CN113880816A - Piperazine-containing aminopyrimidine derivative and application thereof - Google Patents
Piperazine-containing aminopyrimidine derivative and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses piperazine-containing aminopyrimidine derivatives with a structure shown in a general formula I, which belong to kinase CDK4, CDK6 and/or CDK9 inhibitors, can be widely used for treating various cancers and have great clinical application value.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to an aminopyrimidine derivative containing piperazine and application thereof. In particular to a pyrimidine derivative and a pharmaceutically acceptable salt, ester or solvate thereof, belonging to a Cyclin Dependent Kinase (CDK) inhibitor, and a preparation method and a pharmaceutical application of the compound in preventing or treating diseases related to CDK.
Background
Cyclin-dependent kinases (CDKs) are a class of serine (Ser)/threonine (Thr) kinases that are important signal transduction molecules in cells, and CDK-cyclin complexes formed by cyclins, are involved in the growth, proliferation, dormancy or entry into apoptosis of cells. Wherein CDK4/6(cyclin-dependent kinase 4/6) regulates cell trafficking by binding to cyclin D (cyclin D)1The phase is switched to the S phase. Cell cycle runaway is an important factor in the development and progression of cancer, and CDK4/6 is a key factor in cell cycle runaway. Whereas CDK9 binding to cyclin T has been shown to be involved in cellular transcriptional regulation, inhibitors of CDK9 are believed to be useful in the treatment of a variety of cancers.
CDK binds to cyclins to form heterodimeric complexes that phosphorylate their substrates on serine and threonine residues, which in turn initiate events required for cell cycle transcription and progression. Since uncontrolled cellular proliferation is a hallmark of cancer, and most cancer cells exhibit dysregulation of CDKs, inhibition of CDKs has become a possible therapy for a wide variety of cancers, with selective inhibitors of CDK4/6 currently being viewed as a promising class of potential anti-cancer or anti-inflammatory agents, due to the important role of both CDK4/6 in regulating cellular proliferation and the toxic effects associated with inhibiting other members of the CDK family.
The cancer targeted therapy is an effective treatment scheme, has strong specificity and small toxic and side effects, basically does not damage normal tissues, and can more effectively provide further reference for the selection of clinical treatment schemes. With the deepening of pharmacological and molecular biological researches, the research and application of targeted drugs have made breakthrough progress, the research and development of new therapeutic target drugs have become a focus of attention of people, the cancer therapy is led to step into the personalized and precise era, and the good news is brought to more cancer patients. Compared with a plurality of existing antitumor drugs, the CDK small molecule inhibitor has more potential advantages when being applied to targeted anticancer treatment, and the risk of secondary tumor development can be reduced.
Most of CDK small molecule inhibitors disclosed in the prior art are CDK4/6 inhibitors, for example, the CDK4/6 inhibitors which are approved to be on the market are: palbociclib (pyroxene, approved by FDA at month 2 in 2015 and approved by CFDA at month 9 in 2018), Ribociclib (norway, approved by FDA at month 3 in 2017 and not yet approved by CFDA), Abemaciclib (gift, approved by FDA at month 10 in 2017 and not yet approved by CFDA). However, no CDK9 inhibitor has been approved for sale.
Through retrieval, patent documents related to Abemaciclib and structural modification and reconstruction around Abemaciclib specifically include:
the patent document with publication number WO 2010075074a1 (chinese family CN 102264725a) discloses a compound of structural formula 1, which is characterized in that: with frenum substituents R attached to amino groups of aminopyrimidines4The nitrogen-containing aromatic heterocycle of (1).
Patent publication No. CN 105294683a discloses a compound of structural formula 2, which is characterized by the following structural features: linked with amino in aminopyrimidine, is a B ring which is a para-substituted (disubstituted) benzene ring or a nitrogen-containing aromatic heterocycle.
the patent document with publication number WO 2016014904a1 (chinese family CN 106687454a) discloses compounds of structural formula 3 and structural formula 4, which are characterized by the following structural features: linked to the amino group of the aminopyrimidine, is a pyrimidine.
Several of the aforementioned patent documentsIn (b), only the activity inhibition data (IC) of some compounds on CDK4, CDK6 at the enzymatic or cellular level are disclosed50Value), no inhibition of activity was shown for CDK 9.
In addition, a patent related to phenylaminopyrimidine derivatives is searched, namely a patent document with publication number WO 2018019204A1 (Chinese family is CN 108602802A) discloses a compound with structural formula 5, which is characterized in that: with frenum substituents Y and R bound to amino groups of aminopyrimidines2The benzene ring of (2).
In conclusion, how to develop a novel CDK inhibitor, which has better activity inhibition effect on CDK4, CDK6 or CDK9 than Abemaciclib, is even effective on specific tumor diseases such as lung cancer, brain glioma and breast cancer, and on the basis of the activity inhibition effect, the development of the chinese innovative medicine with independent intellectual property rights is a technical problem which needs to be solved urgently by the technical personnel in the field.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a piperazine-containing aminopyrimidine derivative with a brand-new structure, which can inhibit the kinase activity of CDK4, CDK6 or CDK9 and has obvious antitumor activity.
In order to solve the technical problems, the invention adopts the following technical scheme:
an aminopyrimidine derivative containing piperazine is a compound shown as a formula I or a pharmaceutically acceptable salt thereof:
wherein W is selected from C1-C6Alkyl, - (CH)2)nCO(CH2)m-；
Ring A is substituted by one or more substituents R8Substituted piperazines, or substituted by one or more substituents R8Substituted piperazinones;
R1and R2Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl or halo C1-C6An alkoxy group;
R3、R4and R7Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, hydroxy, carboxy, cyano, amino, C1-C6Alkylamino, 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl;
R5、R6and R11Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, substituted or unsubstituted 5-to 12-membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
And, R5And R6Not hydrogen at the same time;
R8selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carbonyl, carboxyl, amino, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
R9And R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, or substituted or unsubstituted 5-to 12-membered heteroaryl;
the substituent on the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered aryl, 5-12 membered heteroaryl is selected from hydrogen, C1-C6Alkyl, hydroxy or amino;
m and n are each independently selected from 0,1, 2, 3, 4,5 or 6, and m and n are not both 0.
Preferably, the compound is represented by formula II or a pharmaceutically acceptable salt thereof:
wherein W is selected from C1-C6Alkyl, - (CH)2)nCO(CH2)m-；
Ring A is
R3And R4Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy or halo C1-C6An alkyl group;
R5and R6Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, substituted or unsubstituted 5-to 12-membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
And, R5And R6Not hydrogen at the same time;
R8selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
R9、R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, or substituted or unsubstituted 5-to 12-membered heteroaryl;
the substituent on the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered aryl, 5-12 membered heteroaryl is selected from hydrogen, C1-C6Alkyl, hydroxy or amino;
n is selected from 0,1, 2, 3, 4,5 or 6, and m is selected from 1, 2, 3, 4,5 or 6.
