CN117700397A

CN117700397A - 2-oxo indoline derivative and preparation method and application thereof

Info

Publication number: CN117700397A
Application number: CN202311448997.2A
Authority: CN
Inventors: 余聂芳; 夏伟; 吴文涛; 张锦华; 毕欣
Original assignee: Xunuo Pharmaceutical Nanjing Co ltd
Current assignee: Xunuo Pharmaceutical Nanjing Co ltd
Priority date: 2022-11-02
Filing date: 2023-11-02
Publication date: 2024-03-15

Abstract

The invention discloses a 2-oxo indoline derivative, a preparation method and medical application thereof. More specifically, these compounds are useful as medicaments for the treatment of proliferative disorders and other diseases associated with abnormal expression of various kinases. In particular, these compounds are useful as medicaments for the treatment of proliferative disorders and other diseases associated with abnormal expression of various kinases such as RET, PDGFR, VEGFR. The structure of the novel pyrimidine is shown as a general formula (I), wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、L ¹ 、L ² And X is defined in the specification.

Description

2-oxo indoline derivative and preparation method and application thereof

Technical Field

The invention relates to a novel 2-oxo indoline derivative, a preparation method and application thereof. In particular to a novel 2-oxo indoline derivative with the functions of inhibiting the growth of a wild tumor strain with high expression of kinase or a tumor cell strain with mutation of corresponding kinase and a preparation method thereof. In particular, these compounds are useful as medicaments for the treatment of proliferative disorders, and other diseases associated with abnormal expression of various kinases such as RET, PDGFR, VEGFR. Furthermore, the invention relates to medicaments containing these compounds and to the use of these compounds for the preparation of medicaments.

Background

Tumors are one of the major diseases threatening human health. Chemotherapy remains one of the important means of tumor treatment during the course of tumor treatment. Especially small molecule targeted therapies for tumors and in combination with other methods are playing an increasingly important role. Among the numerous targeted therapeutic agents, inhibitors acting on kinases, in particular RET, PDGFR (PDGFR alpha and PDGFR beta), inhibitors of VEGFR, are of great interest.

RET is a neuronal growth factor receptor tyrosine kinase and is also a transmembrane glycoprotein. RET is expressed by protooncogene RET (Rearranged durIng TransfectIon) located on chromosome 10 and plays an important role in the development of the renal and enteric nervous systems at embryonic stage, and is also critical in various tissue homeostasis such as neurons, neuroendocrine, hematopoietic tissues, male germ cells, and the like. RET, unlike other RTKs, does not bind directly to ligand molecules: such as neurotensin (Artemin), glial-derived neurotrophic factor (GDNF), neurturin and persephin, which are ligands belonging to the GNDF Family (GFLs). These ligand GFLs typically bind to GDNF family receptor alpha (gfrα) and the resulting GFLs-gfrα complex mediates the autophosphorylation of RET protein, causes trans autophosphorylation of tyrosine on intracellular domains, recruits related adaptor proteins, activates signaling cascades such as cell proliferation, and related signaling pathways including MAPK, PI3K, JAK-STAT, PKA, PKC, and the like. ((1) Maria Grazia Borrello, elena Ardini, laura D location, angela Greco, lisa Licitra & Marco APierotti (2013). RET Inhibition: implicatIons in cancer treatment. Expert Opinion on Therapeutic Targets,17:4, 403-419) (2) Samule A. Wells, jr, furio Pacini, bruce G. Robinson, and Massimo Santoro. Multiple Endocrine Neoplasia Type 2and Familiai Meduliary Thyroid Carcinoma:An Update.J Clin Endocrinol Metab 98:3149-3164,2013).

There are two main mechanisms of oncogenic activation of RET: first, chromosomal rearrangements create new fusion proteins, typically fusion of the kinase domain of RET and a protein comprising a self-dimerization domain; secondly, RET mutations activate the kinase activity of RET either directly or indirectly. These alterations in somatic or germ cell levels are involved in the pathogenesis of a variety of cancers. RET chromosome rearrangement is present in 5% -10% of papillary thyroid cancer patients; whereas 60% of RET point mutations were found in medullary thyroid medullary carcinoma; in all NSCLC patients, approximately 1-2% have RET fusion proteins, with KIF5B-RET being most common.

These facts all indicate an ideal therapeutic approach for treating tumors associated with sustained activation of RET. Research on RET inhibitors has been widely paid attention to and has also been rapidly developed. Among them, RET inhibitors represented by Pralsetiib (WO 2017011776A1 Array Loxo 292) and Selpercatinib (WO 2017079140A1 Blu 667) were approved by the FDA for the treatment of various related fusion tumors without tumor differentiation and succeeded. And in turn motivated various other development attempts. ((1) Lucille Lopez-Delisle, ccIle Pierre-Eug's ne, caroline Louis-Brenneot, dier Surdez, virgine Raynal, sylvain Baullan de, valentina Boeva, sandrine Grosset E-Laiami, valirie Combiaret, michel Peuchmaur6, olivier Delattre, isabelle Janoueix-Lerosey. Active ALK signals through the ERK-ETV5-RET pathway to drive neuroblastoma oncogenic, oncogene (2018) 37:1417-1429 (2) WO 2014/141187A1.RET Kinase Inhibitors May Treat Cancer and Gastrointestinal Disorders (3) Minoso Song. Progress In Discovery of KIF B-RET Kinase Inhibitors for the Treatment of Non-Smallpell-Cell Minipctitive J. Med. 3681, 58, 362.)

Platelet derived growth factor (platelet derived growth factor, PDGF) is directed to almost all mesenchymal-derived cellsA family of potent mitogens. PDGF exerts its cellular effects through PDGF receptor alpha (pdgfrα) and PDGF receptor beta (pdgfrβ). Pdgfrα is structurally similar to pdgfrβ and is capable of forming heterodimers and homodimers. Examples of the currently reported inhibitors against both pdgfrα and pdgfrβ include nindaanib (nintadanib) and the like. They have inhibitory effects on cKIT, BCR-ABL, etc., in addition to PDGFRa and PDGFRss. (Anoverview of kinasedownregulatorsand recentadvancesindiscoveryapproac hes.Beilei Wang,Hong Wu,Chen Hu,Haizhen Wang,Jing Liu,Wenchao Wang,and Qingsong Liu.Signal Transduction and Targeted Therapy(2021)6:423)

Vascular endothelial growth factors (Vascular endothelial growth factors, VEGFs) were originally found as vascular permeability factors (vascular permeability factor, VPF), a cytokine secreted by tumor cells that increases vascular permeability. It has now been shown that VEGFs (vascular endothelial growth factor) are hormonal modulators of endothelial cell differentiation, which bind to VEGFR (vascular endothelial growth factor receptor) tyrosine kinase, which is specifically and highly expressed on the surface of neovascular endothelial cells, activating the tyrosine kinase and thus exerting biological functions. It was found that VEGFR inhibitors are capable of blocking VEGFR in vitro, thereby inhibiting vascular endothelial growth factor binding to VEGFR. Related kinase inhibitors such as Lenvatinib mesylate have been marketed with FDA approval for the treatment of renal cancer, liver cancer, and thyroid cancer (Overview of Lenvatinib as a targeted therapy for advanced hepatocellular carpinoma. Obaid Rehman, uroj Jaferi, inderbir Padda, nimrate Khehra, harshan Atwal, dina Mossabeh, ranvir bhangu.clin Exp HEPATOL 2021;7, 3:249-257).

As described above, research and development of RET-targeted kinase inhibitors have been largely successful in treating fusion tumors (Alexander Drilon, zishuo I.Hu, gilliane G.Y. Lai & Daniel S.W. Tan Targeting RET-drive targets: lessons from evolving preclinical and clinical land caps. Nature Reviews Clinical Oncology volume15,2018,151-167). However, inhibition of RET and inhibition of a plurality of kinases such as PDGFR, VEGFR, FGFR, FLT, aurora-A, aurora-B, TRK, B-RAF, RET and Abl can be achieved at the same time, which is potentially useful for solving the problem of drug resistance of the relevant drugs. Therefore, the application is intended to research kinase multi-target inhibitors aiming at RET, PDGFR, VEGFR and other kinases so as to meet huge social needs.

Disclosure of Invention

The invention aims at disclosing a novel 2-oxo indoline derivative. The compounds act on PDGFR, VEGFR, FGFR, FLT3, aurora-A, aurora-B, TRK, B-RAF, RET or Abl and other kinases, and can be used for treating tumors, endocrine disorders, immune system diseases, genetic diseases and neurodegenerative diseases.

The second purpose of the invention is to disclose a preparation method of the 2-oxo indoline derivative.

More specifically, the invention relates to a novel 2-oxo-indoline derivative, a preparation method and medical application thereof. More specifically, these compounds are useful as medicaments for the treatment of proliferative disorders and other diseases associated with abnormal expression of various kinases. In particular, these compounds are useful as medicaments for the treatment of proliferative disorders and other diseases associated with abnormal expression of various kinases such as RET, PDGFR, VEGFR. The structure of the novel pyrimidine is shown as a general formula (I), wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、L ¹ 、L ² And X is defined as follows:

in the above-mentioned general formula (I),

R ¹ selected from: hydrogen, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, carboxyalkyl, carboxycycloalkyl; any of the above groups, independently of one another, may be unsubstituted or may be substituted with one or more substituentsSome substituents include, but are not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, amino, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is C1-C8 straight chain or branched alkyl;

R ² Selected from: hydroxy, alkyl, aryl, alkoxy, heteroalkoxy, arylalkoxy, C3-C8 cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is C1-C8 straight chain or branched alkyl;

R ³ 、R ⁴ each independently selected from: hydrogen atom, halogen, isotope, hydroxy, amino, carboxyl, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkyloxy, heteroalkyloxy, arylalkyloxy, cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino A group, a heteroarylamino group, a heteroarylalkylamino group, a heterocycloalkylamino group, a carboxyl group, a carboxyalkylaminocarbonyl group, a cycloalkylaminocarbonyl group, a heteroarylaminocarbonyl group; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is C1-C8 straight chain or branched alkyl;

R ⁵ selected from: hydrogen atom, isotope, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is C1-C8 straight chain or branched alkyl;

R ⁶ Selected from: hydrogen atom, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, heteroarylalkyl, heterocycloalkyl; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including alkyl, alkoxy; the alkyl is C1-C8 straight chain or branched alkyl;

R ⁷ selected from: hydrogen atom, isotope, halogen, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl; alkoxy, heteroalkoxy, arylalkoxy, cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, alkylaminocarbonyl, any of the foregoing independently of each other may be unsubstituted or substituted with one or more substituents including, but not limited to, halogen, alkyl, alkoxy; the alkyl is C1-C8 straight chain or branched alkyl;

