KR20160138136A - Pharmaceutical composition for treating and preventing leukemia, containing thienopyrimidine derivative or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating leukemia disease, which comprises a thienopyrimidine derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for treating and preventing leukemia, which comprises a thienopyrimidine derivative or a pharmaceutically acceptable salt thereof. The present invention relates to a pharmaceutical composition for the treatment and prevention of leukemia comprising a thienopyrimidine derivative or a pharmaceutically acceptable salt thereof,

The present disclosure relates to a pharmaceutical composition for treating and preventing leukemia comprising a thienopyrimidine derivative or a pharmaceutically acceptable salt thereof.

Receptor tyrosine kinase, FLT3 (Fms-like tyrosine kinase 3), is one of the receptor III tyrosine kinase families including PDGFR, KIT and FMS. FLT3 is normally expressed by hematopoietic cells in hematopoietic progenitor cells and plays an important role in the expression of normal stem cells and the immune system. Abnormal overexpression and mutations of FLT3 are often observed in patients with leukemia. In particular, various mutations such as D835V, D835Y and ITD (internal tandem duplication) of FLT3 are observed in acute myelogenous leukemia (AML). Acute myelogenous leukemia (AML) is a hematopoietic stem cell disorder characterized by abnormal proliferation and differentiation of myeloid and peripheral blood blood cells. AML cells induce molecular defects, such as leukocyte proliferation, abnormalities of differentiation, and resistance to apoptosis. When the level of transcription of FLT3 is elevated in AML, it affects the phosphorylation of FLT3. Phosphorylation and activation of FLT3 receptors activates downstream kinase pathways such as Ras / Mitogen-activated protein kinase (MAPK), leading to abnormal cell growth and gene regulation. For this reason, FLT3 has recently been regarded as one of the most important targets from the therapeutic point of AML, and various studies on abnormal symptoms related to FMS-like tyrosine kinase 3 (FLT3), RAS, and p53 gene for the treatment of AML .

Mutations in the FLT3 gene are found in approximately 30% of adult AML, while mutations in RAS and p53 in adult AML are reported to be approximately 20% and approximately 5%, respectively. The most typical problem with AML is that mutations in FLT3, which cause a poor prognosis, are activated. FLT3-active mutations are classified into two types. One is internal tandem duplications (ITD) in the juxtamembrane region and the other is a point mutation in the tyrosine kinase domain (TKD). Approximately 23% of patients with early AML are active with FLT3 / ITD, the most frequently detected mutant. Patients with an ITD mutation show a poor prognosis and a high relapse rate. Another major FLT3-active mutation is the FLT3 TKD mutation, which accounts for about 7% of the initial AML cases. Point mutations in residues of aspartate 835 (D835), which are replaced by various amino acids, are one of the less common, but most common, mutations of the ITD mutation. In addition, another major method of activation of FLT3 in AML is the overexpression of wild-type FLT3 protein. Overexpression of the wt-FLT3 protein is relatively less frequent in the AML case, but even in the absence of FLT3 / ITD, the overexpression was found to serve as an undesirable prognostic factor.

Thus, FLT3-activated mutation is the most common mutation in AML, so inhibition of FLT3 is a major therapeutic target in AML. In particular, in AML, FLT3 / ITD has been identified as a negative prognostic factor, and FLT3 / ITD is a key target in the treatment of AML.

Therefore, a number of studies have been developed as low-molecular inhibitors of FLT3 tyrosine kinase for the purpose of treating AML a few years ago, and some of the following compounds are undergoing clinical trials.

As first-generation FLT3 inhibitors, sorafenib (BAY-43-9006) [16], lestaurtinib (CEP-701) [17], sunitinib (SU11248) and tandutinib (MLN518) Since they are not developed or optimized, they have to inhibit FLT3 as well as many other kinases, and as a result, these compounds are very likely to cause side effects in the treatment of AML. Thus, quizartinib (AC220) was devised as an inhibitor of second generation FLT3. These inhibitors effectively inhibited FLT in in vivo and cell experiments of FLT3-ITD AML and were also active in clinical trials. However, most of the substances have insufficient FLT inhibitory activity and can not prevent the occurrence of various mutations in FLT kinase. Such resistance to AML therapy has hampered the use of FLT3 inhibitors.

Accordingly, the thienopyrimidine derivative of the present invention is not only effective in suppressing inflammation and inhibiting cancer, but further aims to provide a thienopyrimidine derivative as a therapeutic agent targeted at the treatment and prevention of leukemia, particularly AML. The thienopyrimidine derivatives of the present invention selectively exhibit excellent inhibitory activity against FLT3. Therefore, the thienopyrimidine compound of the present invention, unlike the conventional FLT3 inhibitor, does not participate in other kinase pathways except for the FLT3 kinase pathway, and thus has a more excellent therapeutic effect on AML caused by the FLT3 / ITD mutation Is predicted.

On the other hand, conventional thienopyrimidine derivatives inhibit the activity of IκB kinase-β (IKKβ or IKK-2), thereby inhibiting the activity of the nuclear factor kappa B (NF-κB) Although it has been found that the compounds can be used for the prophylaxis and treatment of diseases associated with activity, particularly for the treatment of inflammatory diseases and cancers such as rheumatism, the therapeutic effect on leukemia, particularly AML, has not been disclosed.

The present invention provides a pharmaceutical composition comprising a thienopyrimidine derivative or a pharmaceutically acceptable salt thereof for the treatment and prevention of acute myelogenous leukemia (AML) with excellent FLT3 inhibitory activity.

An embodiment of the present invention provides a pharmaceutical composition comprising a thienopyrimidine derivative or a pharmaceutically acceptable salt thereof, which has excellent therapeutic and prophylactic effects against leukemia, including myeloid leukemia (AML).

The pharmaceutical composition comprising the thienopyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof has excellent therapeutic and prophylactic effects against leukemia, especially acute myelogenous leukemia (AML) as well as excellent anticancer activity.

Best Mode for Carrying Out the Invention

The present invention constitutes a pharmaceutical composition for preventing or treating leukemia, comprising a thienopyrimidine derivative or a pharmaceutically acceptable salt thereof having excellent therapeutic and prophylactic effects on myelogenous leukemia (AML). More specifically, the thienopyrimidine derivative is a thieno [2,3-d] pyrimidine derivative represented by the following formula (1).

[Chemical Formula 1]

In this formula,

이며; R ₁ is H; Linear or branched C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkenyl, or C ₁ -C ₁₀ alkynyl; - (CH _{2) n} -COOR; -O- (CH ₂ ) _n -NRR '; - (CH _{2) n} -OH; - (CH _{2) n} -OR; -Y- (CH ₂ ) _n -MR; C ₅ -C ₂₀ heteroaryl which is unsubstituted or substituted by C ₁ -C ₁₀ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen and which is selected from the group consisting of S, O and N atoms or C ₅ -C ₂₀ heteroaryl groups containing two heteroatoms; or

;

이거나; 또는 R₁ 및 R₃가 서로 결합하여 C₁-C₃ 알킬, C₂-C₃ 알케닐, C₂-C₃ 알키닐 또는 할로겐으로 치환 또는 비치환된, S, O 및 N 원자로 이루어진 군으로부터 선택되는 1 또는 2개의 헤테로 원자를 포함하는 C₃-C₂₀ 헤테로시클릴기를 형성하며;R ₃ is H; -OH; -CN; Linear or branched C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkenyl, or C ₁ -C ₁₀ alkynyl; - (CH _{2) n} -COOR; -CONH- (CH ₂ ) _n -NRR '; -O- (CH ₂ ) _n -NRR '; -CO- (CH ₂ ) _n -NRR '; - (CH _{2) n} -OH; - (CH _{2) n} -OR; C ₆ -C ₂₀ aryl substituted or unsubstituted with C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen; C ₅ -C ₂₀ heteroaryl which is unsubstituted or substituted by C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen, and is selected from the group consisting of S, O and N atoms 1, or C ₅ -C ₂₀ containing two heteroatoms heteroaryl; or

; Or from the group consisting of S, O and N atoms, wherein R ₁ and R ₃ are bonded to _one another and are substituted with C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen Form a C ₃ -C ₂₀ heterocyclyl group containing one or two heteroatoms selected;

이며;R ₂ is H; -OH; -NRR '; Linear or branched C ₁ -C ₁₀ alkyl; C ₁ -C ₁₀ alkenyl, or C ₁ -C ₁₀ alkynyl; - (CH _{2) n} -Z; -Y- (CH _{2) n} -Z; - (CH ₂ ) _n -C ₃ to C ₇ cycloalkyl; C ₁ -C ₃ alkyl; C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or C ₅ -C ₂₀ heteroaryl which is unsubstituted or substituted by halogen and which contains one or two heteroatoms selected from the group consisting of S, O and N atoms C ₅ -C ₂₀ heteroaryl; Substituted or unsubstituted C ₆ -C ₂₀ aryl; or

;

,

,

,

이거나, 또는 R₄ 및 R₅가 서로 결합하여 C₁-C₃ 알킬, C₂-C₃ 알케닐, C₂-C₃ 알키닐 또는 할로겐으로 치환 또는 비치환된, S, O 및 N 원자로 이루어진 군으로부터 선택되는 1 또는 2개의 헤테로 원자를 포함하는 C₃-C₂₀ 헤테로시클릴기를 형성하며;R ₄ and R ₅ are each independently H, linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, -NR'R ", -Y- (CH ₂ ) _n -NR'R ", -Y- (CH ₂ ) _n -Z,