More preferably, it is a compound represented by formula IIa or a pharmaceutically acceptable salt thereof:
wherein W is selected from C1-C6Alkyl, - (CH)2)nCO(CH2)m-；
R3And R4Each independently selected from halogen, C1-C6Alkyl or halo C1-C6An alkyl group;
R5and R6Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, substituted or unsubstituted 5-to 12-membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
And, R5And R6Not hydrogen at the same time;
R8is selected from C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
R9、R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, or substituted or unsubstituted 5-to 12-membered heteroaryl;
the substituent on the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered aryl, 5-12 membered heteroaryl is selected from hydrogen, C1-C6Alkyl, hydroxy or amino;
n is selected from 0,1, 2, 3, 4,5 or 6, and m is selected from 1, 2, 3, 4,5 or 6.
More preferably, it is a compound represented by formula IIb or a pharmaceutically acceptable salt thereof:
wherein W is selected from C1-C6Alkyl, - (CH)2)nCO(CH2)m-；
R3And R4Each independently selected from halogen, C1-C6Alkyl or halo C1-C6An alkyl group;
R5and R6Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, substituted or unsubstituted 5-to 12-membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
And, R5And R6Not hydrogen at the same time;
R8selected from hydrogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
R9、R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, or substituted or unsubstituted 5-to 12-membered heteroaryl;
the substituent on the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered aryl, 5-12 membered heteroaryl is selected from hydrogen, C1-C6Alkyl, hydroxy or amino;
n is selected from 0,1, 2, 3, 4,5 or 6, and m is selected from 1, 2, 3, 4,5 or 6.
More preferably, it is a compound represented by formula III or a pharmaceutically acceptable salt thereof:
wherein R is3And R4Each independently selected from halogen, C1-C6Alkyl or halo C1-C6An alkyl group;
R5and R6Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, substituted or unsubstituted 5-to 12-membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
And, R5And R6Not hydrogen at the same time;
R8is selected from C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
R9、R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, or substituted or unsubstituted 5-to 12-membered heteroaryl;
R11selected from halogen, C1-C6Alkyl or halo C1-C6An alkyl group;
the substituent on the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered aryl and 5-12 membered heteroaryl is selected from hydrogen and C1-C6Alkyl, hydroxy or amino;
n is selected from 0,1, 2, 3, 4,5 or 6, and m is selected from 1, 2, 3, 4,5 or 6.
Preferably, halogen is F or Cl; the 3-10 membered heterocyclic group and the 5-12 membered heteroaryl group contain one or more heteroatoms, and the heteroatoms are N, O, S.
An aminopyrimidine derivative containing piperazine, which is selected from compounds with the following structures or pharmaceutically acceptable salts thereof, wherein the compounds are numbered from BT-A-1-0, BT-A-1 to BT-A-14:
the term "compound" as used herein includes all stereoisomers, geometric isomers, tautomers and isotopes.
The "compounds" of the present invention may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the invention containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The "compound" of the present invention also includes tautomeric forms. Tautomeric forms result from the exchange of one single bond with an adjacent double bond and the concomitant migration of one proton.
The solvent compound of the compound is selected from hydrate, ethanol compound, methanol compound, acetone compound, diethyl ether compound or isopropanol compound.
The invention also includes all isotopic atoms, whether in the intermediate or final compound. Isotopic atoms include those having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.
Compounds containing the foregoing general structure, the terms used herein have the following meanings:
the term "hydroxy" refers to-OH.
The term "carboxyl" refers to-COOH.
The term "carbonyl" refers to-CO.
The term "cyano" refers to — CN.
The term "halogen" denotes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
The term "alkyl" denotes a straight or branched chain saturated aliphatic hydrocarbon radical consisting of carbon and hydrogen atoms, such as C1-C20Alkyl, preferably C1-C6Alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl, isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylhexyl, and the like.
The term "alkoxy" refers to a straight or branched chain alkyl group attached through an oxygen atom, such as C1-C6Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy (including n-propoxy, isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, tert-butoxy), pentoxy (including n-pentoxy, isopentoxy, neopentoxy), n-hexoxy, 2-methylhexoxy, and the like.
The term "amino" refers to the group-NH2。
The term "alkylamino" refers to an open-chain alkyl group containing a nitrogen atom, such as C1-C6Alkylamino groups, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, and the like.
The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or polycyclic alkyl group consisting of carbon and hydrogen atoms, and which may be attached to the remainder of the molecule by a single bond via any suitable carbon atom; when polycyclic, they may be fused, bridged or spiro. In one aspect, typical monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "heterocycloalkyl" refers to a saturated cyclic group having heteroatoms, the group containing 1 or more heteroatoms independently selected from N, O, S, the remainder being carbon-containing groups of a stable 3-to 10-membered saturated heterocyclic ring system. Unless otherwise specifically indicated in the specification, a heterocycloalkyl group may be a monocyclic, bicyclic, or polycyclic ring system; when polycyclic, they may be fused, bridged or spiro. In one aspect, typical 4-6 membered monocyclic heterocycloalkyl groups containing 1 or more heteroatoms independently selected from N, O, S include, but are not limited to
And the like. In one aspect, typical 7-10 membered bicyclic heterocycloalkyl groups containing 1 or more heteroatoms independently selected from N, O, S include, but are not limited to
And the like.
The term "aryl" refers to an all-carbon aromatic group having a fully conjugated pi-electron system, which may be a single ring or a fused ring, generally having 6 to 14 carbon atoms, preferably having 6 to 12 carbon atoms, and most preferably having 6 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "heteroaryl" refers to an aromatic group containing a heteroatom, which may be a single ring or a fused ring, preferably containing 1-4 5-12 membered heteroaryl groups independently selected from N, O, S, including but not limited to pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, indolyl, and the like. In one aspect, typical 5-6 membered monocyclic heteroaryl groups containing 1 or more heteroatoms independently selected from N, O, S include, but are not limited to
And the like.
The term "halo C1-C6Alkyl group "," halogeno C1-C6Alkoxy "refers to a group in which one or more (especially 1 to 3) hydrogensThe atoms being substituted by halogen atoms, in particular fluorine or chlorine atoms.
