Compound used as RET kinase inhibitor and application thereof
The present invention belongs to the field of medical technology and specifically disclosed is a compound represented by formula (I′), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and each symbol therein is as defined in the claims. The compound of the present invention may be used as a drug for regulating RET kinase activity or treating RET-related diseases, and has better pharmacokinetic properties.
1 . A compound, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof has a structure represented by Formula 6′,
wherein X 2 , X 9 , and X 10 are each independently selected from N or CR 5 ;
X 7 and X 8 are each independently selected from N or C; and
R 5 is each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, C1-C6 heteroalkyl, cycloalkyl, nitro, cyano, or amino; wherein alkyl, alkenyl, alkynyl, alkoxy, alkylamino, heteroalkyl, and cycloalkyl are each independently substituted by 0-5 R a ; R a is selected from C1-C6 alkyl, halogen, hydroxy, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkylamino, cycloalkyl, heterocycloalkyl, or cyano;
ring Q2 is selected from five-membered, six-membered or seven-membered saturated ring, unsaturated ring, aromatic ring, or heteroaromatic ring, and can contain 0-3 heteroatoms selected from N, O, or S, and any hydrogen atom on the ring Q2 can be substituted by deuterium, hydroxy, halogen, cyano, ester, amide, ketocarbonyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 cycloalkylamino, aryl, or heteroaryl.
2 . A compound, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein the compound is selected from the following compounds:
3 . The compound of claim 1 , or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, or acid phosphate; the organic acid salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, hydroxyacetate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, or camphor sulfonate.
4 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 , or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable carrier.
5 . A method of modulating RET kinase activity or treating RET-related diseases comprising administering to a subject in need thereof an effective amount of the compound of claim 1 , or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
6 . The method of claim 5 , wherein the RET-related diseases comprise a cancer.
7 . The compound of claim 1 , or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein
is selected from
R 5 is independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, nitro, cyano, or amino;
Y 2 and Y 3 are each independently selected from O, N, and CR 13 ;
R 13 is each independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, cyano, or amino.
8 . A pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound of claim 2 , or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable carrier.
9 . A method of modulating RET kinase activity or treating RET-related diseases comprising administering to a subject in need thereof an effective amount of the compound of claim 2 , or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
10 . The method of claim 9 , wherein the RET-related diseases comprise a cancer.