CN105622638B

CN105622638B - Pyrimidine or pyridopyridine ketone compounds and its preparation method and application

Info

Publication number: CN105622638B
Application number: CN201410597511.6A
Authority: CN
Inventors: 蔡雄; 钱长庚; 刘斌; 李军旗; 林明生; 卿远辉; 翁运幄; 王艳艳; 薛伟才; 游华金; 周石清
Original assignee: GUANGZHOU BEBETTER MEDICINE TECHNOLOGY Co Ltd
Current assignee: Guangzhou Bebet Pharmaceutical Co ltd
Priority date: 2014-10-29
Filing date: 2014-10-29
Publication date: 2018-10-02
Anticipated expiration: 2034-10-29
Also published as: CN105622638A

Abstract

The invention discloses pyrimidines or pyridopyridine ketone compounds and its preparation method and application shown in a kind of formula I, belong to field of medicine preparing technology.Such compound has the activity of efficient and selective inhibition cell cycle dependent kinase (Cdks) CDK4 and CDK6, and then by inhibiting CDK4/CDK6 to prevent tumour cell division.Therefore, the compound of the present invention, which can be used in the participated in cell cycle control imbalances of CDK4 and CDK6, leads to various diseases, the treatment especially suitable for malignant tumour.

Description

Pyrimidine or pyridopyridine ketone compounds and its preparation method and application

Technical field

The present invention relates to field of medicine preparing technology, more particularly to a kind of pyrimidine or pyridopyridine ketone compounds and Preparation method and application.

Background technology

Cyclin dependent kinase (cyclin-dependent kinase, CDK) and cyclin (cyclin) It is the important factor in cell cycle regulating.CDK can be combined with cyclin and be formed heterodimer, and wherein CDK is catalytic subunit, Cyclin is to adjust subunit, forms various cyclin-CDK compounds, keeps different substrate phosphorylations, cell cycle different Phase plays propulsion and transformation.

At least there are 9 kinds of CDK in mammals.Cell is converted from G1 phases to the S phases and is mainly controlled by G1 phase CDK kinases. The CDK kinases combined with G1 phases cyclin (cycling) includes mainly CDK2, CDK4 and CDK6.Cyclin D are main It is combined with CDK4 and CDK6 and adjusts the latter's activity；Cyclin E are combined in the G1/S phases with CDK2, and the kinase activity of CDK2 is presented Cell is promoted to enter the S phases.The G2/M phases, Cyclin A, cyclin B were combined with CDK1, and CDK1 makes bottom mainly by CDK1 kinase regulatories Object protein phosphorylation leads to chromosome condensation if by histone h1 phosphorylation, makes nuclear membrane if by lamin phosphorylation Disintegrate.In the M phases, m phage promoting factor,MPF M APC after M phases contributing factor (MPF) activation, by ubiquitinbond in cycli A and cyclin B On, it is acted on by more ubiquitinations, them is made to be degraded by proteasome, complete a cell cycle (Malumbres M.et al: Nat Cell Biol 11:1275,2009；Malumbres M.et al Nat Rev Cancer 9:153,2009).

It is a big common trait of human tumor that cell cycle is out of control.Unconventional proliferation, gene usually occur for tumour cell Group unstability (DNA mutation increases and chromosome aberration) and chromosome instability (increasing chromosome quantitative).Cell cycle Regulated and controled by CDKs family kinases.Tumour cell is due to CDKs itself or their modulator or the upstream passages phase of mitogenesis Correlation gene and table gene change, and lead to abnormal (the Cicenas J.J Cancer Res Clin Oncol of CDKs activity 147:1409,2011；Rizzolio F,et al.Curr Drug Targets.11:279,2010).

Over the past decade, CDK inhibitor is developed into a hot spot of global medicine company as anti-cancer agent, has more than 20 A CDK inhibitor enters clinical development.It is most in the early time although the antitumor preclinical pharmacodynamics of San result of CDK inhibitor is notable Clinical test results are unsatisfactory.Main problem is included in solid tumor and lacks curative effect and be more toxic.(Nat Rev Drug Dis 11:892,2012).CDK inhibitor AG-24322 ﹑ ZK-304709 ﹑ SNS-032 ﹑ R547 ﹑ Seliciclib and AZD5438 because Curative effect and toxicity reason cause clinical research to terminate.And it is found after the reason of analysis generates serious toxic side effect, these drugs CDK hypotypes are inhibited to lack selectivity, therefore produce serious toxic side effect.

Recent study shows CDK1 for participating in normal cell-cycle regulation and control.It is repressed in other CDKs, Retain CDK1 activity to be enough to maintain normal cell-cycle.The toxic side effect of CDK inhibitor is related with the inhibition of CDK1 and CDK2 (JNCI J Natl Cancer Inst 2012).In contrast, CDK4 and CDK6 hypotypes are not that mammalian cell period institute is required, They only play an important role in special cells type proliferation, become the crucial target spot for inhibiting tumour.

CDK4 and CDK6 is two closely related kinases, is combined with Cyclin D in tumour cell cycle and promotes the G1 phases It is necessary to DNA replication dna and fissional cell cycle progression into the S phases.And it is more than to be sent out in 90% human tumor Now the interim process control mechanism of G1-S phases is caused to change by various genes and biochemical adaptation.P16 and human retinoblastoma Albumen (retinoblastoma, Rb) is inhibited to be important tumor suppressor protein, it can cell cycle regulation.P16 gene proteins Inhibit the backfeed loop of CDK4, CyclinD1 and Rb, and the protein active by adjusting Rb, to prevent cell hyperproliferation, To achieve the purpose that inhibit tumour.Verified in human tumor (such as breast cancer and myeloma), CDK4 and CDK6 activation are led It causes the cell cycle to change to occur.And inhibit CDK4 and CDK6, the inactivation and interference tumour cell of tumor suppressor protein Rb can be prevented Cycle progress (Choi YJ and Anders L, Oncogene 33：1890-903,2014).

Nearest research also found, CDK6 as transcription complex a part of inducing tumor suppressor genes p16INK4a and The expression of angiogenic factors VEGF-A.CDK6 can play its tumour by enhancing cell Proliferation and angiogenesis stimulation Facilitation (Cancer Cell 24-167,2013).

Palbociclib (PD-0332991) is capable of the inhibition CDK4 and CDK6 of selectivity, restores cell cycle control, from And block tumor cell proliferation.(Pfizer) company of Pfizer is May in this year according to wherein clinical trial phase result to U.S.'s food Drug Administration (FDA) files an application NDA.It is studied according to the Pfizer II phases, in postmenopausal women estrogen receptor positive (ER⁺), human epidermal growth factor receptor 2's feminine gender (HER₂ ^-) in Locally Advanced or metastatic breast cancer patient, it is bent with standard care drug Azoles (letrozole) treatment group compares, the progressive free life cycle of palbociclib and letrozole drug combination groups (PFS) the notable extension (20.2 months vs 10.2 months, p=0.0004) on statistical significance is achieved, research has been reached Primary Endpoint.Different from nonselective CDK inhibitor, the side effect of CDK4/6 inhibitor PD-0332991 is less.Include mainly The side effect of Neuroleptic Leukocytopenia and tired (Pfizer Press Release 2014.4.6) are less.

Selective CDK4 and CDK6 inhibitor Palbociclib ﹑ LY2835219 and LEE011 enter for treating late period breast The phase iii clinical trial of gland cancer.Since CDK4/6 plays pass in the control imbalance of the cell cycle of various entity tumors and neoplastic hematologic disorder Key acts on.Currently, the clinical evaluation of these drugs further includes metastatic breast cancer, and embryonal-cell lipoma, non-small cell lung cancer, liver cancer, Oophoroma, glioblastoma, melanoma, Huppert's disease and lymthoma.

Invention content

Based on this one is provided it is an object of the invention to overcome the defect of CDK inhibitor shortage selectivity in the prior art Kind pyrimidine or pyridopyridine ketone compounds, such compound are capable of the inhibition cell cycle dependent kinase of selectivity (Cdks) CDK4 and CDK6, can be used for the cell cycle control imbalance that CDK4 and CDK6 are participated in leads to various diseases, especially In the treatment of malignant tumour.

To achieve the above object, the present invention takes following technical scheme：

Pyrimidine or pyridopyridine ketone compounds or its pharmaceutically acceptable salt or stereoisomer shown in formula I Or its prodrugs：

Wherein：X is selected from：CH or N；

Y is selected from：C or N, and as Y selection N, then without R₆Substitution；

R₁It is selected from：C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 naphthenic base substituent methyls；

R₂It is selected from：Halogen, COR₇, COOR₇, CONR₇R₈, C ≡ R₉；

R₃It is selected from：H, C1-C6 alkyl；

R₆It is selected from：H, F, CN, CH₃；

R₇、R₈It is respectively and independently selected from：H, C1-C6 alkyl, C1-C6 contain fluoroalkyl；C3-C6 naphthenic base；

R₉It is selected from：C1-C6 alkyl, C1-C6 contain fluoroalkyl, contain O, the heteroatomic C1-C6 alkyl of N, S, C3-C6 naphthenic base, Arbitrary 0-3 R₁₂Substituted or unsubstituted phenyl, arbitrary 0-3 R₁₂Substituted or unsubstituted 5-6 membered ring heteroaryls；

R₁₂It is selected from：C1-C6 alkyl, C1-C6 contain fluoroalkyl, contain O, the heteroatomic C1-C6 alkyl of N, S, halogen, nitro, hydroxyl Base, C1-C6 alkoxies, cyano, amino, ester group, amide groups；R₁₁Selected from following group：

Wherein：Q is selected from：Methyl or C=O；

Z is selected from：C or N；

M is selected from：0 or 1；

N is selected from：1 or 2；

R₁₀It is selected from：H, C1-C6 alkyl, C3-C6 naphthenic base, benzyl, acetyl group, methylsulphur base, hydroxyl replace C1-C4 alkane Base, C1-C3 alkoxies replace C1-C4 alkyl, amino to replace C1-C4 alkyl, C1-C3 alkyl substituted amidos, C1-C3 alkyl amine groups Replace C1-C4 alkyl, C3-C6 cyclammonium bases；

Also, when Y is selected from N, R₁₁It does not include following group：

In wherein some embodiments, the pyrimidine or pyridopyridine ketone compounds are selected from the compound as shown in Formula Il：

Wherein：R₄Selected from following group：

In wherein some embodiments, the pyrimidine or pyridopyridine ketone compounds are selected from following formula III shownization Close object：

Wherein：R₅Selected from following group：

In wherein some embodiments, X is selected from：CH.

In wherein some embodiments, R₁It is selected from：C3-C6 naphthenic base.

In wherein some embodiments, R₃It is selected from：H, C1-C6 alkyl, preferably methyl or ethyl.

In wherein some embodiments, R₂It is selected from：Halogen, COR₇, COOR₇, CONR₇R₈；Halogen is selected from：Cl, Br；R₇、R₈ It is respectively and independently selected from：H, C1-C6 alkyl, preferably methyl.

In wherein some embodiments, R₁It is selected from：C3-C6 naphthenic base, optimization cyclopentane；R₂It is selected from：COR₇；R₇It is selected from： C1-C6 alkyl, preferably methyl；R₃It is selected from：C1-C6 alkyl, preferably methyl.

In wherein some embodiments, R₂It is selected from：C≡R₉；

R₉It is selected from：C1-C6 alkyl, C1-C6 contain fluoroalkyl, contain O, the heteroatomic C1-C6 alkyl of N, S, C3-C6 naphthenic base, Arbitrary 0-3 R₁₂Substituted or unsubstituted phenyl, arbitrary 0-3 R₁₂Substituted or unsubstituted 5-6 membered ring heteroaryls.

In wherein some embodiments, R₉It is selected from：Methyl, ethyl, propyl, methylol, 2- hydroxyethyls, 1- hydroxyl second Base, acetyl group, amide groups, methoxy substitution methyl, amine methyl, methylamine ylmethyl, dimethylamino methyl, arbitrary 0-3 R₁₂It takes Generation or unsubstituted phenyl, arbitrary 0-3 R₁₂Substituted or unsubstituted heteroaryl；

The heteroaryl is selected from：Pyridyl group, pyrimidine radicals, furyl, benzofuranyl, benzoxazolyl；

R₁₂It is selected from：Halogen, methyl, ethyl, isopropyl, hydroxyl, methoxyl group, ethyoxyl, methoxy ethoxy (CH₃OCH₂CH₂O-), amino, methylamino, dimethylamino, amine methyl, methylol, cyano, trifluoromethyl, ester group, amide groups, first Sulfonamido.

In wherein some embodiments, R₁It is selected from：C3-C6 naphthenic base, preferably cyclopenta；

R₃It is selected from：C1-C6 alkyl, preferably methyl；

R₉It is selected from：Methylol, 2- hydroxyethyls, 1- hydroxyethyls, methoxy substitution methyl, arbitrary 0-3 R₁₂Substitution or Unsubstituted phenyl, arbitrary 0-3 R₁₂Substituted or unsubstituted heteroaryl；

R₁₂It is selected from：Amino, methylamino, dimethylamino, amine methyl, amide groups, methanesulfonamido.

In wherein some embodiments, Y is selected from：C or N；R₆It is selected from：H.

In wherein some embodiments, R₁₁Or R₄Or R₅Selected from following group：

Wherein：N is selected from：2；

R₁₀It is selected from：H, C1-C6 alkyl, benzyl, hydroxyl replace C1-C4 alkyl, C1-C3 alkyl substituted amidos, C3-C6 rings Amido.

In wherein some embodiments, the pyrimidine or pyridopyridine ketone compounds are selected from following compound：

The invention also discloses the preparation methods of above-mentioned pyrimidine or pyridopyridine ketone compounds, including following step Suddenly：

(1) by compound 101 and R₁NH₂Reaction generates chlorine by R₁The intermediate 102 of NH substitutions；The compound 101 is 4- Chloro- 2- methanesulfonyl-pyrimidines -5- carboxylic acid, ethyl esters；

(2) it restores the ester group in intermediate 102 with reducing agent and generates hydroxy compounds 103；

(3) the oxidizing generation aldehyde compound 104 of hydroxy compounds 103；

(4) methyl ketone compounds are generated by manganese dioxide after aldehyde compound 104 is first reacted with methyl-magnesium-bromide 105；

(5) methyl ketone compounds 105 under alkaline condition with triethyl phosphine acyl acetic acid ester or trimethyl-phosphine acyl group second Acid esters hair answers ring closure reaction to generate intermediate 106；

(6) intermediate 106 is reacted with bromine generates bromo compound 107；

(7) methyl mercapto in bromo compound 107 is aoxidized by 2- benzenesulfonyl -3- phenyl oxaziridines and generates first Base sulfinyl intermediate 109；

(8) intermediate 109 is reacted to displacement methylsulfinyl with compound 110 and generates compound 111；

(9) compound 111, which is first reacted under the catalysis of palladium reagent with tributyl (1- ethoxy ethylenes base) tin, generates ethoxy Base vinyl compound, after in acid condition hydrolysis generate target compound；

Reaction route is as follows：

Wherein：Compound 110 is prepared by the following method：

A) by compound 110A and tool R₄The compound of group is reacted, with R₄Bromine in substituted compound 110A, obtains chemical combination Object 110B；Compound 110A is the bromo- 2- nitropyridines of 5- and tool R₄The compound of group is reacted；

B the nitro in compound 110B) is reduced to amino with reducing agent, obtains compound 110；

Reaction route is as follows：

Above compound 110 is by variable groups R₄It constitutes, it can be by the bromo- 2- nitropyridines of 5- and different R₄Reaction, works as R₄Tool There is the amido of nucleophilic, bromine can directly be replaced to generate the compound that nitrogen is connected directly between on pyridine；Work as R₄It is connected with carbon key with pyridine, It can be introduced by coupling reaction.

(1) by compound 201 and R₁NH₂The chlorine of reaction, selective displacement iodine ortho position generates compound 202；The compound 201 be bis- chloro- 5- iodine pyrimidines of 2,4-；

(2) compound 202 is condensed with borine -2- butenoic acid ethyls under palladium reagent catalysis and generates compound 203；

(3) cyclization generates intermediate 204 to compound 203 under alkaline condition；

(4) compound 204 is reacted with bromine generates bromo compound 205；

(5) bromo compound 205 is reacted with compound 110 under alkaline condition generates compound 111；

(6) compound 111, which is first reacted under the catalysis of palladium reagent with tributyl (1- ethoxy ethylenes base) tin, generates ethoxy Base vinyl compound, after in acid condition hydrolysis generate target compound；

Reaction route is as follows：

Wherein：Compound 110 is prepared according to the method described above.

(1) contraposition reacted compound 301 with NIS in chlorine introduces iodine, obtains compound 302；The compound 301 is 2- Chloro- 4- amidos pyridine；

(2) compound 302 and bromo R₁Reaction introduces R₁Substituted compound 303；

(3) compound 303, which is reacted under palladium reagent catalysis with borine -2- butenoic acid ethyls, generates compound 304；

(4) cyclization generates compound 305 to compound 304 under alkaline condition；

(5) compound 305 is reacted with bromine generates bromo compound 306；

(6) bromo compound 306, which reacts under the catalysis of palladium reagent with tributyl (1- ethoxy ethylenes base) tin, generates second Ethoxy ethylene based compound 307；

(7) compound 307, which is reacted under palladium reagent catalysis with compound 308, generates compound 309；

(8) compound 309 hydrolyzes in acid condition generates target compound；

Reaction route is as follows：

Wherein：Compound 308 is prepared by the following method：

A) by compound 110A and tool R₅The compound of group is reacted, with R₅Bromine in substituted compound 110A, obtains chemical combination Object 308A；Compound 110A is the bromo- 2- nitropyridines of 5-；

B the nitro in compound 308A) is reduced to amino with reducing agent, obtains compound 308；

Reaction route is as follows：

Above compound 308 is by variable groups R₅It constitutes, it can be by the bromo- 2- nitropyridines of 5- and different R₅Reaction, works as R₅Tool There is the amido of nucleophilic, bromine can directly be replaced to generate the compound that nitrogen is connected directly between on pyridine；Work as R₅It is connected with carbon key with pyridine, It can be introduced by coupling reaction.