In the present invention, the terms "comprising" and "comprises" are open-ended and not closed-ended, i.e. comprise what is indicated in the present invention, but do not exclude other aspects.
In the present invention, when a substituent is not specifically indicated in the listed groups, such a group means only unsubstituted. For example when "C1-C6When an alkyl group is "without the limitation of" substituted or unsubstituted ", it means only" C1-C6Alkyl "by itself or unsubstituted C1-C6Alkyl groups ".
Linking substituents are described herein and when the structure clearly requires a linking group, the markush variables listed for that group are to be understood as linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
In some specific structures, when an alkyl group is expressly indicated as a linking group, then the alkyl group represents a linked alkylene group, e.g., the group "halo C1-C6C in alkyl1-C6Alkyl is understood to mean C1-C6An alkylene group.
The present invention employs conventional methods of mass spectrometry, elemental analysis, and the various steps and conditions can be referred to those conventional in the art unless otherwise indicated.
It will be understood by those skilled in the art that, in accordance with the convention used in the art, the structural formulae used in describing groups in the present invention
Means that the corresponding group is linked to other fragments, groups in the compound through this site.
The above preferred conditions can be combined arbitrarily to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The invention also provides a preparation method of the piperazine-containing aminopyrimidine derivative, which comprises the following steps: under the protection of nitrogen, respectively adding the intermediate A, the intermediate B, an alkali reagent and a palladium catalyst into a reaction solvent, and carrying out coupling reaction to obtain a final product with a structure shown in a formula I. The reaction formula is as follows:
the invention also provides a pharmaceutical composition, which comprises the compound or the pharmaceutically acceptable salt or the solvate thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.
"pharmaceutical composition" as used herein, refers to a formulation of one or more compounds of the present invention or salts thereof with a carrier generally accepted in the art for delivery of biologically active compounds to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate delivery of the drug to an organism.
The term "pharmaceutically acceptable carrier" refers to a substance that is co-administered with, and facilitates the administration of, an active ingredient, including, but not limited to, any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is acceptable for human or animal (e.g., livestock) use as permitted by the drug administration. For example, including but not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
The pharmaceutical composition can be prepared into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powder, granules, paste, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.
The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
The route of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof includes, but is not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral.
For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient. For example, for pharmaceutical compositions intended for oral administration, tablets may be obtained in the following manner: the active ingredient is combined with one or more solid carriers, the resulting mixture is granulated if necessary, and processed into a mixture or granules, if necessary with the addition of small amounts of excipients, to form tablets or tablet cores. The core may be combined with an optional enteric coating material and processed into a coated dosage form more readily absorbed by an organism (e.g., a human).
The invention also provides the use of a compound or pharmaceutical composition as hereinbefore described in the manufacture of a medicament for the prophylaxis or treatment of a disease mediated by Cyclin Dependent Kinase (CDK) activity.
Preferably, the pharmaceutical use is for the prevention or treatment of a disease associated with altered CDK4, CDK6 or CDK9 activity.
More preferably, the pharmaceutical use is for preventing or treating cancer, including but not limited to breast cancer, lung cancer, intestinal cancer, small cell lung cancer, melanoma, glioma, lymphoma, prostate cancer, rectal cancer, pancreatic cancer, liver cancer, stomach cancer, bladder cancer, ovarian cancer, mantle cell lymphoma, acute myelogenous leukemia or chronic myelogenous leukemia.
Compared with the prior art, the piperazine-containing aminopyrimidine derivative is scientifically and reasonably designed based on a target, and a series of compounds with novel structures are obtained through substitution modification of groups; and a series of compounds with anti-tumor activity are optimally screened by combining the evaluation of in vitro and in vivo experiments, the compounds can be effective on CDK4 or CDK6, part of the compounds show better activity in cancers such as lung cancer, breast cancer, glioma and the like, are better than the CDK inhibitor of Abemaciclib, have great clinical application value on the prevention or treatment of the cancers, and have considerable market potential.
Detailed Description
The following are specific examples of the present invention and further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
Mutexample 1 compound BT-a-1: 1- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amine) phenyl) piperazin-2-one
The synthesis route of the compound BT-A-1 is as follows:
intermediate A1(322mg,1mmol), intermediate B1(323mg,1mmol), cesium carbonate (651mg,2mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (Xantphos,116mg,0.2mmol) were dissolved in 1, 4-dioxane (10mL), and tris (dibenzylideneacetone) dipalladium (Pd) was added under nitrogen protection2(dba)3183mg,0.2mmol), reaction at 90 ℃ for 3 hours until completion, cooling the reaction solution to room temperature, pouring into 10mL of water, extracting with ethyl acetate three times (30 mL. times.3), combining the organic phases, washing the organic phase with saturated brine (50mL), drying over anhydrous sodium sulfate, filtering, spinning off and purifying the solid with a silica gel column (DCM: CH)3OH ═ 20:1) to give a yellow solid, the precursor target compound BT-a-1-0(317mg, 52%), and the compound BT-a-1-0 was deprotected to the Boc protecting group with TFA/DCM to give the target compound BT-a-1(265mg, 100%).
MS(m/z)：510.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.04(s,1H),8.69(d,J＝3.6Hz,1H),8.24(d,J＝1.2Hz,1H),7.83(dd,J＝13.2,2.0Hz,1H),7.66(d,J＝12.0Hz,1H),7.52(dd,J＝8.4,2.0Hz,1H),7.22(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),4.51(s,2H),3.28(s,2H),3.21-3.15(m,3H),2.87(t,J＝5.6Hz,2H),2.65(s,3H),1.62(d,J＝6.8Hz,6H)。
The synthetic route of intermediate a1 is as follows:
step 1: synthesis of isopropyl acetamide (3)
Isopropylamine (1,59.1g,1mol), triethylamine (101.2g,1mol) were dissolved in dichloromethane (DCM,300mL) and acetic anhydride (2,102.1g,1mol) was added dropwise at-10 ℃ and after addition, the mixture was allowed to warm to room temperature to react, after which the reaction was completed, the solvent was distilled off under reduced pressure, ethyl acetate (500mL) and potassium carbonate (200g) were added, the mixture was stirred for 3 hours, filtered under suction, and the solvent was distilled off under reduced pressure to give an oil, i.e., Compound 3(93.2g, 92.1%).
