Benzotriazole derivative as CDKs inhibitor and pharmaceutical composition and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a benzotriazole derivative serving as a CDKs inhibitor, a pharmaceutical composition of the benzotriazole derivative and application of the benzotriazole derivative to preparation of antitumor drugs. The benzotriazole derivative disclosed by the invention has relatively strong activity of inhibiting CDK9 and other CDK subtypes, has relatively strong anti-tumor activity, and has relatively strong inhibitory activity on cell proliferation of human hematologic tumor cells K562 and colorectal cancer cells HCT116. The structure of the benzotriazole derivative disclosed by the invention is as shown in general formula I: # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a benzotriazole derivative as a CDKs inhibitor and a pharmaceutical composition thereof and an application thereof in the preparation of an anti-tumor drug. Background Art

[0002] CDK9 (Cyclin-dependent kinase 9) is a member of the transcriptional CDK subfamily and plays a role in RNAP II transcriptional regulation. CDK9 is located on chromosome 9q34.1, and its active site has a conserved bilobed structure, consisting of an N-terminus and a C-terminus. The N-terminal lobe of CDK9 contains residues 16 to 108, including 5 β-strands and a major α-helical segment. The C-terminal lobe contains residues 109-330, including 4 β-strands and 7 major α-helices. The hinge region of CDK9 and the ATP binding site is located in the cleft between the two lobes of the kinase, and its enzymatic activity depends on the phosphorylation of the threonine residue (Thr186) in the activation region, so the ATP binding site can generally serve as a binding pocket for CDK9-related inhibitors. In terms of biological function, CDK9 is mainly involved in controlling the synthesis and processing of mRNA of eukaryotic RNA polymerase II. About 80% of CDK9 forms heterodimers with Cyclin T1, and the remaining 20% ​​forms complexes with Cyclin T2A, Cyclin T2B or Cyclin K. CDK9 activation mainly depends on the formation of CDK9 / Cyclin T1 heterodimers, which can form the catalytic subunit of positive transcription elongation factor b (P-TEFb) and play a role by driving transcription initiation. Inhibiting CDK9 can inhibit the transcription elongation of some genes, effectively reduce the mRNA level in tumor cells, and thus induce tumor cell apoptosis.

[0003] Currently, there are no drugs targeting CDK9 on the market. The highest global research and development stage of some drugs under development has reached Phase III clinical trials. Among them, Alvocidib, a CDK9 selective inhibitor developed by Sanofi, has obtained EU orphan drug certification for the treatment of acute myeloid leukemia and chronic lymphocytic leukemia. In view of the drugability of CDK9 target and the successful experience of CDK4 / 6 inhibitor research and development, many well-known domestic (Shijiazhuang Pharmaceutical Group, Jinfang Pharmaceutical, etc.) and foreign (Pfizer, Bayer, Merck, Astrazeneca, etc.) companies and research institutions have made layouts on this target. Summary of the invention

[0004] The purpose of the present invention is to provide a benzotriazole derivative and a pharmaceutical composition and application thereof. The benzotriazole derivative of the present invention has the activity of inhibiting CDK9 and other CDK subtypes (CDK2, CDK4, CDK5, CDK6, CDK7, CDK8, CDK12, CDK13, CDK15, CDK18, etc.), and its in vitro anti-tumor activity is preliminarily evaluated, laying a foundation for the development and clinical application of new anti-tumor drugs.

[0005] Specifically, the present invention is realized through the following technical solutions:

[0006] In the first aspect, the present invention provides a benzotriazole derivative or a pharmaceutically acceptable salt thereof, wherein the structure of the benzotriazole derivative is shown in Formula I:

[0007]

[0008] Wherein, ring A is an aryl group containing 6-12 carbon atoms or a heteroaryl group containing 5-12 ring atoms, and the aromatic heterocyclic ring of the heteroaryl group optionally contains 1, 2 or 3 heteroatoms selected from N, O, and S;

[0009] Ring B is an aryl group containing 6-12 carbon atoms or a heteroaryl group containing 5-12 ring atoms, wherein the aromatic heterocyclic ring of the heteroaryl group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; or Ring B is a cycloalkyl group containing 3-12 carbon atoms or a heterocyclic group containing 3-12 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; or B is a C1-C6 alkyl group or -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aminoalkyl or a heterocyclic group containing 3-12 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O, S;

[0010] The C ring is an aryl group containing 6-12 carbon atoms or a heteroaryl group containing 5-12 ring atoms, wherein the aromatic heterocyclic ring of the heteroaryl group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S;

[0011] The D ring is an aryl group containing 6-12 carbon atoms or a heteroaryl group containing 5-12 ring atoms, wherein the aromatic heterocyclic ring of the heteroaryl group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; or the B ring is a cycloalkyl group containing 3-12 carbon atoms or a heterocyclic group containing 3-12 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; or B is a C1-C6 alkyl group or -NR a R b, R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aminoalkyl or a heterocyclic group containing 3-12 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O, S;

[0012] The C ring is fused to the D ring;

[0013] R is C1-C 12 Alkyl, C1-C 12 Alkoxy or cycloalkyl containing 3 to 10 carbon atoms;

[0014] R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, hydroxy, carboxyl, amino, cyano, nitro, C1-C6 alkylamino or cycloalkyl containing 3-10 carbon atoms;

