[go: up one dir, main page]

WO2025007769A1 - 作为CDKs抑制剂的苯并三唑衍生物及其药物组合物和应用 - Google Patents

作为CDKs抑制剂的苯并三唑衍生物及其药物组合物和应用 Download PDF

Info

Publication number
WO2025007769A1
WO2025007769A1 PCT/CN2024/101071 CN2024101071W WO2025007769A1 WO 2025007769 A1 WO2025007769 A1 WO 2025007769A1 CN 2024101071 W CN2024101071 W CN 2024101071W WO 2025007769 A1 WO2025007769 A1 WO 2025007769A1
Authority
WO
WIPO (PCT)
Prior art keywords
ring
alkyl
heterocyclic
group containing
atoms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/101071
Other languages
English (en)
French (fr)
Inventor
程卯生
李佳
刘洋
孙一立
仲烨
徐晶
唐丽
任兆惠
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong Laboratory Of Yantai Drug Discovery
Shenyang Pharmaceutical University
Original Assignee
Shandong Laboratory Of Yantai Drug Discovery
Shenyang Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong Laboratory Of Yantai Drug Discovery, Shenyang Pharmaceutical University filed Critical Shandong Laboratory Of Yantai Drug Discovery
Publication of WO2025007769A1 publication Critical patent/WO2025007769A1/zh
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • 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.
  • 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 16 to 108 residues, including 5 ⁇ -strands and a major ⁇ -helical segment.
  • the C-terminal lobe contains 109-330 residues, including 4 ⁇ -strands and 7 major ⁇ -helices.
  • CDK9 The hinge region of the CDK9 and ATP binding sites 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.
  • 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.
  • the object of the present invention is to provide a benzotriazole derivative and a pharmaceutical composition and application thereof.
  • Azole derivatives have the activity of inhibiting CDK9 and other CDK subtypes (CDK2, CDK4, CDK5, CDK6, CDK7, CDK8, CDK12, CDK13, CDK15, CDK18, etc.), and their in vitro anti-tumor activity has been preliminarily evaluated, laying the foundation for the development and clinical application of new anti-tumor drugs.
  • the present invention is realized through the following technical solutions:
  • the present invention provides a benzotriazole derivative or a pharmaceutically acceptable salt thereof, wherein the structure of the benzotriazole derivative is shown in general formula I:
  • 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, the aromatic heterocyclic ring of the heteroaryl group optionally containing 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, the heterocyclic ring of the heterocyclic group optionally containing 1, 2 or 3 heteroatoms selected from N, O and S; or B is a C 1 -C 6 alkyl group or -NR a R b , R a and R b are each independently selected from hydrogen, C 1 -C 6 alkyl group, C 1 -C 6 aminoalkyl group or a heterocyclic group containing 3-12 ring atoms, the heterocyclic ring of the heterocyclic group optionally containing 1, 2 or 3 heteroatoms selected from N, O and 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, the aromatic heterocyclic ring of the heteroaryl group optionally containing 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, the heterocyclic ring of the heterocyclic group optionally containing 1, 2 or 3 heteroatoms selected from N, O and S; or B is a C 1 -C 6 alkyl group or -NR a R b , R a and R b are each independently selected from hydrogen, C 1 -C 6 alkyl group, C 1 -C 6 aminoalkyl group or a heterocyclic group containing 3-12 ring atoms, the heterocyclic ring of the heterocyclic group optionally containing 1, 2 or 3 heteroatoms selected from N, O and S;
  • the C ring is fused to the D ring
  • R is a C 1 -C 12 alkyl group, a C 1 -C 12 alkoxy group or a cycloalkyl group containing 3 to 10 carbon atoms;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy alkyl, hydroxy, carboxyl, amino, cyano, nitro, C 1 -C 6 alkylamino or cycloalkyl containing 3 to 10 carbon atoms;
  • R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, hydroxy, carboxyl, amino, cyano, nitro, C 1 -C 6 alkylamino, C 1 -C 6 acyl, C 1 -C 6 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 and S;
  • L is a bond, -CR 9 R 10 -, -O-, -S-, -SO 2 -, -C(O)-, -NR 11 -, -SO 2 NR 11 -, or -NR 11 SO 2 -;
  • R 9 , R 10 and R 11 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), C 6 -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 C 1 -C 6 alkyl optionally substituted by halogen, -OH or oxo;
  • R 12 and R 13 are each independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or oxo, C 2 -C 6 alkenyl optionally substituted by halogen or oxo, or C 2 -C 6 alkynyl optionally substituted by halogen or oxo; or R 12 and R 13 together with the atoms to which they are attached form a 3- to 6-membered heterocyclyl, which is optionally substituted by halogen, oxo, or C 1 -C 6 alkyl optionally substituted by oxo or halogen.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • R is a C 1 -C 8 alkyl group or a C 1 -C 8 alkoxy group.
  • R is methyl, ethyl, n-propyl or isopropyl.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, hydroxy, amino, C 1 -C 6 alkylamino, C 1 -C 6 acyl or cycloalkyl containing 3-8 carbon atoms.
  • R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 acyl or cycloalkyl containing 3 to 6 carbon atoms.
  • L is a bond, -CR 9 R 10 -, -O-, -S-, -SO 2 -, -C(O)- or -NR 11 -.
  • L is -C(O)-.
  • R 9 , R 10 and R 11 are each independently selected from hydrogen or C 1 -C 6 alkyl.
  • R 12 and R 13 are each independently selected from hydrogen or C 1 -C 6 alkyl optionally substituted by halogen or oxo.
  • R 12 and R 13 are each independently selected from hydrogen.
