CN117843563A - CDKs inhibitor derivative containing urea fragment, and pharmaceutical composition and application thereof - Google Patents

CDKs inhibitor derivative containing urea fragment, and pharmaceutical composition and application thereof Download PDF

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CN117843563A
CN117843563A CN202410002495.5A CN202410002495A CN117843563A CN 117843563 A CN117843563 A CN 117843563A CN 202410002495 A CN202410002495 A CN 202410002495A CN 117843563 A CN117843563 A CN 117843563A
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alkyl
carbon atoms
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程卯生
李佳
刘洋
孙一立
仲烨
徐晶
丁绍越
任兆惠
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Shandong Provincial Laboratory For Yantai New Drug Creation
Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a CDKs inhibitor derivative containing urea fragments, a pharmaceutical composition thereof and application thereof in preparing antitumor drugs. The derivative containing the urea fragment has strong activity of inhibiting CDK9 and other CDK subtype, has strong anti-tumor activity, and has strong inhibition activity on cell proliferation of human blood tumor cells K562 and MV411 and colorectal cancer cells HCT116 and HT-29. The structure of the CDKs inhibitor derivative containing the urea fragment is shown as a general formula I:

Description

CDKs inhibitor derivative containing urea fragment, and pharmaceutical composition and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a CDKs inhibitor derivative containing urea fragments, a pharmaceutical composition thereof and application thereof in preparing antitumor drugs.
Background
CDK9 (Cyclin-dependent kinase 9) is one of the members of the transcriptional CDK subfamily and plays a role in RNAPII transcriptional regulation. CDK9 is located on chromosome 9q34.1 and its active site has a conserved biplate structure consisting of one N-terminal and one C-terminal end, respectively. The N-terminal leaf of CDK9 contains 16 to 108 residues, contains 5 β chains and a major α -helical segment. The C-terminal She Baohan residues 109-330, comprising 4 beta strands and 7 major alpha helices. The hinge region of CDK9 and the ATP binding site is located at the cleft between two clefts of the kinase and its enzymatic activity is dependent on phosphorylation of the threonine residue (Thr 186) in the activation region, so this ATP binding site generally acts as a binding pocket for CDK 9-related inhibitors. In terms of biological function, CDK9 is primarily involved in controlling synthesis and processing of mRNA for eukaryotic RNA polymerase II. Of these, 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 is primarily dependent on the formation of CDK9/Cyclin T1 heterodimers that can form the catalytic subunit of the positive transcription elongation factor b (P-TEFb), acting by driving transcription initiation. By inhibiting CDK9, the transcription elongation of partial genes can be inhibited, the mRNA level in tumor cells can be effectively reduced, and the purpose of inducing apoptosis of tumor cells is achieved.
At present, no medicament aiming at CDK9 targets is marketed, and part of the medicament has reached clinical third stage in the global highest research and development stage, wherein Alvocidib, a CDK9 selective inhibitor developed by Sainofil, has been authenticated by European orphan medicament and is used for treating acute myelogenous leukemia and chronic lymphocytic leukemia. In view of the feasibility of CDK9 targets and the experience of successful development of CDK4/6 inhibitors, many domestic (Shi-Yao-Ji, jin-Fang pharmaceutical industries, etc.), foreign (Pfizer, bayer, merck, astrazeneca, etc.) well-known enterprises and research institutions have been currently laying out this target.
Disclosure of Invention
The invention aims to provide a CDKs inhibitor derivative containing urea fragments, a pharmaceutical composition and application thereof. The derivative has the activity of inhibiting CDK9 and other CDK subtype (CDK 2, CDK4, CDK5, CDK6, CDK7, CDK8, CDK12, CDK13, CDK15, CDK18 and the like), and preliminarily evaluates the in vitro anti-tumor activity, thereby laying a foundation for the development and clinical application of novel anti-tumor drugs.