[0015] R 5 , R 6 , R 7 and R 8 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, hydroxyl, carboxyl, amino, cyano, nitro, C1-C6 alkylamino, C1-C6 acyl, C1-C6 sulfonyl, a cycloalkyl group containing 3 to 10 carbon atoms, or a heterocyclic group containing 3 to 10 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O, S;

[0016] L is a key, -CR 9 R 10 -, -O-, -S-, -SO2-, -C(O)-, -NR 11 -、-SO2NR 11 -or-NR 11 SO2-;

[0017] R 9 , R 10 and R 11 Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, -(C1-C3 alkylene)(C3-C6 cycloalkyl), C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN, -OR 12 、-NR 12 R 13or a C1-C6 alkyl group optionally substituted by halogen, -OH or oxo;

[0018] R 12 and R 13 are each independently selected from hydrogen, C1-C6 alkyl optionally substituted by halogen or oxo, C2-C6 alkenyl optionally substituted by halogen or oxo, or C2-C6 alkynyl optionally substituted by halogen or oxo; or R 12 and R 13 Together with the atoms to which it is attached, it forms a 3- to 6-membered heterocyclic group, which is optionally substituted by halogen, oxo, or C1-C6 alkyl optionally substituted by oxo or halogen.

[0019] Preferably, ring A is a heteroaryl group containing 5-8 ring atoms, and the aromatic heterocyclic ring of the heteroaryl group optionally contains 1 or 2 heteroatoms selected from N, O, and S.

[0020] More preferably, ring A is a heteroaryl group containing 5-6 ring atoms, and the aromatic heterocyclic ring of the heteroaryl group optionally contains 1 heteroatom selected from N, O, and S.

[0021] Preferably, the B ring is a cycloalkyl group containing 3-8 carbon atoms or a heterocyclic group containing 3-8 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0022] More preferably, Ring B is a heterocyclic group containing 5-7 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0023] Preferably, the C ring is a heteroaryl group containing 5-8 ring atoms, and the aromatic heterocyclic ring of the heteroaryl group optionally contains 1 or 2 heteroatoms selected from N, O, and S.

[0024] More preferably, the C ring is a heteroaryl group containing 5-6 ring atoms, and the aromatic heterocyclic ring of the heteroaryl group optionally contains 1 heteroatom selected from N, O, and S.

[0025] Preferably, the D ring is a cycloalkyl group containing 3-8 carbon atoms or a heterocyclic group containing 3-8 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0026] More preferably, the D ring is a heterocyclic group containing 5-7 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0027] Preferably, R is a C1-C8 alkyl group or a C1-C8 alkoxy group.

[0028] More preferably, R is methyl, ethyl, n-propyl or isopropyl.

[0029] Preferably, R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy.

[0030] More preferably, R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen.

[0031] Preferably, R 5 , R 6 , R 7 and R 8 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, hydroxy, amino, C1-C6 alkylamino, C1-C6 acyl or cycloalkyl containing 3-8 carbon atoms.

[0032] More preferably, R 5 , R 6 , R 7 and R 8 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 acyl or cycloalkyl containing 3-6 carbon atoms.

[0033] Preferably, L is a bond, -CR 9 R 10 -, -O-, -S-, -SO2-, -C(O)- or -NR 11 -.

[0034] More preferably, L is -C(O)-.

[0035] Preferably, R 9 , R 10 and R 11 Each is independently selected from hydrogen or C1-C6 alkyl.

[0036] More preferably, R 9 , R 10 and R 11 are each independently selected from hydrogen.

[0037] Preferably, R 12 and R 13 Each is independently selected from hydrogen or C1-C6 alkyl optionally substituted by halogen or oxo.

[0038] More preferably, R 12 and R 13 are each independently selected from hydrogen.

[0039] Furthermore, the present invention preferably comprises a benzotriazole derivative represented by the following structural formula:

[0040]

[0041]

[0042] Furthermore, the present invention also provides a method for preparing the benzotriazole derivatives represented by the general formula I, and the synthetic route is as follows:

[0043]

[0044] wherein R is as defined in the above general formula I; X is C; X 1 C or N; X 2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy or halogenated C1-C6 alkyl; R 14 for B and R 6 As defined in Formula I above.

[0045] In the above synthetic route, step I is a substitution reaction, wherein the raw material 2-fluoro-4-bromonitrobenzene reacts with an aliphatic amine or alicyclic amine having 1 to 8 carbon atoms under alkaline conditions, wherein the reaction solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, dichloromethane, chloroform, toluene, tetrahydrofuran, N,N-dimethylacetamide, and 2-methyltetrahydrofuran; the base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, and N,N-diisopropylethylamine; and the reaction temperature is 10-100°C.

[0046] Step II is a nitro reduction reaction, and the reducing agent is selected from one or more of iron powder, zinc powder, stannous chloride, sodium sulfide, sodium thiosulfate, and hydrosulfite; the reaction solvent is selected from one or more of dilute hydrochloric acid (1-10 mol / L), dilute sulfuric acid (1-10 mol / L), ammonium chloride aqueous solution (1-10 mol / L), ethanol, methanol, and isopropanol; and the reaction temperature is 10-100°C.