MS(m/z)：102.1[M+H]+。
Step 2: synthesis of N' - (4-bromo-2-6-difluorophenyl) -N-isopropylacetamidine (5)
Dissolving 4-bromo-2, 6-difluoroaniline (4,20.56g,98.9mmol) and isopropylacetamide (3,20g,197.7mmol) in toluene (150mL), cooling to-10 deg.C, and adding dropwise phosphorus oxychloride (POCl) under nitrogen protection322.7g,148.3mmol), triethylamine (15.0g,148.3mmol) is added dropwise, the mixture is moved into an oil bath pot after the addition, and the mixture is heated and refluxed for reaction for 3 hours at 115 ℃. The reaction solution was cooled to room temperature, poured into a saturated aqueous sodium bicarbonate solution (3000mL), ethyl acetate was added, liquid separation was performed after thorough mixing, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with a saturated saline solution (200mL),dry over anhydrous sodium sulfate, filter, concentrate, and slurry wash with petroleum ether (100mL) for 1 hour, filter, and dry the filter cake to give compound 5(24.2g, 84.1%) as a solid.
MS(m/z)：291.0[M+H]+。
And step 3: synthesis of 1-isopropyl-2-methyl-4-fluoro-6-bromo-1H-benzo [ d ] imidazole (6)
Compound 5(24.2g,83.1mmol) was dissolved in N, N-dimethylformamide (DMF,120mL), potassium tert-butoxide (10.3g,91.4mmol) was added at 0 deg.C, and the mixture was heated to 110 deg.C under nitrogen for 2 hours. The reaction was cooled to room temperature and poured into water (700mL), extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated and washed with petroleum ether (100mL) slurry for 1 hour, filtered and the filter cake dried to give compound 6(20.0g, 88.9%) as a solid.
MS(m/z)：271.0[M+H]+。
And 4, step 4: synthesis of 1-isopropyl-2-methyl-4-fluoro-6-boronic acid pinacol ester-1H-benzo [ d ] imidazole (8)
Compound 6(9.7g,35.8mmol), pinacol ester bisboronic acid (7, B)2(pin)213.6g,53.7mmol), Tricyclohexylphosphine (PCy)31.71g,6.1mmol) and potassium acetate (10.5g,107.2mmol) were dissolved in dimethyl sulfoxide (DMSO, 100mL), and palladium acetate (Pd (OAc) was added under nitrogen protection20.80g,3.6mmol), and the temperature is raised to 80 ℃ for reaction for 4 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was poured into water (300mL), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column separation (PE/EA ═ 4:1) to obtain compound 8(7.64g, 67%) as a solid.
MS(m/z)：319.2[M+H]+。
And 5: synthesis of 1-isopropyl-2-methyl-4-fluoro-6- (2-chloro-5-fluoropyrimidin-4-yl) -1H-benzo [ d ] imidazole (A1)
2, 4-dichloro-5-fluoropyrimidine (9,3.23g,19.36mmol), sodium carbonate (3.66g,34.57mmol) were dissolved in 1, 4-dioxane/water (18mL/4.5mL), and bis-triphenylphosphine palladium dichloride (Pd (PPh) was added under nitrogen protection3)2Cl20.29g, 0.42mmol), literAfter the mixture was warmed to 80 ℃ and a solution of Compound 8(4.4g,13.83mmol) in 1, 4-dioxane (22.5mL) was added dropwise, the reaction was carried out at 80 ℃ for 5 hours. The reaction was cooled to room temperature, poured into ice water (100mL), and a white solid precipitated, filtered to give a residue, and slurried with isopropanol to give compound a1(3.5g, 78.5%).
MS(m/z)：323.1[M+H]+。
The synthetic route of intermediate B2 is as follows:
step 1 Synthesis of 2-fluoro-4-nitrobenzol (11)
2-fluoro-4-nitrobenzoic acid (10,9.25g,50mmol) was dissolved in tetrahydrofuran (30mL), cooled to-15 deg.C, stirred for 10 min and BH was added slowly3The THF solution (1mol/L,150mL,150mmol) was transferred to room temperature for 2 hours after completion of the dropwise addition. After completion of the reaction, the reaction solution was quenched by slowly pouring methanol (50mL) and the organic phase was concentrated to give compound 11(7.7g, 90%) as a white solid.
MS(m/z)：170.2[M-H]-。
Step 2: synthesis of methyl 2-fluoro-4-nitrophenyl-4-methylbenzenesulfonate (12)
Compound 11(3.42g,20mmol) was dissolved in dichloromethane (20mL), triethylamine (4.04g,40mmol) and 4-methylbenzenesulfonyl chloride (5.72g,30mmol) were added, and the reaction was carried out at room temperature under nitrogen for 2 hours. After completion of the reaction, 5mL of water was added to the reaction mixture, and the organic phase was separated, dried over saturated brine and anhydrous sodium sulfate, and concentrated to give compound 12(5.85g, 90%) as a yellow oil.
MS(m/z)：326.3[M+H]+。
And step 3: synthesis of tert-butyl 4- (2-fluoro-4-nitrophenyl) -3-piperazinone-1-carboxylate (13)
Compound 12(1.63g,5mmol) was dissolved in acetonitrile (10mL), triethylamine (757mg,7.5mmol) and tert-butyl 3-piperazinone-1-carboxylate (1.50g,7.5mmol) were added, and the reaction was allowed to proceed overnight at room temperature under nitrogen. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, the reaction mixture was washed with water (10mL), extracted three times (20 mL. times.3) with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate with saturated brine, and the organic phase was concentrated to give compound 13(1.62g, 92%) as a yellow oil.
MS(m/z)：239.2[M+H]+。
And 4, step 4: synthesis of tert-butyl 4- (2-fluoro-4-aminophenyl) -3-piperazinone-1-carboxylate (B1)
Compound 13(1.41g,4mmol) was dissolved in a mixed solvent of 12mL of ethanol and 4mL of water, and ammonium chloride (384mg,7.2mmol) and reduced iron powder (1.57g,28mmol) were added thereto, followed by heating to 80 ℃ for reaction for 2 hours. After the reaction is completed, the system is cooled, filtered, and the filter residue is washed by ethanol. The filtrate was concentrated and saturated potassium carbonate solution was added to adjust the pH to alkaline. Extraction was carried out three times (20 mL. times.3) by adding ethyl acetate, the organic phases were combined, saturated brine and anhydrous sodium sulfate were added to dry, and the organic phase was concentrated to give a yellow oil, Compound B1(1.12g, 87%).
MS(m/z)：324.3[M+H]+。
Mutexample 2 compound BT-a-2: 4- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzoyl) piperazine-1-carboxylic acid ethyl ester
The synthesis route of the compound BT-A-2 is as follows:
referring to the synthesis of BT-A-1 of mut mutexample 1, a yellow solid, compound BT-A-2, is obtained.
