITK, RLK and BMX) and the activity of kinases (e.g., JAK3 or BLK) in which cysteine is present at the same position in the amino acid sequence (Wooyoung Hur, et al, bioorg.med.chem.lett.18, 5916, 2008), compounds that can reversibly, selectively and effectively inhibit variant EGFR, BTK, JAK3, ITK, RLK, BMX and/or BLK have not been developed.

Disclosure of Invention

Accordingly, it is an object of the present invention to provide novel fused pyrimidine derivatives which selectively and effectively inhibit cancers or tumors induced by Epidermal Growth Factor Receptor (EGFR) tyrosine kinase or mutants thereof, and have reduced adverse side effects.

It is another object of the present invention to provide novel fused pyrimidine derivatives which can treat cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases mediated by abnormally activated B lymphocytes, T lymphocytes or both by inhibiting non-receptor tyrosine kinases such as TEC family kinases (e.g., BTK, ITK, BMX or RLK) and janus kinases (e.g., JAK 3).

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease comprising the novel fused pyrimidine derivative.

According to one aspect of the present invention there is provided a compound of formula (I):

wherein the content of the first and second substances,

w is O or S;

x is O, NH, S, SO or SO₂；

Y is a hydrogen atom, a halogen atom, C_1-6Alkyl or C_1-6An alkoxy group;

a and B are each independently a hydrogen atom, a halogen atom or a bis (C)_1-6Alkyl) aminomethyl;

z is aryl or heteroaryl having one or more substituents selected from: hydrogen atom, halogen atom, hydroxy group, nitro group, cyano group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl, di (C)_1-6Alkyl) amino C_2-6Alkoxycarbonyl, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, carbamoyl, C_1-6Alkylcarbamoyl, di (C)_1-6Alkyl) carbamoyl, di (C)_1-6Alkyl) amino C_2-6Alkylcarbamoyl, sulfamoyl, C_1-6Alkylsulfamoyl, di (C)_1-6Alkyl) sulfamoyl, di (C)_1-6Alkyl) amino C_2-6Alkylsulfamoyl, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl, di (C)_1-6Alkyl) phosphono, hydroxy C_1-6Alkyl, hydroxy carbonyl C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylsulfonyl radical C_1-6Alkyl radical, C_1-6Alkylsulfinyl C_1-6Alkyl, di (C)_1-6Alkyl) phosphono C_1-6Alkyl, hydroxy C_2-6Alkoxy radical, C_1-6Alkoxy radical C_2-6Alkoxy, amino C_1-6Alkyl radical, C_1-6Alkylamino radical C_1-6Alkyl, di (C)_1-6Alkyl) amino C_1-6Alkyl, di (C)_1-6Alkyl) aminoacetyl, amino C_2-6Alkoxy radical, C_1-6Alkylamino radical C_2-6Alkoxy, di (C)_1-6Alkyl) amino C_2-6Alkoxy, hydroxy C_2-6Alkylamino radical, C_1-6Alkoxy radical C_2-6Alkylamino radical, amino radical C_2-6Alkylamino radical, C_1-6Alkylamino radical C_2-6Alkylamino radical, di (C)_1-6Alkyl) amino C_2-6Alkylamino, heteroaryl, heterocycle, heterocyclyloxy, heterocyclylthio, heterocyclylsulfinyl, heterocyclosulfonyl C_1-6Alkyl, heterocycle C_1-6Alkoxy, heterocyclic amino, heterocyclic C_1-6Alkylamino, heterocyclylamino C_1-6Alkyl, heterocyclic carbonyl, heterocyclic C_1-6Alkylcarbonyl, heterocyclic carbonyl C_1-6Alkyl, heterocycle C_1-6Alkylthio, heterocyclic C_1-6Alkylsulfinyl, heterocyclic ring C_1-6Alkylsulfonyl, heterocyclylaminocarbonyl, heterocyclo C_1-6Alkylaminocarbonyl, heterocyclic aminocarbonyl C_1-6Alkyl, heterocyclic carboxamido and heterocyclic C_1-6An alkylcarboxamide group;

aryl means C_6-12A cyclic aromatic ring or a bicyclic aromatic ring of (a);

heteroaryl each independently refers to a 5 to 12 membered cyclic or bicyclic aromatic heterocycle having one or more N, O or S;

heterocyclic rings each independently mean having one or more N, O, S, SO or SO₂Wherein the carbon atoms forming the heterocycle optionally have one or more substituents selected from the group consisting of: c_1-6Alkyl, hydroxyRadical C_1-6Alkyl, hydroxycarbonyl, C_1-6Alkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, di (C)_1-6Alkyl) amino C_1-6Alkyl, di (C)_1-6Alkyl) aminocarbonyl, heterocycle C_1-6Alkyl and heteroaryl groups; and wherein if said heterocyclic ring optionally comprises a nitrogen atom, said nitrogen atom optionally has a substituent selected from: hydrogen atom, C_1-6Alkyl, monohalo C_1-6Alkyl, dihalo C_1-6Alkyl, trihalo C_1-6Alkyl radical, C_3-6Cycloalkyl, hydroxy C_2-6Alkyl radical, C_1-6Alkoxy radical C_2-6Alkyl radical, C_1-6Alkylcarbonyl, hydroxy C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl, carbamoyl, C_1-6Alkylcarbamoyl, di (C)_1-6Alkyl) carbamoyl, sulfamoyl, C_1-6Alkylsulfamoyl, di (C)_1-6Alkyl) sulfamoyl, C_1-6Alkylsulfonyl, amino C_2-6Alkyl radical, C_1-6Alkylamino radical C_2-6Alkyl, di (C)_1-6Alkyl) amino C_2-6Alkyl, di (C)_1-6Alkyl) amino C_1-6Alkylcarbonyl, heterocycle, heterocyclyloxy, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, heterocycle C_1-6Alkyl, heterocyclic carbonyl, heterocyclic C_1-6Alkylcarbonyl, heterocycle C_1-6Alkylsulfinyl and heterocycle C_1-6Alkylsulfonyl (wherein, when the nitrogen atom forms a tertiary amine, it is optionally in the form of an N-oxide); and is

Optionally, C_1-6The alkyl radical being partially unsaturated or having C_3-6A cycloalkyl moiety, and the carbon atom in the heterocycle is present as a carbonyl.

According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Drawings

The above and other objects and features of the present invention will become apparent from the following description of the present invention taken in conjunction with the accompanying drawings which respectively show:

FIG. 1: tumor size change by oral administration of the compound obtained in example 2 in nude mice xenografted with NCI-H1975 cancer cells;

FIG. 2: weight change by oral administration of the compound obtained in example 2 in nude mice xenografted with NCI-H1975 cancer cells; and

FIG. 3: change in arthritis clinical score by oral administration of the compound obtained in example 1 in a collagen-induced arthritis (CIA) model.

Detailed Description

In the compound of formula (I), preferred examples of Z include a substituent selected from the group consisting of formulae Z1 to Z203, but are not limited thereto:

more preferred examples of the compounds of formula (I) of the present invention are as follows:

n- (3- (2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-tert-butyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4- (2-fluoro-ethyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (2, 2, 2-trifluoro-ethyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4- (2-methoxy-ethyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4- (2-hydroxy-ethyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-hydroxy-4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (3, 4, 5-trimethyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)]Aza derivatives-7-ylamino) -thieno [3, 2-d]Pyrimidin-4-yloxy) -phenyl) -acrylamides,

N- (3- (2- (2-methoxy-4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (2-methoxy-4- (1-methyl-piperidin-3-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

(4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) phenyl) diethyl phosphate,

N- (3- (2- (4- [1, 4 '] bipiperidinyl-1' -yl-3-fluoro-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- ((2- ((3-chloro-4- (4-methylpiperazin-1-yl) phenyl) amino) thieno [3, 2-d [ pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4- (1-methylpiperidin-4-ylamino) -3-chlorophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (2-fluoro-4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (3-methyl-4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) -2-methyl-N- (1-methylpiperidin-4-yl) benzamide,

N- (4-methyl-3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (4-fluoro-3- (2- (4- (4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (4-methoxy-3- (2- (4- (4-methylpiperazin-1-yl) -phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

4-methyl-piperazine-1-carboxylic acid (4- (4- (3-acryloylamino-phenoxy) -thieno [3, 2-d ] pyrimidin-2-ylamino) -phenyl) -amide,

N- (4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) -2-fluorophenyl) -4-methylpiperazine-1-carboxamide,

N- (3- (2- (4- (4-ethylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-isopropyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (2, 2-difluoro-ethyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4-imidazol-1-yl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (2-dimethylamino-acetyl) -piperazin-1-yl) -3-fluoro-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-chloro-4- (piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (methylsulfonyl) piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-acetylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (morpholine-4-carbonyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1, 4-dimethyl-3-oxo-piperazin-2-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4-morpholinophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((2- (dimethylamino) ethyl) amino) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((2- (4-methylpiperazin-1-yl) ethyl) amino) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4-thiomorpholinophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (1-oxo-1. lamda.))⁴-thiomorpholin-4-yl) -phenylamino) -thieno [3, 2-d]Pyrimidin-4-yloxy) -phenyl) -acrylamides,

(S) -N- (3- (2- (4- (3- (dimethylamino) pyrrolidin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- [1, 4 '] bipiperidinyl-1' -yl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

1- (4- (4- (3-acryloylamino-phenoxy) -thieno [3, 2-d ] pyrimidin-2-ylamino) -phenyl) -piperidine-4-carboxylic acid dimethylamide,

N- (3- (2- (4- (dimethylamino) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (2-hydroxy-ethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (2-dimethylamino-ethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-chloro-4-fluorophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4-hydroxyphenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((4-acetylphenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (1, 4, 5, 6-tetrahydropyrimidin-2-yl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxo) phenyl) acrylamide,

N- (3- (2- (3-fluoro-2-methoxy-4- (4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (3R-imidazol-1-yl-pyrrolidin-1-yl) -phenylamino ] -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (3-imidazol-1-yl-pyrrolidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-imidazol-1-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-dimethylamino-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-morpholin-4-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (4-morpholin-4-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-chloro-4- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-chloro-4- (4-morpholin-4-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-hydroxypiperidin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((4- (4- (hydroxymethyl) piperidin-1-yl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (4- (2-hydroxyethyl) piperidin-1-yl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (ethylsulfonyl) piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- ((4-ethylpiperazin-1-yl) methyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4-diethylaminomethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-morpholin-4-yl-piperidin-1-ylmethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

(E) -N- (3- ((2- ((4- (3- (dimethylamino) prop-1-en-1-yl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((1-methylpiperidin-4-yl) amino) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4-diethylaminomethyl-2-methoxy-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- ((4-methylpiperazin-1-yl) methyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (3-fluoro-4- (4-methyl-piperazin-1-ylmethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (piperidin-1-ylmethyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4-azetidin-1-ylmethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4-pyrrolidin-1-ylmethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (morpholinomethyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((4-hydroxypiperidin-1-yl) methyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((4- (dimethylamino) piperidin-1-yl) methyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

Dimethyl (4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) benzyl phosphate;

n- (3- (2- (4- ((dimethylamino) methyl) -3-fluorophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) 3-fluorophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- ((4- (dimethylamino) piperidin-1-yl) methyl) 3-fluorophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- ((1-methylpiperidin-4-ylamino) methyl) -3-fluorophenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4-dimethylaminomethyl-2-methyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- ((4- (cyclopropylmethyl) piperazin-1-yl) methyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- ((4- (1-methylpiperidin-4-yl) piperazin-1-yl) methyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4-methanesulfonylmethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide (N- (3- (2- (4-methanesulfenylmethyl-phenylamino) -thono [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide),

N- (3- (2- (4- (2-methanesulfonyl-ethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-chloro-4- (4- (1-methyl-piperidin-4-yl) piperazin-1-ylmethyl) phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-cyclohexyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (5- (4-ethylpiperazin-1-yl) pyridin-2-ylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (5- (4- (2-hydroxy-ethyl) -piperazin-1-yl) -pyridin-2-ylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1- (4-ethylpiperazin-1-yl) ethyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-ethylpiperazine-1-carbonyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (2-hydroxy-acetyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4- (2-dimethylamino-acetyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

2- (4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) phenyl) acetic acid,

N- (3- ((2- ((4- (methylsulfinyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (methylsulfonyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) -N-methylbenzamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) -N, N-dimethylbenzamide,

N- (3- ((2- ((4- (morpholine-4-carbonyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (4-methylpiperazine-1-carbonyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (1-methyl-piperidin-4-yl) -piperazine-1-carbonyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-hydroxy-piperidine-1-carbonyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (3-methylamino-pyrrolidine-1-carbonyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (3-dimethylamino-pyrrolidine-1-carbonyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

4- (4- (3-acryloylamino-phenoxy) -thieno [3, 2-d ] pyrimidin-2-ylamino) -N- (2-dimethylamino-ethyl) -benzamide,

N- (3- (2- (3-chloro-4- (4-ethylpiperazine-1-carbonyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((3-chloro-4- ((2- (dimethylamino) ethyl) amino) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

