Compound having anti-tumor activity and use thereof
Provided is a compound having anti-tumor activity and a use thereof. As a PRMT5 inhibitor, the compound has a structure represented by formula (I). Experiments have confirmed that these compounds have strong inhibitory effects on PRMT5 enzyme activity and tumor cell growth, and can be used as promising compounds for treating PRMT5-mediated diseases. Furthermore, a specific synthesis method is further studied. The synthesis method is simple in process, convenient to operate, and beneficial to large-scale industrial production and application.
1 . A compound represented by formula (III), or stereoisomer, geometric isomer, tautomer, pharmaceutical salt, prodrug, hydrate, solvate, or isotope-labeled analogue thereof:
wherein,
R 16 is selected from hydrogen, deuterium, halogen, hydroxy, mercapto, amino, cyano, —R 9 , —OR 9 , —SR 9 , —NH(R 9 ) and —N(R 9 )(R 10 );
at each occurrence, R 9 and R 10 are each independently selected from C1-6alkyl and C3-6cycloalkyl, or R 9 and R 10 together with the N atom to which they are connected form 4-6 membered heterocyclyl;
R 11 is selected from C6-8aryl and 5-6 membered heteroaryl, and the aryl or heteroaryl is optionally substituted by one or more of halogen, C1-6alkyl, and trifluoromethyl;
the heterocyclyl or heteroaryl contains 1, 2 or 3 heteroatoms, which are each independently selected from N, O and S.
2 . The compound represented by formula (III) according to claim 1 , or stereoisomer, geometric isomer, tautomer, pharmaceutical salt, hydrate, solvate, or isotope-labeled analogue thereof, wherein
R 16 is selected from hydrogen, deuterium, —R 9 , —OR 9 , —SR 9 and —N(R 9 )(R 10 ), wherein R 9 and R 10 are as defined in claim 1 .
3 . The compound represented by formula (III) according to claim 1 , or stereoisomer, geometric isomer, tautomer, pharmaceutical salt, hydrate, solvate, or isotope-labeled analogue thereof, wherein
R 11 is selected from phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein the phenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl is optionally substituted by one or more of halogen, methyl, and trifluoromethyl.
4 . The compound represented by formula (III) according to claim 1 , or stereoisomer, geometric isomer, tautomer, pharmaceutical salt, hydrate, solvate, or isotope-labeled analogue thereof, wherein the compound represented by formula (III) has a structure represented by formula (III)A or formula (III)B:
wherein R 11 and R 16 are as defined in claim 1 .
5 . A pharmaceutical composition, which contains a compound according to claim 1 , or stereoisomer, geometric isomer, tautomer, pharmaceutical salt, hydrate, solvate, or isotope-labeled analogue thereof.
6 . A method for preventing and/or treating PRMT5-mediated diseases, which includes administering a therapeutically effective dose of the compound according to claim 1 , or stereoisomer, geometric isomer, tautomer, pharmaceutical salt, hydrate, solvate, or isotope-labeled analogue thereof to a patient.
7 . A pharmaceutical combination, comprising the compound according to claim 1 , or stereoisomer, geometric isomer, tautomer, pharmaceutical salt, hydrate, solvate, or isotope-labeled analogue thereof, and an additional anticancer agent or immune checkpoint inhibitor.
8 . The compound represented by formula (III) according to claim 1 , or stereoisomer, geometric isomer, tautomer, pharmaceutical salt, hydrate, solvate, or isotope-labeled analogue thereof, wherein
R 16 is selected from hydrogen, deuterium, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCH 2 CH(CH 3 ) 2 , —OC(CH 3 ) 3 , —OCH(CH 2 CH 3 ) 2 , —O-cyclopropyl, —O-cyclobutyl, —O-cyclopentyl, —O-cyclohexyl, —SCH 3 , —SCH 2 CH 3 , —SCH(CH 3 ) 2 , —SCH 2 CH(CH 3 ) 2 , —SC (CH 3 ) 3 , —SCH(CH 2 CH 3 ) 2 , —S-cyclopropyl, —S-cyclobutyl, —S-cyclopentyl, —S-cyclohexyl, azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl and 3-azabicyclo [3.1.0] hexan-3-yl.
9 . The compound represented by formula (III) according to claim 1 , or stereoisomer, geometric isomer, tautomer, pharmaceutical salt, hydrate, solvate, or isotope-labeled analogue thereof, wherein
R 11 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, thien-2-yl, thien-3-yl, 1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl.
10 . The compound represented by formula (III) according to claim 1 , or stereoisomer, geometric isomer, tautomer, pharmaceutical salt, hydrate, solvate, or isotope-labeled analogue thereof, wherein the compound is selected from compounds 183, 193, 194, 202, 207, 212, 213, 214, 216, 217, 218, 220, 223, 228, 236, 243, 245, 247, 253, 269, 274, 275, 282, 284, 287, 293, 294, 315, 316, 328, 344, 356, 392, 393, and 401:
No.
Structures
183
193
194
202
207
212
213
214
216
217
218
220
223
228
236
243
245
247
253
269
274
275
282
284
287
293
294
315
316
328
344
356
392
393
401
11 . The method of claim 6 , wherein the PRMT5-mediated disease is cancer or a tumor-related disease.
12 . The method of claim 6 , wherein the PRMT5-mediated disease is lymphoma.