MS(m/z)：582.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.25(s,1H),8.73(d,J＝3.6Hz,1H),8.22(s,1H),7.98(dd,J＝13.2,2.0Hz,1H),7.66(d,J＝12.0Hz,1H),7.55(dd,J＝8.4,2.0Hz,1H),7.34(t,J＝8.2Hz,1H),4.85(p,J＝6.8Hz,1H),4.06(q,J＝6.4Hz,2H),3.68-3.62(m,2H),3.50-3.28(m,6H),2.65(s,3H),1.62(d,J＝6.8Hz,6H),1.18(t,J＝6.4Hz,3H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B2 is as follows:
step 1 Synthesis of Ethyl 4- (2-fluoro-4-nitrophenyl) piperazine-1-carboxylate (14)
2-fluoro-4-nitrobenzoic acid (10,1.85g,10mmol) was dissolved in 30mL DMF and CDI (1.64g,10mmol) was added slowly and reacted at 70 ℃ for 2 h under nitrogen. After completion of the reaction, the temperature was lowered to room temperature, morpholine (0.96g,11mmol) was slowly added, and the reaction was carried out at 40 ℃ for 2 hours. After completion of the reaction, water (50mL) was poured into the reaction mixture, ethyl acetate was added thereto and extracted three times (20mL × 3), the organic phases were combined, saturated brine and anhydrous sodium sulfate were added thereto and dried, and the organic phase was concentrated to obtain a dark brown oil, i.e., compound 14(2.76g, 85%).
MS(m/z)：324.3[M-H]-。
Step 2: synthesis of Ethyl 4- (2-fluoro-4-aminophenyl) piperazine-1-carboxylate (B2)
Compound 14(1.63g,5mmol) was dissolved in a mixed solvent of 12mL of ethanol and 4mL of water, ammonium chloride (481mg,9.0mmol) and reduced iron powder (1.96g,35mmol) were added, and the mixture was heated to 80 ℃ to react for 2 hours. After the reaction is completed, the system is cooled, filtered, and the filter residue is washed by ethanol. The filtrate was concentrated and saturated potassium carbonate solution was added to adjust the pH to alkaline. The combined organic phases were extracted three times with ethyl acetate (20 mL. times.3), saturated brine and anhydrous sodium sulfate were added to dry, and the organic phase was concentrated to give compound B2(1.37g, 93%) as a yellow oil.
MS(m/z)：296.2[M+H]+。
Mutexample 3 compound BT-a-3: 4-nitrophenyl 4- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzoyl) piperazine-1-carboxylate
The synthesis route of the compound BT-A-3 is as follows:
with reference to the procedure for the synthesis of BT-A-1 of mut mutexample 1, the compound BT-A-3-0 was obtained.
The compound BT-A-3-0(124mg,0.24mmol) was dissolved in anhydrous DCM (10mL), TEA (303mg,3mmol) was added, p-nitrophenyl chloroformate (123mg,0.61mmol) was slowly added dropwise, and after the addition was complete, nitrogen was sufficiently replaced. Reacting for 1.5 hours at room temperature under the protection of nitrogen, and adding saturated NaHCO after the reaction is completed3The solution (10mL) was stirred, DCM was used for extraction, the organic phases were combined, the mixture was dried over saturated brine and anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column (DCM: CH)3OH ═ 20:1) to give the target compound BT-a-3(150mg, 91%) as a yellow solid.
MS(m/z)：675.2[M+H]+。
1H NMR(400MHz,Chloroform-d)δppm 8.44(d,J＝3.6Hz,1H),8.28(s,1H),8.26(s,1H),8.22(s,1H),8.10(d,J＝9.2Hz,1H),7.97(d,J＝12.4Hz,1H),7.86(d,J＝11.2Hz,1H),7.64(s,1H),7.43(t,J＝8.0Hz,1H),7.31(s,1H),7.09(d,J＝9.2Hz,1H),4.80(p,J＝6.8Hz,1H),3.95-3.85(m,2H),3.81-3.61(m,4H),3.55-3.46(m,2H),2.82(s,3H),1.75(d,J＝6.8Hz,6H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B3 is as follows:
reference examples2B 2, step 1 only
By replacement with
The remaining procedure was as in B2 of example 2 to give compound B3 as a yellow oil.
MS(m/z)：324.2[M+H]+。
Mutexample 4 compound BT-a-4: isopropyl 2- (4- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzoyl) piperazin-1-yl) ethyl ester
The synthesis route of the compound BT-A-4 is as follows:
with reference to the synthesis of BT-A-3 of mutexample 3, only
By replacement with
The target compound BT-A-4 is obtained as a yellow solid.
MS(m/z)：596.4[M+H]+。
1H NMR(400MHz,Chloroform-d)δppm 8.42(d,J＝3.6Hz,1H),8.21(d,J＝1.2Hz,1H),7.97(d,J＝11.6Hz,1H),7.79(d,J＝11.2Hz,1H),7.57(s,1H),7.39(t,J＝8.0Hz,1H),7.25(td,J＝8.4,2.0Hz,1H),4.95(p,J＝6.4Hz,1H),4.75(p,J＝6.8Hz,1H),3.85-3.75(m,2H),3.63-3.55(m,2H),3.50-3.45(m,2H),3.43-3.35(m,2H),2.73(s,3H),1.72(d,J＝7.2Hz,6H),1.26(d,J＝6.4Hz,6H)。
Mutexample 5 compound BT-a-5: 4- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amine) phenyl) piperazine-1-carboxylic acid methyl ester
The synthesis route of the compound BT-A-5 is as follows:
referring to the synthesis of BT-A-1 of mut mutexample 1, a yellow solid, compound BT-A-5, is obtained.
MS(m/z)：568.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.25(s,1H),8.73(d,J＝3.6Hz,1H),8.22(d,J＝1.2Hz,1H),7.98(dd,J＝13.2,2.0Hz,1H),7.66(d,J＝12.0Hz,1H),7.55(dd,J＝8.4,2.0Hz,1H),7.35(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),3.68-3.60(m,5H),3.50-3.20(m,6H),2.65(s,3H),1.62(d,J＝6.8Hz,6H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B4 is as follows:
referring to the synthesis of B2 of example 2, only step 1 would be
By replacement with
The remaining procedure was as in B2 of example 2 to give compound B4 as a yellow oil.
MS(m/z)：282.2[M+H]+。
Mutexample 6 compound BT-a-6: n-hexyl 2- (4- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzoyl) piperazin-1-yl) ethyl ester
The synthesis route of the compound BT-A-6 is as follows:
with reference to the synthesis of BT-A-3 of mutexample 3, only
By replacement with
The target compound BT-A-6 is obtained as a yellow solid.