,

,

,

Or consisting of S, O and N atoms, wherein R ₄ and R ₅ are bonded to each other to form a C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen, , form a C ₃ -C ₂₀ heterocyclyl comprising 1 or 2 hetero atoms selected from the group, and;

C₂-C₃ 알케닐, C₂-C₃ 알키닐 또는 할로겐으로 치환 또는 비치환된 피롤리딘, 피페리딘, 피페라진, 모르폴린, 티오모르폴린, 2- 또는 3-옥소-피롤리딘, 2-, 3- 또는 4-옥소-피페리딘, 옥사졸, 트리아졸, 피리딘, 이미다졸, 이미다졸리딘, 2,5-디옥소-피롤리딘, 2- 또는 3-옥소-피페라진, 2-옥소-이미다졸리딘, 4,4-에틸렌디옥시-피페리딘, 2- 또는 3-티에닐, 2- 또는 3-퓨릴;Z is -NR'R "; S, O and N atoms comprising the comprising from 1 to 3 hetero atoms selected from the group, substituted or unsubstituted C ₅ -C ₂₀ heteroaryl or heterocyclyl;

C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl; substituted or unsubstituted blood as carbonyl or halogen pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 2-or 3-oxo-pyrrolidine Pyridines, imidazoles, imidazolidines, 2,5-dioxo-pyrrolidines, 2- or 3-oxo-pyrimidines, Piperazine, 2-oxo-imidazolidine, 4,4-ethylenedioxy-piperidine, 2- or 3-thienyl, 2- or 3-furyl;

;

R ₆ is H; halogen; -OH; -OR; -COOR; (CH _{2) n} -OR; Linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl; -NO ₂ ; -Y- (CH _{2) n} -Z; Or -Y- (CH ₂ ) _n -NR'R ";

R ₇ is H; Or linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl;

R ₈ is H; - (CH ₂ ) _n -OR or - (CH ₂ ) _n --NR'R ", _wherein R is selected from the group consisting of hydrogen, C ₁ -C ₅ alkyl, linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl, ₂ ) _n- OH;

R ₉ is H; halogen; -OH; -OR; -NO ₂ ; -COOR; - (CH _{2) n} -OR; _{- (CH 2) n -NR'R "} ; a linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C _{5 alkynyl; -Y- (CH 2) n -Z} ; - Y- (CH ₂ ) _n -NR'R "; -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -OR; _{-Y- (CH 2) n -M- (} CH 2) n -ph; Or -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -NR'R ";

R ₁₀ is H; -OH; -OR; -COOR; (CH ₂ ) _n -OR, linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, -Y- (CH ₂ ) _n -Z -Y- (CH ₂ ) _n -Z- (CH ₂ ) _n -OR, -Y- (CH ₂ ) _n -M- _{R 'R} "; -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -CN; -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -C = C; And Y- (CH _{2) n} -NR'R ", or _{-Y- (CH 2) n -N (} Boc) R -; -Y- (CH 2) n -M- (CH 2) n -C≡C ;

R ₁₁ and R ₁₂ are each independently H; Linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl; Or R ₁₁ and R ₁₂ are bonded to each other to form a substituted or unsubstituted C ₆ -C ₂₀ aryl; Substituted or unsubstituted C ₃ -C ₇ cycloalkyl; Or N; O and to form a C ₅ -C ₂₀ heterocyclic ring containing one or two heteroatoms selected from the group consisting of S, and;

R ₁₃ is -Y- (CH ₂ ) _n -Z, - (CH ₂ ) _n -Z, or - (CH ₂ ) _n -NR'R ";

R, R 'and R "are each independently selected from H; linear or branched C ₁ -C _{5 alkyl; - (CH 2) n -C} 6 H 6; - (CH 2) n -OH; or -CH ₂ CF ₃ ;

Y is O, S, -NH-, -NH-CO-, or -CO-NH-;

M is O, S, -NH-, -NH-CO-, or -CO-NH-;

n is an integer of 0 to 6;

이며,In another embodiment of the present invention, R < ₁ > is H; C ₁ -C ₅ alkyl; - (CH _{2) n} -COOR; -O- (CH ₂ ) _n -NRR '; - (CH _{2) n} -OH; - (CH _{2) n} -OR; -Y- (CH ₂ ) _n -MR; C ₅ -C ₂₀ heteroaryl which is unsubstituted or substituted by C ₁ -C ₁₀ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen and which is selected from the group consisting of S, O and N atoms or C ₅ -C ₂₀ heteroaryl groups containing two heteroatoms; or

Lt;

이거나; 또는 R₁ 및 R₃가 서로 결합하여 C₁-C₃ 알킬, 또는 할로겐으로 치환 또는 비치환된, S, O 및 N 원자로 이루어진 군으로부터 선택되는 1 또는 2개의 헤테로 원자를 포함하는 C₃-C₂₀ 헤테로시클릴기를 형성하며;R ₃ is H; -OH; -CN; Linear or branched C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkenyl, or C ₁ -C ₁₀ alkynyl; - (CH _{2) n} -COOR; -CONH- (CH ₂ ) _n -NRR '; -O- (CH ₂ ) _n -NRR '; -CO- (CH ₂ ) _n -NRR '; - (CH _{2) n} -OH; - (CH _{2) n} -OR; C ₆ -C ₂₀ aryl substituted or unsubstituted with C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen; C ₅ -C ₂₀ heteroaryl which is unsubstituted or substituted by C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen, and is selected from the group consisting of S, O and N atoms 1, or C ₅ -C ₂₀ containing two heteroatoms heteroaryl; or

; Or R ₁ and R ₃ are bonded to each other by C ₁ -C ₃ alkyl, halogen, or substituted or unsubstituted, S, O and N, which C atoms containing one or two heteroatoms selected from the group consisting of -C _{3 20} heterocyclyl group;

이며;R ₂ is H, -OH, -NRR ', linear or branched C ₁ -C _{10 alkyl, - (CH 2) n -Z} , -Y- (CH 2) n -Z, - (CH 2) n -C ₃ to C ₇ cycloalkyl, C ₁ -C ₃ alkyl, halogen, or substituted or unsubstituted C ₅ -C ₂₀ a heteroaryl group containing one or two heteroatoms selected from the group consisting of S, O and N atoms C ₅ -C ₂₀ heteroaryl; Or a substituted or unsubstituted C ₆ -C ₂₀ aryl or

;

,

,

,

이거나; 또는 R₄ 및 R₅가 서로 결합하여 C₁-C₃ 알킬, 또는 할로겐으로 치환 또는 비치환된, S, O 및 N 원자로 이루어진 군으로부터 선택되는 1 또는 2개의 헤테로 원자를 포함하는 C₃-C₂₀ 헤테로시클릴기를 형성하며;R ₄ and R ₅ each is, independently, H, or linear or branched C ₁ -C _{5 alkyl, -NR'R ", -Y- (CH 2} ) n -NR'R", -Y- (CH 2 ) _n -Z,

,

,

,

; Or R ₄ and R ₅ is C ₃ to join, including 1 or 2 hetero atoms selected from C ₁ -C ₃ alkyl, halogen, or substituted or unsubstituted, S, O and N atoms with each other the group consisting of -C ₂₀ heterocyclyl group;

이며;Z is -NR'R ", pyrrolidine, piperidine, piperazine, morpholino, substituted or unsubstituted C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen Pyrrole, thiomorpholine, 2- or 3-oxo-pyrrolidine, 2-, 3- or 4-oxo-piperidine, oxazole, triazole, pyridine, imidazole, imidazolidine, 2- dioxo-pyrrolidine, 2- or 3-oxo-piperazine, 2-oxo-imidazolidine, 4,4-ethylenedioxypiperidine, 2- or 3-thienyl, 2- or 3- 3-furyl;

;

R ₆ is H; -OH; -OR; -COOR; (CH _{2) n} -OR; Linear or branched C ₁ -C ₅ alkyl; -NO ₂ ; -Y- (CH _{2) n} -Z; Or -Y- (CH ₂ ) _n -NR'R ";

R ₇ is H; Or linear or branched C ₁ -C ₅ alkyl;

R ₈ is H; Linear or branched C ₁ -C ₅ alkyl; - (CH ₂ ) _n -NR'R "; - (CH ₂ ) _n -OR or - (CH ₂ ) _n -OH;

R ₉ is H; halogen; -OH; -OR; -NO ₂ ; -COOR; - (CH _{2) n} -OR; _{- (CH 2) n -NR'R "} ; a linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl; C ₁ -C ₃ alkyl; C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, or a halogen-substituted or unsubstituted with pyrrolidine; piperidine; piperazine _{-Y- (CH 2) n -Z;} -Y- (CH 2) n -NR ' R " -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -OR; _{-Y- (CH 2) n -M- (} CH 2) n -ph; Or -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -NR'R ";

R ₁₀ is H; -OH; -OR; -COOR; (CH ₂ ) _n -OR, linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, -Y- (CH ₂ ) _n -Z ; Y- (CH ₂ ) _n -Z- (CH ₂ ) _n -OR -Y- (CH ₂ ) _n -M-R'R "; -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -CN; -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -C = C; And Y- (CH _{2) n} -NR'R ", or _{-Y- (CH 2) n -N (} Boc) R -; -Y- (CH 2) n -M- (CH 2) n -C≡C ;