  • the present invention preferably comprises a benzotriazole derivative represented by the following structural formula:
  • R is as defined in the above general formula I; X is C; X1 is C or N; X2 is hydrogen, halogen, C1 - C6 alkyl, C1 - C6 alkoxy or halogenated C1 - C6 alkyl; R14 is B and R 6 are as defined in Formula I above.
  • 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; and the base is selected from One or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, N,N-diisopropylethylamine; the reaction temperature is 10-100°C.
  • the reaction solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, dichloromethane, chloroform, to
  • Step II is a nitro reduction reaction
  • 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
  • the reaction temperature is 10-100°C.
  • 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.
  • 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.
  • 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.
  • Step VI 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,
  • 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.
  • Step VIII is a condensation reaction.
  • the condensation conditions may be DCC/EDCI/HOBt/HOAt/DMAP, HATU/HBTU/HCTU/TBTU/DIPEA/Et 3 N/DBU, PyBop or T3P.
  • the reaction solvent may be one or more of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, acetonitrile, toluene, tetrahydrofuran, N,N-dimethylacetamide and 2-methyltetrahydrofuran.
  • the reaction temperature may be 10-100°C.
  • 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,
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • 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.
  • 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 ⁇ -electron system.
  • 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.
  • 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.
  • heteroatom allows the aromaticity of 5-membered ring and 6-membered ring.
  • 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.
  • heteroaryl often includes, but is not limited to pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl.
  • 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.
  • 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.
  • heterocyclyl is used interchangeably to refer to a non-aromatic saturated ring system containing the specified number of ring atoms, which includes at least one heteroatom selected from N, O and S as a ring member.
  • the heterocyclyl groups of the present invention contain 3 to 12
  • the number of ring atoms in the heterocyclic group is preferably 3-8, and more preferably 3-6.
  • heterocyclic groups often include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, etc.
  • halogen means fluorine, chlorine, bromine or iodine.
  • 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.
  • alkoxy refers to an alkyl group with the stated number of carbon atoms connected via an oxygen bridge.
  • alkoxy encompasses the above definition of alkyl.
  • 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.
  • 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.
  • 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.
  • examples of C 1 -C 6 aminoalkyl groups often include, but are not limited to, aminomethyl (-CH 2 NH 2 ), N,N-dimethylaminoethyl (-CH 2 CH 2 N(CH 3 ) 2 ), 3-(N-cyclopropylamino)-propyl (-CH 2 CH 2 CH 2 NH- c Pr) and N-pyrrolidinylethyl (-CH 2 CH 2 -N-pyrrolidinyl).
  • acyl refers to a monovalent group -C(O)alkyl, wherein the alkyl portion has a specified number of carbon atoms (usually C1 - C8 , preferably C1 - C6 or C1 - C4 ) and may be optionally substituted with groups applicable to alkyl groups, such as F, OH or alkoxy.
  • optionally substituted -C(O) C1 - C4alkyl 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.
  • acyl such as -C(O) CH3 (i.e., acetyl) and -C(O) CH2CH3 (i.e., propionyl
  • substituted acyl such as -C(O) CF3 (trifluoroacetyl), -C( O ) CH2OH (
  • the present invention has the following beneficial effects:
  • 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.
  • 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%.
  • 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%.
  • 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%.
  • 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%.
  • 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 was isolated as a yellow solid with a yield of 86.7%.
  • 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 with a 2-fold concentration gradient to 10 concentration points, 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, and 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.
  • CCK-8 method was used to detect the cell proliferation inhibition effect (GI 50 ) of human blood tumor cells K562 and colorectal cancer cells HCT116
  • the cells were cultured in the corresponding culture medium until the logarithmic growth phase, and inoculated in a 96-well plate at a number of 5000/well and incubated at 37°C for 24 hours. Then, the DMSO stock dilution of the test sample of the corresponding concentration was added, and the blank group and the positive control group were retained, with three replicates in each group. After incubation for 48 hours, 10 ⁇ L CCK-8 was added to each well and incubated for 3 hours. Subsequently, the absorbance value of each well at 450 nm was measured using 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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明属于药物化学技术领域，具体涉及一种作为CDKs抑制剂的苯并三唑衍生物及其药物组合物和在制备抗肿瘤药物中的应用。本发明的苯并三唑衍生物具有较强的抑制CDK9及其他CDK亚型的活性，且具有较强的抗肿瘤活性，对人血液肿瘤细胞K562，结直肠癌细胞HCT116的细胞增殖都具有较强的抑制活性。本发明的苯并三唑衍生物的结构如通式（I）所示。