MS(m/z)：638.4[M+H]+。
1H NMR(400MHz,Chloroform-d)δppm 8.42(d,J＝3.6Hz,1H),8.22(d,J＝1.2Hz,1H),7.96(dd,J＝12.0,2.0Hz,1H),7.81(d,J＝11.2Hz,1H),7.55(s,1H),7.39(t,J＝8.0Hz,1H),7.24(td,J＝8.8,2.0Hz,1H),4.77(p,J＝6.8Hz,1H),4.10(t,J＝6.8Hz,2H),3.84-3.76(m,2H),3.64-3.56(m,2H),3.52-3.45(m,2H),3.44-3.36(m,2H),3.14-3.07(m,6H),2.77(s,3H),1.73(d,J＝6.8Hz,6H),1.68-1.60(m,2H),0.94-0.85(t,J＝6.4Hz,3H)。
Mutexample 7 compound BT-a-7: ethyl 2- (4- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzoyl) piperazin-1-yl) ethyl ester
The synthesis route of the compound BT-A-7 is as follows:
with reference to the procedure for the synthesis of BT-A-1 of mut mutexample 1, the compound BT-A-3-0 was obtained.
The compound BT-A-3-0(1.20g,2.36mmol) was dissolved in anhydrous DMF (10mL), potassium carbonate (488mg,3.54mmol) was added, ethyl bromomethylacetate (472mg,2.83mmol) was slowly added dropwise, and after completion of the addition, nitrogen was sufficiently replaced. After completion of the reaction at 70 ℃ for 2 hours under nitrogen atmosphere, 10mL of water was added, the mixture was stirred, DCM was mutextracted, the organic phases were combined, dried over saturated saline and anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by a silica gel column (PE/EA/TEA ═ 5:5:1) to obtain the objective compound BT-a-7(1.20g, 85.5%) as a yellow solid.
MS(m/z)：596.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.25(s,1H),8.73(d,J＝3.6Hz,1H),8.22(s,1H),7.97(dd,J＝13.2,2.0Hz,1H),7.66(d,J＝12.0Hz,1H),7.54(dd,J＝8.4,2.0Hz,1H),7.31(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),4.09(q,J＝7.2Hz,2H),3.70-3.60(m,2H),3.32-3.25(m,6H),2.65(s,3H),2.61-2.55(s,2H),1.62(d,J＝6.8Hz,6H),1.19(t,J＝7.2Hz,3H)。
Mutexample 8 compound BT-a-8: 4- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzoyl) -N-methylpiperazine-1-carboxamide
The synthesis route of the compound BT-A-8 is as follows:
with reference to the synthesis of BT-A-3 of mutexample 3, only
By replacement with
A yellow solid is obtained, i.e.The target compound BT-A-8.
MS(m/z)：567.3[M+H]+。
1H NMR(400MHz,Chloroform-d)δppm 8.41(d,J＝3.6Hz,1H),8.20(d,J＝1.2Hz,1H),7.97(dd,J＝12.4,2.0Hz,1H),7.76(d,J＝11.6Hz,1H),7.59(s,1H),7.38(t,J＝8.0Hz,1H),7.23(td,J＝8.4,2.0Hz,1H),4.74(p,J＝6.8Hz,1H),4.60(d,J＝5.2Hz,1H),3.81(s,2H),3.55-3.42(m,6H),2.84(d,J＝4.4Hz,3H),2.70(s,3H),1.71(d,J＝6.8Hz,6H)。
Mutexample 9 compound BT-a-9: n-ethyl-4- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzoyl) piperazine-1-carboxamide
The synthesis route of the compound BT-A-9 is as follows:
with reference to the synthesis of BT-A-3 of mutexample 3, only
By replacement with
The target compound BT-A-9 is obtained as a yellow solid.
MS(m/z)：581.2[M+H]+。
1H NMR(400MHz,Chloroform-d)δppm 8.41(d,J＝3.6Hz,1H),8.20(d,J＝1.2Hz,1H),7.97(dd,J＝12.4,2.0Hz,1H),7.78(d,J＝11.6Hz,1H),7.52(s,1H),7.39(t,J＝8.0Hz,1H),7.24(t,J＝8.8,2.4Hz,1H),4.74(p,J＝6.8Hz,1H),4.55-4.45(m,1H),3.82(s,2H),3.47-3.40(m,6H),3.30-3.26(m,2H),2.72(s,3H),1.72(d,J＝6.8Hz,6H),1.16(t,J＝7.2Hz,3H)。
Mutexample 10 compound BT-a-10: 4- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzoyl) -N, N-dimethylpiperazine-1-carboxamide
The synthesis route of the compound BT-A-10 is as follows:
with reference to the synthesis of BT-A-3 of mutexample 3, only
By replacement with
The target compound BT-A-10 is obtained as a yellow solid.
MS(m/z)：581.3[M+H]+。
1H NMR(400MHz,Chloroform-d)δppm 8.40(d,J＝3.6Hz,1H),8.21(d,J＝1.2Hz,1H),7.96(dd,J＝12.4,2.0Hz,1H),7.77(dd,J＝9.6,1.6Hz,2H),7.37(t,J＝8.0Hz,1H),7.24(dd,J＝8.4,2.0Hz,1H),4.75(p,J＝6.8Hz,1H),3.82(t,J＝4.8Hz,2H),3.46-3.40(m,2H),3.34(t,J＝5.2Hz,2H),3.26-3.20(m,2H),2.87(s,6H),2.71(s,3H),1.72(d,J＝6.8Hz,6H)。
Mutexample 11 Compound BT-A-11: 1- (4-ethylpiperazin-1-yl) -2- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amine) phenyl) acetyl-1-one
The synthesis route of the compound BT-A-11 is as follows:
referring to the synthesis of BT-A-1 of mut mutexample 1, a yellow solid, compound BT-A-11, is obtained.
MS(m/z)：552.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 9.96(s,1H),8.68(d,J＝4.0Hz,1H),8.22(d,J＝1.2Hz,1H),7.79(dd,J＝13.2,2.0Hz,1H),7.66(d,J＝12.0Hz,1H),7.45(dd,J＝8.4,2.0Hz,1H),7.15(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),3.66(s,2H),3.51-3.45(m,4H),2.65(s,3H),2.46-2.18(m,6H),1.62(d,J＝6.8Hz,6H),1.10-0.95(m,3H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B5 is as follows:
referring to the synthesis of B2 of example 2, only step 1 would be
By replacement with
The remaining procedure was as in B2 of example 2 to give compound B5 as a yellow oil.