Specifically, the invention is realized through the following technical schemes:
in a first aspect, the present invention provides a CDKs inhibitor derivative comprising a urea moiety having the structure shown in formula I:
wherein ring A is selected from aryl groups containing 6 to 12 carbon atoms or heteroaryl groups containing 5 to 12 ring atoms, the heteroaromatic ring of which optionally contains 1,2 or 3 heteroatoms selected from N, O, S;
ring B is selected from aryl groups containing 6 to 12 carbon atoms or heteroaryl groups containing 5 to 12 ring atoms, the heteroaromatic ring of which optionally contains 1,2 or 3 heteroatoms selected from N, O, S; or the B ring is selected from cycloalkyl 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, S;
R 1 selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo 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, cycloalkyl containing 3 to 10 carbon atoms, or heterocyclyl containing 3 to 10 ring atoms, the heterocycle of said heterocyclyl optionally containing 1,2, or 3 heteroatoms selected from N, O, S;
R 2 selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo 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, cycloalkyl containing 3 to 10 carbon atoms, or heterocyclyl containing 3 to 10 ring atoms, the heterocycle of said heterocyclyl optionally containing 1,2, or 3 heteroatoms selected from N, O, S; or R is 2 Selected from the group consisting of-CO-NR a R b ，R a 、R b Each independently selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Aminoalkyl, heterocyclyl having 3 to 12 ring atoms or heterocyclylalkyl, the heterocyclylheterocycle optionally having 1,2 or 3 heteroatoms selected from N, O, S, or R a 、R b Together with the N atom, form a heterocyclic group containing 3 to 12 ring atoms, the heterocyclic ring of the heterocyclic group optionally containing 1,2 or 3 heteroatoms selected from N, O, S;
x is selected from N or CH;
y is selected from N or C;
when Y is N, Z is absent; when Y is C, Z is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 An alkyl group.
Preferably, ring A is selected from aryl groups containing 6 to 8 carbon atoms or heteroaryl groups containing 5 to 9 ring atoms, optionally containing 1 or 2 or 3 heteroatoms selected from N, O, S.
More preferably, ring A is selected from aryl groups containing 6 to 7 carbon atoms or heteroaryl groups containing 6 to 9 ring atoms, the heteroaromatic ring of which optionally contains 1 or 2 or 3 heteroatoms selected from N, O.
Preferably, the B ring is selected from aryl groups containing 6-8 carbon atoms or heteroaryl groups containing 5-9 ring atoms, the heteroaromatic ring of which optionally contains 1 or 2 or 3 heteroatoms selected from N, O, S.
More preferably, the B ring is selected from aryl groups containing 6-8 carbon atoms.
Preferably, R 1 Selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, hydroxy, amino, C 1 -C 6 Alkylamino, C 1 -C 6 Acyl or cycloalkyl having 3 to 8 carbon atoms.
More preferably, R 1 Selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or cycloalkyl having 3 to 8 carbon atoms.
Preferably, R 2 Selected from the group consisting of-CO-NR a R b ，R a 、R b Each independently selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Aminoalkyl, heterocyclyl having 3 to 12 ring atoms or heterocyclylalkyl, the heterocyclylheterocycle optionally having 1,2 or 3 heteroatoms selected from N, O, S, or R a 、R b Together with the N atom, form a heterocyclic group containing 3 to 12 ring atoms, whichThe heterocycle of the heterocyclyl group optionally contains 1,2 or 3 heteroatoms selected from N, O, S.
More preferably, R 2 Selected from the group consisting of-CO-NR a R b ，R a 、R b Each independently selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Aminoalkyl, heterocyclyl having 3 to 8 ring atoms or heterocyclylalkyl, the heterocyclylheterocycle optionally having 1,2 or 3 heteroatoms selected from N, O, or R a 、R b Together with the N atom, form a heterocyclic group containing 3 to 8 ring atoms, the heterocyclic ring of said heterocyclic group optionally containing 1,2 or 3 heteroatoms selected from N, O.
Preferably, X is CH.
Preferably, Y is C.
Preferably, when Y is C, Z is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C 1 -C 6 An alkyl group.
More preferably, when Y is C, Z is selected from hydrogen, C 1 -C 6 An alkyl group.
Further, the present invention is preferably a CDKs inhibitor derivative containing a urea fragment represented by the following structural formula:
furthermore, the invention also provides a preparation method of the CDKs inhibitor derivative containing the urea fragment shown in the general formula I, wherein the synthetic route of the derivatives A-1 to A-48 is as follows:
the synthetic routes for the derivatives B-1 to B-48 are shown below:
wherein R is 3 、R 4 、R 5 Each independently selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo 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, cycloalkyl having 3 to 10 carbon atoms, or heterocyclyl having 3 to 10 ring atoms, the heterocycle of said heterocyclyl optionally containing 1,2 or 3 heteroatoms selected from N, O, S.