(1) by compound 401 and iodo R₆Reaction generates 3 R₆Substituted compound 402；The compound 401 is 4- bromo- 2 Chloropyridine；

(2) compound 402 palladium reagent catalysis under with R₁NH₂Reaction generates compound 403；

(3) compound 403 generates compound 404 with NIS iodate；

(4) compound 404, which is reacted under palladium reagent catalysis with borine -2- butenoic acid ethyls, generates compound 405；

(5) cyclization generates compound 406 to compound 405 under alkaline condition；

(6) compound 406 is reacted with bromine generates bromine compounds 407；

(7) compound 407, which is reacted under the catalysis of palladium reagent with tributyl (1- ethoxy ethylenes base) tin, generates ethyoxyl Vinyl compound 408；

(8) compound 408, which is reacted under palladium reagent catalysis with compound 308, generates compound 409；

(9) compound 409 hydrolyzes in acid condition generates target compound；

Reaction route is as follows：

Wherein：Compound 308 is prepared according to the method in claim 17.

(1) compound 501 uses the end proton exchange of organolithium reagent and alkynes first, is then reacted with tributyltin chloride Generate compound 502；

(2) compound 111, which is reacted under palladium reagent catalysis with compound 502, generates target compound；

Reaction route is as follows：

The invention also discloses above-mentioned pyrimidine or pyridopyridine ketone compounds or its pharmaceutically acceptable salt Or stereoisomer or its prodrugs are preparing the application in preventing tumour medicine.

In wherein some embodiments, the tumour is entity tumor and neoplastic hematologic disorder.

In wherein some embodiments, the entity tumor and neoplastic hematologic disorder include breast cancer, embryonal-cell lipoma, non-small cell Lung cancer, liver cancer, oophoroma, glioblastoma, melanoma, Huppert's disease and lymphoma mantle cell.

In wherein some embodiments, the breast cancer includes：In postmenopausal women estrogen receptor positive (ER⁺) and/ Or human epidermal growth factor receptor 2's feminine gender (HER₂ ^-) Locally Advanced or metastatic breast cancer.

The invention also discloses a kind of pharmaceutical composition of anti-curing oncoma, include as active ingredient above-mentioned pyrimidine or Pyridopyridine ketone compounds or its pharmaceutically acceptable salt or stereoisomer or its prodrugs, and pharmaceutically Acceptable carrier.

Compared with prior art, the invention has the advantages that：

Pyrimidine or pyridopyridine ketone compounds shown in the formula I of the present invention, are a series of new compounds, such change Close object can with selective depression CDK4 and CDK6, can be used in CDK4 and CDK6 participated in cell cycle controls lack of proper care cause it is various Disease, the treatment especially suitable for malignant tumour.

Especially which part compound has the characteristics that high selectivity, activity are high and anti-tumour cell proliferative effect is strong, The IC that CDK4 and CDK6 is inhibited₅₀50nM can be reached hereinafter, and to the IC of CDK2 inhibition₅₀More than 500nM, almost unrestraint is lived Property.

In pyrimidine or pyridopyridine ketone compounds shown in the formula I of the present invention, data shows R₂And R₃Take Dai Ji has large effect to the selectivity for enhancing CDK6/CDK4.R₃Preferred small alkyl such as methyl.R2 needs electron rich Group, such as carbonyl and alkynyl.R₂Concrete activity characterization be：In aliphatic alkylyl series, the alkynes of hydroxyl or alkoxy Base shows higher activity；Amido substitution is advantageous to activity on aromatic series alkylyl series, aromatic ring；Work as R₂It is the compound of carbonyl In, acetyl group is first choice.R₁Alkyl and naphthenic base can be contained, be first choice with cyclopenta.R₁₁Or R₄Or R₅Group changeability is larger, But need a nitrogenous cyclic structure with alkalinity.R₆It is sensitive to substituent group type, it is first choice with H, works as R₆It is living when being methyl Property reduce.

Specific implementation mode

Except known in the literature or in addition to the standard method of illustration, can be used as shown in following scheme in laboratory procedure The reaction shown prepares the compounds of this invention.Therefore, following illustrative approach is purpose to illustrate without being limited to listedization It closes object or any specific substituent group, the method to be merely intended to be described, and does not constitute and had to the present invention Range limitation.

Scheme one

Scheme two

Scheme three

Scheme four

Scheme five

The preparation (being prepared according to one circuit of scheme) of 1 compound 1 of embodiment

Step 1a：4- cyclopentamine base -2- methylthiopyrimidine -5- carboxylic acid, ethyl esters (4-Cyclopentylamino -2- Methylsulfanyl-pyrimidine-5-carboxylic Acid Ethyl Ester) (compound 102) preparation：It will The chloro- 2- methanesulfonyl-pyrimidines -5- carboxylic acid, ethyl esters (101) of 4- (30.06 grams, 129 mMs, 1.0 equivalents) are dissolved in tetrahydrofuran In (300 milliliters), then cyclopentamine (12.3 grams, 141.6 mMs, 1.1 equivalents) and triethylamine (39.6 grams, 387 mMs, 3.0 equivalents) it is gradually slowly added in the solution, and stirred the mixture for 14 hours in room temperature.The salt of precipitation is filtered, and will Removing is concentrated under reduced pressure in solvent at reduced pressure conditions.Gained grease is dissolved in ethyl acetate, saturated sodium bicarbonate water is used in combination Solution washs.Organic phase is dried over sodium sulfate.Salt is filtered, and solvent is concentrated under reduced pressure to removing at reduced pressure conditions, is obtained 4- cyclopentamine base -2- methylthiopyrimidine -5- carboxylic acid, ethyl esters, be orange (33.7 grams, yield：92.5%).

Step 1b：(4- cyclopentamine base -2- methylthiopyrimidine -5- bases)-methanol ((4- (cyclopentylamino) -2- (methylthio) pyrimidin-5-yl) methanol) (compound 103) preparation：Under nitrogen protection, tetrahydrochysene lithium aluminium (6.822 grams, 0.18 mole, 1.5 equivalents) are suspended in anhydrous tetrahydrofuran (200 milliliters), are cooled with an ice bath.Compound 102 (33.7 grams, 0.12 mole, 1.0 equivalents) are dissolved in dry tetrahydrofuran (200 milliliters), and are keeping reaction temperature Less than at 12 DEG C, being added dropwise in cooling tetrahydrochysene lithium aluminium solution.After being stirred at room temperature 4 hours, by being slowly added into ice Water (7 milliliters) quenches reaction, and 15% sodium hydroxide solution (14 milliliters) is then added, adds water (7 milliliters).White solid Sediment filter, and in a vacuum by mother liquor be concentrated under reduced pressure remove.By the solid of gained, with heptane wash, filtering obtains (4- cyclopentamine base -2- methylthiopyrimidines -5- bases-methanol, be light yellow solid (29.03 grams, yield：100%).

Step 1c：4- cyclopentamine base -2- methylthiopyrimidine -5- formaldehyde (4- (cyclopentylamino) -2- (methylthio) pyrimidine-5-carbaldehyde) (compound 104) preparation：By compound (103) (29.03 Gram, 0.12 mole, 1.0 equivalents) it is dissolved in chloroform (500 milliliters), manganese dioxide is then added, and (80.5 grams, 0.926 rubs You, 7.7 equivalents), and mixture is stirred at room temperature 16 hours.It is filtered to remove solid by Celite pad, three chloromethanes are used in combination Alkane washs.Decompression is concentrated under reduced pressure removing solvent and obtains compound 4- cyclopentamine base -2- methylthiopyrimidine -5- formaldehyde, is light yellow Solid (24.9 grams, yield：86.8%).

Step 1d：5- acetyl group -4- cyclopentamine base -2- methylthiopyrimidines (1- (4- (cyclopentylamino) -2- (methylthio) pyrimidin-5-yl) ethan-1-one) (compound 105) preparation：By compound 104 (24.88 grams, 0.105 mole, 1.0 equivalents) it is dissolved in tetrahydrofuran (100 milliliters), under nitrogen protection, then it is cooled with an ice bath, methyl Magnesium bromide (37.548 grams, 0.315 mole, 3.0 equivalents) is slowly added into solution.By reaction mixture stirring 1.5 hours, so It is quenched afterwards with a small amount of saturated aqueous ammonium chloride, water is added.Mixture is extracted with ethyl acetate, by organic phase sodium sulphate It is dry.Filtrate is filtered to take, and solvent is concentrated under reduced pressure to removing in a vacuum, obtains a kind of grease (23.98 grams, crude product).It should Grease is dissolved in dichloromethane (500 milliliters), and manganese dioxide (96.5 grams, 1.11 moles) is added in the solution.It will be anti- Mixture is answered to be stirred at room temperature 16 hours.It is filtered to remove extra manganese dioxide by Celite pad, chloroform is used in combination to wash. Removing solvent is concentrated under reduced pressure in a vacuum and obtains 5- acetyl group -4- cyclopentamine base -2- methylthiopyrimidines, is light yellow solid (23.78 grams, yield：84.6%).

Step 1e：- 7 ketone (8- of 8- cyclopenta -5- methyl -2- methyl mercapto -8H- pyridos [2,3-d] pyrimidine Cyclopentyl-5-methyl-2-methylsulfanyl-8H-pyrido- [2,3-d] pyrimidin-7-one (compounds 106) preparation：Under nitrogen protection, to sodium hydride cooling in tetrahydrofuran (200 milliliters) (4.8 grams, 0.2 mole, 60% dispersion in mineral oil, 16.8 equivalents) in suspension, be added portionwise triethyl phosphine acyl acetic acid ester (48.8 grams, 0.2 Mole, 16.8 equivalents).Be dissolved in after cooling bath is removed in 100 milliliters of tetrahydrofurans compound 105 (6.0 grams, 11.9 MM, 1.0 equivalents) solution is slowly added dropwise in preformed anion solutions.By reaction mixture reflux 36 Hour.Reaction mixture is cooled to room temperature, water and ethyl acetate is used in combination to dilute.Detach each layer, and by aqueous layer with ethyl acetate Extraction.Combined organic layer is washed with brine and is dried with sodium sulphate, filters, filtrate decompression is concentrated, compound 8- is obtained - 7 ketone of cyclopenta -5- methyl -2- methyl mercapto -8H- pyridos [2,3-d] pyrimidine, be waxy solid (20.04 grams, yield： 77.7%).

Target product characterize data：¹H NMR(500MHz,DMSO-d₆):δ8.92(s,1H),6.45(s,1H),5.90- 5.72 (m, 1H), 2.59 (s, 3H), 2.41 (s, 3H), 2.22 (s, 2H), 1.98 (s, 2H), 1.79 (s, 2H), 1.63 (d, J= 4.7Hz,2H)。

Step 1f：The bromo- 8- cyclopenta -5- methyl -2- methylsulfanyl pyridines of 6- simultaneously [2,3-d] pyrimidine -7 (8H- ketone (6- bromo-8-cyclopentyl-5-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one) The preparation of (compound 107)：Compound 106 (4 grams, 14.6 mMs) is dissolved in dichloromethane (100 milliliters), is slowly added Enter bromine (1.47 milliliters), reaction mixture is stirred at room temperature 16 hours.The thiosulfuric acid that reaction mixture is saturated Sodium solution (15 milliliters), then with (20 milliliters) quenchings of solution of the sodium carbonate of saturation.By organic layer separation, organic layer is washed with water It is dried over sodium sulfate and be concentrated under reduced pressure with salt water washing, obtain the bromo- 8- cyclopenta -5- methyl -2- methyl mercaptos of compound 6- Pyrido [2,3-d] pyrimidine -7 (8H) -one (19.7 grams, yield：96%).

Target product characterize data：¹H NMR(500MHz,CDCl₃)δ8.79(s,1H),6.14–5.91(m,1H),2.62 (s, 6H), 2.28 (d, J=7.3Hz, 2H), 2.10 (s, 2H), 1.89 (s, 2H), 1.68 (d, J=4.4Hz, 2H).

Step 1g.2- benzenesulfonyl -3- phenyl oxaziridines (2-Benzenesulfonyl-3- Phenyloxaziridine) the preparation of (compound 108)：By benzsulfamide (44 grams, 289 mMs, 1.0 equivalents) and benzene first Aldehyde dimethylacetal (50 grams, 318 mMs, 1.1 equivalents), which is placed in single port bottle, is heated to 130 degree, is distilled off produced by reaction Methanol, until the reaction is complete.Temperature is cooled to room temperature, petroleum ether and a small amount of dichloromethane is added, filters white solid Body (Z)-N- benzylidenes benzsulfamide (62 grams, yield：87.5%).Under nitrogen protection by (Z)-N- benzylidene benzene sulfonyls Amine (28 grams, 114 mMs, 1.0 equivalents), chlorinating benzyl triethylamine (2.85 grams, 11.4 mMs, 0.1 equivalent) are dissolved in 200 In the chloroform of milliliter.Metachloroperbenzoic acid (25.4 grams, 137 mMs, 1.2 equivalents) is dissolved in 300 milliliters of chloroformic solutions It is added drop-wise under 0 degree Celsius in above-mentioned reaction solution.It is stirred at room temperature 6 hours, solution of sodium bisulfite is added and is quenched, uses saturated common salt Water washing.Organic phase is dried with anhydrous sodium sulfate, and low-temperature reduced-pressure is concentrated to give 2- benzenesulfonyl -3- phenyl oxaziridines (17 grams, yield：57.1%).

Step 1h：Bromo- 8- cyclopenta -5- methyl -2- methylsulfinyls pyrido [2,3-d] pyrimidine -7 (8H) -one of 6- (6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7 (8H)-one) (compound 109) preparation：By compound 107 (19.7 grams, 55.8 mMs) and 2- benzenesulfonyl -3- phenyl Oxaziridine (108) (15.9 grams, 61.4 mMs) is dissolved in dichloromethane (400 milliliters), and is stirred at room temperature It mixes 18 hours.Mixture is depressurized lower be concentrated under reduced pressure to remove to grease, which recrystallizes in ethylacetate/ether, It filters and is dried in a vacuum, obtain the bromo- 8- cyclopenta -5- methyl -2- methylsulfinyls pyridos [2,3-d] of compound 6- Pyrimidine -7 (8H) -one, be white solid (8.4 grams, yield：40.9%).

Step 1i:2- amidos -5- (5- benzyls hexahydropyrrolo [3,4-c] pyrroles -2 (1H)-yl) pyridine (5- (5- Benzylhexahydropyrrolo [3,4-c] pyrrol-2 (1H)-yl) pyridin-2-amine) (compound 110-1) It prepares：By the bromo- 2- nitropyridines of 5- (2.0 grams, 9.85 mMs, 1.0 equivalents), tetrabutyl ammonium fluoride, (0.182 gram, 0.49 in the least Mole, 0.5 equivalent), 2- benzyl octahydro pyrrole radicals [3,4-c] pyrroles (2.59 grams, 13 mMs, 1.3 equivalents) and potassium carbonate (1.77 grams, 13 mMs, 1.3 equivalents) are dissolved in 15 milliliters of dimethyl sulfoxide (DMSO)s.It, will be anti-after reaction is stirred overnight under 80 degree It answers liquid to be cooled to room temperature to be extracted with dichloromethane and water, obtained organic phase saturated common salt water washing, anhydrous sodium sulfate drying, It is concentrated again with Rotary Evaporators dry.Product after concentration obtains yellow solid 2- benzyls -5- (6- nitro pyrroles after silica gel column chromatography Pyridine -3- bases) octahydro pyrrole radicals [3,4-c] pyrroles (2.34 grams, yield 73.4%).Its LCMS (ESI):m/z325[M+1]⁺。

By above-mentioned product (0.98 gram, 3 mMs, 1.0 equivalents) and palladium carbon (50 milligrams, 0.46 mM, 0.15 equivalent) It is dissolved in 50 milliliters of methanol, sodium borohydride (0.5 gram, 13 mMs, 4.3 equivalents) is then added portionwise in reflux 3 hours Afterwards, it is filtered, is extracted with dichloromethane and water after filtrate is concentrated, obtained organic phase saturated common salt water washing with diatomite, Anhydrous sodium sulfate is dried, then is concentrated and done with Rotary Evaporators.Product after concentration obtains brown solid 2- after silica gel column chromatography Amido -5- (5- benzyls hexahydropyrrolo [3,4-c] pyrroles -2 (1H)-yl) pyridine (0.8 gram, yield：90%).

Target product characterize data：LCMS(ESI):m/z295[M+1]⁺.¹H NMR (500MHz, CDCl₃):δ 8.17 (d, J =9.0Hz, 1H), 7.85 (d, J=2.6Hz, 1H), 7.30 (s, 4H), 6.88 (dd, J=9.1,2.6Hz, 1H), 3.73-3.67 (m, 2H), 3.64 (s, 2H), 3.34 (d, J=10.2Hz, 2H), 3.07 (s, 2H), 2.66 (s, 4H).