R ⁷ c which can be linked to the benzimidazole ring ⁴ -、C ⁵ -、C ⁶ -or C ⁷ -in the position;

L ¹ selected from: covalent bonds, alkylene, heteroalkylene, -NH, -C (O) -NH-, -NH-C (O) -, alkylene-C (O) -, -C (O) -C (O) -, alkylene-C (O) -NH, alkylene-C (O) -, alkylene-NH-; the alkylene is a C1-C8 straight or branched alkyl; any of the above groups, independently of each other, may be substituted with one or more substituents including a hydrogen atom, an alkyl group;

L ² selected from: hydrogen atom, alkyl group, heteroalkyl group, alkenyl group, alkynyl group, arylalkyl group, C3-C14 cycloalkyl group, aryl group, heteroaryl group, heteroarylalkyl group, heterocycloalkyl group, alkoxy group, heteroalkoxy group, arylalkoxy group, cycloalkoxy group, aryloxy group, heteroaryloxy group, heteroarylalkoxy group, heterocycloalkoxy group, amino group, alkylamino group, heteroalkylamino group, arylalkylamino group, cycloalkylamino group, arylamino group, heteroarylamino group, heteroarylalkylamino group, heterocycloalkylamino group, carboxyl group, carboxyalkylaminocarbonyl group, cycloalkylaminocarbonyl group, heteroarylaminocarbonyl group; any of the above groups, independently of each other, may be unsubstituted or substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, benzene Acyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is C1-C8 straight chain or branched alkyl;

x is selected from: a nitrogen atom, a carbon atom;

L ³ selected from: absence, covalent bond, alkylene, heteroalkylene, -NH, -C (O) -NH-, -NH-C (O) -, alkylene-C (O) -, -C (O) -C (O) -, alkylene-C (O) -NH, alkylene-C (O) -, alkylene-NH-; the alkylene is a C1-C8 straight or branched alkyl; any of the above groups, independently of each other, may be substituted with one or more substituents including a hydrogen atom, an alkyl group;

R ⁸ selected from: non-existent, hydrogen atom, hydroxyl group, alkyl group, hydroxyalkyl group, heteroalkyl group, alkenyl group, alkynyl group, arylalkyl group, C3-C14 cycloalkyl group, aryl group, heteroaryl group, heteroarylalkyl group, heterocycloalkyl group, alkoxy group, heteroalkoxy group, arylalkoxy group, cycloalkoxy group, aryloxy group, heteroaryloxy group, heteroarylalkoxy group, heterocycloalkoxy group, amino group, alkylamino group, heteroalkylamino group, arylalkylamino group, cycloalkylamino group, arylamino group, heteroarylamino group, heteroarylalkylamino group, heterocycloalkylamino group, carboxyl group, alkylaminocarbonyl group, carboxyalkylaminocarbonyl group, cycloalkylaminocarbonyl group, heteroarylaminocarbonyl group; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, Alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is C1-C8 straight chain or branched alkyl;

(R ⁶ ) N may be linked to C on the benzimidazole ring ⁴ -、C ⁵ -、C ⁶ -or C ⁷ -in position, where formula (I) is selected from:

in certain embodiments, R is according to formula (I) above ¹ Selected from the group consisting of hydrogen, alkyl, heteroalkyl, arylalkyl, cycloalkyl, heteroarylalkyl, heterocycloalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfinyl; in the above groups, each may be unsubstituted or substituted with one or more substituents including: halogen, isotope, =o, -CF3, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl.

In certain embodiments, R is according to formula (I) above ¹ Selected from: methyl, ethyl or propyl.

In certain embodiments, R is according to formula (I) above ¹ Selected from C1-C5 alkyl, C3-C8 cycloalkyl.

R ² Selected from: hydroxy, alkyl, aryl, alkoxy, heteroalkoxy, arylalkoxy, C3-C8 cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl A group, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is a C1-C8 straight chain or branched alkyl.

In certain embodiments, R is according to formula (I) above ² Independently selected from: hydroxy, C1-C5 straight or branched chain alkyl alkoxy, heteroalkoxy, arylalkoxy, C3-C8 cycloalkoxy, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino; any of the above groups, independently of each other, may be substituted with one or more substituents including, but not limited to, halogen, carboxyl, phenyl, =o, -CF3, alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl.

In certain embodiments, R is according to formula (I) above ² Selected from: methoxy, ethoxy, propoxy.

R ³ 、R ⁴ Each independently selected from: hydrogen atom, halogen, isotope, hydroxy, amino, carboxyl, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkyloxy, heteroalkyloxy, arylalkyloxy, cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, carboxyalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups, independently of each other, may be unsubstituted or substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, Aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is a C1-C8 straight chain or branched alkyl.

In certain embodiments, when R is according to formula (I) above ³ R is hydrogen atom ⁴ Selected from: hydrogen, halogen, isotope, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkoxy, heteroalkoxy, arylalkoxy, cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxy, carboxyalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl; the alkyl is a C1-C8 straight chain or branched alkyl.

In certain embodiments, when R is according to formula (I) above ⁴ R is hydrogen atom ³ Selected from: hydrogen atom, halogen, isotope, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkoxy, heteroalkoxy, arylalkoxy, cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylaminoA group, a heteroarylamino group, a heteroarylalkylamino group, a heterocycloalkylamino group, a carboxyl group, a carboxyalkylaminocarbonyl group, a cycloalkylaminocarbonyl group, a heteroarylaminocarbonyl group; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl; the alkyl is a C1-C8 straight chain or branched alkyl.

In certain embodiments, R is according to formula (I) above ⁴ Selected from: cyclopropane, cyclobutane, cyclopentane, methyl, ethyl, propyl, isopropyl, halophenyl, allyl, and allyl.

In certain embodiments, R is according to formula (I) above ⁴ Selected from: p-fluorophenyl, p-chlorophenyl, p-bromophenyl, and p-iodophenyl.

In certain embodiments, R is according to formula (I) above ⁵ Selected from: hydrogen atom, isotope, alkyl, heteroalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl; the alkyl is a C1-C8 straight chain or branched alkyl.

R ⁵ Selected from: benzene ring, pyrazole, pyrimidine,Methyl, ethyl, propyl.

In certain embodiments, according to the aboveOf the general formula (I), R ⁶ Selected from: hydrogen atom, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, heteroarylalkyl, heterocycloalkyl; any of the above groups, independently, may be unsubstituted or may be substituted with one or more alkyl groups, alkoxy groups; the alkyl is a C1-C8 straight chain or branched alkyl.

In certain embodiments, R is according to formula (I) above ⁶ Selected from: hydrogen atom, alkyl, C3-C14 cycloalkyl.

In certain embodiments, R is according to formula (I) above ⁷ Selected from: hydrogen atom, isotope, halogen, alkyl, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl; alkoxy, heteroalkoxy, arylalkoxy, cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, alkyl, alkoxy; the alkyl is a C1-C8 straight chain or branched alkyl.

In certain embodiments, R7 may be linked to C on the benzimidazole ring according to formula (I) above ⁴ -、C ⁵ -、C ⁶ -or C ⁷ -on the bit.

In certain embodiments, L is according to formula (I) above ¹ Independently selected from: covalent bonds, alkylene, heteroalkylene, -NH-, -C (O) -NH-, -NH-C (O) -, alkylene-C (O) -, -C (O) -C (O) -, alkylene-C (O) -NH, alkylene-C (O) -, alkylene-NH-; the alkylene is a C1-C8 straight or branched alkyl; any of the above groups, independently of each other, may be substituted with one or more substituents including hydrogen atoms, alkyl groups.

In certain embodiments, L is according to formula (I) above ¹ Selected from: ethylene-NH-CO-, ethylene, methylene, propylene.

In certain embodiments, L is according to formula (I) above ² Independently selected from: hydrogen atoms, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkylA group, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkoxy, heteroalkoxy, arylalkoxy, cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, carboxyalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is a C1-C8 straight chain or branched alkyl.

In other certain embodiments, L is according to formula (I) above ² More preferably independently selected from: methyl group,

Benzene ring, m-fluorophenyl, ">

In certain embodiments, according to formula (I) above, L is at the X carbon atom ³ Selected from: covalent bond, alkylene, heteroalkylene, -NH, -C (O) -NH-, -NH-C (O) -, alkylene-C (O) -, and-C (O) -, alkylene-C (O) -NH, alkylene-C (O) -, alkylene-NH-; the alkylene is a C1-C8 straight or branched alkyl; any of the above groups, independently of each other, may be substituted with one or more substituents including hydrogen atoms, alkyl groups.

L ³ Selected from: ethylene, methylene, alkylene-C (O) -NH, alkylene-C (O) -, alkylene-NH-C (O) -.

In certain embodiments, R is, according to formula (I) above, at the X carbon atom ⁸ Independently selected from: hydrogen, hydroxy, alkyl, heteroalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkoxy, heteroalkoxy, arylalkoxy, cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxy, alkylaminocarbonyl, carboxyalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is a C1-C8 straight chain or branched alkyl.

In other certain embodiments, R is according to formula (I) above ⁸ More preferably independently selected from: methyl, -CF3, Benzene ring, m-fluorophenyl, ">

In certain embodiments, according to formula (I) above, (R ⁶ ) N may be linked to C on the benzimidazole ring ⁴ -、C ⁵ -、C ⁶ -or C ⁷ -on the bit. (R) ⁶ ) N is more preferably C linked to the benzimidazole ring ⁵ -、C ⁶ In the position where formula (I) is selected from:

the invention also claims a preparation method of the compound shown in the general formula (I), which comprises the following steps:

when (R) ⁶ ) N may be linked to C on the benzimidazole ring ⁵ In the position, and R ¹ ＝R ³ ＝R ⁴ ＝R ⁶ ＝H，R ² ＝OCH ₃ And x=carbon atom, the preparation method comprises the steps of:

s1, cyclizing the substituted 4-nitro-2-aminobenzene derivative (VI) with aldehyde (VII) or triethyl orthoformate to convert into a corresponding 5-nitrobenzimidazole derivative (VIII);

s2, reducing the 5-nitrobenzimidazole derivative (VIII) to obtain a 5-aminobenzimidazole derivative (IX), and then reacting with a 2-oxo indoline derivative (X) to obtain a target compound (XI);

the synthetic route is as follows:

when (R) ⁶ ) N may be linked to C on the benzimidazole ring ⁵ In the position, and R ¹ ＝R ³ ＝R ⁴ ＝R ⁶ ＝H，R ² When=oc2h5 and x=carbon atom, the preparation method comprises the following steps:

s1, heating and reacting a substituted 4-bromo-2-oxo indoline derivative (XII) with a boric acid derivative (XIII) palladium reagent to obtain a condensation product (XIV);

S2, the condensation product (XIV) reacts with orthoformate to obtain an intermediate (XV),

s3, reacting the intermediate (XV) with benzimidazole (XVI) to obtain a target compound (XVII) shown in the general formula (I);

the synthetic route is as follows:

in some embodiments, the compounds of the present invention have one of the following structures, or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof.

