RET inhibitors, pharmaceutical compositions and uses thereof

A compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, or a pharmaceutically acceptable salt thereof,

• wherein,
• each of X1, X2, X3, X4 and X5 is independently CR4 or N, wherein 0, 1, or 2 of X1, X2, X3, X4 are N;
• E is a bond, —NR6— or —O—;
• A is Cyc or hetCyc, wherein each of Cyc and hetCyc is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, oxo, NR5R6, R5O—, R5(C═O)NR6—, NR5R6 alkyl, NR5R6(C═O) alkoxyalkyl, NR6R7 alkoxy, NR6R7 alkoxyalkyl, alkyl, haloalkyl, hydroxyalkyl, Cyc, hetCyc, hetCyc-alkyl, alkoxyalkyl, hetCyc-alkoxyalkyl, cycloalkylidene and heterocyclylidene;
• Q is —(C═O)—, —O—, —(C═O)NR5—, —(C═S)NR5—, —S(═O)2—, —S(═O)2NR5—, —NR5(C═O)—, —NR5(C═O)O—, —NR5(C═O)NR5—, —NR5—, —(C═O)O— or a bond;
• M is —(C═O)—, alkylene, alkenylene, alkynylene, alkylarylene, alkylheteroarylene, alkenylarylene, alkynylarylene, alkenylheteroarylene, alkynylheteroarylene, arylene, heteroarylene, Cyc, hetCyc, arylalkylene, heteroarylalkylene, Cyc-alkyl, hetCyc-alkyl, wherein each of alkylene, alkenylene, alkynylene, alkylarylene, alkylheteroarylene, alkenylarylene, alkynylarylene, alkenylheteroarylene, alkynylheteroarylene, arylene, heteroarylene, Cyc, hetCyc, arylalkylene, heteroarylalkylene, Cyc-alkyl and hetCyc-alkyl is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, CF3, NR5R6, oxo, alkoxy, cycloalkylidene, heterocyclylidene, hydroxyalkyl, alkyl, cycloalkyl and heterocyclic group
• R1 is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein each of alkyl and cycloalkyl is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2;
• R2 is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group can be independently and optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, alkyl, Cyc, hetCyc, arylalkyl, heteroarylalkyl and alkyl hetCyc;
• wherein each of alkyl, Cyc, hetCyc, arylalkyl and alkyl hetCyc can be further independently and optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, R5O—, R5(C═O)—, R5O(C═O)—, NR5R6, NR5R6(C═O)—, R5S(═O)2—, alkyl, Cyc, hetCyc and alkoxy;
• R3 is H, D, alkyl, alkynyl, Cyc, hetCyc, aryl, heteroaryl, Cyc-alkyl, hetCyc-alkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein each of alkyl, alkynyl, Cyc, hetCyc, aryl, heteroaryl, Cyc-alkyl, hetCyc-alkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl and aminoalkyl is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, NR5R6, R5O—, R5O(C═O)—, R5(C═O)—, NR5R6(C═O)NR5—, R5S(═O)2—, NO2, CN, CF3, alkyl and cycloalkyl;
• R4 is H, D, alkyl, F, Cl, Br or alkoxy, wherein each of alkyl and alkoxy can be independently and optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2;
• R5 is H, D, alkyl, Cyc, hetCyc, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl, aryloxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, Cyc-alkyl or hetCyc-alkyl, wherein each of alkyl, Cyc, hetCyc, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl, aryloxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, Cyc-alkyl and hetCyc-alkyl is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NR6R7, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl;
• R6 is H or alkyl;
• R7 is alkyl, arylalkyl or heteroarylalkyl;
• each Cyc is independently cycloalkyl, bridged carbocyclyl or spirocarbocyclyl;
• and
• each hetCyc is independently heterocyclyl, bridged heterocyclyl or spiroheterocyclyl.