In the synthetic route, the step I is a Suzuki coupling reaction, and the catalyst is one or more of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, bis triphenylphosphine palladium dichloride, tetra-triphenylphosphine palladium and palladium acetate; the alkali is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium acetate, sodium acetate and potassium phosphate; the reaction solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran, N-dimethylacetamide and 2-methyltetrahydrofuran; the reaction shielding gas is nitrogen, helium or argon; the reaction temperature is 10-100 ℃.
Step II is nucleophilic addition reaction of urea, and the reaction promoter is one or more of triethylamine and DIPEA, DBU, CDI; the reaction solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran, N-dimethylacetamide and 2-methyltetrahydrofuran; the reaction shielding gas is nitrogen, helium or argon; the reaction temperature is 10-100 ℃.
Step III is an ester hydrolysis reaction, and alkali is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, N-diisopropylethylamine, lithium iodide and lithium bromide; the reaction temperature is 10-100 ℃; the reaction solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran, N-dimethylacetamide, 2-methyltetrahydrofuran, methanol, ethanol and isopropanol.
Step IV is a condensation reaction under the conditions of DCC/EDCI/HOBt/HOAt/DMAP, HATU/HBTU/HCTU/TBTU/DIPEA/Et3N/DBU, pyBop or T3P; the reaction solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, dichloromethane, acetonitrile, toluene, tetrahydrofuran, N-dimethylacetamide and 2-methyltetrahydrofuran; the reaction temperature is 10-100 ℃.
Step V is substitution reaction, namely reacting raw material 2-fluoro-4-bromonitrobenzene with aliphatic amine or alicyclic amine with 1-8 carbon atoms under alkaline condition, wherein a reaction solvent is one or more selected from dimethyl sulfoxide, N-dimethylformamide, acetonitrile, dichloromethane, chloroform, toluene, tetrahydrofuran, N-dimethylacetamide and 2-methyltetrahydrofuran; the alkali is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, triethylamine and N, N-diisopropylethylamine; the reaction temperature is 10-100 ℃.
Step VI is a nitroreduction reaction, wherein the reducing agent is one or more of iron powder, zinc powder, stannous chloride, sodium sulfide, sodium thiosulfate and sodium hydrosulfite; the reaction solvent is 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 ℃.
Step VII is aryl triazole ring-opening reaction, and reactants are sodium nitrite, nitrous acid or tert-butyl nitrite; the reaction solvent is selected from dilute hydrochloric acid (1-10 mol/L) and dilute sulfuric acid (1-10 mol/L); the reaction temperature is-10-30 ℃.
Step VIII is Miyaura reaction, and the reactant is pinacol biborate; the catalyst is selected from [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, bis triphenylphosphine palladium dichloride and tetra triphenylphosphine palladium acetate; the alkali can be one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium acetate, sodium acetate and potassium phosphate; the reaction solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran, N-dimethylacetamide and 2-methyltetrahydrofuran; the reaction shielding gas is nitrogen, helium or argon; the reaction temperature is 10-100 ℃.
In a second aspect, the present invention provides a pharmaceutical composition comprising a CDKs inhibitor derivative having a urea fragment of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
In a third aspect, the invention provides an application of a CDKs inhibitor derivative containing urea fragments shown in a general formula I or pharmaceutically acceptable salts thereof or a pharmaceutical composition in preparing antitumor drugs.
In the present invention, the term "aryl" means an optionally substituted mono-or fused bi-or polycyclic ring system having well known aromatic character, wherein at least one ring contains a fully conjugated pi-electron system. Typically, aryl groups contain 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, anthryl, phenanthryl, indanyl, indenyl, and tetrahydronaphthyl.
In the present invention, the term "heteroaryl" means a monocyclic or fused bicyclic or polycyclic ring system having well-known aromatic character, which contains the indicated number of ring atoms and which includes at least one heteroatom selected from N, O and S as a ring member in the aromatic ring. The inclusion of heteroatoms allows for aromaticity of the 5-membered ring and the 6-membered ring. Typically, heteroaryl groups contain 5 to 20 ring atoms, preferably 5 to 14 ring atoms, more preferably 5 to 12 ring atoms. The heteroaryl ring is attached to the base molecule through a ring atom of the heteroaryl ring, thereby preserving aromaticity. Examples of heteroaryl groups often include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or benzotriazole groups.