MS(m/z)：266.3[M+H]+。
Mutexample 12 compound BT-a-12: n- (4-bromo-3- (4-ethylpiperazin-1-yl) -5-fluorophenyl) -5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
The synthesis route of the compound BT-A-12 is as follows:
with reference to the synthesis method of BT-A-1 of mut mutexample 1, a yellow solid, i.e., the target compound BT-A-12, can be obtained.
MS(m/z)：588.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.09(s,1H),8.71(d,J＝3.6Hz,1H),8.17(s,1H),7.70(m,2H),7.43(s,1H),4.85(p,J＝6.8Hz,1H),3.00(m,4H),2.65(s,3H),2.54(m,4H),2.40(q,J＝7.2Hz,2H),1.61(d,J＝6.8Hz,6H),1.04(t,J＝7.2Hz,3H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B6 is as follows:
step 1: synthesis of 1- (2-bromo-3-fluoro-5-nitrophenyl) -4-ethylpiperazine (19)
2-bromo-1, 3-difluoronitrobenzene (19,2.37g,10mmol) was dissolved in 20mL DMF and triethylamine (1.52g,15mmol) was added and the reaction was allowed to proceed overnight at 65 ℃. After completion of the reaction, the reaction mixture was slowly washed with water (50mL), extracted three times with ethyl acetate (20 mL. times.3), the organic phases were combined, saturated brine and anhydrous sodium sulfate were added to dry, and the organic phase was concentrated to give compound 21(1.49g, 45.0%) as a reddish brown solid.
MS(m/z)：332.2[M+H]+。
Step 2: synthesis of 1- (2-bromo-3-fluoro-5-aminophenyl) -4-ethylpiperazine (B6)
Compound 20(993mg,3mmol) was dissolved in a mixed solvent of 12mL of ethanol and 4mL of water, and ammonium chloride (288mg,5.4mmol) and reduced iron powder (1.176g,21mmol) were added thereto, followed by heating to 80 ℃ for reaction for 2 hours. After the reaction is completed, cooling the system, carrying out suction filtration, concentrating the filtrate, adding a saturated potassium carbonate solution, and adjusting; the pH is changed to alkaline. The combined organic phases were extracted three times with ethyl acetate (20 mL. times.3), dried with saturated brine, anhydrous sodium sulfate and concentrated to give compound B7(815mg, 90%) as a yellow oil.
MS(m/z)：302.3[M+H]+。
Inhibition of CDK4 and CDK6 kinases by the compounds of example 13
The compound of the invention is dissolved in DMSO to prepare a stock solution with the concentration of 1000. mu.M. mu.L of the stock solution was diluted stepwise with a proportion of 60. mu.L DMSO to 10 concentrations of compound. 100 μ L of DMSO was added to two empty wells as a no compound control and a no enzyme control. Prepare an intermediate plate, add 10. mu.L of sample solution of different concentrations to the intermediate plate, add 90. mu.L of kinase buffer, mix well with shaking. The appropriate amounts of CDK4, CDK6, and CDK9 kinase were diluted 2.5 times the final concentration with buffer, and the fluorescently labeled peptide and ATP were diluted 2.5 times the final concentration with 1 × kinase buffer, respectively.
To a 384 well plate, 10. mu.L of diluted kinase and 5. mu.L of sample solution at different concentrations were added, and the no compound control and no enzyme control groups were replaced with 10% DMSO, respectively. After 1 hour of incubation at room temperature, 10. mu.L of the diluted fluorescent-labeled peptide and ATP were added to the reaction system, and the mixture was incubated at room temperature for 30 minutes. Add 25. mu.L of stop assay buffer. The fluorescence intensity (emission wavelength: 445nm and 520nm, excitation wavelength: 400nm) was measured with a microplate reader, and IC was calculated with Graphpad Prism V5.0 software50The value is obtained.
Inhibitory activity of compounds of the invention against CDK4 and CDK6 kinases, the results are given in the table below.
Inhibition of CDK4 and CDK6 Activity by Compounds of the invention
| Compound (I) | CDK4 kinase IC50(nM) | CDK6 kinase IC50(nM) |
| Abemaciclib | 2.6 | 18 |
| BT-A-1-0 | <2 | <10 |
| BT-A-1 | <2 | <10 |
From the above table, it can be seen that the compound of the present invention has a strong inhibitory effect on the kinase activity of one or more of CDK4 and CDK6 kinases, and the inhibitory effect is better than that of positive control Abemaciclib.
EXAMPLE 14 SRB assay for inhibition of cancer cell proliferation by Compounds
Measuring proliferation inhibition activity of tested compound and positive control drug Abemaciclib on human breast cancer cell MCF-7, human brain glioma cell U87-MG and human brain glioma cell A172 by using sulforhodamine B (SRB) cell proliferation and toxicity detection kit, wherein IC is used for the activity50The values are represented.
The experimental scheme is as follows: taking cells in logarithmic growth phase, and preparing into 2 × 10 cells by conventional digestion4The cell suspension/mL, was inoculated into a 96-well plate at 100. mu.L/well, and then placed at 37 ℃ in 5% CO2And culturing in a saturated humidity incubator for 12 hours, and adding the tested compounds with different concentration gradients. Placing at 37 ℃ and 5% CO2Culturing in an incubator with saturated humidity for 72 hours; the test compound OD was determined by the SRB method, following strictly the SRB kit instructions, and IC was calculated using GraphPad Prim5.0 software50Values, results are given in the table below.
Inhibition of various cancer cells by the compounds of the Invention (IC)50 nM)
Note: NA means not tested.
As can be seen from the above table, the compound has a strong inhibition effect on the proliferation of one or more of breast cancer cells MCF-7, glioma cells U87-MG and glioma cells A172, and the inhibition effect is better than that of positive control drug Abemaciclib.
Example 15 CCK-8 assay of inhibition of proliferation of Small cell Lung cancer cells
The Cell Counting Kit-8(CCK-8) Cell proliferation and toxicity detection Kit is adopted to measure the proliferation inhibition activity of the tested compound and the positive control drug Abemaciclib on the human small Cell lung cancer Cell H69, and the IC is used for the activity50The values are represented.
The experimental scheme is as follows: taking a certain amount of cells, inoculating to 96-well culture plate with each well at 100 μ L, and placing at 37 deg.C with 5% CO2And culturing in a saturated humidity incubator for 12 hours, and adding the tested compounds with different concentration gradients. Placing at 37 ℃ and 5% CO2Culturing in an incubator with saturated humidity for 72 hours; adding 10 μ L CCK-8 solution, incubating for 2 hr, measuring OD value at 450nm wavelength with microplate reader, and calculating IC with GraphPad Prim5.0 software50Values, results are given in the table below.
