CN113880813A - 2-aminopyrimidine heterocyclic compound and application thereof - Google Patents

2-aminopyrimidine heterocyclic compound and application thereof Download PDF

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CN113880813A
CN113880813A CN202010615654.0A CN202010615654A CN113880813A CN 113880813 A CN113880813 A CN 113880813A CN 202010615654 A CN202010615654 A CN 202010615654A CN 113880813 A CN113880813 A CN 113880813A
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楼金芳
冯恩光
刘嘉诚
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Hangzhou Bio Sincerity Pharma Tech Co ltd
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Abstract

The invention discloses a 2-aminopyrimidine heterocyclic compound with a structure shown in a general formula I and application thereof, belongs to kinase CDK4, CDK6 and/or CDK9 inhibitors, can be widely used for treating various cancers, and has great clinical application value.

Description

2-aminopyrimidine heterocyclic compound and application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to a 2-aminopyrimidine heterocyclic compound 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) kinase, an important signal transduction molecule in cells, and a CDK-cyclin complex formed by cyclins, are involved in the growth, proliferation, dormancy or 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).
Figure BDA0002563657710000021
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.
Figure BDA0002563657710000022
Wherein ring B is selected from:
Figure BDA0002563657710000023
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.
Figure BDA0002563657710000024
In the aforementioned patent documents, only the activity inhibition data (IC) of some compounds on CDK4 and CDK6 at the enzymatic or cellular level are disclosed50Value), no inhibition of activity was shown for CDK 9.
In addition, a related phenylaminopyrimidine derivative is also searchedThe patent of (1), namely the patent document with publication number WO 2018019204a1 (chinese family is CN 108602802a), discloses a compound of structural formula 5, which is characterized in that: with frenum substituents Y and R bound to amino groups of aminopyrimidines2The benzene ring of (2).
Figure BDA0002563657710000025
Wherein Y is H or selected from the following structures:
Figure BDA0002563657710000026
Figure BDA0002563657710000031
(double bond or triple bond structure with unsaturated bond). However, this patent is an improvement over the third generation EGFR inhibitor AZD9291, whose activity test data indicate efficacy against EGFR and wild-type EGFR, and no knowledge of whether CDK4, CDK6, or CDK9 is effective.
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 invention aims to solve the technical problem of providing a 2-aminopyrimidine heterocyclic compound 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:
a2-aminopyrimidine heterocyclic compound is a compound shown as a formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0002563657710000032
wherein W is selected from a single bond and C1-C6Alkyl, - (CH)2)nO(CH2)m-、-(CH2)nCO(CH2)m-、-(CH2)nNH(CH2)m-or- (CH)2)nNHCO(CH2)m-；
Ring A is substituted by one or more substituents R8Substituted 3-to 10-membered cycloalkyl, substituted by one or more substituents R8Substituted 3-10 membered heterocycloalkyl, substituted by one or more substituents R8Substituted 5-12 membered aryl, or substituted by one or more substituents R8Substituted 5-12 membered heteroaryl, but excluding piperazine;
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, carboxy, 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.
Preferably, the compound is represented by formula II or a pharmaceutically acceptable salt thereof:
Figure BDA0002563657710000041
wherein W is selected from a single bond and C1-C6Alkyl, - (CH)2)nO(CH2)m-、-(CH2)nCO(CH2)m-、-(CH2)nNH(CH2)m-or- (CH)2)nNHCO(CH2)m；
Ring A is
Figure BDA0002563657710000042
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, carboxy, amino, - (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;
3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered arylThe substituent on the 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.
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.
A2-aminopyrimidine heterocyclic compound is selected from compounds with the following structures or pharmaceutically acceptable salts thereof, wherein the compounds are numbered from BT-B-1 to BT-B-16:
Figure BDA0002563657710000051
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
Figure BDA0002563657710000061
Figure BDA0002563657710000071
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
Figure BDA0002563657710000072
Figure BDA0002563657710000073
Figure BDA0002563657710000074
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 thatIn one embodiment, typical 5-6 membered monocyclic heteroaryl groups containing 1 or more heteroatoms independently selected from N, O, S include, but are not limited to
Figure BDA0002563657710000075
Figure BDA0002563657710000076
And the like.