Description

作为CDKs抑制剂的苯并三唑衍生物及其药物组合物和应用
相关申请的交叉引用
本申请要求2023年07月04日提交的中国申请号2023108163557的权益。所述申请号2023108163557据此全文以引用方式并入本文。
技术领域
本发明属于药物化学技术领域，具体涉及一种作为CDKs抑制剂的苯并三唑衍生物及其药物组合物和在制备抗肿瘤药物中的应用。
背景技术
CDK9(Cyclin-dependent kinase 9)为转录CDK亚家族成员之一，在RNAP II转录调控中发挥作用。CDK9定位于染色体9q34.1，其活性位点具有保守的双叶结构，分别由一个N-末端和一个C-末端组成。CDK9的N-末端叶包含16至108残基，含有5个β链和一个主要的α螺旋区段。C-末端叶包含109-330残基，包括4个β链和7个主要的α螺旋。CDK9与ATP结合位点铰链区位于激酶的两个裂片之间裂缝处，其酶活性依赖于活化区域中的苏氨酸残基(Thr186)的磷酸化，所以该ATP结合位点一般可作为CDK9相关抑制剂的结合口袋。在生物学功能方面，CDK9主要参与控制真核RNA聚合酶II的mRNA的合成与加工。其中约80％的CDK9与Cyclin T1形成异源二聚体，其余20％与Cyclin T2A，Cyclin T2B或Cyclin K形成复合物。CDK9活化主要依赖于CDK9/Cyclin T1异源二聚体的形成，该二聚体可形成阳性转录延伸因子b(P-TEFb)的催化亚基，通过驱动转录起始发挥作用。通过抑制CDK9可抑制部分基因的转录延长，有效降低肿瘤细胞内mRNA水平，进而起到诱发肿瘤细胞凋亡的目的。
目前暂未有针对CDK9靶点的药物上市，部分在研药物的全球最高研发阶段已达到临床三期，其中由赛诺菲开发的CDK9选择性抑制剂Alvocidib已获得欧盟孤儿药认证，用于急性髓系白血病及慢性淋巴细胞白血病的治疗。鉴于CDK9靶点的成药可行性及参考CDK4/6抑制剂的研发成功经验，目前已有较多国内(石药集团、劲方药业等)、外(Pfizer、Bayer、Merck、Astrazeneca等)知名企业及研究机构在此靶点予以布局。
发明内容
本发明的目的在于提供一种苯并三唑衍生物及其药物组合物和应用。本发明的苯并三 唑衍生物具有抑制CDK9及其他CDK亚型(CDK2、CDK4、CDK5、CDK6、CDK7、CDK8、CDK12、CDK13、CDK15、CDK18等)的活性，并初步评价了其体外抗肿瘤活性，为新型抗肿瘤药物的开发和临床应用打下基础。
具体地，通过以下几个方面的技术方案实现了本发明：
在第一个方面中，本发明提供了一种苯并三唑衍生物或其药学上可接受的盐，所述苯并三唑衍生物的结构如通式I所示：
其中，A环是含有6-12个碳原子的芳基或含有5-12个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1、2或3个选自N、O、S的杂原子；
B环是含有6-12个碳原子的芳基或含有5-12个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1、2或3个选自N、O、S的杂原子；或者B环是含有3-12个碳原子的环烷基或含有3-12个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；或者B是C1-C6烷基或-NRaRb，Ra、Rb各自独立地选自氢、C1-C6烷基、C1-C6氨基烷基或含有3-12个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；
C环是含有6-12个碳原子的芳基或含有5-12个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1、2或3个选自N、O、S的杂原子；
D环是含有6-12个碳原子的芳基或含有5-12个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1、2或3个选自N、O、S的杂原子；或者B环是含有3-12个碳原子的环烷基或含有3-12个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；或者B是C1-C6烷基或-NRaRb，Ra、Rb各自独立地选自氢、C1-C6烷基、C1-C6氨基烷基或含有3-12个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；
C环与D环稠合；
R为C1-C12烷基、C1-C12烷氧基或含有3-10个碳原子的环烷基；
R1、R2、R3和R4各自独立地选自氢、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷 基、羟基、羧基、氨基、氰基、硝基、C1-C6烷胺基或含有3-10个碳原子的环烷基；
R5、R6、R7和R8各自独立地选自氢、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、羟基、羧基、氨基、氰基、硝基、C1-C6烷胺基、C1-C6酰基、C1-C6磺酰基、含有3-10个碳原子的环烷基或含有3-10个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；
L为键、-CR9R10-、-O-、-S-、-SO2-、-C(O)-、-NR11-、-SO2NR11-或-NR11SO2-；
R9、R10和R11各自独立地选自氢、C1-C6烷基、C3-C6环烷基、-(C1-C3亚烷基)(C3-C6环烷基)、C6-C14芳基、5元至6元杂芳基或3元至6元杂环基，其中的每一个独立地任选地被以下取代：卤素、氧代基、-CN、-OR12、-NR12R13或任选地被卤素、-OH或氧代基取代的C1-C6烷基；
R12和R13各自独立地选自氢、任选地被卤素或氧代基取代的C1-C6烷基、任选地被卤素或氧代基取代的C2-C6烯基、或任选地被卤素或氧代基取代的C2-C6炔基；或R12和R13与其所连接的原子一起形成3元至6元杂环基，其任选地被卤素、氧代基或任选地被氧代基或卤素取代的C1-C6烷基取代。
优选的，A环是含有5-8个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1或2个选自N、O、S的杂原子。
更优选的，A环是含有5-6个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1个选自N、O、S的杂原子。
优选的，B环是含有3-8个碳原子的环烷基或含有3-8个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子。
更优选的，B环是含有5-7个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子。
优选的，C环是含有5-8个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1或2个选自N、O、S的杂原子。
更优选的，C环是含有5-6个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1个选自N、O、S的杂原子。
优选的，D环是含有3-8个碳原子的环烷基或含有3-8个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子。
更优选的，D环是含有5-7个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子。
优选的，R为C1-C8烷基或C1-C8烷氧基。
更优选的，R为甲基、乙基、正丙基或异丙基。
优选的，R1、R2、R3和R4各自独立地选自氢、卤素、C1-C6烷基或C1-C6烷氧基。
更优选的，R1、R2、R3和R4各自独立地选自氢。
优选的，R5、R6、R7和R8各自独立地选自氢、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、羟基、氨基、C1-C6烷胺基、C1-C6酰基或含有3-8个碳原子的环烷基。
更优选的，R5、R6、R7和R8各自独立地选自氢、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6酰基或含有3-6个碳原子的环烷基。
优选的，L为键、-CR9R10-、-O-、-S-、-SO2-、-C(O)-或-NR11-。
更优选的，L为-C(O)-。
优选的，R9、R10和R11各自独立地选自氢或C1-C6烷基。
更优选的，R9、R10和R11各自独立地选自氢。
优选的，R12和R13各自独立地选自氢或任选地被卤素或氧代基取代的C1-C6烷基。
更优选的，R12和R13各自独立地选自氢。
进一步地，本发明优选以下结构式所示的苯并三唑衍生物：