R ₁₁ and R ₁₂ are each independently H; Linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl; Halogen; Or R ₁₁ and R ₁₂ are bonded to each other to form a substituted or unsubstituted C ₆ -C ₂₀ aryl; Substituted or unsubstituted C ₃ -C ₇ cycloalkyl; Or N; O and C comprising one or two heteroatoms selected from the group consisting of -C S ₅ is a group forming a ₂₀ heterocycle;

R ₁₃ is -Y- (CH ₂ ) _n -Z; - (CH ₂ ) _n -Z or - (CH ₂ ) _n -NR'R ";

R; R 'and R "are each independently selected from the group consisting of H, linear or branched C ₁ -C ₅ alkyl, - (CH ₂ ) _n -C ₆ H _6, - (CH ₂ ) _n -OH or -CH ₂ CF ₃ ;

Y is O, S, -NH-, -NH-CO-, or -CO-NH-;

M is O; S is -NH-; -NH-CO- or -CO-NH-;

n is an integer of 0 to 3;

In another embodiment of the present invention, R ₁ in the general formula (1) is H, -Me, -Et, -ph, -ph-F, -CH ₂ -ph, -ph-OH, -CH ₂ OH, -CH ₂ -ph-OMe, -ph-OME, -ph-ME, -CONH ₂ , -COOME, -COOEt, -CH ₂ -COOEt, -ph-OC ₂ H ₅ -NR'R " _{2 -ph-OC 3 H 7 -NR'R} ",

R ₃ is selected from the group consisting of H, -OH, -CN, -Me, -Et, -COOH, -COOME, -CONH ₂ , -CONH-CH ₂ CH ₂ -N (CH ₂ ) ₃ , -CH ₂ -ph, -ph-OH, -CH ₂ -ph -OH, -ph-NO ₂ , -ph-ME, -CH ₂ OH, -C ₂ H ₅ OH, ME, -ph-OC ₂ H ₅ -NH-CH ₂ -ph, pH-OC ₂ H ₅ -NH-C ₃ H ₇ - (CH ₂ ) ₃ , -ph-OC ₂ H ₅ -NR ₂ , -ph -C ₂ H ₅ -NH-C ₂ H ₅ -OR, -ph-NO ₂ , -ph-C ₂ H ₅ -NH ₂ ,

또는 R₁ 및 R₃

가 서로 결합하여 C₁-C₃ 알킬로 치환 또는 비치환된 피페리딘을 형성하며,

Or R ₁ and R ₃

Are bonded to each other to form a piperidine substituted or unsubstituted with C ₁ -C ₃ alkyl,

R ₂ is selected from the group consisting of -Me, -Et, propyl, tert-butyl, thiophenyl, -NH ₂ , -ph-NH ₂ , -ph-OMe, pH-F, -ph-OC ₂ H ₅ -NRR ',

R ₄ and R ₅ are each independently H, -CH ₂ -ph, -NH ₂ , -C ₂ H ₅ -NH,

으로부터 선택될 수 있다.

Lt; / RTI >

In another embodiment of the present invention, in another embodiment of the present invention, the compound represented by formula (1) may be any one of the following formulas.

Another embodiment of the present invention provides a pharmaceutical composition for preventing or treating leukemia comprising a thienopyrimidine derivative represented by the following general formula (2) or a pharmaceutically acceptable salt thereof.

(2)

The compounds represented by formula (I) of the present invention may be prepared as pharmaceutically acceptable salts and solvates according to methods conventional in the art, and may be prepared by adding pharmaceutically acceptable carriers, excipients, diluents or a combination thereof .

[Chemical Formula 1]

As the salt of the compound represented by the formula (1), an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The acid addition salt is prepared in a conventional manner, for example, by dissolving the compound in an excess amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.

As the free acid, an organic acid and an inorganic acid can be used. As the inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acid include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycollic acid, glucuronic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like. It does not.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble compound salt, and evaporating and drying the filtrate. At this time, as the metal salt, it is preferable to produce sodium, potassium or calcium salt in particular, but it is not limited thereto. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

The pharmaceutically acceptable salts of the compounds of formula (1) include, unless otherwise indicated, salts of acidic or basic groups which may be present in the compounds of formula (1). For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxy groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, (Mesylate) and p-toluenesulfonate (tosylate) salts and the like, and there can also be used a process for preparing salts or the like known in the art, such as, for example, hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate Can be manufactured through a manufacturing process.

In addition, the compound of formula (1) may exist in different enantiomeric forms because of its asymmetric center, and all optical isomers and R or S stereoisomers of the compound of formula (1) and mixtures thereof are also included within the scope of the present invention. The present invention includes the use of racemates, one or more enantiomeric forms, one or more diastereoisomeric forms, or mixtures thereof, and includes methods of separation or preparation of isomers known in the art.

The present invention provides a process for preparing a thienopyrimidine derivative represented by the above formula (1). Preferably, the thienopyrimidine derivative of Formula 1 is chemically prepared by the method shown in the following reaction schemes, but is not limited thereto. In particular, those skilled in the art will appreciate that the thienopyrimidine derivatives of Formula 1 of the present invention can be prepared by a variety of methods using well known techniques well known in the art.

The following reaction schemes show the preparation method of the representative compounds according to the present invention according to the preparation steps. Various compounds of the present invention can be prepared by reacting reagents, solvents and reaction sequence used in the production of Reaction 1 to Reaction Scheme 3 And the like. Some of the compounds of the present invention were prepared according to procedures not included in the ranges of Reaction 1 to Reaction 3, and the detailed preparation of these compounds is described in detail in each of these Examples.

Scheme 1 illustrates a method for preparing compounds of one embodiment of the invention in a reaction scheme in which compounds 8a to 8e are prepared from 2-acetylthiophene. In Scheme 1, first, Knoevenagel condensation reaction of 2-acetylthiophene with malononitrile was performed in the presence of NH4OAc and AcOH to give 2- [1- (thiophen n-2-yl) ethylidene] malononitrile 2 And then treated with sulfur and piperidine to obtain thiophene 3a. Compound 3a is then heated with formamide at 180 ° C to form thiepopyrimidine 4a, which is then subjected to Sandmeyer reaction in the presence of CuCl 2 and t-BuONO to yield compound 5a. Compound 5a is then firstly treated with hydrazine hydrate stepwise and then treated with one of the appropriate furans 7a to 7e to give compounds 8a to 8e.

As a method for synthesizing the thienopyrimidine derivative compounds 13a to 13m, which is another embodiment of the present invention, there are, for example, two methods (see Reaction Scheme 2 and Reaction Scheme 3 below). Compounds 3b to 3e are heated with commercially available, substituted cyanide under acidic conditions at 110 ° C to obtain thienopyrimidines 4b to 4e, and the resulting thienopyrimidines 4b to 4e are converted to the corresponding compounds of CuCl2 and t-BuONO (See Scheme 2 above) by the Sandmeyer reaction. Substituted 2-aminothiophene-3-carboxylate compounds 10a to 10i can be obtained by the Gewald reaction, as described in Scheme 3 above. Compounds 11a to 11i can be simply synthesized by heating the carboxylate compounds 10a to 10i with the appropriate carbonitrile under acidic conditions and chlorinated by POCl3 at 100 ° C to give 4-chloro-thieno [2, 3-d] pyrimidines 12a to 12i. Thieno [2,3-d] pyridin-4-amine derivatives 13a to 13m are prepared by first heating compounds 5a to 5d or compounds 12a to 12i with hydrazine hydrate and then converting them into 3-methylfuran- Can be obtained by heating.

Reaction Schemes 1 to 3 are described as an embodiment of the present invention, and the present invention can be also produced by other well-known methods.

The present invention provides a pharmaceutical composition for the prevention or treatment of leukemia disease, which comprises a thienopyrimidine derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, wherein, in a preferred embodiment, The above-mentioned pharmaceutical composition containing may further comprise an appropriate carrier, excipient or diluent according to a conventional method.

[Chemical Formula 1]

Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, , Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The composition containing the compound of the present invention can be formulated in the form of powders, granules, tablets, capsules, oral preparations such as suspensions, emulsions, syrups and aerosols, external preparations, suppositories or sterilized injection solutions, Can be used.

Specifically, when formulating the composition, it may be prepared by using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant or the like which is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose ( lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients other than water, liquid paraffin, which are commonly used simple diluents, such as wetting agents, sweeteners, fragrances and preservatives . Agents for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.

The preferred dosage of the compound according to the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compound of formula (I) of the present invention may be administered in an amount of 0.0001-500 mg / kg, preferably 0.01-300 mg / kg, once or several times a day. In the composition of the present invention, the compound of Formula 1 may be formulated in an amount of 0.0001 to 50% by weight based on the total weight of the composition.

In addition, the pharmaceutical dosage forms of the compounds according to the invention may be in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds, as well as in suitable combinations.

The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, humans, and the like in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.

Hereinafter, the present invention will be described in detail with reference to the following examples. These examples are provided for illustrating the present invention, and the scope of the present invention is not limited thereby.

DETAILED DESCRIPTION OF THE INVENTION

Example:

The reagents and solvents used in this example were purchased in the market and used without further purification. The < 1 > H NMR spectrum was measured on a Varian 400 Mercury plus spectrometer at 400 MHz and the unit of chemical shift was delta (ppm), based on tetramethylsilane (TMS). Mass spectra (MS) were measured using an Applied Biosystems API 2000 mass spectrometer and an Agilent 1200 series LC system. High resolution mass spectra were performed on a 3200 QTRAP LC / MS / MS system (Santa Clara, Calif., USA).