The term "halo C1-C6Alkyl group "," halogeno C1-C6Alkoxy "means a group in which one or more (especially 1 to 3) hydrogen atoms are replaced 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 the "used in describing the structural formulae of the groups in the present invention means that the corresponding group is attached to other fragments, groups in the compound through the site, according to the convention used in the art.
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 2-aminopyrimidine heterocyclic compound, 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:
Figure BDA0002563657710000081
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 2-aminopyrimidine heterocyclic compound is scientifically and reasonably designed based on a target, and a series of compounds with novel structures are obtained through substituent 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.
Example 1 compound BT-B-1: n- (3-fluoro-4-piperidin-methyl) phenyl) -5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
Figure BDA0002563657710000101
The synthesis route of the compound BT-B-1 is as follows:
Figure BDA0002563657710000102
intermediate A1(322mg,1mmol), intermediate B1(208mg,1mmol), cesium carbonate (651mg,2mmol), 4, 5-bisDiphenylphosphine-9, 9-Dimethylxanthene (Xantphos,116mg,0.2mmol) was 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 the target compound BT-B-1(257mg, 52%) as a yellow solid.
MS(m/z)：495.3[M+H]+。
1HNMR(400MHz,DMSO-d6)δppm 9.98(s,1H),8.68(d,J＝3.6Hz,1H),8.24(s,1H),7.78(dd,J＝12.8,2.0Hz,1H),7.66(d,J＝12.0Hz,1H),7.47(dd,J＝8.4,2.0Hz,1H),7.27(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),3.42(s,2H),2.65(s,3H),2.33(m,4H),1.62(d,J＝6.8Hz,6H),1.48(m,4H),1.37(m,2H)。
The synthetic route of intermediate a1 is as follows:
Figure BDA0002563657710000103
Figure BDA0002563657710000111
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 ℃. After the reaction solution was cooled to room temperature, it was 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), dried over anhydrous sodium sulfate, filtered, concentrated and then washed with petroleum ether (100mL) for 1 hour, filtered, and the filter cake was dried to obtain a solid, i.e., Compound 5(24.2g, 84.1%).
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. Cooling the reaction solution to room temperature, pouring the reaction solution into water (300mL), extracting with ethyl acetate, combining organic phases, washing the organic phases with saturated saline (100mL), drying the organic phases with anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by using a silica gel column (PE/EA is 4:1) to obtain the compoundTo solid, compound 8(7.64g, 67%).
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), and a solution of Compound 8(4.4g,13.83mmol) in 1, 4-dioxane (22.5mL) was added dropwise at 80 ℃ and reacted 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 B1 is as follows:
Figure BDA0002563657710000121
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 1- (2-fluoro-4-nitrophenyl) piperidine (13)
Compound 12(1.63g,5mmol) was dissolved in acetonitrile (10mL), triethylamine (757mg,7.5mmol) and piperidine (639mg,7.5mmol) were added, and the mixture was reacted at room temperature under nitrogen atmosphere overnight. 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(1.1g, 92%) as a yellow oil.
MS(m/z)：239.2[M+H]+。
And 4, step 4: synthesis of 1- (2-fluoro-4-aminophenyl) piperidine (B1)
Compound 13(952mg,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, 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. Extraction was carried out 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 B1(724mg, 87%) as a yellow oil.
MS(m/z)：209.2[M+H]+。
Example 2 compound BT-B-2: n- (4- ((4-dimethylamino) piperidin-1-yl) methyl) -3-fluorophenyl) -5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
Figure BDA0002563657710000131
The synthesis route of the compound BT-B-2 is as follows:
Figure BDA0002563657710000132
with reference to the synthesis of BT-B-1 of example 1, a yellow solid, the target compound BT-B-2, was obtained.
MS(m/z)：538.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.00(s,1H),8.69(d,J＝4.0Hz,1H),8.23(d,J＝0.8Hz,1H),7.79(dd,J＝12.8,2.0Hz,1H),7.66(d,J＝12.0Hz,1H),7.47(dd,J＝8.8,2.4Hz,1H),7.27(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),3.43(s,2H),2.85(m,2H),2.65(s,3H),2.16(s,6H),2.03(m,1H),1.93(m,2H),1.69(m,2H),1.62(d,J＝6.8Hz,6H),1.35(m,2H)。
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:
Figure BDA0002563657710000141
referring to the synthesis of B1 of example 1, only step 3 will be
Figure BDA0002563657710000142
By replacement with
Figure BDA0002563657710000143
The remaining procedure was as in B1 of example 1 to give compound B2 as a yellow oil.
