WO2025093058A1 - 2-oxoindoline derivatives, preparation method therefor and use thereof - Google Patents

Abstract

Disclosed in the present invention are 2-oxoindoline derivatives, a preparation method therefor and the pharmaceutical use thereof. More specifically, the compounds can be used as a drug for treating proliferative disorders and other diseases associated with the abnormal expression of various kinases. In particular, the compounds can be used as a drug for treating proliferative disorders and other diseases associated with the abnormal expression of various kinases such as RET, PDGFR and VEGFR. The new pyrimidine structure of the present invention is as shown in general formula (I), wherein the definitions of R1, R2, R3, R4, R5, R6, R7, L1, L2 and X can be found in the description.

Description

2-Oxoindoline derivatives and preparation method and application thereof Technical Field

The present invention relates to a novel 2-oxoindoline derivative, a preparation method and application thereof. Specifically, the present invention relates to a novel 2-oxoindoline derivative having the ability to inhibit the growth of wild tumor strains with high kinase expression or tumor cell strains with corresponding kinase mutations and a preparation method thereof. In particular, these compounds can be used as drugs for treating proliferative diseases and other diseases related to abnormal expression of various kinases such as RET, PDGFR, VEGFR, etc. In addition, the present invention relates to drugs containing these compounds and the application of these compounds in the preparation of drugs.

Background Art

Tumor is one of the major diseases that threaten human health. Chemotherapy is still one of the important means of tumor treatment. In particular, small molecule targeted therapy for tumors and combined therapy with other methods are playing an increasingly important role. Among the many targeted therapy drugs, inhibitors acting on kinases, especially RET, PDGFR (PDGFRα and PDGFRβ), and VEGFR inhibitors have received widespread attention.

RET is a neuronal growth factor receptor tyrosine kinase and a transmembrane glycoprotein. RET is expressed by the proto-oncogene RET (Rearranged durIng TransfectIon) located on chromosome 10. It plays an important role in the development of the kidney and enteric nervous system in the embryonic stage. It is also critical for the homeostasis of various tissues, such as neurons, neuroendocrine, hematopoietic tissues and male germ cells. Unlike other RTKs, RET does not directly bind to ligand molecules: such as artemin, glial cell-derived neurotrophic factor (GDNF), neurturin and persephin, which are all GNDF family ligands (GFLs). These ligands GFLs usually bind to the GDNF family receptor α (GFRα), and the formed GFLs-GFRα complex mediates the self-dimerization of RET protein, causing trans-autophosphorylation of tyrosine on the intracellular domain, recruiting related adaptor proteins, and activating cascade reactions of signal transduction such as cell proliferation. Related signaling pathways include MAPK, PI3K, JAK-STAT, PKA, PKC, etc. ((1)Maria Grazia Borrello,Elena Ardini,Laura D Locati,Angela Greco,Lisa Licitra&Marco A Pierotti(2013).RET Inhibition:ImplicatIons in cancer therapy.Expert Opinion on Therapeutic Targets,17:4,403-419) (2) Samuel A. Wells, Jr, Furio Pacini, Bruce G. Robinson, and Massimo Santoro. Multiple Endocrine Neoplasia Type 2 and Familiai Meduliary Thyroid Carcinoma: An Update. J Clin Endocrinol Metab 98:3149–3164, 2013).

There are two main mechanisms of RET oncogenic activation: one is that chromosomal rearrangement produces a new fusion protein, usually a fusion of the RET kinase domain and a protein containing a self-dimerization domain; the other is that RET mutations directly or indirectly activate the kinase activity of RET. These changes at the somatic or germ cell level are involved in the pathogenesis of a variety of cancers. 5%-10% of patients with papillary thyroid cancer have RET chromosomal rearrangements; and 60% of patients with medullary thyroid carcinoma have RET point mutations; among all NSCLC patients, approximately 1-2% have RET fusion proteins, of which KIF5B-RET is the most common.

These facts indicate that it is an ideal treatment for tumors associated with persistent RET activation. The research on RET inhibitors has received widespread attention and has made rapid progress. Among them, RET inhibitors represented by Pralsetinib (WO2017011776A1 Array Loxo292) and Selpercatinib (WO2017079140A1Blu667) have been approved by the FDA for marketing and have been used to treat various related fusion tumors regardless of tumor type and have achieved success. This has inspired various other development attempts. ((1) Lucille Lopez-Delisle, CécIle Pierre-Eugène, Caroline Louis-Brennetot, Didier Surdez, Virginie Raynal, Sylvain Baulande, Valentina Boeva, Sandrine Valérie Combaret,Michel Peuchmaur6,Olivier Delattre,Isabelle Janoueix-Lerosey.Activated ALK signals through the ERK–ETV5–RET pathway to drive neuroblastoma oncogenesis.Oncogene(2018)37:1417–1429.(2)WO2014/141187A1.RET Kinase Inhibitors May Treat Cancer and Gastrointestinal Disorders.(3)Minsoo Song.Progress In Discovery of KIF5B-RET Kinase Inhibitors for the Treatment ofNon-Small-Cell Lung Cancer.Miniperspective.J.Med.Chem.2015,58,3672-3681.)

Platelet derived growth factor (PDGF) is a family of effective mitogens for almost all mesenchyme-derived cells. PDGF exerts its cellular effects through PDGF receptor α (PDGFRα) and PDGF receptor β (PDGFRβ). PDGFRα is similar to PDGFRβ in structure and can form heterodimers and homodimers. Currently reported examples of inhibitors for both PDGFRα and PDGFRβ include Nintedanib and the like. In addition to their inhibitory effects on PDGFRα and PDGFRβ, they also have inhibitory effects on cKIT, BCR-ABL, etc. ( An overview of kinase downregulators and recent advances in discovery approaches .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 (VEGFs) were originally discovered as vascular permeability factors (VPF). They are cytokines secreted by tumor cells that can increase vascular permeability. Studies have now shown that VEGFs (vascular endothelial growth factors) are hormone regulators of endothelial cell differentiation. VEGFs bind to VEGFR (vascular endothelial growth factor receptor) tyrosine kinases that are specifically and highly expressed on the surface of newborn vascular endothelial cells, activating tyrosine kinases to exert biological functions. Studies have found that VEGFR inhibitors can block VEGFR in vitro, thereby inhibiting the binding of vascular endothelial growth factor to VEGFR. Related kinase inhibitors, such as lenvatinib mesylate, have been approved by the FDA for marketing and are clinically used to treat renal cancer, liver cancer, and thyroid cancer (Overview of lenvatinib as a targeted therapy for advanced hepatocellular carcinoma. Obaid Rehman, Urooj Jaferi, Inderbir Padda, Nimrat Khehra, Harshan Atwal, Dina Mossabeh, Ranvir Bhangu. Clin Exp HEPATOL 2021; 7, 3: 249–257).

As mentioned above, the research and development of kinase inhibitors targeting RET has achieved great success in the treatment of fusion tumors (Alexander Drilon, Zishuo I. Hu, Gillianne G. Y. Lai & Daniel S. W. Tan Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nature Reviews Clinical Oncology volume 15, 2018, 151–167). However, if it is possible to simultaneously inhibit multiple kinases such as PDGFR, VEGFR, FGFR, FLT3, Aurora-A, Aurora-B, TRK, B-RAF, RET or Abl while inhibiting RET, it will potentially help solve the problem of drug resistance of related drugs. Therefore, this application intends to study kinase multi-target inhibitors targeting kinases such as RET, PDGFR, VEGFR, etc. to meet the huge social needs.

Summary of the invention

One of the purposes of the present invention is to disclose a novel 2-oxoindoline derivative. This type of compound acts on multiple kinases such as PDGFR, VEGFR, FGFR, FLT3, Aurora-A, Aurora-B, TRK, B-RAF, RET or Abl, and can be used for the treatment of tumors, endocrine disorders, immune system diseases, genetic diseases and neurodegenerative diseases.

The second purpose of the present invention is to disclose the preparation method of the 2-oxoindoline derivatives.

More specifically, the present invention relates to a novel 2-oxoindoline derivative, a preparation method and medical application. More specifically, these compounds can be used as drugs for treating proliferative diseases and other diseases associated with abnormal expression of various kinases. In particular, these compounds can be used as drugs for treating proliferative diseases and other diseases associated with abnormal expression of various kinases such as RET, PDGFR, VEGFR, etc. The structure of the novel pyrimidine of the present invention is shown in the general formula (I), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , L ¹ , L ² and X are defined as follows:

In the above general formula (I),

R ¹ is selected from: hydrogen atom, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, carboxylalkyl, carboxylcycloalkyl; any of the above groups independently may be unsubstituted or may be substituted by one or more substituents, and these 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 a C1-C8 straight chain or branched alkyl;

^R2 is selected from the group consisting of hydroxy, alkyl, aryl, alkoxy, heteroalkoxy, heteroalkoxy, arylalkoxy, C3-C8 cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino; any of the above groups may be independently unsubstituted or may be substituted with one or more substituents, including but not limited to halogen, isotope, alkyl, alkylamino, alkylamino, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl group is a C1-C8 straight chain or branched chain alkyl group;

^R3 and ^R4 are independently selected from the group consisting of hydrogen, halogen, isotope, hydroxyl, amino, carboxyl, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkyloxy, heteroalkyloxy, arylalkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, carboxylalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups is selected from the group consisting of A group may be unsubstituted or substituted with one or more substituents, which 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, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl group is a C1-C8 straight chain or branched alkyl group;

R ⁵ is selected from the group consisting of: hydrogen atom, isotope, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl; any of the above groups independently may be unsubstituted or may be substituted by one or more substituents, and these 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, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl group is a C1-C8 straight chain or branched alkyl group;