4- (4- (3-acryloylamino-phenoxy) -thieno [3, 2-d ] pyrimidin-2-ylamino) -2-chloro-N, N-dimethyl-benzamide,

N- (3- (2- (3-chloro-4- (4-ethanesulfonyl-piperazine-1-carbonyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino-2-chloro-N- (1-methylpiperidin-4-yl) benzamide,

N- (3- (2- (4- (4-ethylpiperazin-1-ylsulfonyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((methylsulfinyl) methyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (2- (methylsulfinyl) ethyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4-sulfamoylphenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (morpholinosulfonyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (N-cyclopropylsulfamoyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (N- (2- (dimethylamino) ethyl) sulfamoyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (N- (1-methylpiperidin-4-yl) sulfamoyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (N- (1-isopropylpiperidin-4-yl) sulfamoyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

3- (dimethylamino) propyl 4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) benzoate (3- (dimethylamino) propyl-4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) benzoate),

N- (3- (2- (4- (2- (4-ethylpiperazin-1-yl) ethyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (2-piperidin-1-yl-ethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1, 1-dioxo-1. lamda.))⁶-thiomorpholin-4-yl) -phenylamino) -thieno [3, 2-d]Pyrimidin-4-yloxy) -phenyl) -acrylamides,

N- (3- (2- (4- (2- (4-ethylpiperazin-1-yl) acetyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (1-ethylpiperidin-4-yloxy) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (3-fluoro-4- (1-methyl-piperidin-4-yloxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (2-morpholinoethoxy) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (2-methoxy-ethoxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- ((2- ((4- (2- (dimethylamino) ethoxy) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (2- (diethylamino) ethoxy) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((2, 3, 4, 5-tetrahydrobenzo [ b ]][1，4]Oxazazem-7-yl) amino) thieno [3, 2-d]Pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (2, 3-dihydro-benzo [1, 4 ]) derivatives]IIEngland-6-ylamino) -thieno [3, 2-d]Pyrimidin-4-yloxy) -phenyl) -acrylamides,

N- (3- (2- (3-fluoro-4- (2-methoxy-ethoxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (2-dimethylamino-ethoxy) -3-fluoro-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (2-diethylamino-ethoxy) -3-fluoro-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (2- (4-methyl-piperazin-1-yl) -ethoxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-methoxy-4- (2-morpholin-4-yl-ethoxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

(E) -4- (dimethylamino) -N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) but-2-enamide,

N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-ylamino) phenyl) acrylamide,

N- (3- (2- (4- (4-ethyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4- (4-isopropyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4- (1-methyl-piperidin-3-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4-dimethylaminomethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4-piperidin-1-ylmethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4- (2-dimethylamino-ethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- ((2- ((4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) amino) phenyl) acrylamide,

N- (3- (2- (4- (2-dimethylamino-ethoxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4- (3-dimethylamino-propoxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (1-methyl-piperidin-4-ylamino) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (2-methoxy-4-piperidin-1-ylmethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (4-fluoro-3- (2- (4- (4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (4-fluoro-3- (2- (3-fluoro-4- (4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-ylthio) phenyl) acrylamide,

N- (3- (2- (3-fluoro-4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylsulfanyl) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4-morpholin-4-yl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylsulfanyl) -phenyl) -acrylamide,

(E) -4- (dimethylamino) -N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-ylsulfanyl) phenyl) but-2-enamide,

N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-ylsulfinyl) phenyl) acrylamide,

(Z) -3-chloro-N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

(E) -3-chloro-N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-ethylpiperazin-1-yl) -2-methoxyphenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (2-methoxy-4-morpholinophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) -2-methoxy-N- (1-methylpiperidin-4-yl) benzamide,

N- (3- (2- (4- (piperidin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (pyrrolidin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

1- (4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) phenyl) piperidine-4-carboxylic acid,

N- (3- (2- (4- (4-dimethylaminomethyl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-piperidin-1-ylmethyl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1-methyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1-ethyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1-isopropyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1-methyl-piperidin-3-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4-dimethylaminomethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-chloro-4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

4- (4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-ylamino) -N- (2- (pyrrolidin-1-yl) ethyl) benzamide,

N- (3- ((2- ((4- (2- ((1-methylpiperidin-4-yl) amino) -2-oxoethyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4- (3-piperidin-1-yl-propenyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (3-pyrrolidin-1-yl-propionylamino) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino-N- (tetrahydro-2H-pyran-4-yl) benzamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino-N- (1-methylpiperidin-4-yl) benzamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) -N- (1-isopropylpiperidin-4-yl) benzamide,

4- (4- (3-acryloylamino-phenoxy) -thieno [3, 2-d ] pyrimidin-2-ylamino) -3-methoxy-N- (2-pyrrolidin-1-yl-ethyl) -benzamide,

N- (3- (2- (4- (N, N-dimethylsulfamoyl) piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (2- (4- (ethylsulfonyl) piperazin-1-yl) ethyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (6- (4-methylpiperazin-1-yl) pyridin-3-ylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- (pyridin-3-ylamino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6-morpholinopyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- (4-isopropylpiperazin-1-yl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- (4- (dimethylamino) piperidin-1-yl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- ([1, 4 '-bipiperidin ] -1' -yl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- ((4-methylpiperazin-1-yl) methyl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- ((2- (piperidin-1-yl) ethyl) amino) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- ((1-isopropylpiperidin-4-yl) amino) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- (methylsulfinyl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (3-fluoro-4-morpholinophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((3-fluoro-4- ((1-methylpiperidin-4-yl) amino) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((3-fluoro-4- ((1-isopropylpiperidin-4-yl) amino) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (3-fluoro-4- (4- (methylsulfonyl) piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (ethanesulfonylpiperazin-1-yl) -3-fluoro-phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) acrylamide,

N- (3- (2- (4- (2, 6-cis-dimethylmorpholino) -3-fluorophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (3-fluoro-4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (1-methyl-piperidin-3-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (2-morpholin-4-yl-ethoxy) phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- ((2- ((4- ((2- (dimethylamino) ethyl) amino) -3-fluorophenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((3, 5-difluoro-4- (4-methylpiperazin-1-yl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((2- (dimethylamino) ethyl) amino) -3, 5-difluorophenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((3, 5-difluoro-4- ((1-methylpiperidin-4-yl) amino) phenyl) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4- (1-amino-cyclopropyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- [1- (2-dimethylamino-acetyl) -2, 3-dihydro-1H-indol-5-ylamino ] -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (1-methyl-1H-indol-5-ylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- ((2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (4-isopropylpiperazin-1-yl) phenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4-morpholinophenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((dimethylamino) methyl) phenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((4- (dimethylamino) piperidin-1-yl) methyl) phenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((3-fluoro-4- (1-methylpiperazin-4-yl) phenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (2-dimethylamino) ethyl) amino) -3-fluorophenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((3-fluoro-4- ((1-methylpiperidin-4-yl) amino) phenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (3-methoxy-4- (4-methyl-piperazin-1-yl) -phenylamino) -furo [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide, and

n- (3- ((2- ((4-sulfamoylphenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide.

The compounds of formula (I) of the present invention may be prepared by the steps shown in reaction scheme (I):

reaction scheme (I)

Wherein the content of the first and second substances,

A. b, W, X, Y and Z are as defined above;

r is hydrogen, methyl or ethyl; and is

N' is nitro or amino protected with tert-butoxycarbonyl (Boc).

As shown in reaction scheme (I), the condensation reaction of a compound of formula (VIII) with urea in an organic solvent (e.g., N-dimethylformamide, N-dimethylacetamide, or N-methylpyrrolidone) at a temperature of from reflux temperature to 200 ℃; or by condensation reaction with potassium cyanate at a temperature of from room temperature to 100 ℃ under acidic conditions (e.g., 6% to 50% aqueous acetic acid) to give the condensation compound of formula (VII).

The thus-obtained compound of formula (VII) is stirred under reflux in the presence of a chlorinating agent (e.g., phosphorus oxychloride or thionyl chloride) to obtain a chlorinated compound of formula (VI),and then at a temperature of room temperature to 100 ℃ in the presence of an inorganic base (e.g., cesium carbonate, sodium carbonate, or potassium carbonate) in an organic solvent (e.g., dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 1, 4-bis (methyl pyrrolidone)Alkane, toluene or benzene) to induce substitution of the aniline, phenol or thiophenol derivative of formula (V) at the C-4 position of the compound of formula (VI) to give the compound of formula (IV).

The compound of formula (IV) is reacted with Z-NH in an alcoholic solution (e.g. 2-propanol or 2-butanol) at a temperature of from 70 ℃ to reflux temperature and in the presence of a mineral acid (e.g. hydrochloric acid) or an organic acid (e.g. trifluoroacetic acid)₂Carrying out reaction; or at a temperature of about 100 ℃ in the presence of a palladium catalyst (e.g., palladium (II) acetate or tris (dibenzylideneacetone) dipalladium (0)) and a ligand (e.g., bis (diphenylphosphine) (xanthene) (Xantphos) or 2, 2 '-bis (diphenylphosphine) -1, 1' -Binaphthyl (BINAP)) and an inorganic base (e.g., cesium carbonate or sodium tert-butoxide) in an organic solvent (e.g., 1, 4-bisAlkyl) with Z-NH₂Reacting to obtain a compound having Z-NH₂A compound of formula (III).

Hydrogenation of a compound of formula (III) wherein N' is nitro using a palladium/carbon catalyst, or Fe mediated reduction, gives an aniline compound of formula (II) wherein the nitro group is replaced by an amino group. The compound of formula (III) wherein N' is an amino group protected with a tert-butyloxycarbonyl group (Boc) is reacted with an acid (e.g. trifluoroacetic acid or hydrochloric acid) in an organic solvent (e.g. dichloromethane) to give the deprotected aniline compound of formula (II).

Then, reacting the aniline compound of formula (II) with acryloyl chloride substituted with a and B in an organic solvent (e.g., dichloromethane or tetrahydrofuran) or a mixed solvent (e.g., 50% aqueous tetrahydrofuran) at a low temperature of-10 to 10 ℃ in the presence of an inorganic base (e.g., sodium bicarbonate) or an organic base (e.g., triethylamine or diisopropylethylamine); or reacting the aniline compound of formula (II) with acrylic acid substituted with a and B in pyridine using a coupling agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) or 2- (1H-7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium Hexafluorophosphate (HATU) to give the compound of formula (I) having an acrylamido group.

The compounds of formula (I) of the present invention may also be prepared in the form of pharmaceutically acceptable salts formed using, for example, inorganic or organic acids such as: hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, mandelic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, methanesulfonic, benzenesulfonic and toluenesulfonic acids.

The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of formula (I) in a water-miscible organic solvent (e.g., acetone, methanol, ethanol and acetonitrile), adding thereto an excess of an aqueous solution of an organic or inorganic acid to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and separating the precipitated salt.

The compounds of the present invention of formula (I) or pharmaceutically acceptable salts thereof may include hydrates and solvates thereof.

Accordingly, the present invention provides the use of a compound of the invention in the manufacture of a medicament for the prevention or treatment of cancer, a tumour, an inflammatory disease, an autoimmune disease or an immune-mediated disease.

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease, which comprises the compound of the present invention as an active ingredient.

Furthermore, the present invention provides a method for preventing or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease, comprising administering the compound of the present invention to a mammal in need thereof.

The compounds of the present invention of formula (I) or pharmaceutically acceptable salts thereof selectively and effectively inhibit the growth of cancer cells induced by Epidermal Growth Factor (EGFR) tyrosine kinase or mutants thereof, as well as drug resistance. Accordingly, the present invention provides a pharmaceutical composition for preventing or treating cancer or tumor induced by EGFR tyrosine kinase or a mutant thereof, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

Representative examples of cancers or tumors can include, but are not limited to, liver cancer, hepatocellular cancer, thyroid cancer, colorectal cancer, testicular cancer, bone cancer, oral cancer, basal cell cancer, ovarian cancer, brain tumor, gall bladder cancer, bile duct cancer, head and neck cancer, colorectal cancer, bladder cancer, tongue cancer, esophageal cancer, glioma, glioblastoma, renal cancer, malignant melanoma, gastric cancer, breast cancer, sarcoma, pharyngeal cancer, uterine cancer, cervical cancer, prostate cancer, rectal cancer, pancreatic cancer, lung cancer, skin cancer, and other solid cancers.

The compound of the present invention of formula (I) or a pharmaceutically acceptable salt thereof can provide enhanced anticancer effects when administered in combination with another anticancer agent for treating cancer or tumor.

Representative examples of anticancer agents for use in the treatment of cancer or tumor can include, but are not limited to, cell signaling inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib sodium, panitumumab, etc.), mitotic inhibitors (e.g., paclitaxel, vincristine, vinblastine, etc.), alkylating agents (e.g., cisplatin, cyclophosphamide, chlorambucil (chromabucil), carmustine, etc.), antimetabolites (e.g., methotrexate, 5-FU, etc.), intercalating anticancer agents (e.g., actinomycin, anthracyclines, bleomycin, mitomycin C, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, teniposide, etc.), immunotherapeutic agents (e.g., interleukins, interferons, etc.) and anti-hormonal agents (e.g., tamoxifen, raloxifene, etc.), and at least one anti-cancer agent selected therefrom may be included in the pharmaceutical compositions of the invention.