MS(m/z)：252.3[M+H]+。
Example 3 compound BT-B-3: n- (3-fluoro-4- (morpholin-1-ylmethyl) phenyl) -5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
Figure BDA0002563657710000144
The synthesis route of the compound BT-B-3 is as follows:
Figure BDA0002563657710000145
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-3, can be obtained.
MS(m/z)：497.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.00(s,1H),8.68(d,J＝3.6Hz,1H),8.23(s,1H),7.81(dd,J＝13.2Hz,2.0Hz,1H),7.66(d,J＝12.0Hz,1H),7.48(dd,J＝8.4Hz,2.0Hz,1H),7.29(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),3.56(t,J＝4.4Hz,4H),3.46(s,2H),2.65(s,3H),2.37(t,J＝4.4Hz,4H),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 B3 is as follows:
Figure BDA0002563657710000151
referring to the synthesis of B1 of example 1, only step 3 will be
Figure BDA0002563657710000152
By replacement with
Figure BDA0002563657710000153
The remaining procedure was as in B1 of example 1 to give compound B3 as a yellow oil.
MS(m/z)：211.2[M+H]+。
Example 4 compound BT-B-4: n- (4- ((4, 4-difluoropiperidin-1-yl) methyl) -3-fluorophenyl) -5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
Figure BDA0002563657710000154
The synthesis route of the compound BT-B-4 is as follows:
Figure BDA0002563657710000155
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-4, can be obtained.
MS(m/z)：531.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.02(s,1H),8.69(d,J＝3.6Hz,1H),8.23(d,J＝1.6Hz,1H),7.82(dd,J＝13.2,2.4Hz,1H),7.66(d,J＝12.8Hz,1H),7.48(dd,J＝8.4,2.0Hz,1H),7.30(t,J＝8.4Hz,1H),4.85(p,J＝7.2Hz,1H),3.56(s,2H),2.65(s,3H),2.51(m,4H),1.95(m,4H),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:
Figure BDA0002563657710000161
referring to the synthesis of B1 of example 1, only step 3 will be
Figure BDA0002563657710000162
By replacement with
Figure BDA0002563657710000163
The remaining procedure was as in B1 of example 1 to give compound B4 as a yellow oil.
MS(m/z)：245.2[M+H]+。
Example 5 compound BT-B-5: n- (1- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzyl) piperidin-4-yl) acetamide
Figure BDA0002563657710000164
The synthesis route of the compound BT-B-5 is as follows:
Figure BDA0002563657710000165
with reference to the synthesis method of BT-B-1 of example 1, the target compound BT-B-5 can be obtained as a yellow solid.
MS(m/z)：552.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.00(s,1H),8.68(d,J＝3.6Hz,1H),8.24(d,J＝1.2Hz,1H),7.80(dd,J＝12.8,2.0Hz,1H),7.74(d,J＝7.6Hz,1H),7.66(d,J＝12.4Hz,1H),7.47(dd,J＝8.4,2.0Hz,1H),7.27(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),3.48(m,1H),3.44(s,2H),2.76(m,2H),2.65(s,3H),2.01(m,2H),1.77(s,3H),1.69(m,2H),1.62(d,J＝6.8Hz,6H),1.34(m,2H)。
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:
Figure BDA0002563657710000171
referring to the synthesis of B1 of example 1, only step 3 will be
Figure BDA0002563657710000172
By replacement with
Figure BDA0002563657710000173
The remaining procedure was as in B1 of example 1 to give compound B5 as a yellow oil.
MS(m/z)：266.3[M+H]+。
Example 6 Compound BT-B-6: 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) -N- (3-fluoro-4- (pyrrolidin-1-ylmethyl) phenyl) pyrimidin-2-amine
Figure BDA0002563657710000174
The synthesis route of the compound BT-B-6 is as follows:
Figure BDA0002563657710000175
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-6, can be obtained.
MS(m/z)：481.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 9.99(s,1H),8.69(d,J＝4.0Hz,1H),8.23(d,J＝1.2Hz,1H),7.80(dd,J＝13.2,2.0Hz,1H),7.66(d,J＝12.4Hz,1H),7.46(dd,J＝8.4,2.0Hz,1H),7.29(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),3.56(s,2H),2.65(s,3H),2.44(m,4H),1.67(m,4H),1.62(d,J＝7.2Hz,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 B6 is as follows:
Figure BDA0002563657710000181
referring to the synthesis of B1 of example 1, only step 3 will be
Figure BDA0002563657710000182
By replacement with
Figure BDA0002563657710000183
The remaining procedure was as in B1 of example 1 to give compound B6 as a yellow oil.