^R6 is selected from the group consisting of: hydrogen atom, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, heteroarylalkyl, heterocycloalkyl; any of the above groups may be independently unsubstituted or substituted by one or more substituents, including alkyl and alkoxy; the alkyl is a C1-C8 straight chain or branched alkyl;

R ⁷ is selected from the group consisting of: hydrogen atom, isotope, halogen, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl; alkoxy, heteroalkoxy, arylalkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, alkylaminocarbonyl, any of the above groups independently may be unsubstituted or may be substituted by one or more substituents, and these substituents include but are not limited to halogen, alkyl, alkoxy; the alkyl is a C1-C8 straight chain or branched alkyl;

R ⁷ can be linked to the C ⁴ -, C ⁵ -, C ⁶ -, or C ⁷ -position on the benzimidazole ring;

L ¹ is selected from the group consisting of: covalent bond, alkylene, heteroalkylene, -NH, -C(O)-NH-, -NH-C(O)-, alkylene-C(O)-, -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 chain or branched alkyl; any of the above groups may be independently substituted by one or more substituents, which include hydrogen atoms and alkyl groups;

^L2 is selected from the group consisting of: hydrogen atom, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkoxy, heteroalkoxy, arylalkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, carboxylalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups may be independently selected from the group consisting of: Substituted 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, hydroxyl, 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;

X is selected from: nitrogen atom, carbon atom;

^L3 is selected from: absence, covalent bond, alkylene, heteroalkylene, -NH, -C(O)-NH-, -NH-C(O)-, alkylene-C(O)-, -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 chain or branched alkyl; any of the above groups can be independently substituted by one or more substituents, which include hydrogen atoms, alkyl groups;

^R8 is selected from the group consisting of: absent, hydrogen atom, hydroxyl, alkyl, hydroxyalkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkoxy, heteroalkoxy, arylalkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, alkylaminocarbonyl, carboxylalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups The groups independently 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, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl group is a C1-C8 straight chain or branched alkyl group;

(R ⁶ )N can be linked to the C ⁴ -, C ⁵ -, C ⁶ - or C ⁷ -position of the benzimidazole ring, in which case the general formula (I) is selected from:

In certain embodiments, according to the above general formula (I), R ¹ is selected from hydrogen atom, alkyl, heteroalkyl, arylalkyl, cycloalkyl, heteroarylalkyl, heterocycloalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfinyl; in the above groups, each may be unsubstituted or substituted by one or more substituents, and these substituents include: halogen, isotope, =O, -CF3, alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl.

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

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

^R2 is selected from the group consisting of hydroxy, alkyl, aryl, alkoxy, heteroalkoxy, heteroalkoxy, arylalkoxy, C3-C8 cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino; any of the above groups may be independently unsubstituted or may be substituted with one or more substituents, including but not limited to halogen, isotope, halogen, 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, according to the above general formula (I), ^R2 is independently selected from: hydroxyl, C1-C5 straight chain or branched alkylalkoxy, heteroalkoxy, heteroalkoxy, arylalkoxy, C3-C8 cycloalkoxy, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino; any of the above groups may be independently substituted by one or more substituents, and these substituents include but are not limited to halogen, carboxyl, phenyl, =O, -CF3, alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, and cycloalkyl.

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

^R3 and ^R4 are independently selected from the group consisting of hydrogen, halogen, isotope, hydroxyl, amino, carboxyl, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkyloxy, heteroalkyloxy, arylalkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, carboxylalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups is selected from the group consisting of A group may be unsubstituted or substituted with one or more substituents, which may be, 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, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl group is a C1-C8 straight chain or branched alkyl group.

In certain embodiments, according to the above general formula (I), when R ³ is a hydrogen atom, R ⁴ is selected from the group consisting of: a hydrogen atom, a halogen, an isotope, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an arylalkyl group, a C3-C14 cycloalkyl group, an aryl group, a heteroaryl group, a heteroarylalkyl group, a heterocycloalkyl group, an alkoxy group, a heteroalkoxy group, an arylalkoxy group, a cycloalkyloxy group, an aryloxy group, a heteroaryloxy group, a heteroarylalkoxy group, a heterocycloalkyloxy group, an amino group, an alkylamino group, a heteroalkylamino group, an arylalkylamino group, a cycloalkylamino group, an arylamino group, a heteroarylamino group, a heteroarylalkylamino group, a heterocycloalkylamino group, a carboxyl group, a carboxylalkylaminocarbonyl group, a cycloalkylaminocarbonyl group, a heteroarylaminocarbonyl group, a heteroarylaminocarbonyl group; Any group in the group may be unsubstituted or substituted by one or more substituents independently, and these 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, alkylamino, aminoalkyl, alkylaminocarbonyl; the alkyl is a C1-C8 straight chain or branched alkyl.

In certain embodiments, according to the above general formula (I), when R ⁴ is a hydrogen atom, R ³ is selected from: a hydrogen atom, a halogen, an isotope, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an arylalkyl group, a C3-C14 cycloalkyl group, an aryl group, a heteroaryl group, a heteroarylalkyl group, a heterocycloalkyl group, an alkoxy group, a heteroalkoxy group, an arylalkoxy group, a cycloalkyloxy group, an aryloxy group, a heteroaryloxy group, a heteroarylalkoxy group, a heterocycloalkyloxy group, an amino group, an alkylamino group, a heteroalkylamino group, an arylalkylamino group, a cycloalkylamino group, an arylamino group, a heteroarylamino group, a heteroarylalkylamino group, a heterocycloalkylamino group, a carboxyl group, a carboxylalkylaminocarbonyl group, a cycloalkylaminocarbonyl group, a heteroarylaminocarbonyl group, a heteroarylaminocarbonyl group; Any group in the group may be unsubstituted or substituted by one or more substituents independently, and these 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, alkylamino, aminoalkyl, alkylaminocarbonyl; the alkyl is a C1-C8 straight chain or branched alkyl.

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

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

In certain embodiments, according to the above general formula (I), R ⁵ is selected from: hydrogen atom, isotope, alkyl, heteroalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl; any of the above groups may be independently unsubstituted or substituted by one or more substituents, and these substituents include but are 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 is selected from: benzene ring, pyrazole, pyrimidine, Methyl, ethyl, propyl.

In certain embodiments, according to the above general formula (I), ^R6 is selected from: hydrogen atom, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, heteroarylalkyl, heterocycloalkyl; any of the above groups may be unsubstituted or may be substituted by one or more alkyl, alkoxy groups; the alkyl group is a C1-C8 straight chain or branched alkyl group.

In certain embodiments, according to the above general formula (I), R ⁶ is selected from: a hydrogen atom, an alkyl group, a C3-C14 cycloalkyl group.

In certain embodiments, according to the above general formula (I), ^R7 is 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 may be unsubstituted or substituted by one or more substituents, and these substituents include but are not limited to halogen, alkyl, alkoxy; the alkyl is a C1-C8 straight chain or branched alkyl.

In certain embodiments, according to the above general formula (I), R7 can be linked to the ^C4- , ^C5- , ^C6- or ^C7 -position on the benzimidazole ring.

In certain embodiments, according to the above general formula (I), ^L1 is independently selected from: covalent bond, alkylene, heteroalkylene, -NH-, -C(O)-NH-, -NH-C(O)-, alkylene-C(O)-, -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 chain or branched alkyl; any of the above groups can be independently substituted by one or more substituents, and these substituents include hydrogen atoms and alkyl groups.

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

In certain embodiments, according to the above general formula (I), ^L2 is independently selected from: hydrogen atom, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkoxy, heteroalkoxy, arylalkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, carboxylalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups independently may not The invention can be substituted or can be substituted by one or more substituents, which 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, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is a C1-C8 straight chain or branched alkyl.

In certain other embodiments, according to the above general formula (I), ^L2 is preferably independently selected from: methyl, Benzene ring, m-fluorophenyl,

In certain embodiments, according to the above general formula (I), when X is a carbon atom, ^L3 is selected from: a covalent bond, an alkylene group, a heteroalkylene group, -NH, -C(O)-NH-, -NH-C(O)-, an alkylene group-C(O)-, -C(O)-, -C(O)-C(O)-, an alkylene group-C(O)-NH, an alkylene group-C(O)-, an alkylene group-NH-C(O)-, and an alkylene group-NH-; the alkylene group is a C1-C8 straight chain or branched alkyl group; any of the above groups may be independently substituted by one or more substituents, and these substituents include hydrogen atoms and alkyl groups.

^L3 is selected from the group consisting of ethylene, methylene, alkylene-C(O)-NH, alkylene-C(O)-, and alkylene-NH-C(O)-.

In certain embodiments, according to the above general formula (I), when X is a carbon atom, ^R8 is independently selected from the group consisting of: hydrogen atom, hydroxyl, alkyl, heteroalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkoxy, heteroalkoxy, arylalkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, alkylaminocarbonyl, carboxylalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups is independently The alkyl radicals may be unsubstituted or substituted with one or more substituents, and these 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, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl radical is a C1-C8 straight chain or branched chain alkyl radical.