In addition, the compound of the present invention of formula (I) or a pharmaceutically acceptable salt thereof selectively and effectively inhibits Bruton Tyrosine Kinase (BTK), janus kinase 3(JAK3), interleukin-2 inducible T cell kinase (ITK), Resting Lymphocyte Kinase (RLK) and bone marrow tyrosine kinase (BMX) which are mainly expressed in abnormally activated B lymphocytes and/or T lymphocytes. That is, the compound of the present invention of formula (I) or a pharmaceutically acceptable salt thereof can treat or prevent cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases caused by abnormally activated B lymphocytes, T lymphocytes or both. Accordingly, the present invention also provides a pharmaceutical composition for treating or preventing cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease, comprising the compound of the present invention of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

Representative examples of inflammatory, autoimmune and immune-mediated diseases can include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, Systemic Lupus Erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, lung inflammation, Adult Respiratory Distress Syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia reperfusion injury, inflammatory bowel disease, crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, sjogren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis, and immune-mediated diseases, Scleroderma, organ transplant rejection, xenografts, Idiopathic Thrombocytopenic Purpura (ITP), parkinson's disease, alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), hairy cell leukemia, hodgkin's disease, non-hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative tumors (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

The compounds of the present invention of formula (I) or pharmaceutically acceptable salts thereof can provide enhanced therapeutic effects when administered in combination with another therapeutic agent useful for the treatment of inflammatory diseases, autoimmune diseases, and immune-mediated diseases.

Representative examples of therapeutic agents for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroid drugs (e.g., prednisone, prednisolone, methyl prednisolone, cortisone, hydrocortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNF α agents (e.g., etanercept, infliximab, adalimumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected therefrom may be included in the pharmaceutical composition of the present invention.

The compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered orally or parenterally as an active ingredient in an effective amount ranging from 0.1 to 2,000mg/kg body weight/day, preferably 1 to 1,000mg/kg body weight/day in the case of mammals including humans (body weight about 70kg), and administered in single or 4 divided doses per day, or with/without following a predetermined time. The dosage of the active ingredient may be adjusted according to a variety of relevant factors, such as the condition of the subject to be treated, the type and severity of the disease, the rate of administration and the opinion of the physician. In some cases, amounts less than the above dosages may be suitable. Amounts greater than the above doses may be used if they do not cause harmful side effects and may be administered in divided doses per day.

The pharmaceutical composition of the present invention may be formulated in the form of tablets, granules, powders, capsules, syrups, emulsions or microemulsions for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes) according to any of the conventional methods.

Pharmaceutical compositions of the invention for oral administration may be prepared by mixing the active ingredient with a carrier such as: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents, and diluents. Examples of carriers employed in the injectable compositions of the present invention are water, saline solutions, glucose-like solutions, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerol esters, surfactants, suspending agents, and emulsifiers.

The present invention is further described and illustrated in the examples provided below, which are not intended to limit the scope of the present invention.

Example 1: preparation of N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide

Step 1) thieno [3, 2-d]Preparation of pyrimidine-2, 4(1H, 3H) -dionePrepare for

Methyl 3-aminothiophene-2-carboxylate (4.9g, 31.3mmol) and urea (19g, 187mmol) were dissolved in N, N-dimethylformamide (10mL), and the reaction temperature was raised to 190 ℃ and then stirred for 12 hours. After completion of the reaction, the reaction mixture was added to 1N aqueous NaOH, cooled to room temperature and filtered under reduced pressure to remove insoluble precipitate. The filtrate was acidified (pH2) with 2N aqueous HCl solution, and the resulting solid was filtered under reduced pressure and washed with distilled water. The resulting solid was dried under reduced pressure to give the title compound (yield: 3.2g, 61.5%).

¹H-NMR(300MHz，CDCl₃)11.59(s，1H)，11.14(s，1H)，8.00(d，1H)，6.90(d，1H).

Step 2)2, 4-dichlorothieno [3, 2-d]Preparation of pyrimidines

The compound obtained in step 1 (3.2g, 19.4mmol) was dissolved in phosphorus oxychloride (12mL) and stirred at reflux at 200 ℃ for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, added dropwise to 4 ℃ distilled water and stirred vigorously. The resulting solid was then filtered under reduced pressure and washed with distilled water, and the resulting solid was dried under reduced pressure to give the title compound (yield: 2.9g, 73.3%).

¹H-NMR(300MHz，DMSO-d₆)8.74(d，1H)，7.78(d，1H).

Step 3) 2-chloro-4- (3-nitrophenoxy) thieno [3, 2-d]Preparation of pyrimidines

The compound (2.9g, 14.2mmol) obtained in step 2 was dissolved in N, N-dimethylsulfonamide (70mL), and then 3-nitrophenol (1.9g, 14.2mmol) and cesium carbonate (9.2g, 28.4mmol) were added thereto, and stirred at room temperature for 1 hour. After completion of the reaction, distilled water was added to the reaction mixture, and then the resulting solid was filtered under reduced pressure and washed with distilled water. The resulting solid was dried under reduced pressure to give the title compound (yield: 4.0g, 91.8%).

¹H-NMR(300MHz，CDCl₃)8.25-8.17(m，2H)，8.08(s，1H)，7.69-7.66(m，2H)，7.57(d，1H).

Step 4) N- (4- (4-methylpiperazin-1-yl) phenyl) -4- (3-nitrophenoxy) thieno [3, 2-d]Pyrimidine- Preparation of 2-amines

The compound obtained in step 3 (4g, 12.9mmol) was dissolved in 2-butanol (70mL), and then 4- (4-methylpiperazin-1-yl) aniline (2.7g, 12.9mmol) and trifluoroacetic acid (1.5mL, 12.9mmol) were added thereto. The mixture was stirred at 100 ℃ for 16 hours to complete the reaction, diluted with dichloromethane and then saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried over anhydrous sodium sulfate, then filtered and distilled under reduced pressure. The residue was separated by column chromatography (dichloromethane: methanol 20: 1 (vol.%)) to give the title compound (yield: 2.67g, 42%).

¹H-NMR(300MHz，CDCl₃)8.20(s，1H)，7.91(m，1H)，7.84(d，1H)，7.66(m，2H)，7.36(s，1H)，7.26(m，2H)，6.57(d，1H)，6.29(m，1H)，3.82(s，3H)，3.19(m，4H)，2.62(m，4H)，2.36(s，3H).

Step 5)4- (3-aminophenoxy) -N- (4- (4-methylpiperazin-1-yl) phenyl) thieno [3, 2-d]Pyrimidine- Preparation of 2-amines

Iron (1.5g, 27.1mmol) and 12N aqueous HCl (0.18mL, 2.17mmol) were diluted with 50% aqueous ethanol (30mL) and stirred at 100 ℃ for 10 min. The compound obtained in step 4 (2.67g, 5.42mmol) was dissolved in 50% aqueous ethanol (30mL), and then added to a reaction flask in which iron was activated, followed by stirring at 100 ℃ for 1 hour. After completion of the reaction, the reaction mixture was filtered with celite to remove iron, and the filtrate was distilled under reduced pressure. The residue was extracted with dichloromethane and saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried over anhydrous sodium sulfate, then filtered and distilled under reduced pressure. The residue was separated by column chromatography (dichloromethane: methanol 10: 1 (vol.%)) to give the title compound (yield: 1.7g, 67.8%).

¹H-NMR(300MHz，CDCl₃)8.20(s，1H)，7.91(m，1H)，7.84(d，1H)，7.66(m，2H)，7.36(s，1H)，7.26(m，2H)，6.57(d，1H)，6.29(m，1H)，3.82(s，3H)，3.19(m，4H)，2.62(m，4H)，2.36(s，3H).

Step 6) N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d]Pyrimidin-4-yloxy Radical) phenyl) acrylamide preparation

The compound (1.7g, 3.69mmol) obtained in step 5 and NaHCO were extracted with tetrahydrofuran (40mL) and distilled water (6mL)₃(930mg, 11.07mmol) and acryloyl chloride (0.36mL, 3.69mmol) was then added slowly thereto at 0 ℃ and stirred for 15 minutes. After completion of the reaction, the reaction mixture was extracted with dichloromethane and then saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried over anhydrous sodium sulfate, then filtered and distilled under reduced pressure, and the residue was separated by column chromatography (chloroform: methanol ═ 20: 1 (volume ratio)) to give the title compound (yield: 1.3g, 68.2%).

¹H-NMR(300MHz，CDCl₃)7.96(m，1H)，7.83(d，1H)，7.70(d，1H)，7.61(s，1H)，7.45(m，2H)，7.25(m，2H)，7.01(m，1H)，6.45(d，1H)，6.35-6.32(m，3H)，5.71(dd，1H)；

MS(ESI⁺)：m/z＝517.1[M+H]⁺.

Except using a catalyst consisting of Z-NH₂The procedure of example 1 was repeated except that various amine derivatives represented by (Z was the same as defined above) were substituted for 4- (4-methylpiperazin-1-yl) aniline in step 4, thereby preparing the compounds of examples 2 to 156 shown in tables 1a to 1v below.

< Table 1a >

< Table 1b >

< Table 1c >

< Table 1d >

< Table 1e >

< Table 1f >

< Table 1g >

< Table 1h >

< Table 1i >

< Table 1j >

< Table 1k >

< Table 1l >

< Table 1m >

< Table 1n >

< Table 1o >

< Table 1p >

< Table 1q >

< Table 1r >

< Table 1s >

< Table 1t >

< Table 1u >

< Table 1v >

Example 157: preparation of N- (3- (2- (4- (4-methyl-4-oxy-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide

The compound obtained in example 1 (100mg, 0.21mmol) was dissolved in dichloromethane (2mL), and m-chloroperoxybenzoic acid (71mg, 0.42mmol) was added thereto, followed by stirring at 45 ℃ for 12 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried over anhydrous sodium sulfate, then filtered and distilled under reduced pressure, and the residue was separated by column chromatography (chloroform saturated with ammonia: methanol 4: 1 (volume ratio)) to give the title compound (yield: 25mg, 40%).

¹H-NMR(300MHz，DMSO-d₆)10.38(s，NH)，9.27(s，NH)，8.28(d，1H)，7.74(s，1H)，7.60(d，1H)，7.46(m，3H)，7.33(d，1H)，7.05(d，1H)，6.78(d，2H)，6.43(m，1H)，6.28(m，1H)，5.76(m，1H)，3.57(m，4H)，2.98(s，3H)，2.95(m，2H)，2.50(m，2H)；

MS(ESI⁺)：m/z＝503.1[M+H]⁺.

Example 158: preparation of N- (3- (2- (4- (piperazin-1-yl) phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide

Step 1)4- (4- (4- (3-acrylamido-phenoxy) -thieno [3, 2-d)]Pyrimidin-2-ylamino) -benzenes Preparation of tert-butyl yl) -piperazine-1-carboxylate

The procedure of step 4 of example 1 was repeated except for using tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate instead of 4- (4-methylpiperazin-1-yl) aniline to obtain the title compound (yield: 610mg, 91%).

¹H-NMR(300MHz，CDCl₃)7.82-7.80(m，1H)，7.59-7.52(m，3H)，7.43-7.34(m，3H)，7.06-7.03(m，1H)，6.92(s，1H)，6.80-6.77(m，2H)，6.47-6.41(m，1H)，6.27-6.24(m，1H)，5.79-5.75(m，1H)，3.57(m，4H)，3.02-2.99(m，4H)，1.48(s，9H).

Step 2) N- (3- (2- (4- (piperazin-1-yl) -phenylamino) -thieno [3, 2-d]Pyrimidin-4-yloxy) -benzenes Preparation of aryl) -acrylamides

The compound obtained in step 1 (600mg, 1.05mmol) was dissolved in dichloromethane (10mL), and trifluoroacetic acid (1.62mL, 21.0mmol) was added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove the solvent and saturated NaHCO was used₃The aqueous solution was basified (pH 8) and then extracted 2 times with chloroform. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, then filtered and distilled under reduced pressure. The residue was separated by column chromatography (chloroform: methanol 10: 1 (volume ratio)) to give the title compound (yield: 316mg, 72%).

¹H-NMR(300MHz，CDCl₃)10.28(brs，1H)，9.15(brs，1H)，8.26-8.24(m，1H)，7.68(s，1H)，7.62-7.59(m，1H)，7.50-7.41(m，1H)，7.31-7.29(m，1H)，7.06-7.00(m，1H)，6.74-6.71(m，2H)，6.44-6.38(m，1H)，6.27-6.21(m，1H)，5.78-5.74(m，1H)，3.31(m，4H)，3.04-2.96(m，4H)；

MS(ESI⁺)：m/z＝473.4[M+H]⁺.