Example 1: Preparation of 2- [1- (thiophen-2-yl) ethylidene] malononitrile (2)

A stirred solution of 2-acetylthiophene (500 mg, 3.96 mmol) and malononitrile (300 mg, 4.75 mmol) in toluene (20 ml) was treated with NH4OAc (915 mg, 11.88 mmol) and AcOH (0.7 ml, 11.88 mmol ). The resulting mixture was refluxed for 16 hours in a Dean-Stark trap for 16 hours. The cooled mixture was then poured into ice water and extracted with EtOAc. The combined organic layers were washed with 1N HCl aqueous solution, dried over Na2SO4, and concentrated to dryness. The residue was then purified by flash column chromatography (n-Hx: EtOAc = 5: 1) to give compound 2 (350 mg, 51%) as a brown oil.

Example 2: Preparation of 5'-amino-2,3'-bithiophene-4'-carbonitrile (3a)

To a stirred solution of 2- [l- (thiophen-2-yl) ethylidinyl] malononitrile 2 (300 mg, 1.72 mmol) in EtOH (20 ml) was added sulfur (66 mg, 2.06 mmol) (0.2 ml, 2.06 mmol) were successively added. The resulting mixture was heated to 80 [deg.] C and stirred for 5 hours. After cooling at room temperature, the reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with a concentrated aqueous NH ₄ Cl solution, dried over Na ₂ SO ₄ and concentrated to dryness. Residue by flash column chromatography (n-Hx: EtOAc = 5 : 1) to give the compound (3) (to give a (230 mg, 65%) as a yellow oil ^{1 H NMR (400 MHz, CDCl3} ):. Δ ^{7.45 (d, 1 H, J} = 3.6 Hz), 7.26 (d, 2H, J = 4.4 Hz,), 7.05 (dd, 1 H, JA = 3.6 Hz, JB = 4.8 Hz), 4.92 (s, 2H) .

Example 3: Preparation of 5- (thiophen-2-yl) thieno [2,3-d] pyrimidin-

The 5'-amino-2,3'-bithiophene-4'-carbonitrile 3a (100 mg, 0.48 mmol) was dissolved in formamide (3 ml) and the reaction mixture was stirred at 180 ° C for 18 hours . After cooling at room temperature, the reaction mixture was poured into ice water and extracted with EtOAc. Concentrate the combined organic layers NaHCO ₃ And washed with an aqueous solution, dried over Na ₂ SO _4, concentrated and dried. The residue was purified by flash column chromatography (n-Hx: EtOAc = 1: 2) to give compound (4a) (40 mg, 35%) as a white solid. ^{1 H NMR (400 MHz, CDCl3} ) δ 8.44 (s, 1 H), 7.43 (t, 1 H, J = 3.6 Hz), 7.26 (s, 1 H), 7.15 (d, 2H, J = 3.2 Hz) , 5.77 (br s, 2H).

Example 4: Preparation of 4-chloro-5- (thiophen-2-yl) thieno [2,3-d] pyrimidine (5a)

CuCl ₂ (69 mg, 0.51 mmol) and t-BuONO (76 μl, 0.64 mmol) were dissolved in MeCN (5 ml) and the resulting mixture was stirred at 70 ° C for 30 minutes. Then, a solution of 5- (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-amine 4a (100 mg, 0.43 mmol) in THF (2 ml) Lt; / RTI > for 2 hours. The resulting mixture was heated to 80 [deg.] C and stirred for 5 hours. The cooled reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with a concentrated aqueous NH ₄ Cl solution, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by flash column chromatography (n-Hx: EtOAc = 5: 1) to give compound 5a (62 mg, 57%) as a white solid.

Example 5: Preparation of 3,4-disubstituted (unsubstituted) -1- (5-thiophen-2-yl-thieno [2,3- d] pyrimidin- , Production of 5-dione derivatives (8a to 8e)

To a stirred solution of 4-chloro-5- (thiophen-2-yl) thieno [2,3-d] pyrimidine 5a (70 mg, 0.28 mmol) in THF (5 ml) was added hydrazine monohydrate , 0.56 mmol). The reaction mixture was stirred at 180 ° C for 4 hours. After cooling, the solvent was removed under reduced pressure and concentrated in vacuo. The residue containing compound 6a was dissolved in CHCl ₃ followed by the slow addition of anhydrous 3,4-disubstituted (unsubstituted) -tetraconic, 7a-7e (0.84 mmol). The resulting mixture was heated to 80 [deg.] C and stirred for 20 hours. The reaction mixture was cooled to room temperature and washed with water. The organic layer was dried with Na ₂ SO _4, and concentrated to dryness. The residue was purified by flash column chromatography to give the final products 8a to 8e

1- [5- (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ylamino] - ¹ H- pyrrole-2,5-dione (8a)

^{1 H NMR (400 MHz, DMSO} -d6) δ 8.54 (s, 1 H), 7.80 (s, 1 H), 7.72 (d, 1 H, J = 5.2Hz), 7.37 (d, 1 H, J = ^{4.4Hz), 7.22 (t, 1} H, J = 4.4Hz), 6.38 (s, 2H); ESI (m / z) 291 (MH < + >).

3-methyl-1- [5- (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ylamino] - ¹ H- pyrrole-2,5-dione (8b)

^{1 H NMR (400 MHz, CDCl3} ) δ 8.50 (s, 1 H), 7.43 (d, 1 H, J = 4.8Hz), 7.38 (s, 1 H), 7.34 (d, 1 H, J = 4.0Hz ), 7.14 (m, 2H) , 6.49 (s, 1 H), 2.16 (d, 3H, J = 1.6Hz); ESI (m / z) 343 (MH < + >); HRMS (ESI) calcd for C15H10N4O2S2 [MH +]: 343.0323, found: 343.0309.

Example 6: 3,4-Di-methyl-1- [5- (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ylamino] - ¹ H- pyrrole-2,5 - Dion (8c)

^{1 H NMR (400 MHz, DMSO} -d6) δ 8.48 (s, 1 H), 8.38 (s, 1 H), 7.83 (s, 1 H), 7.68 (d, 1 H, J = 4.4Hz), 7.29 -7.20 (m, 2 H), 1.94 (s, 6 H); ESI (m / z) 357 (MH < + >); HRMS (ESI) calcd for C16H12N4O2S2 [MH +]: 357.0480, found: 357.0469.

2,3-d] pyrimidin-4-ylamino] isoindolin-l, 3-dione (8d)

^{1 H NMR (400 MHz, DMSO} -d6) δ 8.44 (s, 1 H), 8.33 (s, 1 H), 7.99-7.93 (m, 4H), 7.86 (s, 1 H), 7.69 (d, 1 ^{. H, J = 5 1 Hz} ), 7.37 (d, 1 H, J = 3.3Hz), 7.21 (t, 1 H, J = 3.6Hz); ESI (m / z) 379 (MH < + >); HRMS (ESI) calcd for C18H10N4O2S2 [MH +]: 379.0323, found: 379.0306.

2,3-d] pyrimidin-4-ylamino] ^-1 H-pyrrolo [3,4-c] - Dion (8e)

^{1 H NMR (400 MHz, DMSO} -d6) δ 9.06 (d, 1 H, J = 5. 1 Hz), 8.41-8.38 (m, 2H), 8.31 (s, 1 H), 7.90-7.82 (m, ^{2H), 7.66 (d, 1} H, J = 4.4Hz), 7.39 (d, 1 H, J = 3.3Hz), 7.18 (t, 1 H, J = 4.4Hz); ESI (m / z) 380 (MH < + >).

Example 7: Preparation of methyl 2-cyano-3- (thiophen-2-yl) bute-2-nooate (9a)

To a stirred solution of 2-acetylthiophene (1.0 g, 7.92 mmol) in toluene (20 ml) was added methyl cyanoacetate (0.84 ml, 9.51 mmol), ammonium acetate (1.80 g, 23.77 mmol) and acetic acid (1.36 ml, 23.77 mmol). After refluxing for 16 hours, the reaction mixture was poured into ice water and extracted with EtOAc. Washing the combined organic layers with 1N HCl solution, dried over Na ₂ SO ₄ and was concentrated to dryness. The residue was then purified by flash column chromatography (n-Hx: EtOAc = 5: 1) to give compound 9a (810 mg, 53%) as a yellow oil. ^{1 H NMR (400 MHz, CDCl3} ) δ 8.03 (d, 1 H, J = 4.0 Hz), 7.80 (d, 1 H, J = 4.8 Hz), 7.78 (t, 1 H, J = 4.4 Hz), 3.88 (s, 3 H) 2.71 (s, 3 H).

Example 8: Preparation of methyl 5'-amino-2,3'-bithiophene-4'-carboxylate (10a)

To a stirred solution of methyl 2-cyano-3- (thiophen-2-yl) but-2-nnaate 9a (250 mg, 1.21 mmol) and sulfur (46 mg, 1.45 mmol) in ethanol (10 ml) Piperidine (143 [mu] l, 1.45 mmol) was added and the resulting mixture was stirred at 80 [deg.] C for 18 hours. After cooling at room temperature, the reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with aqueous NH ₄ Cl solution, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was then purified by flash column chromatography (n-Hx: EtOAc = 5: 1) to give compound 10a (88 mg, 31%) as a yellow solid. ^{1 H NMR (400 MHz, CDCl3} ) δ 7.25 (d, 1 H, J = 3.6 Hz), 7.01 (m, 2H), 6.22 (s, 1 H), 6.11 (s, 2H), 3.67 (s, 3H ).