Step 1j:2- (5- (5- benzyls hexahydropyrrolo [3,4-c] pyrroles -2 (1H)-yl) pyridine -2- amidos) bromo- 8- of -6- Cyclopenta -5- picolines simultaneously [2,3-d] pyrimidine -7 (8H) -one (2- (5- (5-benzylhexahydropyrrolo [3,4-c] pyrrol-2(1H)-yl)pyridin-2-ylamino)-6-bromo-8-cyclopentyl-5-methylpyrido[2,3- D] pyrimidin-7 (8H)-one) (compound 111-1) preparation：By compound 110-1 (600 milligrams, 2.05 mMs, 1.0 equivalents) and compound 109 (0.5 gram, 2.35 mMs, 1.15 equivalents) be dissolved in 15 milliliters of toluene.Under nitrogen protection After back flow reaction 18 hours, toluene is concentrated with Rotary Evaporators and is removed.Crude product after concentration obtains nothing after silica gel column chromatography Color grease 2- (5- (5- benzyls hexahydropyrrolo [3,4-c] pyrroles -2 (1H)-yl) pyridine -2- amidos) bromo- 8- cyclopenta-of -6- 5- picolines simultaneously [2,3-d] pyrimidine -7 (8H) -one (0.6 gram, yield：7.4%).LCMS(ESI):m/z600[M+1]⁺。

Step 1k:6- acetyl group -2- (5- (5- benzyls hexahydropyrrolo [3,4-c] pyrroles -2 (1H)-yl) pyridine -2- amine Base) -8- cyclopenta -5- picolines simultaneously [2,3-d] pyrimidine -7 (8H) -one (6-acetyl-2- (5- (5- benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-8- Cyclopentyl-5-methylpyrido [2,3-d] pyrimidin-7 (8H)-one) (compound 1) preparation：By compound 111-1 (90 milligrams, 0.15 mM, 1.0 equivalents), tetra-triphenylphosphine palladium (0.021 gram, 0.018 mM, 0.12 equivalent) and Tributyl (1- ethoxy ethylenes base) tin (0.138 gram, 0.375 mM, 2.5 equivalents) is dissolved in 5 milliliters of toluene, in nitrogen The lower return stirring of displacement protection 4 hours.Toluene is removed with Rotary Evaporators after cooling, the product after concentration is after silica gel column chromatography Obtain yellow solid (60 milligrams, yield：67.7%), LCMS (ESI):m/z592[M+1]⁺.Solid is dissolved in 5 milliliters of dichloros In methane, it is cooled to 0 degree Celsius, is stirred 10 minutes after the hydrochloric acid of 3 milliliter of 4 mol/L is added.Saturated sodium bicarbonate solution is added To meta-alkalescence (PH：8~9), dichloromethane and water is then used to extract, after mixed organic phase is dried with anhydrous sodium sulfate, It filters, then is concentrated and done with Rotary Evaporators.Product after concentration obtains product 6- acetyl group -2- (5- (5- after silica gel column chromatography Benzyl hexahydropyrrolo [3,4-c] pyrroles -2 (1H)-yl) pyridine -2- amidos) simultaneously [2,3-d] is phonetic for -8- cyclopenta -5- picolines Pyridine -7 (8H) -one (40 milligrams, yellow solid, yield：70%).

Target product characterize data：LCMS(ESI):m/z564[M+1]⁺.¹H NMR (500MHz, CDCl₃):δ 8.77 (s, 1H), 8.07 (d, J=8.8Hz, 1H), 7.85-7.74 (m, 2H), 7.32-7.30 (m, 4H), 7.24 (m, 1H), 7.06 (dd, J =9.0,3.0Hz, 1H), 5.88 (dt, J=17.9,8.9Hz, 1H), 3.62 (s, 2H), 3.51-3.39 (m, 2H), 3.17 (dd, J=9.2,3.3Hz, 2H), 2.97 (d, J=12.3Hz, 2H), 2.81-2.75 (m, 2H), 2.55 (s, 3H), 2.48 (dd, J= 9.2,3.5Hz, 2H), 2.37 (m, 5H), 2.06 (s, 2H), 1.94-1.82 (m, 2H), 1.69 (dd, J=10.6,5.5Hz, 2H)。

The preparation (being prepared according to one circuit of scheme) of 2 compound 3 of embodiment

Step 1i in the preparation of compound 110-3, synthetic method such as embodiment 1 is only by wherein 2- benzyls octahydro pyrroles Base [3,4-c] pyrroles replaces with bicyclic (2.2.1) heptane-2-t-butyl formates of 2.5-, and 5- (6- amido pyridines-3- are prepared Base) -2,5- diazabicyclos [2.2.1] heptane -2- t-butyl formates (tert-butyl5- (6-aminopyridin-3-yl) - 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate) (compound 110-3).Target product characterize data： LCMS(ESI):m/z 291[M+1]⁺。

1j in the preparation of compound 111-3, synthetic method such as embodiment 1 is only to replace with compound 110-1 therein 5- (6- ((bromo- 8- cyclopenta -5- methyl -7- oxos -7,8- dihydro-pyrimidin [2, the 3-d] -2- pyrimidines of 6-) are prepared in 110-3 Amine) -3- pyridines) -2,5- diazabicyclos [2.2.1] heptane -2- t-butyl formates (tert-butyl5- (6- ((6-bromo- 8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino) Pyridin-3-yl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate) (compound 111-3).Target Characterization of The Products data：LCMS(ESI):m/z 597[M+1]⁺。

The preparation of compound 3, by compound 111-3 according to the method for step 1k in embodiment 1 be prepared 2- 5- (2, 5- diazabicyclos [2.2.1] heptane -2- bases) pyridine -2- amidos } -6- acetyl group -8- cyclopenta -5- methyl -8H- pyridos [2,3-D] pyrimidin-7-ones (2- ((5- (2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-2-yl) Amino) -6-acetyl-8-cyclopentyl-5-methylpyrido [2,3-d] pyrimidin-7 (8H)-one) (chemical combination Object 3).

Target product characterize data：LCMS(ESI):m/z 460[M+1]⁺.¹H NMR(500MHz,CDCl₃)：δ8.70(s, 1H), 8.23 (d, J=2.4Hz, 1H), 7.75 (dd, J=8.9,2.6Hz, 1H), 7.09 (s, 1H), 6.41 (d, J=8.9Hz, 1H), 5.83-5.71 (m, 1H), 4.96 (s, 1H), 4.32 (s, 1H), 3.68-3.61 (m, 2H), 3.32 (q, J=10.7Hz, 2H), 2.53 (d, J=7.5Hz, 3H), 2.34 (s, 3H), 2.28 (dd, J=11.2,7.9Hz, 3H), 2.12-2.05 (m, 2H), 1.89(s,2H),1.82(s,2H),1.61(s,2H)。

The preparation (being prepared according to two circuit of scheme) of 3 compound 2 of embodiment

Step 3a:The chloro- 4- cyclopentamines yl pyrimidines (5-iodine-2-chloro-4-cyclopentyl- of the iodo- 2- of 5- Aminopyrimidine) the preparation of (compound 202)：By 2,4-, bis- chloro- 5- iodine pyrimidines (compound 201) (80.00 grams, 0.291 mole, 1.0 equivalents) it is dissolved in ethyl alcohol (800 milliliters), triethylamine is added, and (88.18 grams, 0.873 mole, 3.0 work as Amount), then mixture is placed under ice bath and is stirred, when temperature is down to 0 DEG C -5 DEG C, start be added dropwise cyclopentamine (49.50 grams, 0.582 mole, 2.0 equivalents), it is added dropwise within 30 minutes, then maintains the temperature at 5 DEG C or so stirrings.HPLC is monitored, as 2,4- bis- When the peak area ratio of chloro- 5- iodine pyrimidines is less than 1%, reaction is terminated.It is dilute that ethyl acetate (300 milliliters) is added after reaction solution is concentrated It releases, water (300 milliliters), extraction, liquid separation is added.Water phase is extracted with ethyl acetate (200 milliliters × 2).Merge organic phase, organic phase After (200 milliliters) extractions of saturated salt solution, dried with anhydrous sodium sulfate.It is concentrated in vacuo organic phase, by residue silicagel column Obtained after separation the chloro- N- cyclopenta -5- iodine pyrimidines -4- amine of compound 2- (87.88 grams, yield：93.5%).MS(ESI):m/z 324[M+1]⁺。

Step 3b：(E) -3- (the chloro- 4- cyclopentamines yl pyrimidines -5- bases of 2-) -2- butenoic acid ethyls ((E)-Ethyl-3- (2- Chloro-4- (cyclopentylamino) pyrimidin-5-yl) but-2-enoate) (compound 203) preparation：By 2- Chloro- N- cyclopenta -5- iodine pyrimidine -4- amine (compound 202) (20.00 grams, 0.0619 mole, 1.0 equivalents) is dissolved in dimethyl In formamide (200 milliliters), water (20 milliliters) is then sequentially added, sodium carbonate (16.40 grams, 0.1547 mole, 2.5 equivalents), PdCl₂(PPh₃)₂(2.17 grams, 0.0031 mole, 0.05 equivalent).Under the protection of nitrogen, mixture is placed under 90 DEG C of oil baths Stirring when temperature rises to 90 DEG C starts that (Z) -3- (4,4,5,5- tetramethyls -1,3,2- bis- Evil borine -2- bases) -2- fourths are added dropwise Olefin(e) acid ethyl ester (ethyl (Z) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) but-2- Enoate) (19.32 grams, 0.0805 mole, 1.3 equivalents), are added dropwise, then maintain the temperature at 90 DEG C or so and stir for 30 minutes It mixes.HPLC monitoring terminates reaction when the peak area ratio of the chloro- N- cyclopenta -5- iodine pyrimidines -4- amine of 2- is less than 1%.By reaction solution It is cooled to room temperature, filters, filter cake is washed with methyl tertiary butyl ether(MTBE) (100 milliliters).Methyl tertiary butyl ether(MTBE) (200 millis are added toward filtrate Rise) and water (400 milliliters), extraction, liquid separation.Water phase is extracted with methyl tertiary butyl ether(MTBE) (200 milliliters × 2).Merge organic phase, it is organic Mutually with after (200 milliliters) extractions of saturated salt solution, dried with anhydrous sodium sulfate.It is concentrated in vacuo organic phase, by residue silica gel Obtained after post separation compound (E) -3- (the chloro- 4- cyclopentamines yl pyrimidines -5- bases of 2-) -2- butenoic acid ethyls (13.85 grams, yield： 72.4%).LCMS(ESI):m/z 310[M+1]⁺。

Step 3c：Chloro- 8- cyclopenta -5- methyl -8H- pyridos [2,3-d] pyrimidin-7-ones (2-Chloro-8- of 2- Cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one) (compound 204) preparation：By chemical combination Object 203 (20.00 grams, 0.0647 mole, 1.0 equivalents) is dissolved in dimethylformamide (200 milliliters), and cesium carbonate is then added (42.16 grams, 0.1294 mole, 2.0 equivalents), are stirred at room temperature.HPLC monitoring is less than when the peak area ratio of compound 203 When 1%, reaction is terminated.Reaction solution is filtered, filter cake is washed with methyl tertiary butyl ether(MTBE) (100 milliliters).Methyl- tert is added toward filtrate Butyl ether (200 milliliters) and water (400 milliliters), extraction, liquid separation.Water phase is extracted with methyl tertiary butyl ether(MTBE) (200 milliliters × 2).It closes And organic phase is dried after organic phase (200 milliliters) extractions of saturated salt solution with anhydrous sodium sulfate.It is concentrated in vacuo organic phase, it will Chloro- 8- cyclopenta -5- methyl -8H- pyridos [2,3-d] pyrimidin-7-ones of compound 2- are obtained after residue silica gel post separation (13.94 grams, yield：81.9%).LCMS(ESI):m/z 264[M+1]⁺。

Step 3d：Chloro- 8- cyclopenta -5- methyl -8H- pyridos [2,3-d] pyrimidin-7-ones (6-bromo-2- of the bromo- 2- of 6- Chloro-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d] pyrimidin-7-one) (compound 205) system It is standby：Compound 204 (19.84 grams, 0.0754 mole, 1.0 equivalents) is dissolved in acetic acid (200 milliliters), sodium acetate is added (24.75 grams, 0.3017 mole, 4.0 equivalents), are stirred at room temperature, be slowly added dropwise bromine (48.26 grams, 0.3017 mole, 4.0 Equivalent), it is added dropwise within 20 minutes, then mixture is placed under 50 DEG C of oil bath and is stirred.HPLC monitoring is when the peak of compound 204 When area ratio is less than 1%, reaction is terminated.Saturated aqueous sodium sulfite (200 milliliters) is added after reaction solution is cooled to room temperature, Dichloromethane (300 milliliters), extraction, liquid separation is added.Water phase is extracted with dichloromethane (150 milliliters × 2).Merge organic phase, has After machine mutually uses saturated sodium bicarbonate aqueous solution (200 milliliters × 3) extraction, dried with anhydrous sodium sulfate.It is concentrated in vacuo organic phase, it will Chloro- 8- cyclopenta -5- methyl -8H- pyridos [2,3-d] pyrimidines-of the bromo- 2- of compound 6- are obtained after residue silica gel post separation 7- ketone (21.50 grams, yield：83.1%) .LCMS (ESI):m/z 344[M+1]⁺。

Step 3e：5- (hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) pyridine -2- amine (5- (hexahydrocyclopenta [c] pyrrol-2 (1H)-yl) pyridin-2-amine) (compound 110-2) preparation：It will The bromo- 2- nitropyridines of 5- (1.5 grams, 7.4 mMs, 1 equivalent), (1.362 grams, 3.69 mMs, 0.5 works as tetrabutylammonium iodide Amount), (3.06 grams, 22.14 in the least for octahydro cyclopenta [C] pyrroles (1.569 grams, 10.8 mMs, 1.5 equivalents) and potassium carbonate Mole, 3 equivalents) it is mixed in dimethyl sulfoxide (DMSO) (30 milliliters).Reaction is heated to 80 degrees Celsius, and is stirred to react overnight.It is cold But to water, dichloromethane extraction after room temperature, is added.Merging organic phase and is washed with salt, anhydrous sodium sulfate drying is concentrated under reduced pressure, Residue is purified with silica gel column chromatography, and obtaining yellow solid compound 2- (6- nitropyridine -3- bases),-octahydro pentamethylene is simultaneously [c] Pyrroles's (2.28 grams, crude product), LCMS (ESI):m/z234[M+1]⁺.By above compound (3 grams, 12.87 mMs, 1 equivalent) It is dispersed in 50 ml methanols with palladium carbon (0.067 gram, 0.64 mM, 0.05 equivalent), sodium borohydride is then added portionwise (1.47 grams, 38.61 mMs, 3 equivalents).It is warming up to reflux and reacts 3 hours.Filtering, filter cake are washed with methanol, and filtrate decompression is dense Contracting.Residue with Ethyl acetate dissolves, and sodium bicarbonate solution is washed, and anhydrous sodium sulfate drying is concentrated under reduced pressure, obtains red solid 5- (hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) pyridine -2- amine (1.305 grams, yield：50%), LCMS (ESI):m/z204[M +1]⁺。

Step 3f；The bromo- 8- cyclopenta -2- of 6- [5 (hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) pyridine -2- amidos] - 5- methyl -8H- pyridos [2,3-D] pyrimidin-7-ones (6-bromo-8-cyclopentyl-2- ((5- (hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)-5-methylpyrido[2, 3-d] p yrimidin-7 (8H)-one) (compound 111-2) preparation：By compound 110-2 (475 milligrams, 2.34 mmoles You, 2.1 equivalents) it is dissolved in 8 milliliters of dry toluene.Ice-water bath cools down and under the atmosphere of nitrogen, by LHMDS (2.34 mmoles You, 2.1 equivalents, 2.34 milliliters, 1 mole every liter of tetrahydrofuran solution) it is added drop-wise in reaction system.Then 2 milliliters of changes are added dropwise Close the toluene solution of object 205 (380 milligrams, 1.11 mMs, 1 equivalent).It is stirred 1.5 hours under the lower condition of ice bath of reaction.Reaction It is quenched, is filtered with saturated sodium bicarbonate, filter cake toluene and water washing obtain the bromo- 8- cyclopenta -2- of yellow solid compound 6- [5 (hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) pyridine -2- amidos] -5- methyl -8H- pyridos [2,3-D] pyrimidin-7-ones (400 milligrams, yield：70.92%) .LCMS (ESI)：m/z 509[M+1]⁺。

Step 3g:6- acetyl group -8- cyclopenta -2- [5 (hexahydro pentamethylene simultaneously [c] pyrroles -2- (1H)-yl) pyridine -2- amine Base] -5- methyl -8H- pyridos [2,3-D] pyrimidin-7-ones (6-acetyl-8-cyclopentyl-2- ((5- (hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)-5-methylpyrido[2, 3-d] p yrimidin-7 (8H)-one) (compound 2) preparation：Under nitrogen protection, by compound 111-2 (100 milligrams, 0.196 mM, 1 equivalent), four triphenyl phosphorus palladiums (22.7 milligrams, 0.0196 mM, 0.1 equivalent) and tributyl (1- ethoxies Base vinyl) tin (0.106 gram, 0.294 mM, 1.5 equivalents) is scattered in 5 milliliters of dry toluenes.Reaction is warming up to reflux, and Reaction 3.5 hours.After reaction, it is concentrated under reduced pressure, residue is purified with silica gel column chromatography, and obtaining yellow solid, (92 milligrams, receive Rate：93.65%).LCMS(ESI):m/z501[M+1]⁺Yellow solid is dissolved in 15 milliliters of dichloromethane.In ice-water bath Under conditions of, 4 moles of hydrochloric acid (2 milliliters) is added dropwise.Reaction is stirred at room temperature 0.5 hour.It is adjusted with saturated sodium carbonate solution PH value to 8-9, dichloromethane extraction, organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, and residue silica gel column chromatography is pure Change, obtains yellow solid 6- acetyl group -8- cyclopenta -2- [5 (hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) pyridine -2- amine Base] and -5- methyl -8H- pyridos [2,3-D] pyrimidin-7-ones (15 milligrams, yield：16.8%).

Target product characterize data：LCMS(ESI)m/z473[M+1]⁺.¹H NMR (500MHz, DMSO-D₆)：δ 9.92 (s, 1H), 8.92 (s, 1H), 7.80-7.72 (m, 2H), 7.12 (dd, J=9.0,3.0Hz, 1H), 5.79 (dd, J=18.0, 9.1Hz, 1H), 3.41 (dd, J=9.4,7.9Hz, 2H), 3.01 (dd, J=9.6,3.7Hz, 2H), 2.77 (d, J=3.6Hz, 2H), 2.42 (s, 3H), 2.30 (s, 3H), 2.24 (dd, J=11.2,7.8Hz, 2H), 1.90-1.63 (m, 7H), 1.62-1.52 (m, 3H), 1.52-1.43 (m, 2H).

