The present invention relates to a novel fused pyrimidine derivative having an inhibitory activity for tyrosine kinases, and a pharmaceutical composition for preventing or treating cancers, tumors, inflammatory diseases, autoimmune diseases, or immunologically mediated diseases comprising same as an active ingredient.
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0. 31. A method of inhibiting epidermal growth factor receptor (EGFR), EGFR L858R/T790M mutant, bruton's tyrosine kinase (BTK), janus kinase 3 (JAK3), interleukin-2 inducing T-cell kinase (ITK), resting lymphocyte kinase (RLK), and/or bone marrow tyrosine kinase (BMX), comprising administering to a mammal in need thereof a therapeutically effective amount of the compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the mammal is suffering from cancer, tumors, inflammatory diseases, autoimmune diseases, or immunologically mediated diseases.
0. 33. A method of inhibiting epidermal growth factor receptor (EGFR), EGFR L858R/T790M mutant, bruton's tyrosine kinase (BTK), janus kinase 3 (JAK3), interleukin-2 inducing T-cell kinase (ITK), resting lymphocyte kinase (RLK), and/or bone marrow tyrosine kinase (BMX), comprising administering to a mammal in need thereof a therapeutically effective amount of the compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein the mammal is suffering from cancer, tumors, inflammatory diseases, autoimmune diseases, or immunologically mediated diseases.
0. 32. A method of inhibiting epidermal growth factor receptor (EGFR), EGFR L858R/T790M mutant, bruton's tyrosine kinase (BTK), janus kinase 3 (JAK3), interleukin-2 inducing T-cell kinase (ITK), resting lymphocyte kinase (RLK), and/or bone marrow tyrosine kinase (BMX), comprising administering to a mammal in need thereof a therapeutically effective amount of the compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein the mammal is suffering from cancer, tumors, inflammatory diseases, autoimmune diseases, or immunologically mediated diseases.
##STR00297##
wherein,
W is S;
X is O, NH, S, SO or SO2;
Y is hydrogen atom, halogen atom, C1-6alkyl or C1-6alkoxy;
A and b are each independently hydrogen atom, halogen atom, or di(C1-6alkyl)aminomethyl;
Z is aryl or heteroaryl having one or more substituents selected from the group consisting of: hydrogen atom, halogen atom, hydroxy, nitro, cyano, C1-6alkyl, C1-6alkoxy, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, di(C1-6alkyl)aminoC2-6alkoxycarbonyl, amino, C1-6alkylamino, di(C1-6alkyl)amino, carbamoyl, C1-6alkylcarbamoyl, di(C1-6alkyl)carbamoyl, di(C1-6alkyl)aminoC2-6alkylcarbamoyl, sulfamoyl, C1-6alkylsulfamoyl, di(C1-6alkyl)sulfamoyl, di(C1-6alkyl)aminoC2-6alkylsulfamoyl, C1-6alkylsulfonyl, C1-6alkylsulfinyl, di(C1-6alkyl)phosphonyl, hydroxyC1-6alkyl, hydroxycarbonylC1-6alkyl, C1-6alkoxyC1-6alkyl, C1-6alkylsulfonylC1-6alkyl, C1-6alkylsulfinylC1-6alkyl, di(C1-6alkyl)phosphonylC1-6alkyl, hydroxyC2-6alkoxy, C1-6alkoxyC2-6alkoxy, aminoC1-6alkyl, C1-6alkylaminoC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)aminoacetyl, aminoC2-6alkoxy, C1-6alkylaminoC2-6alkoxy, di(C1-6alkyl)aminoC2-6alkoxy, hydroxyC2-6alkylamino, C1-6alkoxyC2-6alkylamino, aminoC2-6alkylamino, C1-6alkylaminoC2-6alkylamino, di(C1-6alkyl)aminoC2-6alkylamino, heteroaryl, heterocycle, heterocyclic oxy, heterocyclic thio, heterocyclic sulfinyl, heterocyclic sulfonyl, heterocyclic sulfamoyl, heterocyclic C1-6alkyl, heterocyclic C1-6alkoxy, heterocyclic amino, heterocyclic C1-6alkylamino, heterocyclic aminoC1-6alkyl, heterocyclic carbonyl, heterocyclic C1-6alkylcarbonyl, heterocyclic carbonylC1-6alkyl, heterocyclic C1-6alkylthio, heterocyclic C1-6alkylsulfinyl, heterocyclic C1-6alkylsulfonyl, heterocyclic aminocarbonyl, heterocyclic C1-6alkylaminocarbonyl, heterocyclic aminocarbonylC1-6alkyl, heterocyclic carboxamido, and heterocyclic C1-6alkylcarboxamido;
the aryl refers to a C6-12 cyclic or bicyclic aromatic ring;
the heteroaryls each independently refer to a 5- to 12-membered cyclic or bicyclic aromatic hetero ring having one or more N, O or S;