Example 9: Preparation of 2,5-di (thiophen-2-yl) thieno [2,3-d] pyrimidin-

Carboxylate 10a (100 mg, 0.48 mmol) and 2-thiophenecarbonitrile (58 [mu] L, 0.62 mmol) 3.6M HCl 1,4- Dioxane solution (6 ml), and the resulting mixture was stirred at 110 ° C for 36 hours. After cooling, the reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford the title compound 11a (67 mg, 51%) as a yellow solid. ^{1 H NMR (400 MHz, DMSO} -d6) δ 8.19 (d, 1 H, J = 4.4 Hz), 7.84 (d, 1 H, J = 5.2 Hz), 7.71 (d, 1 H, J = 3.6 Hz) , 7.51 (m, 2H), 7.22 (m, 1 H), 7.10 (m, 1 H).

Example 10: Preparation of 4-chloro-2,5-di (thiophen-2-yl) thieno [2,3-d] pyrimidine (12a)

To a solution of 2,5-di (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ol 11a (272 mg, 0.86 mmol) in POCl ₃ (3 ml) Lt; RTI ID = 0.0 > 110 C < / RTI > After cooling at room temperature, the reaction mixture was poured into ice water and extracted with EtOAc. Concentrate the combined organic layers NaHCO ₃ And washed with an aqueous solution, dried over Na ₂ SO _4, concentrated and dried. The residue was purified by flash column chromatography (n-Hx: EtOAc = 1: 2) to give compound (12a) (234 mg, 81%) as a yellow solid. ^{1 H NMR (400 MHz, CDCl3} ) δ 8.06 (d, 1 H, J = 4.0 Hz), 7.50 (d, 1 H, J = 5.6 Hz), 7.46 (s, 1 H), 7.40 (d, 1 H , J = 5.6 Hz), 7.16 (m, 2H), 7.12 (dd, 1 H, JA = 3.2 Hz, JB = 5.2 Hz).

Typical Preparation of ¹ H- pyrrole-2,5-dione derivatives (13a-m) - 3- methyl-1- (thieno [2,3-d] pyrimidin-4-ylamino): Example 11

To a stirred solution of compounds 5b to 12e or compounds 12a to 12i (1 mmol) in THF (5 ml) was added hydrazine monohydrate (3 mmol) and the mixture was stirred at 80 ° C for 3 hours. After cooling, the solvent was removed under reduced pressure and concentrated in vacuo. 6b to the residue were dissolved in CHCl ₃ to 6n, Citra conic anhydride (3mmol) was added slowly. The resulting mixture was heated to 80 [deg.] C and stirred for 10-18 h. The reaction mixture was cooled to room temperature and washed with water. The organic layer was dried with Na ₂ SO _4, and concentrated to dryness. The residue was purified by flash column chromatography to give the final product.

1- (2,5-di (2-yl) thieno [2,3-d] pyrimidin-4-yl) -3-methyl - ¹ H- pyrrole-2,5-dione (13a )

^{1 H NMR (400 MHz, CDCl3} ) δ 7.80 (d, 1 H, J = 4.0 Hz), 7.45 (d, 1 H, J = 4.8 Hz), 7.38 (m, 2H), 7.30 (s, 1 H) ^{, 7.18 (m, 1 H)} , 7.14 (br s, 3H), 7.07 (dd, 1 H, JA = 4.0 Hz, JB = 5.2 Hz), 6.59 (d, 1 H, J = 1.6 Hz), 2.23 ( s, ¹ H); ESI (m / z) 425 (MH < + >); HRMS (ESI) calcd for C19H12N4O2S3 [MH +]: 425.0201, found: 425.0189.

3-methyl-1- [2-phenyl-5- (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ylamino] - ¹ H- pyrrole-2,5-dione ( 13b)

^{1 H NMR (400 MHz, CDCl3} ) δ 8.23 (d, 2H, J = 7.2 Hz), 7.45 (d, 1 H, J = 4.4 Hz), 7.41 -7.38 (m, 4H), 7.34 (s, 1 H ), 7.20 -7.17 (m, 2H ), 6.59 (s, 1 H), 2.22 (s, 3H); ESI (m / z) 419 (MH < + >); ^{HRMS (ESI) calcd for C2 1} H14N4O2S2 [MH +]: 419.0636, found: 419.0631.

3-methyl-1- [2- (pyridin-4-yl) -5- (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ylamino] - ¹ H- pyrrole- The 2,5-dione (13c)

^{1 H NMR (400 MHz, DMSO} -d6) δ 8.85 (br s, 1 H), 8.73 (d, 2H, J = 5.8 Hz), 8.24 (d, 2H, J = 6.2 Hz), 7.87 (d, 1 H, J = 5.8 Hz), 7.75 -7.73 (m, 2H), 7.32 -7.30 (m, 1 H), 7.26 -7.24 (m, 1 H), 2.18 (s, 3H); ESI (m / z) 420 (MH < + >).

1- [2-cyclopropyl-5- (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ylamino] -3-methyl - ¹ H- pyrrole-2,5-dione ( 13d)

^{1 H NMR (400 MHz, CDCl3} ) δ 7.43 (m, 1 H), 7.36 (m, 1 H), 7.31 (s, 1 H), 7.18 (m, 1 H), 7.02 (s, 1 H), ^{6.48 (s, 1 H),} 2.13 (s, 3H), 2.05 (m, 1 H), 0.90 (m, 2H), 0.81 (m, 2H); ESI (m / z) 383 (MH < + >); HRMS (ESI) calcd for C18H14N4O2S2 [MH +]: 383.0636, found: 383.0624.

1- [2- (furan-2-yl) -5- (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ylamino] ^-3-methyl-1 H- pyrrole- The 2,5-dione (13e)

^{1 H NMR (400 MHz, DMSO} -d6) δ 7.86 (br s, 1 H), 7.63 (s, 1 H), 7.49 (dd, 1 H, JA = 4.8 Hz, JB = 0.8 Hz), 7.47 (s ^{, 1 H), 7.38 (dd} , 1 H, JA = 3.6 Hz, JB = 0.8 Hz), 7.20 (dd, 1 H, JA = 5.2 Hz, JB = 3.2 Hz), 7.13 (d, 1 H, J = 3.2 Hz), 6.62 (m, 1 H), 6.55 (dd, 1 H, JA = 3.2 Hz, JB = 1.6 Hz), 2.22 (s, 3H); ESI (m / z) 409 (MH < + >); HRMS (ESI) calcd for C19H12N4O3S2 [MH +]: 409.0429, found: 409.0418.

1- [2- (3-methoxyphenyl) -5- (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ylamino] ^-3-methyl-1 H- pyrrole- 2,5-dione (13f)

^{1 H NMR (400 MHz, DMSO} -d6) δ 7.84 (m, 2H), 7.48 -7.30 (m, 5H), 7.22 -7.19 (m, 1 H), 7.01 -6.98 (m, 1 H), 6.61 ( ^{s, 1 H), 3.86 (} s, 3H), 2.22 (s, 3H); ESI (m / z) 449 (MH < + >); HRMS (ESI) calcd for C22H16N4O3S2 [MH +]: 449.0742, found: 449.0728.

1- [2- (4-methoxyphenyl) -5- (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ylamino] ^-3-methyl-1 H- pyrrole- 2,5-dione (13 g)

^{1 H NMR (400 MHz, DMSO} -d6) δ 8.57 (s, 1 H), 8.11 (d, 2H, J = 8.8 Hz), 7.75 (s, 1 H), 7.68 (d, 1 H, J = 5.2 ^{Hz), 7.32 (d, 1} H, J = 3.6 Hz), 7.22 (t, 1 H, J = 5.2 Hz), 7.01 (d, 2H, J = 8.8 Hz), 6.95 (s, 1 H), 3.81 (s, 3 H), 2.14 (s, 3 H); ESI (m / z) 449 (MH < + >); HRMS (ESI) calcd for C22H16N4O3S2 [MH +]: 449.0742, found: 449.0734.

3-methyl-1- [2- (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ylamino] - ¹ H- pyrrole-2,5-dione (13h)

^{1 H NMR (400 MHz, DMSO} -d6) δ 7.77 (d, 1 H, J = 6.0 Hz), 7.70 -7.65 (m, 3H), 7.14 (t, 1 H, J = 4.4 Hz), 7.01 (s ^{, 1 H), 2.18 (s} , 3H); ESI (m / z) 343 (MH < + >); HRMS (ESI) calcd for C15H10N4O2S2 [MH +]: 343.0323, found: 343.0315.

Thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ylamino] -lH-pyrrole-2,5-dione (13i )

^{1 H NMR (400 MHz, CDCl3} ) δ 7.78 (d, 1 H, J = 3.6 Hz), 7.40 (s, 1 H), 7.37 (d, 1 H, J = 5.2 Hz), 7.07 (t, 1 H , J = 4.4 Hz), 6.87 (s, 1 H), 6.62 (s, 1 H), 2.58 (s, 3H), 2.26 (s, 3H); ESI (m / z) 357 (MH +); HRMS (ESI) calcd for C16H12N4O2S2 [MH +]: 357.0480, found: 357.0464.

2- (thiophen-2-yl) thieno [2, 3-dihydro-lH- 3-d] pyrimidin-5-yl] acetate (13j)

^{1 H NMR (400 MHz, CDCl3} ) δ 9.63 (s, 1 H), 7.69 (m, 2H), 7.57 (s, 1 H), 7.14 (t, 1 H, J = 4.0 Hz), 6.99 (d, ¹ H, J = 2.0 Hz), 4.20 (s, 2H), 4.08 (m, 2H), 2.16 (s, 3H), 1.18 (t, 3H, J = 7.2 Hz); ESI (m / z) 429 (MH < + >); HRMS (ESI) calcd for C19H16N4O4S2 [MH +]: 429.0691, found: 429.0668.