进一步地，本发明还提供了通式I所示的苯并三唑衍生物的制备方法，合成路线如下所示：
其中，R如上述通式I中所定义；X为C；X1为C或N；X2为氢、卤素、C1-C6烷基、C1-C6烷氧基或卤代C1-C6烷基；R14为B和R6如上述通式I中所定义。
上述合成路线中，步骤I为取代反应，原料2-氟-4-溴硝基苯与1-8个碳原子的脂肪胺或脂环胺在碱性条件下反应，其中反应溶剂选自二甲基亚砜、N,N-二甲基甲酰胺、乙腈、二氯甲烷、氯仿、甲苯、四氢呋喃、N,N-二甲基乙酰胺、2-甲基四氢呋喃中一种或多种；碱选自 碳酸钾、碳酸钠、碳酸铯、氢氧化钾、氢氧化钠、三乙胺、N,N-二异丙基乙胺中一种或多种；反应温度为10-100℃。
步骤II为硝基还原反应，还原剂选用铁粉、锌粉、氯化亚锡、硫化钠，硫代硫酸钠、保险粉中一种或多种；反应溶剂选用稀盐酸(1-10mol/L)、稀硫酸(1-10mol/L)、氯化铵水溶液(1-10mol/L)、乙醇、甲醇、异丙醇中一种或多种；反应温度为10-100℃。
步骤III为芳基三氮唑扣环反应，反应物为亚硝酸钠、亚硝酸或亚硝酸叔丁酯；反应溶剂选用稀盐酸(1-10mol/L)和稀硫酸(1-10mol/L)；反应温度为-10-30℃。
步骤IV为Miyaura反应，反应物为联硼酸频哪醇酯；催化剂选用[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双三苯基膦二氯化钯、四三苯基膦钯、醋酸钯；碱可用碳酸钾、碳酸钠、碳酸铯、醋酸钾、醋酸钠、磷酸钾中一种或多种；反应溶剂选用二甲基亚砜、N,N-二甲基甲酰胺、乙腈、甲苯、四氢呋喃、N,N-二甲基乙酰胺、2-甲基四氢呋喃中一种或多种；反应保护气为氮气、氦气或氩气；反应温度为10-100℃。
步骤V为Suzuki偶联反应，催化剂选用[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双三苯基膦二氯化钯、四三苯基膦钯、醋酸钯中一种或多种；碱选用碳酸钾、碳酸钠、碳酸铯、醋酸钾、醋酸钠、磷酸钾中一种或多种；反应溶剂选用二甲基亚砜、N,N-二甲基甲酰胺、乙腈、甲苯、四氢呋喃、N,N-二甲基乙酰胺、2-甲基四氢呋喃中一种或多种；反应保护气为氮气、氦气或氩气；反应温度为10-100℃。
步骤VI为Buchwald-Hartwig反应，催化剂选用[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双三苯基膦二氯化钯、四三苯基膦钯、醋酸钯中一种或多种；配体选用P(o-tolyl)3、P(t-Bu)3、CyPF-t-Bu、JosiPhos、Binap、XantPhos、DPPF、BrettPhos、RuPhos、XPhos、SPhos、BippyPhos中一种或多种；碱选用碳酸钾、碳酸钠、碳酸铯、醋酸钾、醋酸钠、磷酸钾中一种或多种；反应溶剂选用二甲基亚砜、N,N-二甲基甲酰胺、乙腈、甲苯、四氢呋喃、N,N-二甲基乙酰胺、2-甲基四氢呋喃中一种或多种；反应保护气为氮气、氦气或氩气；反应温度为10-120℃。
步骤VII为酯基水解反应，碱选用碳酸钾、碳酸钠、碳酸铯、氢氧化钾、氢氧化钠、三乙胺、N,N-二异丙基乙胺、碘化锂、溴化锂中一种或多种；反应温度为10-100℃；反应溶剂选用二甲基亚砜、N,N-二甲基甲酰胺、乙腈、甲苯、四氢呋喃、N,N-二甲基乙酰胺、2-甲基四氢呋喃，甲醇、乙醇、异丙醇中一种或多种。
步骤VIII为缩合反应，缩合条件可为DCC/EDCI/HOBt/HOAt/DMAP、HATU/HBTU/HCTU/TBTU/DIPEA/Et3N/DBU、PyBop或T3P；反应溶剂选用二甲基亚砜、N,N-二甲基甲酰胺、二氯甲烷、乙腈、甲苯、四氢呋喃、N,N-二甲基乙酰胺、2-甲基四氢呋喃中一种或多种；反应温度为10-100℃。
步骤IX为Buchwald-Hartwig反应，催化剂选用[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双三苯基膦二氯化钯、四三苯基膦钯、醋酸钯中一种或多种；配体选用P(o-tolyl)3、P(t-Bu)3、CyPF-t-Bu、JosiPhos、Binap、XantPhos、DPPF、BrettPhos、RuPhos、XPhos、SPhos、BippyPhos中一种或多种；碱选用碳酸钾、碳酸钠、碳酸铯、醋酸钾、醋酸钠、磷酸钾中一种或多种；反应溶剂选用二甲基亚砜、N,N-二甲基甲酰胺、乙腈、甲苯、四氢呋喃、N,N-二甲基乙酰胺、2-甲基四氢呋喃中一种或多种；反应保护气为氮气、氦气或氩气；反应温度为10-120℃。
步骤X为还原胺化反应，反应用酸选用冰醋酸、甲酸、稀盐酸(1-10mol/L)、稀硫酸(1-10mol/L)中一种或多种；还原剂选用硼氢化钠、氰基硼氢化钠、三乙酰氧基硼氢化钠、三异丙酰氧基硼氢化钠中一种或多种；反应溶剂选用二甲基亚砜、N,N-二甲基甲酰胺、乙腈、甲苯、四氢呋喃、N,N-二甲基乙酰胺、2-甲基四氢呋喃，甲醇、乙醇、异丙醇中一种或多种；反应温度为10-100℃。
在第二个方面中，本发明提供了一种药物组合物，所述药物组合物包含通式I所示的苯并三唑衍生物或其药学上可接受的盐和药学上可接受的载体或赋形剂。
在第三个方面中，本发明提供了一种通式I所示的苯并三唑衍生物或其药学上可接受的盐或所述的药物组合物在制备抗肿瘤药物中的应用。
在本发明中，术语“芳基”表示具有公知的芳香性特征的任选地被取代的单环或稠合二环或多环环系，其中至少一个环含有完全共轭的π-电子系统。通常，芳基含有6-20个碳原子作为环成员，优选6-14个碳原子或更优选6-12个碳原子。芳基的例子包括、但不限于苯基、联苯、萘基、蒽基、菲基、茚满基、茚基和四氢萘基。
在本发明中，术语，“杂芳基”表示具有公知的芳香性特征的单环或稠合二环或多环环系，其含有指定数目的环原子并且包括至少一个选自N、O和S的杂原子作为芳环中的环成员。杂原子的包含允许5-元环以及6-元环的芳香性。通常，杂芳基含有5-20个环原子，优选5-14个环原子，更优选5-12个环原子。杂芳基环通过杂芳环的环原子连接至基础分子，从而保持芳香性。杂芳基的例子经常包括、但不限于吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、异噁唑基、噁唑基、异噻唑基、噻唑基、三唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基。
在本发明中，术语“环烷基”表示含有指定数目的碳原子的非芳族饱和碳环环系，其可以是通过环烷基环的碳原子连接至基础分子的单环、螺环、桥连或稠合二环或多环环系。通常，本发明的环烷基含有3-12个碳原子，优选3-8个碳原子。环烷基的例子经常包括、但不限于环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基等。
在本发明中，术语“杂环基”可以互换地用于表示含有指定数目的环原子的非芳族饱和环系，其包括至少一个选自N、O和S的杂原子作为环成员。通常，本发明的杂环基含有3-12 个环原子，优选3-8个环原子，更优选3-6个环原子。杂环基的例子经常包括、但不限于氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基等。