the heterocycles each independently refer to a saturated or partially unsaturated 3- to 12-membered cyclic or bicyclic hetero ring having one or more N, O, S, SO or SO2, in which a carbon atom forming the heterocycle optionally has one or more substituents selected from the group consisting of C1-6alkyl, hydroxy, hydroxyC1-6alkyl, hydroxycarbonyl, C1-6alkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, di(C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)aminocarbonyl, heterocycle, heterocyclic C1-6alkyl, and heteroaryl, and in which, provided that the heterocycle optionally comprises a nitrogen atom, the nitrogen atom optionally has a substituent selected from the group consisting of hydrogen atom, C1-6alkyl, monohalogenoC1-6alkyl, dihalogenoC1-6alkyl, trihalogenoC1-6alkyl, C3-6cycloalkyl, hydroxyC2-6alkyl, C1-6alkoxyC2-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkylcarbonyl, C1-6alkoxycarbonyl, carbamoyl, C1-6alkylcarbamoyl, di(C1-6alkyl)carbamoyl, sulfamoyl, C1-6alkylsulfamoyl, di(C1-6alkyl)sulfamoyl, C1-6alkylsulfonyl, aminoC2-6alkyl, C1-6alkylaminoC2-6alkyl, di(C1-6alkyl)aminoC2-6alkyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, heterocycle, heterocyclic oxy, heterocyclic thio, heterocyclic sulfinyl, heterocyclic sulfonyl, heterocyclic C1-6alkyl, heterocyclic carbonyl, heterocyclic C1-6alkylcarbonyl, heterocyclic C1-6alkylsulfinyl, and heterocyclic C1-6alkylsulfonyl (,
wherein, when the nitrogen atom forms tertiary amine, it is optionally of an N-oxide form); and
optionally, the C1-6alkyl is partially unsaturated or has a C3-6cycloalkyl moiety, and a carbon atom in the heterocycle exists in a carbonyl form.
2. The compound of
##STR00298##
##STR00299##
##STR00300##
##STR00301##
##STR00302##
##STR00303##
##STR00304##
##STR00305##
##STR00306##
##STR00307##
##STR00308##
##STR00309##
##STR00310##
##STR00311##
##STR00312##
##STR00313##
##STR00314##
##STR00315##
##STR00316##
##STR00317##
##STR00318##
##STR00319##
##STR00320##
##STR00321##
##STR00322##
##STR00323##
##STR00324##
##STR00325##
##STR00326##
##STR00327##
##STR00328##
##STR00329##
##STR00330##
##STR00331##
##STR00332##
##STR00333##
##STR00334##
##STR00335##
##STR00336##
##STR00337##
##STR00338##
##STR00339##
3. The compound of
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)-phenyl amino)-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-(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]azepin-7-ylamino)-thieno[3,2-d]pyrimidin-4-yloxy)phenyl)-acrylamide;
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;
Diethyl(4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino)phenyl)phosphonate;
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-piperazin-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-methylpiperazin-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-(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-(morpholin-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-1λ4-thiomorpholin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)acrylamide;
(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-[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide; 1-(4-(4-(3-acryloylamino-phenoxy)-thieno[3,2-d]pyrimidin-2-ylamino)-phenyl)-piperidin-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[3,2d]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)benzylphosphonate;
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-methanesulfonylmetyl-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)-piridin-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-ethylpiperazin-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-(morpholin-4-carbonyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;
N-(3-((2-((4-(4-methylpiperazin-1-carbonyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;
N-(3-(2-(4-(4-(1-methyl-piperidin-4-yl)-piperazin-1-carbonyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;
N-(3-(2-(4-(4-hydroxy-piperidin-1-carbonyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;
N-(3-(2-(4-(3-methylamino-pyrrolidin-1-carbonyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;
N-(3-(2-(4-(3-dimethylamino-pyrrolidin-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-ethylpiperazin-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-piperazin-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-1λ6-thiomorpholin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;
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]oxazepin-7-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;
N-(3-(2-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;
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-ylthio)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)piperidin-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-piridin-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-(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-(pyridine-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-c]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-c]pyrimidin-4-yl)oxy)phenyl)acrylamide;
N-(3-(2-(3-fluoro-4-morpholinophenylamino)thieno[3,2-c]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-fluorophenylamino)thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)acrylamide;
N-(3-(2-(4-(2,6-cis-dimethylmorpholino)-3-fluorophenylamino)thieno[3,2-c]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; and
N-(3-(2-(1-methyl-/H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide.