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

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

The present invention also claims a method for preparing the compound represented by the above general formula (I), which is as follows:

When (R ⁶ )N can be linked to the C ⁵ -position on the benzimidazole ring, and R ¹ =R ³ =R ⁴ =R ⁶ =H, R ² =OCH ₃ and X = carbon atom, the preparation method comprises the following steps:

S1. A substituted 4-nitro-2-aminobenzene derivative (VI) is cyclized with an aldehyde (VII) or triethyl orthoformate to form a corresponding 5-nitrobenzimidazole derivative (VIII);

S2. The 5-nitrobenzimidazole derivative (VIII) is reduced to obtain a 5-aminobenzimidazole derivative (IX), which is then reacted with a 2-oxoindoline derivative (X) to obtain the target compound (XI);

The synthetic route is as follows:

When (R ⁶ )N can be linked to the C ⁵ -position on the benzimidazole ring, and R ¹ =R ³ =R ⁴ =R ⁶ =H, R ² =OC2H5 and X = carbon atom, the preparation method comprises the following steps:

S1, heating a substituted 4-bromo-2-oxoindoline derivative (XII) and a boronic acid derivative (XIII) under the catalysis of a palladium reagent to obtain a condensation product (XIV);

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

S3, the intermediate (XV) reacts with benzimidazole (XVI) to obtain the target compound (XVII) represented by the general formula (I);

The synthetic route is as follows:

In some embodiments, the compounds described herein have one of the following structures, or a stereoisomer, geometric isomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

The present invention also includes a pharmaceutical composition containing the compound represented by the above-mentioned general formula (I) or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs.

The present invention also includes a pharmaceutical composition comprising the compound represented by the above-mentioned general formula (I) or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, prodrugs; and used in combination with one or more other drugs.

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

The present invention provides a method for treating diseases caused by, associated with or accompanied by the disruption of cell proliferation and/or angiogenesis by using an effective amount of a compound represented by general formula (I) alone or in combination with other drugs.

In certain embodiments, the disorder is a proliferative disease.

In certain embodiments, the proliferative disease is cancer.

The present invention also includes the use of the compound represented by the above general formula (I) or its pharmaceutically acceptable salt or the above pharmaceutical composition for inhibiting the activity of kinase.

In certain embodiments, the inhibition of kinase activity is inhibition of RET, PDGFR, VEGFR, FGFR, FLT3, Aurora-A, Aurora-B, TRK, RAF, RET or Abl activity.

The present invention also includes a method for treating a patient's condition caused by, or associated with, or accompanied by the destruction of cell proliferation and/or angiogenesis, the method comprising administering to the patient a therapeutically effective amount of a compound represented by the above-mentioned general formula (I) or a pharmaceutically acceptable salt thereof.

The present invention also includes a method for treating a disease that can be treated by inhibiting kinase in a patient, the method comprising administering to the patient a therapeutically effective amount of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.

Conditions caused, associated or accompanied by cell proliferation and/or angiogenesis include, but are not limited to: bone cancers, including: Ewing's sarcoma, osteosarcoma, chondrosarcoma, etc.; brain and CNS tumors, including: acoustic neuroma, neuroblastoma, glioma and other brain tumors, spinal cord tumors, breast cancer, colorectal cancer, advanced colorectal adenocarcinoma; endocrine cancers, including: adrenal cortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymic carcinoma, multiple endocrine tumors; gastrointestinal Cancers, including: gastric cancer, esophageal cancer, small intestine cancer, liver cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumors, gallbladder cancer; genitourinary cancers, including: testicular cancer, penis cancer, prostate cancer; gynecological cancers, including: cervical cancer, ovarian cancer, vaginal cancer, uterine/endometrial cancer, genital cancer, gestational trophoblastic tumor, fallopian tube cancer, uterine sarcoma; head and neck tumors, including: oral cancer, lip cancer, salivary gland cancer, laryngeal cancer, hypopharyngeal cancer, orthopharyngeal cancer, nasal cancer, paranasal sinus cancer, nasopharyngeal cancer; blood cancer Cancer, including: childhood leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell leukemia; bone marrow cancer blood diseases, including: myelodysplastic syndrome, myeloproliferative disorders, aplastic anemia, Fanconi anemia, idiopathic macroglobulinemia; lung cancer, including: small cell lung cancer, non-small cell lung cancer; lymphoma, including: Hodgkin's disease, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, AIDS-related lymphoma; eye cancers, including retinoblastoma, uveal melanoma; skin cancers, including melanoma, non-melanoma skin cancer, Merkel cell carcinoma; soft tissue sarcomas, such as childhood soft tissue sarcoma, adult soft tissue sarcoma, Kaposi's sarcoma; urinary system cancers, including renal cancer, Wilms' tumor, bladder cancer, urethral cancer and metastatic cell carcinoma.

In certain embodiments, in the above methods, the patient is undergoing surgery or radiotherapy, and the compound is administered to the patient concomitantly with, before, or after the surgery or radiotherapy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 shows the changes in tumor growth in mice bearing TT cell xenograft tumor models after administration of compound 53;

FIG2 shows the changes in body weight of mice bearing TT cell xenograft tumor model after administration of compound 53.

DETAILED DESCRIPTION

The present invention discloses a preparation method and medical application of novel 2-oxoindoline derivatives. These compounds can be used as, but not limited to, kinase inhibitors. The aminopyrazole derivatives disclosed in the present invention can be used alone or together with other drugs or pharmaceutically acceptable carriers, diluents or excipients, and are suitable for preventing or treating diseases caused by, associated with or accompanied by the destruction of cell proliferation and/or angiogenesis. One example of these diseases is cancer.

As used herein, the term "cancer" generally refers to a broad range of disorders characterized by the uncontrolled abnormal growth of cells.

The compounds of the present invention are expected to be useful in treating a variety of cancers, including, but not limited to: bone cancers, including: Ewing's sarcoma, osteosarcoma, chondrosarcoma, etc.; brain and CNS tumors, including: acoustic neuroma, neuroblastoma, glioma and other brain tumors, spinal cord tumors, breast cancer, colorectal cancer, advanced colorectal adenocarcinoma; endocrine cancers, including: adrenal cortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymic carcinoma, multiple endocrine neoplasms; gastrointestinal cancers, Includes: gastric cancer, esophageal cancer, small intestine cancer, liver cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumors, gallbladder cancer; genitourinary cancers, including: testicular cancer, penis cancer, prostate cancer; gynecological cancers, including: cervical cancer, ovarian cancer, vaginal cancer, uterine/endometrial cancer, genital cancer, gestational trophoblastic tumor, fallopian tube cancer, uterine sarcoma; head and neck tumors, including: oral cancer, lip cancer, salivary gland cancer, laryngeal cancer, hypopharyngeal cancer, orthopharyngeal cancer, nasal cancer, paranasal sinus cancer, nasopharyngeal cancer; blood cancers , including: childhood leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell leukemia; bone marrow cancer blood diseases, including: myelodysplastic syndrome, myeloproliferative disorders, aplastic anemia, Fanwohn anemia, idiopathic macroglobulinemia; lung cancer, including: small cell lung cancer, non-small cell lung cancer; lymphoma, including: Hodgkin's disease , non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, AIDS-related lymphoma; eye cancers, including retinoblastoma, uveal melanoma; skin cancers, including melanoma, non-melanoma skin cancer, Merkel cell carcinoma; soft tissue sarcomas, such as childhood soft tissue sarcoma, adult soft tissue sarcoma, Kaposi's sarcoma; urinary system cancers, including renal cancer, Wilms' tumor, bladder cancer, urethral cancer and metastatic cell carcinoma.

The compounds disclosed in the present invention can be used to treat cancers including: breast cancer, lung cancer, liver cancer, ovarian cancer, prostate cancer, head and neck cancer, kidney cancer, stomach cancer and brain cancer.

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

The term "unsubstituted" as used herein means no substituent or substitution with only hydrogen.

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

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

"Isotope" means the same as the compounds listed herein, but one or more atoms therein are replaced by another atom, and the atomic mass or mass number of the atom is different from the atomic mass or mass number commonly found in nature. Isotopes that can be introduced into the compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, fluorine, and sulfur, i.e., ^2H , ^3H , ^13C , ^14C , ^15N , ^17O , ^18O , ^18F , ^35S . Compounds of formula (I) and stereoisomers thereof containing the above-mentioned isotopes and/or other atomic isotopes, as well as pharmaceutically acceptable salts of the compounds and stereoisomers should all be included within the scope of the present invention.

"=O" means oxo.

" _-CF3 " refers to trifluoromethyl.

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

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

"Carbonyl" means

"Alkyl" when used as a group or part of a group refers to a straight chain or branched aliphatic hydrocarbon group. Preferably, the alkyl group is C1-C14 alkyl; more preferably, C1-C10 alkyl; most preferably, C1-C6 alkyl, unless otherwise specified. Examples of straight chain 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" and "condensed ring" refer to cyclic groups formed by two or more cyclic structures sharing two adjacent carbon atoms. They include 4-14-membered saturated condensed cycloalkyls and 6-14-membered partially saturated condensed cycloalkyls, and specific examples thereof include but are not limited to the following structures:

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

"Cycloalkyl" refers to a saturated or partially saturated monocyclic, bicyclic, condensed or spirocyclic carbocyclic ring. Rings consisting of 3-14 carbon atoms are preferred. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The definitions of the "bicyclic", "condensed" or "spirocyclic" parts are provided in the relevant sections of this article.

"Heteroalkyl" refers to a group containing a straight chain or a branched chain alkyl group, and in the main chain, contains at least one or more heteroatoms selected from S, O and N. Preferably, the chain contains 2-14 atoms. Heteroalkyl includes, but is not limited to, ethers, thioethers, alkyl esters, second or third alkylamines, alkyl sulfinic acids, etc.

"Heterocycloalkyl" refers to a group formed by replacing one or more (preferably 1, 2 or 3) carbon atoms in the "cycloalkyl" defined above with oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atoms (preferably oxygen, sulfur or nitrogen). Wherein, heterocycloalkyl and alkyl parts are defined in this document. Preferably, it contains 1-3 heteroatoms. The preferred ring is a 3-14-membered ring (i.e., a 3-14-membered heterocycloalkyl), and the more preferred ring is a 4-7-membered ring (i.e., a 4-7-membered heterocycloalkyl). Heterocycloalkyl includes, but is not limited to: pyrrolidinyl, dihydropyrrolyl, tetrahydropyrrolyl, dihydropyrazolyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, oxirane, azirane or 2-pyrazolinyl, as well as lactams, lactones, cyclic imides and cyclic anhydrides. Heterocycloalkyl may be substituted by one or more substituents.