The procedure of example 158 was repeated except for using tert-butyl 4- (4-amino-2-chlorophenyl) piperazine-1-carboxylate or tert-butyl [1- (4-aminophenyl) chloropropyl ] carbamate instead of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate in step 4, to prepare the compounds of examples 159 and 160 shown in table 2 below.

< Table 2>

Example 161: preparation of (Z) -3-chloro-N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide

The compound (50mg, 0.12mmol) obtained in step 5 of example 1 was dissolved in pyridine (1.5mL), and cis-3-chloroacrylic acid (18mg, 0.17mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (44mg, 0.23mmol) were added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction mixture was diluted with a mixed solvent (chloroform: 2-propanol: 3: 1 (volume ratio) and washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, then filtered and distilled under reduced pressure, and the residue was separated by column chromatography (dichloromethane: methanol: 6: 1 (volume ratio)) to give the title compound (yield: 15mg, 24%).

¹H-NMR(300MHz，CDCl₃)8.24(s，1H)，7.82(d，1H)，7.62(s，1H)，7.57(d，1H)，7.44(d，1H)，7.39(d，1H)，7.35(s，1H)，7.26(d，1H)，7.08(m，1H)，6.98(s，1H)，6.81(d，2H)，6.62(d，1H)，6.34(d，1H)，3.13(t，4H)，2.59(t，4H)，2.36(s，3H)；

MS(ESI⁺)：m/z＝521.4[M+H]⁺.

The procedure of example 161 was repeated except for using trans-3-chloroacrylic acid and (E) -4- (dimethylamino) -2-butenoic acid to prepare the compounds of examples 162 and 163 shown in table 3 below.

< Table 3>

Example 164: preparation of N- (4-methyl-3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide

A procedure similar to the procedure of example 1 was conducted, except for using 2-methyl-5-nitrophenol (25mmol) instead of 3-nitrophenol in step 3), to obtain the title compound (30mg, final yield: 34%).

¹H-NMR(300MHz，DMSO-d₆)10.27(s，1H)，9.21(s，1H)，8.25(d，1H)，7.62(s，1H)，7.55(d，1H)，7.33(m，4H)，6.69(m，2H)，6.39(m，1H)，6.25(m，1H)，5.75(d，1H)，2.96(m，4H)，2.42(m，4H)，2.20(s，3H)，2.07(s，3H)；

MS(ESI⁺)：m/z＝501.2[M+H]⁺.

Similar procedures to those conducted in example 164 were conducted except for using 2-fluoro-5-nitrophenol and 2-methoxy-5-nitrophenol to obtain compounds of examples 165 and 166, respectively.

< Table 4>

Example 167: preparation of N- (3- (2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide

Step 1) N- (5- (4-methylpiperazin-1-yl) pyridin-2-yl) -4- (3-nitrophenoxy) thieno [3, 2-d] Preparation of pyrimidin-2-amines

0.6g (1.94mmol) of the compound obtained in step 3 of example 1 and 0.75g (3.88mmol) of 5- (4-methylpiperazin-1-yl) pyridin-2-amine were dissolved in 8ml of 1, 4-bisAn alkane, to which 178mg (0.2mmol) of tris (dibenzylideneacetone) dipalladium (0) and 122mg (0.2mmol) of 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl were then added, and stirred at room temperature for 5 minutes. 1.27g (3.88mmol) of cesium carbonate was added thereto and stirred at 100 ℃ for 3 hours. After completion of the reaction, the resulting mixture was cooled to room temperature and filtered through a short bed of celite filter, then diluted with dichloromethane and washed with water. Separating the organic layer over anhydrous Na₂SO₄Dried, filtered and distilled under reduced pressure. The resulting residue was subjected to column chromatography (dichloromethane: methanol (20: 1, v/v)) to give 630mg of a standardThe title compound (yield: 70%).

¹H-NMR(300MHz，DMSO-d₆)9.42(s，1H)，8.33(m，2H)，8.20(m，1H)，7.91(m，2H)，7.80(m，1H)，7.59(m，1H)，7.39(m，1H)，7.05(m，1H)，3.05(m，4H)，2.49(m，4H)，2.22(s，3H).

Step 2) N- (3- (2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) thieno [3, 2-d]Pyrimidine-4- Preparation of aryloxy) phenyl) acrylamide

The procedures of steps 5) and 6) of example 1 were repeated in this order except for using the compound (1.35mmol) obtained in step 1) instead of N- (4- (4-methylpiperazin-1-yl) phenyl) -4- (3-nitrophenoxy) thieno [3, 2-d ] pyrimidin-2-amine to obtain 50mg of the title compound (final yield: 34%).

¹H-NMR(300MHz，DMSO-d₆)10.50(s，1H)，9.37(s，1H)，8.10(d，1H)，7.90(d，1H)，7.72(m，1H)，7.64(m，2H)，7.47(dd，1H)，7.37(d，1H)，7.09(m，2H)，6.42(dd，1H)，6.25(dd，1H)，5.77(dd，1H)，3.01(m，4H)，2.42(m，4H)，2.22(s，3H)；

MS(ESI⁺)：m/z＝488.3[M+H]⁺.

Except for the use of various Z-NH₂The procedure of example 167 or a similar procedure was repeated except for substituting 5- (4-methylpiperazin-1-yl) pyridin-2-amine in example 167, step 1) (the meaning of Z is the same as defined in the present invention) for an amine derivative to give the title compounds of examples 168 to 205 as shown in tables 5a to 5 f.

< Table 5a >

< Table 5b >

< Table 5c >

< Table 5d >

< Table 5e >

< Table 5f >

Example 206: preparation of N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-ylamino) phenyl) acrylamide

The procedure of example 1 was repeated except for using 3-nitroaniline (0.05mmol) instead of 3-nitrophenol in step 3) of example 1 to obtain 5mg of the title compound (final yield: 55%).

¹H-NMR(300MHz，CDCl₃)8.10(m，1H)，7.90(d，1H)，7.51(m，3H)，7.42(m，1H)，7.28(t，1H)，7.10(d，1H)，6.89(d，2H)，6.39(m，2H)，5.79(d，1H)，3.29(m，4H)，2.68(m，4H)，2.38(s，3H)；

MS(ESI⁺)：m/z＝486.2[M+H]⁺.

Except for the use of various Z-NH₂The procedure of example 206 or a similar procedure was repeated except for substituting 5- (4-methylpiperazin-1-yl) pyridin-2-amine in example 1 with an amine derivative (the meaning of Z is the same as defined in the present invention) to give the title compounds of examples 207 to 217 as shown in tables 6a and 6 b.

< Table 6a >

< Table 6b >

Example 218: preparation of N- (4-fluoro-3- (2- (4- (4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide

Step 1) preparation of N- (4-fluoro-3-nitro-phenyl) -acrylamide

2g (12.81mmol) of 4-fluoro-3-nitroaniline and 3.2g (38.43mmol) of sodium bicarbonate were diluted in 20mL of tetrahydrofuran and 5mL of distilled water, and then 1.14mL (14.09mmol) of acryloyl chloride was slowly added thereto at 0 ℃ and stirred for 1 hour. After the reaction is completedThe resulting mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. Separating the organic layer over anhydrous Na₂SO₄Drying, filtration and distillation under reduced pressure gave 2g of the title compound (yield: 74%).

¹H-NMR(300MHz，DMSO-d₆)10.58(s，1H)，8.58(m，1H)，7.91(m，1H)，7.54(t，1H)，6.35(m，2H)，5.81(m，1H)；

Step 2) preparation of N- (3-amino-4-fluoro-phenyl) -acrylamide

2.65g (47.59mmol) of iron and 0.31mL (3.80mmol) of 12N aqueous hydrochloric acid are diluted in 40mL of 50% aqueous ethanol and stirred at 100 ℃ for 1 hour. 2.00g (9.51mmol) of the compound obtained in step 1 was added thereto and stirred at 100 ℃ for 1 hour. After completion of the reaction, the resulting mixture was filtered through a short bed of a celite filter to remove iron, and then distilled under reduced pressure. The resulting residue was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. Separating the organic layer over anhydrous Na₂SO₄Dried, filtered and distilled under reduced pressure. The resulting residue was subjected to column chromatography (n-hexane: ethyl acetate (1: 1, v/v)) to give 1.5g of the title compound (yield: 75%).

¹H-NMR(300MHz，DMSO-d₆)9.87(s，1H)，7.17(m，1H)，6.89(t，1H)，6.75(m，1H)，6.39(m，1H)，6.20(m，1H)，5.70(m，1H)，5.16(s，2H)；

Step 3) N- (3- (2-chloro-thieno [3, 2-d)]Process for preparing pyrimidin-4-ylamino) -4-fluoro-phenyl) -acrylamides Prepare for

The compound obtained in step 2) of example 1 and 461mg (2.22mmol) of the compound obtained in step 2) were dissolved in 5mL of 1-propanol, to which 0.6mL (3.33mmol) of diisopropylethylamine was then added and stirred at 110 ℃ for 24 hours. After completion of the reaction, the resultant mixture was cooled to 0 ℃ to form a solid, and then filtered under reduced pressure while being washed with propanol. The resulting mixture was dried under reduced pressure to obtain 270mg of the title compound (yield: 36%).

¹H-NMR(300MHz，DMSO-d₆)10.31(s，1H)，10.22(s，1H)，8.25(d，1H)，7.86(m，1H)，7.59(m，1H)，7.40(d，1H)，7.32(t，1H)，6.42(m，1H)，6.29(m，1H)，5.76(m，1H)；

Step 4) N- (4-fluoro-3- (2- (4- (4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d]Pyrimidine- Preparation of 4-ylamino) -phenyl) -acrylamide

100mg (0.30mmol) of the compound obtained in step 3) was dissolved in 3ml of 2-butanol, and then 55mg (0.28mmol) of 4- (4-methylpiperazin-1-yl) aniline and 42. mu.L (0.57mmol) of trifluoroacetic acid were added thereto, and stirred at 100 ℃ for 5 hours. After completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. Separating the organic layer over anhydrous Na₂SO₄Dried, filtered and distilled under reduced pressure. The residue was subjected to column chromatography (dichloromethane: methanol (10: 1, v/v)) to give 77mg of the title compound (yield: 50%).

¹H-NMR(300MHz，DMSO-d₆)10.26(s，1H)，9.38(s，1H)，8.77(s，1H)，8.02(d，1H)，7.82(d，1H)，7.62(m，1H)，7.44(d，2H)，7.30(t，1H)，7.15(d，1H)，6.68(m，2H)，6.40(m，1H)，6.22(m，1H)，5.73(m，1H)，2.96(m，4H)，2.42(m，4H)，2.20(s，3H)；

MS(ESI⁺)：m/z＝504.1[M+H]⁺.

Example 219: preparation of N- (4-fluoro-3- (2- (3-fluoro-4- (4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide

A procedure similar to that of example 218 step 4) was carried out, except for using 3-fluoro-4- (4-methylpiperazin-1-yl) aniline (0.03mmol) instead of 4- (4-methylpiperazin-1-yl) aniline in example 218 step 4), to obtain 8mg of the title compound (final yield: 50%).

¹H-NMR(300MHz，DMSO-d₆)10.25(s，1H)，9.50(s，1H)，9.08(s，1H)，8.07(d，1H)，7.85(d，1H)，7.59(m，2H)，7.26(m，2H)，7.19(d，1H)，6.78(t，1H)，6.38(m，1H)，6.27(m，1H)，5.75(m，1H)，2.87(m，4H)，2.25(m，4H)，2.21(s，3H)；

MS(ESI⁺)：m/z＝522.2[M+H]⁺.

Example 220: preparation of N- (3- (2- (4-dimethylaminomethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide

A procedure similar to step 4) of example 218 was carried out, except for using 0.67g (1.94mmol) of N- (3- (2-chloro-thieno [3, 2-d ] pyrimidin-4-ylamino) phenyl) acrylamide obtained in steps 1) to 3) of example 218 and 0.29g (1.94mmol) of 4- ((dimethylamino) methyl) aniline, to obtain 0.69g of the title compound (yield: 80%).

¹H-NMR(300MHz，CDCl₃)8.11(d，2H)，7.63(dd，3H)，7.55(m，4H)，7.18(m，2H)，7.05(s，1H)，6.45(d，1H)，6.30(q，1H)，5.74(d，1H)，3.38(s，2H)，2.01(s，6H)；

MS(ESI⁺)：m/z＝467.1[M+H]⁺.

The title compounds of examples 221 and 222 as shown in table 7 were obtained by carrying out the steps similar to those of example 220 except that 4- (piperidin-1-yl) methylaniline and 2-methoxy-4- (piperidin-1-yl) methylaniline were used.

< Table 7>

Example 223: preparation of N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-ylthio) phenyl) acrylamide

Step 1)3- (2-chlorothieno [3, 2-d)]Preparation of pyrimidin-4-ylthio) phenylcarbamic acid tert-butyl ester

1.1g (5.32mmol) of the compound obtained in step 2) of example 1 was dissolved in 30ml of N, N-dimethylsulfonamide, and then 1.2g (5.32mmol) of tert-butyl 3-mercaptophenylcarbamate and 3.4g (10.6mmol) of cesium carbonate were added thereto, and stirred at room temperature for 1 hour. After completion of the reaction, distilled water was added to the resultant mixture to form a solid, and then the resultant mixture was filtered under reduced pressure while being washed with distilled water. The resulting solid was dried under reduced pressure to obtain 1.5g of the title compound (yield: 70%).