In the present invention, the term "cycloalkyl" means a non-aromatic saturated carbocyclic ring system containing the indicated number of carbon atoms, which may be a monocyclic, spiro, bridged or fused bicyclic or polycyclic ring system connected to the base molecule through a carbon atom of the cycloalkyl ring. Typically, cycloalkyl groups of the present invention contain 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms. Examples of cycloalkyl groups often include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and the like.
In the present invention, the term "heterocyclyl" may be used interchangeably to denote a non-aromatic saturated ring system containing the indicated number of ring atoms, which includes at least one heteroatom selected from N, O and S as ring member. Typically, the heterocyclyl groups of the present invention contain 3 to 12 ring atoms, preferably 3 to 8 ring atoms, more preferably 3 to 6 ring atoms. Examples of heterocyclyl groups often include, but are not limited to, aziridine, oxetane, thiirane, azetidine, oxetane, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, and the like.
In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.
In the present invention, the term "alkyl" (including when used alone and included in other groups) means branched and straight chain saturated hydrocarbon groups including 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 5 carbon atoms, and most preferably 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4-dimethylpentyl, 2, 4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof, and the like.
In the present invention, the term "alkoxy" means an alkyl group having the number of carbon atoms connected through an oxygen bridge. Thus, "alkoxy" includes the definition of alkyl above.
In the present invention, the term "alkenyl" refers to a straight-chain, branched-chain hydrocarbon group containing the specified number of carbon atoms and at least one carbon-carbon double bond. Preferably there is one carbon-carbon double bond, more preferably through which the other part of the compound is attached. The number of carbon atoms may be 2 to 12, preferably 2 to 5, more preferably 2, such as vinyl, 1-propenyl, 1-butenyl, and the like.
In the present invention, the term "alkynyl" refers to a straight-chain, branched-chain hydrocarbon group containing the indicated number of carbon atoms and at least one carbon-carbon triple bond. Preferably there is one carbon-carbon triple bond, more preferably through which other parts of the compound are attached. The number of carbon atoms may be 2 to 12, preferably 2 to 5, more preferably 2, such as ethynyl, 1-propynyl, 1-butynyl, and the like.
In the present invention, the term "aminoalkyl" refers to an alkyl group having the indicated number of carbon atoms, which is substituted with one or more substituted or unsubstituted amino groups. Aminoalkyl groups typically contain 1-6 carbon atoms in the alkyl portion and are substituted with 1,2, or 3 amino substituents. Thus C 1 -C 6 Examples of 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).
In the present invention, the term "acyl" denotes a monovalent radical-C (O) alkyl, wherein the alkyl moiety has the indicated number of carbon atoms (typically C 1 -C 8 Preferably C 1 -C 6 Or C 1 -C 4 ) And may optionally be substituted with groups suitable for alkyl groups, for example F, OH or alkoxy. Thus, optionally substituted-C (O) C 1 -C 4 Alkyl includes unsubstituted acyl groups, e.g. -C (O) CH 3 (i.e., acetyl) and-C (O) CH 2 CH 3 (i.e., propionyl), and substituted acyl groups, e.g., -C (O) CF 3 (trifluoroacetyl), -C (O) CH 2 OH (hydroxyacetyl), -C (O) CH 2 OCH 3 (methoxyacetyl), -C (O) CF 2 H (difluoroacetyl), and the like.
Compared with the prior art, the invention has the following beneficial effects:
the urea fragment-containing derivative disclosed by the invention is novel in structure, has strong activity of inhibiting CDK9 and other CDK subtypes, has strong anti-tumor activity, has strong inhibition activity on cell proliferation of human blood tumor cells K562 and MV411 and colorectal cancer cells HCT116 and HT-29, and lays a foundation for development and clinical application of novel anti-tumor drugs.
Detailed Description
The following detailed description of the embodiments of the present invention is provided for better illustration of the present invention, but is not to be construed as limiting the invention.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or equipment used were conventional products available for purchase through regular channels, with no manufacturer noted.
The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, are all commercially available products.