The preparation (being prepared according to two circuit of scheme) of 4 compound 4 of embodiment

4- (6- amidos pyridin-3-yl) piperidines -1- t-butyl formates (tert-butyl-4- (6-aminopyridin-3- Yl) piperidine-1-carboxylate) (compound 110-4) preparation：By bromo- 2 nitropyridines of 5-, (2.6 grams, 12.8 in the least Mole, 1.0 equivalents), 4- (4,4,5,5- tetramethyls -1,3,2- bis- Evil borine -2- bases) -5,6- dihydropyridines -1 (2H)-formic acid The tert-butyl ester (tert-butyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6- Dihydropyridine-1 (2H)-carboxylate) (4.8 grams, 15.5 mMs, 1.2 equivalents), bi triphenyl phosphorus dichloride Palladium (0.9 gram, 1.28 mMs, 0.1 equivalent), cesium carbonate (8.4 grams, 25.8 mMs, 2 equivalents) be dissolved in 15 milliliters of water and In 150 milliliters of N,N-dimethylformamides.Under nitrogen protection, reaction system is placed in pre-heated 90 degree of oil baths, is added Thermal response 1 hour.After the completion of reaction, reaction system is cooled to room temperature, ethyl acetate extraction, by organic phase saturated salt solution Washing is multiple, is then dried with anhydrous sodium sulfate, is concentrated under reduced pressure.Finally purified to obtain yellow solid, i.e. 6- with silica gel column chromatography Nitropyridine -3 ', 6 '-dihydros-[3,4'- pyridine] -1'(2'H) and-t-butyl formate (3.53 grams, yield：90%).MS(ESI): m/z 306[M+H]⁺.Above compound (3.53 grams, 11.6 mMs, 1.0 equivalents) is dissolved in 100 ml methanols, then Palladium carbon (0.353 gram) is added.Under hydrogen atmosphere, reaction is stirred at room temperature overnight.After the completion of reaction, filtering, to remove reaction solution In palladium carbon, it is multiple to wash filter cake with methanol, filtrate decompression is concentrated.Finally purified to obtain yellow solid with silica gel column chromatography, I.e. 4- (6- amidos pyridin-3-yl) piperidines -1- t-butyl formates (2.5 grams, yield：78%).MS(ESI):m/z 278[M+H ]⁺。

6- acetyl group -8- cyclopenta -5- methyl -2- (5- (piperidin-4-yl) pyridine -2- amidos) -8H- pyridos [2,3- D] pyrimidin-7-ones (6-acetyl-8-cyclopentyl-5-methyl-2- ((5- (piperidin-4-yl) pyridin-2- Yl) amino) pyrido [2,3-d] pyrimidin-7 (8H)-one) (compound 4) preparation：Synthetic method such as embodiment 3, Only it is that compound 110-2 therein is replaced with into compound 110-4.

Target product characterize data：LCMS(ESI):m/z 447[M+H]⁺.¹H NMR(500MHz,DMSO-D₆):δ10.21 (s, 1H), 8.99 (s, 1H), 8.22 (s, 1H), 7.98 (d, J=8.5Hz, 1H), 7.69 (d, J=8.6Hz, 1H), 5.84 (m, 1H), 3.03 (d, J=11.9Hz, 2H), 2.60 (dd, J=23.9,11.9Hz, 3H), 2.43 (s, 3H), 2.32 (s, 3H), 2.26 (s, 3H), 1.90 (s, 2H), 1.79 (s, 2H), 1.70 (d, J=12.0Hz, 2H), 1.55 (ddd, J=21.3,11.3, 7.0Hz,4H)。

The preparation (being prepared according to two circuit of scheme) of 5 compound 5 of embodiment

By the compound 4 (100 milligrams, 0.224 mM, 1.0 equivalents) of the gained of embodiment 4 and potassium carbonate (62 milligrams, 0.448 mM, 2.0 equivalents) it is scattered in 20 milliliters of n,N-Dimethylformamide.Under nitrogen protection, into reaction system Iodoethane (0.02 milliliter, 0.268 mM, the 1.2 equivalents) solution for being dissolved in 3 milliliters of n,N-Dimethylformamide, room temperature is added dropwise It is stirred to react 5 hours.After complete reaction, it is concentrated under reduced pressure, finally obtains white solid, i.e. 6- acetyl with preparing chromatogram purification Base -8- cyclopenta -2- (5- (1- ethyl piperidine -4- bases) pyridine -2- amidos) -5- methyl -8H- pyrido [2,3-d] pyrimidines -7- Ketone (6-acetyl-8-cyclopentyl-2- ((5- (1-ethylpiperidin-4-yl) pyridin-2-yl) amino) -5- Methylpyrido [2,3-d] pyrimidin-7 (8H)-one) and (compound 5) (27 milligrams, yield：25%).

Target product characterize data：MS(ESI):m/z 475[M+1]⁺。¹H NMR(500MHz,DMSO-D₆):δ10.20 (s,1H),8.99(s,1H),8.24(s,1H),7.99(s,1H),7.74(s,1H),5.84(s,1H),2.99(s,2H),2.42 (s, 3H), 2.32 (dd, J=30.4,18.1Hz, 8H), 1.93 (d, J=31.4Hz, 4H), 1.69 (m, 8H), 1.02 (s, 3H).

The preparation (being prepared according to two circuit of scheme) of 6 compound 6 of embodiment

By the compound 4 (100 milligrams, 0.224 mM, 1.0 equivalents) of the gained of embodiment 4 and triethylamine (0.06 milliliter, 0.448 mM, 2.0 equivalents) it is scattered in 20 milliliters of tetrahydrofurans.Under condition of ice bath, methylsulphur is added dropwise into reaction system Reaction 0.5 hour is stirred at room temperature in acyl chlorides (0.026 milliliter, 0.336 mM, 1.5 equivalents).After complete reaction, dichloromethane is used Alkane extracts, and organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure.Finally purified to obtain white solid, i.e. 6- with silica gel column chromatography Acetyl group -8- cyclopenta -5- methyl -2- (5- (1- methanesulphonylpiperidine -4- bases) pyridine -2- amidos) -8H- pyridos [2,3- D] pyrimidin-7-ones (6-acetyl-8-cyclopentyl-5-methyl-2- ((5- (1- (methylsulfonyl) Piperidin-4-yl) pyridin-2-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H)-one) (compound 6) (26 milligrams, yield：22%).

Target product characterize data：MS(ESI):m/z 525[M+1]⁺。¹H NMR(500MHz,DMSO-D₆):δ10.25 (s, 1H), 9.00 (s, 1H), 8.28 (s, 1H), 8.01 (d, J=8.5Hz, 1H), 7.77 (d, J=6.5Hz, 1H), 5.85 (m, 1H), 3.70 (d, J=12.1Hz, 2H), 2.91 (s, 3H), 2.83 (t, J=11.2Hz, 2H), 2.69 (t, J=12.3Hz, 1H), 2.43 (s, 3H), 2.32 (s, 3H), 2.27 (s, 2H), 1.90 (d, J=11.7Hz, 4H), 1.74 (m, 4H), 1.60 (d, J =5.0Hz, 2H).

The preparation (being prepared according to two circuit of scheme) of 7 compound 7 of embodiment

By the compound 4 (100 milligrams, 0.224 mM, 1.0 equivalents) of the gained of embodiment 4 and potassium carbonate (62 milligrams, 0.448 mM, 2.0 equivalents) it is scattered in 20 milliliters of n,N-Dimethylformamide.Under nitrogen protection, into reaction system Ethylene bromohyrin (0.032 milliliter, 0.448 mM, the 2.0 equivalents) solution for being dissolved in 3 milliliters of n,N-Dimethylformamide is added dropwise, adds Heat is stirred to react overnight to 80 degree.After complete reaction, it is concentrated under reduced pressure, finally obtains white solid with preparing chromatogram purification, i.e., 6- acetyl group -8- cyclopenta -2- (5- (1- (2- ethoxys) piperidin-4-yl) pyridine -2- amidos) -5- picolines simultaneously [2,3- D] pyrimidine -7 (8H) -one (6-acetyl-8-cyclopentyl-2- ((5- (1- (2-hydroxyethyl) piperidin-4- Yl) pyridin-2-yl) amino) -5-methylpyrido [2,3-d] pyrimidin-7 (8H)-one) (compound 7) (62 Milligram, yield：57%).

Target product characterize data：MS(ESI):m/z 491[M+1]₊。¹H NMR(500MHz,DMSO-D₆):δ10.21 (s, 1H), 8.99 (s, 1H), 8.24 (d, J=2.1Hz, 1H), 7.98 (d, J=8.5Hz, 1H), 7.72 (dd, J=8.6, 2.3Hz, 1H), 5.84 (p, J=8.9Hz, 1H), 4.33 (s, 1H), 3.52 (s, 2H), 2.98 (d, J=11.4Hz, 2H), 2.42 (m, 5H), 2.28 (m, 5H), 2.07 (dd, J=11.6,9.4Hz, 2H), 1.90 (s, 2H), 1.69 (m, 9H).

The preparation (being prepared according to scheme three-route) of 8 compound 16 of embodiment

Step 8a：Chloro- 4- amidos -5- iodine pyridines (the 2-chloro-5-iodopyridin-4-amine) (compounds of 2- 302) preparation：Under nitrogen protection, the chloro- 4- amidos pyridines of 2- (15 grams, 0.116 mole, 1 equivalent) are dissolved in acetonitrile (200 Milliliter), oil bath heating is slowly added to NIS (33 grams, 0.139 mole, 1.2 equivalents) to 70 degrees Celsius, stirs 16 hours.It is cooling To room temperature, saturated aqueous sodium carbonate is added, reacting system PH value is adjusted to 9-10, (500 milliliters) extractions of ethyl acetate are added It takes.Organic phase is separated, is used in combination saturated salt solution (100 milliliters) to wash 2 times, after being dried with anhydrous sodium sulfate, reduced under vacuum obtains 2- Chloro- 4- amidos -5- iodine pyridines (23 grams, yield：78.1%), LCMS (ESI):m/z 255[M+1]⁺。

Step 8b：The chloro- 4- cyclopentamines base -5- iodine pyridines (2-chloro-N-cyclopentyl-5-iodopyridin- of 2- 4-amine) the preparation of (compound 303)：Under nitrogen protection, by compound 302 (23 grams, 90.6 mMs, 1 equivalent), carbon Sour caesium (177 grams, 0.544 mole, 6 equivalents), bromocyclopentane (81 grams, 0.544 mole, 6 equivalents) are added in reaction bulb, two Chlorine sulfoxide (500 milliliters) is heated to 90 degrees Celsius as solvent and is stirred to react 36 hours.Filtering, ethyl acetate extraction, organic phase are used Water (500 milliliters) is washed three times, and saturated salt solution (400 milliliters) is washed three times, and anhydrous sodium sulfate drying is concentrated in vacuo to obtain the chloro- 4- of 2- Cyclopentamine base -5- iodine pyridines (6 grams, yield：20.5%), LCMS (ESI):m/z 323[M+1]⁺。

Step 8c:(E) -3- [the chloro- 4- cyclopentamines yl pyridines -3- bases of 6-] -2- butenoic acid ethyls (ethyl (E) -3- (6- Chloro-4- (cyclopentylamino) pyridin-3-yl) but-2-enoate) (compound 304) preparation：In nitrogen Under protection, compound 303 (6 grams, 18.6 mMs, 1 equivalent), sodium carbonate (4.93 grams, 46.5 mMs, 2.5 equivalents), (Z)- 3- (4,4,5,5- tetramethyl -1,3,2- Er Evil borine -2- bases) -2- butenoic acid ethyls (ethyl (Z) -3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) but-2-enoate) (5.8 grams, 24.2 mMs, 1.3 equivalents) and Bi triphenyl phosphorus palladium chloride (1.31 grams, 1.86 mMs, 0.1 equivalent) is put into DMF and water (10 in reaction bulb:1) make solvent, 90 degrees Celsius are heated to, is reacted 3.5 hours.Ethyl acetate (400 milliliters) is added, water (200 milliliters) is washed 3 times, brine (100 millis Rise) it washes 1 time, crude product is obtained after concentration, and (E) -3- [chloro- 4- cyclopentamines yl pyridines -3- of 6- are obtained by silica gel column chromatography separating purification Base] and -2- butenoic acid ethyls (5.2 grams, yield：90.9%), LCMS (ESI):m/z 309[M+1]⁺。

Step 8d：The chloro- 1- cyclopenta -4- methyl-1s of 7-, (1H) -one of 6- naphthyridines -2 (7-chloro-1-cyclopentyl- 4-methyl-1,6-naphthyridin-2 (1H)-one) (compound 305) preparation：By compound 304 (5.2 grams, 16.9 MM, 1 equivalent) it is dissolved in toluene (20 milliliters), DBU (2.57 grams, 1.69 mMs, 0.1 equivalent) is added, is heated to flowing back, Stirring 16 hours.It is down to room temperature, concentrates, the chloro- 1- cyclopenta -4- methyl-1s of 7-, 6- naphthyridines -2 is obtained by column chromatographic isolation and purification (1H) -one (3.7 grams, yield：83.4%).LCMS(ESI):m/z 263[M+1]⁺。

Step 8e：The chloro- 1- cyclopenta -4- methyl-1s of the bromo- 7- of 3-, (1H) -one of 6- naphthyridines -2 (3-bromo-7-chloro- 1-cyclopentyl-4-methyl-1,6-naphthyridin-2 (1H)-one) (compound 306) preparation：Compound 305 (3.7 grams, 14.1 mMs, 1 equivalent) are dissolved in glacial acetic acid (10 milliliters), and sodium acetate is added, and (4.62 grams, 56.4 mMs, 4 work as Amount), 50 degrees Celsius are heated to, bromine (4.9 grams, 15.5 mMs, 1.1 equivalents) is dissolved in acetic acid, is slowly dropped into reaction bulb.It stirs It mixes 3.5 hours.It is cooled to room temperature, is slowly added to saturated aqueous sodium thiosulfate to clarifying, instills saturated aqueous sodium carbonate Reacting system PH value is adjusted to 9-10, (200 milliliters) extractions of DCM are added, crude product is obtained after concentration, is detached by silica gel column chromatography Purify to obtain the chloro- 1- cyclopenta -4- methyl-1s of the bromo- 7- of 3-, and 6- naphthyridines -2 (H) -one (3 grams, yield：62.6%).LCMS(ESI): m/z 341[M+1]⁺。

Step 8f：The chloro- 1- cyclopenta -3- of 7- (1- ethoxy ethylenes base) -4- methyl-1s, (1H) -one of 6- naphthyridines -2 (7- chloro-1-cyclopentyl-3-(1-ethoxyvinyl)-4-methyl-1,6-naphthyridin-2(1H)-one) The preparation of (compound 307)：Under nitrogen protection, by compound 306 (1.5 grams, 4.41 mMs, 1 equivalent), four triphenyl phosphorus Palladium (509 milligrams, 0.44 mM, 0.1 equivalent) and tributyl (1- ethoxy ethylenes) tin (2.07 grams, 5.73 mMs, 1.3 Equivalent) it is placed in reaction bulb and is dissolved in toluene (20 milliliters), it is heated to back flow reaction 16 hours.Crude product is concentrated under reduced pressure to obtain, passes through silica gel Column chromatography for separation purifies to obtain the chloro- 1- cyclopenta -3- of 7- (1- ethoxy ethylenes base) -4- methyl-1s, 6- naphthyridines -2 (1H) -one (1.0 Gram, yield：68.3%).LCMS(ESI):m/z333[M+1]⁺。

Step 8g：4- (6- amidos pyridin-3-yl) piperazine -1- t-butyl formates (tert-butyl 4- (6- Aminopyridin-3-yl) piperazine-1-carboxylate) (compound 308-16) preparation：By the bromo- 2- nitros of 5- Pyridine (40 grams, 197 mMs, 1.0 equivalents), tetrabutylammonium iodide (29.95 grams, 216.7 mMs, 1.1 equivalents), piperazine (20.06 grams, 256.1 mMs, 1.3 equivalents) and potassium carbonate (29.95 grams, 216.7 mM of 1.1 equivalent) are dissolved in 450 millis It rises in dimethyl sulfoxide (DMSO).After reaction is stirred overnight under 80 degree, reaction solution is cooled to room temperature and is extracted with dichloromethane and water, is obtained The organic phase arrived saturated common salt water washing, anhydrous sodium sulfate drying, then concentrated and done with Rotary Evaporators.Product warp after concentration Yellow solid 4- (6- nitropyridine -3- bases) piperazine -1- t-butyl formates (48.9 grams, crude product) are obtained after silica gel column chromatography.It will The compound (48.9 grams, 197 mMs, 1.0 equivalents) and zinc powder (51.52 grams, 788 mMs, 4.0 equivalents) of above-mentioned gained are molten Ammonium chloride (42.15 grams, 788 mMs, 4.0 equivalents) is added in 1000 milliliters of methanol in solution.After being stirred at room temperature 1 hour, use Diatomite filters, and is extracted with dichloromethane and water after filtrate is concentrated, obtained organic phase saturated common salt water washing, anhydrous sulphur Sour sodium drying, then concentrated and done with Rotary Evaporators.Product after concentration obtains brown solid 4- (6- amidos after silica gel column chromatography Pyridin-3-yl) and piperazine -1- t-butyl formates (26.0 grams, two step total recoverys：90%).¹H NMR(500MHz,CDCl₃)：δ9.11 (s,1H),6.19–5.97(m,1H),2.98(s,3H),2.72(s,3H),2.23(s,2H),2.14(s,2H),1.95(s, 2H),1.70(s,2H)。

Step 8h：4- (6- (1- cyclopenta -3- (1- ethoxy ethylenes base) -4- methyl -2- oxo -1,2- dihydros -1,6- Naphthyridines -7- amidos) pyridin-3-yl) piperazine -1- carboxylic acid tert-butyl esters (tert-butyl 4- (6- ((1-cyclopentyl-3- (1- ethoxyvinyl)-4-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)amino)pyridin- 3-yl) piperazine-1-carboxylate) (compound 309-16) preparation：Under nitrogen protection, compound 307 (120 Milligram, 0.361 mM, 1 equivalent), compound 308-16 (151 milligrams, 0.542 mM, 1.5 equivalents), cesium carbonate (259 Milligram, 0.794 mM, 2.2 equivalents), tris(dibenzylideneacetone) dipalladium (33 milligrams, 0.036 mM, 0.1 equivalent), 4, Bis- diphenylphosphine -9, the 9- xanthphos of 5- (21 milligrams, 0.036 mM, 0.1 equivalent) are put into equipped with toluene (20 milliliters) Reaction bulb, be heated to back flow reaction 6 hours.Crude oil is concentrated under reduced pressure to obtain, 4- (6- are obtained by silica gel column chromatography separating purification (1- cyclopenta -3- (1- ethoxy ethylenes base) -4- methyl -2- oxo -1,2- dihydro -1,6- naphthyridines -7- amidos) pyridine -3- Base) and piperazine -1- carboxylic acid tert-butyl esters (100 milligrams, yield：48.5%).LCMS(ESI):m/z 575[M+1]⁺。

Step 8i：3- acetyl group -1- cyclopenta -4- methyl -7- (5- (piperazine -1- bases) pyridine -2- amidos) -1,6- naphthalenes Pyridine -2 (1H) -one (3-acetyl-1-cyclopentyl-4-methyl-7- ((5- (piperazin-1-yl) pyridin-2- Yl) amino) -1,6-naphthyridin-2 (1H)-one) (compound 16) preparation：Compound 309-16 (100 milligrams, 0.175 mM, 1 equivalent) it is dissolved in dichloromethane, 3 milliliters 6 moles every liter of aqueous hydrochloric acid solution is added and is stirred to react 3 hours, uses For aqueous sodium carbonate regulation system pH value to 9-10, yellow solid 3- acetyl group -1- rings penta are concentrated under reduced pressure to obtain in dichloromethane extraction Base -4- methyl -7- (5- (piperazine -1- bases) pyridine -2- amidos) -1,6- naphthyridines -2 (1H) -one (60 milligrams, yield：77.1%).