¹H-NMR(300MHz，CDCl₃)7.92(d，1H)，7.77(s，1H)，7.56(d，1H)，7.45-7.36(m，3H)，1.54(s，9H).

Step 2)3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d]Pyrimidin-4-ylthio) benzenes Preparation of tert-butyl radical carbamate

1.5g (3.72mmol) of the compound obtained in step 1) was dissolved in 30mL of 2-butanol, and then 0.8g (3.72mmol) of 4- (4-methylpiperazin-1-yl) aniline and 0.4mL (3.72mmol) of trifluoroacetic acid were added thereto. The mixture was stirred at 100 ℃ for 10 hours, after completion of the reaction, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was passed over anhydrous Na₂SO₄Dried, filtered and distilled under reduced pressure. The residue was subjected to column chromatography (dichloromethane: methanol (20: 1, v/v)) to give 1.0g of the title compound (yield: 46%).

¹H-NMR(300MHz，CDCl₃)7.73(d，1H)，7.63(m，1H)，7.60(m，1H)，7.39-7.30(m，2H)，7.28-7.21(m，2H)，7.15(d，1H)，6.76(d，2H)，3.25(m，4H)，2.58(m，4H)，2.33(s，3H)，1.54(s，9H).

Step 3)4- (3-aminophenylthio) -N- (4- (4-methylpiperazin-1-yl) phenyl) thieno [3, 2-d]Pyrimidine as one kind of food Preparation of pyridine-2-amines

1.0g (1.82mmol) of the compound obtained in step 2 was dissolved in 20mL of dichloromethane, and then 10mL of trifluoroacetic acid was added thereto, and stirred at room temperature for 2 hours. After the completion of the reaction, the resultant mixture was distilled under reduced pressure to remove the solvent, and then the resultant residue was basified with saturated aqueous sodium bicarbonate solution (pH 8) and extracted with chloroform. Separating the organic layer over anhydrous Na₂SO₄Drying, filtering anddistillation under reduced pressure and then drying gave 603mg of the title compound (yield: 75%).

¹H-NMR(300MHz，CD₃OD)7.96(d，1H)，7.33(d，2H)，7.21(t，1H)，7.17(d，1H)，7.02(m，1H)，6.94(m，2H)6.80(d，2H)，3.14(m，4H)，2.65(m，4H).

Step 4) N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d]Pyrimidin-4-ylthio Radical) phenyl) acrylamide preparation

A procedure similar to that of example 1, step 6) was carried out, except that the compound obtained in step 3) was used instead of the compound obtained in step 5, to obtain 452mg of the title compound (yield: 67%).

¹H-NMR(300MHz，CDCl₃)7.78(m，1H)，7.75(d，1H)，7.46-7.41(m，3H)，7.20(d，2H)，7.18(d，1H)，6.77(d，2H)，6.41(d，1H)，6.21(dd，1H)，5.78(d，1H)，3.12(m，4H)，2.60(m，4H)，2.36(s，3H)；

MS(ESI⁺)：m/z＝503.7[M+H]⁺.

The procedure of example 223 or similar procedure was repeated except for using 3-fluoro-4-morpholin-4-ylaniline and 3-fluoro-4- (1-methyl-piperidin-4-yl) aniline instead of 54- (4-methylpiperazin-1-yl) aniline in step 2) of example 223 to obtain the title compounds of examples 224 and 225 as shown in table 8.

< Table 8>

Example 226: (E) preparation of (E) -4- (dimethylamino) -N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-ylsulfanyl) phenyl) but-2-enamide

40mg (0.09mmol) of the compound obtained in step 2 of example 223 was dissolved in 1.5mL of pyridine, and then 22mg (0.14mmol) of (E) -4- (dimethylamino) -2-butenoic acid hydrochloride and 35mg (0.18mmol) of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride were added thereto, and stirred at 80 ℃ for 30 minutes. After completion of the reaction, the resulting mixture was diluted with a mixed solvent of chloroform: 2-propanol (3: 1(v/v)) and washed with saturated brine. Separating the organic layer over anhydrous Na₂SO₄Dried, filtered and distilled under reduced pressure. The residue was separated by column chromatography (dichloromethane: methanol ═ 6: 1(v/v)) to give 2mg of the title compound (yield: 4%).

¹H-NMR(300MHz，CDCl₃)8.10(m，1H)，8.02(d，1H)，7.93(s，1H)，7.50(t，1H)，7.42(m，1H)，7.21(m，3H)，6.90(m，1H)，6.74(d，2H)，6.28(d，1H)，3.20(d，2H)，3.10(t，4H)，2.66(t，4H)，2.39(s，3H)，2.17(s，6H)；

MS(ESI⁺)：m/z＝560.2[M+H]⁺.

Example 227: preparation of N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-ylsulfinyl) phenyl) acrylamide

11mg (0.02mmol) of the compound obtained in example 223 was dissolved in 1.0mL of dichloromethane, and then 20mg (0.04mmol) of m-chloroperoxybenzoic acid was added thereto, and stirred at room temperature for 60 minutes. After completion of the reaction, the resulting mixture was diluted with chloroform and washed with a saturated aqueous sodium bicarbonate solution. Separating the organic layer over anhydrous Na₂SO₄Drying, filtering and distilling under reduced pressure. The residue was separated by column chromatography (dichloromethane: methanol ═ 6: 1(v/v)) to give 3.0mg of the title compound (yield: 25%).

¹H-NMR(300MHz，CD₃OD)8.08(m，1H)，8.01(d，1H)，7.92(m，1H)，7.51(t，1H)，7.46(m，1H)，7.22(m，3H)，6.73(d，1H)，6.38(m，2H)，5.76(dd，1H)，3.63-3.56(m，4H)，3.42-3.34(m，4H)，3.23(s，3H)；

MS(ESI⁺)：m/z＝519.3[M+H]⁺.

Example 228: preparation of N- (3- ((2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide

Step 1) 2-chloro-4- (3-nitrophenoxy) -furo [3, 2-d]Preparation of pyrimidines

6.4g (33.9mmol) of 2, 4-dichlorofuro [3, 2-d ] pyrimidine (see International publication Nos. WO 2008073785 and WO 2008152394) was dissolved in 32mL of methanol, and then 5.7g (40.6mmol) of 3-nitrophenol and 12mL (67.7mmol) of diisopropylethylamine were added thereto, and stirred at room temperature for 24 hours. After completion of the reaction, the resulting solid was filtered and dried under reduced pressure to obtain 6.3g of the title compound (yield: 64%).

¹H-NMR(300MHz，DMSO-d₆)8.61(s，1H)，8.33(s，1H)，8.21(d，1H)，7.90(d，1H)，7.79(m，1H)，7.27(s，1H)；

Step 2) N- [4- (4-methyl-piperazin-1-yl) -phenyl]-4- (3-nitrophenoxy) -furo [3, 2-d]Pyrimidine as one kind of food Preparation of pyridine-2-amines

2.5g (8.6mmol) of the compound obtained in step 1) were dissolved in 50mL of 2-butanol, and then 2.0g (10.3mmol) of 4- (4-methyl-piperazin-1-yl) aniline and 1.5mL (8.6mmol) of trifluoroacetic acid were added thereto. The reaction mixture was stirred at 100 ℃ for 12 hours, after completion of the reaction, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. Separating the organic layer over anhydrous Na₂SO₄Dried, filtered and distilled under reduced pressure, and then dried. The resulting residue was separated by column chromatography (dichloromethane: methanol ═ 20: 1(v/v)) to give 2.0g of the title compound (yield: 53%).

¹H-NMR(300MHz，CDCl₃)8.20(s，2H)，7.85(s，1H)，7.64(s，2H)，7.30(s，1H)，6.79(m，4H)，3.14(m，4H)，2.60(m，4H)，2.37(s，3H)；

Step 3)4- (3-aminophenoxy) -N- [4- (4-methyl-piperazin-1-yl) -phenyl]-furo [3, 2-d]Pyrimidine as one kind of food Preparation of pyridine-2-amines

1.3g (22.4mmol) of iron and 2mL of 12N aqueous hydrochloric acid solution were diluted in 10mL of 50% aqueous ethanol and stirred at 100 ℃ for 10 minutes. 2.0g (4.5mmol) of the compound obtained in step 2) was dissolved in 10mL of 50% aqueous ethanol, added to a flask in which iron was activated, and stirred at 100 ℃ for 1 hour. After completion of the reaction, the resulting mixture was filtered through a short bed of celite filter to remove iron, and then distilled under reduced pressure. The resulting residue was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. Separating the organic layer over anhydrous Na₂SO₄Drying, filtration and distillation under reduced pressure gave 1.8g of the title compound (yield: 97%).

¹H-NMR(300MHz，CDCl₃)7.79(s，1H)，7.32(d，2H)，7.24(m，1H)，6.84(m，2H)，6.75(s，1H)，6.65(m，3H)，3.22(m，4H)，2.60(m，4H)，2.36(s，3H)；

Step 4) N- (3- {2- [4- (4-methyl-piperazin-1-yl) -phenylamino]-furo [3, 2-d]Pyrimidin-4-yl Preparation of oxy } -phenyl) -acrylamide

1.8g (4.3mmol) of the compound obtained in step 3) and 1.1g (23.0mmol) of sodium hydrogencarbonate were diluted with 20mL of tetrahydrofuran and 5mL of distilled water, and then 0.4mL (4.3mmol) of acryloyl chloride was slowly added thereto at 0 ℃ and stirred for 30 minutes. After completion of the reaction, the resulting mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. Separating the organic layer over anhydrous Na₂SO₄Dried, filtered and distilled under reduced pressure, and then dried. The resulting residue was separated by column chromatography (chloroform: methanol ═ 20: 1(v/v)) to give 940mg of the title compound (yield: 46%).

¹H-NMR(300MHz，CD₃OD)8.04(s，1H)，7.68(d，2H)，7.45(t，1H)，7.32(d，2H)，7.03(d，1H)，6.78(m，3H)，6.45(m，2H)，5.80(d，1H)，3.08(m，4H)，2.61(m，4H)，2.35(s，3H)；

MS(ESI⁺)：m/z＝470.2[M+H]⁺.

Except for the use of various Z-NH₂The procedure of example 228 or a similar procedure was repeated except for substituting 4- (4-methylpiperazin-1-yl) aniline in step 2) of example 228 with an amine derivative (the meaning of Z is the same as defined in the present invention) to give the title compounds of examples 229 to 237 as shown in tables 9a and 9 b.

< Table 9a >

< Table 9b >

Preparation of example 1

Tablets for oral administration containing one of the compounds of formula (I) obtained in examples 1 to 237 as an active ingredient were prepared by a conventional method based on the formulation of table 10.

< Table 10>

Composition (I)	Measuring/tablet
		Active ingredient	100mg
Corn starch	80mg
		Lactose	80mg
Magnesium stearate	5mg

Preparation of example 2

Hard gelatin capsules for oral administration containing one of the compounds of formula (I) obtained in examples 1 to 237 as an active ingredient were prepared by a conventional method based on the formulation of table 11.

< Table 11>

Composition (I)	Measuring/tablet
		Active ingredient	100mg
Corn starch	40mg
		Lactose	80mg
Crystalline cellulose	80mg
		Magnesium stearate	5mg

Preparation of example 3

Based on the formulations of table 12, injection preparations containing one of the compounds of formula (I) obtained in examples 1 to 237 as an active ingredient were prepared by a conventional method, wherein the pH value was not controlled when the salt of the compound of formula (I) was used.

< Table 12>

Composition (I)	Measuring/tablet
		Active ingredient	20mg
5% glucose solution	10ml
		HCl(1N)	Adjusting to pH 4

Preparation of example 4

Injection preparations containing one of the compounds of formula (I) obtained in examples 1 to 237 as an active ingredient were prepared by a conventional method based on the formulation of table 13.

< Table 13>

Composition (I)	Measuring/tablet
		Active ingredient	20mg

Polyethylene glycol 400	2ml
		Sterile water	8ml

Test example 1: inhibition of growth of EGFR expressing cancer cells

To confirm that the compounds of the present invention obtained in examples 1 to 237 selectively inhibit the growth of cancer cells expressing EGFR mutants other than EGFR WT, an inhibition test of the growth of cancer cells by the compounds of the present invention was performed as follows. For testing, a skin cancer cell line (EGFR over-expressing wild-type (WT)) a431, a lung cancer cell line (in-frame deletion at exon 19 of EGFR tyrosine kinase) HCC827, and NCI-H1975 expressing EGFR L858R/T790M mutant, which are resistant to approved EGFR inhibitors (e.g., gefitinib or erlotinib), were used.

The inhibition test of the compounds of the present invention against the growth of cancer cells was carried out in A431(ATCC CRL-1555), HCC827(ATCC CRL-2868) and NCI-H1975(ATCC CRL-5908) cell lines.

