KR20190139640A - Composition for preventing or treating solid tumor comprising compound inhibiting interactions between AIMP2-DX2 and K-Ras and novel compound inhibiting interactions between AIMP2-DX2 and K-Ras - Google Patents

Abstract

The present invention relates to: a composition for preventing or treating solid cancer comprising a compound which inhibits combination between AIMP2-DX2 and K-Ras; and a novel compound inhibiting combination between AIMP2-DX2 and K-Ras. The compound represented by chemical formula 1 according to the present invention inhibits the combination of AIMP2-DX2 and K-Ras, thereby lowering a level of K-Ras protein in cancer cells and inhibiting the development and progression of cancer. Therefore, the compound can be usefully used for preventing or treating solid cancer which overexpresses AIMP2-DX2.

Description

Composition for preventing or treating solid cancer comprising a compound that inhibits the binding of AIMP2-DX2 and K-Ras and a novel compound that inhibits the binding of AIMP2-DX2 and K-Ras AIMP2-DX2 and K-Ras and novel compound inhibiting interactions between AIMP2-DX2 and K-Ras}

The present invention relates to a composition for preventing or treating solid cancer comprising a compound that inhibits the binding of AIMP2-DX2 and K-Ras and a novel compound that inhibits the binding of AIMP2-DX2 and K-Ras.

Genes that have the potential to be converted into oncogenes by a variety of factors are called proto-oncogenes. The gene Ras is also one of these genes. The Ras protein formed by the Ras gene has a molecular weight of 21 kDa, which is specifically expressed in eukaryotic cells. In all animal cells, there are three types of Ras proteins, H-Ras, K-Ras and N-Ras. Ras proteins are activated in response to external stimuli that activate tyrosine kinase receptors. When autophosphorylation of tyrosine kinase receptors occurs by external stimulation, Grb2, an adapter protein that connects a signal protein to an activated receptor, calls for SOS protein to form a complex. SOS proteins are linked to activated receptors, resulting in a GDP / GTP exchange of inactive Ras GDP bound to the surrounding plasma membrane, which activates Ras. Activated Ras plays a role in regulating cell proliferation and differentiation by activating various signaling processes such as the Raf-MAP kinase pathway.

Cancer cells are constantly dividing and proliferating, and reports in several articles suggest a model for cancer proliferation and metastasis from experimental animal models. In particular, cancer cells caused by K-Ras, a carcinogenic gene, are surprisingly resistant to cancer therapy and radiation therapy. K-Ras in normal tissues regulates cell growth and differentiation, but cancer cells are affected by tumor microenvironmental factors around tumor cells and become abnormal due to rapid division and activation of abnormal division and maintenance pathways. It is proposed to acquire and ultimately cause cancer to recur.

On the other hand, AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein 2) is one of the proteins involved in the formation of aminoacyl-tRNA synthetase (ARS) complex. AIMP2 is known to have a function of enhancing TGF-β signaling through direct interaction with Smad2 / 3 as a novel cancer suppressor, in addition to its main function of constituting the ARS complex. In addition, TNF-α and DNA damage signals promote cell death through binding to TRAF-2 and P53, respectively.

신호의 기능 이상을 초래하는 것으로 나타났다. 이는 AIMP2-DX2와 암 발생과 진행 사이에 밀접한 관련성이 있음을 보여주는 것이라 할 수 있다. Referring to Republic of Korea Patent No. 10-0762995, AIMP2-DX2, a variant of exon 2 deficient in AIMP2, is expressed in various cancer cell lines and tissues such as lung cancer, liver cancer, skin cancer, breast cancer, kidney cancer, and osteosarcoma. Was observed. In addition, transforming normal cells to overexpress AIMP2-DX2 significantly reduces the level of wild-type (WT) AIMP2, inhibits AIMP2 activity, such as preventing AIMP2 from moving to the nucleus, and c-myc expression. Increases, cell growth is promoted, etc. TGF-

It has been shown to cause abnormal signal function. This suggests that there is a close relationship between AIMP2-DX2 and cancer development and progression.

As such, AIMP2-DX2, which is closely related to the differentiation and proliferation of cancer cells, directly binds to K-Ras, stabilizes K-Ras protein, and consequently plays a crucial role in the survival and differentiation of cancer cells. (Korean Patent Publication No. 10-2018-0015847). Thus, compounds capable of inhibiting the binding of AIMP2-DX2 and K-Ras may have effects of lowering K-Ras protein levels in cancer cells and inhibiting the development and progression of cancer, but have not yet achieved AIMP2-DX2 and K-Ras. No compound has been reported that exhibits excellent anticancer effects by directly inhibiting the binding of -Ras.

Accordingly, the present inventors have made diligent efforts to find compounds exhibiting excellent anticancer activity in solid cancers overexpressing AIMP2-DX2 by directly inhibiting the binding of AIMP2-DX2 and K-Ras. The present invention has been found to be excellent in such activity and exhibits very good cancer cell growth inhibitory effect and cytotoxicity in solid cancers overexpressing AIMP2-DX2.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition for preventing or treating solid cancer, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

Where

R ₁ is C 1 -C 6 alkyl unsubstituted or substituted with C 2 -C 10 hetero aryl including at least one hetero atom selected from the group consisting of N, O and S; C1-C6 alkyl substituted with C6-C12 aryl unsubstituted or substituted with C1-C6 alkoxy; Thiophene unsubstituted or substituted with C1-C6 alkyl; Furan; Pyrrole; Thiazole; C3-C7 cycloalkyl; Or C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylamino, amino, C1-C6 alkyl, hydroxy and halogen,

R ₂ is hydrogen; Straight or branched C1-C6 alkyl; C1-C6 alkoxycarbonyl; Thiophene; Or C1-C6 alkoxy, hydroxy, linear or branched C1-C6 alkyl, heterosubstituted or unsubstituted with C2-C10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S. C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of cycloalkyloxy and halogen,

이며, R ₃ is hydrogen; Cyano; C1-C6 alkoxy; C1-C6 alkoxycarbonyl; Aminocarbonyl; C3-C10 alkoxycarbonylalkyl; C3-C10 heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, O and S; Thiophene; C2-C10 hetero aryl unsubstituted or substituted with straight or branched C1-C6 alkyl or C3-C10 cycloalkyl; C1-C6 alkyl; C1-C6 alkyl substituted with C6-C12 aryl unsubstituted or substituted with hydroxy or C1-C6 alkoxy; C6-C12 aryl substituted with unsubstituted C1-C6 alkoxy; C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of hydroxy, nitro, halogen and cyano; or

Is,

R ₄ is C 1 -C 6 alkylamino unsubstituted or substituted with one or more selected from the group consisting of C 1 -C 6 alkylamino, hydroxy, C 1 -C 6 alkoxy, cyano and halogen; C2-C10 heterocycloalkyl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 aminoalkyl, C2-C10 alkylaminoalkyl and C2-C6 alkylcarbonyl; Amino; C2-C6 alkenylamino; C2-C6 alkynylamino; C2-C10 spiroheterocycloalkyl; And benzylamino is one or more selected from the group consisting of

N is an integer of 1 to 5.

Another object of the present invention is 1-[[6-[(4-fluorophenyl) -2- (2-furyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino ] -3-methyl-pyrrole-2,5-dione;

1-[[6-[(4-fluorophenyl) -5-methyl-2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione;

1-[[6-[(4-fluorophenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl -Pyrrole-2,5-dione;

1-[[2-cyclopropyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;

1-[[2-cyclopentyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;

1-[[6-[(4-fluorophenyl) -2- (2-furyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;

1-[[6-[(4-fluorophenyl) -2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidin-4-yl] amino] -3 -Methyl-pyrrole-2,5-dione;

1-[[6-[(4-fluorophenyl) -2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2 , 5-dione;

1-[[2- (2-furyl) -5,6-dimethyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- (4-methoxyphenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione; And

Ethyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2-thiazol-5-yl-thieno [2,3-d] pyrimidine- It is to provide a compound selected from the group consisting of 6-carboxylate or a pharmaceutically acceptable salt thereof.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating solid cancer, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

Where

R ₁ is C 1 -C 6 alkyl unsubstituted or substituted with C 2 -C 10 hetero aryl including at least one hetero atom selected from the group consisting of N, O and S; C1-C6 alkyl substituted with C6-C12 aryl unsubstituted or substituted with C1-C6 alkoxy; Thiophene unsubstituted or substituted with C1-C6 alkyl; Furan; Pyrrole; Thiazole; C3-C7 cycloalkyl; Or C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylamino, amino, C1-C6 alkyl, hydroxy and halogen,

R ₂ is hydrogen; Straight or branched C1-C6 alkyl; C1-C6 alkoxycarbonyl; Thiophene; Or C1-C6 alkoxy, hydroxy, linear or branched C1-C6 alkyl, heterosubstituted or unsubstituted with C2-C10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S. C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of cycloalkyloxy and halogen,

이며, R ₃ is hydrogen; Cyano; C1-C6 alkoxy; C1-C6 alkoxycarbonyl; Aminocarbonyl; C3-C10 alkoxycarbonylalkyl; C3-C10 heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, O and S; Thiophene; C2-C10 hetero aryl unsubstituted or substituted with straight or branched C1-C6 alkyl or C3-C10 cycloalkyl; C1-C6 alkyl; C1-C6 alkyl substituted with C6-C12 aryl unsubstituted or substituted with hydroxy or C1-C6 alkoxy; C6-C12 aryl substituted with unsubstituted C1-C6 alkoxy; C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of hydroxy, nitro, halogen and cyano; or

Is,

R ₄ is C 1 -C 6 alkylamino unsubstituted or substituted with one or more selected from the group consisting of C 1 -C 6 alkylamino, hydroxy, C 1 -C 6 alkoxy, cyano and halogen; C2-C10 heterocycloalkyl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 aminoalkyl, C2-C10 alkylaminoalkyl and C2-C6 alkylcarbonyl; Amino; C2-C6 alkenylamino; C2-C6 alkynylamino; C2-C10 spiroheterocycloalkyl; And benzylamino is one or more selected from the group consisting of

N is an integer of 1 to 5.