MS(m/z)：195.2[M+H]+。
Example 7 compound BT-B-7: 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) -N- (3-fluoro-4- (methylthiomorpholine) phenyl) pyrimidin-2-amine
Figure BDA0002563657710000184
The synthesis route of the compound BT-B-7 is as follows:
Figure BDA0002563657710000185
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-7, can be obtained.
MS(m/z)：513.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.01(s,1H),8.69(d,J＝3.6Hz,1H),8.23(d,J＝1.2Hz,1H),7.81(dd,J＝13.2,2.4Hz,1H),7.66(d,J＝12.4Hz,1H),7.48(dd,J＝8.0,2.0Hz,1H),7.28(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),3.50(s,2H),2.61(m,11H),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 B7 is as follows:
Figure BDA0002563657710000191
referring to the synthesis of B1 of example 1, only step 3 will be
Figure BDA0002563657710000192
By replacement with
Figure BDA0002563657710000193
The remaining procedure was as in B1 of example 1 to give compound B7 as a yellow oil.
MS(m/z)：227.2[M+H]+。
Example 8 Compound BT-B-8: 1- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzyl) piperidin-3-ol
Figure BDA0002563657710000194
The synthesis route of the compound BT-B-8 is as follows:
Figure BDA0002563657710000195
with reference to the synthesis of BT-B-1 of example 1, a yellow solid, the target compound BT-B-8, was obtained.
MS(m/z)：511.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.69(d,J＝3.6Hz,1H),8.24(d,J＝1.2Hz,1H),7.79(dd,J＝12.8,2.0Hz 1H),7.66(d,J＝12.0Hz,1H),7.47(dd,J＝8.4,2.0Hz,1H),7.27(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),4.57(d,J＝5.2Hz,1H),3.44(m,3H),3.07-3.00(m,2H),2.79(m,1H),2.65(m,5H),1.86(m,1H),1.71(m,2H),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 B8 is as follows:
Figure BDA0002563657710000201
referring to the synthesis of B1 of example 1, only step 3 will be
Figure BDA0002563657710000202
By replacement with
Figure BDA0002563657710000203
The remaining procedure was as in B1 of example 1 to give compound B8 as a yellow oil.
MS(m/z)：225.2[M+H]+。
Example 9 compound BT-B-9: 1- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzyl) piperidin-4-ol
Figure BDA0002563657710000204
The synthesis route of the compound BT-B-9 is as follows:
Figure BDA0002563657710000205
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-9, can be obtained.
MS(m/z)：511.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.00(s,1H),8.69(d,J＝3.6Hz,1H),8.24(d,J＝1.6Hz,1H),7.80(d,J＝2.4Hz,1H),7.66(d,J＝12.0Hz,1H),7.47(dd,J＝8.4,2.0Hz,1H),7.27(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),4.53(d,J＝4.4Hz,1H),3.44(s,3H),2.65(m,5H),2.05(m,2H),1.68(m,2H),1.62(d,J＝6.8Hz,6H),1.37(m,2H)。
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 B9 is as follows:
Figure BDA0002563657710000211
referring to the synthesis of B1 of example 1, only step 3 will be
Figure BDA0002563657710000212
By replacement with
Figure BDA0002563657710000213
The remaining procedure was as in B1 of example 1 to give compound B9 as a yellow oil.
MS(m/z)：225.2[M+H]+。
Example 10 compound BT-B-10: 2- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amine) phenyl) -1-morpholineacetyl-1-one
Figure BDA0002563657710000214
The synthesis route of the compound BT-B-10 is as follows:
Figure BDA0002563657710000215
with reference to the synthesis method of BT-B-1 of example 1, the target compound BT-B-10 was obtained as a yellow solid.
