主权项 |
1. A fused pyrimidine compound represented by formula I, a pharmaceutically acceptable salt, hydrate, and solvate thereof, an optical isomer or a prodrug thereof, wherein: X is S or O; R1 is hydrogen, deuterium, halogen, an alkyl, an alkoxy, an alkenyl, an alkynyl, a cycloalkyl, a heterocycloalkyl, an aryl or a heteroaryl; R2 is hydrogen, deuterium, halogen, CN, —(CR8R9)mNR5R6, —(CR8R9)mNR7C(═Y)R5, —(CR8R9)mNR7S(O)2R5, —(CR8R9)mOR5, —(CR8R9)mS(O)2R5, —(CR8R9)mS(O)2NR5R6, —C(OR5)R6R8, —C(═Y)R5, —C(═Y)OR5, —C(═Y)NR5R6, —C(═Y)NR7OR5, —C(═O)NR7S(O)2R5, —C(═O)NR(CR8R9)mNR5R6, —NR7C(═Y)R6, —NR7C(═Y)OR6, —NR7C(═Y)NR5R6, —NR7S(O)2R5, —NR7S(O)2NR5R6, —SR5, —S(O)2R5, —S(O)2NR5R6, —SC(═Y)R5, —SC(═Y)OR5, a C1-12 alkyl, a C2-8 alkenyl, a C2-8 alkynyl, a C3-12 carbocyclyl, a C2-20 heterocyclyl, a C6-20 aryl or a C1-20 heteroaryl; (R3)k represents that the hydrogens attached to the morpholine ring are substituted by 0-k occurrences of R3, at each occurrence the R3 is the same or different from each other, and independently selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, or any two of the R3 may be linked by a single bond, C1-6 alkylene or C1-6 alkylene substituted by one or more heteroatoms, the heteroatom is O, N, or S; A is N or CR4a; D is N or CR4b; E is N or CR4d; G is N or CR4e; A, D, E and G are not N at the same time; each of R4, R4a, R4b, R4d and R4e is independently hydrogen, halogen, —CN, an alkyl, an alkoxy, an alkenyl, an alkynyl, a cycloalkyl, a heterocycloalkyl, —NR5R6, —OR5, —SR5, —C(O)R5, —NR5C(O)R6, —N(C(O)R6)2, —NR5C(O)NR5′R6, —NR7S(O)2R5, —C(═O)OR5 or —C(═O)NR5R6, or R4 or R4d, with R4e, and the atoms to which they are attached form a saturated, unsaturated or partially unsaturated 5-membered or 6-membered heterocycle, the 5-membered or 6-membered heterocycle contains at least two heteroatoms selected from O, N, or S, the 5-membered or 6-membered heterocycle is fused to the 6-membered ring containing A, D, E and G; each of R5, R5′, R6, R7 and R7′ is independently hydrogen, a C1-12 alkyl, a C2-8 alkenyl, a C2-8 alkynyl, a C3-12 carbocyclyl, a C2-20 heterocyclyl, a C6-20 aryl or a C1-20 heteroaryl, or R5, R6 together with the nitrogen to which they are attached form an heterocycle optionally substituted by a substituent selected from the group consisting of: oxo, —(CH2)mOR7, —NR7R7′, —CF3, halogen, —SO2R7, —C(═O)R7, —NR7C(═Y)R7′, —NR7S(O)2R7, —C(═Y)NR7R7′, C1-12 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-12 carbocyclyl, C2-20 heterocyclyl, C6-20 aryl and C1-20 heteroaryl; R8 is hydrogen, deuterium, halogen, —CN, a hydroxy, an alkoxy, a cycloalkoxy, a C1-12 alkyl, a C2-12 alkenyl, a C2-12 alkynyl, a C3-12 cycloalkyl, a C6-12 aryl, a 3-12 membered heterocycloalkyl or a 5-12 membered heteroaryl; (CR8R9)m represents that 0-m (CR8R9) is connected, wherein each of R8 and R9 is the same or different from each other, and independently selected from hydrogen, deuterium, halogen, —CN, a hydroxy, an alkoxy, a C1-12 alkyl, a C2-12 alkenyl, a C2-12 alkynyl, a C3-12 cycloalkyl, a C6-12 aryl, a 3-12 membered heterocycloalkyl or a 5-12 membered heteroaryl; or R8, R9 together with the atoms to which they are attached form a saturated or partially unsaturated C3-12 carbocyclic ring or C2-20 heterocyclic ring; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle, heterocycle, heterocycloalkyl, aryl, or heteroaryl is optionally substituted by a substituent selected from the group consisting of: halogen, —CN, —CF3, —NO2, Oxo, R5, —C(═Y)R5, —C(═Y)OR5, —C(═Y)NR5R6, —(CR8R9)mNR5R6, —(CR8R9)mOR5, —NR5R6, —NR7C(═Y)R5, —NR7C(═Y)OR6, —NR7C(═Y)NR5R6, —(CR8R9)mNR7SO2R5, ═NR7, OR5, —OC(═Y)R5, —OC(═Y)OR5, —OC(═Y)NR5R6, —OS(O)2(OR5), —OP(═Y)(OR5)(OR6), —OP(OR5)(OR6), —SR5, —S(O)R5, —S(O)2R5, —S(O)2NR5R6, —S(O)(OR5), —S(O)2(OR5), —SC(═Y)R5, —SC(═Y)OR5, —SC(═Y)NR5R6, C1-12 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-12 carbocyclyl, C2-20 heterocyclyl, C6-20 aryl or C1-20 heteroaryl; Y is O, S, or NR7; m and k are independently 0, 1, 2, 3, 4, 5 or 6. |