Example 1:1- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) -3- (3- (4-methylpiperazine-1-carbonyl) phenyl) urea (A-1)
The preparation method of the A-1 compound comprises the following operation steps:
(1) 2- (4-fluoro-2-methoxyphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (5 g,19.83 mmol) was dissolved in dioxane/water=4/1 mixed solution, and 2-amino-4-bromopyridine (3.43 g,19.83 mmol), tetrakis triphenylphosphine palladium (2.3 g,1.98 mmol) and sodium carbonate (4.2 g,39.66 mmol) were added to react at 100℃for 3 hours. After the reaction, the mixture was filtered with suction, the filtrate was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and isolated by silica gel column chromatography (cyclohexane/ethyl acetate=1/1) to give intermediate 1 as a white solid in 88.7% yield.
(2) Intermediate 1 (3 g,13.76 mmol) and phenyl 3- (methoxycarbonyl) isocyanate (2.44 g,13.76 mmol) were dissolved in tetrahydrofuran and reacted at 50℃for 6 hours. After the reaction, the intermediate 2 is filtered by suction to obtain a white solid with a yield of 85.3%.
(3) Intermediate 2 was dissolved in methanol, and an aqueous solution of sodium hydroxide was added thereto to react at 80℃for 3 hours. After the reaction is finished, the solvent is removed by rotary evaporation, the pH value of the system is adjusted to 3 by using 1N dilute hydrochloric acid, and the intermediate 3 is obtained by suction filtration as white solid with the yield of 85.9 percent.
(4) Intermediate 3 (1 g,2.62 mmol) was dissolved in N, N-dimethylformamide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.6 g,3.14 mmol), 1-hydroxybenzotriazole (0.42 g,3.14 mmol), N-methylpiperazine (0.31 g,3.14 mmol) were added, respectively, reacted at room temperature for 3 hours, after the reaction was completed, extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, and the A-1 compound was isolated as a white solid by silica gel column chromatography (cyclohexane/ethyl acetate=1/3) in 86.7% yield, ESI-LC-MS:464.2[ M+H ]] + ， 1 HNMR(600MHz,DMSO-d 6 )δ9.50(s,1H),9.27(s,1H),8.13-8.20(m,3H),7.92(m,1H),7.75-7.83(m,3H),7.45(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.43(m,4H),2.31(m,4H),2.18(s,3H)。
Example 2:1- (3- (4-ethylpiperazine-1-carbonyl) phenyl) -3- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) urea (A-2)
The compound (A-2) was produced in the same manner as in example 1 except that N-ethylpiperazine was used instead of N-methylpiperazine of step IV in example 1, and the compound (A-2) was isolated as a white solid in 79.4% yield. ESI-LC-MS 478.3[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.43(m,4H),2.31(m,4H),2.18(m,2H),1.03(m,3H)。
Example 3:1- (3- (4-isopropylpiperazine-1-carbonyl) phenyl) -3- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) urea (a-3)
The compound (A-3) was produced in the same manner as in example 1 except that N-isopropylpiperazine was used instead of N-methylpiperazine of step IV in example 1, and the compound (A-3) was isolated as a white solid in a yield of 78.5%. ESI-LC-MS 492.2[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.43(m,4H),2.31(m,4H),2.29(m,1H),1.03(d,J＝5.6Hz,6H)。
Example 4:1- (3- (4-morpholine-1-carbonyl) phenyl) -3- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) urea (a-4)
The compound (A-4) was produced in the same manner as in example 1 except that morpholine was used instead of N-methylpiperazine in step IV of example 1, and the compound (A-4) was isolated as a white solid in a yield of 76.1%. ESI-LC-MS 451.2[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.43(m,4H),2.31(m,4H)。
Example 5:1- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) -3- (piperazine-1-carbonyl) phenyl) urea (a-5)
The compound (A-5) was produced in the same manner as in example 1 except that piperazine was used instead of N-methylpiperazine of step IV in example 1, and the compound A-5 was isolated as a white solid in a yield of 56.7%. ESI-LC-MS 450.2[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.43(m,4H),2.31(m,4H)。
Example 6:1- (3- (4-cyclopropylpiperazine-1-carbonyl) phenyl) -3- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) urea (A-6)
The compound (A-6) was produced in the same manner as in example 1 except that N-cyclopropylpiperazine was used instead of N-methylpiperazine of step IV in example 1, and the compound (A-6) was isolated as a white solid in 77.6% yield. ESI-LC-MS 490.2[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.43(m,4H),2.31(m,4H),2.18(m,1H),1.82(m,4H)。
Example 7:1- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) -3- (3- (3-oxopiperazine-1-carbonyl) phenyl) urea (a-7)
The preparation method of the (A-7) compound is the same as in example 1, except that 2-piperazinone is used instead of N-methylpiperazine of step IV in example 1, and the A-7 compound is isolated as whiteSolid, yield 78.9%. ESI-LC-MS 464.2[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.43(m,4H),2.31(m,4H)。