MS(m/z)：525.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 9.98(s,1H),8.68(d,J＝3.6Hz,1H),8.22(d,J＝1.2Hz,1H),7.81(dd,J＝13.2,2.0Hz,1H),7.66(d,J＝12.0Hz,1H),7.45(dd,J＝8.4,2.0Hz,1H),7.16(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),3.68(s,2H),3.61-3.53(m,6H),3.47-3.45(m,2H),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 B10 is as follows:
Figure BDA0002563657710000221
step 1 Synthesis of 2- (2-fluoro-4-nitrophenyl) -1-morpholinoethyl-1-one (22)
2-fluoro-4-nitrophenylacetic acid (10,1.99g,10mmol) was dissolved in 30mL of DMF and CDI (1.64g,10mmol) was added slowly and reacted at 70 ℃ for 2 hours 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 22(2.28g, 85%).
MS(m/z)：269.2[M-H]-。
Step 2: synthesis of 2- (2-fluoro-4-aminophenyl) -1-morpholinoethyl-1-one (B10)
Compound 22(1.34g,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), dried with saturated brine, anhydrous sodium sulfate and concentrated to give compound B10(1.10g, 93%) as a yellow oil.
MS(m/z)：239.3[M+H]+。
Example 11 Compound BT-B-11: 7- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzyl) -7-azaspiro [3.5] non-2-one
Figure BDA0002563657710000222
The synthesis route of the compound BT-B-11 is as follows:
Figure BDA0002563657710000231
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-11, can be obtained.
MS(m/z)：549.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.01(s,1H),8.69(d,J＝3.6Hz,1H),8.23(d,J＝1.2Hz,1H),7.80(dd,J＝12.8,2.0Hz,1H),7.66(d,J＝12.0Hz,1H),7.47(dd,J＝8.4,2.0Hz,1H),7.29(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),3.46(s,2H),2.74(m,4H),2.65(s,3H),2.35(m,4H),1.66(t,J＝5.6Hz,4H),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 B11 is as follows:
Figure BDA0002563657710000232
referring to the synthesis of B1 of example 1, only step 3 will be
Figure BDA0002563657710000233
By replacement with
Figure BDA0002563657710000234
The remaining procedure was as in B1 of example 1 to give compound B11 as a yellow oil.
MS(m/z)：263.2[M+H]+。
Example 12 compound BT-B-12: 1- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzyl) piperidin-4-one
Figure BDA0002563657710000235
The synthesis route of the compound BT-B-12 is as follows:
Figure BDA0002563657710000241
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-12, can be obtained.
MS(m/z)：509.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.03(s,1H),8.70(d,J＝4.0Hz,1H),8.23(d,J＝1.2Hz,1H),7.84(dd,J＝13.2,2.0Hz,1H),7.67(d,J＝12.0Hz,1H),7.50(dd,J＝8.4,2.0Hz,1H),7.36(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),3.63(s,2H),2.71(t,J＝6.0Hz,4H),2.65(s,3H),2.35(t,J＝6.0Hz,4H),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 B12 is as follows:
Figure BDA0002563657710000242
referring to the synthesis of B1 of example 1, only step 3 will be
Figure BDA0002563657710000243
By replacement with
Figure BDA0002563657710000244
The remaining procedure was as in B1 of example 1 to give compound B12 as a yellow oil.
MS(m/z)：223.2[M+H]+。
Example 13 Compound BT-B-13: n- (4- ((3, 3-difluoroazapyridin-1-yl) methyl) -3-fluorophenyl) -5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
Figure BDA0002563657710000245
The synthesis route of the compound BT-B-13 is as follows:
Figure BDA0002563657710000251
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-13, can be obtained.
MS(m/z)：503.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.05(s,1H),8.70(d,J＝3.6Hz,1H),8.22(d,J＝1.2Hz,1H),7.85(dd,J＝13.2,2.4Hz,1H),7.66(d,J＝12.0Hz,1H),7.48(dd,J＝8.4,2.0Hz,1H),7.31(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),3.70(s,2H),3.61(t,J＝12.4Hz,4H),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 B13 is as follows:
Figure BDA0002563657710000252
referring to the synthesis of B1 of example 1, only step 3 will be
Figure BDA0002563657710000253
By replacement with
Figure BDA0002563657710000254
The remaining procedure was as in B1 of example 1 to give compound B13 as a yellow oil.
MS(m/z)：217.1[M+H]+。
Example 14 Compound BT-B-14: (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) phenyl) (morpholine) methanone
Figure BDA0002563657710000255
The synthesis route of the compound BT-B-14 is as follows:
Figure BDA0002563657710000261
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-14, can be obtained.