Inhibitory Effect (IC) of the Compound of the present invention on Small cell Lung cancer cell line H6950 nM)
| Compound (I) | Small cell lung carcinoma cell H69 |
| Abemaciclib | 469.70 |
| BT-A-1-0 | <200 |
| BT-A-1 | <200 |
| BT-A-4 | <300 |
| BT-A-3 | <400 |
| BT-A-5 | <100 |
| BT-A-7 | <100 |
| BT-A-8 | <200 |
| BT-A-9 | <300 |
| BT-A-10 | <50 |
| BT-A-11 | <50 |
| BT-A-12 | <200 |
As can be seen from the table, the compound of the invention has strong inhibition effect on cell proliferation in small cell lung cancer cells H69, and the inhibition effect is better than that of positive control drug Abemaciclib.
Claims (12)
1. An aminopyrimidine derivative containing piperazine is a compound shown as a formula I or a pharmaceutically acceptable salt thereof:
wherein W is selected from C1-C6Alkyl, - (CH)2)nCO(CH2)m-；
Ring A is substituted by one or more substituents R8Substituted piperazines, or substituted by one or more substituents R8Substituted piperazinones;
R1and R2Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl or halo C1-C6An alkoxy group;
R3、R4and R7Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, hydroxy, carboxy, cyano, amino, C1-C6Alkylamino, 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl;
R5、R6and R11Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, substituted or unsubstituted 5-to 12-membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
And, R5And R6Not hydrogen at the same time;
R8selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carbonyl, carboxyl, amino, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
R9And R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, or substituted or unsubstituted 5-to 12-membered heteroaryl;
the substituent on the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered aryl and 5-12 membered heteroaryl is selected from hydrogen and C1-C6Alkyl, hydroxy or amino;
m and n are each independently selected from 0,1, 2, 3, 4,5 or 6, and m and n are not both 0.
2. The piperazine-containing aminopyrimidine derivative according to claim 1 is a compound of formula ii or a pharmaceutically acceptable salt thereof:
wherein W is selected from C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,-(CH2)nCO(CH2)m-；
Ring A is
R3And R4Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy or halo C1-C6An alkyl group;
R5and R6Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, substituted or unsubstituted 5-to 12-membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
And, R5And R6Not hydrogen at the same time;
R8selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
R9、R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered ringAn alkyl group, a substituted or unsubstituted 3-10 membered heterocycloalkyl group, a substituted or unsubstituted 5-12 membered aryl group, or a substituted or unsubstituted 5-12 membered heteroaryl group;
the substituent on the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered aryl and 5-12 membered heteroaryl is selected from hydrogen and C1-C6Alkyl, hydroxy or amino;
n is selected from 0,1, 2, 3, 4,5 or 6, and m is selected from 1, 2, 3, 4,5 or 6.
3. The piperazine-containing aminopyrimidine derivative according to claim 2 is a compound of formula ila:
wherein W is selected from C1-C6Alkyl, - (CH)2)nCO(CH2)m-；
R3And R4Each independently selected from halogen, C1-C6Alkyl or halo C1-C6An alkyl group;
R5and R6Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, substituted or unsubstituted 5-to 12-membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
And, R5And R6Is not simultaneouslyHydrogen;
R8is selected from C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
R9、R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, or substituted or unsubstituted 5-to 12-membered heteroaryl;
the substituent on the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered aryl and 5-12 membered heteroaryl is selected from hydrogen and C1-C6Alkyl, hydroxy or amino;
n is selected from 0,1, 2, 3, 4,5 or 6, and m is selected from 1, 2, 3, 4,5 or 6.
4. The piperazine-containing aminopyrimidine derivative according to claim 2 is a compound of formula IIb or a pharmaceutically acceptable salt thereof:
wherein W is selected from C1-C6Alkyl, - (CH)2)nCO(CH2)m-；
R3And R4Each independently selected from halogen, C1-C6Alkyl or halo C1-C6An alkyl group;
R5and R6Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, substituted or unsubstituted 5-to 12-membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
And, R5And R6Not hydrogen at the same time;
R8selected from hydrogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
R9、R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, or substituted or unsubstituted 5-to 12-membered heteroaryl;
the substituent on the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered aryl and 5-12 membered heteroaryl is selected from hydrogen and C1-C6Alkyl, hydroxy or amino;
n is selected from 0,1, 2, 3, 4,5 or 6, and m is selected from 1, 2, 3, 4,5 or 6.
5. An aminopyrimidine derivative containing piperazine, which is a compound represented by formula III or a pharmaceutically acceptable salt thereof:
wherein R is3And R4Each independently selected from halogen, C1-C6Alkyl or halo C1-C6An alkyl group;
R5and R6Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, substituted or unsubstituted 5-to 12-membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
And, R5And R6Not hydrogen at the same time;
R8is selected from C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10；
R9、R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, or substituted or unsubstitutedUnsubstituted 5-12 membered heteroaryl;
R11selected from halogen, C1-C6Alkyl or halo C1-C6An alkyl group;
the substituent on the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered aryl and 5-12 membered heteroaryl is selected from hydrogen and C1-C6Alkyl, hydroxy or amino;
n is selected from 0,1, 2, 3, 4,5 or 6, and m is selected from 1, 2, 3, 4,5 or 6.
6. A piperazine-containing aminopyrimidine derivative according to any one of claims 1 to 4, wherein the halogen is F or Cl; the 3-10-membered heterocyclic group and the 5-12-membered heteroaryl group contain one or more heteroatoms, and the heteroatoms are N, O, S.
7. An aminopyrimidine derivative containing piperazines selected from compounds of the following structure or pharmaceutically acceptable salts thereof:
8. a pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, as an active ingredient, together with one or more pharmaceutically acceptable carriers.
9. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 in the manufacture of a medicament for the prevention or treatment of a disease mediated by cyclin dependent kinase activity.
10. The use according to claim 9 wherein the cyclin dependent kinase activity-mediated disorder is a disorder associated with altered CDK4, CDK6 or CDK9 activity.
11. The use according to claim 10, wherein the disease is cancer.
12. The use according to claim 11, wherein the cancer is selected from breast cancer, lung cancer, intestinal cancer, small cell lung cancer, melanoma, glioma, lymphoma, prostate cancer, rectal cancer, pancreatic cancer, liver cancer, stomach cancer, bladder cancer, ovarian cancer, mantle cell lymphoma, acute myelogenous leukemia or chronic myelogenous leukemia.
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