The invention also includes a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof.

The invention also comprises a pharmaceutical composition which contains the compound shown in the general formula (I) or stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof; in combination with one or more other drugs.

The invention comprises any pharmaceutical dosage form formed by the compound represented by the general formula (I) and a pharmaceutically acceptable diluent, excipient or carrier.

The present invention provides methods of treating conditions caused by, associated with, or associated with disruption of cell proliferation and/or angiogenesis using an effective amount of a compound of formula (I), alone or in combination with other agents.

In certain embodiments, the disorder is a proliferative disease.

In certain embodiments, the proliferative disease is cancer.

The invention also includes the use of a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above for inhibiting kinase activity.

In certain embodiments, the kinase inhibiting activity is an activity that inhibits RET, PDGFR, VEGFR, FGFR, FLT3, aurora-A, aurora-B, TRK, RAF, RET, or Abl.

The invention also includes a method for treating a condition caused by, associated with, or associated with disruption of cell proliferation and/or angiogenesis in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) above, or a pharmaceutically acceptable salt thereof.

The invention also includes a method of treating a condition treatable by inhibition of a kinase in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof.

Disorders caused, associated, or accompanied by cell proliferation and/or angiogenesis include, but are not limited to: bone cancers, comprising: ewing's sarcoma, osteosarcoma, chondrosarcoma, etc.; brain and CNS tumors, comprising: auditory neuroma, neuroblastoma, neuroglioblastoma and other brain tumors, spinal cord tumors, breast cancer, colorectal cancer, stage-advanced colorectal adenocarcinoma; endocrine cancers, including: adrenal cortex cancer, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, and multiple endocrine tumors; gastrointestinal cancers, including: gastric cancer, esophageal cancer, small intestine cancer, liver cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumor and gallbladder cancer; genitourinary cancers, comprising: green pill cancer, penile cancer, and prostate cancer; a gynaecological cancer class comprising: cervical cancer, ovarian cancer, vaginal cancer, uterine/endometrial cancer, pudendum cancer, gestational trophoblastic tumor, fallopian tube cancer, uterine sarcoma; head and neck neoplasms, comprising: oral cancer, lip cancer, salivary gland cancer, laryngeal cancer, hypopharyngeal cancer, orthopharyngeal cancer, nasal cancer, sinus cancer, and nasopharyngeal cancer; a blood cancer group comprising: childhood leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell leukemia; a bone marrow cancer hematological disorder comprising: myelodysplastic syndrome, myeloproliferative disorders, aplastic anemia, fan Heni anemia, idiopathic macroglobulinemia; a lung cancer class comprising: small cell lung cancer, non-small cell lung cancer; lymphomas, including: hodgkin's disease, non-hodgkin's lymphoma, cutaneous T-cell lymphoma, peripheral T-cell Lin Baliu, AIDS-related lymphoma; eye cancers, comprising: retinoblastoma, uveal melanoma; skin cancers, comprising: melanoma, non-melanoma skin cancer, merkel cell carcinoma; soft tissue sarcomas, for example: soft tissue sarcomas in children, soft tissue sarcomas in adults, kaposi's sarcoma; urinary system cancer, comprising: kidney cancer wilms' tumor, skin cancer, urinary tract cancer and metastatic cell cancer.

In certain embodiments, in the above methods, the patient is undergoing surgery or radiation therapy, and the compound is administered to the patient concomitantly with, or prior to, or subsequent to the surgery or radiation therapy.

Drawings

FIG. 1 shows tumor growth changes in TT cell xenograft model tumor-bearing mice following administration of compound 53;

FIG. 2 shows the change in body weight of tumor-bearing mice in TT cell xenograft model following administration of compound 53.

Detailed Description

The invention discloses a preparation method and medical application of novel 2-oxo indoline derivatives. These compounds are useful as, but are not limited to, kinase inhibitors. The aminopyrazole derivatives disclosed herein can be used alone or in combination with other pharmaceutical or pharmaceutically acceptable carriers, diluents or excipients, and are useful for preventing or treating conditions caused by, associated with, or associated with the disruption of cell proliferation and/or angiogenesis. One example of such a condition is cancer.

The term "cancer" as used herein generally refers to a broad range of conditions characterized by uncontrolled abnormal growth of cells.

The compounds of the invention are expected to be useful in the treatment of a variety of cancers, including but not limited to: bone cancers, comprising: ewing's sarcoma, osteosarcoma, chondrosarcoma, etc.; brain and CNS tumors, comprising: auditory neuroma, neuroblastoma, neuroglioblastoma and other brain tumors, spinal cord tumors, breast cancer, colorectal cancer, stage-advanced colorectal adenocarcinoma; endocrine cancers, including: adrenal cortex cancer, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, and multiple endocrine tumors; gastrointestinal cancers, including: gastric cancer, esophageal cancer, small intestine cancer, liver cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumor and gallbladder cancer; genitourinary cancers, comprising: green pill cancer, penile cancer, and prostate cancer; a gynaecological cancer class comprising: cervical cancer, ovarian cancer, vaginal cancer, uterine/endometrial cancer, pudendum cancer, gestational trophoblastic tumor, fallopian tube cancer, uterine sarcoma; head and neck neoplasms, comprising: oral cancer, lip cancer, salivary gland cancer, laryngeal cancer, hypopharyngeal cancer, orthopharyngeal cancer, nasal cancer, sinus cancer, and nasopharyngeal cancer; a blood cancer group comprising: childhood leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell leukemia; a bone marrow cancer hematological disorder comprising: myelodysplastic syndrome, myeloproliferative disorders, aplastic anemia, fan Heni anemia, idiopathic macroglobulinemia; a lung cancer class comprising: small cell lung cancer, non-small cell lung cancer; lymphomas, including: hodgkin's disease, non-hodgkin's lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, AIDS-related lymphoma; eye cancers, comprising: retinoblastoma, uveal melanoma; skin cancers, comprising: melanoma, non-melanoma skin cancer, merkel cell carcinoma; soft tissue sarcomas, for example: soft tissue sarcomas in children, soft tissue sarcomas in adults, kaposi's sarcoma; urinary system cancer, comprising: kidney cancer wilms' tumor, skin cancer, urinary tract cancer and metastatic cell cancer.

The disclosed compounds of the present invention may be used to treat cancers comprising, first: breast cancer, lung cancer, liver cancer, ovarian cancer, prostate cancer, head and neck cancer, kidney, stomach and brain cancer.

Preferred cancers that can be treated by the compounds of the present invention are solid tumors and hematological malignancies.

The term "unsubstituted" as used herein means unsubstituted or substituted with hydrogen only.

Some of the terms used in the present invention are defined as follows:

"halogen" refers to fluorine, chlorine, bromine and iodine.

"isotope" means the same compound as that listed herein, but in which one or more atoms are replaced by another atom, the atomic mass or mass number of which is different from that which is common in nature. Isotopes that can be incorporated into compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, i.e ² H, ³ H、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ¹⁸ F、 ³⁵ S, S. Compounds of formula (I) and stereoisomers thereof, as well as pharmaceutically acceptable salts of such compounds, stereoisomers, containing isotopes and/or other atomic isotopes, are intended to be encompassed within the scope of this invention.

"=o" refers to oxo.

“-CF ₃ "means trifluoromethyl.

"-CO-NH-" is "-amide-".

"-NH-CO-" is "-aminoacyl-".

"carbonyl" means

"alkyl" when taken as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group. Preferably, the alkyl group is a C1-C14 alkyl group; more preferred choices are: C1-C10 alkyl; most preferably C1-C6, unless otherwise indicated. Examples of straight or branched C1-C6 alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, hexyl and the like.

"bicyclic ring" and "fused ring" refer to cyclic groups in which the ring system is formed from two or more cyclic structures sharing two adjacent carbon atoms with each other. Including 4-14 membered saturated fused ring alkyl groups and 6-14 membered partially saturated fused ring alkyl groups, specific examples of which include, but are not limited to, the following structures:

"Spiro" refers to a structure containing 7-14 carbon atoms or/and heteroatoms, such as nitrogen, oxygen, sulfur, etc., formed by at least two rings sharing one atom. The 7-14 membered spiro ring includes 7-14 membered saturated spiro ring and 7-14 membered partially saturated spiro ring. By 7-14 membered saturated spiro ring is meant that all rings in the spiro ring are saturated cyclic groups, specific examples include, but are not limited to:

"cycloalkyl" refers to a saturated or partially saturated monocyclic, bicyclic, fused, or spiro carbocyclic ring. Preferably, a ring of 3 to 14 carbon atoms is used. Examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The definition of "bicyclic", "fused ring" or "spiro" moieties herein is given in the relevant sections.

"heteroalkyl" refers to a straight-chain or branched-chain alkyl-containing group and contains at least one or more heteroatoms selected from S, O, and N in the backbone. Preferably, the chain contains 2 to 14 atoms. Heteroalkyl groups include, but are not limited to: ethers, thioethers, alkyl esters, second or third alkylamines, alkylsulfinates, and the like.

"heterocycloalkyl" refers to a group formed by substitution of one or more (preferably 1, 2 or 3) carbon atoms in a "cycloalkyl" group as defined above with an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atom (preferably oxygen, sulfur or nitrogen). Wherein heterocycloalkyl and alkyl moieties are defined herein. Preferably containing 1 to 3 heteroatoms. Preferred rings are 3-14 membered rings (i.e., 3-14 membered heterocycloalkyl), more preferred rings are 4-7 membered rings (i.e., 4-7 membered heterocycloalkyl). Heterocycloalkyl groups include, but are not limited to: pyrrolidinyl, dihydropyrrolyl, tetrahydropyrrolyl, dihydropyrazolyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, oxacyclopropyl, aziridinyl, or 2-pyrazolinyl, as well as lactams, lactones, cyclic imines, cyclic anhydrides, and the like. Heterocycloalkyl groups can be substituted with one or more substituents.

"Heterocyclylalkylalkyl" means: (heterocycloalkyl-alkyl) -groups. Wherein heterocycloalkyl and alkyl moieties are defined herein. Heterocyclylalkylalkyl groups include, but are not limited to: (2-tetrahydrofuranyl) methyl, (2-tetrahydrothiofuranyl) methyl, and the like.

"alkylamino" includes both monoalkylamino and dialkylamino unless otherwise indicated. "monoalkylamino" means: (alkyl-NH) -groups; "dialkylamino" refers to: ((alkyl) ₂ N) -group. Wherein alkyl is as defined herein. The alkyl group is preferably a C1-C6 alkyl group. Examples include, but are not limited to: n-methylamino, N-ethylamino, N-isopropylamino, N- (diethyl) amino, and the like.