Example 8: n- (2- (dimethylamino) ethyl) -3- (3- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) urea (A-8)
The preparation of the (A-8) compound was carried out in the same manner as in example 1 except that N, N-dimethylethylenediamine was used in place of N-methylpiperazine in step IV of example 1, and the A-8 compound was isolated as a white solid in 66.8% yield. ESI-LC-MS:452.2[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),7.12(m,1H),6.99(m,1H),3.79(s,3H),3.60(m,2H),2.47(m,2H),2.19(s,6H)。
Example 9: n- (2- (dimethylamino) ethyl) -3- (3- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) ureido) -N-methylbenzamide (A-9)
The compound (A-9) was produced in the same manner as in example 1 except that N1, N1, N2-trimethylethane-1, 2-diamine was used instead of N-methylpiperazine of step IV in example 1, and the compound (A-9) was isolated as a white solid in 71.4% yield. ESI-LC-MS 466.2[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.63(m,3H),3.60(m,2H),2.47(m,2H),2.19(s,6H)。
Example 10:3- (3- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) ureido) -N- (2-morpholinoethyl) benzamide (A-10)
The preparation of the (A-10) compound was carried out in the same manner as in example 1 except that N- (2-aminoethyl) morpholine was used instead of N-methylpiperazine in step IV of example 1, and the A-10 compound was isolated as a white solid in 66.7% yield. ESI-LC-MS 494.2[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.60(m,2H),3.43(m,4H),2.47(m,2H),2.31(m,4H)。
Example 11:3- (3- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) ureido) -N- (tetrahydro-2H-pyran-4-yl) benzamide (A-11)
The compound (A-11) was produced in the same manner as in example 1 except that 4-aminotetrahydropyran was used instead of N-methylpiperazine of step IV in example 1, and the compound (A-11) was isolated as a white solid in 86.9% yield. ESI-LC-MS:465.2[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.10(m,1H),2.60(m,4H),1.47(m,4H)。
Example 12:3- (3- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) ureido) -N- (1-methylpiperidin-4-yl) benzamide (A-12)
The preparation of the compound (A-12) was carried out in the same manner as in example 1 except that 4-amino-1-methylpiperidine was used instead of N-methylpiperazine in step IV of example 1, and the compound (A-12) was isolated as a white solid in a yield of 76.2%. ESI-LC-MS 478.2[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.10(m,1H),2.60(m,4H),1.47(m,4H),1.33(s,3H)。
Example 13:1- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) -3- (3- (4- (oxetan-3-yl) piperazine-1-carbonyl) phenyl) urea (A-13)
The compound (A-13) was produced in the same manner as in example 1 except that 1- (oxetan-3-yl) piperazine was used instead of N-methylpiperazine of step IV in example 1, and the compound (A-13) was isolated as a white solid in 55.1% yield. ESI-LC-MS 506.2[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.10(m,4H),2.60(m,4H),2.47(m,4H),2.33(m,1H),1.98(m,4H)。
Example 14:1- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) -3- (3- (4- (tetrahydro-2H-pyran-4-yl) piperazine-1-carbonyl) phenyl) urea (a-14)
The preparation of the (A-14) compound was carried out in the same manner as in example 1 except that 1- (tetrahydropyran-4-yl) piperazine was used instead of N-methylpiperazine of step IV in example 1, and the A-14 compound was isolated as a white solid in a yield of 56.8%. ESI-LC-MS 506.2[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.10(m,4H),2.60(m,4H),2.47(m,4H),2.33(m,1H),2.02(m,4H),1.98(m,4H)。
Example 15:1- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) -3- (3- (piperidine-1-carbonyl) phenyl) urea (A-15)
The compound (A-15) was produced in the same manner as in example 1 except that piperidine was used instead of N-methylpiperazine of step IV in example 1, and the compound A-15 was isolated as a white solid in 78.6% yield. ESI-LC-MS 449.2[ M+H ]] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.10(m,4H),2.60(m,4H),1.68(m,2H)。
Example 16:1- (4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) -3- (3- (piperidine-1-carbonyl) phenyl) urea (A-16)
The preparation of the (A-16) compound was carried out in the same manner as in example 1 except that 4, 4-difluoropiperidine was used instead of N-methylpiperazine in step IV of example 1, and the A-16 compound was isolated as a white solid in a yield of 70.9%. 485.2[ M+H ] ESI-LC-MS] + ， 1 H NMR(600MHz,DMSO-d 6 )δ9.70(s,1H),9.25(s,1H),8.15-8.19(m,3H),7.92(m,1H),7.76-7.82(m,3H),7.44(m,1H),7.32(m,1H),6.99(m,1H),3.79(s,3H),3.10(m,4H),2.60(m,4H)。
Synthesis of A-17 to A-48 in the same manner as in the above examples, except for 2- (4-fluoro-2-ethoxyphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan or 2- (4-fluoro-2-isopropoxyphenyl) bolane 4, 5-tetramethyl-1, 3, 2-dioxaborolan replaces 2- (4-fluoro-2-methoxyphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan.
