PYRIMIDINE-2,4-DIAMINE DERIVATIVES FOR CANCER TREATMENT Russian patent published in 2018 - IPC C07D239/48 C07D409/04 C07D405/12 C07D401/12 C07D403/12 C07D403/04 A61K31/505 A61K31/506 A61P35/00 

FIELD: medicine; pharmaceuticals.

SUBSTANCE: invention relates to a novel compound of formula (I) or a pharmaceutically acceptable salt thereof. Compound has the properties of an inhibitor of MTH1 and can be used in the treatment of diseases mediated by the activity of MTH1, such as cancer, selected, for example, from oncological diseases of soft tissues: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung cancer diseases: bronchogenic cancer (squamous cell, undifferentiated small cell, undifferentiated large cell cancer, adenocarcinoma), alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, etc. In compound of formula I (I) R¹ is heteroaryl selected from benzofuran-3-yl, benzothiophen-3-yl, dihydrobenzofuran-7-yl, indol-3-yl, indol-4-yl, indol-5-yl, isoquinolin-4-yl, pyridine-3-yl, pyridin-4-yl, pyrrol-2-yl and quinolin-5-yl, where heteroaryl is linked to a pyrimidine of formula I through the carbon atom of the heteroaryl cycle, and this heteroaryl is optionally substituted with one or more substituents selected from Y¹ or -C_1-6-alkyl, optionally substituted with one or more Y²; or aryl, represented by ; E³ and E⁴ are hydrogen atoms; and E¹ represents -F, and E² represents -F, -Cl, -CH₃ or -CF₃; or E¹ represents -Cl, and E² represents -F, -Cl, -CH₃ or -CF₃; or E¹ represents -CH₃, and E² represents -F, -Cl, -CH₃, -CF₃ or -CN; R² is hydrogen; R³ represents -C_2-6-alkyl in which two adjacent carbon atoms can form a cyclopropyl group substituted with Z¹; each Y¹ is independently halogen or -CN; each Y² independently represents halogen; Z¹ represents -C(O)N(R^c2)R^d2, -N(R^f2)R^g2, -N(R^h2)C(O)Rⁱ², -N(R^l2)C(O)N(R^m2)Rⁿ², -N(R^o2)S(O)₂R^p2, -OR^q2, -S(O)_mR^t2, -S(O)₂N(R^u2)R^v2, or aryl, represented by , R^c2, R^f2, R^h2, R^l2, R^m2, R^o2 and R^u2 are hydrogen atoms; and R^d2, R^g2, Rⁱ², Rⁿ² R^p2, R^q2, R^t2 and R^v2 is phenyl, optionally substituted with one or more substituents selected from W⁶, or 5-10 membered heteroaryl having 1-3 nitrogen atoms, one oxygen atom and/or one sulphur atom, and optionally substituted with one or more substituents selected from W⁶; every W⁶ independently represents halogen, -R^a3, -CN, -N (R^h3) C (O) Rⁱ³, -OR^q3, -S (O)_mR^t3, -S (O)₂N (R^u3) R^v3, a 5- or 6-membered heterocycloalkyl having 1-3 heteroatoms selected from nitrogen and oxygen, optionally substituted with one or more substituents selected from G¹, phenyl, optionally substituted with one or more substituents selected from G², 5-10-membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and/or sulphur, optionally substituted with one or more substituents selected from G², or =O; W⁷ and W¹¹ are hydrogen atoms; each W⁸ and W¹⁰ independently represents hydrogen, halogen, -R^a3, -CN, -OR^q3, -S(O)_mR^t3 or -S(O)₂N(R^u3)R^v3; W⁹ is a halogen, -R^a3, -CN, -S(O)_mR^t3, -S(O)₂N(R^u3)R^v3; each R^a3, R^h3, Rⁱ³, R^q3, R^t3, R^u3 and R^v3 independently represents hydrogen or C_1-6-alkyl, optionally substituted with one or more G³; or any two R^u3 and R^v3 linked with the formation, together with the nitrogen atom to which they are attached, a 4-6-membered ring, which optionally contains one heteroatom and which is optionally substituted with one or more G²; each G¹ and G² independently represents halogen or -R^a4; G³ is a halogen; each R^a4 independently represents hydrogen, -C_1-6-alkyl, optionally substituted with one or more -F; and each m is independently 0, 1, or 2.

EFFECT: pyrimidine-2,4-diamine derivatives for treating cancer are disclosed.

17 cl, 2 dwg, 458 ex