IP Library › Granted Patent US 12,630,530

Granted Patent B2

US 12,630,530 · App. 18/167,227 · Granted May 19, 2026

FGFR inhibitor compound and use thereof

Inventors: Liang Lu (Zhengzhou, CN); Saisai Zhao (Zhengzhou, CN); Jixuan Zhang (Zhengzhou, CN); Hai Huang (Zhengzhou, CN); Longzheng Zhang (Zhengzhou, CN)

Assignee: HENAN MEDINNO PHARMACEUTICAL TECHNOLOGY CO., LTD.

C07D401/14 C07D401/12 C07D405/14 C07B2200/05

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Quick Facts

Patent No.: US 12,630,530
App. No.: 18/167,227
Granted: May 19, 2026
Kind: B2

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Abstract

The present disclosure relates to FGFR inhibitor compounds and its use. Specifically, the present disclosure discloses a compound represented by formula (I), isotopically labeled compound thereof, or optical isomer thereof, geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof. The present disclosure also relates to use of the above compound in medicine.

Claims (64)

1 . A compound or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound selected from formula (II), formula (III), formula (IV) and formula (V), or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof

wherein

R 4 is H;

0 to 8 R 5 (s) are present, and each R 5 is independently selected from the group consisting of H, halogen, —OH, —NO 2 , —CN, —SF 5 , —SH, —S—C 1-4 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 tricycloalkyl, 8-15 membered tricycloheteroalkyl, C 5-8 aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7-11 membered bicycloheteroaryl, —C 1-4 alkyl-(C 3-7 cycloalkyl), —C 1-4 alkyl-(3-10 membered heterocycloalkyl), —C 1-4 alkyl-(C 6-12 bicycloalkyl), —C 1-4 alkyl-(6-12 membered bicycloheteroalkyl), —C 1-4 alkyl-(C 8-15 -tricycloalkyl), —C 1-4 alkyl-(8-15 membered tricycloheteroalkyl), —N(R 7 )(R 8 ), —N(R 7 )(C(═O) R 8 ), —N(R 7 )(C(═O)—OR 8 ), —N(R 7 )(C(═O)—N(R 8 )(R 9 ), —C(═O)—N(R 7 )(R 8 ), —C(═O)—R 7 , —C(═O)—OR 7 , —OC(═O) R 7 , —N(R 7 )(S(═O) 2 R 8 ), —S(═O) 2 —N(R 7 )(R 8 ), —SR 7 , and —OR 7 , wherein the —S—C 1-4 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 tricycloalkyl, 8-15 membered tricycloheteroalkyl, C 5-8 aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7-11 membered bicycloheteroaryl, —C 1-4 alkyl-(C 3-7 cycloalkyl), —C 1-4 alkyl-(3-10 membered heterocycloalkyl), —C 1-4 alkyl-(C 6-12 bicycloalkyl), —C 1-4 alkyl-(6-12 membered bicycloheteroalkyl), —C 1-4 alkyl-(C 8-15 tricycloalkyl), and —C 1-4 alkyl-(8-15 membered tricycloheteroalkyl) are each optionally substituted with 0 to 4 R 5a (s);

each R 5a is independently selected from the group consisting of H, halogen, —OH, —NO 2 , —CN, —SF 5 , —SH, —S—C 1-4 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 tricycloalkyl, 8-15 membered tricycloheteroalkyl, C 5-8 aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7-11 membered bicycloheteroaryl, —C 1-4 alkyl-(C 3-7 cycloalkyl), —C 1-4 alkyl-(3-10 membered heterocycloalkyl), —C 1-4 alkyl-(C 6-12 bicycloalkyl), —C 1-4 alkyl-(6-12 membered bicycloheteroalkyl), —N(R 7 )(R 8 ), —N(R 7 )(C(═O) R 8 ), —N(R 7 )(C(═O)—OR 8 ), —N(R 7 )(C(═O)—N(R 8 )(R 9 ), —C(═O)—N(R 7 )(R 8 ), —C(═O)—R 7 , —C(═O)—OR 7 , —OC(═O) R 7 —N(R 7 )(S(═O) 2 R 8 ), —S(═O) 2 —N(R 7 )(R 8 ), —SR 7 , and —OR 7 , wherein the —S—C 1-4 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 tricycloalkyl, 8-15 membered tricycloheteroalkyl, C 5-8 aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7-11 membered bicycloheteroaryl, —C 1-4 alkyl-(C 3-7 cycloalkyl), —C 1-4 alkyl-(3-10 membered heterocycloalkyl), —C 1-4 alkyl-(C 6-12 bicycloalkyl) and —C 1-4 alkyl-(6-12 membered bicycloheteroalkyl) are each optionally substituted with 0 to 4 R 5b ;

each R 5b is independently selected from the group consisting of H, halogen, —OH, —CN, —NO 2 , SF 5 , —SH, —S—C 1-4 alkyl, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, —C 1-4 alkyl-(C 3-7 cycloalkyl), —C 1-4 alkyl-(3-10 membered heterocycloalkyl), —N(R 7 )(R 8 ), —N(R 7 )(C(═O) R 8 ), —N(R 7 )(C(═O)—OR 8 ), —N(R 7 )(C(═O)—N(R 8 )(R 9 )), —C(═O)—N(R 7 )(R 8 ), —C(═O)—R 7 , —C(═O)—OR 7 , —OC(═O) R 7 , —N(R 7 )(S(═O) 2 R 8 ), and —S(═O) 2 —N(R 7 )(R 8 ), wherein the —S—C 1-4 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, —C 1-4 alkyl-(C 3-7 cycloalkyl), and —C 1-4 alkyl-(3-10 membered heterocycloalkyl) are each optionally substituted with 0 to 4 substitutes each independently selected from the group consisting of halogen, —OH, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —CN, —NO 2 , —SF 5 , —SH, —S—C 1-4 alkyl, oxo, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-4 hydroxyalkyl, —S—C 1-4 alkyl, —C(═O) H, —C(═O)—C 1-4 alkyl, —C(═O)—O—C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)—N(C 1-4 alkyl) 2 , C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy; and

0 to 3 R 6 (s) are present, and each R 6 is independently selected from the group consisting of H, halogen, —CN, —NO 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, and 4-6 membered heterocycloalkyl; and

X 1 and X 2 are each independently selected from the group consisting of —CH N and C in case of being directly connected with R 5 .