"Heterocycloalkylalkyl" refers to a group of (heterocycloalkyl-alkyl)-, wherein the heterocycloalkyl and alkyl parts are as defined herein. Heterocycloalkylalkyl groups include, but are not limited to, (2-tetrahydrofuranyl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

"Alkylamino" includes both monoalkylamino and dialkylamino, unless otherwise specified. "Monoalkylamino" refers to a group of (alkyl-NH)-; "dialkylamino" refers to a group of ((alkyl) ₂ N)-. The alkyl group is defined in this document. The alkyl group is preferably a C1-C6 alkyl group. Examples include, but are not limited to, N-methylamino, N-ethylamino, N-isopropylamino, N,N-(diethyl)amino, and the like.

"Heteroalkylamino" refers to both mono-heteroalkylamino and di-heteroalkylamino, unless otherwise specified. Mono-heteroalkylamino refers to a group of (heteroalkyl-)NH-; di-heteroalkylamino refers to a group of (heteroalkyl) ₂ N-. The definition of the "heteroalkyl" part is given in the relevant part of this document.

"Aminoalkyl" refers to a group of (amino-alkyl)-. The "alkyl" part is defined in this document. The aminoalkyl is preferably amino C1-C6 alkyl. It should be noted that "amino-C1-C6 alkyl" refers to a C1-C6 alkyl substituted by "amino", and its examples include but are not limited to: aminoethyl, 1-aminopropyl, 2-aminopropyl, etc.

"Arylamino" includes both mono-arylamino and di-arylamino, unless otherwise specified. Mono-arylamino refers to a group of (aryl-)NH-; di-arylamino refers to a group of formula (aryl) ₂ N-; the definition of aryl is given in the relevant part of this document.

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

"Acylamide" includes (alkyl-CONH)- and (aryl-CONH)- groups, unless otherwise specified. Wherein, alkyl or aryl are as defined herein. Examples of acylamide include, but are not limited to, acetylamide, propionylamide, butyramide, isobutyramide, benzylamide, 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 can be straight chain or branched. Alkenyl groups with C2-C14 are preferred. C2-C12 is more preferred; C2-C6 is most preferred. The group can contain multiple double bonds in its main chain and their conformation can be E or Z. Examples of alkenyl groups include, but are not limited to: vinyl, propenyl, etc.

"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 chain or branched. It is preferably C2-C14 alkynyl, more preferably C2-C12 alkynyl, and most preferably C2-C6 alkynyl. Examples of the alkynyl 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-methylprop-2-yn-1-yl, pent-1-yn-1-yl, pent-4-yn-1-yl, hex-1-yn-1-yl, hex-5-yn-1-yl, etc.

"Alkoxy" refers to a group of (alkyl-O)-. The "alkyl" part thereof is defined in this document. The alkoxy is preferably a C1-C8 alkoxy, and more preferably a C1-C6 alkoxy. Examples of the alkoxy 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-hexyloxy, isohexyloxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, etc. In addition, "alkoxycarbonyl" means a group in which the "alkoxy" defined above is bonded to a carbonyl group, for example, methoxycarbonyl, ethoxycarbonyl, etc. can be cited.

"Alkenyloxy" refers to a group of (alkenyl-O)-, wherein alkenyl is as defined herein. C1-C6 alkenyloxy is preferred.

"Alkynyloxy" refers to a group of (alkynyl-O)-, wherein alkynyl is as defined herein. C1-C6 alkynyloxy is preferred.

"Alkoxycarbonyl" refers to a group of (alkyl-O-C(O))-, wherein alkyl is as defined herein. The preferred alkyl group is C1-C6 alkyl. Examples thereof include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and the like.

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

"Alkylsulfonyl" refers to a group of (alkyl-S(O) ₂ -O)-, wherein alkyl is as defined herein. The preferred alkyl is a C1-C6 alkyl group, examples of which include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.

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

"Cycloalkylalkyl" refers to a cycloalkyl-alkyl group. The cycloalkyl and alkyl moieties are as defined herein. Monocyclic alkyl 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.

"Aryl" as a group or part of a group refers to: (1) an aromatic monocyclic or condensed ring; preferably an aromatic carbocyclic ring (a ring structure in which all the ring atoms are carbon) having 5-12 carbon atoms. Examples of aryl include, but are not limited to, phenyl and naphthyl; (2) partially saturated carbocyclic rings may be connected, for example, phenyl and C5-7 cycloalkyl or C5-7 cycloalkenyl groups are fused to form a ring structure. Examples include, but are not limited to, tetrahydronaphthyl, indenyl or hydroindenyl. Aryl groups may be substituted by one or more substituents.

"Arylalkenyl" refers to a group of (aryl-alkenyl)-, wherein aryl and alkenyl are as defined herein. Exemplary arylalkenyl groups include, but are not limited to, phenylpropenyl, and the like.

"Aralkyl" refers to a group of (aryl-alkyl)-, wherein the aryl and alkyl parts 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 polycyclic ring system. It contains at least one carbon-carbon double bond and each ring preferably has 5-10 carbon atoms. 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" refers to a monocyclic or condensed 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 atoms, preferably the aromatic group is a 4-15 membered heteroaryl group, more preferably a 5-7 membered heteroaryl group. Examples of the heteroaryl group include, for example, furanyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, pyridinyl, imidazolyl, 3-phenylpyrrolyl, thiazolyl-oxazolyl, tetrazolyl, isoxazolyl, indazolyl, pyridazinyl, quinolyl, purinyl, carbazolyl, acridinyl, pyrimidinyl, 2,3'-bifuranyl and isoquinolyl.

"Heteroarylalkyl" refers to a group of (heteroaryl-alkyl)-, wherein the heteroaryl and alkyl parts are as defined herein. Exemplary heteroarylalkyl groups include, but are not limited to, 2-furylmethyl, 3-furylmethyl, 2-pyridylmethyl, and the like.

"Alkoxy" refers to a group of: (alkyl)-O-, wherein the "alkyl" part is as defined herein.

"Cycloalkoxy" refers to a group of: (cycloalkyl)-O-, wherein the "cycloalkyl" part is as defined herein.

"Heteroalkoxy" refers to a group of: (heteroalkyl)-O-, wherein the "heteroalkyl" part is as defined herein.

"Aryloxy" refers to a group of: (aryl)-O-, wherein the "aryl" part is as defined herein.

"Arylalkoxy" refers to a group of: (aryl-alkyl)-O-, wherein the "aryl" and "alkyl" parts are as defined herein.

"Heteroaryloxy" refers to a group of (heteroaryl)-O-, wherein the "heteroaryl" part is as defined herein.

"Heteroarylalkoxy" refers to a group of: (heteroaryl-alkyl)-O-, wherein the "heteroaryl" and "alkyl" parts are as defined herein.

"Heterocycloalkoxy" refers to a group of: (heterocycloalkyl)-O-, wherein the "heterocycloalkyl" part is as defined herein.

"Heterocycloalkylamino" refers to both mono-heterocycloalkylamino and di-heterocycloalkylamino, unless otherwise specified. Mono-heterocycloalkylamino refers to a group of (heterocycloalkyl-)NH-; di-heterocycloalkylamino refers to a group of (heterocycloalkyl) ₂ -N-. The definition of the "heterocycloalkyl" part is given in the relevant part of this document.

"Arylalkylamino" refers to both mono-arylalkylamino and di-arylalkylamino, unless otherwise specified. Mono-arylalkylamino refers to a group of (aryl-alkyl)-NH-; di-arylalkylamino refers to a group of (aryl-alkyl) ₂ -N-. The definitions of "aryl" and "alkyl" are as given in the relevant part of this document.

"Cycloalkylamino" refers to both mono-cycloalkylamino and di-cycloalkylamino, unless otherwise specified. Mono-cycloalkylamino refers to a group of (cycloalkyl)-NH-; di-arylalkylamino refers to a group of (cycloalkyl) ₂ -N-. The definition of the "cycloalkyl" part is given in the relevant part of this document.

"Arylamino" refers to both mono-arylamino and di-arylamino, unless otherwise specified. Mono-arylamino refers to a group of (aryl)-NH-; di-arylamino refers to a group of (aryl) ₂ -N-. The definition of the "aryl" part is given in the relevant part of this document.

"Heteroarylamino" refers to both mono-heteroarylamino and di-heteroarylamino, unless otherwise specified. Mono-heteroarylamino refers to a group of (heteroaryl)-NH-; di-heteroarylamino refers to a group of (heteroaryl) ₂ -N-. The definition of the "heteroaryl" part is given in the relevant part of this document.

"Heteroarylalkylamino" refers to both mono-heteroarylalkylamino and di-heteroarylalkylamino, unless otherwise specified. Mono-heteroarylalkylamino refers to a group of (heteroaryl-alkyl)-NH-; di-heteroarylalkylamino refers to a group of (heteroaryl-alkyl) ₂ -N-. The definitions of "heteroaryl" and "alkyl" are given in the relevant part of this document.