Target product characterize data：LCMS(ESI):m/z 447[M+1]⁺。¹H NMR(500MHz,DMSO-D₆)：δ9.85 (s, 1H), 8.74 (s, 1H), 8.10 (s, 1H), 7.88 (d, J=2.8Hz, 1H), 7.42 (dd, J=9.1,2.9Hz, 1H), 7.36 (d, J=9.0Hz, 1H), 5.65 (m, 1H), 3.00 (m, 4H), 2.85 (m, 4H), 2.43 (s, 3H), 2.33 (s, 3H), 2.24(m,2H),2.15(m,2H),1.88(m,2H),1.73(m,2H)。

The preparation (being prepared according to three circuit of scheme) of 9 compound 17 of embodiment

4- (6- (1- cyclopenta -3- (1- ethoxy ethylenes base) -4- methyl -2- oxo -1,2- dihydro -1,6- naphthyridines -7- Amido) pyridin-3-yl) pyridine -1- t-butyl formates (tert-butyl 4- (6- ((1-cyclopentyl-3- (1- ethoxyvinyl)-4-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)amino)pyridin- 3-yl) piperidine-1-carboxylate) (compound 309-17) preparation：By compound 307, (150 milligrams, 0.45 in the least Mole, 1.0 equivalents), 110-4 (165 milligrams, 0.585 mM, 1.3 equivalents), cesium carbonate (300 milligrams, 0.9 mM, 2.0 Equivalent), 4,5- bis- diphenylphosphine -9,9- xanthphos (21 milligrams, 0.036 mM, 0.08 equivalent) are scattered in 30 millis It rises in toluene.Under nitrogen protection, Pd is added₂(dba)₃(milligram, 0.018 mM, 0.04 equivalent).The reaction system is set It is heated to reflux, is stirred to react 6 hours in pre-heated 130 DEG C of oil baths.It after the completion of reaction, is cooled to room temperature, is concentrated under reduced pressure. Finally purified to obtain yellow solid, i.e. 4- (6- (1- cyclopenta -3- (1- ethoxy ethylenes base) -4- methyl-with silica gel column chromatography 2- oxo -1,2- dihydro -1,6- naphthyridines -7- amidos) pyridin-3-yl) pyridine -1- t-butyl formates (176 milligrams, yield： 68%).MS(ESI):m/z 574[M+H]⁺。

3- acetyl group -1- cyclopenta -4- methyl -7- (5- (piperidin-4-yl) pyridine -2- amidos) -1,6- naphthyridines -2 (1H) - Ketone (3-acetyl-1-cyclopentyl-4-methyl-7- ((5- (piperidin-4-yl) pyridin-2-yl) amino)- 1,6-naphthyridin-2 (1H)-one) (compound 17) preparation：Synthetic method such as embodiment 8, being only will be therein 309-16 replaces with 309-17.Target product characterize data：MS(ESI):m/z 446[M+1]⁺。¹H NMR(500MHz,DMSO- D⁶)：δ 10.08 (d, J=17.5Hz, 1H), 8.77 (d, J=11.5Hz, 1H), 8.30 (s, 1H), 8.14 (d, J=9.4Hz, 1H), 7.61 (m, 1H), 7.41 (d, J=8.6Hz, 1H), 5.70 (m, 1H), 3.36 (m, 3H), 2.98 (t, J=11.5Hz, 1H), 2.86 (t, J=11.9Hz, 1H), 2.43 (s, 3H), 2.36 (d, J=8.5Hz, 3H), 2.26 (m, 4H), 1.85 (m, 8H)。

The preparation (being prepared according to three circuit of scheme) of 10 compound 18 of embodiment

5- (4- (pyrrolidines -1-) piperidines -1-) pyridine -2- ammonia (5- (4- (pyrrolidin-1-yl) piperidin-1- Yl) pyridin-2-amine) (compound 308-18) preparation：By 4,4- piperidines diol hydrochloride (12 grams, 0.078 mole, 1.0 equivalents) it is dissolved in 100 milliliters of water.In the solution, sequentially adding sodium hydroxide, (3.44 grams, 0.086 mole, 1.1 work as Amount), di-tert-butyl dicarbonate (15.77 milliliters, 0.078 mole, 1.0 equivalents) and tetrahydrofuran (100 milliliters), stir at room temperature It mixes.After reaction 16 hours, reaction solution is extracted in three times for 600 milliliters, then wash organic phase with saturated common salt with dichloromethane.Gained Organic phase is dried via anhydrous sodium sulfate, filter, be concentrated under reduced pressure, obtain white crystal N- tertbutyloxycarbonyl -4- piperidones (15 grams, Yield：98.6%).

This white crystalline Compound (4.5 grams, 0.0226 mole, 1.0 equivalents), and sodium acetate (2.8 grams, 0.034 mole, 1.5 Equivalent), acetic acid (2.2 milliliters) and pyrrolidines (2.2 grams, 0.031 mole, 1.4 equivalents) are dissolved in tetrahydrofuran (100mL), room After temperature stirring 1 hour, acetic acid sodium borohydride (9.6 grams, 0.0452 mole, 2.0 equivalents) is added inward.After reaction 16 hours, subtract Pressure concentration is adjusted to alkalinity, dichloromethane extraction with sodium hydrate aqueous solution.Gained organic phase is dried via anhydrous sodium sulfate, Filtering, be concentrated under reduced pressure, obtain colourless oil liquid 4- pyrrolidinyl piperidines -1- t-butyl formates (4.5 grams, yield：79%). LCMS(ESI):m/z255[M+1]⁺。

Above compound (4.5 grams, 0.0177 mole, 1.0 equivalents) is dissolved in trifluoroacetic acid (50 milliliters), is stirred at room temperature 16 Hour, it is concentrated under reduced pressure to give brown oil fluid product 4- pyrrolidinyls piperidines (2.5 grams, crude product).By this compound (2.7 grams, 17.5 mMs, 1.3 equivalents), the bromo- 2- nitropyridines of 5- (2.97 grams, 13.5 mMs, 1.0 equivalents), tetrabutylammonium iodide (0.247 gram, 6.7 mMs, 0.5 equivalent) and potassium carbonate (4.65 grams, 33.7 mMs, 2.5 equivalents) are dissolved in dimethyl sulfoxide (DMSO) In (50 milliliters), it is warming up to 80 degree and reacts 16 hours.After being cooled to room temperature, it is poured into 100 milliliters of water, then use dichloromethane Extraction three times.Gained organic phase is dried via anhydrous sodium sulfate, is filtered, and is concentrated under reduced pressure, and silica gel column chromatography purifies to obtain 2- nitros- 5- (4- (pyrrolidines -1-) piperidines -1-) pyridine (1.85 grams, yield：50%).LCMS(ESI):m/z277[M+1]⁺。

By above compound (3.0 grams, 10.9 mMs, 1.0 equivalents), (4.9 grams, 92.7 mMs, 8.5 work as ammonium chloride Amount) and water (3 milliliters) be dissolved in ethyl alcohol (50 milliliters), be added portionwise inward under stirring condition iron powder (4.9 grams, 87.5 mMs, 8.0 equivalents).Temperature rising reflux reacts 2 hours, cooling, filtering, and ethyl acetate and methanol washing are concentrated under reduced pressure, silica gel column chromatography is pure Change obtains brown solid 5- (4- (pyrrolidines -1-) piperidines -1-) pyridine -2- ammonia (1.5g, yield：56%).LCMS(ESI):m/ z247[M+1]⁺。

3- acetyl group -1- cyclopenta -4- methyl -7- (5- (4- (pyrroles -1- bases) piperidin-1-yl) pyridine -2- amidos) -1, 6- naphthyridines -2 (1H) -one (3-acetyl-1-cyclopentyl-4-methyl-7- ((5- (4- (pyrrolidin-1-yl) Piperidin-1-yl) pyridin-2-yl) amino) -1,6-naphthyridin-2 (1H)-one) and (compound 18) system It is standby：Synthetic method such as embodiment 8, is only that 308-16 therein is replaced with 308-18.

Target product characterize data：LCMS(ESI):m/z 515[M+1]⁺。¹H NMR(500MHz,DMSO-D₆)：δ9.84 (s, 1H), 8.74 (s, 1H), 8.09 (s, 1H), 7.91 (d, J=2.9Hz, 1H), 7.44 (dd, J=9.1,3.0Hz, 1H), 7.35 (d, J=9.0Hz, 1H), 5.65 (p, J=9.4Hz, 1H), 3.53 (d, J=12.3Hz, 2H), 2.71 (t, J= 10.6Hz,2H),2.51(s,3H),2.43(s,3H),2.33(m,3H),2.17(m,6H),1.90(m,4H),1.72(m,6H), 1.53 (td, J=13.6,3.7Hz, 2H).

The preparation (being prepared according to three circuit of scheme) of 11 compound 19 of embodiment

2- amidos -5- (4- dimethylamino-piperidine -1- bases) pyridine (5- (4- (dimethylamino) piperidin-1- Yl) pyridin-2-amine) (compound 308-19) preparation：Synthetic method such as embodiment 10 is only by pyrrolidines therein Replace with dimethylamine hydrochloride.

Target product characterize data：LCMS(ESI):m/z 221[M+1]⁺。

3- acetyl group -1- cyclopenta -7- [5- (4- dimethylamino-piperidine -1- bases) pyridine -2- amidos] -4- methyl-1s, 6- Naphthyridines -2 (1H) -one (3-acetyl-1-cyclopentyl-7- ((5- (4- (dimethylamino) piperidin-1-yl) Pyridin-2-yl) amino) -4-methyl-1,6-naphthyridin-2 (1H)-one) (compound 19) preparation：Synthesis Method such as embodiment 8, is only that 308-16 therein is replaced with 308-19.

Target product characterize data：Fusing point：209-211℃.LCMS(ESI):m/z 489[M+1]⁺。¹H NMR(500MHz, MeOD)：δ 8.72 (s, 1H), 8.10 (s, 1H), 7.98 (d, J=2.7Hz, 1H), 7.46 (dd, J=8.9,2.9Hz, 1H), 7.21 (d, J=9.0Hz, 1H), 5.69 (m, 1H), 3.70 (d, J=12.4Hz, 2H), 2.76 (m, 2H), 2.70 (m, 1H), 2.53 (s, 6H), 2.47 (s, 3H), 2.39 (s, 3H), 2.34 (m, 2H), 2.18 (m, 2H), 2.07 (m, 2H), 1.97 (d, J= 9.1Hz,2H),1.83–1.68(m,5H).

The preparation (being prepared according to three circuit of scheme) of 12 compound 21 of embodiment

5- (4- ethyl piperidines -1-) picoline -2- ammonia (5- ((4-ethylpiperazin-1-yl) methyl) Pyridin-2-amine) the preparation of (compound 308-21)：By 6- bromopyridine -3- formaldehyde, (5 grams, 26.9 mMs, 1.0 work as Amount) and 4- ethyl piperidines be dissolved in dichloromethane (100 milliliters), after stirring 2 hours, acetic acid sodium borohydride (6.2 is added portionwise inward Gram, 29.2 mMs, 1.1 equivalents).Reaction 16 hours is added 2 moles every liter of sodium hydrate aqueous solution and adjusts PH to alkali inward Property, then extracted with dichloromethane, be concentrated under reduced pressure to give white solid 1- (6- bromopyridines -3-) methyl -4- ethyl piperidines (6.98g, Yield：91.4%), MS (ESI):M/z=285 [M+H]⁺。

By above compound (6.98 grams, 24.6 mMs, 1.0 equivalents), cuprous oxide (97 milligrams, 1.23 mMs, 0.05 equivalent) and methanol (10 milliliters) be dissolved in ammonium hydroxide (30 milliliters), be warming up to 70 degree react 16 hours.Cold filtration, dichloromethane Alkane extract, be concentrated under reduced pressure, by silica gel column chromatography separating purification obtain 5- (4- ethyl piperidines -1-) picoline -2- ammonia (2.0g, Yield：36.4%).MS(ESI):M/z=221 [M+H]⁺。

3- acetyl group -1- cyclopenta -7- (5- (4- ethyl piperidine -1- bases) picoline -2- amidos) -4- methyl-1s, 6- (1H) -one of naphthyridines -2 3-acetyl-1-cyclopentyl-7- ((5- ((4-ethylpiperazin-1-yl) methyl) Pyridin-2-yl) amino) -4-methyl-1,6-naphthyridin-2 (1H)-one (compound 21) preparation：Synthesis Method such as embodiment 8, is only that 308-16 therein is replaced with 308-21.

Target product characterize data：LCMS(ESI):m/z 489[M+1]⁺。^{1H NMR}(500MHz,MeOD)δ8.76(s, 1H), 8.40 (s, 1H), 8.21 (s, 1H), 7.66 (dd, J=8.5,2.1Hz, 1H), 7.23 (d, J=8.5Hz, 1H), 5.73 (p, J=9.2Hz, 1H), 3.52 (s, 2H), 2.42 (m, 18H), 2.24 (s, 2H), 1.98 (m, 2H), 1.82 (m, 2H), 1.09 (t, J=7.2Hz, 3H).

The preparation (being prepared according to five circuit of scheme) of 13 compound 29 of embodiment

Step 13a：Fert-butyidimethylsilyl (3- (tributyl tinbase) propine -1- bases)-oxosilane (tert- Butyldimethyl ((3- (tributylstannyl) prop-2-yn-1-yl) oxy) silane) (compound 502-29) It prepares：By tert-butyl chloro-silicane (15 grams, 93.6 mMs, 1.05 equivalents), (5 grams, 89 mMs, 1.0 work as propilolic alcohol Amount) and imidazoles (12 grams, 178 mMs, 2.0 equivalents) be dissolved in n,N-Dimethylformamide (70 milliliters), and at room temperature It is stirred overnight.Reaction solution is poured into water, is extracted with ethyl acetate, organic phase washes two to three times with saturated common salt, then uses Anhydrous sodium sulfate is dried, then is concentrated.Residue crosses column purification and obtains yellow oily compound tert-butyl group dimethyl-(propinyl- 1-) oxosilane (7.82 grams, yield：52%).Under nitrogen protection, by obtained fert-butyidimethylsilyl-(propinyl -1-) oxygen Silane (1.80 grams, 10.6 mMs, 1.0 equivalents) is dissolved in dry tetrahydrofuran (50 milliliters), is then cooled to -60 DEG C, n-BuLi (6 milliliters, 13.8 mMs, 1.3 equivalents) is added dropwise, then stirs at this temperature half an hour, then at 0 DEG C Stir half an hour.Reaction is down to -60 DEG C again, and tributyltin chloride (3.4 grams, 10.6 mMs, 1.0 equivalents), stirring half is added dropwise Stirring 5 hours is warmed to room temperature after hour.Reaction is quenched with water, is then extracted with ethyl acetate.Organic phase saturated salt solution is clear It washes, then is dried with anhydrous sodium sulfate, concentrated.The quick column purification of crossing of residue obtains yellow oily compound tert-butyl group dimethyl (3- (tributyl tinbase) propine -1- bases)-oxosilane (2.78 grams, yield：57%).

Step 13b：4- (6- ((bromo- 8- cyclopenta -5- methyl -7- oxos -7,8- dihydro pyridos [2,3-d] pyrimidines-of 6- 2- amidos) pyridin-3-yl) piperazine -1- t-butyl formates (tert-butyl 4- (6- ((6-bromo-8-cyclopentyl-5- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl) Piperazi ne-1-carboxylate) (compound 111-29) preparation：By compound 109 (500 milligrams, 1.35 mmoles You, 1.0 equivalents) and compound 308-16 (524 milligrams, 1.62 mMs, 1.2 equivalents) be dissolved in toluene and be heated to reflux stirring 21 hours.By yellow solid 4- (6- ((the bromo- 8- cyclopenta -5- methyl -7- of 6- of reaction solution cold filtration toluene and water washing Oxo -7,8- dihydro pyrido [2,3-d] pyrimidine -2- amidos) pyridin-3-yl) (209 milligrams, receive piperazine -1- t-butyl formates Rate：26.5%).