[0047] Step III is a ring-fastening reaction of an aromatic triazole, the reactants are sodium nitrite, nitrous acid or tert-butyl nitrite; the reaction solvent is dilute hydrochloric acid (1-10 mol / L) and dilute sulfuric acid (1-10 mol / L); the reaction temperature is -10-30°C.

[0048] Step IV is a Miyaura reaction, the reactant is pinacol diboron; the catalyst is selected from [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, bistriphenylphosphine palladium dichloride, tetratriphenylphosphine palladium, palladium acetate; the base can be one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium acetate, sodium acetate, potassium phosphate; the reaction solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran, N,N-dimethylacetamide, 2-methyltetrahydrofuran; the reaction protection gas is nitrogen, helium or argon; the reaction temperature is 10-100°C.

[0049] Step V is a Suzuki coupling reaction, the catalyst is selected from one or more of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bistriphenylphosphine palladium dichloride, tetratriphenylphosphine palladium, palladium acetate; the base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium acetate, sodium acetate, potassium phosphate; the reaction solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran, N,N-dimethylacetamide, 2-methyltetrahydrofuran; the reaction protection gas is nitrogen, helium or argon; the reaction temperature is 10-100°C.

[0050] Step VI is a Buchwald-Hartwig reaction, wherein the catalyst is selected from one or more of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bistriphenylphosphine palladium dichloride, tetratriphenylphosphine palladium, and palladium acetate; the ligand is selected from one or more of P(o-tolyl)3, P(t-Bu)3, CyPF-t-Bu, JosiPhos, Binap, XantPhos, DPPF, BrettPhos, RuPhos, XPhos, SPhos, and BippyPhos; the base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium acetate, sodium acetate, and potassium phosphate; the reaction solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran, N,N-dimethylacetamide, and 2-methyltetrahydrofuran; the reaction protective gas is nitrogen, helium, or argon; and the reaction temperature is 10-120°C.

[0051] Step VII is an ester hydrolysis reaction, the base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, N,N-diisopropylethylamine, lithium iodide, and lithium bromide; the reaction temperature is 10-100° C.; the reaction solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran, N,N-dimethylacetamide, 2-methyltetrahydrofuran, methanol, ethanol, and isopropanol.

[0052] Step VIII is a condensation reaction, and the condensation conditions can be DCC / EDCI / HOBt / HOAt / DMAP, HATU / HBTU / HCTU / TBTU / DIPEA / Et3N / DBU, PyBop or T3P; the reaction solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, acetonitrile, toluene, tetrahydrofuran, N,N-dimethylacetamide, and 2-methyltetrahydrofuran; the reaction temperature is 10-100°C.

[0053] Step IX is a Buchwald-Hartwig reaction, the catalyst is selected from one or more of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bistriphenylphosphine palladium dichloride, tetratriphenylphosphine palladium, and palladium acetate; the ligand is selected from one or more of P(o-tolyl)3, P(t-Bu)3, CyPF-t-Bu, JosiPhos, Binap, XantPhos, DPPF, BrettPhos, RuPhos, XPhos, SPhos, and BippyPhos; the base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium acetate, sodium acetate, and potassium phosphate; the reaction solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran, N,N-dimethylacetamide, and 2-methyltetrahydrofuran; the reaction protective gas is nitrogen, helium, or argon; and the reaction temperature is 10-120°C.

[0054] Step X is a reductive amination reaction, the acid used in the reaction is selected from one or more of glacial acetic acid, formic acid, dilute hydrochloric acid (1-10 mol / L), and dilute sulfuric acid (1-10 mol / L); the reducing agent is selected from one or more of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and sodium triisopropionyloxyborohydride; the reaction solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran, N,N-dimethylacetamide, 2-methyltetrahydrofuran, methanol, ethanol, and isopropanol; and the reaction temperature is 10-100°C.

[0055] In a second aspect, the present invention provides a pharmaceutical composition comprising a benzotriazole derivative represented by general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0056] In a third aspect, the present invention provides a use of a benzotriazole derivative represented by general formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in the preparation of an anti-tumor drug.

[0057] In the present invention, the term "aryl" means an optionally substituted monocyclic or fused bicyclic or polycyclic ring system having known aromatic characteristics, wherein at least one ring contains a completely conjugated π-electron system. Typically, an aryl group contains 6 to 20 carbon atoms as ring members, preferably 6 to 14 carbon atoms or more preferably 6 to 12 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl and tetrahydronaphthyl.

[0058] In the present invention, term, " heteroaryl " represents the monocyclic or fused bicyclic or polycyclic ring system with known aromaticity characteristics, it contains the ring atoms of specified number and includes at least one heteroatom selected from N, O and S as the ring member in aromatic ring. The inclusion of heteroatom allows the aromaticity of 5-membered ring and 6-membered ring. Usually, heteroaryl contains 5-20 ring atoms, preferably 5-14 ring atoms, more preferably 5-12 ring atoms. Heteroaryl ring is connected to the basic molecule by the ring atoms of heteroaromatic ring, so as to keep aromaticity. The example of heteroaryl often includes, but is not limited to pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl.