Unless otherwise specified, the subunit of the present invention refers to a divalent group, that is, a group in which one hydrogen atom in a monovalent group is replaced by a valency. For example, "heteroalkylene" refers to a heteroalkyl group in which one of the hydrogen atoms is replaced by a valence; "heterocyclylene" refers to a heterocyclyl group in which one of the hydrogen atoms is replaced by a valence; "arylene" refers to an aryl group in which one of the hydrogen atoms is replaced by a valence; "alkylene" refers to an alkyl group in which one of the hydrogen atoms is replaced by a valence; "alkenylene" refers to an alkenyl group in which one of the hydrogen atoms is replaced by a valence; "cycloalkylene" refers to a cycloalkyl group in which one of the hydrogen atoms is replaced by a valence; "heteroarylene" refers to a heteroaryl group in which one of the hydrogen atoms is replaced by a valence; "heterocycloalkylene" refers to a heterocycloalkyl group in which one of the hydrogen atoms is replaced by a valence; "heterocycloalkenylene" refers to a heterocycloalkenyl group in which one of the hydrogen atoms is replaced by a valence; "alkyleneoxy" refers to an alkoxy group in which one of the hydrogen atoms is replaced by a valence; "alkenyleneoxy" refers to an alkenyloxy group in which one of the hydrogen atoms is replaced by a valence; "alkynyleneoxy" refers to an alkynyloxy group in which one of the hydrogen atoms is replaced by a valence, and the like. Wherein, the definitions of the above-mentioned heterocyclic group, aryl, alkyl, alkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, etc. can be found in the relevant definitions herein.

The present invention includes compounds represented by the general formula (I) and possible various isomeric forms thereof, including non-mirror isomers, mirror isomers, tautomers, and geometric isomers of "E" or "Z" configuration isomers, etc. Any chemist with a certain foundation can separate the above optically pure or stereoisomerically pure compounds.

The present invention includes the general formula (I) and the compounds represented by the general formula and possible racemates and/or mirror isomers and/or mixtures of diastereomers.

In addition, the compounds represented by general formula (I) also include solvated and unsolvated forms of the compounds. Therefore, each formula includes compounds having the specified structure, including hydrated and unhydrated forms thereof.

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

The term "pharmaceutically acceptable salt" refers to certain salts of the above compounds that can maintain the original biological activity and are suitable for medical use. The pharmaceutically acceptable salts of the compounds represented by general formula (I) have two forms: one is a salt formed with an acid; the other is a salt formed with a base or an alkali metal. Acids that form pharmaceutically acceptable salts with the compounds represented by general formula (I) include inorganic acids and organic acids. Suitable inorganic acids include: hydrochloric acid, sulfuric acid and phosphoric acid. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic acids and sulfonic acid 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, aromatic sulfonic acid, etc. Alkali metals that form pharmaceutically acceptable salts with the compounds represented by the general formula (I) include: lithium, sodium, potassium, magnesium, calcium, aluminum, zinc, etc.; bases that form pharmaceutically acceptable salts with the compounds represented by the general formula (I) include: choline, diethanolamine, morpholine, etc.

"Prodrug" is a derivative represented by general formula (I), which is converted into a compound represented by general formula (I) in vivo by means of in vivo metabolism (e.g., by hydrolysis, reduction or oxidation). For example, a compound represented by general formula (I) containing a hydroxyl group can be reacted with an acid to prepare a corresponding ester. The corresponding ester is a prodrug, which can be hydrolyzed into 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-β-hydroxynaphthoic acid, gentisic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

The kinase inhibitors referred to in the present invention include those compounds with an IC ₅₀ value of 10 μM or less. The kinases used in the present invention include but are not limited to RET, PDGFR, VEGFR, FGFR, FLT3, Aurora-A, Aurora-B, TRK, BRAF, RET or Abl

The administration of the compound represented by general formula (I) can be either enteral or parenteral. Enteral administration: oral or rectal. Parenteral administration includes: subcutaneous, intramuscular, intravenous and intradermal routes. Generally, the active compound represented by general formula (I) can be administered with 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 can be administered in one or more doses. Generally, the effective amount is sufficient to alleviate, improve, stabilize, slow down or delay the further development of the disease.

The compounds of the present invention can be used alone or in combination with one or more other drugs; or in combination with surgery or radiotherapy; or in combination with pharmaceutically acceptable carriers, diluents or excipients to form a certain dosage form for administration. The specific dosage form depends on the route of administration.

The pharmaceutical formulation for parenteral injection of the present invention comprises a pharmaceutically acceptable sterile aqueous solution or non-aqueous solution, a dispersant, a suspending agent or an emulsifier, and a powder injection which is prepared into an injectable sterile aqueous solution before use.

If desired, and for more effective distribution, the compounds of the invention can be incorporated into slow-release or targeted-delivery systems such as 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 mixed 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 starches, lactose, sucrose, glucose, mannitol and salicylic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin polyvinylpyrrolidone, sucrose and acacia; c) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; d) dissolution delaying agents, such as paraffin; e) absorption accelerators, such as quaternary ammonium compounds; f) wetting agents, such as cetyl alcohol and glyceryl monostearate; g) adsorbents, such as kaolin and bentonite; and h) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols.

Solid dosage forms of tablets, dragees, capsules, troches and granules can be prepared with coatings or shells.

The active compounds can also be administered in microencapsulated form, with one or more of the above-mentioned excipients, if desired.

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

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

The suspension may contain, in addition to the active compound, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters.

Compositions for rectal or vaginal administration are preferably in the form of suppositories. These may be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers.

Dosage forms for topical administration of the compounds of this invention include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives, buffers or propellants.

The preferred dosage range is about 0.01-400 mg per kilogram of body weight per day. The more preferred dosage range is 0.2-100 mg per kilogram of body weight per day. An appropriate dosage may also be selected for multiple divided doses per day.

The compounds of the present invention can be used as, but not limited to, kinase inhibitors. The pyrimidine derivatives disclosed in the present invention can be used alone or together with other drugs or pharmaceutically acceptable carriers, diluents or excipients, and are suitable for preventing or treating diseases caused by, or associated with or accompanied by, the destruction of cell proliferation and/or angiogenesis. One example of these diseases is cancer.

The compounds of the present invention can also be used to treat diseases that are regulated at least in part by the activity of PDGFR, VEGFR, FGFR, FLT3, Aurora-A, Aurora-B, TRK, B-RAF, RET or and Abl, wherein RET, PDGFR, VEGFR activity is known to play a role in promoting the onset of the disease, or such symptoms are known or have been shown to be alleviated by RET, PDGFR, VEGFR inhibitors. Disorders of this type that are expected to be treated 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 diseases, Parkinson's disease, Alzheimer's disease, epileptic seizures, striatonigral degeneration, progressive supranuclear palsy, torsion dystonia, spasmodic torticollis and movement disorders, familial tremor, Tourette 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 diseases, including type 2 diabetes; ocular degenerative diseases, including glaucoma, age-related macular degeneration, rubroiridis glaucoma; inflammatory diseases and/or immune system disorders, including rheumatoid arthritis (RA), osteoarthritis, Arthritis, juvenile chronic arthritis, graft-versus-host disease, psoriasis, asthma, spondyloarthropathies, psoriasis, Crohn's disease, inflammatory bowel disease, colon ulcers, alcoholic hepatitis, diabetes, Sjoegrens syndrome, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, disc pain, systemic lupus erythematosus; diseases involving angiogenesis, including cancer, psoriasis, rheumatoid arthritis; psychological disorders, including bipolar disorder, schizophrenia , mania, depression and dementia; cardiovascular diseases including; heart failure, restenosis and arteriosclerosis; fibrotic diseases including: liver fibrosis, cystic fibrosis and angiofibroma; infectious diseases including: fungal infections such as: Candida albicans, bacterial infections; viral infections such as: herpes simplex; protozoan infections such as: malaria, Leishmania infection, Trypanosoma brucei infection, toxoplasmosis and coccidiosis; hematopoietic disorders including: thalassemia, anemia and sickle cell anemia.

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

The compounds of the present invention are expected to be useful in treating a variety of cancers, including but not limited to: bone cancers, including: Ewing's sarcoma, osteosarcoma, chondrosarcoma, etc.; brain and CNS tumors, including: acoustic neuroma, neuroblastoma, glioma and other brain tumors, spinal cord tumors, breast cancer, colorectal cancer, advanced colorectal adenocarcinoma; endocrine cancers, including: adrenal cortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymic carcinoma, multiple endocrine tumors; gastrointestinal cancers, Includes: gastric cancer, esophageal cancer, small intestine cancer, liver cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumors, gallbladder cancer; genitourinary cancers, including: testicular cancer, penis cancer, prostate cancer; gynecological cancers, including: cervical cancer, ovarian cancer, vaginal cancer, uterine/endometrial cancer, genital cancer, gestational trophoblastic tumor, fallopian tube cancer, uterine sarcoma; head and neck tumors, including: oral cancer, lip cancer, salivary gland cancer, laryngeal cancer, hypopharyngeal cancer, orthopharyngeal cancer, nasal cancer, paranasal sinus cancer, nasopharyngeal cancer; blood cancers , including: childhood leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell leukemia; bone marrow cancer blood diseases, including: myelodysplastic syndrome, myeloproliferative disorders, aplastic anemia, Fanwohn anemia, idiopathic macroglobulinemia; lung cancer, including: small cell lung cancer, non-small cell lung cancer; lymphoma, including: Hodgkin's disease , non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, AIDS-related lymphoma; eye cancers, including retinoblastoma, uveal melanoma; skin cancers, including melanoma, non-melanoma skin cancer, Merkel cell carcinoma; soft tissue sarcomas, such as childhood soft tissue sarcoma, adult soft tissue sarcoma, Kaposi's sarcoma; urinary system cancers, including renal cancer, Wilms' tumor, bladder cancer, urethral cancer and metastatic cell carcinoma.

Cancers that the compounds of the present invention can be used to treat include, but are not limited to, breast cancer, lung cancer, ovarian cancer, thyroid cancer, colorectal cancer, prostate cancer, head and neck cancer, kidney cancer, stomach cancer, and brain cancer.