In order to achieve the other object of the present invention, the present invention provides 1-[[6-[(4-fluorophenyl) -2- (2-furyl) -5-methyl-thieno [2,3-d] pyrimidine -4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6-[(4-fluorophenyl) -5-methyl-2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione;

1-[[6-[(4-fluorophenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl -Pyrrole-2,5-dione;

1-[[2-cyclopropyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;

1-[[2-cyclopentyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;

1-[[6-[(4-fluorophenyl) -2- (2-furyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;

1-[[6-[(4-fluorophenyl) -2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidin-4-yl] amino] -3 -Methyl-pyrrole-2,5-dione;

1-[[6-[(4-fluorophenyl) -2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2 , 5-dione;

1-[[2- (2-furyl) -5,6-dimethyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- (4-methoxyphenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione; And

Ethyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2-thiazol-5-yl-thieno [2,3-d] pyrimidine- It provides a compound selected from the group consisting of 6-carboxylate or a pharmaceutically acceptable salt thereof.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

The present invention provides a pharmaceutical composition for preventing or treating solid cancer, comprising the compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

Where

R ₁ is C 1 -C 6 alkyl unsubstituted or substituted with C 2 -C 10 hetero aryl including at least one hetero atom selected from the group consisting of N, O and S; C1-C6 alkyl substituted with C6-C12 aryl unsubstituted or substituted with C1-C6 alkoxy; Thiophene unsubstituted or substituted with C1-C6 alkyl; Furan; Pyrrole; Thiazole; C3-C7 cycloalkyl; Or C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylamino, amino, C1-C6 alkyl, hydroxy and halogen,

R ₂ is hydrogen; Straight or branched C1-C6 alkyl; C1-C6 alkoxycarbonyl; Thiophene; Or C1-C6 alkoxy, hydroxy, linear or branched C1-C6 alkyl, heterosubstituted or unsubstituted with C2-C10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S. C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of cycloalkyloxy and halogen,

이며, R ₃ is hydrogen; Cyano; C1-C6 alkoxy; C1-C6 alkoxycarbonyl; Aminocarbonyl; C3-C10 alkoxycarbonylalkyl; C3-C10 heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, O and S; Thiophene; C2-C10 hetero aryl unsubstituted or substituted with straight or branched C1-C6 alkyl or C3-C10 cycloalkyl; C1-C6 alkyl; C1-C6 alkyl substituted with C6-C12 aryl unsubstituted or substituted with hydroxy or C1-C6 alkoxy; C6-C12 aryl substituted with unsubstituted C1-C6 alkoxy; C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of hydroxy, nitro, halogen and cyano; or

Is,

R ₄ is C 1 -C 6 alkylamino unsubstituted or substituted with one or more selected from the group consisting of C 1 -C 6 alkylamino, hydroxy, C 1 -C 6 alkoxy, cyano and halogen; C2-C10 heterocycloalkyl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 aminoalkyl, C2-C10 alkylaminoalkyl and C2-C6 alkylcarbonyl; Amino; C2-C6 alkenylamino; C2-C6 alkynylamino; C2-C10 spiroheterocycloalkyl; And benzylamino is one or more selected from the group consisting of

N is an integer of 1 to 5.

According to an embodiment of the present invention, R ₁ is thiophene unsubstituted or substituted with methyl; Benzene unsubstituted or substituted with one or more selected from the group consisting of methoxy, dimethylamino, amino, methyl, hydroxy and fluoro; Furan; Pyrrole; Thiazole; Cyclopropane; Cyclopentane; Or methyl substituted with one or more selected from the group consisting of benzene, thiophene and methoxybenzene.

According to another embodiment of the present invention, R ₂ is hydrogen; C1-C2 alkyl; Ethoxycarbonyl; Thiophene; Or benzene unsubstituted or substituted with one or more selected from the group consisting of methoxy, hydroxy, methyl, morpholinoethoxy, piperazinylethoxy, piperidyloxy and fluoro.

According to another embodiment of the present invention, R ₃ is hydrogen; Methoxycarbonyl; Methoxy; Thiophene; Aminocarbonyl; Ethoxycarbonylethyl; Cyano; Ethoxycarbonyl; Morpholino; methyl; t-butyloxadiazolyl; Cyclohexyloxadiazolyl; Methyloxadiazolyl; Hydroxybenzyl; Methoxybenzyl; Or methoxy, hydroxy, nitro, aminoethoxy, (diethylamino) ethoxy, pyrrolidinylethoxy, (dimethylamino) ethoxy, (isopentylamino) ethoxy, (benzylamino) ethoxy, ( Piperidyl) ethoxy, morpholinoethoxy, (methyl (propyl) amino) ethoxy, thiomorpholinoethoxy, ((aminoethyl) piperazinyl) ethoxy, ((((dimethylamino) ethyl- Methyl) amino) ethoxy, ((dimethylaminoethyl) piperazinyl) ethoxy, acetylpiperazinylethoxy, (hydroxyethyl (methyl) amino) ethoxy, (methoxyethyl (methyl) amino) ethoxy , (1,4-dioxa-8-azaspiro [4,5] decanyl) ethoxy, methoxyethylaminoethoxy, cyanoethylaminoethoxy, trifluoroethylaminoethoxy, (buty-2 -Nylamino) ethoxy, allylaminoethoxy, fluoro and tetrahydrofuranylmethoxy may be one or more substituted or unsubstituted benzenes selected from the group consisting of The.

In the present invention, the compound of Formula 1 may be selected from the group consisting of the following compounds:

1-[[6-[(4-fluorophenyl) -2- (2-furyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione;

1-[[6-[(4-fluorophenyl) -5-methyl-2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione;

1-[[6-[(4-fluorophenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl -Pyrrole-2,5-dione;

1-[[2-cyclopropyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;

1-[[2-cyclopentyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;

1-[[6-[(4-fluorophenyl) -2- (2-furyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;

1-[[6-[(4-fluorophenyl) -2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidin-4-yl] amino] -3 -Methyl-pyrrole-2,5-dione;

1-[[6-[(4-fluorophenyl) -2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2 , 5-dione;

1-[[2- (2-furyl) -5,6-dimethyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- (4-methoxyphenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione;

Ethyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2-thiazol-5-yl-thieno [2,3-d] pyrimidine- 6-carboxylate;

1-[[5- (4-methoxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;

1-[[5- (4-hydroxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;

3-methyl-1-[[5- (p-tolyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;

3-methyl-1-[[5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;

Ethyl 4-[(3-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-5-carboxylate;

1-[[5- (3-hydroxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;

1-[[5- (3-methoxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;

3-methyl-1-[[5- [3- (2-morpholinoethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino ] Pyrrole-2,5-dione;

3-methyl-1-[[5- [3- (2-piperazin1-ylethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl ] Amino] pyrrole-2,5-dione;

3-methyl-1-[[5-phenyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;

1-[[2- (4-methoxyphenyl) -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[2- (3-methoxyphenyl) -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[2- [4- (dimethylamino) phenyl] -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ;

1-[[2- [4-aminophenyl] -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- [4-methoxyphenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione;

1-[[6- [4-hydroxyphenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione;

3-methyl-1-[[5-methyl-6-phenyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;

1-[[6- (3-hydroxyphenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione;

1-[[6- (4-methoxyphenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione;

Methyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6 Carboxylates;

1-[[6- (4-hydroxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;

1-[[6-methoxy-5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5- Diones;

3-methyl-1-[[5-methyl-6- (4-nitrophenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2 , 5-dione;

1-[[6- [4-hydroxyphenyl) methyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl -Pyrrole-2,5-dione;

1-[[6- [4- (2-aminoethoxy) phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino]- 3-methyl-pyrrole-2,5-dione;

1-[[6- [4- [2- (diethylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl ] Amino] -3-methyl-pyrrole-2,5-dione;

3-methyl-1-[[5-methyl-6- [4- (2-pyrrolidin-1-ylethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] pyrrole-2,5-dione;

1-[[6- [4- [2- (dimethylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] -Methyl-amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- [4- [2- (isopentylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl ] Amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- [4- [2- (benzylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione;

3-methyl-1-[[2-phenyl-5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;

1-[[2,5-bis (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[2- (4-methoxyphenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;

1-[[2- (3-methoxyphenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;

1-[[2- (2-furyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ;

3-methyl-1-[[2- (5-methyl-2-thienyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2 , 5-dione;

1-[[2-benzyl-5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

3-methyl-1-[[2- (p-tolyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;

1-[[2,6-bis (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

3-methyl-1-[[5- (2-thienyl) -2- (2-thienylmethyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5- Diones;

1-[[2- (4-hydroxyphenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;

3-methyl-1-[[5- (2-thienyl) -2- (3-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione ;

3-methyl-1-[[2- (2-thienyl) -5- (3-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione ;

3-methyl-1-[[5- (2-thienyl) -2- (3-thienylmethyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5- Diones;

1-[[2- (3-fluorophenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;

1-[[2-[(4-methoxyphenyl) methyl] -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole- 2,5-dione;

1-[[2- [4- (dimethylamino) phenyl] -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2 , 5-dione;