Target product characterize data：LCMS(ESI):m/z584.2[M+1]⁺.¹H NMR(500MHz,CDCl3)δ8.79(s, 1H), 8.19-8.17 (d, J=10.0Hz, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.35-7.33 (d, J=10.0Hz, 1H),6.00-5.97(m,1H),3.61(s,4H),3.12(s,4H),2.61(s,3H),2.32(s,2H),2.11(s,2H), 1.89(s,2H),1.69(s,2H)。

Step 13c：8- cyclopenta -6- (3- hydroxypropyn -1- bases) -5- methyl -2- [5- (piperazine -1- bases) pyridine -2- amine Base] -8H- pyridos [2,3-D] pyrimidin-7-ones (8-cyclopentyl-6- (3-hydroxyprop-1-yn-1-yl) -5- methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)- One) the preparation of (compound 29).By compound 111-29 (150 milligrams, 0.25 mM, 1.0 equivalents), tetra-triphenylphosphine palladium (30 milligrams, 0.025 mM, 0.1 equivalent) and compound 502-29 (133 milligrams, 0.4 mM, 1.6 equivalents) are dispersed in first In benzene (10 milliliters), then it is heated to reflux under nitrogen protection 4.5 hours.Reaction mixture is cooled to room temperature, and concentration obtains Residue cross column purification obtain yellow solid (104 milligrams, yield：61.7%).LCMS(ESI):m/z674[M+1]⁺。

Above-mentioned solid is dissolved in dichloromethane (100 milliliters), then ice bath cools down.Trifluoroacetic acid is added dropwise to reaction solution (3 milliliters), are then stirred at room temperature overnight.With the pH value of saturated sodium carbonate solution tune reaction solution to 8-9, liquid separation.Organic phase is used Anhydrous sodium sulfate is dried, and is spin-dried for solvent and is obtained yellow solid, purifies to obtain yellow solid compound 8- cyclopenta -6- by column chromatography (3- hydroxypropyn -1- bases) -5- methyl -2- [5- (piperazine -1- bases) pyridine -2- amidos] -8H- pyridos [2,3-D] pyrimidine -7- Ketone (42 milligrams, yield：60.8%).

Target product characterize data：LCMS(ESI):m/z460[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.07 (s, 1H), 8.88 (s, 1H), 8.04 (d, J=2.6Hz, 1H), 7.87 (d, J=9.0Hz, 1H), 7.46 (dd, J=9.0, 2.7Hz, 1H), 5.91-5.80 (m, 1H), 5.29 (s, 1H), 4.35 (s, 2H), 3.17-3.07 (m, 4H), 2.96 (d, J= 4.4Hz, 4H), 2.56 (s, 3H), 2.19 (d, J=3.3Hz, 2H), 1.90 (s, 2H), 1.76 (d, J=4.8Hz, 2H), 1.58 (d, J=4.7Hz, 2H).

The preparation (being prepared according to five circuit of scheme) of 14 compound 30 of embodiment

4- (tributyl tinbase) -3- butyne-2-alcohols (4- (tributylstannyl) but-3-yn-2-ol) (compound Preparation 502-30)：By compound 3- butyne-2-alcohols (0.5 gram, 7.14 mMs, 1.0 equivalents) and trimethyl silicane potassium alcoholate (1.83 grams, 14.28 mMs, 2.0 equivalents) are dissolved in tetrahydrofuran (75 milliliters), and normal-butyl oxidation is then added into solution Tin (7.27 milliliters, 14.28 mMs, 2.0 equivalents) is simultaneously stirred at room temperature 4 hours.Reaction solution is poured into water, with acetic acid second Ester extracts, and organic phase washes two to three times with saturated common salt, is then dried with anhydrous sodium sulfate, then concentrate.It is pure that residue crosses column Change obtain yellow oily target compound 4- (tributyl tinbase) -3- butyne-2-alcohols (1.86 grams, yield：68%).

8- cyclopenta -6- (3- hydroxyl -1- butine -1- bases) -5- methyl -2- [5- (piperazine -1- bases) pyridine -2- amidos] - 8H- pyridos [2,3-D] pyrimidin-7-ones (8-cyclopentyl-6- (3-hydroxybut-1-yn-1-yl) -5-methyl- 2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-on e) The preparation of (compound 30)：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-30.

Target product characterize data：LCMS(ESI):m/z 474[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.03 (s, 1H), 8.88 (s, 1H), 8.02 (s, 1H), 7.86 (d, J=9.1Hz, 1H), 7.44 (d, J=9.3Hz, 1H), 5.92- 5.78 (m, 1H), 5.46 (d, J=5.2Hz, 1H), 4.66-4.59 (m, 1H), 3.06 (s, 4H), 2.85 (s, 4H), 2.55 (s, 3H), 2.19 (s, 2H), 1.90 (s, 2H), 1.75 (s, 2H), 1.59 (s, 2H), 1.40 (d, J=6.5Hz, 3H)

The preparation (being prepared according to five circuit of scheme) of 15 compound 31 of embodiment

Tributyl (2- methyl-1s, 3- bis- Yang Evil ring -2- acetenyls) stannane (tributyl ((2-methyl-1,3- Dioxolan-2-yl) ethynyl) stannane) (compound 502-31) preparation：By compound 3- crotonylenes -one (1.0 Gram, 14.7 mMs, 1.0 equivalents), ethylene glycol (1 milliliter, 18.4 mMs, 1.25 equivalents) and p-methyl benzenesulfonic acid (2 milligrams) It is dissolved in dichloromethane (8 milliliters), and is heated to reflux 4 hours until the reaction was complete.Reaction solution is poured into water after cooling, is used Dichloromethane extracts, and organic phase washes two to three times with saturated sodium bicarbonate solution, and salt is washed 2 times, and anhydrous sodium sulfate is then used It is dry, then colorless oil compound 2- acetenyl -2- methyl-1s are concentrated to give, 3- bis- Yang oxanes (260 milligrams, yield： 15.8%).

Under nitrogen protection, by upper step 2- acetenyls -2- methyl-1s obtained by the reaction, 3- bis- Yang oxanes (260 milligrams, 2.32 mMs, 1.0 equivalents) it is dissolved in dry tetrahydrofuran (25 milliliters), -60 DEG C are cooled to, n-BuLi is added dropwise (1.3 milliliters, 3.12 mMs, 1.3 equivalents), are then stirred half an hour at this temperature, then half an hour is stirred at 0 DEG C.Reaction Liquid is subsequently reduced to -60 DEG C, and tributyltin chloride (746 milligrams, 2.32 mMs, 1.0 equivalents) is added dropwise, and is risen to after stirring half an hour It is stirred at room temperature 5 hours.Reaction is quenched with water, is then extracted with ethyl acetate.Organic phase is cleaned with saturated salt solution, then with anhydrous Sodium sulphate is dried, concentration.The quick column purification of crossing of residue obtains colorless oil compound tributyl (2- methyl-1s, 3- bis- Yang Evil Ring -2- acetenyls) and stannane (903 milligrams, yield：96.7%).

8- cyclopenta -- 6- (3- hydroxyl -1- butine -1- bases) -- 2- [5- (piperazine -1- bases) pyridine -2- amidos] -8H- pyrroles Pyridine simultaneously [2,3-D] pyrimidin-7-ones (8-cyclopentyl-5-methyl-6- (3-oxobut-1-yn-1-yl) -2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H)-one) (compound 31) preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-31.

Target product characterize data：LCMS(ESI):m/z 472[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.27 (s, 1H), 8.98 (s, 1H), 8.05 (d, J=3.0Hz, 1H), 7.83 (d, J=9.0Hz, 1H), 7.46 (dd, J=9.0, 3.0Hz,1H),5.88–5.77(m,1H),3.18–3.06(m,4H),2.98–2.83(m,4H),2.63(s,3H),2.44(s, 3H), 2.20 (s, 2H), 1.90 (s, 2H), 1.77 (s, 2H), 1.58 (d, J=5.2Hz, 2H).

The preparation (being prepared according to five circuit of scheme) of 16 compound 32 of embodiment

Tributyl-(3- methoxyl group propine -1- bases) stannane tributyl (3-methoxyprop-1-yn-1-yl) The preparation of stannane (compound 502-32)：Under nitrogen protection, sodium hydride (961 milligrams, 40.05 mMs, 1.5 equivalents) Be suspended in 35 milliliters of dry tetrahydrofurans, then ice bath cooling under be slowly added dropwise propilolic alcohol (1.5 grams, 26.7 mMs, 1.0 equivalents), it drips off and is heated to 40 DEG C of reactions overnight.Under nitrogen protection, reaction solution is cooled to -60 DEG C, and n-BuLi is added dropwise (11.1 milliliters, 26.7 mMs, 1.0 equivalents), are then stirred half an hour at this temperature, and half an hour is then stirred at 0 DEG C.So After react and be down to -60 DEG C again, be warmed to room temperature stirring 5 after tributyltin chloride (8.69 grams, 26.7 mMs, 1.0 equivalents) is added dropwise Hour.Reaction is quenched with water, is then extracted with ethyl acetate.Organic phase is cleaned with saturated salt solution, then dry with anhydrous sodium sulfate It is dry, concentration.The quick column purification of crossing of residue obtains colorless oil compound tributyl-(3- methoxyl group propine -1- bases) stannane (3.72 grams, crude product).

8- cyclopenta -6- (3- methoxyl group propine -1- bases) -5- methyl -2- [5- (piperazine -1- bases) pyridine -2- amidos] - 8H- pyridos [2,3-D] pyrimidin-7-ones 8-cyclopentyl-6- (3-methoxyprop-1-yn-1-yl) -5-methyl- 2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H)-one (changes Close object 32) preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-32.

Target product characterize data：LCMS(ESI):m/z 474[M+1]⁺.^{1H NMR}(500MHz,DMSO-D6)δ10.05 (s, 1H), 8.90 (s, 1H), 8.05 (d, J=3.0Hz, 1H), 7.87 (d, J=9.0Hz, 1H), 7.46 (dd, J=9.1, 3.0Hz, 1H), 5.90-5.77 (m, 1H), 4.38 (s, 2H), 3.36 (s, 3H), 3.16 (dd, J=10.1,5.4Hz, 4H), 3.03-2.91 (m, 4H), 2.56 (s, 3H), 2.21 (dd, J=11.4,7.8Hz, 2H), 1.90 (s, 2H), 1.81-1.69 (m, 2H),1.62–1.54(m,2H).

The preparation (being prepared according to five circuit of scheme) of 17 compound 33 of embodiment

Cyclopenta tributyl tin propinyl ether (tributyl (3- (cyclopentyloxy) prop-1-yn-1-yl) Stannane) the preparation of (compound 502-33)：Cyclopentanol (3 grams, 34.9 mMs, 1.0 equivalents) is dissolved in 100 milliliters of dryings Tetrahydrofuran in, under 0 degree Celsius, be slowly added to 80% sodium hydride (2 grams, 69.8 mMs, 2.0 equivalents), stirring one 3- propargyl bromides (5 grams, 41.9 mMs, 1.2 equivalents) are added after a hour.After reaction is placed in normal-temperature reaction 12 hours, 100 milliliters of ice water are added at 0 degree, then dichloromethane (100 milliliters × 3) are used to extract, mixed organic phase anhydrous sodium sulfate It is dry, then filter, be concentrated under reduced pressure, obtained after silica gel column chromatography yellow oil propine cyclopentyl ether (2.5 grams, yield： 57.8%).Compound obtained above (3.4 grams, 27.4 mMs, 1.0 equivalents) is dissolved in 100 milliliters of dry tetrahydrofurans In, under conditions of minus 78 degree, 1M n-BuLis (32.9 mMs, 1.2 equivalents) are slowly added to, tributyl chlorination is then added Tin (8.9 grams, 27.4 mMs, 1.0 equivalents).After being reacted 2 hours at minus 78 degree, normal-temperature reaction is moved to 16 hours, decompression is dense Contracting, silica gel column chromatography obtain yellow oil cyclopenta tributyl tin propinyl ether (11.7 grams, yield：100%).

8- cyclopenta -6- (3- cyclopentyloxy -1- propinyls) -5- methyl -2- (5- (piperazine -1- bases) pyridine -2- amidos) - 7,8- dihydropyridines [2,3-d] pyrimidin-7-ones (8-Cyclopentyl-6- (3-cyclopentyloxy-prop-1-ynyl)- 5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7- One) the preparation of (compound 33)：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-33.

Target product characterize data：LCMS(ESI):m/z528[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.03 (s, 1H), 8.90 (s, 1H), 8.04 (d, J=3.0Hz, 1H), 7.86 (d, J=9.0Hz, 1H), 7.45 (dd, J=9.1, 3.0Hz,1H),5.90–5.80(m,1H),4.39(s,2H),4.17(m,1H),3.10–3.04(m,4H),2.90–2.83(m, 4H),2.57(s,3H),2.22(m,2H),1.91(m,2H),1.81–1.57(m,10H),1.55–1.49(m,2H).

The preparation (being prepared according to five circuit of scheme) of 18 compound 34 of embodiment

4- (6- (bromo- 8- cyclopenta -5- methyl -7- oxos -7,8- dihydro pyridos [2,3-d] pyrimidine -2- amidos of 6-) pyrroles Pyridine -3- methyl) piperazine -1- t-butyl formates (tert-butyl 4- ((6- ((6-bromo-8-cyclopentyl-5- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl) Methyl) piperazine-1-carboxylate) (111-34) preparation：By Boc piperazines (1.1 grams, 5.9 mMs, 1.1 Equivalent) it is added to the dichloromethane (100 of compound 6-bromonicotinaldehyde (1.0 grams, 5.4 mMs, 1 equivalent) Milliliter) in solution.Mixed system is stirred at room temperature 2 hours.Acetic acid sodium borohydride is added on a small quantity in batches, and (5.15 grams, 24.3 in the least Mole, 4.5 equivalents), reaction is stirred at room temperature overnight in reaction system.Reaction is quenched with the sodium hydroxide solution of 2N, is used in combination two Chloromethanes extracts.Merge organic phase, anhydrous sodium sulfate drying is concentrated under reduced pressure, obtains 4- (6- bromopyridine -3- methyl) piperazine -1- The amidocarbonic acid tert-butyl ester (2.25 grams, crude product).LCMS(ESI):m/z 357[M+1]⁺。

30 milliliters of ammonium hydroxide are added to above compound (1.5 grams, 4.21 mMs, 1 equivalent) and cuprous oxide (20 millis Gram, 0.14 mM, 30 equivalents) methanol (40 milliliters) solution in, mixture be heated to 70 DEG C and be stirred to react overnight.Instead It answers system to be cooled to room temperature, filters.Filtrate decompression concentrates, after dichloromethane dissolving with the sodium hydroxide solution of 2N adjust PH to 12-14.Merge organic phase, anhydrous sodium sulfate drying is concentrated under reduced pressure, and residue silica gel column chromatography purifies to obtain compound 4- (6- Amido pyridine -3- methyl) piperazine -1- amidocarbonic acids tert-butyl ester (1.24 grams, crude product) .LCMS (ESI):m/z 293[M+1]⁺。

Under the protection of nitrogen, the compound (613 milligrams, 2.1 mMs, 2.1 equivalents) of above-mentioned preparation is dissolved in drying Toluene (10 milliliters).It is cooled to 0 DEG C, LiHMDS is slowly added dropwise under stirring conditions, and (2.1 milliliters, 2.1 mMs, 2.1 work as Amount).Mixed system is stirred for 10min at 0 DEG C.Then by 20 milliliters of compound 1-1-B5, (342 milligrams, 1 mM, 1 works as Amount) toluene solution be added to system, at room temperature stir 1 hour.Reaction is quenched with sodium bicarbonate solution, filtering, filter cake With toluene and washing, compound as white solid 4- (6- (the bromo- 8- cyclopenta -5- methyl -7- oxos -7,8- of 6- bis- are obtained after drying Pyridinium hydroxide simultaneously [2,3-d] pyrimidine -2- amidos) pyridine -3- methyl) piperazine -1- t-butyl formates (290 milligrams, yield： 48.4%) .LCMS (ESI):m/z 599[M+1]⁺。

8- cyclopenta-6- (3- hydroxypropyn-1- bases)-5- methyl-2- (5-(piperazine-1- methyl)-pyridine-2- amidos]- 8H- pyridos [2,3-D] pyrimidin-7-ones (8-cyclopentyl-6- (3-hydroxyprop-1-yn-1-yl) -5-methyl- 2-((5-(piperazin-1-ylmethyl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimi din-7(8H)- One) the preparation of (compound 34)：Synthetic method such as embodiment 13, is only that 111-29 therein is replaced with 111-34.

Target product characterize data：LCMS(ESI):m/z 474[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.25 (s, 1H), 8.94 (s, 1H), 8.22 (s, 1H), 8.03 (d, J=8.5Hz, 1H), 7.72 (d, J=7.6Hz, 1H), 5.93- 5.81 (m, 1H), 5.33 (s, 1H), 4.36 (d, J=4.7Hz, 2H), 3.42 (s, 2H), 2.70 (s, 4H), 2.58 (s, 3H), 2.30(s,4H),2.21(s,2H),1.93(s,2H),1.78(s,2H),1.60(s,2H)。

The preparation (being prepared according to five circuit of scheme) of 19 compound 35 of embodiment

By 111-34 (0.12 gram, 0.2 mM, 1.0 equivalents), four triphenyl phosphorus palladiums (0.021 gram, 0.02 mM, 0.1 equivalent) and 502-30 (1.86 grams, 5.15 mMs, 25 equivalents) be scattered in 15 milliliters of toluene, by step 13c methods close At obtaining yellow solid 8- cyclopenta -6- (3- hydroxyl butine -1- bases) -5- methyl -2- (5- (piperazine -1- methyl) pyridine -2- Amido) -8H- pyridos [2,3-d] (8H) -one 8-cyclopentyl-6- of pyrimidine -7 (3-hydroxybut-1-yn-1-yl) - 5-methyl-2-((5-(piperazin-1-ylmethyl)pyri din-2-yl)amino)pyrido[2,3-d] Pyrimidin-7 (8H)-one (61 milligrams, yield：71%).