4. A pharmaceutical composition comprising the compound of formula (I) or its pharmaceutically acceptable salt of
5. A method of inhibiting epidermal growth factor receptor (EGFR), EGFR L858R/T790M mutant, bruton's tyrosine kinase (BTK) janus kinase 3 (JAK3), interleukin-2 inducing T-cell kinase (ITK), resting lymphocyte kinase (RLK), and/or bone marrow tyrosine kinase (BMX), comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt of
6. A pharmaceutical composition comprising the compound of formula (I) or its pharmaceutically acceptable salt of
7. A pharmaceutical composition comprising the compound of formula (I) or its pharmaceutically acceptable salt of
8. The method according to
9. The method of
10. The method of
11. The method of
12. The method of
13. The method of
14. A method of inhibiting epidermal growth factor receptor (EGFR), EGFR L858R/T790M mutant, bruton's tyrosine kinase (BTK) janus kinase 3 (JAK3), interleukin-2 inducing T-cell kinase (ITK), resting lymphocyte kinase (RLK), and/or bone marrow tyrosine kinase (BMX), comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt of
15. A method of inhibiting epidermal growth factor receptor (EGFR), EGFR L858R/T790M mutant, bruton's tyrosine kinase (BTK) janus kinase 3 (JAK3), interleukin-2 inducing T-cell kinase (ITK), resting lymphocyte kinase (RLK), and/or bone marrow tyrosine kinase (BMX), comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt of
16. The method of
17. The method of
18. The method of
19. The method of
20. The method of
21. The method of
22. The method of
23. The method of
24. The method of
25. The method of
26. The method of
27. The method of
0. 28. The compound
##STR00340##
or a pharmaceutically acceptable salt thereof.
0. 29. The compound
##STR00341##
or a pharmaceutically acceptable salt thereof.
0. 30. The compound
##STR00342##
or a pharmaceutically acceptable salt thereof.
0. 34. The method according to claim 31, wherein the cancers or tumors are induced by EGFR tyrosine kinase or EGFR L858R/T790M mutant.
0. 35. The method of claim 31, wherein the mammal in need thereof suffers from cancers, tumors, inflammatory diseases, autoimmune diseases, or immunologically mediated diseases that are mediated by at least one kinase selected from the group consisting of BTK, JAK3, ITK, RLK, and BMX.
0. 36. The method according to claim 31, wherein the mammal in need thereof suffers from cancers, tumors, inflammatory diseases, autoimmune diseases, or immunologically mediated diseases that are mediated by abnormally activated b-lymphocytes, T-lymphocytes or both.
0. 37. The method according to claim 31, wherein the inflammatory diseases, autoimmune diseases, or immunologically mediated diseases are arthritis, rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic condition, lupus, systemic lupus erythematosus (SLE), skin-related disease, psoriasis, eczema, dermatitis, atopic dermatitis, pain, pulmonary disorder, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, artherosclerosis, myocardial infarction, congestive heart failure, cardiac reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, sjogren syndrome, autoimmunity thyroid disease, urticaria (cnidosis), multiple sclerosis, scleroderma, organ transplantation rejection, heteroplastic graft, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetic associated disease, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, b-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), diffuse large b-cell lymphoma, or follicular lymphoma.
0. 38. The method according to claim 31, wherein the compound or its pharmaceutically acceptable salt is administered in combination with an anticancer agent selected from the group consisting of: cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, intercalating anticancer agents, topoisomerase inhibitors, immunotherapeutic agents, antihormonal agents, and a mixture thereof.