[0059] In the present invention, the term "cycloalkyl" means a non-aromatic saturated carbocyclic ring system containing a specified number of carbon atoms, which can be a monocyclic, spirocyclic, bridged or fused bicyclic or polycyclic ring system connected to the base molecule through the carbon atoms of the cycloalkyl ring. Typically, the cycloalkyl of the present invention contains 3-12 carbon atoms, preferably 3-8 carbon atoms. Examples of cycloalkyl often include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.

[0060] In the present invention, the term "heterocyclyl" is used interchangeably to refer to a non-aromatic saturated ring system containing a specified number of ring atoms, which includes at least one heteroatom selected from N, O and S as a ring member. Typically, the heterocyclyl of the present invention contains 3-12 ring atoms, preferably 3-8 ring atoms, and more preferably 3-6 ring atoms. Examples of heterocyclyls often include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, etc.

[0061] In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.

[0062] In the present invention, the term "alkyl" (including when used alone and contained in other groups) means branched and straight-chain saturated hydrocarbon groups including 1-20 carbon atoms, preferably 1-12 carbon atoms, more preferably 1-5 carbon atoms, and most preferably 1-3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof, etc.

[0063] In the present invention, the term "alkoxy" refers to an alkyl group with the stated number of carbon atoms connected via an oxygen bridge. Thus, "alkoxy" encompasses the above definition of alkyl.

[0064] In the present invention, the term "alkenyl" refers to a straight chain or branched hydrocarbon group containing a specified number of carbon atoms and at least one carbon-carbon double bond. Preferably, there is one carbon-carbon double bond, and more preferably, the carbon-carbon double bond is connected to the other parts of the compound. The number of carbon atoms can be 2-12, preferably 2-5, and more preferably 2, such as vinyl, 1-propenyl, 1-butenyl, etc.

[0065] In the present invention, the term "alkynyl" refers to a straight chain or branched hydrocarbon group containing a specified number of carbon atoms and at least one carbon-carbon triple bond. Preferably, there is a carbon-carbon triple bond, and more preferably, the other parts of the compound are connected through the carbon-carbon triple bond. The number of carbon atoms can be 2-12, preferably 2-5, and more preferably 2, such as ethynyl, 1-propynyl, 1-butynyl, etc.

[0066] In the present invention, the term "aminoalkyl" means an alkyl group having a specified number of carbon atoms, which is substituted by one or more substituted or unsubstituted amino groups. Aminoalkyl groups typically contain 1-6 carbon atoms in the alkyl portion and are substituted by 1, 2 or 3 amino substituents. Thus, examples of C1-C6 aminoalkyl groups often include, but are not limited to, aminomethyl (-CH2NH2), N,N-dimethylaminoethyl (-CH2CH2N(CH3)2), 3-(N-cyclopropylamino)-propyl (-CH2CH2CH2NH- c Pr) and N-pyrrolidinylethyl (-CH2CH2-N-pyrrolidinyl).

[0067] In the present invention, the term "acyl" refers to a monovalent group -C (O) alkyl, wherein the alkyl moiety has a specified number of carbon atoms (usually C1-C8, preferably C1-C6 or C1-C4) and can be optionally substituted with groups suitable for alkyl, such as F, OH or alkoxy. Thus, optionally substituted -C (O) C1-C4 alkyl includes unsubstituted acyl, such as -C (O) CH3 (i.e. acetyl) and -C (O) CH2CH3 (i.e. propionyl), and substituted acyl, such as -C (O) CF3 (trifluoroacetyl), -C (O) CH2OH (hydroxyacetyl), -C (O) CH2OCH3 (methoxyacetyl), -C (O) CF2H (difluoroacetyl) and the like.

[0068] Compared with the prior art, the present invention has the following beneficial effects:

[0069] The benzotriazole derivative of the present invention has a relatively novel structure, has strong activity in inhibiting CDK9 and other CDK subtypes, and has strong anti-tumor activity. It has strong inhibitory activity on the cell proliferation of human blood tumor cells K562 and colorectal cancer cells HCT116, laying a foundation for the development and clinical application of new anti-tumor drugs. DETAILED DESCRIPTION

[0070] The embodiments of the present invention are described in detail below. The embodiments are given to better illustrate the contents of the present invention and are only used to explain the present invention, but should not be understood as limiting the present invention.

[0071] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0072] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0073] Example 1: (6-((4-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)pyridin-2-yl)amino)pyridin-3-yl)(morpholinyl)methanone (A-1)

[0074]

[0075] The preparation method of compound A-1, the operation steps are as follows:

[0076] (1) 2-Fluoro-4-bromonitrobenzene (10.0 g, 45.67 mmol) was dissolved in N,N-dimethylformamide, potassium carbonate (7.63 g, 54.81 mmol) and isopropylamine (3.24 g, 54.81 mmol) were added respectively, and the mixture was reacted at room temperature for 5 hours. After the reaction was completed, the reaction mixture was poured into an ice-water mixture and stirred for 2 hours. Intermediate 1 was obtained by suction filtration as a yellow solid with a yield of 95.4%;

[0077] (2) Intermediate 1 (5 g, 19.38 mmol) was dissolved in ethanol, and reduced iron powder (5.42 g, 96.9 mmol) was added, followed by an aqueous solution of ammonium chloride (5.18 g, 96.9 mmol), and the mixture was reacted at 80°C for 1 hour. The mixture was then filtered and the solvent was removed by rotary evaporation. The residue was re-dissolved in ethyl acetate and separated by silica gel column chromatography (cyclohexane / ethyl acetate = 3 / 1) to obtain intermediate 2 as a brown solid with a yield of 89.1%.