Thieno [2,3-d] pyrimidin-4-ylamino] -1H-pyrrole-2,5-dione (13k )

^{1 H NMR (400MHz, DMSO-} d6) δ 8.41 (s, 1 H), 7.72 (br s, 3H), 7.51 (m, 5H), 7.16 (s, 1 H), 6.93 (s, 1 H), 2.12 (s, 3 H); ESI (m / z) 419 (MH < + >); HRMS (ESI) calcd for C2 ¹ H14N4O2S2 [MH +]: 419.0636, found: 419.0615.

Thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ylamino] -3-methyl- , 5-dione (13l)

^{1 H NMR (400 MHz, DMSO} -d6) δ 8.23 (s, 1 H), 7.73 -7.70 (m, 2H), 7.64 (s, 1 H), 7.30 (t, 1 H, J = 7.6 Hz), ^{7.16 (m, 1 H),} 6.94 (m, 3H), 6.87 (m, 1 H), 2.12 (s, 3H); ESI (m / z) 435 (MH < + >); HRMS (ESI) calcd for C2 ¹ H14N4O3S2 [MH +]: 435.0586, found: 435.0566.

1- [5- (4-hydroxyphenyl) -2- (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-ylamino] ^-3-methyl-1 H- pyrrole- 2,5-dione (13m)

^{1 H NMR (400 MHz, DMSO} -d6) δ 9.43 (br s, 1 H), 8.19 (s, 1 H), 7.69 (m, 2H), 7.51 (s, 1 H), 7.35 (d, 2H, J = 8.4 Hz), 7.13 ( t, 1 H, J = 4.2 Hz), 6.90 (s, 1 H), 6.87 (d, 2H, J = 8.4 Hz), 2.16 (s, 3H); ESI (m / z) 435 (MH < + >); HRMS (ESI) calcd for C2 ¹ H14N4O3S2 [MH +]: 435.0586, found: 435.0566.

Example 12: Preparation of 4-chloro-5- (3- (2- (piperidin-1-yl) ethoxy) phenyl) -2- (thiophen- Preparation of pyrimidine (14a)

A mixture of 3- (4-chloro-2- (thiophen-2-yl) thieno [2,3-d] pyrimidin-5-yl) phenol 12h (100 mg, 0.29 mmol) and PPh3 Piperidine ethanol (42 [mu] l, 0.32 mmol) and diisopropyl laodicarboxylate (DIAD, 63 [mu] l, 0.32 mmol) were added to a stirred portion of methanol (99 mg, 0.38 mmol) at 0 ° C. The resulting mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM: MeOH = 10: 1) to give the title compound (14) as a colorless oil. ^{1 H NMR (400 MHz, CDCl3} ) δ 8.08 (dd, 1 H, JA = 3.6 Hz, JB = 1.2 Hz), 7.52 (dd, 1 H, JA = 4.8 Hz, JB = 1.6 Hz), 7.35 -7.31 ( m, 2H), 7.16 (t , 1 H, J = 4.4 Hz), 7.01 -6.96 (m, 3H), 4.16 (t, 2H, J = 6.4 Hz), 2.81 (t, 2H, J = 6.0 Hz) , 2.53 (m, 4H), 1.61 (m, 4H), 1.25 (m, 2H).

Example 13: Preparation of 3-methyl-1- (5- (3- (2- (piperidin-1-yl) ethoxy) phenyl) -2- (thiophen- Preparation of ¹ H- pyrrole-2,5-dione (16a) - -d] pyrimidin-4-ylamino)

2- (thiophen-2-yl) thieno [2,3-d (4-fluorophenyl) ] Pyrimidine 14a (180 mg, 0.39 mmol) was added hydrazine monohydrate (76 [mu] l, 1.58 mmol). The resulting mixture was stirred at 80 ° C for 4 hours. After cooling, the solvent was removed under reduced pressure and concentrated in vacuo. It was dissolved the residue in CHCl ₃ 15a, the sheet la conic anhydride (106 μl, 1.18 mmol) was added slowly. The resulting mixture was heated to 80 [deg.] C and stirred for 12 hours. The reaction mixture was cooled to room temperature and washed with water. The organic layer was dried with Na ₂ SO _4, and concentrated to dryness. The residue was purified by flash column chromatography (CHCl ₃ : MeOH = 10: 1) to give the title compound 16a (210 mg, 97%) as a pale yellow solid. ^{1 H NMR (400 MHz, CDCl3} ) δ 7.80 (dd, 1 H, JA = 3.6 Hz, JB = 1.2 Hz), 7.42 (t, 1 H, J = 8.0 Hz), 7.38 (dd, 1 H, JA = 4.8 Hz, JB = 1.2 Hz) , 7.20 (m, 2H), 7.12 (t, 1 H, J = 2.0 Hz), 7.07 (t, 1 H, J = 4.4 Hz), 7.02 -6.99 (m, 1 H ^{), 6.92 (s, 1 H} ), 6.56 (dd, 1 H, JA = 3.2 Hz, JB = 1.6 Hz), 4.34 (t, 2H, J = 5.2 Hz), 3.12 (t, 2H, J = 5.2 Hz ), 2.86 (m, 4H), 2.21 (s, 3H), 1.75 (m, 4H), 1.52 (m, 2H).

Example 14: 1- (5- (substituted-phenyl) -2- (thiophen-2-yl) thieno [2,3-d] pyrimidin-4-yl) ^-3-methyl-1 H - pyrrole-2,5-dione hydrochloride derivative (17a-d)

At 0 ° C, a solution of 4M HCl 1,4-dioxane (2.9 ml) was added to a stirred solution of 16a-16d (0.38 mmol) of compound 16 in 1,4-dioxane (5 ml). After stirring for 10 hours, the reaction mixture was concentrated in vacuo to give the final compounds 17a-17d.

Phenyl] -2- (thiophen-2-yl) thieno [2,3-d] pyrimidin- -4-ylamino) - ¹ H- pyrrole-2,5-dione hydrochloride (17a)

^{1 H NMR (400MHz, DMSO-} d6) δ 10.67 (s, 1 H), 8.51 (s, 1 H), 7.72 (m, 3H), 7.47 (t, 1 H, J = 8.4 Hz), 7.25 (m ^{, 1 H), 7.16 (m} , 2H), 7.08 (m, 1 H), 6.95 (s, 1 H), 4.50 (m, 2H), 3.48 (m, 4H), 2.98 (m, 2H), 2.14 (s, 3 H), 1.78 (m, 6 H); ESI (m / z) 546 (MH < + >); HRMS (ESI) calcd for C28H27N5O3S2 [MH +]: 546.1634, found: 546.1621.

Phenyl] -2- (thiophen-2-yl) thieno [2,3-d] pyrimidine

^{1 H NMR (400MHz, DMSO-} d6) δ 11.10 (s, 1 H), 8.47 (s, 1 H), 7.72 (m, 3H), 7.48 (t, 1 H, J = 8.4 Hz), 7.17 (m , 4H), 6.95 (s, 1 H), 4.52 (m, 2H), 4.11 -3.81 (m, 4H), 3.51 (m, 4H), 3.20 (br s, 2H), 2.14 (s, 3H); ESI (m / z) 548 (MH < + >); HRMS (ESI) calcd for C27H25N5O4S2 [MH +]: 548.1427, found: 548.1408.

2,3-d] pyrimidin-4-ylamino) -3, 3-dihydro- ^-methyl-1 H- pyrrole-2,5-dione hydrochloride (17c)

^{1 H NMR (400MHz, DMSO-} d6) δ 8.49 (s, 1 H), 7.72 (m, 3H), 7.47 (t, 1 H, J = 8.0 Hz), 7.25 (d, 1 H, J = 7.6 Hz ), 7.16 (m, 2H) , 7.06 (d, 1 H, J = 8.0 Hz), 6.94 (s, 1 H), 4.44 (t, 2H, J = 4.8 Hz), 3.52 (m, 2H), 2.83 (s, 3 H), 2.82 (s, 3 H), 2.14 (s, 3 H); ESI (m / z) 506 (MH < + >); HRMS (ESI) calcd for C25H23N5O3S2 [MH +]: 506.1321, found: 506.1302.

Phenyl) -2- (thiophen-2-yl) thieno [2,3-d] pyrimidin- -4-ylamino) - ¹ H- pyrrole-2,5-dione hydrochloride (17d)

^{1 H NMR (400MHz, DMSO-} d6) δ 10.43 (s, 1 H), 9.52 (s, 1 H), 8.76 (d, 2H, J = 5.2 Hz), 7.54 (d, 2H, J = 8.0 Hz) , 7.15 (m, 3H), 7.02 (s, 1 H), 4.52 (s, 2H), 3.62 (m, 4H), 3.01 (m, 2H), 2.14 (s, 3H), 1.81 -1.69 (m, ^{5H), 1.20 (m, 1} H); ESI (m / z) 546 (MH < + >).

Example 15

Compounds described in the following Table 1 were prepared in the same or similar manner as the methods described in Examples 1-13.

[Table 1]

Experimental Example 1: Kinase panel test

KinaseProfiler (TM), Merck Millipore, UK) was performed on the following 22 kinases, including the IKK beta kinase assay, in order to identify the signaling pathway of the kinase with thienopyrimidine derivatives active. The evaluation method of the representative kinase FLT3 (h) among the 22 kinases is as follows. Compounds 13k and 17a synthesized in the above examples were used as test compounds.

