US 12,312,348 B2
RET inhibitors, pharmaceutical compositions and uses thereof
Hongming Xie, Dongguan (CN); Ming Luo, Dongguan (CN); Jianli Wu, Dongguan (CN); Yingjun Zhang, Dongguan (CN); and Yingchao Cheng, Dongguan (CN)
Assigned to SUNSHINE LAKE PHARMA CO., LTD., Dongguan (CN)
Appl. No. 17/289,192
Filed by SUNSHINE LAKE PHARMA CO., LTD., Guangdong (CN)
PCT Filed Dec. 6, 2019, PCT No. PCT/CN2019/123698
§ 371(c)(1), (2) Date Apr. 27, 2021,
PCT Pub. No. WO2020/114494, PCT Pub. Date Jun. 11, 2020.
Claims priority of application No. 201811496406.8 (CN), filed on Dec. 7, 2018; application No. 201910245269.9 (CN), filed on Mar. 28, 2019; and application No. 201910248485.9 (CN), filed on Mar. 29, 2019.
Prior Publication US 2022/0119382 A1, Apr. 21, 2022
Int. Cl. C07D 471/04 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/04 (2013.01) [C07D 519/00 (2013.01)] 18 Claims
 
1. A compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate or a pharmaceutically acceptable salt thereof,

OG Complex Work Unit Chemistry
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)—, alkyl, alkenyl, alkynyl, alkylaryl, alkylheteroaryl, alkenylaryl, alkynylaryl, alkenylheteroaryl, alkynylheteroaryl, aryl, heteroaryl, Cyc, hetCyc, arylalkyl, heteroarylalkyl, Cyc-alkyl or hetCyc-alkyl, wherein each of alkyl, alkenyl, alkynyl, alkylaryl, alkylheteroaryl, alkenylaryl, alkynylaryl, alkenylheteroaryl, alkynylheteroaryl, aryl, heteroaryl, Cyc, hetCyc, arylalkyl, heteroarylalkyl, 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, cycloalkylalkynyl and heterocyclic group;
R1 is H, D, CN, F, Cl, Br, alkyl, alkenyl or cycloalkyl, wherein each of alkyl, alkenyl and cycloalkyl is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2;
G is H, D, alkyl, hetCyc-alkyl, Cyc-alkyl, heteroarylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, R5O(C═O)NR6 alkyl, R5(C═O)NR6 alkyl, NR5R6(C═O)alkyl, R5(C═O)alkyl, NR5R6(C═O)— or R5O-alkyl, wherein each of alkyl, hetCyc-alkyl, Cyc-alkyl, heteroarylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, and an alkyl moiety in R5O(C═O)NR6 alkyl, R5(C═O)NR6 alkyl, R5(C═O)alkyl, NR5R6(C═O)alkyl and R5O alkyl is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, cycloalkylidene, heterocyclylidene, alkyl, alkoxy, alkoxyalkyl, R5(C═O)—, R5O(C═O)—;
R3 is H, D, alkyl, Cyc, hetCyc, aryl, heteroaryl, Cyc-alkyl, hetCyc-alkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein each of alkyl, 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.