The A431 cell line was incubated in high glucose DMEM (Dulbecco's Modified Eagle's Medium) supplemented with 10% Fetal Bovine Serum (FBS) and 1% penicillin/streptomycin (Gibco BRL), and the HCC827 and NCI-H1975 cell lines were incubated in RPMI Medium supplemented with 10% FBS, 1% penicillin/streptomycin, and 1% sodium pyruvate.

Cancer cell lines stored in a liquid nitrogen tank were each thawed rapidly at 37 ℃ and then centrifuged to remove the medium. Mixing the obtained cell pellet with culture medium at 37 deg.C and 5% CO₂Incubate in flask for 2 to 3 days, then remove the medium residual cells with DPBS (Dulbecco's phosphate buffered saline) washing, then use trypsin-EDTA from the flask separation of cells with culture medium dilution to a concentration of 1 × 10⁵A431 cellsWhereas for HCC827 and NCI-H1975 cells, it was diluted to 5 × 10⁴Individual cells/ml. 100 μ l of diluted cell solution was added to each well of a 96-well plate and incubated at 37 ℃ and 5% CO₂Incubate for 1 day. NCI-H1975 cells were starved in RPMI-1640 medium containing 0.1% FBS and 1% penicillin/streptomycin to maximize the reactivity of the cells to the test compound on the next day.

The compounds obtained in examples 1 to 237 were each dissolved in 99.5% Dimethylsulfoxide (DMSO) to a concentration of 25 mM. If the test compound is not soluble in DMSO, 1% HCl is added thereto and treated in a water bath at 40 ℃ for 30 minutes until complete dissolution is obtained. The DMSO solution containing the test compound was diluted with the medium to a final concentration of 100. mu.M and then diluted 10-fold stepwise to 10^-6μ M (final concentration of DMSO less than 1%).

The medium was removed from each well of the 96-well plate. Then, 100. mu.l of test compound solution was added to each well containing cultured cells, and the plate was incubated at 37 ℃ and 5% CO₂Incubation was performed for 72 hours (but NCI-H1975 cells were incubated for 48 hours). After removing the medium from the plate, 50 μ l of 10% trichloroacetic acid was added to each well, and the plate was maintained at 4 ℃ for 1 hour to fix the cells at the bottom of the plate. The added 10% trichloroacetic acid solution was removed from each well, the plate was dried, 100. mu.l of SRB (sulforhodamine B) dye solution having a concentration of 0.4% dissolved in 1% acetic acid was added thereto, and then the resulting mixture was reacted at room temperature for 10 minutes. After removal of the dye liquor, the plates were washed with water and allowed to dry thoroughly. When the dye liquor was not effectively removed by water, 1% acetic acid was used. Mu.l of 10mM trisma base was added to each well and the absorbance at 540nm wavelength was determined with a microplate reader. For NCI-H1975, cell viability was determined as absorbance at 490nm using Celltiter 96Aqueous One solution (MTS, promega).

GI was assessed as the difference between the final density of the test cells and the initial concentration of cells incubated in wells not treated with test compound (considered as 100%)₅₀(concentration at which 50% inhibition occurred). GI Using Microsoft Excel₅₀And the results were analyzed, and the results are shown in tables 14a to 14 f. Wherein A means GI₅₀Less than or equal to 50nM, B means GI₅₀Is 50-100nM, C means GI₅₀Is 100-1,000nM, and D means GI₅₀≥1,000nM。

< Table 14a >

< Table 14b >

< Table 14c >

< Table 14d >

< Table 14e >

< Table 14f >

As shown in tables 14a to 14f, almost all of the compounds of the present invention showed selective inhibition of expression of EGFExcellent anti-cancer Activity of HCC827 and NCI-H1975 non-Small cell Lung cancer (NSCLC) cell growth of R mutant (GI)₅₀Either a or B) and no anti-cancer activity (GI) on a431 cells expressing EGFR WT₅₀D). This inhibition mechanism of the compounds of the invention is very different from that of commercially available EGFR tyrosine kinases (e.g., erlotinib and lapatinib) or the material under development (BIBW 2992).

As shown in Table 14f, erlotinib, as a first generation EGFR inhibitor, was very effective in inhibiting the growth of NSCLC cell lines expressing EGFR mutants (HCC827, GI)₅₀A), but it has no inhibitory activity on NSCLC cell lines expressing EGFR T790M point mutation (NCI-H1975, GI₅₀D). Furthermore, currently available lapatinib, which inhibits both EGFR and HER-2, shows weak inhibitory activity against NSCLC cell lines (HCC827, GI)₅₀═ C) or no inhibitory activity (NCI-H1975, GI)₅₀D). In addition, the irreversible inhibitor BIBW2992(boehringer ingelheim) having a quinazoline structure, which is currently in phase III, exhibits strong inhibitory activity against pan-HER and effectively inhibits all cancer cell lines disclosed in tables 14a to 14f (including a431 cell line (GI cell line)₅₀A)). However, such irreversible inhibitors having a quinazoline structure may cause serious adverse side effects (e.g., diarrhea, rash, and weight loss) when treated in an amount for inhibiting EGFR T790M, and thus there is still a need to develop safe drugs for overcoming the problem of development of resistance to EGFR T790M. Therefore, the compounds of the present invention showed highly improved inhibitory activity against EGFR mutants (including EGFR T790M) and no inhibitory activity against EGFR WT expressed in normal cells, indicating that the compounds of the present invention can be used as more effective and safe anticancer agents for NSCLC patients.

Test example 2: inhibition assay for EGFR WT and L858R/T790M kinase activity

The inhibitory activity of the compounds of the present invention obtained in examples 1 to 237 against EGFR WT and L858R/T790M kinase was determined using a z-lyte kinase assay kit (z-lyte kinase assay kit, Invitrogen, PV 3191). The kinases used in this test were purchased from Invitrogen.

The compounds obtained in examples 1 to 237 were each prepared as a 10mM DMSO solution, and then a solution containing 4% DMSO was prepared therefrom and diluted to a concentration of 1 μ M to 0.0001 μ M. Then, the approximate Kd value for each kinase was calculated and kinase buffer (50mM HEPES (pH7.4), 10mM MgCl₂1mM EGTA and 0.01% BRIJ-35) to a concentration of 1 to 100 ng/assay. The test was performed in 384 well polystyrene flat bottom plates. Mu.l of a diluted solution of each compound was added to each well, and 10. mu.l of a mixture of a peptide substrate and a kinase at an appropriate concentration and 5. mu.l of a 5-300. mu.M ATP solution were successively added thereto, followed by incubation in a stirrer at room temperature for 60 minutes. After 60 minutes, 10. mu.l of a staining reagent was added to the resulting mixture to initiate a fluorescence reaction of the peptide substrate, and then a stop solution was added thereto to stop the reaction. Fluorescence values were determined for each well at 400nm (excitation filter) and 520nm (emission filter) using a fluorometer (Molecular Device). According to the kit protocol, the inhibitory activity of the test compound on the kinase was determined as percent (%) phosphorylation compared to the control group and IC was measured₅₀(concentration on the x-axis where 50% inhibition was observed). IC Using Microsoft Excel₅₀Calculation of (2) and result analysis. The results are shown in Table 15. Wherein A means IC₅₀Less than or equal to 50nM, B means IC₅₀Is 50-100nM, C means IC₅₀Is 100-1,000nM, and D means IC₅₀≥1,000nM。

< Table 15a >

As shown in Table 15, the compounds of the present invention showed relatively low inhibitory activity (IC) against EGFR WT associated with adverse reactions₅₀C or D), and exhibit excellent inhibitory activity (IC) against EGFR L858R/T790M mutant, which is resistant to commercially available EGFR inhibitors₅₀A). As with the results of test example 1, this inhibition mechanism of the compounds of the present invention is comparable to that of commercially available EGFR tyrosine kinase (e.g., Ello @)Tinib and lapatinib) or a candidate compound (BIBW2992) (IC) under development that strongly inhibits EGFR WT₅₀The inhibition mechanisms of a or B) are very different. Therefore, since it shows potent superior inhibitory activity against EGFR mutants (including EGFR t790M) and has no inhibitory activity against EGFR WT expressed in normal cells, the compounds of the present invention are effective and safe drugs useful for NSCLC patients.

Test example 3: inhibition assay for BTK and JAK3 kinase activity

The inhibitory activity of the compounds of the present invention obtained in examples 1 to 237 on BTK and JAK3 kinase was measured, respectively. The procedure of test example 2 was repeated except that BTK and JAK3 kinase (Invitrogen) were used instead of using EGFR kinase. The results are shown in tables 16a to 16 c. Wherein A means IC₅₀Less than or equal to 50nM, B means IC₅₀Is 50-100nM, C means IC₅₀Is 100-1,000nM, and D means IC₅₀≥1,000nM。

< Table 16a >

< Table 16b >

< Table 16c >

As shown in tables 16a to 16c, the compounds of the present invention exhibited excellent inhibitory activity (IC) against BTK and JAK kinase₅₀A or B).

Test example 4: inhibition assay for BMX, ITX and RLK kinase activity

The inhibitory activity of the compound obtained in example 1 on TEC family kinases (i.e., BMX, ITK, TEX and RLK) was measured. The measurement was performed in the same manner as in example 2, except that BMX, ITK, TEC, and RLK enzyme (Invitrogen) were used instead of EGFR enzyme. The results are shown in Table 17. The letter 'A' in the table means IC₅₀Less than or equal to 50nM, 'B' means IC₅₀'C' means IC 50-100nM₅₀100-₅₀≥1,000nM。

< Table 17>

As shown in Table 17, the compound of example 1 of the present invention effectively inhibited TEC family kinases, such as BTK, BMX, ITX and RLK kinase (IC)₅₀A or B).

Test example 5: anticancer efficacy testing in nude mice xenografted with NCI-H1975 cancer cells

The compounds of the present invention (example 2) were tested for their anticancer effects and toxicity in NCI-H1975 cancer cell xenografted nude mice that exhibited resistance to erlotinib, which was previously approved for the treatment of non-small cell lung cancer, due to the EGFR T790M point mutation. To evaluate the anticancer efficacy and toxicity of the compounds of the present invention, BIBW2992(Boehringer Ingelheim), which currently exhibits excellent activity against non-small cell lung cancer and is under active development, was also used in the present test.

NCI-H1975 cells (lung cancer cells) were purchased from the American Type Culture Collection (ATCC). The mice were injected subcutaneously on their backs with 1 × 10⁸After tumor formation from a suspension of individual cells/0.3 mL of tumor cells, passaging is performed and at least a third generation of tumor is used for this test.

In the test, a sixth generation tumor isolated from an individual was cut into a size of 30mg and subcutaneously transplanted in the right flank of a mouse using a 12-gauge trocar. After measuring the long diameter (L) and the short diameter (S) twice a week in an 18 day test using a vernier caliper, the tumor volume (V) was calculated according to the following equation 1. All the test materials were orally administered once a day for a total of 10 days, and then tumor growth inhibition rate (IR: tumor growth inhibition rate (%) calculated based on the vehicle-treated control group) and maximum body weight loss (mwwl: maximum body weight loss calculated based on the body weight before administration) were calculated using the following equations 2 and 3. The results are shown in table 6 and fig. 1 and 2.

< equation 1>

V＝L×S²/2

Wherein L is a long diameter and S is a short diameter,

< equation 2>

IR (%) - (1- (RTG of test material-treated group)/(RTG of control group) × 100

Where RTG is relative tumor growth and is the average tumor volume in a particular day based on the daily average tumor volume.

< equation 3>

Bmbl (%) ═ 1- (average body weight on day x/average body weight before administration)) × 100

Where day x is the day of greatest weight loss during the test period.

Table 18 below is the results for IR and mBML in the NCI-H1975 in vivo model.

< Table 18>

Compound (I)	BIBW2992	Example 2
			Dosage form	50mg/kg	70mg/kg
	77％	75％
				9.1％	-7.6％

1) Measured on day 16 after administration;

2) measured on day 10 after application.

The compound does not inhibit EGFR WT and shows excellent activity on EGFR mutants (active mutants: EGFR DelR746_ A750, EGFR L858R, acquired mutation: EGFR T790M) specific to non-small cell lung cancer. As shown in table 18 and fig. 1 and 2, the EGFR inhibitor showed comparable efficacy to BIBW2992 in NCI-H1975 (the animal model most difficult to show efficacy) (IR 77% versus 75%), and it did not show any adverse side effects (e.g., skin disease and weight loss) caused by pharmacological effects (BIBW 2992: weight loss 9.1%, example 2: weight gain 7.6% (therapeutic equivalent dose)). These experimental results show that the compounds of the present invention selectively and effectively inhibit cancer growth and drug resistance caused by EGFR mutation and show no side effects.

Test example 6: inhibition of collagen-induced arthritis in mice

To evaluate the efficacy of the compounds of the invention on rheumatoid arthritis, the compounds were tested in a collagen-induced arthritis (CIA) modelAn arthritis inhibition test was performed. The CIA model is a widely used representative autoimmune arthritis model, which arthritis is produced by injecting a mixture of type II collagen and an immunoadjuvant into a patient with H-2^qOr H-2^rAnd in a particular strain of mouse with class II Major Histocompatibility Complex (MHC), thereby abnormally activating CD4+ T cells and B cells that specifically respond to type II collagen.