在本发明中，术语“卤素”表示氟、氯、溴或碘。
在本发明中，术语“烷基”(包括单独使用及包含在其它基团中时)意指包括1-20个碳原子的支链和直链饱和烃基，优选1-12个碳原子，更优选1-5个碳原子，最优选1-3个碳原子，比如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、庚基、辛基、壬基、癸基、4,4-二甲基戊基、2,2,4-三甲基戊基、十一烷基、十二烷基，及它们的各种异构体等等。
在本发明中，术语“烷氧基”表示通过氧桥连接的具有所述碳原子数目的烷基。由此，“烷氧基”包含以上烷基的定义。
在本发明中，术语“烯基”是指含有指定数目碳原子和至少一个碳碳双键的直链、支链烃基。优选的存在一个碳碳双键，更优选的通过所述碳碳双键连接化合物的其他部分。碳原子的数目可以是2-12个，优选2-5个，更优选为2个，比如乙烯基、1-丙烯基、1-丁烯基等等。
在本发明中，术语“炔基”是指含有指定数目碳原子和至少一个碳碳三键的直链、支链烃基。优选的存在一个碳碳三键，更优选的通过所述碳碳三键连接化合物的其他部分。碳原子的数目可以是2-12个，优选2-5个，更优选为2个，比如乙炔基、1-丙炔基、1-丁炔基等等。
在本发明中，术语“氨基烷基”表示具有指定数目的碳原子的烷基，其被一个或多个被取代的或未被取代的氨基基团取代。氨基烷基通常在烷基部分中含有1-6个碳原子且被1、2或3个氨基取代基取代。因而，C1-C6氨基烷基的例子经常包括、但不限于氨基甲基(-CH2NH2)、N,N-二甲基氨基乙基(-CH2CH2N(CH3)2)、3-(N-环丙基氨基)-丙基(-CH2CH2CH2NH-cPr)和N-吡咯烷基乙基(-CH2CH2-N-吡咯烷基)。
在本发明中，术语“酰基”表示单价基团-C(O)烷基，其中所述烷基部分具有指定数目的碳原子(通常C1-C8，优选C1-C6或C1-C4)并且可以任选地被适用于烷基的基团取代，例如被F、OH或烷氧基取代。因此，任选地被取代的-C(O)C1-C4烷基包括未被取代的酰基，例如-C(O)CH3(即乙酰基)和-C(O)CH2CH3(即丙酰基)，以及被取代的酰基，例如-C(O)CF3(三氟乙酰基)、-C(O)CH2OH(羟基乙酰基)、-C(O)CH2OCH3(甲氧基乙酰基)、-C(O)CF2H(二氟乙酰基)等。
本发明相对于现有技术，具有以下有益效果：
本发明的苯并三唑衍生物结构较为新颖，具有较强的抑制CDK9及其他CDK亚型的活性，且具有较强的抗肿瘤活性，对人血液肿瘤细胞K562，结直肠癌细胞HCT116的细胞增殖都具有较强的抑制活性，为新型抗肿瘤药物的开发和临床应用打下基础。
具体实施方式
下面详细描述本发明的实施例，所举实施例是为了更好地对本发明的内容进行说明，仅用于解释本发明，而不能理解为对本发明的限制。
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为市售产品。
实施例1：(6-((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)吡啶-2-基)氨基)吡啶-3-基)(吗啉基)甲酮(A-1)
A-1化合物的制备方法，其操作步骤如下：
(1)将2-氟-4-溴硝基苯(10.0g,45.67mmol)溶于N,N-二甲基甲酰胺中，分别加入碳酸钾(7.63g,54.81mmol)和异丙胺(3.24g,54.81mmol)，室温反应5小时。反应完成后将反应混合物倒入冰水混合物中搅拌2小时，抽滤得中间体1为黄色固体，收率95.4％；
(2)将中间体1(5g,19.38mmol)溶于乙醇，加入还原铁粉(5.42g,96.9mmol)，随后加入氯化铵(5.18g,96.9mmol)水溶液，80℃反应1小时。随后抽滤，旋蒸除去溶剂，残余物使用乙酸乙酯复溶，经硅胶柱层析(环己烷/乙酸乙酯＝3/1)分离得中间体2为棕色固体，收率89.1％。
(3)将中间体2(5g,20.92mmol)溶于浓盐酸，加入亚硝酸钠(2.17g,31.38mmol)水溶液，室温反应3小时。随后用1N氢氧化钠水溶液调节体系pH至8，使用乙酸乙酯进行萃取，合并有机相后使用无水硫酸钠干燥，经硅胶柱层析(环己烷/乙酸乙酯＝20/1)分离得中间体3为白色固体，收率86.3％。
(4)将中间体3(5g,20.92mmol)溶于二氧六环，加入联硼酸频那醇酯(7.97g,31.38 mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1.53g,2.09mmol)，醋酸钾(4.11g,41.84mmol)，110℃反应6小时。反应结束后抽滤，滤液使用乙酸乙酯萃取，合并有机相后使用无水硫酸钠干燥，经硅胶柱层析(环己烷/乙酸乙酯＝5/1)分离得中间体4为白色固体，收率91.7％。
(5)将中间体4(3g,10.45mmol)溶于二氧六环/水＝4/1混合溶液，加入2-氨基-4-溴吡啶(1.8g,10.45mmol)，四三苯基膦钯(1.21g,1.05mmol)和碳酸钠(2.21g,20.9mmol)，100℃反应3小时。反应结束后抽滤，滤液使用二氯甲烷萃取，合并有机相后使用无水硫酸钠干燥，经硅胶柱层析(环己烷/乙酸乙酯＝1/1)分离得中间体5为白色固体，收率88.7％。
(6)将中间体5(2g,7.90mmol)溶于N,N-二甲基甲酰胺中，分别加入6-溴烟酸甲酯(2.05g,9.48mmol)，三(二亚苄基丙酮)二钯(0.36g,0.39mmol)，碳酸铯(6.1g,15.8mmol)，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.41g,0.79mmol)，100℃反应6小时。反应结束后使用二氯甲烷萃取，合并有机相后使用无水硫酸钠干燥，经硅胶柱层析(环己烷/乙酸乙酯＝1/1)分离得中间体6为黄色固体，收率65.9％。
(7)将中间体6(1g,2.58mmol)溶于甲醇，加入氢氧化钠(1g,25.8mmol)水溶液，80℃反应3小时。反应结束后旋蒸除去溶剂，用1N稀盐酸调体系pH至3，抽滤得中间体7为白色固体，收率85.9％。
(8)将中间体7(0.5g,1.34mmol)溶于N,N-二甲基甲酰胺中，分别加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.31g,1.61mmol)，1-羟基苯并三唑(0.22g,1.61mmol)，吗啉(0.14g,1.61mmol)，室温反应3小时，反应结束后使用二氯甲烷萃取，合并有机相后使用无水硫酸钠干燥，经硅胶柱层析(环己烷/乙酸乙酯＝1/3)分离得A-1为黄色固体，收率86.7％，ESI-LC-MS:444.2[M+H]+，1H 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)。
实施例2：(6-((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)吡啶-2-基)氨基)吡啶-3-基)(4-甲基哌嗪-1-基)甲酮(A-2)