1-[[2-[(3-methoxyphenyl) methyl] -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole- 2,5-dione;

3-methyl-1-[[5-methyl-6- [4- [2- (1- (piperidyl) ethoxy] phenyl] -2- (2-thienyl) thieno [2,3-d ] Pyrimidin-4-yl] amino] pyrrole-2,5-dione;

1-[[2- (4-aminophenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5- Diones;

5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6- Carboxamide;

1-[[6- (3-methoxyphenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione;

Ethyl 3- [5-methyl-4-[(3-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyri Midin-6-yl] propanoate;

1-[[6-[(3-methoxyphenyl) methyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3- Methyl-pyrrole-2,5-dione;

3-methyl-1-[[5-methyl-6- [4- (2-morpholinoethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidine-4 -Yl] amino] pyrrole-2,5-dione;

3-methyl-1-[[5-methyl-6- [4- [2- [methyl (propyl) amino] ethoxy] phenyl] -2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] pyrrole-2,5-dione;

3-methyl-1-[[5-methyl-2- (2-thienyl) -6- [4- (2-thiopolynoethoxy) phenyl] thieno [2,3-d] pyrimidine-4 -Yl] amino] pyrrole-2,5-dione;

1-[[6- [4- [2- [4- (2-aminoethyl) piperazin-1-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2 , 3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- [4- [2- (dimethylamino) methoxy] phenyl] -5-ethyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- [4- [2- [2- (dimethylamino) ethyl-methyl-amino] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3- d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- [4- [2- [4- [2- (dimethylamino) ethyl] piperazin-1-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thier No [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- [4- [2- [4-acetylpiperazin-1-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- [4- [2- [2-hydroxyethyl (methyl) amino] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- [4- [2- [2-methoxyethyl (methyl) amino] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- [4- [2- [1,4-dioxa-8-azaspiro [4.5] decan-8-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl ) Thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- [4- [2- (2-methoxyethylamino)] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidine -4-yl] amino] -3-methyl-pyrrole-2,5-dione;

3- [2- [4- [5-methyl-4-[(3-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2, 3-d] pyrimidin-6-yl] phenoxy] ethylamino] propanenitrile;

3-methyl-1-[[5-methyl-2- (2-thienyl) -6- [4- [2- (2,2,2-trifluoroethylamino) ethoxy] phenyl] thieno [ 2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;

1-[[6- [4- [2- (butyn-2-ylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidine- 4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- [4- [2- (allylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- (4-fluorophenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione;

5-methyl-4- [5-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6-carbo Nitrile;

Ethyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6 Carboxylates;

3-methyl-1-[[5- [4- (4-piperidyloxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] Pyrrole-2,5-dione;

3-methyl-1-[[5-methyl-6-morpholino-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5- Diones;

1-[[6-[(4-fluorophenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;

1-[[6-[(4-methoxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;

1-[[2-[(4-fluorophenyl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ;

1-[[2-[(4-fluorophenyl) -6-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

3-methyl-1-[[5-methyl-6- [4- (tetrahydrofuran-2-ylmethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidine- 4-yl] amino] pyrrole-2,5-dione;

1-[[5-ethyl-6-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ;

1-[[5-[(4-fluorophenyl) -6-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione;

1-[[6- (5- ~ {tert} -butyl-1,3,4-oxadiazol-2-yl) -5-methyl-2- (2-thienyl) thieno [2,3- d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6- (5-cyclohexyl-1,3,4-oxadiazol-2-yl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidine -4-yl] amino] -3-methyl-pyrrole-2,5-dione;

3-methyl-1-[[5-methyl-6- [5-methyl-1,3,4-oxadiazol-2-yl] -2- (2-thienyl) thieno [2,3-d ] Pyrimidin-4-yl] amino] pyrrole-2,5-dione; And

3-methyl-1-[[6-methyl-5-phenyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione.

The structural formulas of the compounds of Formula 1 or salts thereof listed above are summarized in Table 1 below:

　

　

　

　

　

　

　

　

　

　

1-[[6- (4-methoxyphenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione; 　

Ethyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2-thiazol-5-yl-thieno [2,3-d] pyrimidine- 6-carboxylate 　

1-[[5- (4-methoxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; hydrochloride 　

1-[[5- (4-hydroxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 　

3-methyl-1-[[5- (p-tolyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 　

3-methyl-1-[[5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 　

Ethyl 4-[(3-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-5-carboxylate; Hydrochloride 　

1-[[5- (3-hydroxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 　

1-[[5- (3-methoxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 　

3-methyl-1-[[5- [3- (2-morpholinoethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino ] Pyrrole-2,5-dione; Hydrochloride 　

3-methyl-1-[[5- [3- (2-piperazin1-ylethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl ] Amino] pyrrole-2,5-dione; Hydrochloride 　

3-methyl-1-[[5-phenyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 　

1-[[2- (4-methoxyphenyl) -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[2- (3-methoxyphenyl) -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[2- [4- (dimethylamino) phenyl] -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ; Hydrochloride 　

1-[[2- [4-aminophenyl] -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4-methoxyphenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione; Hydrochloride 　

1-[[6- [4-hydroxyphenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione; Hydrochloride 　

3-methyl-1-[[5-methyl-6-phenyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 　

1-[[6- (3-hydroxyphenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione; 　

1-[[6- (4-methoxyphenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione; Hydrochloride 　

Methyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6 Carboxylates; Hydrochloride 　

1-[[6- (4-hydroxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 　

1-[[6-methoxy-5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5- Diones; Hydrochloride 　

3-methyl-1-[[5-methyl-6- (4-nitrophenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2 , 5-dione; Hydrochloride 　

1-[[6- [4-hydroxyphenyl) methyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl -Pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- (2-aminoethoxy) phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino]- 3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- (diethylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl ] Amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

3-methyl-1-[[5-methyl-6- [4- (2-pyrrolidin-1-ylethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- (dimethylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] -Methyl-amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- (isopentylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl ] Amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- (benzylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

3-methyl-1-[[2-phenyl-5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 　

1-[[2,5-bis (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[2- (4-methoxyphenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 　

1-[[2- (3-methoxyphenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 　

1-[[2- (2-furyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ; Hydrochloride

3-methyl-1-[[2-phenyl-5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; 　

3-methyl-1-[[2- (5-methyl-2-thienyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2 , 5-dione; Hydrochloride 　

1-[[2-benzyl-5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

3-methyl-1-[[2- (p-tolyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 　

1-[[2,6-bis (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

3-methyl-1-[[5- (2-thienyl) -2- (2-thienylmethyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5- Diones; Hydrochloride 　

1-[[2- (4-hydroxyphenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 　

3-methyl-1-[[5- (2-thienyl) -2- (3-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione ; Hydrochloride 　

3-methyl-1-[[2- (2-thienyl) -5- (3-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione ; Hydrochloride 　

3-methyl-1-[[5- (2-thienyl) -2- (3-thienylmethyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5- Diones; Hydrochloride 　

1-[[2- (3-fluorophenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 　

1-[[2-[(4-methoxyphenyl) methyl] -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole- 2,5-dione; Hydrochloride 　

1-[[2- [4- (dimethylamino) phenyl] -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2 , 5-dione; Hydrochloride 　

1-[[2-[(3-methoxyphenyl) methyl] -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole- 2,5-dione; Hydrochloride 　

3-methyl-1-[[5-methyl-6- [4- [2- (1- (piperidyl) ethoxy] phenyl] -2- (2-thienyl) thieno [2,3-d ] Pyrimidin-4-yl] amino] pyrrole-2,5-dione; hydrochloride 　

1-[[2- (4-aminophenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5- Diones; Hydrochloride 　

5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6- Carboxamide; Hydrochloride 　

1-[[6- (3-methoxyphenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione; Hydrochloride 　

Ethyl 3- [5-methyl-4-[(3-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyri Midin-6-yl] propanoate; 　

1-[[6-[(3-methoxyphenyl) methyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3- Methyl-pyrrole-2,5-dione; Hydrochloride 　

3-methyl-1-[[5-methyl-6- [4- (2-morpholinoethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidine-4 -Yl] amino] pyrrole-2,5-dione; Hydrochloride 　

3-methyl-1-[[5-methyl-6- [4- [2- [methyl (propyl) amino] ethoxy] phenyl] -2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 　

3-methyl-1-[[5-methyl-2- (2-thienyl) -6- [4- (2-thiopolynoethoxy) phenyl] thieno [2,3-d] pyrimidine-4 -Yl] amino] pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- [4- (2-aminoethyl) piperazin-1-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2 , 3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- (dimethylamino) methoxy] phenyl] -5-ethyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- [2- (dimethylamino) ethyl-methyl-amino] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3- d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- [4- [2- (dimethylamino) ethyl] piperazin-1-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thier No [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- [4-acetylpiperazin-1-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- [2-hydroxyethyl (methyl) amino] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- [2-methoxyethyl (methyl) amino] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- [1,4-dioxa-8-azaspiro [4.5] decan-8-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl ) Thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- (2-methoxyethylamino)] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidine -4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

3- [2- [4- [5-methyl-4-[(3-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2, 3-d] pyrimidin-6-yl] phenoxy] ethylamino] propanenitrile; Hydrochloride 　

3-methyl-1-[[5-methyl-2- (2-thienyl) -6- [4- [2- (2,2,2-trifluoroethylamino) ethoxy] phenyl] thieno [ 2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- (butyn-2-ylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidine- 4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- [4- [2- (allylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 　

1-[[6- (4-fluorophenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione; 　

5-methyl-4- [5-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6-carbo Nitrile; 　

Ethyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6 Carboxylate 　

3-methyl-1-[[5- [4- (4-piperidyloxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] Pyrrole-2,5-dione; Hydrochloride 　

3-methyl-1-[[5-methyl-6-morpholino-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5- Diones; 　

1-[[6-[(4-fluorophenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione; 　

1-[[6-[(4-methoxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione; 　

1-[[2-[(4-fluorophenyl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ; 　

1-[[2-[(4-fluorophenyl) -6-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; 　

3-methyl-1-[[5-methyl-6- [4- (tetrahydrofuran-2-ylmethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidine- 4-yl] amino] pyrrole-2,5-dione; 　

1-[[5-ethyl-6-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ; 　

1-[[5-[(4-fluorophenyl) -6-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione; 　

1-[[6- (5- ~ {tert} -butyl-1,3,4-oxadiazol-2-yl) -5-methyl-2- (2-thienyl) thieno [2,3- d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; 　

1-[[6- (5-cyclohexyl-1,3,4-oxadiazol-2-yl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidine -4-yl] amino] -3-methyl-pyrrole-2,5-dione; 　

3-methyl-1-[[5-methyl-6- [5-methyl-1,3,4-oxadiazol-2-yl] -2- (2-thienyl) thieno [2,3-d ] Pyrimidin-4-yl] amino] pyrrole-2,5-dione; 　

3-methyl-1-[[6-methyl-5-phenyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;

The compound represented by Formula 1 of the present invention may be prepared as a pharmaceutically acceptable salt or solvate according to a conventional method in the art.

Meanwhile, as the salt of the compound represented by Formula 1, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.

In this case, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like. It doesn't work.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. In this case, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salts, but is not limited thereto.

Corresponding silver salts may also be obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).

Pharmaceutically acceptable salts of the compounds of formula 1 of the present invention include salts of acidic or basic groups which may be present in compounds of formula 1 unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfates, hydrogen sulphates, phosphates, hydrogen phosphates, Dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts and the like. It can be manufactured through the manufacturing process.

In addition, since the compound of Formula 1 has an asymmetric center and may exist in different enantiomeric forms, all optical isomers and R or S type stereoisomers and mixtures thereof of the compound of Formula 1 are also included in the scope of the present invention.

The present invention encompasses the use of racemates, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof, and includes methods or processes for the separation of isomers known in the art.

On the other hand, according to an embodiment of the present invention, the compound of Formula 1 or a pharmaceutically acceptable salt thereof is very excellent in inhibiting the binding of AIMP2-DX2 and K-Ras, K-Ras protein in cancer cells It was judged that the effect of reducing the level of and suppressing the development and progression of cancer could be considered.

In the present invention, the solid cancer is preferably colon cancer, colon cancer, lung cancer, liver cancer, stomach cancer, esophageal cancer, pancreatic cancer, gallbladder cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer, chorionic cancer, ovarian cancer, breast cancer , Thyroid cancer, brain cancer, head and neck cancer, and malignant melanoma.

In addition, in the present invention, since the compound of Formula 1 exhibits an activity that directly inhibits the binding of AIMP2-DX2 and K-Ras, the compound of Formula 1 may exhibit an excellent therapeutic effect against solid cancers overexpressing AIMP2-DX2.

The pharmaceutical composition according to the present invention may contain the compound of Formula 1 or a pharmaceutically acceptable salt thereof alone or may further contain one or more pharmaceutically acceptable carriers, excipients or diluents.

Pharmaceutically acceptable carriers may further include, for example, carriers for oral administration or carriers for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. In addition, carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose and glycols, and the like, and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Other pharmaceutically acceptable carriers may be referred to those described in the following documents (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).

The pharmaceutical composition of the present invention can be administered to any mammal, including humans. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration. Can be. For example, the pharmaceutical composition of the present invention can be prepared in an injectable formulation and administered by lightly pricking the skin with a 30 gauge thin needle or by applying it directly to the skin.

The pharmaceutical composition of the present invention may be formulated into a preparation for oral or parenteral administration according to the route of administration as described above.

In the case of preparations for oral administration, the compositions of the present invention may be formulated using methods known in the art as powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions and the like. Can be. For example, oral formulations can be obtained by tablets or dragees by combining the active ingredients with solid excipients and then grinding them, adding suitable auxiliaries and processing them into granule mixtures. Examples of suitable excipients include sugars, including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol and starch, cellulose, including starch, corn starch, wheat starch, rice starch and potato starch, and the like. Fillers such as cellulose, gelatin, polyvinylpyrrolidone, and the like, including methyl cellulose, sodium carboxymethylcellulose, hydroxypropylmethyl-cellulose, and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid or sodium alginate and the like may optionally be added as a disintegrant. Furthermore, the pharmaceutical composition of the present invention may further include an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, a preservative, and the like.

Formulations for parenteral administration may be formulated by methods known in the art in the form of injections, creams, lotions, external ointments, oils, humectants, gels, aerosols and nasal inhalants. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a prescription generally known in all pharmaceutical chemistries.

The total effective amount of the pharmaceutical composition of the present invention may be administered to a patient in a single dose and may be administered by a fractionated treatment protocol which is administered in multiple doses for a long time. . The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the extent of the disease. Preferably, the total dose of the pharmaceutical composition of the present invention may be about 0.01 ug to 1,000 mg, most preferably 0.1 ug to 100 mg per kg of patient body weight per day. However, the dosage of the pharmaceutical composition of the present invention is effective for the patient in consideration of various factors such as the age, weight, health condition, sex, severity of the disease, diet and excretion rate, as well as the route and frequency of treatment. In this regard, one of ordinary skill in the art will be able to determine an appropriate effective dosage according to the specific use of the pharmaceutical composition of the present invention as a therapeutic agent for neurodegenerative diseases. The pharmaceutical composition according to the present invention is not particularly limited to its formulation, route of administration and method of administration as long as the effect of the present invention is shown.

In the present invention, the term 'treatment' refers generically to ameliorating symptoms related to solid cancer, which may preferably include curing, substantially preventing, or ameliorating a solid cancer overexpressing AIMP2-DX2. And alleviating, healing or preventing one or most of the symptoms resulting from these solid cancers.

The present invention is also a novel compound that inhibits the binding of AIMP2-DX2 and K-Ras,

1-[[6-[(4-fluorophenyl) -2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidin-4-yl] amino] -3 -Methyl-pyrrole-2,5-dione;

1-[[6-[(4-fluorophenyl) -2- (2-furyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;

1-[[2- (2-furyl) -5,6-dimethyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;

1-[[6-[(4-fluorophenyl) -5-methyl-2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione;

1-[[2-cyclopropyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;

1-[[6-[(4-fluorophenyl) -2- (2-furyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione;

1-[[6-[(4-fluorophenyl) -2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2 , 5-dione;

1-[[6-[(4-fluorophenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl -Pyrrole-2,5-dione;

1-[[2-cyclopentyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;

1-[[6- (4-methoxyphenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione; And

Ethyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2-thiazol-5-yl-thieno [2,3-d] pyrimidine- It provides a compound selected from the group consisting of 6-carboxylate or a pharmaceutically acceptable salt thereof.

Compound represented by the formula (1) according to the present invention by inhibiting the binding of AIMP2-DX2 and K-Ras lowers the level of K-Ras protein in cancer cells and is very excellent in inhibiting the development and progression of cancer, AIMP2 It can be very useful for the prevention or treatment of solid cancer overexpressing DX2.

Hereinafter, the present invention will be described in detail.

However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

<Example 1>

Preparation of the compound

All chemical reagents and solutions used in this example were purchased from commercial vendors and used without further purification. All reactions were observed using thin layer chromatography on silica gel 60 F ₂₅₄ (Merck, Mumbai, India) and UV light (254 nm and 365 nm). ¹ H NMR spectra were identified with a Varian 400 Mercury Plus spectrometer (Varian, PaloAlto, CA, USA) at 400 MHz. The unit of chemical shift was δ (ppm) and was based on tetramethylsilane (TMS). High resolution mass spectra were measured by electrosprayionization (ESI) using an Agilent 6530 series accurate-mass Q-TOF LC / MS system (Agilent, Santa Clara, Ca, USA).

The preparation results and the analytical results of the compounds for Examples 1-1 to 1-11 are shown below:

Scheme 1

R ₁ , R ₂ and R ₃ in Scheme 1 are as defined in Chemical Formula 1.

Scheme 1 shows a process for preparing a thienopyrimidine compound (8a-8k) using a ketone compound which can be easily obtained commercially or prepared in a general manner.

In the first step, ethyl 2-aminothiophen-3-carboxylate and commercially available ketones or aldehydes are dissolved in ethanol or dimethylamide solvent, sulfur is added, morpholine, triethylamine, piperidine and the like. Compound (3a-3e) was prepared by Gewald reaction using a base of. At this time, the reaction temperature was performed by heating to about 60 ℃.

In the second step, the compound (3a-3e) prepared in the first step and the commercially available carbonitrile compound (4a-4e) are reacted at 60 ° C and acidic conditions in a 1,4-dioxane solvent. Compound (5a-5k) was prepared.

In the third step, compound (6a-6k) was prepared by refluxing the compound (5a-5k) prepared in the second step in a phosphorus oxychloride solution.

In the fourth step, the chloro compound (6a-6k) obtained in the third step is dissolved in an organic solvent such as tetrahydrofuran and then reacted while slowly adding hydrazine hydrate to prepare a hydrazine compound (7a-7k). The reaction temperature at this time was preferably performed under reflux.

In the fifth step, the hydrazine compound (7a-7k) obtained in step 4 was dissolved in a chloroform solvent, citraconic anhydride was added and the final derivative (8a-8k) was prepared through reflux.