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

In addition, the compounds of the present invention can be used to treat proliferative diseases that are resistant to other chemotherapeutic treatments; and to treat hyperproliferative diseases, such as leukemia, psoriasis, and the like.

Synthesis of 2-Oxoindoline Derivatives

The compound represented by the general formula (I) can be synthesized using the synthetic route and method discussed below. The raw materials used are readily available. However, the synthetic route and method used in the present invention can be widely applied to the synthesis of analogs, and only the starting raw materials need to be changed. For example, the synthesis of compounds not described in detail in the examples herein can be synthesized by replacing the starting raw materials with the starting raw materials of the corresponding target compound, and slightly changing the reaction conditions when necessary according to common chemical knowledge to synthesize the desired target compound.

The reagents of each specific embodiment can be prepared using the reaction pathways or synthetic flow charts described below. The preparation of specific compounds of the specific embodiments is described in detail in the following examples. However, those skilled in the art know that the chemical reactions described can be applied to the preparation of a variety of other compounds in different specific embodiments. For example: the synthesis of non-exemplified compounds can be successfully carried out by obvious modifications to those skilled in the art, or by changing to other appropriate reagents known in the art. For a list of suitable protecting groups in organic synthesis, see T.W. Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, 1981. Other reactions disclosed herein or known in the art can be identified as having applicability for preparing other compounds of each specific embodiment.

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

In the following examples, all temperatures are in degrees Celsius unless otherwise indicated.

All starting materials and reagents were obtained from commercial suppliers, including but not limited to Aldrich Chemical Company, Lancaster Synthesis Ltd, etc. Commercially available starting materials and reagents were used directly without further purification unless otherwise specified.

The glassware was oven dried and/or heat dried. The reaction was followed on glass silica gel-60 F254 plates (0.25 mm) (TLC). Analytical thin layer chromatography was developed with appropriate solvent ratios (v/v). The end point of the reaction was when the starting material was exhausted on TLC.

Usually, the subsequent treatment is to double the volume of the reaction solution with the solvent used in the reaction, and then extract three times with 25% of the total volume of the extraction solvent, unless otherwise specified. The product-containing extract is dehydrated with anhydrous sodium sulfate, filtered on a rotary evaporator, and the solvent is evaporated under reduced pressure and attention is paid to the removal of the solvent in vacuum. Finally, the target compound is separated by flash column chromatography (J. Org. Chem., 1978; 43: 2923).

¹ H NMR spectra were obtained using a Bruker instrument (400 MHz) and chemical shifts are expressed in ppm. Chloroform was used as a reference standard (7.25 ppm) or tetramethylsilane as an internal standard (0.00 ppm). Other solvents commonly used in NMR may be used as needed. ¹ H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplet. Coupling constants, when provided, are in Hz.

Mass spectra were obtained using LC/MS, with ESI or APCI ionization. All melting points are uncorrected.

The following examples are only used to illustrate the synthesis methods of the specific compounds invented. However, there is no limitation on the synthesis methods. Compounds not listed below can also be prepared by the same synthesis routes and methods as below, by selecting appropriate starting materials and slightly adjusting the reaction conditions according to common sense where necessary.

synthesis

The compound shown in the general formula (I), when (R ⁶ )N can be linked to the C ⁵ -position on the benzimidazole ring, and R ¹ = R ³ = R ⁴ = R ⁶ = H, R ² = OCH ₃ and X = carbon atom, can be synthesized as follows: a suitable substituted 4-nitro-2-aminobenzene derivative (VI) is cyclized with a suitable aldehyde (VII) or triethyl orthoformate to be converted into the corresponding 5-nitrobenzimidazole derivative (VIII). The 5-aminobenzimidazole derivative (IX) obtained after reduction of the latter is reacted with a suitable 2-oxoindoline derivative (X) to obtain the target compound (XI) shown in the general formula (I) (see Synthesis Route 1 for details).

Synthetic route 1

The compound shown in the general formula (I), when (R ⁶ )N can be linked to the C ⁵ -position on the benzimidazole ring, 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: a suitable substituted 4-bromo-2-oxoindoline derivative (XII) and a boric acid derivative (XIII) are heated under the catalysis of a palladium reagent to obtain a condensation product (XIV). The latter reacts with an orthoformate to obtain an intermediate (XV). The benzimidazole (XVI) is reacted with the intermediate (XV) to obtain the target compound (XVII) shown in the general formula (I) (see Synthesis Route 2 for details).

Synthetic route 2

The content of the present invention is further explained below with reference to examples. The purpose is to allow technicians with basic knowledge in the field to more clearly understand and practice the specific content of the present invention. However, the protection scope of the present invention is not limited to these examples.

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

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

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

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

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

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

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

Example 2-88

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

Table 1 Representative 2-oxoindoline derivatives of general formula (I)

In addition, referring to the method of Example 1, as long as the starting materials are appropriately selected, a wider variety of derivatives can be synthesized. For example, the compounds listed in Table 2 are some examples.

Table 2 Other derivatives included in the general formula (1)

Biological experiments and pharmacodynamic analysis

1. Detection of kinase activity

There are many literature reports on the test of kinase activity, and there are also related kinase detection kits available. Products from Cisbio can be selected but are 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 operation steps are as follows.

1. Experimental methods and steps:

1.1 Prepare the test compound into a 10 mM (mmol/L) DMSO solution.

1.2 Dilute the 10mM compound with kinase buffer to 2.5μM (2.5× compound) working solution, then dilute the compound to be tested 2.5× working solution to 9 concentrations in a 3-fold gradient with 2.5μM as the highest concentration, and the concentrations are: 2.5, 0.833333, 0.277778, 0.092593, 0.030864, 0.010288, 0.003429, 0.001143, 0 .000381μM; dilute 10mM control compound with kinase buffer to 2.5μM working solution, and then take 2.5μM as the highest concentration, dilute it in 3-fold gradient, and continuously dilute the 2.5× working solution of the test compound to 9 concentrations, namely: 2.5, 0.833333, 0.277778, 0.092593, 0.030864, 0.010288, 0.003429, 0.001143, 0.000381μM.

1.3 Take 4 μL of 2.5× compound working solution and add it to a 384-well plate (Greiner, Cat#781280), set up Blank wells (no compound and kinase) and Control wells (only kinase without compound), and add 4 μL kinase buffer to the Blank and Control wells.

1.4 Prepare the kinase storage solution with kinase buffer into the corresponding 5× working solution, take 2μL of 5× kinase working solution and add it to each well containing compound working solution, add 2μL kinase buffer to the Blank well, and add 2μL 5× kinase working solution to the Control well.

1.5 Take 2μL of 5× substrate storage solution (TK Antibody-Cryptate) and add it to each well containing compound and kinase working solution, add 2μL kinase buffer to the Blank well, and add 2μL 5× substrate storage solution to the Control well.

1.6 Take 2 μL of ATP working solution (5×) and add it to each detection well.

1.7 Cover the 384-well plate with a sealing film and incubate at 37°C for 1 hour, then add 5 μL (4X) of reaction stop solution (Streptavidin-XL665) to each well;

1.8 Continue to seal the 384-well plate, incubate at 37°C for 1 hour, and then detect the 665 and 620 signal values on the 2104 EnVision plate reader.

Preparation of 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 BLANK (665/620)) * 100%. The inhibition rate of different concentrations of the compound was calculated in Excel, and then the IC ₅₀ was calculated using GraphPad Prism 5 software.

3. Activity inhibition test results of wild-type RET and mutant RET kinases

Some biological activity test results are shown in Table 3

Table 3 Kinase inhibitory activity of target compounds

The target compound claimed in the present invention has good inhibitory activity on both wild-type RET and mutant RET kinases.

At the same time, the present invention also uses the compounds of the present invention to test other kinases, and it is also found that the compounds of the present invention also have a significant inhibitory effect on kinases (activity of PDGFR (PDGFRα and PDGFRβ), VEGFR, FGFR, FLT3, Aurora-A, Aurora-B, TRK, B-RAF, RET or Abl) (see Table 4 for details).

Table 4 Inhibitory activity of target compounds on PDGFRα, PDGFRβ and VEGFR2 kinases

The following table compares the inhibitory activities of compound 53 and the reference substance Nintedanib on some enzymes.

Table 5 Comparison of some enzyme inhibition activities of compound 53 and Nintedanib

2. Detection of tumor cell inhibitory activity

The cell activity test uses CTG (CELL TITER-GLO) luminescence method to test the activity of the target compound. The principle is: ATP adenine nucleoside triphosphate (ATP for short) participates in a variety of enzymatic reactions in the body and is an indicator of living cell metabolism. Its content directly reflects the number and state of cells. During the experiment, an equal volume of CellTiter-Glo ^TM reagent is added to the cell culture medium to measure the luminescence value. In the light signal and system, the luminescence value is proportional to the amount of ATP, and ATP is positively correlated with the number of living cells and inversely proportional to the activity of anti-tumor drugs. By detecting the fluorescence signal of ATP, the anti-proliferation activity data of the compound on tumor cells can be obtained according to the calculation formula.

The test of tumor cell inhibitory activity was carried out in two parts: using kinase as the target, the target compound was examined for its effects on human thyroid ductal carcinoma cells (TT) and human colon cancer cells (KM12); in order to determine its activity on RET Fusion, the growth inhibitory activity of the target compound on KIF5B-RET fusion cells was specifically tested.