[0078] (3) Intermediate 2 (5 g, 20.92 mmol) was dissolved in concentrated hydrochloric acid, and an aqueous solution of sodium nitrite (2.17 g, 31.38 mmol) was added and reacted at room temperature for 3 hours. Then, the pH of the system was adjusted to 8 with a 1N aqueous sodium hydroxide solution, and ethyl acetate was used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (cyclohexane / ethyl acetate = 20 / 1) to obtain Intermediate 3 as a white solid with a yield of 86.3%.

[0079] (4) Intermediate 3 (5 g, 20.92 mmol) was dissolved in dioxane, and diboric acid pinacol ester (7.97 g, 31.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (1.53 g, 2.09 mmol), and potassium acetate (4.11 g, 41.84 mmol) were added, and the mixture was reacted at 110°C for 6 hours. After the reaction was completed, the mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (cyclohexane / ethyl acetate = 5 / 1) to obtain intermediate 4 as a white solid with a yield of 91.7%.

[0080] (5) Intermediate 4 (3 g, 10.45 mmol) was dissolved in a 4 / 1 dioxane / water mixed solution, and 2-amino-4-bromopyridine (1.8 g, 10.45 mmol), tetrakistriphenylphosphine palladium (1.21 g, 1.05 mmol) and sodium carbonate (2.21 g, 20.9 mmol) were added, and the mixture was reacted at 100°C for 3 hours. After the reaction was completed, the mixture was filtered, and the filtrate was extracted with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (cyclohexane / ethyl acetate = 1 / 1) to obtain intermediate 5 as a white solid with a yield of 88.7%.

[0081] (6) Intermediate 5 (2 g, 7.90 mmol) was dissolved in N,N-dimethylformamide, and methyl 6-bromonicotinate (2.05 g, 9.48 mmol), tris(dibenzylideneacetone)dipalladium (0.36 g, 0.39 mmol), cesium carbonate (6.1 g, 15.8 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.41 g, 0.79 mmol) were added respectively, and the mixture was reacted at 100°C for 6 hours. After the reaction, the mixture was extracted with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. Intermediate 6 was separated by silica gel column chromatography (cyclohexane / ethyl acetate = 1 / 1) to obtain a yellow solid with a yield of 65.9%.

[0082] (7) Intermediate 6 (1 g, 2.58 mmol) was dissolved in methanol, and an aqueous solution of sodium hydroxide (1 g, 25.8 mmol) was added and reacted at 80°C for 3 hours. After the reaction, the solvent was removed by rotary evaporation, and the pH of the system was adjusted to 3 with 1N dilute hydrochloric acid. Intermediate 7 was obtained by suction filtration as a white solid with a yield of 85.9%.

[0083] (8) Intermediate 7 (0.5 g, 1.34 mmol) was dissolved in N,N-dimethylformamide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.31 g, 1.61 mmol), 1-hydroxybenzotriazole (0.22 g, 1.61 mmol), and morpholine (0.14 g, 1.61 mmol) were added respectively. The mixture was reacted at room temperature for 3 hours. After the reaction, the mixture was extracted with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. A-1 was separated by silica gel column chromatography (cyclohexane / ethyl acetate = 1 / 3) to obtain a yellow solid. The yield was 86.7%. ESI-LC-MS: 444.2 [M+H] + , 1 H NMR (600MHz, DMSO-d6) δ10.11(s,1H),8.36-8.39(m,2H),8.28(m,1H),8.18-8.20(m,1H),8.12(m,1H),7.89-7. 90(m,1H),7.73-7.79(m,2H),7.40(m,1H),5.36(hept,J=6.4Hz,1H),3.55-3.63(m,8H),1.69(d,J=6.4Hz,6H).

[0084] Example 2: (6-((4-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)pyridin-2-yl)amino)pyridin-3-yl)(4-methylpiperazin-1-yl)methanone (A-2)

[0085]

[0086] The preparation method of compound A-2 is the same as that of compound A-1, except that N-methylpiperazine is used instead of morpholine in step (8) of Example 1. A-2 is isolated as a yellow solid with a yield of 79.4%. ESI-LC-MS: 457.3 [M+H] + , 1 HNMR(600MHz,DMSO-d6)δ10.02(s,1H),8.46-8.48(m,2H),8.34(m,1H),8.17-8.19(m,1H),8.15(m,1H),7.93-8.01(m, 1H),7.83-7.89(m,2H),7.54(m,1H),5.37(hept,J=6.6Hz,1H),3.57-3.61(m,8H),2.18(s,3H),1.69(d,J=6.6Hz,6H).