1.1. Preparation of Thieno [2,3-d] pyrimidin-4 (3H) -one Intermediate 3a-e

Compounds 3c and 3e were purchased from Tokyo chemical industry (TCI) and used.

1.1.1. Ethyl 2-amino-5- (4-fluorophenyl) -4-methylthiophen-3-carboxylate (3a)

1- (4-fluorophenyl) propan-2-one (3.3 g, 21. 9 mmol), ethylcyanoacetate (3.7 g, 32.8 mmol), sulfur (350 mg, 1.37 mmol), and piperidine ( 2.8 g, 32.8 mmol) was stirred in ethanol (5 mL) at 60 ° C. overnight. The reaction mixture was cooled down and concentrated at reduced pressure. The residue was purified by flash column chromatography (EtOAc: hexane = 1: 7) to give compound 3a (yellow oil) as a yellow liquid.

ESI (m / z) 280 (MH ⁺ ).

1.1.2. Ethyl 2-amino-5- (4-fluorophenyl) thiophene-3-carboxylate (3b)

Preparation method using 2- (4-fluorophenyl) acetaldehyde as a starting material 1.1.1. The reaction was carried out in the same manner to obtain the target compound 3b.

ESI (m / z) 266 (MH ⁺ ).

1.1.3. Ethyl 2-amino-5- (4-methoxyphenyl) -4methylthiophen-3-carboxylate (3d)

Preparation method using 1- (3-methoxyphenyl) propan-2-one as starting material 1.1.1. The reaction was carried out in the same manner as to obtain the target compound 3d.

1.2. Preparation of thieno [2,3-d] pyrimidin-4 (3H) -one intermediate 5a-5k

A mixture of ethyl 2-aminothiophen-3-carboxylate intermediate 3 (2.34 mmol) and carbonitrile intermediate 4 (2.57 mmol) in 4M HCl 1,4-dioxane solution (15 ml) was It was stirred overnight at 60 ° C. under argon gas conditions. The reaction mixture was cooled down and concentrated under reduced pressure. The reaction residue was triturated with diethyl ether and filtered. The resulting compound 5a-5k was dried in vacuo and used in the next step without further purification.

1.3. Preparation of Thieno [2,3-d] pyrimidine Derivatives 8a-8k

The reaction compound 5 (1.87 mmol) in 4 ml of phosphoryl chloride was refluxed overnight. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc: hexane = 1: 7) to give compound 6a-6k. The compound was stirred at room temperature in tetrahydrofuran (2 ml) solvent and hydrazine monohydrate (0.26 mmol) was added dropwise. The reaction mixture was refluxed overnight. After completion of the reaction, cooling and concentration under reduced pressure. Results Compounds 7a-7k were used in the next step without further purification. Compound 7 and citraconic anhydride (0.14 mmol) in chloroform (2 ml) were refluxed overnight. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc: hexane = 1: 1) to give compounds 8a-8k.

Example 1-1 1-[[6- (4-fluorophenyl) -2- (2-furyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino ] -3-methyl-pyrrole-2,5-dione (8a)

1 H NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1 H), 7.82 (s, 1 H), 7.59 (q, J = 5.6 Hz, 2H), 7.35 (t, J = 8.8 Hz, 2H), 6.95 (d, J = 1.6 Hz, 1H), 6.90 (d, J = 3.2 Hz, 1H), 6.60 (m, 1H), 2.58 (s, 3H), 2.14 (s, 3H).

Example 1-2 1-[[6- (4-fluorophenyl) -5-methyl-2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyri Midin-4-yl] amino] -3-methyl-pyrrole-2,5-dione (8b)

1 H NMR (400 MHz, DMSO-d6): δ 11.58 (s, 1 H), 9.42 (s, 1 H), 7.58 (q,

J = 5.6 Hz, 2H), 7.34 (t, J = 8.8 Hz, 2H), 6.95 (d, J = 1.2 Hz, 1H), 6.86 (s, 1H), 6.51 (s,

1H), 6.08 (m, 1H), 2.57 (s, 3H), 2.14 (s, 3H)

Example 1-3 1-[[6- (4-Fluorophenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione (8c)

1 H NMR (400 MHz, DMSO-d6): δ 9.74 (s, 1 H), 9.13 (s, 1 H), 8.33 (s, 1 H), 7.60 (q, J = 5.6 Hz, 2H), 7.36 (t, J = 8.8 Hz, 2H), 6.99 (m, 1H), 2.59 (s, 3H), 2.17 (s, 3H).

Example 1-4 1-[[2-cyclopropyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3 -Methyl-pyrrole-2,5-dione (8d)

1 H NMR (400 MHz, DMSO-d6): δ 9.49 (s, 1H), 7.63-7.58 (m, 2H), 7.41-7.35 (m, 2H), 6.95 (d, J = 1.8 Hz, 1H), 2.58 ( s, 3H), 2.15 (d, J = 1.8 Hz, 3H), 2.01-1.92 (m, 1H), 0.92 (q, J = 3.3 Hz, 2H), 0.67 (q, J = 4.2 Hz, 2H).

Example 1-5 1-[[2-cyclopentyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3 -Methyl-pyrrole-2,5-dione (8e)

1 H NMR (400 MHz, DMSO-d6): δ 9.50 (s, 1H), 7.62-7.57 (m, 2H), 7.40-7.34 (m, 2H), 6.94 (d, J = 1.8 Hz, 1H), 3.15- 3.05 (m, 1H), 2.59 (s, 3H), 2.12 (d, J = 1.8 Hz, 3H), 1.90-1.83 (m, 2H), 1.63-1.55 (m, 6H).

Example 1-6 1-[[6- (4-fluorophenyl) -2- (2-furyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl -Pyrrole-2,5-dione (8f)

1 H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1 H), 7.92 (s, 1 H), 7.82 (s, 1 H), 7.73 (q, J = 5.2 Hz, 2H), 7.34 (t, J = 8.8 Hz, 2H), 6.95 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 3.2 Hz, 1H), 6.60 (q, J = 1.6 Hz, 1H), 2.13 (s, 3H).

Example 1-7 1-[[6- (4-fluorophenyl) -2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidine-4- Yl] amino] -3-methyl-pyrrole-2,5-dione (8 g)

1 H NMR (400 MHz, DMSO-d6): δ 11.55 (s, 1 H), 10.47 (s, 1 H), 7.87 (s, 1 H), 7.72 (q, J = 5.2 Hz, 2 H), 6.94 (m, 1 H) , 6.86 (m, 1 H), 6.53 (m, 1 H), 6.09-6.08 (m, 1 H), 2.13 (s, 3 H)

Example 1-8 1-[[6- (4-fluorophenyl) -2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidine-4- Yl] amino] -3-methyl-pyrrole-2,5-dione (8h)

1 H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1 H), 9.13 (s, 1 H), 8.33 (s, 1 H), 7.94 (s, 1 H), 7.74 (q, J = 5.6 Hz, 2 H) , 7.36 (t, J = 8.8 Hz, 2H), 6.99 (m, 1H), 2.15 (s, 3H)

Example 1-9 1-[[2- (2-furyl) -5,6-dimethyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole 2,5-dione (8i)

1 H NMR (400 MHz, DMSO-d6): δ 9.42 (s, 1 H), 7.79 (s, 1 H), 6.93 (s, 1 H), 6.84 (d, J = 3.2 Hz, 1 H), 6.57 (m, 1 H) ), 2.48 (s, 3H), 2.42 (s, 3H), 2.13 (s, 3H); HRMS (ESI) calculated for C 29 H 21 FN 4 O 3 S 2 [MH +]: 557.1112, detected: 557.1073.

Example 1-10 1-[[6- (4-methoxyphenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione (8j)

1 H NMR (400 MHz, DMSO-d6): δ 9.74 (s, 1H), 9.17 (d, J = 0.4 Hz, 1H), 8.36 (d, J = 0.6 Hz, 1H), 7.52 (d, J = 8.8 Hz , 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 1.6 Hz, 1H), 3.84 (s, 3H), 2.64 (s, 3H), 2.21 (d, J = 1.6 Hz , 3H).

Example 1-11 Ethyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2-thiazol-5-yl-thieno [2, 3-d] pyrimidine-6-carboxylate (8k)

1 H NMR (400 MHz, DMSO-d6): δ 9.97 (s, 1H), 9.17 (s, 1H), 8.36 (s, 1H), 7.00 (s, 1H), 4.32 (q, J = 7.0 Hz, 2H ), 2.95 (s, 3H), 2.16 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H).