"Heteroalkylamino" means: both mono-heteroalkylamino and di-heteroalkylamino, unless otherwise indicated. Mono-heteroalkylamino means: a (heteroalkyl-) NH-group; di-heteroalkylamino means (heteroalkyl) ₂ N-radicals. Wherein the "heteroalkyl" moiety is defined in the relevant section herein.

"aminoalkyl" means: (amino-alkyl) -groups. Wherein the "alkyl" moiety is as defined herein. The aminoalkyl group is preferably an amino C1-C6 alkyl group. "amino-C1-C6 alkyl" refers to a C1-C6 alkyl group substituted with "amino", examples of which include, but are not limited to: aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like.

"arylamino" includes both mono-arylamino and di-arylamino unless otherwise indicated. Mono-arylamino refers to: a (aryl-) NH-group; di-arylamino refers to the formula (aryl) ₂ A group of N-; aryl is defined in the relevant section herein.

"acyl" includes both (alkyl-CO) -groups and (aryl-CO) -groups, unless otherwise indicated. Wherein alkyl or aryl are as defined herein. Examples of acyl groups include, but are not limited to: acetyl, propionyl, isobutyryl, benzoyl, and the like.

"amide groups" include both (alkyl-CONH) -groups and (aryl-CONH) -groups, unless otherwise indicated. Wherein alkyl or aryl are as defined herein. Examples of amide groups include, but are not limited to: acetamido, propionamido, butyrylamino, isobutyrylamino, benzamido, and the like.

"alkenyl" as a group or part of a group refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be straight or branched. Alkenyl groups having C2-C14 are preferred. C2-C12 are more preferred; most preferred are C2-C6 alkenyl groups. The group may contain multiple double bonds in its backbone and its conformation may each be E or Z. Examples of alkenyl groups include, but are not limited to: ethenyl, propenyl, and the like.

"alkynyl" as a group or part of a group refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which may be straight or branched. Preferably C2-C14 alkynyl, more preferably C2-C12 alkynyl, most preferably C2-C6 alkynyl. Examples of such alkynyl groups include, but are not limited to: ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-3-yn-1-yl, 1-methylpropan-2-yn-1-yl, pent-1-yn-1-yl, pent-4-yn-1-yl, hex-1-yn-1-yl, hex-5-yn-1-yl, and the like.

"alkoxy" refers to a group of (alkyl-O) -. Wherein the "alkyl" moiety is as defined herein. The alkoxy group is preferably a C1-C8 alkoxy group, more preferably a C1-C6 alkoxy group. Examples of such alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexoxy, isohexoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-dimethylbutoxy, 2-dimethylbutoxy, 1-dimethylbutoxy, 1, 2-dimethylbutoxy, 1, 3-dimethylbutoxy, 2, 3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, and the like. The "alkoxycarbonyl group" represents a group in which the "alkoxy group" defined above is bonded to a carbonyl group, and examples thereof include methoxycarbonyl group and ethoxycarbonyl group.

"alkenyloxy" refers to a group of (alkenyl-O) -. Wherein alkenyl is as defined herein. The alkenyloxy radical of C1-C6 is preferred.

"alkynyloxy" refers to a group of (alkynyl-O) -type. Wherein alkynyl is as defined herein. The alkynyloxy group of C1-C6 is preferable.

"alkoxycarbonyl" refers to a group of (alkyl-O-C (O)) -. Wherein alkyl is as defined herein. Preferred alkyl groups are C1-C6 alkyl groups. Examples include, but are not limited to: methoxycarbonyl, ethoxycarbonyl, and the like.

"Alkylsulfinyl" refers to a group of the formula (alkyl-S (O)) -. Wherein alkyl is as defined herein. Preferred alkyl groups are C1-C6 alkyl groups. Alkylsulfinyl groups include, but are not limited to: methylsulfinyl, ethylsulfinyl, and the like.

"alkylsulfonyl" means (alkyl-S (O)) ₂ -O) -groups. Wherein alkyl is as defined herein. The preferred alkyl groups are C1-C6 alkyl groups. Examples include, but are not limited to: methanesulfonyl, ethanesulfonyl, and the like.

"Alkylaminocarbonyl" refers to an alkylamino-carbonyl group. Wherein alkylamino is as defined herein.

"cycloalkylalkyl" refers to a cycloalkyl-alkyl group. Wherein cycloalkyl and alkyl moieties are as defined herein. Monocycloalkyl groups include, but are not limited to: cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, and the like.

"heterocycloalkenyl" refers to a heterocycloalkyl group containing at least one double bond. Heterocycloalkyl is defined herein in relation to the definition.

"aryl" as a group or part of a group means: (1) an aromatic monocyclic or fused ring; preference is given to aromatic carbocycles having from 5 to 12 carbon atoms (ring structures in which the ring atoms are all carbon). Examples of aryl groups include, but are not limited to: phenyl, naphthyl; (2) a partially saturated carbocyclic ring may be attached, for example: phenyl and C5-7 cycloalkyl or C5-7 cycloalkenyl groups are fused to each other to form a cyclic structure. Examples include, but are not limited to: tetrahydronaphthyl, indenyl, or hydroindenyl, and the like. The aryl group may be substituted with one or more substituents.

"arylalkenyl" refers to: (aryl-alkenyl) -groups. Wherein aryl and alkenyl are as defined herein. Exemplary arylalkenyl groups include, but are not limited to: phenylpropenyl and the like.

"aralkyl" means: (aryl-alkyl) -groups. Wherein aryl and alkyl moieties are as defined herein. Exemplary aralkyl groups include, but are not limited to: benzyl, phenethyl, 1-naphthylmethyl, and the like.

"cycloalkenyl" refers to a non-aromatic monocyclic or multicyclic ring system. Which contains at least one carbon-carbon double bond and preferably has 5 to 10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include, but are not limited to: cyclopentene, cyclohexene or cycloheptene. The cycloalkenyl group may be substituted with one or more substituents.

"heteroaryl" means a monocyclic or fused polycyclic aromatic heterocyclic group, preferably an aromatic group having one or more (preferably 3 to 14, more preferably 5 to 10, particularly preferably 5 or 6) carbon atoms, and one or more (preferably 1, 2,3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N) as ring-forming atoms, preferably the aromatic group is a 4-15 membered heteroaryl, more preferably a 5-7 membered heteroaryl. Examples of the heteroaryl group may be cited, for example: furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, pyridyl, imidazolyl, 3-phenylpyrrolyl, thiazolyl-oxazolyl, tetrazolyl, isoxazolyl, indazolyl, pyridazinyl, quinolinyl, purinyl, carbazolyl, acridinyl, pyrimidinyl, 2,3' -bisfuryl and isoquinolinyl.

"heteroarylalkyl" means: (heteroaryl-alkyl) -groups. Wherein heteroaryl and alkyl moieties are as defined herein. Exemplary heteroaralkyl groups include, but are not limited to: 2-furanmethyl, 3-furanmethyl, 2-picolyl, and the like.

"alkoxy" means: (alkyl) -O-. Wherein the "alkyl" moiety is as defined herein.

"Cycloalkoxy" means: (cycloalkyl) -O-groups. Wherein the "cycloalkyl" moiety is as defined herein.

"heteroalkoxy" refers to: (heteroalkyl) -O-. Wherein the "heteroalkyl" moiety is defined herein.

"aryloxy" means: (aryl) -O-groups. Wherein the "aryl" moiety is as defined herein.

"arylalkoxy" means: (aryl-alkyl) -O-. Wherein the "aryl" and "alkyl" moieties are defined herein.

"heteroaryloxy" means: (heteroaryl) -O-. Wherein the "heteroaryl" moiety is as defined herein.

"heteroarylalkoxy" means: (heteroaryl-alkyl) -O-. Wherein the "heteroaryl" and "alkyl" moieties are defined herein.

"Heterocyclyloxy" means: (heterocycloalkyl) -O-. Wherein the "heterocycloalkyl" moiety is defined herein.

"Heterocyclylamino" refers to: both mono-and di-heterocyclylalkylamino groups unless otherwise indicated. Mono-heterocyclylalkylamino means: (heterocycloalkane)A radical-NH-; di-heterocycloalkyl amino means (heterocycloalkyl) ₂ -a group of N-. Wherein the "heterocycloalkyl" moiety is defined in the relevant section herein.

"arylalkylamino" means: both mono-and di-arylalkylamino groups unless otherwise indicated. Mono-arylalkylamino means: (aryl-alkyl) -NH-groups; di-arylalkylamino means (aryl-alkyl) ₂ -a group of N-. Wherein the "aryl" and "alkyl" moieties are defined in the relevant sections herein.

"cycloalkylamino" means: both mono-cycloalkylamino and di-cycloalkylamino, unless otherwise indicated. Mono-cycloalkylamino refers to: a (cycloalkyl) -NH-group; di-arylalkylamino means (cycloalkyl) ₂ -a group of N-. Wherein the "cycloalkyl" moiety is defined in the relevant section herein.

"arylamino" refers to: both mono-arylamino and di-arylamino groups unless otherwise indicated. Mono-arylamino refers to: (aryl) -NH-groups; di-arylamino refers to (aryl) ₂ -a group of N-. Wherein the "aryl" moiety is defined in the relevant section herein.

"heteroarylamino" means: both mono-and di-heteroarylamino, unless otherwise indicated. Mono-heteroarylamino refers to: (heteroaryl) -NH-groups; di-heteroarylamino means (heteroaryl) ₂ -a group of N-. Wherein the "heteroaryl" moiety is defined in the relevant section herein.

"heteroaryl alkylamino" means: both mono-heteroarylalkylamino and di-heteroarylalkylamino unless otherwise indicated. Mono-heteroarylalkylamino means: (heteroaryl-alkyl) -NH-groups; di-heteroarylalkylamino means (heteroaryl-alkyl) ₂ -a group of N-. Wherein "heteroaryl" and "alkyl" moieties are defined in the relevant sections herein.

