Fused-cyclic pyrazolone formamide compound and preparation method therefor, pharmaceutical composition and use thereof

Patent metadata

Field	Value
Publication number	US-12497394-B2
Application number	US-201917057199-A
Country	US
Kind code	B2
Filing date	May 21, 2019
Priority date	May 21, 2018
Publication date	Dec 16, 2025
Grant date	Dec 16, 2025

Abstract

Provided are a class of fused-cyclic pyrazolone formamide compounds and a preparation method therefor, a pharmaceutical composition and the use thereof. Specifically, provided is a compound having the structure as shown in formula (I) (with each group defined in the description). The compound can be used as an AXL inhibitor in the preparation of a pharmaceutical composition for treating tumors.

First claim

The invention claimed is:

1 . A fused-cyclic pyrazolone formamide compound having the structure of formula I, or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or the mixture thereof:

wherein:
n is an integer of 0-2;
X, Y and Z are each independently CH or N;
R 1 and R 2 are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, and —O[(CH 2 ) q O] r R 3 ; wherein the “substituted” refers to one or more hydrogen atoms on the group replaced by a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen-substituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkyl, halogen-substituted C 3 -C 8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C 6 -C 10 aryl, and 3-12 membered heterocyclic group;
R 3 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, and hydroxymethyl;
q is 1, 2, 3, or 4;
r is 0, 1, 2, 3 or 4;

or two R 1 and their adjacent carbon atoms together form a group selected from the group consisting of a benzene ring and a 5-8 membered heteroaromatic ring;
or two R 2 and their adjacent carbon atoms together form a group selected from the group consisting of a benzene ring and a 5-8 membered heteroaromatic ring;
ring is selected from the group consisting of substituted or unsubstituted 7-20 membered polycyclic heterocyclic ring, substituted or unsubstituted 7-20 membered polycyclic aromatic ring, and substituted or unsubstituted 7-20 membered polycyclic aromatic heterocyclic ring,
wherein the “substituted” refers to the hydrogen atom on the group is replaced by 1, 2, 3 or 4 substituents selected from the group consisting of deuterium (D), tritium (T), halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, —O[(CH 2 ) q O] r R 3 , —NH[(CH 2 ) q O] r R 3 , —NH(C═O)[(CH 2 ) q O] r R 3 , —NH(SO 2 )[(CH 2 ) q O] r R 3 , —O(CH 2 ) s Ar, substituted or unsubstituted C 3 -C 8 cycloalkoxy, substituted or unsubstituted C 3 -C 8 cycloalkylamino, substituted or unsubstituted C 3 -C 8 epoxy alkyl, substituted or unsubstituted C 3 -C 8 cycloaminoalkyl, cyano, nitro, amino, C 1 -C 6 amino, hydroxyl, hydroxymethyl, carboxyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted 3-12 membered heterocyclyloxy and substituted or unsubstituted 3-12 membered heterocyclylamino;
wherein each of the aromatic heterocyclic group, heterocyclic group independently contains 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; or two adjacent substituents and their adjacent carbon atoms together form a structure of substituted or unsubstituted 6-20 membered heterocyclic ring, and
wherein the heterocyclic ring optionally includes 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S;
s is selected from the group consisting of 0, 1, 2, 3 and 4;
Ar is selected from the group consisting of substituted or unsubstituted C 6 -C 12 aryl, and substituted or unsubstituted 5-12 membered heteroaryl;
unless otherwise specified, the “substituted” refers to one or more hydrogen atoms on the group replaced by a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, halogen-substituted C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl.

2 . The fused-cyclic pyrazolone formamide compound of formula I of claim 1 , or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, wherein, R 1 and R 2 are each independently selected from group consisting of hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, cyano, hydroxyl, carboxyl; wherein, the “substituted” refers to one or more hydrogen atoms replaced by a substituent selected from group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, cyano, amino, hydroxyl, hydroxymethyl, carboxyl; or two R 1 and their adjacent carbon atoms together form a group selected from group consisting of benzene ring, 5-8 membered heteroaromatic ring.

3 . The fused-cyclic pyrazolone formamide compound of formula I of claim 1 , or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, wherein the ring is selected from the group consisting of:

wherein, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are 1-4 substituents selected from group consisting of H, D, T, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, —O[(CH 2 ) q O] r R3, —NH[(CH 2 ) q O] r R 3 , —NH(C═O)[(CH 2 ) q O] r R3, —NH(SO 2 )[(CH 2 ) q O] r R 3 , —O(CH 2 ) s Ar, substituted or unsubstituted C 3 -C 8 cycloalkoxy, substituted or unsubstituted C 3 -C 8 cycloalkylamino, substituted or unsubstituted C 3 -C 8 epoxy alkyl, substituted or unsubstituted C 3 -C 5 cycloamine alkyl, cyano, nitro, amino, C 1 -C 6 amino, hydroxyl, hydroxymethyl, carboxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted 3-12 membered heterocyclyloxy and substituted or unsubstituted 3-12 membered heterocyclic amino; or two adjacent groups mentioned above and their connected atoms t may together form a structure selected from substituted or unsubstituted 6-20 membered heterocycle, wherein the heterocycle may optionally include 1, 2, 3 or 4 heteroatoms selected from N, O or S.

4 . The fused-cyclic pyrazolone formamide compound of formula I of claim 2 , or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, wherein the ring is selected from the group consisting of:

5 . The fused-cyclic pyrazolone formamide compound of formula I of claim 4 , or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, wherein R 4 and R 5 are respectively 1-4 substituents selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkoxy, —O[(CH 2 ) q O] r R 3 , —NH[(CH 2 ) q O] r R 3 , —NH(C═O)[(CH 2 ) q O] r R 3 , —NH(SO 2 )[(CH 2 ) q O] r R 3 , —O(CH 2 ) s Ar, substituted or unsubstituted 3-12 membered heterocyclyloxy and substituted or unsubstituted 3-12 membered heterocyclylamino; or two adjacent groups and their connected atoms together form a structure selected from substituted or unsubstituted 6-20 membered heterocycle, wherein the heterocycle may optionally include 1, 2, 3, or 4 heteroatoms selected from N, O or S.

6 . The fused-cyclic pyrazolone formamide compound of formula I of claim 1 , or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, wherein the fused cyclic pyrazolone carboxamide compound is selected from the group consisting of:

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

• Liu Hong
• Geng Meiyu
• Zhou Yu
• Ding Jian
• Fang Feifei
• Ai Jing
• Li Jian
• Peng Xia
• Jiang Hualiang
• Ji Yinchun
• Chen Kaixian

Classifications

• C07D519/00

  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

• C07D491/056

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/519

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