Examples 1-12 to 1-98 compounds are listed below, and these compounds were prepared with reference to Korean Patent Publication No. 10-2016-0138136:

Example IUPAC Name 1-12 1-[[5- (4-methoxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; hydrochloride 1-13 1-[[5- (4-hydroxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 1-14 3-methyl-1-[[5- (p-tolyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 1-15 3-methyl-1-[[5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 1-16 Ethyl 4-[(3-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-5-carboxylate; Hydrochloride 1-17 1-[[5- (3-hydroxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 1-18 1-[[5- (3-methoxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 1-19 3-methyl-1-[[5- [3- (2-morpholinoethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino ] Pyrrole-2,5-dione; Hydrochloride 1-20 3-methyl-1-[[5- [3- (2-piperazin1-ylethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl ] Amino] pyrrole-2,5-dione; Hydrochloride 1-21 3-methyl-1-[[5-phenyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 1-22 1-[[2- (4-methoxyphenyl) -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-23 1-[[2- (3-methoxyphenyl) -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-24 1-[[2- [4- (dimethylamino) phenyl] -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ; Hydrochloride 1-25 1-[[2- [4-aminophenyl] -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-26 1-[[6- [4-methoxyphenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione; Hydrochloride 1-27 1-[[6- [4-hydroxyphenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione; Hydrochloride 1-28 3-methyl-1-[[5-methyl-6-phenyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 1-29 1-[[6- (3-hydroxyphenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione; 1-30 1-[[6- (4-methoxyphenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione; Hydrochloride 1-31 Methyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6 Carboxylates; Hydrochloride 1-32 1-[[6- (4-hydroxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 1-33 1-[[6-methoxy-5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5- Diones; Hydrochloride 1-34 3-methyl-1-[[5-methyl-6- (4-nitrophenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2 , 5-dione; Hydrochloride 1-35 1-[[6- [4-hydroxyphenyl) methyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl -Pyrrole-2,5-dione; Hydrochloride 1-36 1-[[6- [4- (2-aminoethoxy) phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino]- 3-methyl-pyrrole-2,5-dione; Hydrochloride 1-37 1-[[6- [4- [2- (diethylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl ] Amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-38 3-methyl-1-[[5-methyl-6- [4- (2-pyrrolidin-1-ylethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 1-39 1-[[6- [4- [2- (dimethylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] -Methyl-amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-40 1-[[6- [4- [2- (isopentylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl ] Amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-41 1-[[6- [4- [2- (benzylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-42 3-methyl-1-[[2-phenyl-5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 1-43 1-[[2,5-bis (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-44 1-[[2- (4-methoxyphenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 1-45 1-[[2- (3-methoxyphenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 1-46 1-[[2- (2-furyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ; Hydrochloride 1-47 3-methyl-1-[[2-phenyl-5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; 1-48 3-methyl-1-[[2- (5-methyl-2-thienyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2 , 5-dione; Hydrochloride 1-49 1-[[2-benzyl-5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-50 3-methyl-1-[[2- (p-tolyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 1-51 1-[[2,6-bis (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-52 3-methyl-1-[[5- (2-thienyl) -2- (2-thienylmethyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5- Diones; Hydrochloride 1-53 1-[[2- (4-hydroxyphenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 1-54 3-methyl-1-[[5- (2-thienyl) -2- (3-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione ; Hydrochloride 1-55 3-methyl-1-[[2- (2-thienyl) -5- (3-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione ; Hydrochloride 1-56 3-methyl-1-[[5- (2-thienyl) -2- (3-thienylmethyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5- Diones; Hydrochloride 1-57 1-[[2- (3-fluorophenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione; Hydrochloride 1-58 1-[[2-[(4-methoxyphenyl) methyl] -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole- 2,5-dione; Hydrochloride 1-59 1-[[2- [4- (dimethylamino) phenyl] -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2 , 5-dione; Hydrochloride 1-60 1-[[2-[(3-methoxyphenyl) methyl] -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole- 2,5-dione; Hydrochloride 1-61 3-methyl-1-[[5-methyl-6- [4- [2- (1- (piperidyl) ethoxy] phenyl] -2- (2-thienyl) thieno [2,3-d ] Pyrimidin-4-yl] amino] pyrrole-2,5-dione; hydrochloride 1-62 1-[[2- (4-aminophenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5- Diones; Hydrochloride 1-63 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6- Carboxamide; Hydrochloride 1-64 1-[[6- (3-methoxyphenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione; Hydrochloride 1-65 Ethyl 3- [5-methyl-4-[(3-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyri Midin-6-yl] propanoate; 1-66 1-[[6-[(3-methoxyphenyl) methyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3- Methyl-pyrrole-2,5-dione; Hydrochloride 1-67 3-methyl-1-[[5-methyl-6- [4- (2-morpholinoethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidine-4 -Yl] amino] pyrrole-2,5-dione; Hydrochloride 1-68 3-methyl-1-[[5-methyl-6- [4- [2- [methyl (propyl) amino] ethoxy] phenyl] -2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 1-69 3-methyl-1-[[5-methyl-2- (2-thienyl) -6- [4- (2-thiopolynoethoxy) phenyl] thieno [2,3-d] pyrimidine-4 -Yl] amino] pyrrole-2,5-dione; Hydrochloride 1-70 1-[[6- [4- [2- [4- (2-aminoethyl) piperazin-1-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2 , 3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-71 1-[[6- [4- [2- (dimethylamino) methoxy] phenyl] -5-ethyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-72 1-[[6- [4- [2- [2- (dimethylamino) ethyl-methyl-amino] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3- d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-73 1-[[6- [4- [2- [4- [2- (dimethylamino) ethyl] piperazin-1-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thier No [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-74 1-[[6- [4- [2- [4-acetylpiperazin-1-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-75 1-[[6- [4- [2- [2-hydroxyethyl (methyl) amino] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-76 1-[[6- [4- [2- [2-methoxyethyl (methyl) amino] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-77 1-[[6- [4- [2- [1,4-dioxa-8-azaspiro [4.5] decan-8-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl ) Thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-78 1-[[6- [4- [2- (2-methoxyethylamino)] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidine -4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-79 3- [2- [4- [5-methyl-4-[(3-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2, 3-d] pyrimidin-6-yl] phenoxy] ethylamino] propanenitrile; Hydrochloride 1-80 3-methyl-1-[[5-methyl-2- (2-thienyl) -6- [4- [2- (2,2,2-trifluoroethylamino) ethoxy] phenyl] thieno [ 2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione; Hydrochloride 1-81 1-[[6- [4- [2- (butyn-2-ylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidine- 4-yl] amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-82 1-[[6- [4- [2- (allylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione; Hydrochloride 1-83 1-[[6- (4-fluorophenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione; 1-84 5-methyl-4- [5-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6-carbo Nitrile; 1-85 Ethyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6 Carboxylate 1-86 3-methyl-1-[[5- [4- (4-piperidyloxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] Pyrrole-2,5-dione; Hydrochloride 1-87 3-methyl-1-[[5-methyl-6-morpholino-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5- Diones; 1-88 1-[[6-[(4-fluorophenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione; 1-89 1-[[6-[(4-methoxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione; 1-90 1-[[2-[(4-fluorophenyl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ; 1-91 1-[[2-[(4-fluorophenyl) -6-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; 1-92 3-methyl-1-[[5-methyl-6- [4- (tetrahydrofuran-2-ylmethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidine- 4-yl] amino] pyrrole-2,5-dione; 1-93 1-[[5-ethyl-6-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ; 1-94 1-[[5-[(4-fluorophenyl) -6-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione; 1-95 1-[[6- (5- ~ {tert} -butyl-1,3,4-oxadiazol-2-yl) -5-methyl-2- (2-thienyl) thieno [2,3- d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione; 1-96 1-[[6- (5-cyclohexyl-1,3,4-oxadiazol-2-yl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidine -4-yl] amino] -3-methyl-pyrrole-2,5-dione; 1-97 3-methyl-1-[[5-methyl-6- [5-methyl-1,3,4-oxadiazol-2-yl] -2- (2-thienyl) thieno [2,3-d ] Pyrimidin-4-yl] amino] pyrrole-2,5-dione; 1-98 3-methyl-1-[[6-methyl-5-phenyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;

<Example 2>

Evaluation of the Inhibitory Activity of AIMP2-DX2 and K-Ras Binding

Whether the compounds of Examples 1-1 to 1-98 exhibited the activity of inhibiting the binding of AIMP2-DX2 and K-Ras was evaluated according to the following method.

1. CHO-K cells (ATCC) were cultured in RPMI-1640 (Hyclone, GE lifesciences) medium containing 10% FBS (Fetal bovine serum, Hyclone, GE lifesciences), 1% penicillin (Hyclone, GE lifesciences). Each cell was incubated under conditions of 5% CO ₂ , 37 ° C.

2. AIMP2-DX2 and Kras genes were cloned into pBiT1.1-N [TK / LgBiT] Vector and pBiT2.1-N [TK / SmBiT] vectors, respectively, and transformed into CHO-K cells using Turibofect (Thermo scientific). Infection was performed.

3. After culturing the transfected CHO-K cells at 5% CO ₂ , 37 ° C. for one day, the cells were washed, trypsin removed and seeded at 25,000 cell / well in a 96 well plate (Corning). It was.

4. After one day, each of the compounds of Examples 1-1 to 1-98 dissolved in DMSO in serum-free medium was diluted, and the prepared cells were incubated at a concentration of 3 μM for 4 hours.

5. Add nano-Glo (Promega) luciferase substrate and buffer to each well, mix well, and incubate for another 10 minutes. Luminescence was detected with a Luminometer (Glomax 96 microplate luminometer, Promega). The binding inhibitory activity of AIMP2-DX2 and K-Ras was evaluated by comparing the negative control group treated with DMSO and the compound treated group in each well.

The results are shown in Table 3 below.