Unless otherwise indicated, the subunit of the present invention refers to a divalent group, i.e., a group in which one hydrogen atom in a monovalent group is replaced by a valence. For example, "heteroalkylene" refers to a heteroalkyl group in which one hydrogen atom is replaced with a valence; "Heterocyclylene" refers to a heterocyclic group in which one hydrogen atom is replaced by a valence; "arylene" refers to an aryl group in which one hydrogen atom is replaced by a valence; "alkylene" refers to an alkyl group in which one hydrogen atom is replaced by a valence; "alkenylene" refers to an alkenyl group in which one hydrogen atom is replaced by a valence; "cycloalkylene" refers to a cycloalkyl group in which one hydrogen atom is replaced by a valence; "heteroarylene" refers to a heteroaryl group in which one hydrogen atom has been replaced by a valence; "Heterocyclylene" refers to a heterocycloalkyl in which one hydrogen atom is replaced with a valence; "heterocycloalkenylene" refers to a heterocycloalkenyl group in which one hydrogen atom is replaced with a valence; "Alkyloxy" refers to an alkoxy group in which one hydrogen atom is replaced by a valence; "alkenylene oxy" refers to an alkenylene oxy in which one hydrogen atom is replaced by a valence; "alkynyloxy" refers to an alkynyloxy group or the like in which one hydrogen atom is replaced with a valence. Wherein the above-mentioned heterocyclic group, aryl group, alkyl group, alkenyl group, cycloalkyl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, alkoxy group, alkenyloxy group, alkynyloxy group and the like are defined in the relevant definitions herein.

The invention includes compounds represented by the general formula (I) and the various isomeric forms thereof possible. Comprising the following steps: non-mirror image isomers, tautomers, geometric isomers of "E" or "Z" configuration isomers, and the like. Any chemist with a certain basis can isolate the optically pure or stereoisomerically pure compounds described above.

The invention includes compounds of formula (I) and formula (II) and possible racemates and/or mirror image isomers and/or non-mirror image isomers thereof.

In addition, the compounds of formula (I) are also intended to encompass solvated and unsolvated forms of such compounds. Thus, each formula includes a compound having the indicated structure, including hydrated and anhydrous versions thereof.

In addition to the compounds represented by the general formula (I), kinase inhibitors of various embodiments include: pharmaceutically acceptable salts, prodrugs and active metabolites of such compounds. And pharmaceutically acceptable salts of such metabolites.

The term "pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of compounds of the general formula (I) have two forms: firstly, salts with acids; the other is a salt with a base or an alkali metal. Acids forming pharmaceutically acceptable salts with the compounds represented by the general formula (I) include inorganic acids and organic acids. Suitable mineral acids include: hydrochloric acid, sulfuric acid and phosphoric acid. Suitable organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulphonic organic acids; examples include, but are not limited to: formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, glycine, arginine, citric acid, fumaric acid, alkylsulfonic acid, arylsulfonic acid, and the like. Alkali metals which form pharmaceutically acceptable salts with the compounds represented by the general formula (I) include: lithium, sodium, potassium, magnesium, calcium, aluminum, zinc, etc.; bases which form pharmaceutically acceptable salts with compounds represented by the general formula (I) include: choline, diethanolamine, morpholine, and the like.

A "prodrug" is a derivative of formula (I) which is converted in vivo by means of metabolism in vivo (e.g., by hydrolysis, reduction or oxidation) to a compound of formula (I). For example, the compound having a hydroxyl group represented by the general formula (I) can be reacted with an acid to prepare the corresponding ester. The corresponding ester is a prodrug and can hydrolyze the parent drug in vivo. Acids suitable for preparing "prodrugs" include, but are not limited to: acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, oxalic acid, salicylic acid, succinic acid, fumaric acid, maleic acid, methylene-bis-beta-hydroxynaphthoic acid, gentisic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

The kinase inhibitors of the present invention include IC ₅₀ Those compounds having a value of 10 μm or less. Kinases for use in the present invention include, but are not limited to, those associated with RET, PDGFR, VEGFR, FGFR, FLT3, aurora-A, aurora-B, TRK, BRAF, RET or Abl

The compound represented by the general formula (I) may be administered parenterally or parenterally. Gastrointestinal administration: oral or rectal. Parenteral modes of administration include: subcutaneous, intramuscular, intravenous and intradermal routes. In general, the active compound represented by the general formula (I) may be administered using a pharmaceutically acceptable carrier or diluent.

"therapeutically effective amount" or "therapeutic amount" refers to an amount sufficient to produce a therapeutic effect. The effective amount may be administered in one or more divided doses. Generally, an effective amount is sufficient to alleviate, ameliorate, stabilize, slow or delay further progression of the disease.

The compounds of the present invention may be used alone or in combination with one or more other agents; or in combination with surgery or radiotherapy; or can be made into a certain dosage form with pharmaceutically acceptable carrier, diluent or excipient for administration. The particular dosage form will depend upon the route of administration.

The pharmaceutical formulation for parenteral injection comprises a pharmaceutically acceptable sterile aqueous solution or nonaqueous solution, a dispersing agent, a suspending agent or an emulsifying agent and is prepared into a powder injection of injectable sterile aqueous solution before use.

If desired, and for more efficient distribution, the compounds of the invention may be incorporated into a slow release or targeted delivery system, for example: polymer matrices, liposomes and microspheres.

Solid dosage forms for oral administration include: capsules, tablets, troches, powders and granules. In these solid dosage forms, the active compound represented by the general formula (I) is contained in admixture with at least one inert and pharmaceutically acceptable excipient or carrier. These excipients or carriers include sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as: starch, lactose, sucrose, glucose, mannitol and salicylic acid; b) Binding agents, for example: carboxymethyl cellulose, alginate, gelatin polyvinylpyrrolidone, sucrose and acacia; c) Disintegrants, for example: the starch of the potato or the potato, alginic acid, certain silicates and sodium carbonate; d) Dissolution retarders, such as: paraffin wax; e) Absorption accelerators, for example: a quaternary ammonium compound; f) Humectants, for example: cetyl alcohol and glycerol monostearate; g) Adsorbents, for example: senior earth and bentonite; and h) a lubricant, such as: talcum powder, calcium stearate, magnesium stearate and solid polyethylene glycol.

Tablets, dragees, capsules, pills and granules of solid dosage form may be prepared with coatings or shells.

The active compounds can also be administered in the form of microcapsules. If desired, one or more of the above-mentioned excipients may be provided.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsifiers, solutions, suspensions, syrups and the like. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as: water or other solvents, stabilizers and emulsifiers, for example: ethyl alcohol, ethyl carbonate, ethyl acetate, benzoic alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuranol, polyethylene glycols, fatty acid esters of sorbitan and the like.

In addition to inert diluents, oral compositions can also include: adjuvants, for example: humectants, emulsifiers and suspending agents, sweeteners, flavorants and flavoring agents.

Suspensions, in addition to the active compounds, may contain suspending agents, for example: ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, and the like.

The compositions for rectal or vaginal administration are preferably suppositories. The preparation may be obtained by mixing the compounds of the invention with suitable non-irritating excipients or carriers.

Formulations for topical administration of the compounds of the present invention include powders, patches, sprays, ointments and inhalants. The active compound is obtained by mixing under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives, buffers or propellants.

The preferred dosage range is about 0.01 mg to about 400 mg per kg of body weight per day. More preferred dosage ranges are 0.2 to 100 milligrams per kilogram of body weight per day. The appropriate dosage may also be selected to be administered in divided doses a plurality of times per day.

The compounds of the invention are useful as, but not limited to, kinase inhibitors. Pyrimidine derivatives are disclosed which may be used alone or in combination with other pharmaceutical or pharmaceutically acceptable carriers, diluents or excipients, and are useful in the prevention or treatment of conditions resulting from, or associated with, disruption of cell proliferation and/or angiogenesis. One example of such a condition is cancer.

The compounds of the invention may also be used for the treatment of conditions involving or at least partially modulated by PDGFR, VEGFR, FGFR, FLT3, aurora-A, aurora-B, TRK, B-RAF, RET or Abl activity, where RET, PDGFR, VEGFR activity is known to play a role in promoting disease onset or where symptoms are known or shown to be alleviated by RET, PDGFR, VEGFR inhibitors. Disorders of this type contemplated to be treatable by the compounds of the invention include, but are not limited to, the following: antiproliferative disorders (e.g., cancer); neurodegenerative diseases, including: huntington's disease, polyglutamine disease, parkinson's disease, alzheimer's disease, seizures, striatal degeneration, progressive supranuclear palsy, torsionally incomplete, spastic torticollis and dyskinesia, familial tremor, tourette's syndrome, diffuse lewy body disease, progressive supranuclear palsy, pick's disease, intracranial hemorrhage, primary lateral sclerosis, spinal muscular atrophy, amyotrophic lateral sclerosis, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, progressive ataxia, and Shy-Drager syndrome; metabolic disease, including: type 2 diabetes; an ocular degenerative disease comprising: glaucoma, age-related macular degeneration, and iris red degeneration glaucoma; inflammatory diseases and/or immune system disorders, including: rheumatoid Arthritis (RA), osteoarthritis, juvenile chronic arthritis, graft versus host disease, psoriasis, asthma, spondyloarthropathies, psoriasis, crohn's disease, inflammatory bowel disease, colonic ulcers, alcoholic hepatitis, diabetes, sjoegrens syndrome, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, discogenic pain, systemic lupus erythematosus; diseases involving angiogenesis, including: cancer, psoriasis, rheumatoid arthritis; a psychological condition, comprising: bipolar disorder, schizophrenia, mania, depression and dementia; cardiovascular diseases include; heart failure, restenosis, and arteriosclerosis; fibrotic disease, comprising: liver fibrosis, cystic fibrosis and vascular fibromas; infectious diseases, including: fungal infections, such as: candida albicans, bacterial infection; viral infections, such as: herpes simplex; protozoal infections, such as: malaria, leishmania infection, trypanosoma brucei infection, toxoplasmosis, and coccidiosis; a hematopoietic disorder comprising: marine anemia, and sickle cell anemia.

The term "cancer" as used in this specification generally refers to a broad range of conditions characterized by uncontrolled abnormal growth of cells.

Cancers for which the compounds of the invention may be used to treat include, but are not limited to: breast cancer, lung cancer, ovarian cancer, thyroid cancer, rectal cancer, prostate cancer, head and neck cancer, kidney, stomach and brain cancer.

Furthermore, the compounds of the invention are useful in the treatment of proliferative diseases that are resistant to other chemotherapeutic treatments; and for the treatment of hyperproliferative diseases, such as: leukemia, psoriasis, etc.

Synthesis of 2-oxoindoline derivatives

The compounds represented by the general formula (I) can be synthesized by the synthetic routes and synthetic methods discussed below. The raw materials are convenient and easy to obtain. However, the synthetic route and method used in the present invention can be widely applied to the synthesis of analogues, and only the starting materials need to be changed. For example, the synthesis of a compound not described in detail in the examples herein, the desired target compound can be synthesized by changing the starting material to that of the corresponding target compound, and by changing the reaction conditions slightly as necessary, according to the general knowledge of chemistry.

Reagents for various embodiments may be prepared using the reaction pathways or synthetic schemes described below. The preparation of specific compounds of the specific embodiments is detailed in the examples below. Those skilled in the art will recognize that the chemical reactions described may be adapted to produce a variety of other compounds in different embodiments. For example: the synthesis of non-exemplified compounds can be successfully performed by modifications apparent to those skilled in the art, or by modification to other suitable reagents known in the art. A list of suitable protecting groups in organic synthesis may be found in T.W. Greene Protective Groups in Organic Synthesis, john Wiley & Sons,1981. Other reactions disclosed herein or known in the art may be considered to have applicability for preparing other compounds of each particular embodiment.