2 . The compound according to claim 1 or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 is H.

3 . The compound according to claim 1 or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R 5 is selected from halogen, C 1-6 alkyl, C 3-7 cycloalkyl, and 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-7 cycloalkyl, and 3-10 membered heterocycloalkyl are each optionally substituted with 0 to 4 substituents each independently selected from the group consisting of: halogen, —CN, —OH, C 1-4 alkyl, C 3-6 cycloalkyl.

4 . The compound according to claim 1 or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein H is optionally replaced by D at each occurrence.

5 . The compound according to claim 1 or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((R)-3-hydroxypyrrolidin-1-yl)phenyl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-morpholinopyridin-3-yl)-1H-indazole-3-carboxamide,

N-(1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide,

5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide,

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-((3S,5R)-3,5-dimethylpiperazin-1-yl) pyridin-3-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide,

N-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-hydroxypiperidin-1-yl)phenyl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(1-hydroxycyclopropyl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(5-((3S,5R)-3,5-dimethylpiperazin-1-yl) pyridin-2-yl)-1H-indazole-3-carboxamide,

5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S, 5R)-3, 5-dimethylpiperazin-1-yl)-3-fluorophenyl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(1-ethylpiperidin-4-yl)phenyl)-1H-indazole-3-carboxamide,

5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-N-(1-ethyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

N-(1-cyclobutyl-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(morpholinomethyl)phenyl)-1H-indazole-3-carboxamide,

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((S)-2-hydroxypropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((R)-2-hydroxypropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-ethyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-ethylazetidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-ethylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpyrrolidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpiperidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpiperidin-2-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

5-(1-(3,5-dichloropyridin-4-yl) propoxy)-N-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, and

(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylazetidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide.

6 . A pharmaceutical composition comprising the compound according to claim 1 , or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, adjuvants, or excipients.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 10, 2023

From: LU, LIANG; ZHAO, SAISAI; ZHANG, JIXUAN; HUANG, HAI; ZHANG, LONGZHENG

To: HENAN MEDINNO PHARMACEUTICAL TECHNOLOGY CO., LTD.

Reel/Frame 062654/0990 →

Priority Claims (1)

CN 202010800657.1 · Aug 11, 2020 · national

Continuity (2)

Continuation PCTCN2021111774 · Aug 10, 2021

Related Publication 20230192656A1 · Jun 22, 2023

References Cited (24)

US 10519133B2 · Chen · 2019 [cited by examiner]

CN 1556702A · 2004 [cited by applicant]

CN 101622244A · 2010 [cited by applicant]

CN 102421769A · 2012 [cited by applicant]

CN 103193773A · 2013 [cited by applicant]

CN 103534239A · 2014 [cited by applicant]

CN 106279119A · 2017 [cited by applicant]

JP 2012526126A · 2012 [cited by applicant]

JP 2018531218A · 2018 [cited by applicant]

WO 2017024968A1 · 2017 [cited by applicant]

WO 2019109995A1 · 2019 [cited by applicant]

WO 2021138391A1 · 2021 [cited by applicant]

The Extended European Search Report for the European Patent Application No. 21855524.1, issued on Dec. 14, 2023. [cited by applicant]

The First Office Action issued by the European Patent Office dated Jan. 26, 2024 for the European Patent Application No. 21855524.1. [cited by applicant]

The First Office Action issued by the Japanese Patent Office dated Feb. 6, 2024 for the Japanese Patent Application No. 2023-507336. (English translation included). [cited by applicant]

China National Intellectual Property Administration; First Office Action issued in App No. 202110911922.8 dated Oct. 11, 2024. [cited by applicant]

International Search Report and Written Opinion of PCT/CN2021/111774, dated Nov. 10, 2021. [cited by applicant]

Casadei et al. “Targeted therapies for advanced bladder cancer: new strategies with FGFR inhibitors.” Therapeutic advances in medical oncology, 11, 2019. [cited by applicant]

Dai et al. “Fibroblast growth factor receptors (FGFRs): structures and small molecule inhibitors.” Cells 8(6), 614, Jun. 2019. [cited by applicant]

Lau et al. “Mechanisms of acquired resistance to fibroblast growth factor receptor targeted therapy.” Cancer Drug Resistance 2(3), 568, 2019. [cited by applicant]

Tan et al. “Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.” Proceedings of the National Academy of Sciences 111(45), E4869-E4877, Oct. 2014. [cited by applicant]

Wu et al. “LY2874455 potently inhibits FGFR gatekeeper mutants and overcomes mutation-based resistance.” Chemical Communications 54, 2089-12092, 2018. [cited by applicant]

Fumarola et al. “Expanding the arsenal of FGFR inhibitors: a novel chloroacetamide derivative as a new irreversible agent with anti-proliferative activity against FGFR1-amplified lung cancer cell lines.” Frontiers in On… [cited by applicant]

Stahl et al. “Handbook of pharmaceutical salts: properties, selection and use.” Chemistry International, 24(3), 2002. [cited by applicant]