Male DBA/1J mice (8 weeks old) were initially immunized by intradermal injection of 0.7mL of suspension in which an equal volume of 2mg/mL type II collagen was emulsified in 4mg/mL complete Freund's adjuvant supplemented with tubercle bacillus. After 21 days, mice were immunized twice by injection as above except using a suspension in which an equal volume of 2mg/mL type II collagen was emulsified in 4mg/mL complete Freund's adjuvant without tubercle bacillus. One week after the second immunization, the clinical scores of the mice were evaluated according to table 19, and 7 mice were grouped so that the experimental group averaged 1 to 2. Test samples at given concentrations and vehicle were orally administered in an amount of 10 mL/body weight per day using a probe for 14 days. The clinical score of arthritis was evaluated three times a day (David D Brand et al, Nature protocol.2(5), 1269, 2007).

The compound of example 1 reduced edema and flushing in the 10mg/kg and 30mg/kg groups until the last day of the test (day 14) compared to the control group; and in the 30mg/kg group edema, inflammation and flushing were significantly reduced (fig. 3).

As shown in tables 16a, 16b and 16c and table 3, the compounds of the present invention inhibit the activity of BTK and JAK3 kinase; and the inhibition results in a reduction in edema, inflammation and flushing as well as anti-collagen antibody values in a CIA model of autoimmune arthritis compared to a control group; but also reduces pannus formation in histopathological testing. The above results in rodent models of arthritis indicate that the compounds of the invention can provide clinical effects for patients with rheumatoid arthritis.

Furthermore, the compounds of the invention significantly reduced the secretion of interleukin-6 (IL-6) and TNF- α in human Peripheral Blood Mononuclear Cells (PBMC) and in murine splenocytes enriched in T lymphocytes, B lymphocytes, cells and macrophages, after treatment with phorbol-12-myristate-13-acetate (PMA), Phytohemagglutinin (PHA), renomycin and other substances that stimulate lymphocytes, compared to the control group. This demonstrates that the compounds of the present invention inhibit lymphocyte activation.

< Table 19>

Evaluation of arthritis clinical scores

Grade	Feature(s)
		0	No edema and flushing in the paw, ankle and ankle joints
1	Flushing and mild edema in the ankle or ankle joint
		2	Flushing and mild edema generally occur from ankle to ankle
3	Flushing and edema from ankle to toe
		4	Severe edema or spastic quadriplegia in the entire joints, claws and toes

While the invention has been described in terms of the above specific embodiments, it will be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined in the appended claims.

The following corresponds to the original claims of the parent application

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

w is O or S;

x is O, NH, S, SO or SO₂；

Y is a hydrogen atom, a halogen atom, C_1-6Alkyl or C_1-6An alkoxy group;

a and B are each independently a hydrogen atom, a halogen atom or a bis (C)_1-6Alkyl) aminomethyl;

z is aryl or heteroaryl having one or more substituents selected from: hydrogen atom, halogen atom, hydroxy group, nitro group, cyano group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl, di (C)_1-6Alkyl) amino C_2-6Alkoxycarbonyl, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, carbamoyl, C_1-6Alkylcarbamoyl, di (C)_1-6Alkyl) carbamoyl, di (C)_1-6Alkyl) amino C_2-6Alkylcarbamoyl, sulfamoyl, C_1-6Alkylsulfamoyl, di (C)_1-6Alkyl) sulfamoyl, di (C)_1-6Alkyl) amino C_2-6Alkylsulfamoyl, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl, di (C)_1-6Alkyl) phosphono groupHydroxy group C_1-6Alkyl, hydroxy carbonyl C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylsulfonyl radical C_1-6Alkyl radical, C_1-6Alkylsulfinyl C_1-6Alkyl, di (C)_1-6Alkyl) phosphono C_1-6Alkyl, hydroxy C_2-6Alkoxy radical, C_1-6Alkoxy radical C_2-6Alkoxy, amino C_1-6Alkyl radical, C_1-6Alkylamino radical C_1-6Alkyl, di (C)_1-6Alkyl) amino C_1-6Alkyl, di (C)_1-6Alkyl) aminoacetyl, amino C_2-6Alkoxy radical, C_1-6Alkylamino radical C_2-6Alkoxy, di (C)_1-6Alkyl) amino C_2-6Alkoxy, hydroxy C_2-6Alkylamino radical, C_1-6Alkoxy radical C_2-6Alkylamino radical, amino radical C_2-6Alkylamino radical, C_1-6Alkylamino radical C_2-6Alkylamino radical, di (C)_1-6Alkyl) amino C_2-6Alkylamino, heteroaryl, heterocycle, heterocyclyloxy, heterocyclylthio, heterocyclylsulfinyl, heterocyclosulfonyl C_1-6Alkyl, heterocycle C_1-6Alkoxy, heterocyclic amino, heterocyclic C_1-6Alkylamino, heterocyclylamino C_1-6Alkyl, heterocyclic carbonyl, heterocyclic C_1-6Alkylcarbonyl, heterocyclic carbonyl C_1-6Alkyl, heterocycle C_1-6Alkylthio, heterocyclic C_1-6Alkylsulfinyl, heterocyclic ring C_1-6Alkylsulfonyl, heterocyclylaminocarbonyl, heterocyclo C_1-6Alkylaminocarbonyl, heterocyclic aminocarbonyl C_1-6Alkyl, heterocyclic carboxamido and heterocyclic C_1-6An alkylcarboxamide group;

the aryl group is C_6-12The monocyclic aromatic ring or the bicyclic aromatic ring of (a);

each of said heteroaryl groups independently refers to a 5 to 12 membered monocyclic or bicyclic aromatic heterocycle having one or more N, O or S;

each of said heterocycles independently refers to a heterocyclic ring having one or more of N, O, S, SO or SO₂Saturated or partially unsaturated 3 to 12 memberedWherein the carbon atoms forming the heterocycle optionally have one or more substituents selected from the group consisting of: c_1-6Alkyl, hydroxy C_1-6Alkyl, hydroxycarbonyl, C_1-6Alkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, di (C)_1-6Alkyl) amino C_1-6Alkyl, di (C)_1-6Alkyl) aminocarbonyl, heterocycle C_1-6Alkyl and heteroaryl groups; and wherein if said heterocyclic ring optionally comprises a nitrogen atom, said nitrogen atom optionally has a substituent selected from: hydrogen atom, C_1-6Alkyl, monohalo C_1-6Alkyl, dihalo C_1-6Alkyl, trihalo C_1-6Alkyl radical, C_3-6Cycloalkyl, hydroxy C_2-6Alkyl radical, C_1-6Alkoxy radical C_2-6Alkyl radical, C_1-6Alkylcarbonyl, hydroxy C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl, carbamoyl, C_1-6Alkylcarbamoyl, di (C)_1-6Alkyl) carbamoyl, sulfamoyl, C_1-6Alkylsulfamoyl, di (C)_1-6Alkyl) sulfamoyl, C_1-6Alkylsulfonyl, amino C_2-6Alkyl radical, C_1-6Alkylamino radical C_2-6Alkyl, di (C)_1-6Alkyl) amino C_2-6Alkyl, di (C)_1-6Alkyl) amino C_1-6Alkylcarbonyl, heterocycle, heterocyclyloxy, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, heterocycle C_1-6Alkyl, heterocyclic carbonyl, heterocyclic C_1-6Alkylcarbonyl, heterocycle C_1-6Alkylsulfinyl and heterocycle C_1-6Alkylsulfonyl, wherein, when said nitrogen atom forms a tertiary amine, it is optionally in the form of an N-oxide; and is

Optionally, said C_1-6The alkyl radical being partially unsaturated or having C_3-6A cycloalkyl moiety, and the carbon atom in the heterocycle is present as a carbonyl.

2. The compound of claim 1, wherein Z is selected from formulas Z1 through Z203:

3. the compound of claim 1, wherein the compound of formula (I) is selected from:

n- (3- (2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-tert-butyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4- (2-fluoro-ethyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (2, 2, 2-trifluoro-ethyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4- (2-methoxy-ethyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4- (2-hydroxy-ethyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-hydroxy-4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (3, 4, 5-trimethyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (1-methyl-2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [ b)]Aza derivatives-7-ylamino) -thieno [3, 2-d]Pyrimidin-4-yloxy) -phenyl) -acrylamides,

N- (3- (2- (2-methoxy-4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (2-methoxy-4- (1-methyl-piperidin-3-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

(4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) phenyl) diethyl phosphate,

N- (3- (2- (4- [1, 4 '] bipiperidinyl-1' -yl-3-fluoro-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- ((2- ((3-chloro-4- (4-methylpiperazin-1-yl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4- (1-methylpiperidin-4-ylamino) -3-chlorophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (2-fluoro-4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (3-methyl-4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) -2-methyl-N- (1-methylpiperidin-4-yl) benzamide,

N- (4-methyl-3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (4-fluoro-3- (2- (4- (4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (4-methoxy-3- (2- (4- (4-methylpiperazin-1-yl) -phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

4-methyl-piperazine-1-carboxylic acid (4- (4- (3-acryloylamino-phenoxy) -thieno [3, 2-d ] pyrimidin-2-ylamino) -phenyl) -amide,

N- (4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) -2-fluorophenyl) -4-methylpiperazine-1-carboxamide,

N- (3- (2- (4- (4-ethylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-isopropyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (2, 2-difluoro-ethyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4-imidazol-1-yl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (2-dimethylamino-acetyl) -piperazin-1-yl) -3-fluoro-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-chloro-4- (piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (methylsulfonyl) piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-acetylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (morpholine-4-carbonyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1, 4-dimethyl-3-oxo-piperazin-2-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4-morpholinophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((2- (dimethylamino) ethyl) amino) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((2- (4-methylpiperazin-1-yl) ethyl) amino) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4-thiomorpholinophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (1-oxo-1. lamda.))⁴-thiomorpholin-4-yl) -phenylamino) -thieno [3, 2-d]Pyrimidin-4-yloxy) -phenyl) -acrylamides,

(S) -N- (3- (2- (4- (3- (dimethylamino) pyrrolidin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- [1, 4 '] bipiperidinyl-1' -yl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

1- (4- (4- (3-acryloylamino-phenoxy) -thieno [3, 2-d ] pyrimidin-2-ylamino) -phenyl) -piperidine-4-carboxylic acid dimethylamide,

N- (3- (2- (4- (dimethylamino) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (2-hydroxy-ethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (2-dimethylamino-ethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-chloro-4-fluorophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4-hydroxyphenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((4-acetylphenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (1, 4, 5, 6-tetrahydropyrimidin-2-yl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxo) phenyl) acrylamide,

N- (3- (2- (3-fluoro-2-methoxy-4- (4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (3R-imidazol-1-yl-pyrrolidin-1-yl) -phenylamino ] -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (3-imidazol-1-yl-pyrrolidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-imidazol-1-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-dimethylamino-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-morpholin-4-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (4-morpholin-4-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-chloro-4- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-chloro-4- (4-morpholin-4-yl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-hydroxypiperidin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((4- (4- (hydroxymethyl) piperidin-1-yl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (4- (2-hydroxyethyl) piperidin-1-yl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (ethylsulfonyl) piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- ((4-ethylpiperazin-1-yl) methyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4-diethylaminomethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-morpholin-4-yl-piperidin-1-ylmethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

(E) -N- (3- ((2- ((4- (3- (dimethylamino) prop-1-en-1-yl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((1-methylpiperidin-4-yl) amino) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4-diethylaminomethyl-2-methoxy-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- ((4-methylpiperazin-1-yl) methyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (3-fluoro-4- (4-methyl-piperazin-1-ylmethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (piperidin-1-ylmethyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4-azetidin-1-ylmethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4-pyrrolidin-1-ylmethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (morpholinomethyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((4-hydroxypiperidin-1-yl) methyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((4- (dimethylamino) piperidin-1-yl) methyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

Dimethyl (4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) benzyl phosphate;

n- (3- (2- (4- ((dimethylamino) methyl) -3-fluorophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) 3-fluorophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- ((4- (dimethylamino) piperidin-1-yl) methyl) 3-fluorophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- ((1-methylpiperidin-4-ylamino) methyl) -3-fluorophenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4-dimethylaminomethyl-2-methyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- ((4- (cyclopropylmethyl) piperazin-1-yl) methyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- ((4- (1-methylpiperidin-4-yl) piperazin-1-yl) methyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4-methanesulfonylmethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (2-methanesulfonyl-ethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-chloro-4- (4- (1-methyl-piperidin-4-yl) piperazin-1-ylmethyl) phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-cyclohexyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (5- (4-ethylpiperazin-1-yl) pyridin-2-ylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (5- (4- (2-hydroxy-ethyl) -piperazin-1-yl) -pyridin-2-ylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1- (4-ethylpiperazin-1-yl) ethyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-ethylpiperazine-1-carbonyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (2-hydroxy-acetyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4- (2-dimethylamino-acetyl) -piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