Reagents useful in synthesizing the compounds may be obtained or prepared according to techniques known in the art.

In the examples below, all temperatures are in degrees celsius unless otherwise indicated.

Various starting materials and reagents are available commercially. Suppliers include, but are not limited to: aldrich Chemical Company, lancaster Synthesis Ltd, etc. Both the commercial starting materials and reagents were used without further purification unless otherwise indicated.

The glassware is oven dried and/or heat dried. The reaction was followed on a glass silica gel-60F 254 plate (0.25 mm) (TLC). Analytical thin layer chromatography was performed with appropriate solvent ratios (v/v). The reaction was terminated when the starting material was consumed on TLC.

Typically, the subsequent treatment is to double the volume of the reaction solution with the solvent used for the reaction, and then to extract three times with 25% of the total volume of the extraction solvent, unless otherwise indicated. The product-containing extract was dehydrated over anhydrous sodium sulfate, filtered on a rotary evaporator, the solvent was evaporated under reduced pressure and the removal of the solvent in vacuo was noted. Finally, the target compound is isolated by flash column chromatography (J.org.chem., 1978; 43:2923).

¹ The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Using chloroform as Is a reference standard (7.25 ppm) or a tetramethylsilane internal standard (0.00 ppm). Other solvents commonly used for NMR may also be used, if desired. ¹ H NMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.

The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI. All melting points were not corrected.

The following examples are merely illustrative of the synthetic methods of the specific compounds of the invention. But there is no limitation in the synthesis method. The compounds not listed below can also be prepared by the same synthetic route and synthetic method as described below, by selecting appropriate starting materials and adjusting the reaction conditions slightly as necessary under the common general knowledge.

Synthesis

The compound represented by the general formula (I), when (R ⁶ ) N may be linked to C on the benzimidazole ring ⁵ In the position, and R ¹ ＝R ³ ＝R ⁴ ＝R ⁶ ＝H，R ² ＝OCH ₃ And x=carbon atom, the synthesis method is as follows: the appropriately substituted 4-nitro-2-aminobenzene derivative (VI) is cyclized with an appropriately aldehyde (VII) or triethyl orthoformate to the corresponding 5-nitrobenzimidazole derivative (VIII). The 5-aminobenzimidazole derivative (IX) obtained after the reduction of the latter is reacted with a suitable 2-oxoindoline derivative (X) to give the target compound (XI) represented by the general formula (I) (see synthetic scheme 1 for details).

Scheme 1

The compound represented by the general formula (I), when (R ⁶ ) N may be linked to C on the benzimidazole ring ⁵ In the position, and R ¹ ＝R ³ ＝R ⁴ ＝R ⁶ ＝H，R ² ＝OC ₂ H ₅ And x=carbon atom, the synthesis method is as follows: the condensation product (XIV) is obtained by heating and reacting the proper substituted 4-bromo-2-oxoindoline derivative (XII) with a palladium reagent of boric acid derivative (XIII). The latter is reacted with orthoformate to give intermediate (XV). The benzimidazole (XVI) is reacted with an intermediate (XV) to give the objective compound (XVII) represented by the general formula (I) (see scheme 2 for details).

Scheme 2

The invention is further illustrated by the following examples. The purpose is to provide a person having ordinary skill in the art with a clear understanding of and practice to the invention. However, the scope of the present invention is not limited to these examples.

Synthesis of (Z) -2-oxo-3- (benzene- ((1- (2- (pyrrol-1-yl) -ethyl) -1H-benzimidazol-5-yl) -amino) -methylene) -indoline-6-carboxylic acid methyl ester (1)

Synthesis of Step-1 5-nitro-1- (2-pyrrol-1-yl) -ethyl) -1H-benzimidazole (VIII-1)

In a 100mL round bottom flask, VI-1 (1.5 g,5.9928mmol,1.0 eq) and acetic acid (60.0 mL,40.0 Vol) were added. Trimethyl orthoformate (4.99 g,33.6707mmol,5.6 eq) was added dropwise to the reaction system at room temperature. The resulting mixture was stirred at 80℃for 4 hours. Concentrating under reduced pressure. Neutralizing with sodium bicarbonate solution, and extracting with ethyl acetate. The organic phase was then washed with sodium bicarbonate solution (200.0 mL. Times.2). Drying and concentration gave compound VIII-1 (1.5 g, 96.1%). ESI-MS (m/z): 261.30[ M+H ] ] ⁺ 。

Synthesis of Step-2 5-amino-1- (2-pyrrol-1-yl) -ethyl) -1H-benzimidazole (IX-1)

In a 100mL round bottom flask, VIII-1 (1.5 g,5.7626mmol,1.0 eq) SnCl was added ₂ .2H ₂ O (3.9 g,17.2849mmol,3.0 eq). Acetic acid (67.5 mL,40.0 Vol) and methanol (7.5 mL,5.0 Vol) were added with stirring at room temperature. The resulting mixture was reacted at 45℃with stirring for 4 hours. Concentrating under reduced pressure. Neutralizing with sodium bicarbonate solution, and extracting with ethyl acetate. The combined organic phases were washed with sodium bicarbonate solution (50.0 mL. Times.2). Drying and concentrating to obtain crude product (300.0 mg) the crude product is purified by silica gel column (eluent DCM: methanol=10:1) to obtain compound IX-1 (900.0 mg, 67.7%). ESI-MS (m/z): 231.15[ M+H)] ⁺ .

Step-3Synthesis of (Z) -2-oxo-3- (benzene- ((1- (2- (pyrrol-1-yl) -ethyl) -1H-benzimidazol-5-yl) -amino) -methylene) -indoline-6-carboxylic acid methyl ester (1)

To a methanol solution (2.0 mL,20.0 Vol) of compound X-1 (100.0 mg,0.3092mmol,1.0 eq) was added IX-1 (81.9 mg,0.3556mmol,1.15 eq). The mixture is stirred at 70-75 ℃ for reaction for 10-15 hours under the protection of nitrogen. Then cooled to 20-30 ℃. Filtered and washed with methanol (2.0 mL). The solid was dried to give the title compound (1) (i.e., XI-1, yellow solid) (100.0 mg, 63.7%) as a yellow solid. ¹ H NMR(400MHz,MeOD)δ8.25(s,1H),7.55-7.10(m,10H),5.91(t,J＝8.4Hz,1H),4.66(t,J＝7.08Hz,2H),3.85(s,3H),3.04(t,J＝7.04Hz,2H),2.57-2.53(m,4H),1.79-1.75(m,4H).ESI-MS(m/z):508.3[M+H] ⁺ .

Examples 2 to 88

According to the method of example 1, a wide variety of derivatives can be synthesized by changing the appropriate starting materials. Examples 2-88 are representative examples of some of these (see Table 1).

Table 1 shows representative 2-oxoindoline derivatives of formula (I)

In addition, with reference to the method of example 1, a wider variety of derivatives can be synthesized as long as the starting materials are properly selected. Such as those listed in table 2 are some examples.

Table 2 contains other derivatives of formula (1)

Biological experiments and pharmacodynamic analysis

1. Detection of kinase Activity

There are many reports of kinase activity assays, and related kinase assay kits are available. Alternatively from Cisbio Inc. but not limited to: HTRF kinase-STK KIT. Taking the detection of RET kinase inhibitory activity by HTRF (homogeneous time resolved fluorescence) kinase detection kit as an example, the experimental procedure is as follows.

1. The experimental method comprises the following steps:

1.1 test compounds were formulated as 10mM (mmol/L) DMSO solutions.

1.2 Compounds at 10mM concentration were diluted with Kinase buffer (Kinase buffer) to 2.5. Mu.M (2.5 XCompound) working solution, then 2.5. Mu.M was used as the highest concentration, and the 2.5 Xworking solution of test compound was serially diluted to 9 concentrations at 3-fold gradient: 2.5, 0.833333, 0.277778, 0.092593, 0.030864, 0.010288, 0.003429, 0.001143, 0.000381 μm; 10mM control compound was diluted with kinase buffer to 2.5. Mu.M working solution, then 2.5. Mu.M was used as the highest concentration, and the 2.5 Xworking solution was serially diluted to 9 concentrations of the test compound at 3-fold gradient: 2.5, 0.833333, 0.277778, 0.092593, 0.030864, 0.010288, 0.003429, 0.001143, 0.000381 μm.

1.3 mu.L of 2.5 XCompound working solution was added to 384-well plates (Greiner, cat # 781280), and Blank wells (without compound and kinase added), control wells (without compound only kinase added) were set, and 4. Mu.L of kinase buffer was added to the Blank and Control wells.

1.4 preparation of the kinase stock solution with a kinase buffer to a corresponding 5 Xworking solution, 2. Mu.L of the 5 Xkinase working solution was added to each well containing the compound working solution, 2. Mu.L of the kinase buffer was added to the Blank well, and 2. Mu.L of the 5 Xkinase working solution was added to the Control well.

1.5 mu.L of 5 Xsubstrate stock solution (TK Antibody-Cryptate) was added to each well containing compound and kinase working solution, 2. Mu.L of kinase buffer was added to the Blank well, and 2. Mu.L of 5 Xsubstrate stock solution was added to the Control well.

1.6 to each test well 2. Mu.L of ATP working solution (5X) was added.

1.7 incubation of 384 well plates with sealing membrane at 37℃for 1 hour, followed by addition of 5. Mu.L (4X) of reaction stop solution (strepitavidin-XL 665) to each well;

1.8 the 384 well plates were further covered with a sealing membrane and after incubation at 37℃for 1 hour, signal values 665, 620 were detected on a 2104EnVision plate reader.

Preparing a detection system working solution:

2. data analysis:

the Inhibition Rate (IR) of the test compound was calculated using the following formula: IR (%) = (RLU CTR (665/620) -RLU compound (665/620))/(RLU CTR (665/620) -RLU blast (665/620)) × 100%. Inhibition rates of compounds at different concentrations were calculated in Excel, and then IC was calculated using GraphPad Prism 5 software ₅₀ 。

3. Activity inhibition assay results of wild-type RET and mutant RET kinase

The results of partial bioactivity test are shown in Table 3

TABLE 3 kinase inhibitory Activity of target Compounds

The target compound disclosed by the invention has better inhibition activity on wild RET and mutant RET kinase.

Meanwhile, the invention also adopts the compound of the invention to test against other kinases, and also discovers that the compound of the invention has obvious inhibition effect on the kinases (PDGFR (PDGFR alpha and PDGFR beta), VEGFR, FGFR, FLT3, aurora-A, aurora-B, TRK, B-RAF, RET or Abl activity) (see in particular Table 4).