A-2化合物的制备方法同A-1化合物，只是使用了N-甲基哌嗪替代了实施例1中步骤(8)的吗啉，分离得A-2为黄色固体，收率79.4％。ESI-LC-MS:457.3[M+H]+，1H 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)。
实施例3：(6-((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)吡啶-2-基)氨基)吡啶-3-基)(4-乙基哌嗪-1-基)甲酮(A-3)
A-3化合物的制备方法同A-1化合物，只是使用了N-乙基哌嗪替代了实施例1中步骤(8)的吗啉，分离得A-3为黄色固体，收率81.2％。ESI-LC-MS:471.3[M+H]+，1H 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)。
实施例4：(6-((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)吡啶-2-基)氨基)吡啶-3-基)(4-异丙基哌嗪-1-基)甲酮(A-4)
A-4化合物的制备方法同A-1化合物，只是使用了N-异丙基哌嗪替代了实施例1中步骤(8)的吗啉，分离得A-4为黄色固体，收率83.5％。ESI-LC-MS:485.3[M+H]+，1H NMR(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)。
实施例5：(6-((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)吡啶-2-基)氨基)吡啶-3-基)(4-甲基-1,4-二氮杂-1-基)甲酮(A-5)
A-5化合物的制备方法同A-1化合物，只是使用了N-甲基高哌嗪替代了实施例1中步骤(8)的吗啉，分离得A-5为黄色固体，收率89.1％。ESI-LC-MS:471.2[M+H]+，1H NMR(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)。
实施例6：(2-((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)吡啶-2-基)氨基)吡啶-4-基)(吗啉基)甲酮(A-6)
A-6化合物的制备方法同A-1化合物，只是使用了2-溴吡啶-4-甲酸甲酯替代了实施例1中步骤(6)的6-溴烟酸甲酯，分离得A-6为黄色固体，收率82.3％。ESI-LC-MS:444.2[M+H]+,1H 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)。
实施例7：(2-((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)吡啶-2-基)氨基)吡啶-4-基)(4-甲基哌嗪-1-基)甲酮(A-7)
A-7化合物的制备方法同A-1化合物，只是使用了2-溴吡啶-4-甲酸甲酯替代了实施例1中步骤(6)的6-溴烟酸甲酯，使用了N-甲基哌嗪替代了实施例1中步骤(8)的吗啉，分离得A-7为黄色固体，收率81.9％。ESI-LC-MS:457.3[M+H]+，1H 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)。
实施例8：(2-((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)吡啶-2-基)氨基)吡啶-4-基)(4-乙基哌嗪-1-基)甲酮(A-8)
A-8化合物的制备方法同A-1化合物，只是使用了2-溴吡啶-4-甲酸甲酯替代了实施例1中步骤(6)的6-溴烟酸甲酯，使用了N-乙基哌嗪替代了实施例1中步骤(8)的吗啉，分离得A-8为黄色固体，收率73.3％。ESI-LC-MS:471.3[M+H]+，1H 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)。
实施例9：(2-((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)吡啶-2-基)氨基)吡啶-4-基)(4-异丙基哌嗪-1-基)甲酮(A-9)
A-9化合物的制备方法同A-1化合物，只是使用了2-溴吡啶-4-甲酸甲酯替代了实施例1中步骤(6)的6-溴烟酸甲酯，使用了N-异丙基哌嗪替代了实施例1中步骤(8)的吗啉，分离得A-9为黄色固体，收率81.2％。ESI-LC-MS:485.3[M+H]+，1H NMR(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)。
实施例10：(2-((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)吡啶-2-基)氨基)吡啶-4-基)(4-甲基-1,4-二氮杂-1-基)甲酮(A-10)
A-10化合物的制备方法同A-1化合物，只是使用了2-溴吡啶-4-甲酸甲酯替代了实施例1中步骤(6)的6-溴烟酸甲酯，使用了N-甲基高哌嗪替代了实施例1中步骤(8)的吗啉， 分离得A-10为黄色固体，收率86.7％。ESI-LC-MS:471.2[M+H]+，1H NMR(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)。
实施例11：药理活性实验部分
(1)采用ADP-Glo法测定本发明部分化合物对CDK9/Cyclin T1复合物的抑制作用(IC50)
将待测样品的DMSO储备液以及CDK9/Cyclin T1用相应缓冲液稀释至目标浓度，本发明化合物稀释按2倍浓度梯度为10个浓度点，最大浓度为500nM。将本发明化合物或DMSO空白组与酶混合至384孔板中，加入ATP与底物启动激酶反应，室温孵育60分钟。加入ADP-Glo试剂终止激酶反应并消耗剩余ATP，之后加入Kinase detection试剂检测新生成的ATP，使用多功能酶标仪的化学发光检测模块检测新生成的ATP含量从而反映酶活程度，结果如表1所示。
(2)采用CCK-8法对人血液肿瘤细胞K562，结直肠癌细胞HCT116的细胞增殖抑制作用(GI50)进行检测
将细胞使用相应培养基培养至对数生长期，并以5000/孔的数量接种于96孔板中37℃孵育24小时，之后加入相应浓度的待测样品的DMSO储备稀释液，并保留空白组以及阳性对照组，每组设三个复孔。孵育48小时后每孔加10μL CCK-8并孵育3小时，随后用Emax Microplate Reader(Molecular Devices,Sunnyvale,CA,USA)测定各孔在450nm处的吸光度值，并根据空白组计算细胞活力抑制率，结果如表1所示。
(3)实验结果
表1 化合物对CDK9/Cyclin T1复合物、K562和HCT116细胞的抑制作用
表1的测试结果表明：本发明的通式I所示的苯并三唑衍生物具有较强的抑制CDK9及其他CDK亚型的活性，是一系列具有全新结构的CDKs抑制剂，且具有较强的抗肿瘤活性，对人血液肿瘤细胞K562，结直肠癌细胞HCT116的细胞增殖都具有较强的抑制活性。具有潜在的应用前景及临床研究价值。
显然，上述实施例仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。