0. 39. The method according to claim 31, wherein the compound or its pharmaceutically acceptable salt is administered in combination with a therapeutic agent selected from the group consisting of: steroid drugs, methotrexates, leflunomides, anti-TNFα agents, calcineurin inhibitors, antihistaminic drugs, and a mixture thereof.
0. 40. The method according to claim 32, wherein the cancers or tumors are induced by EGFR tyrosine kinase or EGFR L858R/T790M mutant.
0. 41. The method of claim 32, wherein the mammal in need thereof suffers from cancers, tumors, inflammatory diseases, autoimmune diseases, or immunologically mediated diseases that are mediated by at least one kinase selected from the group consisting of BTK, JAK3, ITK, RLK, and BMX.
0. 42. The method according to claim 32, wherein the mammal in need thereof suffers from cancers, tumors, inflammatory diseases, autoimmune diseases, or immunologically mediated diseases that are mediated by abnormally activated b-lymphocytes, T-lymphocytes or both.
0. 43. The method according to claim 32, wherein the inflammatory diseases, autoimmune diseases, or immunologically mediated diseases are arthritis, rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic condition, lupus, systemic lupus erythematosus (SLE), skin-related disease, psoriasis, eczema, dermatitis, atopic dermatitis, pain, pulmonary disorder, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, artherosclerosis, myocardial infarction, congestive heart failure, cardiac reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, sjogren syndrome, autoimmunity thyroid disease, urticaria (cnidosis), multiple sclerosis, scleroderma, organ transplantation rejection, heteroplastic graft, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetic associated disease, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, b-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), diffuse large b-cell lymphoma, or follicular lymphoma.
0. 44. The method according to claim 32, wherein the compound or its pharmaceutically acceptable salt is administered in combination with an anticancer agent selected from the group consisting of: cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, intercalating anticancer agents, topoisomerase inhibitors, immunotherapeutic agents, antihormonal agents, and a mixture thereof.
0. 45. The method according to claim 32, wherein the compound or its pharmaceutically acceptable salt is administered in combination with a therapeutic agent selected from the group consisting of: steroid drugs, methotrexates, leflunomides, anti-TNFα agents, calcineurin inhibitors, antihistaminic drugs, and a mixture thereof.
0. 46. The method according to claim 33, wherein the cancers or tumors are induced by EGFR tyrosine kinase or EGFR L858R/T790M mutant.
0. 47. The method of claim 33, wherein the mammal in need thereof suffers from cancers, tumors, inflammatory diseases, autoimmune diseases, or immunologically mediated diseases that are mediated by at least one kinase selected from the group consisting of BTK, JAK3, ITK, RLK, and BMX.
0. 48. The method according to claim 33, wherein the mammal in need thereof suffers from cancers, tumors, inflammatory diseases, autoimmune diseases, or immunologically mediated diseases that are mediated by abnormally activated b-lymphocytes, T-lymphocytes or both.
0. 49. The method according to claim 33, wherein the inflammatory diseases, autoimmune diseases, or immunologically mediated diseases are arthritis, rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic condition, lupus, systemic lupus erythematosus (SLE), skin-related disease, psoriasis, eczema, dermatitis, atopic dermatitis, pain, pulmonary disorder, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, artherosclerosis, myocardial infarction, congestive heart failure, cardiac reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, sjogren syndrome, autoimmunity thyroid disease, urticaria (cnidosis), multiple sclerosis, scleroderma, organ transplantation rejection, heteroplastic graft, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetic associated disease, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, b-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), diffuse large b-cell lymphoma, or follicular lymphoma.
0. 50. The method according to claim 33, wherein the compound or its pharmaceutically acceptable salt is administered in combination with an anticancer agent selected from the group consisting of: cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, intercalating anticancer agents, topoisomerase inhibitors, immunotherapeutic agents, antihormonal agents, and a mixture thereof.
0. 51. The method according to claim 33, wherein the compound or its pharmaceutically acceptable salt is administered in combination with a therapeutic agent selected from the group consisting of: steroid drugs, methotrexates, leflunomides, anti-TNFα agents, calcineurin inhibitors, antihistaminic drugs, and a mixture thereof.
0. 52. A pharmaceutical composition comprising the compound of claim 28, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.
0. 53. A pharmaceutical composition comprising the compound of claim 29, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.
0. 54. A pharmaceutical composition comprising the compound of claim 30, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.
|
|||||||||||||||||||||||
This
wherein, L is a long diameter and S is a short diameter.