[0087] Example 3: (6-((4-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)pyridin-2-yl)amino)pyridin-3-yl)(4-ethylpiperazin-1-yl)methanone (A-3)

[0088]

[0089] The preparation method of compound A-3 is the same as that of compound A-1, except that N-ethylpiperazine is used instead of morpholine in step (8) of Example 1. A-3 is isolated as a yellow solid with a yield of 81.2%. ESI-LC-MS: 471.3 [M+H] + , 1 HNMR(600MHz,DMSO-d6)δ10.12(s,1H),8.56-8.61(m,2H),8.43(m,1H),8.27-8.29(m,1H),8.25(m,1H),8.12-8.17(m,1H),7.98-8.02 (m,2H),7.64(m,1H),5.39(hept,J=6.6Hz,1H),3.58-3.61(m,8H),2.16(q,J=4.5Hz,2H),1.70(d,J=6.6Hz,6H),1.03(t,J=4.5Hz,3H).

[0090] Example 4: (6-((4-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)pyridin-2-yl)amino)pyridin-3-yl)(4-isopropylpiperazin-1-yl)methanone (A-4)

[0091]

[0092] The preparation method of compound A-4 is the same as that of compound A-1, except that N-isopropylpiperazine is used instead of morpholine in step (8) of Example 1. A-4 is isolated as a yellow solid with a yield of 83.5%. ESI-LC-MS: 485.3 [M+H] + , 1 HNMR(600MHz,DMSO-d6)δ10.04(s,1H),8.21-8.23(m,2H),8.18(m,1H),8.16-8.17(m,1H),8.14(m,1H),8.05-8.08(m,1H),7.98-8.02 (m,2H),7.63(m,1H),5.38(hept,J=6.7Hz,1H),3.58-3.61(m,8H),2.69(m,J=5.5Hz,1H),1.70(d,J=6.5Hz,6H),1.03(d,J=5.6Hz,6H).

[0093] Example 5: (6-((4-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)pyridin-2-yl)amino)pyridin-3-yl)(4-methyl-1,4-diazepin-1-yl)methanone (A-5)

[0094]

[0095] The preparation method of compound A-5 is the same as that of compound A-1, except that N-methyl homopiperazine is used instead of morpholine in step (8) of Example 1. A-5 is isolated as a yellow solid with a yield of 89.1%. ESI-LC-MS: 471.2 [M+H] + , 1 HNMR(600MHz,DMSO-d6)δ10.04(s,1H),8.21-8.23(m,2H),8.18(m,1H),8.16-8.17(m,1H),8.14(m,1H),8.05-8.08(m, 1H),7.98-8.02(m,2H),7.63(m,1H),5.38(hept,J=6.7Hz,1H),3.58-3.61(m,10H),2.16(s,3H),1.69(d,J=6.6Hz,6H).

[0096] Example 6: (2-((4-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)pyridin-2-yl)amino)pyridin-4-yl)(morpholinyl)methanone (A-6)

[0097]

[0098] The preparation method of compound A-6 is the same as that of compound A-1, except that 2-bromopyridine-4-carboxylic acid methyl ester is used instead of 6-bromonicotinate methyl ester in step (6) of Example 1. A-6 is isolated as a yellow solid with a yield of 82.3%. ESI-LC-MS: 444.2 [M+H] + , 1 H NMR (600MHz, DMSO-d6) δ10.11(s,1H),8.36-8.39(m,2H),8.28(m,1H),8.18-8.20(m,1H),8.12(m,1H),7.89-7. 90(m,1H),7.73-7.79(m,2H),7.40(m,1H),5.36(hept,J=6.4Hz,1H),3.55-3.63(m,8H),1.69(d,J=6.4Hz,6H).

[0099] Example 7: (2-((4-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)pyridin-2-yl)amino)pyridin-4-yl)(4-methylpiperazin-1-yl)methanone (A-7)

[0100]

[0101] The preparation method of compound A-7 is the same as that of compound A-1, except that 2-bromopyridine-4-carboxylic acid methyl ester is used instead of 6-bromonicotinate methyl ester in step (6) of Example 1, and N-methylpiperazine is used instead of morpholine in step (8) of Example 1. A-7 is isolated as a yellow solid with a yield of 81.9%. ESI-LC-MS: 457.3 [M+H] + , 1 H NMR(600MHz,DMSO-d6)δ10.02(s,1H),8.46-8.48(m,2H),8.34(m,1H),8.17-8.19(m,1H),8.15(m,1H),7.93-8.01(m, 1H),7.83-7.89(m,2H),7.54(m,1H),5.37(hept,J=6.6Hz,1H),3.57-3.61(m,8H),2.18(s,3H),1.69(d,J=6.6Hz,6H). Example 8: (2-((4-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)pyridin-2-yl)amino)pyridin-4-yl)(4-ethylpiperazin-1-yl)methanone (A-8)

[0102]

[0103] The preparation method of compound A-8 is the same as that of compound A-1, except that 2-bromopyridine-4-carboxylic acid methyl ester is used instead of 6-bromonicotinate methyl ester in step (6) of Example 1, and N-ethylpiperazine is used instead of morpholine in step (8) of Example 1. A-8 is isolated as a yellow solid with a yield of 73.3%. ESI-LC-MS: 471.3 [M+H] + , 1 H NMR(600MHz,DMSO-d6)δ10.12(s,1H),8.56-8.61(m,2H),8.43(m,1H),8.27-8.29(m,1H),8.25(m,1H),8.12-8.17(m,1H),7.98-8.02( m,2H),7.64(m,1H),5.39(hept,J=6.6Hz,1H),3.58-3.61(m,8H),2.16(q,J=4.5Hz,2H),1.70(d,J=6.6Hz,6H),1.03(t,J=4.5Hz,3H).