Inhibition rate of AIMP2-DX2 and K-Ras binding (%, 3 μM) Example Inhibitory effect (%) Example Inhibitory effect (%) Example Inhibitory effect (%) 1-1 99.0 1-34 93.6 1-67 94.2 1-2 99.7 1-35 97.7 1-68 97.0 1-3 93.6 1-36 96.2 1-69 96.8 1-4 99.4 1-37 91.3 1-70 85.0 1-5 99.5 1-38 88.1 1-71 95.0 1-6 99.2 1-39 95.3 1-72 97.2 1-7 99.1 1-40 99.1 1-73 94.8 1-8 85.6 1-41 94.5 1-74 91.4 1-9 91.3 1-42 99.6 1-75 93.3 1-10 95.2 1-43 99.1 1-76 97.4 1-11 88.9 1-44 96.3 1-77 97.6 1-12 98.6 1-45 94.6 1-78 98.8 1-13 92.4 1-46 98.9 1-79 95.7 1-14 98.4 1-47 99.8 1-80 90.1 1-15 93.0 1-48 99.5 1-81 99.1 1-16 96.7 1-49 97.5 1-82 97.8 1-17 99.0 1-50 99.7 1-83 99.9 1-18 98.3 1-51 99.4 1-84 90.3 1-19 96.7 1-52 91.7 1-85 99.8 1-20 88.8 1-53 99.3 1-86 98.1 1-21 96.9 1-54 96.7 1-87 95.9 1-22 98.1 1-55 94.8 1-88 99.0 1-23 96.8 1-56 96.7 1-89 99.4 1-24 94.3 1-57 99.6 1-90 99.5 1-25 97.8 1-58 95.3 1-91 99.0 1-26 97.1 1-59 93.9 1-92 88.8 1-27 96.2 1-60 98.2 1-93 99.8 1-28 97.7 1-61 97.8 1-94 97.9 1-29 99.1 1-62 98.0 1-95 98.7 1-30 97.8 1-63 97.6 1-96 99.6 1-31 97.7 1-64 99.5 1-97 89.2 1-32 96.0 1-65 99.5 1-98 98.1 1-33 98.4 1-66 99.8

As can be seen in Table 1, it was confirmed that most of the compounds showed a high inhibition rate of 90% or more, and all compounds more than 85% of AIMP2-DX2 and K-Ras.

On the other hand, after diluting each compound in 1/3 dilution from 3 μM to 0.15 nM by the same method as described above, AIMP2-DX2 and K-Ras binding inhibition IC50 value was calculated and shown in Table 4 below.

Inhibitory Effect of AIMP2-DX2 and K-Ras Coupling (IC50) Example Inhibitory effect IC50 (μM) Example Inhibitory effect IC50 (μM) Example Inhibitory effect IC50 (μM) 1-1 0.0442 1-34 0.6081 1-69 1.3470 1-2 0.4553 1-35 0.9573 1-71 1.6950 1-3 0.7273 1-36 2.2630 1-72 2.1120 1-4 0.8518 1-37 1.7130 1-73 1.9440 1-5 0.6081 1-38 1.7730 1-74 2.0260 1-6 0.5412 1-39 1.2980 1-75 1.7640 1-7 0.8384 1-40 1.3050 1-76 1.9890 1-8 2.618 1-41 1.0140 1-77 1.0650 1-9 0.2482 1-42 0.3020 1-78 3.1590 1-10 1.6170 1-43 0.2538 1-79 1.5350 1-11 2.5400 1-44 0.8180 1-80 0.9617 1-12 0.2726 1-45 1.0530 1-81 1.4430 1-13 0.4862 1-46 0.4298 1-82 1.7350 1-14 0.2336 1-47 0.4181 1-83 0.2660 1-15 0.3087 1-48 0.3899 1-84 0.3406 1-16 0.8176 1-49 1.7920 1-85 0.4772 1-17 0.5316 1-50 0.7805 1-86 0.2626 1-18 0.3669 1-51 0.3355 1-87 0.6720 1-19 0.7796 1-52 1.1240 1-88 0.2939 1-20 0.7147 1-53 0.4675 1-89 0.3490 1-21 0.6445 1-54 0.5999 1-90 1.3020 1-22 1.2320 1-55 0.6121 1-91 1.1640 1-23 1.5070 1-56 2.1390 1-92 1.5610 1-24 0.9880 1-57 0.7498 1-93 0.2387 1-25 1.0020 1-58 2.7590 1-94 0.9038 1-26 0.3083 1-59 0.9900 1-95 0.5403 1-27 1.3470 1-61 1.7270 1-96 0.9377 1-28 0.3829 1-62 1.2020 1-97 1.3130 1-29 0.3553 1-63 0.3233 1-98 0.5018 1-30 0.3147 1-64 0.2482 1-31 0.3282 1-65 2.0570 1-32 4.6140 1-67 1.4980 1-33 0.5854 1-68 1.3550

As described above, AIMP2-DX2, which is closely related to the differentiation and proliferation of cancer cells, directly binds to K-Ras to stabilize K-Ras protein and consequently plays a critical role in the survival and differentiation of cancer cells.

As can be seen in Table 1 and Table 2, the compounds according to the present invention have a very good effect of directly inhibiting the binding of AIMP2-DX2 and K-Ras, lowering the level of K-Ras protein in cancer cells It can be judged that it may have an effect of suppressing the development and progression of cancer.

Compound represented by the formula (1) according to the present invention by inhibiting the binding of AIMP2-DX2 and K-Ras lowers the level of K-Ras protein in cancer cells and is very excellent in inhibiting the development and progression of cancer, AIMP2 It can be very useful for the prevention or treatment of solid cancer overexpressing DX2, so the industrial applicability is excellent.

Claims (8)

A pharmaceutical composition for preventing or treating solid cancer, comprising the compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

Where
R ₁ is C 1 -C 6 alkyl unsubstituted or substituted with C 2 -C 10 hetero aryl including at least one hetero atom selected from the group consisting of N, O and S; C1-C6 alkyl substituted with C6-C12 aryl unsubstituted or substituted with C1-C6 alkoxy; Thiophene unsubstituted or substituted with C1-C6 alkyl; Furan; Pyrrole; Thiazole; C3-C7 cycloalkyl; Or C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylamino, amino, C1-C6 alkyl, hydroxy and halogen,
R ₂ is hydrogen; Straight or branched C1-C6 alkyl; C1-C6 alkoxycarbonyl; Thiophene; Or C 1 -C 6 alkoxy, hydroxy, linear or branched C 1 -C 6 alkyl, hetero substituted or unsubstituted with C 2 -C 10 heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N, O and S; C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of cycloalkyloxy and halogen,
R ₃ is hydrogen; Cyano; C1-C6 alkoxy; C1-C6 alkoxycarbonyl; Aminocarbonyl; C3-C10 alkoxycarbonylalkyl; C3-C10 heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, O and S; Thiophene; C2-C10 hetero aryl unsubstituted or substituted with straight or branched C1-C6 alkyl or C3-C10 cycloalkyl; C1-C6 alkyl; C1-C6 alkyl substituted with C6-C12 aryl unsubstituted or substituted with hydroxy or C1-C6 alkoxy; C6-C12 aryl substituted with unsubstituted C1-C6 alkoxy; C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of hydroxy, nitro, halogen and cyano; or