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

910. Determination of the activity of compounds against human thyroid ductal carcinoma cells and human colon cancer cells

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

Specific experimental operation methods and processes:

1.1 Cell recovery

Immediately place the frozen cells from the liquid nitrogen storage tank in a 37°C constant temperature water bath and shake for 2 minutes. After the cell freezing solution is completely thawed, transfer the cell suspension into a 15mL centrifuge tube, slowly add 4mL of culture solution, centrifuge (1000r/min, 5min), discard the supernatant, aspirate the original solution, add 5mL of the above culture medium, gently blow to a single cell suspension, transfer it to a culture bottle, and place it in an incubator for culture.

1.2 Cell culture

The cells were cultured with complete medium in an incubator at 37°C and 5% CO _2. The cells were passaged regularly and cells in the logarithmic growth phase were used for plating.

1.3 Cell plating

The cells were stained with trypan blue and the living cells were counted. The cell concentration was adjusted to a cell solution with an appropriate medium plate concentration (TT: 50000 cell/mL, KM12: 35000 cell/mL). 90 μL of the cell suspension was added to each well of a 96-well culture plate (Corning, 3599), and blank control wells and vehicle control wells were set up. The culture solution containing cells was added to the blank control wells, and the culture solution without cells was added to the vehicle control wells. The culture plate was then placed in an incubator at 37°C, 5% CO ₂ , and 100% relative humidity for overnight culture.

1.4 Compound preparation

Weigh the compound and prepare a 10mM stock solution with DMSO. Dilute the stock solution of the compound to be tested with serum-free medium to a final concentration of 100μM 10× compound working solution (including reference substance) on a dispensing plate (Beaver, Suzhou). Dilute with serum-free medium in a 3-fold concentration gradient to obtain 9 concentration gradients of 10× compound working solutions, with compound concentrations of 100, 33.33, 11.11, 3.70, 1.23, 0.411, 0.137, 0.046, and 0.015μM, respectively.

1.5 Addition of compounds

Add 10× compound working solution of different concentration gradients to the 96-well cell culture plate, 10 μL/well, add 10 μL DMSO-cell culture solution mixture to the solvent control well and blank control well, the final DMSO concentration is 0.1%, and set 2 replicates for each concentration. Return the 96-well cell plate to the 37°C, 5% carbon dioxide incubator and culture for 5 days.

1.6CTG detection

Take out the cell culture plate and let it stand for 30 minutes to equilibrate to room temperature, add 50 μL (equal to half the volume of the cell culture medium in each well) of Cell Titer-Glo working solution to each well, wrap the cell plate with aluminum foil to avoid light, shake the culture plate on an orbital shaker for 2 minutes to induce cell lysis, leave the culture plate at room temperature for 10 minutes to stabilize the luminescent signal, and detect the luminescent signal on a 2104 EnVision 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 control)/(RLU solvent control-RLU blank control))*100%. Finally, nonlinear regression analysis was performed using the logarithm of compound concentration-inhibition rate in Graphpad prism5 software to obtain the _IC50 value of the compound for inhibiting cell proliferation.

Results The test results are shown in Table 6.

Table 6 Results of the inhibitory activity test on TT cells and KM12 cells obtained by the compounds

The target compound claimed for protection in the present invention has good inhibitory activity on both human thyroid ductal cancer cells and human colon cancer cells.

Using the same cell activity inhibition assay method as above, the growth inhibition activity of the target compound on SNU-16, NCI-H170 and GIST-T1 tumor cells was detected as shown in Table 7.

Table 7 Growth inhibitory activity of target compounds on SNU-16, NCI-H1703 and GIST-T1 tumor cell beads

3. In vivo antitumor activity of the compounds of the present invention:

Some compounds with strong in vitro activity and low toxicity were selected to determine the maximum tolerated dose (MTD) in mice. The anti-tumor activity of the compounds of the present invention in vivo was determined on a human cancer nude mouse xenograft tumor model to explore the dosage, route of administration, frequency and cycle of administration of the test compounds to produce pharmacodynamic effects.

Female BALB/C nude mice aged 5-6 weeks, weighing about 18-20 grams, were raised. Human cancer nude mouse xenograft tumor model was established: human colon cancer cell line TT, human breast cancer cell line KM12, and human lung cancer cell line A549 were obtained from ATCC. Resuscitation and culture: digest and detach the monolayer cultured tumor cells, collect and resuspend them in serum-free culture medium, adjust the concentration to 5×10 ⁶ /0.2 ml, put them in an ice box and take them to the animal room. Use a syringe with a No. 6 needle to directly take 0.2 mL of the cell suspension and transplant it subcutaneously in the scapula behind the left armpit of nude mice, 5×10 ⁶ /0.2 ml/mouse. Measure the tumor volume every 2-3 days. After two weeks, select tumor-bearing nude mice with vigorous tumor growth and no ulceration. Under sterile conditions, remove the tumor, cut the tumor tissue into pieces with a diameter of about 2-3 mm and inoculate them subcutaneously in the scapula behind the left armpit of nude mice. After three generations, when the tumor volume grows to 100 mm ³ , remove the nude mice with tumors that are too large or too small and randomly group them for drug administration.

Randomly divided into 5 groups, including negative control group (solvent), positive control group, high, medium and low dose treatment groups, each group of 8 nude mice, including 16 negative control groups, intraperitoneal injection, once every two days, for 3 consecutive weeks. During this period, the animal weight, tumor volume and animal death were detected every 2 days. The animals were killed 24 hours after the last administration, and the tumor volume, tumor weight and nude mouse weight were measured. The tumor volume growth curve, nude mouse weight growth curve and tumor inhibition rate, animal mortality rate were drawn, and the relative tumor proliferation rate T/C (%) was calculated according to the formula T/C (%) = TRTV/CRTV * 100%. (TRTV: treatment group RTV; CRTV: negative control group RTV, relative tumor volume RTV = Vt/V0, where V0 is the tumor volume during group administration, and Vt is the tumor volume after administration). The results are shown in Figure 1, Figure 2 and Table 8. The relative tumor proliferation rate T/C (%) of the in vivo anti-tumor efficacy of the compound of the present invention is ≤40%, and the difference is statistically significant, with obvious pharmacodynamic effect. It also has almost no effect on the weight of the test mice, indicating that it has small toxic side effects and is highly safe.

Table 8. Inhibitory effect of compound 53 on TT cell xenograft tumor model

The details of the specific examples described in the present invention are not to be construed as limitations thereof. Various synonyms and modifications may be made without departing from the essence and scope of the present invention, and it is known that these synonymous embodiments are part of the present invention.

Claims (26)