[0104] Example 9: (2-((4-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)pyridin-2-yl)amino)pyridin-4-yl)(4-isopropylpiperazin-1-yl)methanone (A-9)

[0105]

[0106] The preparation method of compound A-9 is the same as that of compound A-1, except that 2-bromopyridine-4-carboxylic acid methyl ester is used instead of 6-bromonicotinate methyl ester in step (6) of Example 1, and N-isopropylpiperazine is used instead of morpholine in step (8) of Example 1. A-9 is isolated as a yellow solid with a yield of 81.2%. ESI-LC-MS: 485.3 [M+H] + , 1 HNMR(600MHz,DMSO-d6)δ10.04(s,1H),8.21-8.23(m,2H),8.18(m,1H),8.16-8.17(m,1H),8.14(m,1H),8.05-8.08(m,1H),7.98-8.02 (m,2H),7.63(m,1H),5.38(hept,J=6.7Hz,1H),3.58-3.61(m,8H),2.69(m,J=5.5Hz,1H),1.70(d,J=6.5Hz,6H),1.03(d,J=5.6Hz,6H).

[0107] Example 10: (2-((4-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)pyridin-2-yl)amino)pyridin-4-yl)(4-methyl-1,4-diazepin-1-yl)methanone (A-10)

[0108]

[0109] The preparation method of compound A-10 is the same as that of compound A-1, except that 2-bromopyridine-4-carboxylic acid methyl ester is used instead of 6-bromonicotinate methyl ester in step (6) of Example 1, and N-methyl homopiperazine is used instead of morpholine in step (8) of Example 1. A-10 is isolated as a yellow solid with a yield of 86.7%. ESI-LC-MS: 471.2 [M+H] + , 1 HNMR(600MHz,DMSO-d6)δ10.04(s,1H),8.21-8.23(m,2H),8.18(m,1H),8.16-8.17(m,1H),8.14(m,1H),8.05-8.08(m, 1H),7.98-8.02(m,2H),7.63(m,1H),5.38(hept,J=6.7Hz,1H),3.58-3.61(m,10H),2.16(s,3H),1.69(d,J=6.6Hz,6H).

[0110] Example 11: Pharmacological Activity Experimental Section

[0111] (1) The inhibitory effect of some compounds of the present invention on CDK9 / Cyclin T1 complex was determined by ADP-Glo ​​method (IC 50 )

[0112] The DMSO stock solution of the sample to be tested and CDK9 / Cyclin T1 were diluted to the target concentration with the corresponding buffer. The compound of the present invention was diluted to 10 concentration points according to a 2-fold concentration gradient, and the maximum concentration was 500nM. The compound of the present invention or the DMSO blank group was mixed with the enzyme in a 384-well plate, ATP and substrate were added to start the kinase reaction, and incubated at room temperature for 60 minutes. ADP-Glo ​​reagent was added to terminate the kinase reaction and consume the remaining ATP, and then Kinase detection reagent was added to detect the newly generated ATP. The chemiluminescence detection module of the multifunctional microplate reader was used to detect the newly generated ATP content to reflect the enzyme activity. The results are shown in Table 1.

[0113] (2) The CCK-8 method was used to inhibit the proliferation of human blood tumor cells K562 and colorectal cancer cells HCT116 (GI 50 ) for testing

[0114] The cells were cultured in the corresponding culture medium until the logarithmic growth phase, and inoculated in a 96-well plate at 5000 / well for 24 hours at 37°C, after which the DMSO stock dilution of the sample to be tested was added at the corresponding concentration, and the blank group and the positive control group were retained, with three replicates in each group. After incubation for 48 hours, 10 μL CCK-8 was added to each well and incubated for 3 hours, and then the absorbance value of each well at 450 nm was measured using an Emax Microplate Reader (Molecular Devices, Sunnyvale, CA, USA), and the cell viability inhibition rate was calculated based on the blank group. The results are shown in Table 1.

[0115] (3) Experimental results

[0116] Table 1 Inhibitory effects of compounds on CDK9 / Cyclin T1 complex, K562 and HCT116 cells

[0117]

[0118] The test results in Table 1 show that the benzotriazole derivatives shown in the general formula I of the present invention have strong inhibitory activity on CDK9 and other CDK subtypes, are a series of CDKs inhibitors with a new structure, and have strong anti-tumor activity, and have strong inhibitory activity on the proliferation of human blood tumor cells K562 and colorectal cancer cells HCT116. They have potential application prospects and clinical research value.