Claims (6)

  1. 一种苯并三唑衍生物或其药学上可接受的盐，其特征在于，所述苯并三唑衍生物的结构如通式I所示：
    其中，A环是含有6-12个碳原子的芳基或含有5-12个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1、2或3个选自N、O、S的杂原子；
    B环是含有6-12个碳原子的芳基或含有5-12个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1、2或3个选自N、O、S的杂原子；或者B环是含有3-12个碳原子的环烷基或含有3-12个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；或者B是C1-C6烷基或-NRaRb，Ra、Rb各自独立地选自氢、C1-C6烷基、C1-C6氨基烷基或含有3-12个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；
    C环是含有6-12个碳原子的芳基或含有5-12个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1、2或3个选自N、O、S的杂原子；
    D环是含有6-12个碳原子的芳基或含有5-12个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1、2或3个选自N、O、S的杂原子；或者B环是含有3-12个碳原子的环烷基或含有3-12个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；或者B是C1-C6烷基或-NRaRb，Ra、Rb各自独立地选自氢、C1-C6烷基、C1-C6氨基烷基或含有3-12个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；
    C环与D环稠合；
    R为C1-C12烷基、C1-C12烷氧基或含有3-10个碳原子的环烷基；
    R1、R2、R3和R4各自独立地选自氢、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、羟基、羧基、氨基、氰基、硝基、C1-C6烷胺基或含有3-10个碳原子的环烷基；
    R5、R6、R7和R8各自独立地选自氢、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷 基、羟基、羧基、氨基、氰基、硝基、C1-C6烷胺基、C1-C6酰基、C1-C6磺酰基、含有3-10个碳原子的环烷基或含有3-10个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；
    L为键、-CR9R10-、-O-、-S-、-SO2-、-C(O)-、-NR11-、-SO2NR11-或-NR11SO2-；
    R9、R10和R11各自独立地选自氢、C1-C6烷基、C3-C6环烷基、-(C1-C3亚烷基)(C3-C6环烷基)、C6-C14芳基、5元至6元杂芳基或3元至6元杂环基，其中的每一个独立地任选地被以下取代：卤素、氧代基、-CN、-OR12、-NR12R13或任选地被卤素、-OH或氧代基取代的C1-C6烷基；
    R12和R13各自独立地选自氢、任选地被卤素或氧代基取代的C1-C6烷基、任选地被卤素或氧代基取代的C2-C6烯基、或任选地被卤素或氧代基取代的C2-C6炔基；或R12和R13与其所连接的原子一起形成3元至6元杂环基，其任选地被卤素、氧代基或任选地被氧代基或卤素取代的C1-C6烷基取代。
  2. 根据权利要求1所述的通式I所示的苯并三唑衍生物，其特征在于，通式I中，A环是含有5-8个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1或2个选自N、O、S的杂原子；B环是含有3-8个碳原子的环烷基或含有3-8个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；C环是含有5-8个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1或2个选自N、O、S的杂原子；D环是含有3-8个碳原子的环烷基或含有3-8个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；C环与D环稠合；R为C1-C8烷基或C1-C8烷氧基；R1、R2、R3和R4各自独立地选自氢、卤素、C1-C6烷基或C1-C6烷氧基；R5、R6、R7和R8各自独立地选自氢、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、羟基、氨基、C1-C6烷胺基、C1-C6酰基或含有3-8个碳原子的环烷基；L为键、-CR9R10-、-O-、-S-、-SO2-、-C(O)-或-NR11-；R9、R10和R11各自独立地选自氢或C1-C6烷基；R12和R13各自独立地选自氢或任选地被卤素或氧代基取代的C1-C6烷基。
  3. 根据权利要求1所述的通式I所示的苯并三唑衍生物，其特征在于，通式I中，A环是含有5-6个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1个选自N、O、S的杂原子；B环是含有5-7个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；C环是含有5-6个环原子的杂芳基，所述杂芳基的芳杂环任选地含有1个选自N、O、S的杂原子；D环是含有5-7个环原子的杂环基，所述杂环基的杂环任选地含有1、2或3个选自N、O、S的杂原子；C环与D环稠合；R为甲基、乙基、正丙基或异丙基；R1、R2、R3和R4各自独立地选自氢；R5、R6、R7和R8各自独立地选自氢、卤素、 C1-C6烷基、卤代C1-C6烷基、C1-C6酰基或含有3-6个碳原子的环烷基；L为-C(O)-；R9、R10和R11各自独立地选自氢；R12和R13各自独立地选自氢。
  4. 根据权利要求1所述的通式I所示的苯并三唑衍生物，其特征在于，所述苯并三唑衍生物的结构式如下所示：
  5. 一种药物组合物，其特征在于，其包含权利要求1-4中任意一项所述的通式I所示的苯并三唑衍生物或其药学上可接受的盐和药学上可接受的载体或赋形剂。
  6. 权利要求1-4中任意一项所述的通式I所示的苯并三唑衍生物或其药学上可接受的盐或权利要求5所述的药物组合物在制备抗肿瘤药物中的应用。
PCT/CN2024/101071 2023-07-04 2024-06-24 作为CDKs抑制剂的苯并三唑衍生物及其药物组合物和应用 Pending WO2025007769A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202310816355.7A CN119264111B (zh) 2023-07-04 2023-07-04 作为CDKs抑制剂的苯并三唑衍生物及其药物组合物和应用
CN202310816355.7 2023-07-04