Target product characterize data：LCMS(ESI):m/z 488[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.24 (s, 1H), 8.93 (s, 1H), 8.22 (s, 1H), 8.03 (d, J=8.4Hz, 1H), 7.72 (d, J=8.3Hz, 1H), 5.87 (m, 1H), 5.45 (d, J=5.4Hz, 1H), 4.64 (m, 1H), 3.42 (s, 2H), 2.67 (s, 4H), 2.57 (s, 3H), 2.29 (s, 4H), 2.21 (s, 2H), 1.93 (s, 2H), 1.77 (s, 2H), 1.57 (d, J=23.6Hz, 2H), 1.41 (d, J=6.5Hz, 3H)。

The preparation (being prepared according to five circuit of scheme) of 20 compound 36 of embodiment

3- (tributyl tinbase) -2- propine amidos t-butyl formate (tert-butyl 3- (tributylstannyl) Prop-2-ynylcarbamate) the preparation of (compound 502-36)：By 2- propine amidos t-butyl formate, (0.61 gram, 3.9 rub You, 1.0 equivalents) it is dissolved in 10 milliliters of dry tetrahydrofurans, nitrogen is replaced 3 times, and after being cooled to -60 degree, positive fourth is added dropwise inward Base lithium (4.0 milliliters, 9.6 mMs, 2.5 equivalents) is warming up to 0 degree of stirring half an hour, so after stirring half an hour at this temperature This buff reaction solution is cooled to -60 degree once again afterwards.By (1.65 grams, 5.07 mMs, 1.3 equivalents) drops of tributyltin chloride It is added in reaction solution, then half an hour is stirred under -60 degree, be warming up to and be stirred at room temperature 3 hours.Reaction is quenched with water, second is added Acetoacetic ester is extracted, the organic phase saturated common salt water washing of extraction, anhydrous sodium sulfate drying, then is concentrated with Rotary Evaporators It is dry.Product after concentration obtains the tertiary fourth of brown oil 3- (tributyl tinbase) -2- propine amidocarbonic acids after silica gel column chromatography Ester (1.2 grams, yield：68.5%).

6- (3- amido propine -1- bases) -8- cyclopenta -5- methyl -2- (5- (piperazine -1- bases) pyridine -2- amidos) -8H- Pyrido [2,3-D] pyrimidin-7-ones (6- (3-aminoprop-1-ynyl) -8-cyclopentyl-5-methyl-2- (5- (piperazin-1-yl) pyridin-2-ylamino) pyrido [2,3-d] pyrimidin-7 (8H)-one) (compound 36) Preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-36.

Target product characterize data：LCMS(ESI):m/z459[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ9.98(s, 1H), 8.87 (s, 1H), 8.02 (d, J=2.9Hz, 1H), 7.86 (d, J=9.0Hz, 1H), 7.43 (dd, J=9.1,3.0Hz, 1H),5.95–5.79(m,1H),3.59(s,2H),3.13–3.02(m,4H),2.93–2.81(m,4H),2.56(s,3H), 2.21-2.17(m,2H),1.91(s,2H),1.83–1.70(m,2H),1.67–1.54(m,2H)。

The preparation (being prepared according to five circuit of scheme) of 21 compound 37 of embodiment

N, TMSDMA N dimethylamine base -3- (tributyl tin alkyl) propine (N, N-dimethyl-3- (tributylstannyl) Prop-2-yn-1-amine) (compound 502-37).By compound N, and -1 amine of N- dimethyl 2- propine (300 milligrams, 3.6 mmoles You, 1.0 equivalents) and trimethyl silicane potassium alcoholate (462 milligrams, 3.6 mMs, 1.0 equivalents) be dissolved in tetrahydrofuran (50 milliliters), Add normal-butyl tin oxide (2.15 grams, 3.6 mMs, 1.0 equivalents) into above-mentioned solution and is stirred at room temperature overnight.It will reaction Solvent in vacuo is spin-dried for.Residue crosses column purification and obtains yellow oily target compound N, TMSDMA N dimethylamine base -3- (tributyl stannanes Base) propine (2.104 grams, crude product).

8- cyclopenta -6- (3- dimethyl amido propine -1- bases) -5- methyl -2- [[5- (piperazine -1- bases) pyridine -2- amine Base] -8H- pyridos [2,3-D] pyrimidin-7-ones (8-cyclopentyl-6- (3- (dimethylamino) prop-1-yn-1- yl)-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidi N-7 (8H)-one) (compound 37) preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502- 37。

Target product characterize data：LCMS(ESI):m/z 487[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.03 (s, 1H), 8.88 (s, 1H), 8.06 (s, 1H), 7.88 (d, J=8.3Hz, 1H), 7.47 (d, J=6.9Hz, 1H), 5.84 (s, 1H), 3.51 (s, 2H), 3.19 (s, 4H), 3.02 (s, 4H), 2.57 (s, 3H), 2.25 (d, J=19.7Hz, 8H), 1.90 (s, 2H),1.75(s,2H),1.59(s,2H)。

The preparation (being prepared according to five circuit of scheme) of 22 compound 38 of embodiment

The system of 3- butyl tinbase propioloyl amine (3-tributylstannyl-propynamide) (compound 502-38) It is standby：By propine amide (0.5 gram, 7.24 mMs, 1.0 equivalents) and trimethyl silanol, (0.95 gram, 7.24 mMs, 1.0 work as Amount) it is dissolved in 50 milliliters of tetrahydrofurans.Then into the reaction solution be added tributyltin oxide (3.7 milliliters, 7.24 mmoles You, 1.0 equivalents), reaction 1 hour is stirred at room temperature, decompression is spin-dried for.Last silica gel column chromatography purifies to obtain colourless transparent liquid Tributyl tinbase propioloyl amine (2.03 grams, yield：78%).

4-6- (6- propine amide -8- cyclopenta -5- methyl -7- oxo -7,8- dihydro pyridos [2,3-d] pyrimidine -2- amine Base)-pyridin-3-yl) piperazine (3- (8-cyclopentyl-5-methyl-7-oxo-2- ((5- (piperazin-1-yl) Pyridin-2-yl) amino) -7,8-dihydropyrido [2,3-d] pyrimidin-6-yl) propiolamide) (chemical combination Object 38) preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-38.

Target product characterize data：LCMS(ESI)m/z 473[M+1]⁺.1H NMR(500MHz,DMSO-D6)δ10.11 (s, 1H), 8.93 (s, 1H), 8.07 (m, 2H), 7.83 (m, 1H), 7.59 (s, 1H), 7.43 (d, J=7.8Hz, 1H), 5.86- 5.83(m,1H),3.09(s,4H),2.84(s,4H),2.61(s,3H),2.19(s,2H),1.90(s,2H),1.77(s,2H), 1.59(s,2H)。

The preparation (being prepared according to five circuit of scheme) of 23 compound 39 of embodiment

Tributyl (phenylacetylene base) stannane (tributyl (phenylethynyl) stannane) (compound 502-39) It prepares：Under nitrogen protection, compound phenylacetylene (1.0 grams, 9.8 mMs, 1.0 equivalents) is dissolved in dry tetrahydrofuran In (40 milliliters), -60 DEG C are cooled to, n-BuLi (5.3 milliliters, 12.7 mMs, 1.3 equivalents) is added dropwise by syringe, It is stirred at a temperature of this half an hour, half an hour is then stirred at 0 DEG C.Final reaction is down to -60 DEG C again, and tributyltin chloride is added dropwise (3.15 grams, 9.8 mMs, 1.0 equivalents) are warmed to room temperature stirring 3 hours after stirring half an hour.Reaction is quenched with water, then uses Ethyl acetate extracts.Organic phase is cleaned with saturated salt solution, then is dried with anhydrous sodium sulfate, concentration.The quick column excessively of residue is pure Change obtains yellow oily compound tributyl (phenylacetylene base) stannane (4.35 grams, crude product).

8- cyclopenta -5- methyl -6- phenylacetylene bases -- 2- [5- (piperazine -1- bases) pyridine -2- amidos] -8H- pyridos [2, 3-D] pyrimidin-7-ones (8-cyclopentyl-5-methyl-6- (phenylethynyl) -2- ((5- (piperazin-1-yl) Pyridin-2-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H)-one) (compound 39) preparation：Synthetic method Only it is that 502-29 therein is replaced with into 502-39 such as embodiment 13.

Target product characterize data：LCMS(ESI):m/z506[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.10 (s, 1H), 8.94 (s, 1H), 8.07 (d, J=3.0Hz, 1H), 7.90 (d, J=9.1Hz, 1H), 7.63-7.52 (m, 2H), 7.49-7.39 (m, 4H), 5.89 (dt, J=18.0,9.0Hz, 1H), 3.25-3.14 (m, 4H), 3.12-2.95 (m, 4H), 2.65 (s, 3H), 2.24 (dd, J=11.4,7.9Hz, 2H), 1.93 (s, 2H), 1.86-1.68 (m, 2H), 1.69-1.50 (m, 2H)。

The preparation (being prepared according to five circuit of scheme) of 24 compound 40 of embodiment

Tributyl (4- fluorophenylethynyls) stannane (tributyl ((4-fluorophenyl) ethynyl) stannane) The preparation of (compound 502-40)：Under nitrogen protection, (588 grams, 4.9 mMs, 1.0 equivalents) dissolvings of 1- acetylene -4- fluorobenzene In dry tetrahydrofuran (40 milliliters), be cooled to -60 DEG C, by syringe be added dropwise n-BuLi (2.7 milliliters, 6.4 mmoles You, 1.3 equivalents), reaction mixture stirs half an hour at this temperature, and half an hour is then stirred at 0 DEG C.Reaction is down to -60 again DEG C, tributyltin chloride (1.6 grams, 4.9 mMs, 1.0 equivalents) is added dropwise, stirring 3 hours is warmed to room temperature after stirring half an hour.With Water quenching is gone out after reaction, is extracted with ethyl acetate.Organic phase is cleaned with saturated salt solution, then is dried with anhydrous sodium sulfate, concentration.It is residual The quick column purification of crossing of object is stayed to obtain yellow oily compound tributyl (4- fluorophenylethynyls) stannane (4.69 grams, crude product).

8- cyclopenta -6- (4- fluorophenylethynyls] -5- methyl -2- [5- (piperazine -1- bases) pyridine -2- amidos] -8H- pyrroles Pyridine simultaneously [2,3-D] pyrimidin-7-ones (8-cyclopentyl-6- ((4-fluorophenyl) ethynyl) -5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H)-one) (chemical combination Object 40) preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-40.

Target product characterize data：LCMS(ESI):m/z524[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.08 (s, 1H), 8.94 (s, 1H), 8.05 (d, J=3.0Hz, 1H), 7.88 (d, J=9.0Hz, 1H), 7.67-7.55 (m, 2H), 7.47 (dd, J=9.1,3.1Hz, 1H), 7.35-7.21 (m, 2H), 5.97-5.82 (m, 1H), 3.18-3.10 (m, 4H), 3.01-2.92 (m, 4H), 2.64 (s, 3H), 2.23 (dd, J=11.4,8.0Hz, 2H), 1.92 (s, 2H), 1.83-1.73 (m, 2H), 1.60 (dd, J=10.3,5.3Hz, 2H).

The preparation (being prepared according to five circuit of scheme) of 25 compound 41 of embodiment

Tributyl (4- chlorobenzenes acetenyl) stannane (tributyl ((4-chlorophenyl) ethynyl) stannane) The preparation of (compound 502-41)：Under nitrogen protection, (670 grams, 4.9 mMs, 1.0 equivalents) dissolvings of 1- acetylene -4- chlorobenzenes In dry tetrahydrofuran (40 milliliters), be cooled to -60 DEG C, by syringe be added dropwise n-BuLi (2.7 milliliters, 6.4 mmoles You, 1.3 equivalents), reaction mixture stirs half an hour at this temperature, and half an hour is then stirred at 0 DEG C.Final reaction drops again To -60 DEG C, tributyltin chloride (1.6 grams, 4.9 mMs, 1.0 equivalents) is added dropwise, it is small that stirring 3 is warmed to room temperature after stirring half an hour When.Reaction is quenched with water, is then extracted with ethyl acetate.Organic phase is cleaned with saturated salt solution, then is dried with anhydrous sodium sulfate, Concentration.Residue it is quick cross column purification obtain yellow oily compound tributyl (4- chlorobenzenes acetenyl) stannane (5.52 grams, slightly Product).

8- cyclopenta-6- (4-chlorobenzene acetenyls]-5- methyl-2- [5- (piperazine-1- bases) pyridine-2- amidos]-8H- pyridines And [2,3-D] pyrimidin-7-ones (6- ((4-chlorophenyl) ethynyl) -8-cyclopentyl-5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H)-one) (compound 41) preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-41.

Target product characterize data：LCMS(ESI):m/z 541[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.13 (s, 1H), 8.95 (s, 1H), 8.08 (d, J=2.9Hz, 1H), 7.90 (d, J=9.0Hz, 1H), 7.61-7.54 (m, 2H), 7.53-7.47 (m, 3H), 5.87 (dd, J=17.5,8.7Hz, 1H), 3.24-3.19 (m, 4H), 3.12-3.04 (m, 4H), 2.64 (d, J=6.0Hz, 3H), 2.27-2.19 (m, 2H), 1.93 (s, 2H), 1.79 (d, J=9.2Hz, 2H), 1.68-1.52 (m,2H)。

The preparation (being prepared according to five circuit of scheme) of 26 compound 42 of embodiment

4- ((tributyl tinbase) acetenyl) anilino- t-butyl formate (tert-butyl 4- ((tributylstannyl) ethynyl) phenylcarbamate) (compound 502-42) preparation：By paraiodoaniline (2.2 Gram, 10 mMs, 1.0 equivalents), bi triphenyl phosphorus palladium chloride (0.175 gram, 0.25 mM, 0.025 equivalent) and iodate it is sub- Copper (40 milligrams, 0.35 mM, 0.035 equivalent) is added in 10 milliliters of triethylamines.Reaction solution is placed under nitrogen protection, so After add trimethylsilyl acetylene (1.47 grams, 15 mMs, 1.5 equivalents).After reaction overnight at normal temperatures, by reaction solution second Acetoacetic ester and water extraction, obtained organic phase saturated common salt water washing, anhydrous sodium sulfate drying, then concentrated with Rotary Evaporators It is dry.Product after concentration obtained after silica gel column chromatography brown solid 4- (trimethyl silicon substrate) acetylenylaniline (1.5 grams, yield： 79%).Obtained 4- (trimethyl silicon substrate) acetylenylaniline (1.5 grams, 7.94 mMs, 1.0 equivalents) is dissolved in 10 millis In the tetrahydrofuran risen, at 0 degree Celsius, after ten minutes, tetrabutyl ammonium fluoride is added, and (2 grams, 23.8 mMs, 3.0 work as stirring Amount) after half an hour at normal temperatures, reaction solution ethyl acetate and water are extracted, obtained organic phase saturated common salt water washing, Anhydrous sodium sulfate is dried, then is concentrated and done with Rotary Evaporators.Product after concentration obtains white solid pair after silica gel column chromatography Amido phenylacetylene (0.7 gram, yield：79%).LCMS(ESI):m/z118[M+1]⁺.^{1H NMR}(500MHz,CDCl₃)δ7.32– 7.27(m,2H),6.61–6.56(m,2H),3.82(s,2H),2.96(s,1H)。

Gained is dissolved in 20 milliliters of dichloromethane amido phenylacetylene (0.55 gram, 4.7 mMs, 1.0 equivalents), Addition triethylamine (1.96 milliliters, 14.1 mMs, 2.0 equivalents) inward, di-tert-butyl dicarbonate (2.05 grams, 9.4 mMs, 2.0 equivalents).After reacting 24 hours at normal temperatures, reaction solution dichloromethane and water are extracted, obtained organic phase is eaten with saturation Salt water washing, anhydrous sodium sulfate drying, then concentrated and done with Rotary Evaporators.Product after concentration obtains nothing after silica gel column chromatography Color grease 4- (acetenyl) anilino-s t-butyl formate (0.5 gram, yield：49%).LCMS(ESI):m/z218[M+1]⁺.¹H NMR(500MHz,CDCl₃) δ 7.33-7.30 (m, 2H), 7.25 (d, J=8.7Hz, 2H), 2.92 (s, 1H), 1.43 (s, 9H).

4- (acetenyl) the anilino-s t-butyl formate (0.6 gram, 2.76 mMs, 1.0 equivalents) of gained is dissolved in 10 In milliliter dry tetrahydrofuran, nitrogen is replaced 3 times, and after being cooled to -60 degree, n-BuLi is added dropwise inward, and (2.87 milliliters, 6.9 in the least Mole, 2.5 equivalents), it is warming up to 0 degree of stirring half an hour after stirring half an hour at this temperature, then by this buff reaction solution It is cooled to -60 degrees Celsius once again.Tributyltin chloride (1.16 grams, 3.58 mMs, 1.3 equivalents) is added drop-wise in reaction solution, Half an hour is stirred under -60 degrees Celsius again, is warming up to and is stirred at room temperature 3 hours.Reaction is quenched with water, ethyl acetate is added and carries out Extraction, the organic phase saturated common salt water washing of extraction, anhydrous sodium sulfate drying, then concentrated and done with Rotary Evaporators.After concentration Product orange 4- ((tributyl tinbase) acetenyl) anilino- t-butyl formate (0.8 is obtained after silica gel column chromatography Gram, yield：57.1%)

6- (4- amidos phenylacetylene base) -8- cyclopenta -5- methyl -2- (5- (piperazine -1- bases) pyridine -2- amidos) -8H- pyrroles Pyridine simultaneously [2,3-D] pyrimidin-7-ones (6- ((4-aminophenyl) ethynyl) -8-cyclopentyl-5-methyl-2- (5- (piperazin-1-yl) pyridin-2-ylamino) pyrido [2,3-d] pyrimidin-7 (8H)-one) (compound 42) Preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-42.