The cells were incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 μM EAIYAAPFAKKK, 10 mM magnesium acetate (Mg acetate) and [γ-33P-ATP] (approximately 500 cpm / pmol required for specific activity). The reaction was initiated by the addition of MgATP. After incubation at room temperature for 40 min, the reaction was terminated by the addition of 3% phosphoric acid solution. 10 μL of the reaction solution was filtered through a P30 filter mat and washed three times with 75 mM phosphonic acid for 5 minutes, once with methyl alcohol, then dried and counted through scintillation.

[Table 2]

As a result, as shown in Table 2 above, test compounds 13k and 17a did not inhibit kinase activity such as IKK beta in other signal transduction pathways, but showed excellent inhibitory activity for FLT3 (8% and 10%, respectively, 4% residual activity). Thus, since the test compound is not involved in other kinase pathways, the possibility of side effects is low in the treatment of AML, and it is expected that the treatment and prevention of AML caused by abnormal overexpression and mutation will be excellent.

Experimental Example 2: FLT3 kinase test

Flt3 (h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 μM EAIYAAPFAKKK, 10 mM magnesium acetate and [γ-33P-ATP] (concentration of approximately 500 cpm / pmol required for specific activity) And cultured together. The reaction was initiated by the addition of MgATP. After incubation at room temperature for 40 min, the reaction was terminated by the addition of 3% phosphoric acid solution. 10 μL of the reaction solution was filtered through a P30 filter mat and washed three times with 75 mM phosphonic acid for 5 minutes, once with methyl alcohol, then dried and counted through scintillation. Each compound was treated with Flt3 (h) at five concentrations (10, 1, 0.1, 0.01, and 0.01 μM) with 10 μM ATP to determine IC ₅₀ values. On the other hand, AC220 and MLN518 were used as control groups.

[Table 3]

As can be seen in Table 3 above, most of the test compounds showed an excellent inhibitory profile against FLT3.

Experimental Example 3: Evaluation of inhibition of cancer cell proliferation

In order to evaluate the performance against cancer cell proliferation inhibition, the following experiment was conducted.

Cell line

The human cancer cells (ACHN, HCT15, MDA-MB-231, NCI-H23, NUGC-3, PC-3, MV4-11, THP-1, K562 and HL-60) distributed in the American Type Culture Collection Respectively. Cancer cell lines were cultured in RPMI 1640 medium supplemented with 10% FBS for 72 hours in a 5% CO 2 incubator at 37 ° C.

XTT cell proliferation assay

Cell proliferation experiments were carried out using the thienopyrimidine derivative compounds shown in Table 4 below. The cell proliferation experiments were carried out using the Cell Proliferation Kit II (XTT) assay (Roche). The cancer cell lines (ACHN, HCT15, MDA-MB-231, NCI-H23, NUGC-3, PC- , THP-1, K562, HL-60) at a cell density of 6,000 cells in a 96-well tissue culture plate. The next day, 48 hours after the sample was treated, 50 μl of XTT reagent was added to each well, reacted for 2 hours at 37 ° C, and the absorbance was measured at 490 nm using an ELISA plate reader (Molecular Devices). On the other hand, AC220 and MLN518 (0.12 and 0.102 micromoles, respectively) were used as control groups, and the results are shown in Table 4 below.

As can be seen from the following Table 4, most of the compounds showed excellent inhibitory activity against MV4-11 and THP1. MV4-11 and THP1 are mutant FLT3 / ITD cell lines observed in AML, indicating that the excellent growth inhibitory activity against these cells is also excellent for the treatment and prevention of AML. In particular, most test compounds had better FLT3 / ITD and wt-FLT3 inhibitory activity than AC220, which is known as a selective inhibitor.

[Table 4]

Experimental Example 4: FLT3 (D835Y) kinase test

Flt3 (D835Y) (h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 μM EAIYAAPFAKKK, 10 mM magnesium acetate and [γ-33P-ATP] (approximately 500 cpm / ≪ / RTI > required). The reaction was initiated by the addition of MgATP. After incubation at room temperature for 40 min, the reaction was terminated by the addition of 3% phosphoric acid solution. 10 μL of the reaction solution was filtered through a P30 filter mat and washed three times with 75 mM phosphonic acid for 5 minutes, once with methyl alcohol, then dried and counted through scintillation. Each compound was treated with Flt3 (D835Y) (h) at five concentrations (10, 1, 0.1, 0.01, and 0.01 μM) with 10 μM ATP to determine IC ₅₀ values. On the other hand, AC220 and MLN518 were used as control groups.

[Table 5]

In this experiment, the IC50 for the kinase domain mutant FLT3_D835Y was measured in the above 10 compounds. All of these compounds have excellent IC50 values at 46 nM to 591 nM. Particularly, of these, the chemical formulas 128, 134, 137, 49 and 92 described in Table 5 above have an excellent inhibitory activity against D835Y as compared to A220 and MLN518. The present experimental results show that the thienopyrimidine derivative of the present invention has an inhibitory activity against TKD mutation, suggesting that the problem of the therapeutic resistance of the mutation to the conventional inhibitor can be solved.

Claims (7)

A pharmaceutical composition for preventing or treating leukemia, comprising a thienopyrimidine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In this formula,
R ₁ is H; Linear or branched C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkenyl, or C ₁ -C ₁₀ alkynyl; - (CH _{2) n} -COOR; -O- (CH ₂ ) _n -NRR '; - (CH _{2) n} -OH; - (CH _{2) n} -OR; -Y- (CH ₂ ) _n -MR; C ₅ -C ₂₀ heteroaryl which is unsubstituted or substituted by C ₁ -C ₁₀ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen and which is selected from the group consisting of S, O and N atoms or C ₅ -C ₂₀ heteroaryl groups containing two heteroatoms; or

;
R ₃ is H; -OH; -CN; Linear or branched C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkenyl, or C ₁ -C ₁₀ alkynyl; - (CH _{2) n} -COOR; -CONH- (CH ₂ ) _n -NRR '; -O- (CH ₂ ) _n -NRR '; -CO- (CH ₂ ) _n -NRR '; - (CH _{2) n} -OH; - (CH _{2) n} -OR; C ₆ -C ₂₀ aryl substituted or unsubstituted with C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen; C ₅ -C ₂₀ heteroaryl which is unsubstituted or substituted by C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen, and is selected from the group consisting of S, O and N atoms 1, or C ₅ -C ₂₀ containing two heteroatoms heteroaryl; or

; Or from the group consisting of S, O and N atoms, wherein R ₁ and R ₃ are bonded to _one another and are substituted with C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen Form a C ₃ -C ₂₀ heterocyclyl group containing one or two heteroatoms selected;
R ₂ is H; -OH; -NRR '; Linear or branched C ₁ -C ₁₀ alkyl; C ₁ -C ₁₀ alkenyl, or C ₁ -C ₁₀ alkynyl; - (CH _{2) n} -Z; -Y- (CH _{2) n} -Z; - (CH ₂ ) _n -C ₃ to C ₇ cycloalkyl; C ₁ -C ₃ alkyl; C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or C ₅ -C ₂₀ heteroaryl which is unsubstituted or substituted by halogen and which contains one or two heteroatoms selected from the group consisting of S, O and N atoms C ₅ -C ₂₀ heteroaryl; Substituted or unsubstituted C ₆ -C ₂₀ aryl; or

;
R ₄ and R ₅ are each independently H, linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, -NR'R ", -Y- (CH ₂ ) _n -NR'R ", -Y- (CH ₂ ) _n -Z,

,

,

,

Or consisting of S, O and N atoms, wherein R ₄ and R ₅ are bonded to each other to form a C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen, , form a C ₃ -C ₂₀ heterocyclyl comprising 1 or 2 hetero atoms selected from the group, and;
Z is -NR'R "; S, O and N atoms comprising the comprising from 1 to 3 hetero atoms selected from the group, substituted or unsubstituted C ₅ -C ₂₀ heteroaryl or heterocyclyl;

; C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl; substituted or unsubstituted blood as carbonyl or halogen pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 2-or 3-oxo-pyrrolidine Pyridines, imidazoles, imidazolidines, 2,5-dioxo-pyrrolidines, 2- or 3-oxo-pyrimidines, Piperazine, 2-oxo-imidazolidine, 4,4-ethylenedioxy-piperidine, 2- or 3-thienyl, 2- or 3-furyl;