[0119] Obviously, the above embodiments are only examples for clearly explaining the present invention, and are not intended to limit the implementation methods of the present invention. Those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A benzotriazole derivative or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the benzotriazole derivative is shown in general formula I: Wherein, ring A is an aryl group containing 6-12 carbon atoms or a heteroaryl group containing 5-12 ring atoms, and the aromatic heterocyclic ring of the heteroaryl group optionally contains 1, 2 or 3 heteroatoms selected from N, O, and S; Ring B is an aryl group containing 6-12 carbon atoms or a heteroaryl group containing 5-12 ring atoms, wherein the aromatic heterocyclic ring of the heteroaryl group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; or Ring B is a cycloalkyl group containing 3-12 carbon atoms or a heterocyclic group containing 3-12 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; or B is a C1-C6 alkyl group or -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aminoalkyl or a heterocyclic group containing 3-12 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O, S; The C ring is an aryl group containing 6-12 carbon atoms or a heteroaryl group containing 5-12 ring atoms, wherein the aromatic heterocyclic ring of the heteroaryl group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; The D ring is an aryl group containing 6-12 carbon atoms or a heteroaryl group containing 5-12 ring atoms, wherein the aromatic heterocyclic ring of the heteroaryl group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; or the B ring is a cycloalkyl group containing 3-12 carbon atoms or a heterocyclic group containing 3-12 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; or B is a C1-C6 alkyl group or -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aminoalkyl or a heterocyclic group containing 3-12 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O, S; The C ring is fused to the D ring; R is C1-C 12 Alkyl, C1-C 12 Alkoxy or cycloalkyl containing 3 to 10 carbon atoms; R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, hydroxy, carboxyl, amino, cyano, nitro, C1-C6 alkylamino or cycloalkyl containing 3-10 carbon atoms; R 5 , R 6 , R 7 and R 8 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, hydroxyl, carboxyl, amino, cyano, nitro, C1-C6 alkylamino, C1-C6 acyl, C1-C6 sulfonyl, a cycloalkyl group containing 3 to 10 carbon atoms, or a heterocyclic group containing 3 to 10 ring atoms, wherein the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O, S; L is a key, -CR 9 R 10 -, -O-, -S-, -SO2-, -C(O)-, -NR 11 -、-SO2NR 11 -or-NR 11 SO2-; R 9 , R 10 and R 11 Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, -(C1-C3 alkylene)(C3-C6 cycloalkyl), C6-C 14 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN, -OR 12 、-NR 12 R 13 or a C1-C6 alkyl group optionally substituted by halogen, -OH or oxo; R 12 and R 13 are each independently selected from hydrogen, C1-C6 alkyl optionally substituted by halogen or oxo, C2-C6 alkenyl optionally substituted by halogen or oxo, or C2-C6 alkynyl optionally substituted by halogen or oxo; or R 12 and R 13 Together with the atoms to which it is attached, it forms a 3- to 6-membered heterocyclic group, which is optionally substituted by halogen, oxo, or C1-C6 alkyl optionally substituted by oxo or halogen.

2. The benzotriazole derivative of general formula I according to claim 1, characterized in that: In the general formula I, the A ring is a heteroaryl group containing 5-8 ring atoms, and the aromatic heterocyclic ring of the heteroaryl group optionally contains 1 or 2 heteroatoms selected from N, O, and S; the B ring is a cycloalkyl group containing 3-8 carbon atoms or a heterocyclic group containing 3-8 ring atoms, and the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O, and S; the C ring is a heteroaryl group containing 5-8 ring atoms, and the aromatic heterocyclic ring of the heteroaryl group optionally contains 1 or 2 heteroatoms selected from N, O, and S; the D ring is a cycloalkyl group containing 3-8 carbon atoms or a heterocyclic group containing 3-8 ring atoms, and the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O, and S; the C ring is fused with the D ring; R is a C1-C8 alkyl group or a C1-C8 alkoxy group; R 1 , R 2 , R 3 and R 4 Each is independently selected from hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy; R 5 , R 6 , R 7 and R 8 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, hydroxyl, amino, C1-C6 alkylamino, C1-C6 acyl or cycloalkyl containing 3-8 carbon atoms; L is a bond, -CR 9 R 10 -, -O-, -S-, -SO2-, -C(O)- or -NR 11 -; R 9 , R 10 and R 11 Each is independently selected from hydrogen or C1-C6 alkyl; R 12 and R 13 Each is independently selected from hydrogen or C1-C6 alkyl optionally substituted by halogen or oxo.

3. The benzotriazole derivative represented by general formula I according to claim 1, characterized in that: In the general formula I, ring A is a heteroaryl group containing 5-6 ring atoms, and the aromatic heterocyclic ring of the heteroaryl group optionally contains 1 heteroatom selected from N, O, and S; ring B is a heterocyclic group containing 5-7 ring atoms, and the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O, and S; ring C is a heteroaryl group containing 5-6 ring atoms, and the aromatic heterocyclic ring of the heteroaryl group optionally contains 1 heteroatom selected from N, O, and S; ring D is a heterocyclic group containing 5-7 ring atoms, and the heterocyclic ring of the heterocyclic group optionally contains 1, 2 or 3 heteroatoms selected from N, O, and S; ring C is fused with ring D; R is methyl, ethyl, n-propyl or isopropyl; R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen; R 5 , R 6 , R 7 and R 8 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 acyl or cycloalkyl containing 3-6 carbon atoms; L is -C(O)-; R 9 , R 10 and R 11 are each independently selected from hydrogen; R 12 and R 13 are each independently selected from hydrogen.

4. The benzotriazole derivative represented by general formula I according to claim 1, characterized in that: The structural formula of the benzotriazole derivative is shown below:

5. A pharmaceutical composition, characterized in that It comprises a benzotriazole derivative represented by general formula I according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

6. Use of the benzotriazole derivative of general formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5 in the preparation of antitumor drugs.

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