MS(m/z)：511.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.26(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＝8.0Hz,1H),4.85(p,J＝6.8Hz,1H),3.64(m,4H),3.55(m,2H),3.30(s,2H),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 B14 is as follows:
Figure BDA0002563657710000262
referring to the synthesis of B10 of example 10, only step 1 will be
Figure BDA0002563657710000263
By replacement with
Figure BDA0002563657710000264
The rest of the procedure was the same as B10 in example 10, to give compound B14 as a yellow oil.
MS(m/z)：225.2[M+H]+。
Example 15 Compound BT-B-15: 1- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzyl) piperidine-4-carboxamide
Figure BDA0002563657710000265
The synthesis route of the compound BT-B-15 is as follows:
Figure BDA0002563657710000271
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-15, can be obtained.
MS(m/z)：538.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.01(s,1H),8.69(d,J＝4.0Hz,1H),8.24(d,J＝1.2Hz,1H),7.80(dd,J＝13.2,2.0Hz,1H),7.66(d,J＝12.0Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),7.28(t,J＝8.5Hz,1H),7.20(s,1H),6.72(s,1H),4.85(p,J＝6.8Hz,1H),3.44(s,2H),3.06-3.00(m,1H),2.82(d,J＝11.2Hz,2H),2.65(s,3H),1.97-1.88(m,2H),1.62(d,J＝6.8Hz,6H),1.66-1.49(m,4H)。
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 B15 is as follows:
Figure BDA0002563657710000272
referring to the synthesis of B1 of example 1, only step 3 will be
Figure BDA0002563657710000273
By replacement with
Figure BDA0002563657710000274
The remaining procedure was as in B1 of example 1 to give compound B15 as a yellow oil.
MS(m/z)：252.2[M+H]+。
Example 16 compound BT-B-16: n- (3-fluoro-4- ((4-methyl-1, 4-diazepan-1-yl) methyl) phenyl) -5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
Figure BDA0002563657710000281
The synthesis route of the compound BT-B-16 is as follows:
Figure BDA0002563657710000282
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-16, can be obtained.
MS(m/z)：524.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.00(s,1H),8.68(d,J＝3.6Hz,1H),8.24(d,J＝1.2Hz,1H),7.78(dd,J＝13.2,2.0Hz,1H),7.66(d,J＝12.0Hz,1H),7.48(dd,J＝8.4,2.0Hz,1H),7.32(t,J＝8.4Hz,1H),4.85(p,J＝6.8Hz,1H),3.58(s,2H),2.59(m,11H),2.23(s,3H),1.70(p,J＝6.0Hz,2H),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 B16 is as follows:
Figure BDA0002563657710000283
referring to the synthesis of B1 of example 1, only step 3 will be
Figure BDA0002563657710000284
By replacement with
Figure BDA0002563657710000285
The remaining procedure was as in B1 of example 1 to give compound B16 as a yellow oil.
MS(m/z)：238.3[M+H]+。
Inhibition of CDK4 and CDK6 kinases by the compounds of example 17
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. Termination of additionAssay buffer 25. mu.L. 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-B-1 0.79 1.8
BT-B-3 1.5 7.4
BT-B-4 3.8 ND
BT-B-5 1.3 3.5
BT-B-6 1.1 2.0
BT-B-7 2.2 21
Note: ND means not measured.
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 18 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)
Compound (I) Breast cancer cell MCF-7 Glioma cell U87-MG Glioma cell A172
Abemaciclib 180.90 612.70 251.80
BT-B-1 <50 <10 <10
BT-B-2 <50 <1 <1
BT-B-3 <50 <50 <10
BT-B-4 <50 <500 <10
BT-B-5 <10 <100 <10
BT-B-6 <10 <10 <10
BT-B-7 <50 <300 <10
BT-B-8 <10 <10 <1
BT-B-9 <50 <10 <10
BT-B-10 <50 <100 <50
BT-B-11 <10 <10 <10
BT-B-12 <10 <10 <1
BT-B-13 <50 <10 <10
BT-B-14 <50 <50 <10
BT-B-15 <10 <1 <1
BT-B-16 <50 <10 <1
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 19 CCK-8 assay of inhibition of proliferation of Small cell Lung cancer cells by Compounds
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; addingAdding 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)
Figure BDA0002563657710000301
Figure BDA0002563657710000311
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 (9)

1. A2-aminopyrimidine heterocyclic compound is a compound shown as a formula I or a pharmaceutically acceptable salt thereof:
Figure FDA0002563657700000011
wherein W is selected from a single bond and C1-C6Alkyl, - (CH)2)nO(CH2)m-、-(CH2)nCO(CH2)m-、-(CH2)nNH(CH2)m-or- (CH)2)nNHCO(CH2)m-；
Ring A is substituted by one or more substituents R8Substituted 3-to 10-membered cycloalkyl, substituted by one or more substituents R8Substituted 3-10 membered heterocycloalkyl, substituted by one or more substituents R8Substituted 5-12 membered aryl, or substituted by one or more substituents R8Substituted 5-12 membered heteroaryl, but excluding piperazine;
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, carboxy, 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.