2- (4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) phenyl) acetic acid,

N- (3- ((2- ((4- (methylsulfinyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (methylsulfonyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) -N-methylbenzamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) -N, N-dimethylbenzamide,

N- (3- ((2- ((4- (morpholine-4-carbonyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (4-methylpiperazine-1-carbonyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (1-methyl-piperidin-4-yl) -piperazine-1-carbonyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-hydroxy-piperidine-1-carbonyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (3-methylamino-pyrrolidine-1-carbonyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (3-dimethylamino-pyrrolidine-1-carbonyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

4- (4- (3-acryloylamino-phenoxy) -thieno [3, 2-d ] pyrimidin-2-ylamino) -N- (2-dimethylamino-ethyl) -benzamide,

N- (3- (2- (3-chloro-4- (4-ethylpiperazine-1-carbonyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((3-chloro-4- ((2- (dimethylamino) ethyl) amino) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

4- (4- (3-acryloylamino-phenoxy) -thieno [3, 2-d ] pyrimidin-2-ylamino) -2-chloro-N, N-dimethyl-benzamide,

N- (3- (2- (3-chloro-4- (4-ethanesulfonyl-piperazine-1-carbonyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino-2-chloro-N- (1-methylpiperidin-4-yl) benzamide,

N- (3- (2- (4- (4-ethylpiperazin-1-ylsulfonyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((methylsulfinyl) methyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (2- (methylsulfinyl) ethyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4-sulfamoylphenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (morpholinosulfonyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (N-cyclopropylsulfamoyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (N- (2- (dimethylamino) ethyl) sulfamoyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (N- (1-methylpiperidin-4-yl) sulfamoyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (N- (1-isopropylpiperidin-4-yl) sulfamoyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

3- (dimethylamino) propyl 4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) benzoate,

N- (3- (2- (4- (2- (4-ethylpiperazin-1-yl) ethyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (2-piperidin-1-yl-ethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1, 1-dioxo-1. lamda.))⁶-thiomorpholin-4-yl) -phenylamino) -thieno [3, 2-d]Pyrimidin-4-yloxy) -phenyl) -acrylamides,

N- (3- (2- (4- (2- (4-ethylpiperazin-1-yl) acetyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (1-ethylpiperidin-4-yloxy) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (3-fluoro-4- (1-methyl-piperidin-4-yloxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (2-morpholinoethoxy) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (2-methoxy-ethoxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- ((2- ((4- (2- (dimethylamino) ethoxy) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (2- (diethylamino) ethoxy) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((2, 3, 4, 5-tetrahydrobenzo [ b ]][1，4]Oxazazem-7-yl) amino) thieno [3, 2-d]Pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (2, 3-dihydro-benzo [1, 4 ]) derivatives]IIEngland-6-ylamino) -thieno [3, 2-d]Pyrimidin-4-yloxy) -phenyl) -acrylamides,

N- (3- (2- (3-fluoro-4- (2-methoxy-ethoxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (2-dimethylamino-ethoxy) -3-fluoro-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (2-diethylamino-ethoxy) -3-fluoro-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (2- (4-methyl-piperazin-1-yl) -ethoxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-methoxy-4- (2-morpholin-4-yl-ethoxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

(E) -4- (dimethylamino) -N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) but-2-enamide,

N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-ylamino) phenyl) acrylamide,

N- (3- (2- (4- (4-ethyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4- (4-isopropyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4- (1-methyl-piperidin-3-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4-dimethylaminomethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4-piperidin-1-ylmethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4- (2-dimethylamino-ethyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- ((2- ((4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) amino) phenyl) acrylamide,

N- (3- (2- (4- (2-dimethylamino-ethoxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4- (3-dimethylamino-propoxy) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (1-methyl-piperidin-4-ylamino) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (2-methoxy-4-piperidin-1-ylmethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (4-fluoro-3- (2- (4- (4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (4-fluoro-3- (2- (3-fluoro-4- (4-methyl-piperazin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylamino) -phenyl) -acrylamide,

N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-ylthio) phenyl) acrylamide,

N- (3- (2- (3-fluoro-4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylsulfanyl) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4-morpholin-4-yl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-ylsulfanyl) -phenyl) -acrylamide,

(E) -4- (dimethylamino) -N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-ylsulfanyl) phenyl) but-2-enamide,

N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-ylsulfinyl) phenyl) acrylamide,

(Z) -3-chloro-N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

(E) -3-chloro-N- (3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4-ethylpiperazin-1-yl) -2-methoxyphenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (2-methoxy-4-morpholinophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) -2-methoxy-N- (1-methylpiperidin-4-yl) benzamide,

N- (3- (2- (4- (piperidin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (pyrrolidin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

1- (4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) phenyl) piperidine-4-carboxylic acid,

N- (3- (2- (4- (4-dimethylaminomethyl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (4-piperidin-1-ylmethyl-piperidin-1-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1-methyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1-ethyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1-isopropyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (1-methyl-piperidin-3-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4-dimethylaminomethyl-phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-chloro-4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

4- (4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-ylamino) -N- (2- (pyrrolidin-1-yl) ethyl) benzamide,

N- (3- ((2- ((4- (2- ((1-methylpiperidin-4-yl) amino) -2-oxoethyl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4- (3-piperidin-1-yl-propenyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (4- (3-pyrrolidin-1-yl-propionylamino) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino-N- (tetrahydro-2H-pyran-4-yl) benzamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino-N- (1-methylpiperidin-4-yl) benzamide,

4- ((4- (3-acrylamidophenoxy) thieno [3, 2-d ] pyrimidin-2-yl) amino) -N- (1-isopropylpiperidin-4-yl) benzamide,

4- (4- (3-acryloylamino-phenoxy) -thieno [3, 2-d ] pyrimidin-2-ylamino) -3-methoxy-N- (2-pyrrolidin-1-yl-ethyl) -benzamide,

N- (3- (2- (4- (N, N-dimethylsulfamoyl) piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (2- (4- (ethylsulfonyl) piperazin-1-yl) ethyl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (6- (4-methylpiperazin-1-yl) pyridin-3-ylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- (pyridin-3-ylamino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6-morpholinopyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- (4-isopropylpiperazin-1-yl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- (4- (dimethylamino) piperidin-1-yl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- ([1, 4 '-bipiperidin ] -1' -yl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- ((4-methylpiperazin-1-yl) methyl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- ((2- (piperidin-1-yl) ethyl) amino) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- ((1-isopropylpiperidin-4-yl) amino) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((6- (methylsulfinyl) pyridin-3-yl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (3-fluoro-4-morpholinophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- ((2- ((3-fluoro-4- ((1-methylpiperidin-4-yl) amino) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((3-fluoro-4- ((1-isopropylpiperidin-4-yl) amino) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (3-fluoro-4- (4- (methylsulfonyl) piperazin-1-yl) phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (4- (4- (ethanesulfonylpiperazin-1-yl) -3-fluoro-phenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) acrylamide,

N- (3- (2- (4- (2, 6-cis-dimethylmorpholino) -3-fluorophenylamino) thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) acrylamide,

N- (3- (2- (3-fluoro-4- (1-methyl-piperidin-4-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (1-methyl-piperidin-3-yl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (3-fluoro-4- (2-morpholin-4-yl-ethoxy) phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- ((2- ((4- ((2- (dimethylamino) ethyl) amino) -3-fluorophenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((3, 5-difluoro-4- (4-methylpiperazin-1-yl) phenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((2- (dimethylamino) ethyl) amino) -3, 5-difluorophenyl) amino) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((3, 5-difluoro-4- ((1-methylpiperidin-4-yl) amino) phenyl) thieno [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (4- (1-amino-cyclopropyl) -phenylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- [1- (2-dimethylamino-acetyl) -2, 3-dihydro-1H-indol-5-ylamino ] -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- (2- (1-methyl-1H-indol-5-ylamino) -thieno [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide,

N- (3- ((2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (4-isopropylpiperazin-1-yl) phenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4-morpholinophenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((dimethylamino) methyl) phenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- ((4- (dimethylamino) piperidin-1-yl) methyl) phenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((3-fluoro-4- (1-methylpiperazin-4-yl) phenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((4- (2-dimethylamino) ethyl) amino) -3-fluorophenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- ((2- ((3-fluoro-4- ((1-methylpiperidin-4-yl) amino) phenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N- (3- (2- (3-methoxy-4- (4-methyl-piperazin-1-yl) -phenylamino) -furo [3, 2-d ] pyrimidin-4-yloxy) -phenyl) -acrylamide, and

n- (3- ((2- ((4-sulfamoylphenyl) amino) furo [3, 2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide.

4. Use of a compound of claim 1 for the manufacture of a medicament for the prevention or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases.

5. The use of claim 4, wherein the cancer or tumor is induced by Epidermal Growth Factor Receptor (EGFR) tyrosine kinase or a mutant thereof.

6. The use of claim 4, wherein the cancer, tumor, inflammatory disease, autoimmune disease, or immune-mediated disease is mediated by at least one kinase selected from the group consisting of: bruton Tyrosine Kinase (BTK), janus kinase 3(JAK3), interleukin-2 inducible T-cell kinase (ITK), Resting Lymphocyte Kinase (RLK), and bone marrow tyrosine kinase (BMX).

7. The use of claim 4, wherein the cancer, tumor, inflammatory disease, autoimmune disease, or immune-mediated disease is mediated by aberrantly activated B lymphocytes, T lymphocytes, or both.

8. The use of claim 4, wherein the inflammatory, autoimmune or immune-mediated disease is arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, Systemic Lupus Erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, pulmonary inflammation, Adult Respiratory Distress Syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, sjogren's syndrome, autoimmune thyroid disease, urticaria (rubella), urticaria, Multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, Idiopathic Thrombocytopenic Purpura (ITP), parkinson's disease, alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic rhinosinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), hairy cell leukemia, hodgkin's disease, non-hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative tumors (MPN), diffuse large B-cell lymphoma, or follicular lymphoma.

9. The use of claim 4, which is administered in combination with an anti-cancer agent selected from the group consisting of: cell signaling inhibitors, mitotic inhibitors, alkylating agents, antimetabolites, intercalating anticancer agents, topoisomerase inhibitors, immunotherapeutic agents, anti-hormonal agents, and mixtures thereof.

10. The use of claim 4, administered in combination with a therapeutic agent selected from the group consisting of: steroidal drugs, methotrexate, leflunomide, anti-TNF α agents, calcineurin inhibitors, antihistamines, and mixtures thereof.

11. A pharmaceutical composition for preventing or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease, comprising the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

12. A method for preventing or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease, which comprises administering a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof to a mammal in need thereof.

Claims (13)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

w is O;

x is O;

y is hydrogen;

a and B are each independently hydrogen;

z is selected from the group consisting of formulas Z2, Z4, Z28, Z61, Z100, Z113, Z138, Z164, Z168 and Z189:

2. the compound of claim 1, or a salt thereof, wherein the compound of formula (I) is selected from:

3. use of a compound of claim 1 for the preparation of a medicament for the prevention or treatment of a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease.

4. The use of claim 3, wherein the tumor is induced by epidermal growth factor receptor tyrosine kinase or a mutant thereof.

5. The use of claim 3, wherein the tumor, inflammatory disease, autoimmune disease, or immune-mediated disease is mediated by at least one kinase selected from the group consisting of: bruton tyrosine kinase, janus kinase 3, interleukin-2 inducible T cell kinase, resting lymphocyte kinase, and bone marrow tyrosine kinase.

6. The use of claim 3, wherein the tumor, inflammatory disease, autoimmune disease, or immune-mediated disease is mediated by aberrantly activated B lymphocytes, T lymphocytes, or both.

7. The use of claim 3, wherein the inflammatory, autoimmune or immune-mediated disease is arthritis, lupus, pain, lung disease, cardiovascular disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria, multiple sclerosis, scleroderma, organ transplant rejection, xenografts, idiopathic thrombocytopenic purpura, Parkinson's disease, Alzheimer's disease, diabetes-related diseases, lymphoma, myeloma, acute lymphatic leukemia.

8. The use of claim 3, which is administered in combination with an anti-cancer agent selected from the group consisting of: cell signaling inhibitors, mitotic inhibitors, alkylating agents, antimetabolites, intercalating anticancer agents, topoisomerase inhibitors, immunotherapeutic agents, anti-hormonal agents, and mixtures thereof.

9. The use of claim 3, administered in combination with a therapeutic agent selected from the group consisting of: steroidal drugs, methotrexate, leflunomide, anti-TNF α agents, calcineurin inhibitors, antihistamines, and mixtures thereof.

10. A pharmaceutical composition for preventing or treating tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases, which comprises the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

11. The compound of claim 1 or 2, or a salt thereof, which is a compound of the formula:

12. the compound of claim 1 or 2, or a salt thereof, which is a compound of the formula:

13. a pharmaceutical composition comprising a compound according to any one of claims 1, 2, 11 or 12 and a pharmaceutically acceptable carrier.