Publications (1)

Publication Number Publication Date
WO2025007769A1 true WO2025007769A1 (zh) 2025-01-09

Family

ID=94116500

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/101071 Pending WO2025007769A1 (zh) 2023-07-04 2024-06-24 作为CDKs抑制剂的苯并三唑衍生物及其药物组合物和应用

Country Status (2)

Country Link
CN (1) CN119264111B (zh)
WO (1) WO2025007769A1 (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105153119A (zh) * 2015-09-11 2015-12-16 广州科擎新药开发有限公司 吡啶嘧啶胺类化合物或吡啶吡啶胺类化合物及其应用
WO2016173557A1 (zh) * 2015-04-30 2016-11-03 中国科学院上海药物研究所 一类具有激酶抑制活性的化合物、制备方法和用途
WO2018121766A1 (zh) * 2016-12-30 2018-07-05 上海医药集团股份有限公司 含氮稠杂环化合物、其制备方法、中间体、组合物和应用
CN113121528A (zh) * 2020-01-15 2021-07-16 中国科学院上海药物研究所 多靶点抑制作用化合物、组合物、功能分子及其应用
CN113801108A (zh) * 2020-06-16 2021-12-17 中国药科大学 蛋白激酶抑制剂及其衍生物，制备方法、药物组合物和应用
CN115215848A (zh) * 2021-04-20 2022-10-21 中国药科大学 蛋白激酶抑制剂及其衍生物、制备方法、药物组合物和应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016015605A1 (en) * 2014-07-26 2016-02-04 Sunshine Lake Pharma Co., Ltd. Compounds as cdk small-molecule inhibitors and uses thereof
CN107266421B (zh) * 2016-04-08 2020-12-04 正大天晴药业集团股份有限公司 取代的苯并咪唑类衍生物
WO2018045956A1 (zh) * 2016-09-07 2018-03-15 江苏豪森药业集团有限公司 苯并咪唑类化合物激酶抑制剂及其制备方法和应用
CN108794452B (zh) * 2017-05-05 2021-05-28 上海时莱生物技术有限公司 具有激酶抑制活性的化合物、其制备方法和用途
CN114380800B (zh) * 2022-01-26 2023-05-19 四川大学 吡啶-嘧啶胺-苯并咪唑衍生物及其制备方法和用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016173557A1 (zh) * 2015-04-30 2016-11-03 中国科学院上海药物研究所 一类具有激酶抑制活性的化合物、制备方法和用途
CN105153119A (zh) * 2015-09-11 2015-12-16 广州科擎新药开发有限公司 吡啶嘧啶胺类化合物或吡啶吡啶胺类化合物及其应用
WO2018121766A1 (zh) * 2016-12-30 2018-07-05 上海医药集团股份有限公司 含氮稠杂环化合物、其制备方法、中间体、组合物和应用
CN113121528A (zh) * 2020-01-15 2021-07-16 中国科学院上海药物研究所 多靶点抑制作用化合物、组合物、功能分子及其应用
CN113801108A (zh) * 2020-06-16 2021-12-17 中国药科大学 蛋白激酶抑制剂及其衍生物，制备方法、药物组合物和应用
CN115215848A (zh) * 2021-04-20 2022-10-21 中国药科大学 蛋白激酶抑制剂及其衍生物、制备方法、药物组合物和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHONG YE, XU JING, ZHOU RUOCHEN, TANG LI, DING SHAOYUE, REN ZHAOHUI, SONG NING, HU BAICHUN, YANG HUALI, SUN YILI, CHENG MAOSHENG, : "Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 67, no. 6, 28 March 2024 (2024-03-28), US , pages 4739 - 4756, XP093259204, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.3c02329 *

Also Published As

Publication number Publication date
CN119264111B (zh) 2025-11-21
CN119264111A (zh) 2025-01-07

Similar Documents

Publication Publication Date Title
CN110997669B (zh) 取代五元并六元杂环类化合物、其制备方法、药物组合及其用途
KR20090122300A (ko) 화합물
CN106883213A (zh) 一种新型egfr和alk激酶的双重抑制剂
CN113354622A (zh) 对苯二胺类lsd1抑制剂及其制备方法
CN113166105B (zh) 作为cdk-hdac双通路抑制剂的杂环化合物
CN105254635A (zh) 一类咪唑并吡嗪类化合物及其药物组合物和用途
CN111423379B (zh) 取代3-吲唑类Mcl-1蛋白抑制剂及制备方法和应用
CN102070618B (zh) 一种化合物及其晶体
CN107849045B (zh) 嘌呤基-n-羟基嘧啶甲酰胺衍生物及其制备方法和用途
CN108239071A (zh) 酰胺及硫代酰胺类衍生物及其制备方法和应用
CN105198789A (zh) 取代3-吲哚类Bcl-2蛋白抑制剂及制备方法和应用
CN102134234B (zh) 吲唑脲类化合物及其制法和药物用途
CN109810098A (zh) 含有酞嗪-1(2h)-酮结构的parp-1和pi3k双靶点抑制剂
CN109734677A (zh) 抑制组蛋白赖氨酸甲基转移酶nsd2的小分子化合物及其应用
CN107793417B (zh) 吡咯并[2,3-d]嘧啶类化合物及其盐，及制备方法和药用用途
CN106946896B (zh) 呋喃并[2,3-d]嘧啶-4-胺衍生物
CN112979613B (zh) 2-(1h-吡唑-3-基)吡啶衍生物及其制备方法和用途
CN113166148B (zh) 作为cdk-hdac双通路抑制剂的杂环化合物
CN104876934A (zh) 一种含氮杂环苯基哌啶类化合物及其制备方法与应用
CN111057065B (zh) 噻吩并嘧啶类化合物的制备方法和用途
WO2025007769A1 (zh) 作为CDKs抑制剂的苯并三唑衍生物及其药物组合物和应用
CN116239580B (zh) 三嗪类化合物及其制备方法、药物组合物和应用
CN111848629A (zh) 一类mTOR/HDAC双重抑制剂及其应用
CN115703760B (zh) 2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂及其制备方法和应用
CN110407839A (zh) 含杂芳基酰胺结构的三唑并杂环类化合物的制备及应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24835251

Country of ref document: EP

Kind code of ref document: A1