Is,
R ₄ is C 1 -C 6 alkylamino, hydroxy, C 1 -C 6 alkoxy, cyano and halogen, substituted or unsubstituted C 1 -C 6 alkylamino; C2-C10 heterocycloalkyl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 aminoalkyl, C2-C10 alkylaminoalkyl and C2-C6 alkylcarbonyl; Amino; C2-C6 alkenylamino; C2-C6 alkynylamino; C2-C10 spiroheterocycloalkyl; And benzylamino is one or more selected from the group consisting of
N is an integer of 1 to 5.
The compound of claim 1, wherein R ₁ is thiophene unsubstituted or substituted with methyl; Benzene unsubstituted or substituted with one or more selected from the group consisting of methoxy, dimethylamino, amino, methyl, hydroxy and fluoro; Furan; Pyrrole; Thiazole; Cyclopropane; Cyclopentane; Or methyl substituted with one or more selected from the group consisting of benzene, thiophene and methoxybenzene.
The method of claim 1, wherein R ₂ is hydrogen; C1-C2 alkyl; Ethoxycarbonyl; Thiophene; Or benzene unsubstituted or substituted with one or more selected from the group consisting of methoxy, hydroxy, methyl, morpholinoethoxy, piperazinylethoxy, piperidyloxy and fluoro. Composition.
The method of claim 1, wherein R ₃ is hydrogen; Methoxycarbonyl; Methoxy; Thiophene; Aminocarbonyl; Ethoxycarbonylethyl; Cyano; Ethoxycarbonyl; Morpholino; methyl; t-butyloxadiazolyl; Cyclohexyloxadiazolyl; Methyloxadiazolyl; Hydroxybenzyl; Methoxybenzyl; Or methoxy, hydroxy, nitro, aminoethoxy, (diethylamino) ethoxy, pyrrolidinylethoxy, (dimethylamino) ethoxy, (isopentylamino) ethoxy, (benzylamino) ethoxy, ( Piperidyl) ethoxy, morpholinoethoxy, (methyl (propyl) amino) ethoxy, thiomorpholinoethoxy, ((aminoethyl) piperazinyl) ethoxy, ((((dimethylamino) ethyl- Methyl) amino) ethoxy, ((dimethylaminoethyl) piperazinyl) ethoxy, acetylpiperazinylethoxy, (hydroxyethyl (methyl) amino) ethoxy, (methoxyethyl (methyl) amino) ethoxy , (1,4-dioxa-8-azaspiro [4,5] decanyl) ethoxy, methoxyethylaminoethoxy, cyanoethylaminoethoxy, trifluoroethylaminoethoxy, (buty-2 -Nylamino) ethoxy, allylaminoethoxy, fluoro and tetrahydrofuranylmethoxy being one or more substituted or unsubstituted benzenes selected from the group consisting of A pharmaceutical composition according to claim.
The compound of claim 1, wherein the compound is
1-[[6-[(4-fluorophenyl) -2- (2-furyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione;
1-[[6-[(4-fluorophenyl) -5-methyl-2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione;
1-[[6-[(4-fluorophenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl -Pyrrole-2,5-dione;
1-[[2-cyclopropyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;
1-[[2-cyclopentyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;
1-[[6-[(4-fluorophenyl) -2- (2-furyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;
1-[[6-[(4-fluorophenyl) -2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidin-4-yl] amino] -3 -Methyl-pyrrole-2,5-dione;
1-[[6-[(4-fluorophenyl) -2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2 , 5-dione;
1-[[2- (2-furyl) -5,6-dimethyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- (4-methoxyphenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione;
Ethyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2-thiazol-5-yl-thieno [2,3-d] pyrimidine- 6-carboxylate;
1-[[5- (4-methoxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;
1-[[5- (4-hydroxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;
3-methyl-1-[[5- (p-tolyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;
3-methyl-1-[[5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;
Ethyl 4-[(3-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-5-carboxylate;
1-[[5- (3-hydroxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;
1-[[5- (3-methoxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;
3-methyl-1-[[5- [3- (2-morpholinoethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino ] Pyrrole-2,5-dione;
3-methyl-1-[[5- [3- (2-piperazin1-ylethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl ] Amino] pyrrole-2,5-dione;
3-methyl-1-[[5-phenyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;
1-[[2- (4-methoxyphenyl) -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[2- (3-methoxyphenyl) -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[2- [4- (dimethylamino) phenyl] -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ;
1-[[2- [4-aminophenyl] -5-phenyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- [4-methoxyphenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione;
1-[[6- [4-hydroxyphenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione;
3-methyl-1-[[5-methyl-6-phenyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;
1-[[6- (3-hydroxyphenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione;
1-[[6- (4-methoxyphenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione;
Methyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6 Carboxylates;
1-[[6- (4-hydroxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;
1-[[6-methoxy-5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5- Diones;
3-methyl-1-[[5-methyl-6- (4-nitrophenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2 , 5-dione;
1-[[6- [4-hydroxyphenyl) methyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl -Pyrrole-2,5-dione;
1-[[6- [4- (2-aminoethoxy) phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino]- 3-methyl-pyrrole-2,5-dione;
1-[[6- [4- [2- (diethylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl ] Amino] -3-methyl-pyrrole-2,5-dione;
3-methyl-1-[[5-methyl-6- [4- (2-pyrrolidin-1-ylethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] pyrrole-2,5-dione;
1-[[6- [4- [2- (dimethylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] -Methyl-amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- [4- [2- (isopentylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl ] Amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- [4- [2- (benzylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione;
3-methyl-1-[[2-phenyl-5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;
1-[[2,5-bis (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[2- (4-methoxyphenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;
1-[[2- (3-methoxyphenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;
1-[[2- (2-furyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ;
3-methyl-1-[[2- (5-methyl-2-thienyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2 , 5-dione;
1-[[2-benzyl-5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
3-methyl-1-[[2- (p-tolyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;
1-[[2,6-bis (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
3-methyl-1-[[5- (2-thienyl) -2- (2-thienylmethyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5- Diones;
1-[[2- (4-hydroxyphenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;
3-methyl-1-[[5- (2-thienyl) -2- (3-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione ;
3-methyl-1-[[2- (2-thienyl) -5- (3-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione ;
3-methyl-1-[[5- (2-thienyl) -2- (3-thienylmethyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5- Diones;
1-[[2- (3-fluorophenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;
1-[[2-[(4-methoxyphenyl) methyl] -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole- 2,5-dione;
1-[[2- [4- (dimethylamino) phenyl] -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2 , 5-dione;
1-[[2-[(3-methoxyphenyl) methyl] -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole- 2,5-dione;
3-methyl-1-[[5-methyl-6- [4- [2- (1- (piperidyl) ethoxy] phenyl] -2- (2-thienyl) thieno [2,3-d ] Pyrimidin-4-yl] amino] pyrrole-2,5-dione;
1-[[2- (4-aminophenyl) -5- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5- Diones;
5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6- Carboxamide;
1-[[6- (3-methoxyphenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione;
Ethyl 3- [5-methyl-4-[(3-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyri Midin-6-yl] propanoate;
1-[[6-[(3-methoxyphenyl) methyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3- Methyl-pyrrole-2,5-dione;
3-methyl-1-[[5-methyl-6- [4- (2-morpholinoethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidine-4 -Yl] amino] pyrrole-2,5-dione;
3-methyl-1-[[5-methyl-6- [4- [2- [methyl (propyl) amino] ethoxy] phenyl] -2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] pyrrole-2,5-dione;
3-methyl-1-[[5-methyl-2- (2-thienyl) -6- [4- (2-thiopolynoethoxy) phenyl] thieno [2,3-d] pyrimidine-4 -Yl] amino] pyrrole-2,5-dione;
1-[[6- [4- [2- [4- (2-aminoethyl) piperazin-1-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2 , 3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- [4- [2- (dimethylamino) methoxy] phenyl] -5-ethyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- [4- [2- [2- (dimethylamino) ethyl-methyl-amino] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3- d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- [4- [2- [4- [2- (dimethylamino) ethyl] piperazin-1-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thier No [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- [4- [2- [4-acetylpiperazin-1-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- [4- [2- [2-hydroxyethyl (methyl) amino] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- [4- [2- [2-methoxyethyl (methyl) amino] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] Pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- [4- [2- [1,4-dioxa-8-azaspiro [4.5] decan-8-yl] ethoxy] phenyl] -5-methyl-2- (2-thienyl ) Thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- [4- [2- (2-methoxyethylamino)] ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidine -4-yl] amino] -3-methyl-pyrrole-2,5-dione;
3- [2- [4- [5-methyl-4-[(3-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2, 3-d] pyrimidin-6-yl] phenoxy] ethylamino] propanenitrile;
3-methyl-1-[[5-methyl-2- (2-thienyl) -6- [4- [2- (2,2,2-trifluoroethylamino) ethoxy] phenyl] thieno [ 2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione;
1-[[6- [4- [2- (butyn-2-ylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidine- 4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- [4- [2- (allylamino) ethoxy] phenyl] -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- (4-fluorophenyl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole -2,5-dione;
5-methyl-4- [5-methyl-2,5-dioxo-pyrrol-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6-carbo Nitrile;
Ethyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2- (2-thienyl) thieno [2,3-d] pyrimidine-6 Carboxylates;
3-methyl-1-[[5- [4- (4-piperidyloxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] Pyrrole-2,5-dione;
3-methyl-1-[[5-methyl-6-morpholino-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5- Diones;
1-[[6-[(4-fluorophenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;
1-[[6-[(4-methoxyphenyl) -2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;
1-[[2-[(4-fluorophenyl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ;
1-[[2-[(4-fluorophenyl) -6-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
3-methyl-1-[[5-methyl-6- [4- (tetrahydrofuran-2-ylmethoxy) phenyl] -2- (2-thienyl) thieno [2,3-d] pyrimidine- 4-yl] amino] pyrrole-2,5-dione;
1-[[5-ethyl-6-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione ;
1-[[5-[(4-fluorophenyl) -6-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione;
1-[[6- (5- ~ {tert} -butyl-1,3,4-oxadiazol-2-yl) -5-methyl-2- (2-thienyl) thieno [2,3- d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- (5-cyclohexyl-1,3,4-oxadiazol-2-yl) -5-methyl-2- (2-thienyl) thieno [2,3-d] pyrimidine -4-yl] amino] -3-methyl-pyrrole-2,5-dione;
3-methyl-1-[[5-methyl-6- [5-methyl-1,3,4-oxadiazol-2-yl] -2- (2-thienyl) thieno [2,3-d ] Pyrimidin-4-yl] amino] pyrrole-2,5-dione; And
3-methyl-1-[[6-methyl-5-phenyl-2- (2-thienyl) thieno [2,3-d] pyrimidin-4-yl] amino] pyrrole-2,5-dione A pharmaceutical composition, characterized in that selected from the group consisting of.
According to claim 1, wherein the solid cancer is colon cancer, colon cancer, lung cancer, liver cancer, stomach cancer, esophageal cancer, pancreatic cancer, gallbladder cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer, chorionic cancer, ovarian cancer, breast cancer Pharmaceutical composition, characterized in that selected from the group consisting of thyroid cancer, brain cancer, head and neck cancer and malignant melanoma.
The pharmaceutical composition of claim 1, wherein the solid cancer is a cancer in which AIMP2-DX2 is overexpressed.
1-[[6-[(4-fluorophenyl) -2- (2-furyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione;
1-[[6-[(4-fluorophenyl) -5-methyl-2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidin-4-yl] Amino] -3-methyl-pyrrole-2,5-dione;
1-[[6-[(4-fluorophenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl -Pyrrole-2,5-dione;
1-[[2-cyclopropyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;
1-[[2-cyclopentyl-6- (4-fluorophenyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione;
1-[[6-[(4-fluorophenyl) -2- (2-furyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5 -Dione;
1-[[6-[(4-fluorophenyl) -2- (1 ~ {H} -pyrrol-2-yl) thieno [2,3-d] pyrimidin-4-yl] amino] -3 -Methyl-pyrrole-2,5-dione;
1-[[6-[(4-fluorophenyl) -2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2 , 5-dione;
1-[[2- (2-furyl) -5,6-dimethyl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2,5-dione;
1-[[6- (4-methoxyphenyl) -5-methyl-2-thiazol-5-yl-thieno [2,3-d] pyrimidin-4-yl] amino] -3-methyl- Pyrrole-2,5-dione; And
Ethyl 5-methyl-4-[(3-methyl-2,5-dioxo-pyrrole-1-yl) amino] -2-thiazol-5-yl-thieno [2,3-d] pyrimidine- A compound selected from the group consisting of 6-carboxylate or a pharmaceutically acceptable salt thereof.