A 2-oxoindoline derivative represented by general formula (I), and its optical isomers or pharmaceutically acceptable salts thereof:
In the above general formula (I), R ¹ is selected from: hydrogen atom, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, carboxylalkyl, carboxylcycloalkyl; any of the above groups independently may be unsubstituted or may be substituted by one or more substituents, and these 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, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is a C1-C8 straight chain or branched alkyl; ^R2 is selected from the group consisting of hydroxy, alkyl, aryl, alkoxy, heteroalkoxy, heteroalkoxy, arylalkoxy, C3-C8 cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino; any of the above groups may be independently unsubstituted or may be substituted with one or more substituents, including but not limited to halogen, isotope, alkyl, alkylamino, alkylamino, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl group is a C1-C8 straight chain or branched chain alkyl group; ^R3 and ^R4 are independently selected from the group consisting of hydrogen, halogen, isotope, hydroxyl, amino, carboxyl, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkyloxy, heteroalkyloxy, arylalkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, carboxylalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups is selected from the group consisting of A group may be unsubstituted or substituted with one or more substituents, which 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, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl group is a C1-C8 straight chain or branched alkyl group; R ⁵ is selected from the group consisting of: hydrogen atom, isotope, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl; any of the above groups independently may be unsubstituted or may be substituted by one or more substituents, and these 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 group is a C1-C8 straight chain or branched alkyl group; ^R6 is selected from the group consisting of: hydrogen atom, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, heteroarylalkyl, heterocycloalkyl; any of the above groups may be independently unsubstituted or substituted by one or more substituents, including alkyl and alkoxy; the alkyl is a C1-C8 straight chain or branched alkyl; R ⁷ is selected from the group consisting of: hydrogen atom, isotope, halogen, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl; alkoxy, heteroalkoxy, arylalkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, alkylaminocarbonyl, any of the above groups independently may be unsubstituted or may be substituted by one or more substituents, and these substituents include but are not limited to halogen, alkyl, alkoxy; the alkyl is a C1-C8 straight chain or branched alkyl; R ⁷ can be linked to the C4-, C5-, C6-, or C7-position on the benzimidazole ring; L ¹ is selected from the group consisting of: covalent bond, alkylene, heteroalkylene, -NH-, -C(O)-NH-, -NH-C(O)-, -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 chain or branched alkyl; any of the above groups may be independently substituted by one or more substituents, which include hydrogen atoms and alkyl groups; ^L2 is selected from the group consisting of: hydrogen atom, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkoxy, heteroalkoxy, arylalkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloamino, alkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, carboxylalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups independently may be Substituted or may be substituted with one or more substituents, these 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, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl is a C1-C8 straight chain or branched alkyl; X is selected from: nitrogen atom, carbon atom; ^L3 is selected from: absence, covalent bond, alkylene, heteroalkylene, -NH-, -C(O)-NH-, -NH-C(O)-, alkylene-C(O)-, -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 chain or branched alkyl; the alkylene is a C1-C8 straight chain or branched alkyl; any of the above groups can be substituted by one or more substituents independently, and these substituents include hydrogen atoms, alkyl groups; ^R8 is selected from the group consisting of: absent, hydrogen atom, hydroxyl, alkyl, hydroxyalkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkoxy, heteroalkoxy, arylalkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, alkylaminocarbonyl, carboxylalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups A group may be unsubstituted or substituted with one or more substituents, which 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, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxyalkyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl group is a C1-C8 straight chain or branched alkyl group; (R ⁶ )N can be linked to the C4-, C5-, C6- or C7-position of the benzimidazole ring, in which case the general formula (I) is selected from:
The 2-oxoindoline derivative according to claim 1, characterized in that ^R1 is selected from: hydrogen atom, alkyl, heteroalkyl, arylalkyl, C3-C8 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, carboxylalkyl, carboxylcycloalkyl; any of the above groups can be independently unsubstituted or substituted by one or more substituents, and these 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 a C1-C8 straight chain or branched alkyl. The 2-oxoindoline derivative according to claim 1, characterized in that ^R1 is selected from: methyl, ethyl or propyl. The 2-oxoindolinyl derivative according to claim 1, characterized in that ^R2 is selected from the group consisting of hydroxyl, alkyl, aryl, alkoxy, heteroalkoxy, heteroalkoxy, arylalkoxy, C3-C8 cycloalkoxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkyloxy, heteroalkoxy, heteroalkoxy, arylalkoxy, C3-C8 cycloalkoxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino; any of the above groups may be independently unsubstituted or substituted with one or more substituents, including but not limited to halogen, isotope, amino, carboxyl, alkyl, alkoxy, alkoxyalkyl, heteroalkyl; the alkyl group is a C1-C8 straight chain or branched alkyl group. The 2-oxoindoline derivative according to claim 1, characterized in that ^R2 is selected from the group consisting of methoxy, ethoxy, and propoxy. The 2-oxoindoline derivative according to claim 1, characterized in that R ³ and R ⁴ are independently selected from the group consisting of hydrogen, halogen, isotope, hydroxyl, amino, carboxyl, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkoxy, heteroalkoxy, aryloxy, cycloalkyloxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino, carboxyl, carboxylalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylaminocarbonyl; any of the above groups Each of the groups independently may be unsubstituted or may be substituted with one or more substituents, which 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, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, or aminosulfonyl; the alkyl group is a C1-C8 straight chain or branched alkyl group. The 2-oxoindoline derivative according to claim 5, characterized in that ^R4 is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, methyl, ethyl, propyl, isopropyl, halogenated phenyl, allyl, and butyl. The 2-oxoindoline derivative according to claim 5, characterized in that ^R4 is selected from the group consisting of p-fluorophenyl, p-chlorophenyl, p-bromophenyl and p-iodophenyl. The 2-oxoindoline derivative according to claim 1, characterized in that R ⁵ is selected from: hydrogen atom, isotope, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heteroalkyl; any of the above groups independently may be unsubstituted or may be substituted by one or more substituents, and these 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 a C1-C8 straight chain or branched alkyl. The 2-oxoindoline derivative according to claim 1, characterized in that R ⁵ is selected from the group consisting of: benzene ring, pyrazole, pyrimidine, Methyl, ethyl, propyl, methyl chloride. The 2-oxoindoline derivative according to claim 1, characterized in that ^R6 is selected from the group consisting of: a hydrogen atom, an alkyl group, and a C3-C14 cycloalkyl group. The 2-oxoindolinyl derivative according to claim 1, characterized in that ^R7 is selected from the group consisting of: hydrogen atom, isotope, halogen, alkyl, heteroalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, heterocycloalkoxy, amino, alkylamino, heteroalkylamino, carboxyl, alkylaminocarbonyl; any of the above groups may be substituted by one or more substituents, including but not limited to halogen, alkyl, alkoxy; the alkyl is a C1-C8 straight chain or branched alkyl. The 2-oxoindoline derivative according to claim 1, characterized in that ^L1 is selected from: a covalent bond, an alkylene group, a heteroalkylene group, -C(O)-, -C(O)-C(O)-, -C(O)-NH-, an alkylene group-NH-, an alkylene group-C(O)-NH-, -C(O)-alkylene group, -C(O)-NH-heteroalkylene group, heteroalkylene group-NH-C(O)-, and heteroalkylene group-NH-; the alkylene group is a C1-C8 straight chain or branched alkyl group; any of the above groups can be independently substituted by one or more substituents, and these substituents include hydrogen atoms and alkyl groups. The 2-oxoindoline derivative according to claim 1, characterized in that ^L1 is selected from: ethylene, -C(O)-, -C(O)-C(O)-, -C(O)CH2-ethylene, methylene, and propylene. The 2-oxoindoline derivative according to claim 1, characterized in that ^L2 is selected from: hydrogen atom, alkyl, heteroalkyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkoxy, heteroalkoxy, cycloalkyloxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino; any of the above groups independently may be unsubstituted or may be substituted by one or more substituents, and these 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, alkylamino; the alkyl is a C1-C8 straight chain or branched alkyl. -The 2-oxoindoline derivative according to claim 1, characterized in that L ³ is selected from: methylene, ethylene, -NH-, -C(O)-NH-, -NH-C(O)-, -C(O)-, -C(O)-C(O)-, alkylene-C(O)-. The 2-oxoindoline derivative according to claim 1, characterized in that ^R8 is selected from the group consisting of: absent, hydrogen atom, hydroxyl, alkyl, heteroalkyl, alkenyl, alkynyl, arylalkyl, C3-C14 cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkoxy, heteroalkoxy, arylalkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, heteroarylalkoxy, heterocycloalkyloxy, amino, alkylamino, heteroalkylamino, arylalkylamino, cycloalkylamino, arylamino, heteroarylamino, heteroarylalkylamino, heterocycloalkylamino; any of the above groups is independently Independently, they may be unsubstituted or substituted with one or more substituents, which include but are 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. The 2-oxoindoline derivative according to any one of claims 1 to 17, wherein the structure thereof can be selected from one of the following structures, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:












The method for preparing a 2-oxoindoline derivative according to any one of claims 1 to 18, characterized in that when (R ⁶ )N can be linked to the C ^5- position on the benzimidazole ring, and R ¹ ＝R ³ ＝R ⁴ ＝R ⁶ ＝H, R ² ＝OCH ₃ and X＝carbon atom, the method comprises the following steps: S1. A substituted 4-nitro-2-aminobenzene derivative (VI) is cyclized with an aldehyde (VII) or triethyl orthoformate to form a corresponding 5-nitrobenzimidazole derivative (VIII); S2. The 5-nitrobenzimidazole derivative (VIII) is reduced to obtain a 5-aminobenzimidazole derivative (IX), which is then reacted with a 2-oxoindoline derivative (X) to obtain the target compound (XI); The synthetic route is as follows:
The method for preparing a 2-oxoindoline derivative according to any one of claims 1 to 18, characterized in that when (R ⁶ )N can be linked to the C ⁵ -position on the benzimidazole ring, and R ¹ =R ³ =R ⁴ =R ⁶ =H, R ² =OC2H5 and X = carbon atom, the method comprises the following steps: S1, heating a substituted 4-bromo-2-oxoindoline derivative (XII) and a boronic acid derivative (XIII) under the catalysis of a palladium reagent to obtain a condensation product (XIV); S2, the condensation product (XIV) reacts with orthoformate to obtain intermediate (XV), S3, the intermediate (XV) reacts with benzimidazole (XVI) to obtain the target compound (XVII) represented by the general formula (I); The synthetic route is as follows:
Any pharmaceutical dosage form comprising the 2-oxoindoline derivative according to any one of claims 1 to 18 and a pharmaceutically acceptable diluent, excipient or carrier. The use of the 2-oxoindoline derivative according to any one of claims 1 to 18, characterized in that it is used to prepare a drug for treating a disease caused by, associated with or accompanied by the destruction of cell proliferation and/or angiogenesis, or for inhibiting kinase activity. The use according to claim 22, characterized in that the disease is a proliferative disease. The use according to claim 23, characterized in that the proliferative disease is cancer. The use according to claim 22, characterized in that inhibiting kinase activity comprises inhibiting the activity of RET, PDGFR, VEGFR, FGFR, FLT3, Aurora-A, Aurora-B, TRK, B-RAF, RET or Abl. The use according to claim 22, characterized in that the disease is selected from: bone cancer, including: Ewing's sarcoma, osteosarcoma, chondrosarcoma, etc.; brain and CNS tumors, including: acoustic neuroma, neuroblastoma, glioma and other brain tumors, spinal cord tumors, breast cancer, colorectal cancer, advanced colorectal adenocarcinoma; endocrine cancer, including: adrenal cortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymic carcinoma, multiple endocrine tumors; gastrointestinal cancer, Includes: gastric cancer, esophageal cancer, small intestine cancer, liver cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumors, gallbladder cancer; genitourinary cancers, including: testicular cancer, penis cancer, prostate cancer; gynecological cancers, including: cervical cancer, ovarian cancer, vaginal cancer, uterine/endometrial cancer, genital cancer, gestational trophoblastic tumor, fallopian tube cancer, uterine sarcoma; head and neck tumors, including: oral cancer, lip cancer, salivary gland cancer, laryngeal cancer, hypopharyngeal cancer, orthopharyngeal cancer, nasal cancer, paranasal sinus cancer, nasopharyngeal cancer; blood cancers , including: childhood leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell leukemia; bone marrow cancer blood diseases, including: myelodysplastic syndrome, myeloproliferative disorders, aplastic anemia, Fanwohn anemia, idiopathic macroglobulinemia; lung cancer, including: small cell lung cancer, non-small cell lung cancer; lymphoma, including: Hodgkin's disease , non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, AIDS-related lymphoma; eye cancers, including retinoblastoma, uveal melanoma; skin cancers, including melanoma, non-melanoma skin cancer, Merkel cell carcinoma; soft tissue sarcomas, such as childhood soft tissue sarcoma, adult soft tissue sarcoma, Kaposi's sarcoma; urinary system cancers, including renal cancer, Wilms' tumor, bladder cancer, urethral cancer and metastatic cell carcinoma.