IR(%)=(1−(RTG of the treatment group of test material)/(RTG of the control group))×100 <Equation 2>
wherein, RTG is a relative tumor growth, which is the mean tumor volume on a particular day based on daily mean tumor volume.
mBWL(%)=(1−(mean body weight on day x/mean body weight just before administration))×100 <Equation 3>
wherein, day x is a day on which the body weight loss is largest during the test.
Following Table 18 is the results of IR and mBWL in an NCI-H1975 in vivo model.
TABLE 18
Compound
BIBW2992
Example 2
Dose
50 mg/kg
70 mg/kg
IR1)
77%
75%
mBWL2)
9.1%
−7.6%
1)measured on 16th day after administration;
2)measured on 10th day after administration.
The compound of the present invention did not inhibit EGFR WT and exhibited an excellent activity on EGFR mutant specific to non-small cell lung cancer (active mutant: EGFR DelR746_A750, EGFR L858R; acquired mutation: EGFR T790M). As shown in Table 18 and
In order to evaluate the efficacy of the compound according to the present invention for rheumatoid arthritis, the compound was subjected to arthritis inhibition test in a collagen-induced arthritis (CIA) model. The CIA model is a widely used, representative autoimmune arthritis model, arthritis of which is induced by injecting a mixture of type II collagen and an immunologic adjuvant to a specific mouse strain having major histocompatability complex (MHC) class II with H-2q or H-2r and thus CD4+ T cells and B-cells specifically responsive to the type II collagen are abnormally activated.
Male DBA/1J mice (8 weeks old) were first immunized by intradermal injection of 0.7 mL of a suspension liquid in which an equal volume of 2 mg/mL of type II collagen is emulsified in 4 mg/mL of complete Freund's adjuvant supplemented with bacteria tuberculosis. After 21 days, the mice were second immunized by the injection as above, except for using a suspension liquid in which an equal volume of 2 mg/mL of type II collagen is emulsified in incomplete Freund's adjuvant containing no bacteria tuberculosis. After 1 week of second immunization, mice were evaluated for clinical scores based on Table 19 and seven animals were grouped such that the average of experimental group is between 1 and 2. Test samples and vehicle of given concentrations were orally administered in an amount of 10 mL per body weight for 14 days everyday by using a Sonde. The clinical scores of arthritis (David D Brand et al., Nature Protocol. 2(5), 1269, 2007) were evaluated three times a day.
As shown in Tables 16a, 16b and 16c and
In addition, the compound according to the present invention significantly reduced the secretion of interleukin-6 (IL-6) and TNF-α in human peripheral blood mononuclear cells (PBMCs) and mouse splenocytes abundant in T-lymphocytes, B-lymphocytes, Cytes and macrophages after treatment of phorbol-12-myristate-13-acetate (PMA), phytohemagglutinin (PHA), lonomycin, and others which stimulate lymphocytes, compared to a control group. This demonstrates that the compound according to the present invention inhibits the activation of lymphocytes.
TABLE 19
Evaluation of clinical scores of arthritis
Rate
Characteristics
0
No edema and flare in paws, ankles, and ankle joints
1
Flare and mild edema in ankles or ankle joints
2
Flare and mild edema generally from ankle joints to ankles
3
Flare and edema from ankle joints to toe joints
4
Severe edema or spastic tetraplegia in overall joints,
paws and toes
While the invention has been described with respect to the above specific embodiments, it should 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 by the appended claims.
Lee, Ju Yeon, Ha, Tae Hee, Suh, Kwee Hyun, Kim, Maeng Sup, Kang, Seok Jong, Lee, Kwang Ok, Kwak, Eun Joo, Cha, Mi Young, Kim, Mi Ra, Jeon, Ji Young, Jo, Myoung Gi
| Patent | Priority | Assignee | Title |
| Patent | Priority | Assignee | Title |
| 9345719, | Jun 23 2010 | Hanmi Science Co., Ltd. | Fused pyrimidine derivatives for inhibition of tyrosine kinase activity |
| JP200813527, | |||
| WO2007089768, | |||
| WO2009017838, | |||
| WO2009062258, | |||
| WO2009126515, | |||
| WO2009158571, | |||
| WO2010054285, | |||
| WO2010129053, | |||
| WO2011079231, | |||
| WO9802438, | |||
| WO2013042006, |
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