TABLE 4 inhibition of PDGFR alpha, PDGFR beta and VEGFR2 kinase by Compounds of interest

The following table shows the partial enzyme inhibition activity of compound 53 compared to the control ninterdanib.

Table 5 comparison of Compound 53 with Nintedanib partial enzyme inhibition Activity

2. Detection of tumor cell inhibitory Activity

Cell Activity assay CTG (CELL TITER-GLO) luminescence was used to test the activity of compounds of interest. The principle is as follows: ATP adenosine triphosphate (referred to as adenosine triphosphate) participates in various enzymatic reactions in organisms, and is an index of metabolism of living cells, the content of ATP adenosine triphosphate directly reflects the number and state of cells, and an equal volume of CellTiter-Glo is added to a cell culture medium during an experiment ^TM Reagents, measuring luminescence, in optical signals and systemsThe luminescence value is directly proportional to the ATP amount, the ATP is directly related to the number of living cells and inversely proportional to the activity of the antitumor drug, and the antiproliferative activity data of the compound on the tumor cells can be obtained according to a calculation formula by detecting the fluorescence signal of the ATP.

The test for tumor cell inhibitory activity was performed in two parts: taking kinase as a target spot, and checking the target compounds on human thyroid catheter cancer cells (TT) and human colon cancer cells (KM 12); to determine activity against RET Fusion, the growth inhibitory activity of the compound of interest against KIF5B-RET Fusion cells was examined in a targeted manner.

Reagents used in the experiments: F-12K basal medium (ATCC, 30-2004), fetal bovine serum (Corning, 35-076-CV), diabody (GIBCO, 15240-062), pancreatin (GIBCO, 25200072), DMSO (SIGMA, D2650), DMEM basal medium (Corning, 10-013-CV), fetal bovine serum (Gibco, 10091-148).

910. Activity determination of compound on human thyroid duct cancer cells and human colon cancer cells

The following methods were used to determine the effect of compounds on tumor cell proliferation by using CTG luminescence.

The specific experimental operation method and flow are as follows:

1.1 cell resuscitation

Immediately placing frozen cells into a constant-temperature water bath at 37 ℃ from a liquid nitrogen storage tank, shaking for 2min, transferring the cell suspension into a 15mL centrifuge tube after the frozen cell solution is completely melted, slowly adding 4mL culture solution, centrifuging (1000 r/min,5 min), discarding the supernatant, sucking the stock solution, adding 5mL of the culture medium, gently blowing to form single cell suspension, transferring the single cell suspension into a culture flask, and culturing in a culture box.

1.2 cell culture

Cells were grown in complete medium at 37℃in 5% CO ₂ Is cultured in an incubator of (a). Cells in the logarithmic growth phase were taken for plating at regular passages.

1.3 cell plating

Cell staining with trypan blue and calculation of living cells, cell concentration was adjusted to the appropriate medium plate concentration (TT: 50000cell/mL, KM12:35000 cell/mL)) To a 96-well culture plate (Corning, 3599) was added 90 μl of cell suspension per well, and a blank control well and a vehicle control well were set. Cell-containing culture medium was added to the blank wells and cell-free culture medium was added to the vehicle control wells. The plates were then placed at 37℃in 5% CO ₂ And 100% relative humidity overnight.

1.4 Compound formulation

Compounds were weighed and made up in DMSO to 10mM stock solutions, and stock solutions of test compounds were diluted in serum-free medium on dispensing plates (Beaver, suzhou) to a final concentration of 100 μm in 10 x compound working solution (including control). The mixture was diluted with serum-free medium at a concentration gradient of 3 times to obtain a 10X compound working solution having 9 concentration gradients of 100, 33.33, 11.11, 3.70, 1.23, 0.411, 0.137, 0.046 and 0.015. Mu.M, respectively.

1.5 addition of Compounds

10 Xcompound working solution with different concentration gradients was added to 96-well cell culture plates, 10. Mu.L/well, 10. Mu.L DMSO-cell culture solution mix was added to vehicle control wells and blank control wells, and the final DMSO concentration was 0.1%, with 2 duplicate wells per concentration. 96-well cell plates were placed back at 37℃and incubated in a 5% carbon dioxide incubator for 5 days.

1.6 CTG detection

The Cell culture plates were removed and allowed to equilibrate to room temperature for 30 minutes, 50 μl (equal to half the volume of Cell culture fluid in each well) of Cell Titer-Glo working fluid was added to each well, the Cell plates were wrapped with aluminum foil paper to avoid light, the plates were shaken on an orbital shaker for 2 minutes to induce Cell lysis, the plates were allowed to stand at room temperature for 10 minutes to stabilize the luminescence signal, and the luminescence signal was detected on a 2104EnVision plate reader.

910.7 data analysis

The Inhibition Rate (IR) of the test compound was calculated using the following formula: IR (%) = (1- (RLU compound-RLU blank)/(RLU vehicle control-RLU blank)) = (100%), and finally nonlinear regression analysis was performed with compound concentration log-inhibition rate in Graphpad prism 5 software to obtain compound-inhibited cellsProliferative IC ₅₀ Values.

Results the results of the measurements are shown in Table 6.

Results of detecting the growth inhibitory Activity of the Compounds obtained in Table 6 on TT cells, KM12 cells

The target compound disclosed by the invention has good inhibitory activity on both human thyroid duct cancer cells and human colon cancer cells.

Using the same cell activity inhibition assay as described above, the growth inhibition activity of the target compounds on SNU-16, NCI-H170 and GIST-T1 tumor cell beads was examined in Table 7.

TABLE 7 growth inhibitory Activity of target Compounds against SNU-16, NCI-H1703 and GIST-T1 tumor cell beads

3. In vivo antitumor Activity of the Compounds of the invention:

the fraction of compounds that were active in vitro and low in toxicity were selected for the determination of the Maximum Tolerated Dose (MTD) in mice. The antitumor activity of the compounds of the present invention in vivo was measured on a model of human cancer nude mice allograft tumor, and the dosage, route, frequency and period of administration of the test compounds that produce pharmacodynamic effects were explored.

Female BALB/C nude mice of 5-6 weeks old are bred with a weight of about 18-20 g. Building a human cancer nude mouse allograft tumor model: human colon cancer cell line TT, human breast cancer cell line KM12, and human lung cancer cell line A549 were from ATCC. Resuscitating, culturing, removing wall by digesting tumor cells in monolayer culture, collecting and re-suspending in serum-free culture solution, and adjusting concentration to 5×10 ⁶ 0.2mL, placing in ice box, taking into animal room, directly taking 0.2mL cell suspension with syringe with 6-gauge needle, transplanting into the subcutaneous of shoulder blade behind left armpit of nude mouse, 5×10 ⁶ 0.2 ml/mouse, measuring tumor volume every 2-3 days, selecting tumor-bearing nude mice with vigorous tumor growth and no crumple after two weeks, taking out tumor under aseptic condition, cutting tumor tissue into about 2-3mm diameter, inoculating into the back of left armpit of nude mice, subcutically transferring to three generations, and growing when tumor volume reaches 100mm ³ Nude mice with oversized or undersized tumor mass were randomly dosed.

The treatment groups of three doses, namely a negative control group (solvent), a positive control group and a high, medium and low dose, are randomly divided into 5 groups, and 8 nude mice in each group, wherein the negative control group is 16 nude mice, and the treatment groups are administrated by intraperitoneal injection once every two days for 3 weeks. Animal body weight, tumor volume and animal mortality were measured every 2 days during the period. Animals were sacrificed 24 hours after the last dose, tumor volume size, tumor weight, nude mouse weight were measured, tumor volume growth curve, nude mouse weight growth curve and tumor inhibition rate were drawn, animal mortality was calculated, relative tumor proliferation rate T/C (%), 100% according to formula T/C (%) = TRTV/CRTV. (TRTV: treatment group RTV; CRTV: negative control group RTV, relative tumor volume rtv=vt/V0, where V0 is the tumor volume at the time of group administration and Vt is the tumor volume after administration). The results are shown in figures 1, 2 and 8, the relative tumor proliferation rate T/C (%) of the in-vivo anti-tumor efficacy of the compound of the invention is less than or equal to 40%, and the difference is statistically significant and has obvious efficacy effect. And the weight of the test mice is hardly influenced, which shows that the toxicity and side effects are small and the safety is high.

TABLE 8 inhibition of TT cell xenograft tumor model by Compound 53

The details of specific examples illustrated in this disclosure are not to be construed as limiting. Various equivalents and modifications may be made without departing from the spirit and scope of the invention, and it is known that such equivalents are intended to be part of the invention.

Claims

1. A 2-oxoindoline derivative represented by the general formula (I):

in the above-mentioned general formula (I),

R ¹ selected from: hydrogen, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, carboxyalkyl, carboxycycloalkyl; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is C1-C8 straight chain or branched alkyl;

R ² Selected from: hydroxy, alkyl, aryl, alkoxy, heteroalkoxy, arylalkoxy, C3-)C8 cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is C1-C8 straight chain or branched alkyl;

R ³ 、R ⁴ each independently selected from: hydrogen atom, halogen, isotope, hydroxy, amino, carboxyl, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkyloxy, heteroalkyloxy, arylalkyloxy, cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, carboxyalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl; any of the foregoing groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminoalkyl An alkylcarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl group; the alkyl is C1-C8 straight chain or branched alkyl;

R ⁵ selected from: hydrogen atom, isotope, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, amino, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is C1-C8 straight chain or branched alkyl;

R ⁷ may be linked to the C4-, C5-, C6-or C7-position on the benzimidazole ring;

L ¹ selected from: covalent bonds, alkylene, heteroalkylene, -NH-, -C (O) -NH-, -NH-C (O) -, -C (O) -C (O) -, alkylene-C (O) -NH-, alkylene-C (O) -, alkylene-NH-; the alkylene is a C1-C8 straight or branched alkyl; any of the above groups, independently of each other, may be substituted with one or more substituents including a hydrogen atom, an alkyl group;

L ² Selected from: hydrogen atom, alkyl group, heteroalkyl group, alkenyl group, alkynyl group, arylalkyl group, C3-C14 cycloalkyl group, aryl group, heteroaryl group, heteroarylalkyl group, heterocycloalkyl group, alkoxy group, heteroalkoxy group, arylalkoxy group, cycloalkoxy group, aryloxy group, heteroaryloxy group, heterocycloalkoxy group, amino group, alkylamino group, heteroalkylamino group, arylalkylamino group, cycloamino group, alkylamino group, arylamino group, heteroarylamino group, heteroarylalkylamino group, heterocycloalkylamino group, carboxyl group, carboxyalkylaminocarbonyl group, cycloalkylaminocarbonyl group, heteroarylaminocarbonyl group; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is C1-C8 straight chain or branched alkyl;