;
R ₆ is H; halogen; -OH; -OR; -COOR; (CH _{2) n} -OR; Linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl; -NO ₂ ; -Y- (CH _{2) n} -Z; Or -Y- (CH ₂ ) _n -NR'R ";
R ₇ is H; Or linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl;
R ₈ is H; - (CH ₂ ) _n -OR or - (CH ₂ ) _n --NR'R ", _wherein R is selected from the group consisting of hydrogen, C ₁ -C ₅ alkyl, linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl, ₂ ) _n- OH;
R ₉ is H; halogen; -OH; -OR; -NO ₂ ; -COOR; - (CH _{2) n} -OR; _{- (CH 2) n -NR'R "} ; a linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C _{5 alkynyl; -Y- (CH 2) n -Z} ; - Y- (CH ₂ ) _n -NR'R "; -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -OR; _{-Y- (CH 2) n -M- (} CH 2) n -ph; Or -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -NR'R ";
R ₁₀ is H; -OH; -OR; -COOR; (CH ₂ ) _n -OR, linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, -Y- (CH ₂ ) _n -Z -Y- (CH ₂ ) _n -Z- (CH ₂ ) _n -OR, -Y- (CH ₂ ) _n -M- _{R 'R} "; -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -CN; -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -C = C; And Y- (CH _{2) n} -NR'R ", or _{-Y- (CH 2) n -N (} Boc) R -; -Y- (CH 2) n -M- (CH 2) n -C≡C ;
R ₁₁ and R ₁₂ are each independently H; Linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl; Or R ₁₁ and R ₁₂ are bonded to each other to form a substituted or unsubstituted C ₆ -C ₂₀ aryl; Substituted or unsubstituted C ₃ -C ₇ cycloalkyl; Or N; O and to form a C ₅ -C ₂₀ heterocyclic ring containing one or two heteroatoms selected from the group consisting of S, and;
R ₁₃ is -Y- (CH ₂ ) _n -Z, - (CH ₂ ) _n -Z, or - (CH ₂ ) _n -NR'R ";
R, R 'and R "are each independently selected from H; linear or branched C ₁ -C _{5 alkyl; - (CH 2) n -C} 6 H 6; - (CH 2) n -OH; or -CH ₂ CF ₃ ;
Y is O, S, -NH-, -NH-CO-, or -CO-NH-;
M is O, S, -NH-, -NH-CO-, or -CO-NH-;
n is an integer of 0 to 6; The method of claim 1, further comprising:
R ₁ is H; C ₁ -C ₅ alkyl; - (CH _{2) n} -COOR; -O- (CH ₂ ) _n -NRR '; - (CH _{2) n} -OH; - (CH _{2) n} -OR; -Y- (CH ₂ ) _n -MR; C ₅ -C ₂₀ heteroaryl which is unsubstituted or substituted by C ₁ -C ₁₀ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen and which is selected from the group consisting of S, O and N atoms or C ₅ -C ₂₀ heteroaryl groups containing two heteroatoms; or

Lt;
R ₃ is H; -OH; -CN; Linear or branched C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkenyl, or C ₁ -C ₁₀ alkynyl; - (CH _{2) n} -COOR; -CONH- (CH ₂ ) _n -NRR '; -O- (CH ₂ ) _n -NRR '; -CO- (CH ₂ ) _n -NRR '; - (CH _{2) n} -OH; - (CH _{2) n} -OR; C ₆ -C ₂₀ aryl substituted or unsubstituted with C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen; C ₅ -C ₂₀ heteroaryl which is unsubstituted or substituted by C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen, and is selected from the group consisting of S, O and N atoms 1, or C ₅ -C ₂₀ containing two heteroatoms heteroaryl; or

; Or R ₁ and R ₃ are bonded to each other by C ₁ -C ₃ alkyl, halogen, or substituted or unsubstituted, S, O and N, which C atoms containing one or two heteroatoms selected from the group consisting of -C _{3 20} heterocyclyl group;
R ₂ is H, -OH, -NRR ', linear or branched C ₁ -C _{10 alkyl, - (CH 2) n -Z} , -Y- (CH 2) n -Z, - (CH 2) n -C ₃ to C ₇ cycloalkyl, C ₁ -C ₃ alkyl, halogen, or substituted or unsubstituted C ₅ -C ₂₀ a heteroaryl group containing one or two heteroatoms selected from the group consisting of S, O and N atoms C ₅ -C ₂₀ heteroaryl; Or a substituted or unsubstituted C ₆ -C ₂₀ aryl or

;
R ₄ and R ₅ each is, independently, H, or linear or branched C ₁ -C _{5 alkyl, -NR'R ", -Y- (CH 2} ) n -NR'R", -Y- (CH 2 ) _n -Z,

,

,

,

Or, or R ₄ and R ₅ are combined to C ₁ -C ₃ alkyl, halogen, or C ₃ to comprise a substituted or unsubstituted with one or two hetero atoms selected from a, S, O and N atoms with each other ring group consisting of To form a -C ₂₀ heterocyclyl group;
Z is -NR'R ", pyrrolidine, piperidine, piperazine, morpholino, substituted or unsubstituted C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl or halogen Pyrrole, thiomorpholine, 2- or 3-oxo-pyrrolidine, 2-, 3- or 4-oxo-piperidine, oxazole, triazole, pyridine, imidazole, imidazolidine, 2- dioxo-pyrrolidine, 2- or 3-oxo-piperazine, 2-oxo-imidazolidine, 4,4-ethylenedioxypiperidine, 2- or 3-thienyl, 2- or 3- 3-furyl

;
R ₆ is H; -OH; -OR; -COOR; (CH _{2) n} -OR; Linear or branched C ₁ -C ₅ alkyl; -NO ₂ ; -Y- (CH _{2) n} -Z; Or -Y- (CH ₂ ) _n -NR'R ";
R ₇ is H; Or linear or branched C ₁ -C ₅ alkyl;
R ₈ is H; Linear or branched C ₁ -C ₅ alkyl; - (CH ₂ ) _n -NR'R "; - (CH ₂ ) _n -OR or - (CH ₂ ) _n -OH;
R ₉ is H; halogen; -OH; -OR; -NO ₂ ; -COOR; - (CH _{2) n} -OR; _{- (CH 2) n -NR'R "} ; a linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl; C ₁ -C ₃ alkyl; C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, or a halogen-substituted or unsubstituted with pyrrolidine; piperidine; piperazine _{-Y- (CH 2) n -Z;} -Y- (CH 2) n -NR ' R " -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -OR; _{-Y- (CH 2) n -M- (} CH 2) n -ph; Or -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -NR'R ";
R ₁₀ is H; -OH; -OR; -COOR; (CH ₂ ) _n -OR, linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, -Y- (CH ₂ ) _n -Z ; Y- (CH ₂ ) _n -Z- (CH ₂ ) _n -OR -Y- (CH ₂ ) _n -M-R'R "; -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -CN; -Y- (CH ₂ ) _n -M- (CH ₂ ) _n -C = C; And Y- (CH _{2) n} -NR'R ", or _{-Y- (CH 2) n -N (} Boc) R -; -Y- (CH 2) n -M- (CH 2) n -C≡C ;
R ₁₁ and R ₁₂ are each independently H; Linear or branched C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl; Halogen; Or R ₁₁ and R ₁₂ are bonded to each other to form a substituted or unsubstituted C ₆ -C ₂₀ aryl; Substituted or unsubstituted C ₃ -C ₇ cycloalkyl; Or N; O and C comprising one or two heteroatoms selected from the group consisting of -C S ₅ is a group forming a ₂₀ heterocycle;
R ₁₃ is -Y- (CH ₂ ) _n -Z; - (CH ₂ ) _n -Z or - (CH ₂ ) _n -NR'R ";
R; R 'and R "are each independently selected from the group consisting of H, linear or branched C ₁ -C ₅ alkyl, - (CH ₂ ) _n -C ₆ H _6, - (CH ₂ ) _n -OH or -CH ₂ CF ₃ ;
Y is O, S, -NH-, -NH-CO-, or -CO-NH-;
M is O; S is -NH-; -NH-CO- or -CO-NH-;
n is an integer of 0 to 3; The method according to claim 1,
R ₁ is H, -Me, -Et, -ph, -ph-F, -CH ₂ -ph, -ph-OH, -CH ₂ OH, thiophenyl, -CH ₂ -ph-OMe, , -ph-ME, -CONH ₂ , -COOMe, -COOEt, -CH ₂ -COOEt, -ph-OC ₂ H ₅ -NR'R ", -CH ₂ -ph-OC ₃ H ₇ -NR'R" ,

;

or

;
R ₃ is selected from the group consisting of H, -OH, -CN, -Me, -Et, -COOH, -COOME, -CONH ₂ , -CONH-CH ₂ CH ₂ -N (CH ₂ ) ₃ , -CH ₂ -ph, -ph-OH, -CH ₂ -ph -OH, -ph-NO ₂ , -ph-ME, -CH ₂ OH, -C ₂ H ₅ OH, ME, -ph-OC ₂ H ₅ -NH-CH ₂ -ph, pH-OC ₂ H ₅ -NH-C ₃ H ₇ - (CH ₂ ) ₃ , -ph-OC ₂ H ₅ -NR ₂ , -ph -C ₂ H ₅ -NH-C ₂ H ₅ -OR, -ph-NO ₂ , -ph-C ₂ H ₅ -NH ₂ ,

Or R ₁ and and R ₃ form a substituted or unsubstituted piperidine by C ₁ -C ₃ alkyl bonded to each other,
R ₂ is selected from the group consisting of -Me, -Et, propyl, tert-butyl, thiophenyl, -NH ₂ , -ph-NH ₂ , -ph-OMe, pH-F, -ph-OC ₂ H ₅ -NRR ',

or

;
R ₄ and R ₅ are each independently H, -CH ₂ -ph, -NH ₂ , -C ₂ H ₅ -NH, -NH-C ₂ H ₅ -NH,

And

. The method according to claim 1,
Wherein the compound represented by the formula (1) is any one of the following formulas.

A pharmaceutical composition for preventing or treating leukemia comprising a thienopyrimidine derivative represented by the following formula (2) or a pharmaceutically acceptable salt thereof:
(2)

. 6. The method according to any one of claims 1 to 5,
Wherein said leukemia is acute myelogenous leukemia (AML). 6. The method according to any one of claims 1 to 5,
A pharmaceutical composition, further comprising a pharmaceutically acceptable carrier, excipient, diluent or a combination thereof.