The intermediates required for the synthesis of B-1 to B-48 are mentioned in patent CN202310816355.7, and the synthesis method of B-1 to B-48 is the same as that of the above examples.
Example 17: pharmacological Activity experiment
(1) Determination of the inhibition of CDK9/Cyclin T1 Complex by partial Compounds of the invention by ADP-Glo method (IC 50 )
The DMSO stock solution and CDK9/Cyclin T1 of the sample to be tested are diluted to target concentration by corresponding buffer solutions, the dilution of the compound is 10 concentration points according to 2-time concentration gradient, and the maximum concentration is 500nM. The compounds of the invention or DMSO blank are mixed with enzyme into 384 well plates, ATP is added to initiate kinase reaction with the substrate, and incubated for 60 minutes at room temperature. The kinase reaction was stopped by adding ADP-Glo reagent and the remaining ATP was consumed, and then the newly generated ATP was detected by adding kinase detection reagent, and the newly generated ATP content was detected by using a chemiluminescent detection module of a multifunctional microplate reader to reflect the degree of enzyme activity, and the results are shown in Table 1.
(2) Inhibition of proliferation of human blood tumor cells K562 and MV411, colorectal cancer cells HCT116 and HT29 by CCK-8 (GI 50 ) Performing detection
Cells were cultured to log phase using the corresponding medium and inoculated in 96 well plates at 5000/well for 24 hours at 37 ℃ after which DMSO stock dilutions of the samples to be tested were added at corresponding concentrations and a blank and positive control group were kept, each group being provided with three multiplex wells. After 48 hours incubation, 10 μl CCK-8 was added to each well and incubated for 3 hours, followed by measuring the absorbance at 450nm of each well with Emax Microplate Reader (Molecular Devices, sunnyvale, CA, USA) and calculating the cell viability inhibition rate from the blank group, the results are shown in tables 1-2.
(3) Experimental results
Table 1: inhibition of CDK9/Cyclin T1 complex, K562, MV411, HCT116 and HT29 cells by Compounds
Table 2: inhibition of CDK9/Cyclin T1 complex, K562, MV411, HCT116 and HT29 cells by Compounds
The test results in tables 1-2 show that: the derivative containing urea fragments shown in the general formula I has stronger activity of inhibiting CDK9 and other CDK subtype, is a series of CDKs inhibitors with brand-new structures, has stronger anti-tumor activity, and has stronger inhibition activity on cell proliferation of human blood tumor cells K562 and MV411 and colorectal cancer cells HCT116 and HT-29. Has potential application prospect and clinical research value.
It is apparent that the above examples are only illustrative of the present invention and are not limiting of the embodiments of the present invention. Various modifications and alterations of this invention may be made by those skilled in the art without departing from the spirit and scope of this invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.