X is selected from: a nitrogen atom, a carbon atom;

L ³ selected from: absence, covalent bond, alkylene, heteroalkylene, -NH-, -C (O) -NH-, -NH-C (O) -, alkylene-C (O) -, -C (O) -C (O) -, alkylene-C (O) -NH, alkylene-C (O) -, alkylene-NH-C #O) -, alkylene-NH-; the alkylene is a C1-C8 straight or branched alkyl; the alkylene is a C1-C8 straight or branched alkyl; any of the above groups, independently of each other, may be substituted with one or more substituents including a hydrogen atom, an alkyl group;

R ⁸ selected from: non-existent, hydrogen atom, hydroxyl group, alkyl group, hydroxyalkyl group, heteroalkyl group, alkenyl group, alkynyl group, arylalkyl group, C3-C14 cycloalkyl group, aryl group, heteroaryl group, arylalkyl group, heteroarylalkyl group, heterocycloalkyl group, alkoxy group, heteroalkoxy group, arylalkoxy group, cycloalkoxy group, aryloxy group, heteroaryloxy group, heteroarylalkoxy group, heterocycloalkoxy group, amino group, alkylamino group, heteroalkylamino group, arylalkylamino group, cycloalkylamino group, arylamino group, heteroarylamino group, heteroarylalkylamino group, heterocycloalkylamino group, carboxyl group, alkylaminocarbonyl group, carboxyalkylaminocarbonyl group, cycloalkylaminocarbonyl group, heteroarylaminocarbonyl group; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is C1-C8 straight chain or branched alkyl;

(R ⁶ ) N may be linked to the C4-, C5-, C6-or C7-position on the benzimidazole ring, in which case the general formula (I) is selected from:

2. the 2-oxoindoline derivative according to claim 1, characterized in thatWhere R is ¹ Selected from: hydrogen, alkyl, heteroalkyl, arylalkyl, C3-C8 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, carboxyalkyl, carboxycycloalkyl; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, amino, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is a C1-C8 straight chain or branched alkyl.

3. 2-oxoindoline derivative according to claim 1, characterized in that R ¹ Selected from: methyl, ethyl or propyl.

4. 2-oxoindoline derivative according to claim 1, characterized in that R ² Selected from: hydroxy, alkyl, aryl, alkoxy, heteroalkoxy, arylalkoxy, C3-C8 cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, aralkoxy, heteroalkoxy, arylalkoxy, C3-C8 cycloalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, alkyl, alkoxy, alkoxyalkyl, heteroalkyl; the alkyl is a C1-C8 straight chain or branched alkyl.

5. 2-oxoindoline derivative according to claim 1, characterized in that R ² Selected from: methoxy, ethoxy, propoxy.

6. 2-oxoindoline derivative according to claim 1, characterized in that R ³ 、R ⁴ Each independently selected from: hydrogen atom, halogen, isotope, hydroxy, amino, carboxyl, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkoxy, heteroalkoxy, aryloxy, cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, carboxyalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is a C1-C8 straight chain or branched alkyl.

7. The 2-oxoindoline derivative according to claim 5, wherein R ⁴ Selected from: cyclopropane, cyclobutane, cyclopentane, methyl, ethyl, propyl, isopropyl, halophenyl, allyl, and allyl.

8. The 2-oxoindoline derivative according to claim 5, wherein R ⁴ Selected from: p-fluorophenyl, p-chlorophenyl, p-bromophenyl, and p-iodophenyl.

9. 2-oxoindoline derivative according to claim 1, characterized in that R ⁵ Selected from: hydrogen atom, isotope, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heteroalkyl; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, amino, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is a C1-C8 straight chain or branched alkyl.

10. 2-oxoindoline derivative according to claim 1, characterized in that R ⁵ Selected from: benzene ring, pyrazole, pyrimidine,Methyl, ethyl, propyl, methyl chloride.

11. 2-oxoindoline derivative according to claim 1, characterized in that R ⁶ Selected from: hydrogen atom, alkyl, C3-C14 cycloalkyl.

12. 2-oxoindoline derivative according to claim 1, characterized in that R ⁷ Selected from: hydrogen atom, isotope, halogen, alkyl, heteroalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, heterocycloalkoxy, aminoAlkylamino, heteroalkylamino, carboxy, alkylaminocarbonyl; any of the above groups may each be substituted with one or more substituents including, but not limited to, halogen, alkyl, alkoxy; the alkyl is a C1-C8 straight chain or branched alkyl.

13. 2-oxoindoline derivative according to claim 1, characterized in that L ¹ Selected from: covalent bonds, alkylene, heteroalkylene, -C (O) -C (O) -, -C (O) -NH-, alkylene-C (O) -NH-, -C (O) -alkylene, -C (O) -NH-heteroalkylene, heteroalkylene-NH-C (O) -, heteroalkylene-NH-; the alkylene is a C1-C8 straight or branched alkyl; any of the above groups, independently of each other, may be substituted with one or more substituents including hydrogen atoms, alkyl groups.

14. 2-oxoindoline derivative according to claim 1, characterized in that L ¹ Selected from: ethylene, -C (O) -C (O) -, -C (O) CH 2-ethylene, methylene and propylene.

15. 2-oxoindoline derivative according to claim 1, characterized in that L ² Selected from: hydrogen atom, alkyl group, heteroalkyl group, arylalkyl group, C3-C14 cycloalkyl group, aryl group, heteroaryl group, heterocycloalkyl group, alkoxy group, heteroalkoxy group, cycloalkoxy group, heterocycloalkoxy group, amino group, alkylamino group, heteroalkylamino group, arylalkylamino group, cycloalkylamino group, arylamino group; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, phenyl, benzyl, phenyloxy, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino; the alkyl is a C1-C8 straight chain or branched chain An alkyl group.

16. 2-oxoindoline derivative according to claim 1, characterized in that L ³ Selected from: methylene, ethylene, -NH-, -C (O) -NH-, -NH-C (O) -, -C (O) -C (O) -, alkylene-C (O) -.

17. 2-oxoindoline derivative according to claim 1, characterized in that R ⁸ Selected from: non-existent, hydrogen atom, hydroxyl group, alkyl group, heteroalkyl group, alkenyl group, alkynyl group, arylalkyl group, C3-C14 cycloalkyl group, aryl group, heteroaryl group, heteroarylalkyl group, heterocycloalkyl group, alkoxy group, heteroalkoxy group, arylalkoxy group, cycloalkoxy group, aryloxy group, heteroaryloxy group, heteroarylalkoxy group, heterocycloalkoxy group, amino group, alkylamino group, heteroalkylamino group, arylalkylamino group, cycloalkylamino group, arylamino group, heteroarylamino group, heteroarylalkylamino group, heterocycloalkylamino group; any of the above groups, independently of each other, may be unsubstituted or may be substituted with one or more substituents including, but not limited to, halogen, isotope, amino, carboxyl, =o, -CF3, haloalkyl, alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl; the alkyl is a C1-C8 straight chain or branched alkyl.

18. The 2-oxoindoline derivative according to any one of claims 1-17, having a structure selected from one of the following structures, or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof:

19. the process for the preparation of 2-oxoindoline derivatives according to any one of claims 1-18, characterized in that when (R ⁶ ) N may be linked to C on the benzimidazole ring ^5- In a bit, and R ¹ ＝R ³ ＝R ⁴ ＝R ⁶ ＝H，R ² ＝OCH ₃ And x=carbon atom, the preparation method comprises the steps of:

the synthetic route is as follows:

20. the process for the preparation of 2-oxoindoline derivatives according to any one of claims 1-18, characterized in that when (R ⁶ ) N may be linked to C on the benzimidazole ring ⁵ In the position, and R ¹ ＝R ³ ＝R ⁴ ＝R ⁶ ＝H，R ² When=oc2h5 and x=carbon atom, the preparation method comprises the following steps:

the synthetic route is as follows:

21. a pharmaceutical dosage form comprising a 2-oxoindoline derivative according to any one of claims 1-18 in association with a pharmaceutically acceptable diluent, excipient or carrier.

22. Use of a 2-oxoindoline derivative according to any one of claims 1-18, characterized in that it is used for the preparation of a medicament for the treatment of a condition caused by, associated with or accompanied by a disruption of cell proliferation and/or angiogenesis or for inhibiting kinase activity.

23. The use according to claim 22, wherein the condition is a proliferative disease.

24. The use according to claim 23, wherein the proliferative disease is cancer.

25. The use of claim 22, wherein inhibiting kinase activity comprises inhibiting the activity of RET, PDGFR, VEGFR, FGFR, FLT, aurora-A, aurora-B, TRK, B-RAF, RET, or Abl.

26. The use according to claim 22, wherein the condition is selected from the group consisting of: bone cancers, comprising: ewing's sarcoma, osteosarcoma, chondrosarcoma, etc.; brain and CNS tumors, comprising: auditory neuroma, neuroblastoma, neuroglioblastoma and other brain tumors, spinal cord tumors, breast cancer, colorectal cancer, stage-advanced colorectal adenocarcinoma; endocrine cancers, including: adrenal cortex cancer, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, and multiple endocrine tumors; gastrointestinal cancers, including: gastric cancer, esophageal cancer, small intestine cancer, liver cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumor and gallbladder cancer; genitourinary cancers, comprising: green pill cancer, penile cancer, and prostate cancer; a gynaecological cancer class comprising: cervical cancer, ovarian cancer, vaginal cancer, uterine/endometrial cancer, pudendum cancer, gestational trophoblastic tumor, fallopian tube cancer, uterine sarcoma; head and neck neoplasms, comprising: oral cancer, lip cancer, salivary gland cancer, laryngeal cancer, hypopharyngeal cancer, orthopharyngeal cancer, nasal cancer, sinus cancer, and nasopharyngeal cancer; a blood cancer group comprising: childhood leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell leukemia; a bone marrow cancer hematological disorder comprising: myelodysplastic syndrome, myeloproliferative disorders, aplastic anemia, fan Heni anemia, idiopathic macroglobulinemia; a lung cancer class comprising: small cell lung cancer, non-small cell lung cancer; lymphomas, including: hodgkin's disease, non-hodgkin's lymphoma, cutaneous T-cell lymphoma, peripheral T-cell Lin Baliu, AIDS-related lymphoma; eye cancers, comprising: retinoblastoma, uveal melanoma; skin cancers, comprising: melanoma, non-melanoma skin cancer, merkel cell carcinoma; soft tissue sarcomas, for example: soft tissue sarcomas in children, soft tissue sarcomas in adults, kaposi's sarcoma; urinary system cancer, comprising: kidney cancer wilms' tumor, skin cancer, urinary tract cancer and metastatic cell cancer.