2. The heterocyclic compound of 2-aminopyrimidine according to claim 1, which is a compound of formula ii or a pharmaceutically acceptable salt thereof:
Figure FDA0002563657700000021
wherein W is selected from a single bond and C1-C6Alkyl, - (CH)2)nO(CH2)m-、-(CH2)nCO(CH2)m-、-(CH2)nNH(CH2)m-or- (CH)2)nNHCO(CH2)m；
Ring A is
Figure FDA0002563657700000022
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 5-12 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, carboxy, amino, - (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;
m and n are each independently selected from 0,1, 2, 3, 4,5 or 6.
3. The heterocyclic compound of 2-aminopyrimidine according to claim 1 or 2 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.
4. A2-aminopyrimidine heterocyclic compound selected from compounds of the following structures or pharmaceutically acceptable salts thereof:
Figure FDA0002563657700000031
5. a pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, as an active ingredient, together with one or more pharmaceutically acceptable carriers.
6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 in the manufacture of a medicament for the prevention or treatment of a disease mediated by cyclin dependent kinase activity.
7. The use according to claim 6 wherein the cyclin dependent kinase activity-mediated disorder is a disorder associated with altered CDK4, CDK6 or CDK9 activity.
8. The use according to claim 7, wherein the disease is cancer.
9. The use according to claim 8, wherein the cancer is selected from the group consisting of 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 and chronic myelogenous leukemia.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102007124A (en) * 2008-02-15 2011-04-06 里格尔制药公司 Pyrimidine-2-amine compounds and their use as inhibitors of jak kinases
US20130310340A1 (en) * 2012-05-16 2013-11-21 Rigel Pharmaceuticals, Inc. Method of treating muscular degradation
WO2017007658A1 (en) * 2015-07-07 2017-01-12 Rigel Pharmaceuticals, Inc. A combination for immune mediated cancer treatment
WO2018019204A1 (en) * 2016-07-26 2018-02-01 深圳市塔吉瑞生物医药有限公司 Amino pyrimidine compound for inhibiting protein tyrosine kinase activity
CN107827875A (en) * 2017-09-25 2018-03-23 文韬创新药物研究（北京）有限责任公司 A kind of application of benzimidazoles derivative as the inhibitor of Cyclin dependent kinase 4/6
WO2018140730A1 (en) * 2017-01-27 2018-08-02 Signalrx Pharmaceuticals, Inc. Thienopyranones and furanopyranones as kinase, bromodomain, and checkpoint inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102007124A (en) * 2008-02-15 2011-04-06 里格尔制药公司 Pyrimidine-2-amine compounds and their use as inhibitors of jak kinases
US20130310340A1 (en) * 2012-05-16 2013-11-21 Rigel Pharmaceuticals, Inc. Method of treating muscular degradation
WO2017007658A1 (en) * 2015-07-07 2017-01-12 Rigel Pharmaceuticals, Inc. A combination for immune mediated cancer treatment
WO2018019204A1 (en) * 2016-07-26 2018-02-01 深圳市塔吉瑞生物医药有限公司 Amino pyrimidine compound for inhibiting protein tyrosine kinase activity
WO2018140730A1 (en) * 2017-01-27 2018-08-02 Signalrx Pharmaceuticals, Inc. Thienopyranones and furanopyranones as kinase, bromodomain, and checkpoint inhibitors
CN107827875A (en) * 2017-09-25 2018-03-23 文韬创新药物研究（北京）有限责任公司 A kind of application of benzimidazoles derivative as the inhibitor of Cyclin dependent kinase 4/6

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