Claims (6)

1. A CDKs inhibitor derivative containing a urea fragment or a pharmaceutically acceptable salt thereof, wherein the structure of the CDKs inhibitor derivative containing a urea fragment is shown as a general formula I:
wherein ring A is selected from aryl groups containing 6 to 12 carbon atoms or heteroaryl groups containing 5 to 12 ring atoms, the heteroaromatic ring of which optionally contains 1,2 or 3 heteroatoms selected from N, O, S;
ring B is selected from aryl groups containing 6 to 12 carbon atoms or heteroaryl groups containing 5 to 12 ring atoms, the heteroaromatic ring of which optionally contains 1,2 or 3 heteroatoms selected from N, O, S; or the B ring is selected from cycloalkyl 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, S;
R 1 selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo 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, cycloalkyl containing 3 to 10 carbon atoms, or heterocyclyl containing 3 to 10 ring atoms, the heterocycle of said heterocyclyl optionally containing 1,2, or 3 heteroatoms selected from N, O, S;
R 2 selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo 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, cycloalkyl containing 3 to 10 carbon atoms, or heterocyclyl containing 3 to 10 ring atoms, the heterocycle of said heterocyclyl optionally containing 1,2, or 3 heteroatoms selected from N, O, S; or R is 2 Selected from the group consisting of-CO-NR a R b ，R a 、R b Each independently selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Aminoalkyl, heterocyclyl having 3 to 12 ring atoms or heterocyclylalkyl, the heterocyclylheterocycle optionally having 1,2 or 3 heteroatoms selected from N, O, S, or R a 、R b Together with the N atom, form a heterocyclic group containing 3 to 12 ring atoms, the heterocyclic ring of the heterocyclic group optionally containing 1,2 or 3 heteroatoms selected from N, O, S;
x is selected from N or CH;
y is selected from N or C;
when Y is N, Z is absent; when Y is C, Z is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy groupHalogenated C 1 -C 6 An alkyl group.
2. The CDKs inhibitor derivative containing a urea fragment according to claim 1, or a pharmaceutically acceptable salt thereof, wherein in formula I, ring a is selected from aryl groups containing 6-8 carbon atoms or heteroaryl groups containing 5-9 ring atoms, optionally containing 1 or 2 or 3 heteroatoms selected from N, O, S; ring B is selected from aryl groups containing 6 to 8 carbon atoms or heteroaryl groups containing 5 to 9 ring atoms, the heteroaromatic ring of which optionally contains 1 or 2 or 3 heteroatoms selected from N, O, S; r is R 1 Selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, hydroxy, amino, C 1 -C 6 Alkylamino, C 1 -C 6 Acyl or cycloalkyl having 3 to 8 carbon atoms; r is R 2 Selected from the group consisting of-CO-NR a R b ，R a 、R b Each independently selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Aminoalkyl, heterocyclyl having 3 to 12 ring atoms or heterocyclylalkyl, the heterocyclylheterocycle optionally having 1,2 or 3 heteroatoms selected from N, O, S, or R a 、R b Together with the N atom, form a heterocyclic group containing 3 to 12 ring atoms, the heterocyclic ring of the heterocyclic group optionally containing 1,2 or 3 heteroatoms selected from N, O, S; x is CH; y is C; when Y is C, Z is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C 1 -C 6 An alkyl group.
3. The CDKs inhibitor derivative containing a urea fragment according to claim 1, or a pharmaceutically acceptable salt thereof, wherein in formula I, ring a is selected from aryl groups containing 6-7 carbon atoms or heteroaryl groups containing 6-9 ring atoms, optionally containing 1 or 2 or 3 heteroatoms selected from N, O; ring B is selected from aryl groups containing 6-8 carbon atoms; r is R 1 Selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or rings containing 3-8 carbon atomsAn alkyl group; r is R 2 Selected from the group consisting of-CO-NR a R b ，R a 、R b Each independently selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Aminoalkyl, heterocyclyl having 3 to 8 ring atoms or heterocyclylalkyl, the heterocyclylheterocycle optionally having 1,2 or 3 heteroatoms selected from N, O, or R a 、R b Together with the N atom, form a heterocyclic group containing 3 to 8 ring atoms, the heterocyclic ring of the heterocyclic group optionally containing 1,2 or 3 heteroatoms selected from N, O; x is CH; y is C; when Y is C, Z is selected from hydrogen, C 1 -C 6 An alkyl group.
4. The urea fragment-containing CDKs inhibitor derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural formula of the urea fragment-containing CDKs inhibitor derivative is as follows:
5. a pharmaceutical composition comprising a CDKs inhibitor derivative containing a urea fragment according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
6. Use of a CDKs inhibitor derivative containing a urea fragment according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 5 for the preparation of an antitumor drug.
CN202410002495.5A 2024-01-02 2024-01-02 CDKs inhibitor derivative containing urea fragment, and pharmaceutical composition and application thereof Pending CN117843563A (en)

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