Pyridone-pyrimidine derivative acting as KRAS G12C mutein inhibitor

Patent metadata

Field	Value
Publication number	US-11655248-B2
Application number	US-202117159928-A
Country	US
Kind code	B2
Filing date	Jan 27, 2021
Priority date	Jan 19, 2018
Publication date	May 23, 2023
Grant date	May 23, 2023

Abstract

Provided are a class of KRAS G12C mutein inhibitors, which relate in particular to a compound represented by formula (I), an isomer thereof, and a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein
ring A is selected from 3-8 membered heterocycloalkyl, and the 3-8 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl and C 1-6 heteroalkyl, and the C 1-6 alkyl and C 1-6 heteroalkyl are optionally substituted with 1, 2 or 3 R;
or R 1 and R 2 are connected together to form ring B;
or R 2 and R 3 are connected together to form ring B;
or R 3 and R 4 are connected together to form ring B;
or R 4 and R 5 are connected together to form ring B;
ring B is selected from phenyl, C 5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl, and the phenyl, C 5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are optionally substituted with 1, 2 or 3 R a ;
R a is selected from halogen, OH, NH 2 , CN, C 1-6 alkyl and C 1-6 heteroalkyl, and the C 1-6 alkyl and C 1-6 heteroalkyl are optionally substituted with 1, 2 or 3 R;
R 6 is selected from H, halogen, CF 3 , CHF 2 and CH 2 F;
R 7 is selected from H;
L is selected from a single bond;
L is selected from a single bond and —NH—;
R 8 is selected from H, C 1-6 alkyl and C 1-6 heteroalkyl, and the C 1-6 alkyl and C 1-6 heteroalkyl are optionally substituted with 1, 2 or 3 R;
R is selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl and C 3-6 membered cycloalkyl, and the C 1-6 alkyl, C 1-6 heteroalkyl and C 3-6 membered cycloalkyl are optionally substituted with 1, 2 or 3 R′;
R′ is selected from F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 3 CH 2 , CH 3 O, CF 3 , CHF 2 , CH 2 F, cyclopropyl, n-propyl, isopropyl, N(CH 3 ) 2 and NH(CH 3 );
“hetero” means a heteroatom or a heteroatomic group, the “hetero” in the 3-8 membered heterocycloalkyl, C 1-6 heteroalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl is each independently selected from —C(═O)N(R)—, —N(R)—, —NH—, N, —O—, —S—, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)—, —S(═O) 2 — and —N(R)C(═O)N(R)—;
in any of the cases above, the number of heteroatoms or heteroatomic groups is each independently selected from 1, 2 and 3.

2. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof as defined in claim 1 , wherein R is selected from F, CI, Br, I, OH, NH 2 , CN, CH 3 , CH 3 CH 2 , CH 3 O, CF 3 , CHF 2 , CH 2 F, cyclopropyl, n-propyl, isopropyl, N(CH 3 ) 2 , NH(CH 3 ) and N(CH 2 CH 3 ) 2 .

3. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof as defined in claim 1 , wherein ring A is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, 1,4-diazacycloheptyl and 3,6-diazabicyclo [3.2.0] heptyl, and the aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, 1,4-diazacycloheptyl and 3,6-diazabicyclo [3.2.0] heptyl are optionally substituted with 1, 2 or 3 R;
or, R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 3 CH 2 , (CH 3 ) 2 CH, CH 3 O, CH 3 NH and CH 3 NH(C═O)O, and the CH 3 , CH 3 CH 2 , (CH 3 ) 2 CH, CH 3 O, CH 3 NH and CH 3 NH(C═O)O are optionally substituted with 1, 2 or 3 R;
or, ring B is selected from pyrazolyl, imidazolyl, pyrrolyl, thienyl, furyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl, cyclopentenyl and cyclohexenyl, and the pyrazolyl, imidazolyl, pyrrolyl, thienyl, furyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl, cyclopentenyl and cyclohexenyl are optionally substituted with 1, 2 or 3 R a ;
or, R a is selected from F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 3 CH 2 , (CH 3 ) 2 CH, CH 3 O and CH 3 C(═O);
or, R 6 is selected from H, F, Cl, Br, I, CF 3 , CHF 2 and CH 2 F.

4. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof as defined in claim 3 , wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 3 CH 2 , (CH 3 ) 2 CH, CH 3 O, CH 3 NH, (CH 3 ) 2 N, (CH 3 ) 2 N(C═O)O and CH 3 NH(C═O)O;
or, ring B is selected from phenyl, pyrazolyl, 1-methyl-1H-pyrazolyl and 1-(1H-pyrazole-1-yl)ethanone group.

5. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof as defined in claim 1 , wherein R 8 is selected from H, C 1-4 alkyl and C 1-4 heteroalkyl, and the C 1-4 alkyl and C 1-4 heteroalkyl are optionally substituted with 1, 2 or 3 R.

6. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof as defined in claim 5 , wherein R 8 is selected from H, CH 3 , CH 3 CH 2 , (CH 3 ) 2 CHCH 2 , (CH 3 ) 2 CH, CH 3 O, CH 3 NH, (CH 3 ) 2 N, (CH 3 ) 2 NCH 2 and CH 3 NHCH 2 .

7. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof as defined in claim 1 , wherein the structural unit

 is selected from

 and wherein R 9 is selected from H and C 1-3 alkyl.

8. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof as defined in claim 7 , wherein the structural unit

 is selected from

9. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof as defined in claim 1 , wherein the structural unit

 is selected from

10. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof as defined in claim 1 , selected from

 and wherein L, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 are as defined in claim 1 , R 8 is selected from H and C 1-3 alkyl.

11. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof as defined in claim 10 , selected from

 and wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and L are as defined in claim 10 .

12. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof as defined in claim 11 , selected from

 and wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , L, R 9 and Ra are as defined in claim 11 .

13. A compound of the following formula, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from

Assignees

• Medshine Discovery Inc

Inventors

• Cai Yaxian
• Xu Zhaobing
• Yang Hailong
• Han Shiqi
• Hu Guoping
• Hu Lihong
• Ding Charles Z
• Li Jian
• Chen Shuhui

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title