Target product characterize data：LCMS(ESI):m/z521[M+1]⁺.^{1H NMR}(500MHz,DMSO-D6)δ9.95(s, 1H), 8.89 (s, 1H), 8.02 (d, J=3.0Hz, 1H), 7.88-7.86 (d, J=10.0Hz, 1H), 7.45-7.44 (d, J= 5.0Hz, 1H), 7.21 (d, J=8.5Hz, 2H), 6.57 (d, J=8.5Hz, 2H), 5.87 (m, 1H), 5.56 (s, 2H), 3.09- 3.04(m,4H),2.88–2.82(m,4H),2.60(s,3H),2.23(s,2H),1.92(s,2H),1.77(s,2H),1.60 (s,2H)。

The preparation (being prepared according to five circuit of scheme) of 27 compound 43 of embodiment

3- tributyl tin acetylenylbenzene amido t-butyl formates (3-Tributylstannanylethynyl-phenyl)- Carbamic acid tert-butyl ester) (compound 502-43) preparation：By sodium bicarbonate, (1.43 milliliters, 17 in the least Mole, 2 equivalents) and (2.224 grams, 10.2 mMs, 1.2 equivalents) of BOC acid anhydrides be added to compound 2-14-A1 (1 gram, 8.5 millis Mole, 1 equivalent) tetrahydrofuran (10 milliliters) solution in.After mixed system reacts 10 hours at room temperature, extracted with ethyl acetate It takes.Organic phase is washed with salt, anhydrous sodium sulfate drying, filtering, and decompression is spin-dried for.Residue silica gel column chromatography purifies to obtain yellow oil Shape object (1.95 grams, crude product).The grease (0.5 gram, 2.3 mMs, 1 equivalent) of gained is dissolved in 5 milliliters of dry tetrahydrochysenes In furans.- 60 DEG C are cooled to, n-BuLi (2.4 milliliters, 5.75 mMs, 2.4 equivalents) is slowly added dropwise in 10min.Reaction System reacts 0.5 hour at -60 DEG C and 0.5 hour at 0 DEG C, is then cooled to -60 DEG C.Tributyltin chloride (823.5 Milligram, 2.53 mMs, 1.1 equivalents) it is slowly added dropwise to system and stirs 0.5 hour.Mixed system is slowly returned and is warmed to room temperature simultaneously Stirring 3 hours.Reaction is quenched with water, and is extracted with ethyl acetate.Organic phase is washed with salt, anhydrous sodium sulfate drying, concentration.It is residual Stay object silica gel column chromatography purify to obtain orange product (0.785 gram, yield：67.2%).

6- (3-amidos-phenylacetylene base)-8- cyclopenta-5- methyl-2- (5- (piperazine-1- bases) pyridine-2- amidos)-8H- Pyrido [2,3-D] pyrimidin-7-ones (6- ((3-aminophenyl) ethynyl) -8-cyclopentyl-5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H)-one) (chemical combination Object 43) preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-43.

Target product characterize data：LCMS(ESI):m/z521[M+1]⁺.1H NMR(500MHz,DMSO-D6)δ10.02 (s, 1H), 8.92 (s, 1H), 8.03 (s, 1H), 7.87 (d, J=9.0Hz, 1H), 7.44 (dd, J=9.1,3.1Hz, 1H), 7.06 (t, J=7.8Hz, 1H), 6.78-6.73 (m, 1H), 6.67 (d, J=7.7Hz, 1H), 6.63-6.58 (m, 1H), 5.93- 5.83(m,1H),5.23(s,2H),3.10–3.02(m,4H),2.89–2.82(m,4H),2.63(s,3H),2.26-2.22(m, 2H),1.92(s,2H),1.84–1.71(m,2H),1.68–1.54(m,2H)。

The preparation (being prepared according to five circuit of scheme) of 28 compound 44 of embodiment

2- ((tributyl tinbase) acetenyl) anilino- t-butyl formate (2-tributylstannnany lethynyl- Phenyl) carbamate acid tere-butyl ester) (compound 502-44) preparation：By 2- Iodoanilines (3.0 grams, 13.7 mMs, 1.0 equivalents), bi triphenyl phosphorus palladium chloride (0.87 gram, 1.6 mMs, 0.12 equivalent) and cuprous iodide (78 milligrams, 0.55 mM, 0.04 equivalent) are added in 10 milliliters of triethylamines.Reaction solution is placed under nitrogen protection, then Add trimethylsilyl acetylene (1.8 grams, 18.3 mMs, 1.3 equivalents).After reaction overnight at normal temperatures, by reaction solution second Acetoacetic ester and water extraction, obtained organic phase saturated common salt water washing, anhydrous sodium sulfate drying, then concentrated with Rotary Evaporators It is dry.Product after concentration obtains brown solid 2- ((trimethyl silicon substrate) acetenyl) aniline after silica gel column chromatography, and (1.88 grams, receive Rate 72%).LCMS(ESI):m/z190[M+1]⁺。

2- ((trimethyl silicon substrate) acetenyl) aniline (1.78 grams, 9.4 mMs, 1.0 equivalents) of gained is dissolved in 100 In milliliter dichloromethane, triethylamine (2.8 milliliters, 18.8 mMs, 2.0 equivalents), di-tert-butyl dicarbonate (4.1 are added inward Gram, 18.8 mMs, 2.0 equivalents) after reacts 24 hours at normal temperatures, reaction solution dichloromethane and water are extracted, obtained Organic phase saturated common salt water washing, anhydrous sodium sulfate drying, then concentrated and done with Rotary Evaporators.Product after concentration is through silica gel Obtained after column chromatography colorless oil 2- ((trimethyl silicon substrate) acetenyl) anilino- t-butyl formate (1.8 grams, yield： 67%).By 2- ((trimethyl silicon substrate) acetenyl) anilino- t-butyl formate (1.8 grams, 6.2 mMs, 1.0 equivalents) of gained It is dissolved in 10 milliliters of tetrahydrofuran, at 0 degree Celsius, after ten minutes, tetrabutyl ammonium fluoride is added, and (4.6 grams, 12.4 in the least for stirring Mole, 2.0 equivalents) after half an hour at normal temperatures, reaction solution ethyl acetate and water are extracted, obtained organic phase saturation Brine It, anhydrous sodium sulfate drying, then concentrated and done with Rotary Evaporators.Product after concentration obtains after silica gel column chromatography White solid 2- acetylenylbenzene amidos t-butyl formate (0.8 gram, yield：57%).

The 2- acetylenylbenzene amidos t-butyl formate (0.8 gram, 3.6 mMs, 1.0 equivalents) of gained is dissolved in 10 milliliters In dry tetrahydrofuran, nitrogen replace 3 times, be cooled to -60 degree after, inward be added dropwise n-BuLi (3.75 milliliters, 9.0 mMs, 2.5 equivalents), it is warming up to 0 degree of stirring half an hour after stirring half an hour at this temperature, it is then that this buff reaction solution is cold once again But -60 degree are arrived.Tributyltin chloride (1.56 grams, 4.8 mMs, 1.3 equivalents) is added drop-wise in reaction solution, then under -60 degree Half an hour is stirred, is warming up to and is stirred at room temperature 3 hours.Reaction is quenched with water, be added ethyl acetate extracted, extraction it is organic Saturated common salt water washing, anhydrous sodium sulfate drying are mutually used, then is concentrated and is done with Rotary Evaporators.Product after concentration is through silica gel column layer Obtained after analysis orange 2- ((tributyl tinbase) acetenyl) anilino- t-butyl formate (1.5 grams, yield：79%).

6- (2- amidos phenylacetylene base) -8- cyclopenta -5- methyl -2- (5- (piperazine -1- bases) pyridine -2- amidos) -8H- pyrroles Pyridine simultaneously [2,3-D] pyrimidin-7-ones (6- ((2-aminophenyl) ethynyl) -8-cyclopentyl-5-methyl-2- (5- (piperazin-1-yl) pyridin-2-ylamino) pyrido [2,3-d] pyrimidin-7 (8H)-one) (compound 44) Preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-44.

Target product characterize data：LCMS(ESI):m/z521[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.13 (s, 1H), 8.95 (s, 1H), 8.03 (d, J=2.9Hz, 1H), 7.85 (d, J=8.9Hz, 1H), 7.45 (dd, J=9.1, 2.9Hz, 1H), 7.23 (d, J=6.4Hz, 1H), 7.09 (dd, J=12.0,4.9Hz, 1H), 6.73 (d, J=8.1Hz, 1H), 6.54 (d, J=7.3Hz, 1H), 5.91-5.85 (m, 1H), 5.79 (s, 2H), 3.10-3.01 (m, 4H), 2.87-2.78 (m, 4H),2.64(s,3H),2.27(s,2H),1.90(s,2H),1.78(s,2H),1.60(s,2H)。

The preparation (being prepared according to five circuit of scheme) of 29 compound 45 of embodiment

Methyl-(4- tributyl tins acetenyl-the phenyl)-amidocarbonic acid tert-butyl ester (tert-butyl methyl (4- ((tributylstannyl) ethynyl) phenyl) carbamate) (compound 502-45) preparation：4- (acetenyl) benzene The amidocarbonic acid tert-butyl ester (1.12 grams, 5.15 mMs, 1.0 equivalents), iodomethane (1.09 grams, 7.73 mMs, 1.5 equivalents) and Cesium carbonate (2.52 grams, 7.73 mMs, 1.5 equivalents) is miscible in n,N-Dimethylformamide (50 milliliters) together, then heats It is stirred to react 15 hours to 40 DEG C.Reaction mixture is cooled to room temperature, pours into water then with (50 milliliters) extractions of ethyl acetate. Organic phase water and saline solution clean two to three times, are dried with anhydrous sodium sulfate, are concentrated in vacuo and obtained residue and pass through column layer Analysis purifying obtain target compound (690 milligrams, yield：42.3%).

Target product characterize data：¹H NMR (500MHz, CDCl3) δ 7.48-7.39 (m, 2H), 7.20 (d, J= 8.6Hz, 2H), 3.25 (s, 3H), 3.04 (s, 1H), (670 milligrams, 2.9 mMs, 1.0 work as the product obtained by 1.45 (s, 9H) Amount) be dissolved in dry tetrahydrofuran (40 milliliters), be cooled to -60 DEG C, by syringe be added dropwise n-BuLi (1.5 milliliters, 3.7 mMs, 1.3 equivalents), after mixture stirs half an hour at this temperature, then half an hour is stirred at 0 DEG C.Reaction be down to again- 60 DEG C, stirring 5 hours is warmed to room temperature after tributyltin chloride (944 milligrams, 2.9 mMs, 1.0 equivalents) is added dropwise.It is quenched with water Reaction, is then extracted with ethyl acetate.Organic phase is cleaned with saturated salt solution, then is dried with anhydrous sodium sulfate, concentration.Residue It quickly crosses column purification and obtains yellow oily compound (1.08 grams, 88.5%).

8- cyclopenta -5- methyl -6- (4- methylaminos phenylacetylene base) -2- [5- (piperazine -1- bases) pyridine -2- amidos] -8H- Pyrido [2,3-D] pyrimidin-7-ones (8-cyclopentyl-5-methyl-6- ((4- (methylamino) phenyl) ethynyl)-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7 (8H)-one) (compound 45) preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-45.

Target product characterize data：LCMS(ESI):m/z535[M+1]⁺.^{1H NMR}(500MHz,DMSO-D6)δ9.97(s, 1H), 8.89 (s, 1H), 8.03 (d, J=3.0Hz, 1H), 7.88 (d, J=9.0Hz, 1H), 7.44 (dd, J=9.1,3.0Hz, 1H), 7.27 (d, J=8.6Hz, 2H), 6.56 (d, J=8.7Hz, 2H), 6.14 (q, J=5.0Hz, 1H), 5.94-5.83 (m, 1H), 3.12-3.05 (m, 4H), 2.89-2.83 (m, 4H), 2.71 (d, J=5.0Hz, 3H), 2.60 (s, 3H), 2.25-2.20 (m,2H),1.93(s,2H),1.83–1.74(m,2H),1.62-1.59(m,2H).

The preparation (being prepared according to five circuit of scheme) of 30 compound 46 of embodiment

N, N- dimethyl-(4- tributyl tins acetenyl) aniline (N, N-dimethyl-4- ((tributylstannyl) Ethynyl) aniline) (compound 502-46) preparation：To acetylene aniline compound (500 milligrams, 4.27 mMs, 1.0 Equivalent), iodomethane (0.8 milliliter, 18.23 mMs, 4.2 equivalents) and cesium carbonate (5.94 grams, 18.23 mMs, 4.2 equivalents) It is miscible in together in n,N-Dimethylformamide (50 milliliters), reaction mixture is heated to 40 DEG C and stirs 15 hours.Reaction mixing Object is cooled to room temperature, with (50 milliliters) extractions of ethyl acetate after being poured into water.Organic phase water and saline solution clean two and arrive three times, It is dried with anhydrous sodium sulfate, is concentrated in vacuo and obtained residue and purifies to obtain target compound 4- acetenyl-N by column chromatography, Accelerine (170 milligrams, yield：27.4%).LCMS(ESI):m/z146[M+1]⁺。

4- acetenyls-n,N-Dimethylaniline obtained above (170 milligrams, 1.17 mMs, 1.0 equivalents) is dissolved in In dry tetrahydrofuran (30 milliliters), be then cooled to -60 DEG C, by syringe be added dropwise n-BuLi (0.6 milliliter, 1.52 MM, 1.3 equivalents), reaction mixture stirs half an hour at this temperature, and half an hour is then stirred at 0 DEG C.Finally drop again To -60 DEG C, stirring 5 hours is warmed to room temperature after tributyltin chloride (381 milligrams, 1.17 mMs, 1.0 equivalents) is added dropwise.Use water Reaction is quenched, is then extracted with ethyl acetate.Organic phase is cleaned with saturated salt solution, then is dried with anhydrous sodium sulfate, concentration.It is residual The quick column purification of crossing of object was stayed to obtain colorless oil compound N, N- dimethyl-(4- tributyl tins acetenyl) aniline (379 milligrams, 74.6%).

8- cyclopenta -6- (4- dimethyl amidos phenylacetylene base) -5- methyl -2- [5- (piperazine -1- bases) pyridine -2- amine Base] -8H- pyridos [2,3-D] pyrimidin-7-ones (8-cyclopentyl-6- ((4- (dimethylamino) phenyl) ethynyl)-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyri Midin-7 (8H)-one) (compound 46) preparation：Synthetic method such as embodiment 13, is only to replace with 502-29 therein 502-46。

Target product characterize data：LCMS(ESI):m/z 549[M+1]⁺.^{1H NMR}(500MHz,DMSO-D6)δ10.04 (s, 1H), 8.91 (s, 1H), 8.07 (d, J=2.8Hz, 1H), 7.92 (d, J=9.1Hz, 1H), 7.49 (dd, J=9.1, 2.9Hz, 1H), 7.35 (d, J=8.8Hz, 2H), 6.73 (d, J=8.8Hz, 2H), 5.94-5.84 (m, 1H), 3.23 (s, 4H), 3.08(s,4H),2.97(s,6H),2.62(s,3H),2.24(s,2H),1.92(s,2H),1.78(s,2H),1.61(s,2H)。

The preparation (being prepared according to five circuit of scheme) of 31 compound 47 of embodiment

4- (tributyl tinbase) acetenyl cyanophenyls 4- ((tributylstannyl) ethynyl) benzonitrile (chemical combination Object 502-47) preparation：By 4- ioxynil (2.0 grams, 8.73 mMs, 1.0 equivalents), bi triphenyl phosphorus palladium chloride (184 millis Gram, 0.26 mM, 0.03 equivalent) and cuprous iodide (83 milligrams, 0.44 mM, 0.05 equivalent) be added to 15 milliliter of three second In amine.Reaction solution is placed under nitrogen protection, then adding trimethylsilyl acetylene, (1.34 milliliters, 9.6 mMs, 1.1 work as Amount).After reaction overnight at normal temperatures, reaction solution ethyl acetate and water are extracted, obtained organic phase is washed with saturated common salt It washs, anhydrous sodium sulfate drying, then is concentrated and done with Rotary Evaporators.Product after concentration obtains brown solid after silica gel column chromatography 4- trimethyl silicane ethyl-acetylene base cyanophenyls (1.86 grams, yield 100%).By above-mentioned 4- trimethyl silicanes ethyl-acetylene base benzene obtained by the reaction Nitrile (1.0 grams, 5.0 mMs, 1.0 equivalents), tributyltin oxide (1.2 milliliters, 5.0 mMs, 1.0 equivalents), trimethyl silicane Potassium alcoholate (0.65 gram, 5.0 mMs, 1.0 equivalents) is dissolved in 30 milliliters of tetrahydrofurans, will be anti-after reacting 1 hour at normal temperatures Answer the concentration of liquid Rotary Evaporators dry.Product after concentration obtains colorless oil 4- (tributyl tinbase) after silica gel column chromatography Acetenyl cyanophenyl (1.86 grams, yield：93%).

4- (8- cyclopenta -5- methyl -2- (5- (piperazine -1- bases) pyridine -2- amidos) -7,8- dihydro pyridos [2,3-d] Pyrimidine -6- bases) acetenyl cyanophenyl (4- ((8-cyclopentyl-5-methyl-7-oxo-2- (5- (piperazin-1-yl) pyridin-2-ylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)ethynyl) Benzonitrile) the preparation of (compound 47)：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502- 47。

Target product characterize data：LCMS(ESI):m/z531[M+1]⁺.^{1H NMR}(500MHz,CDCl₃)δ8.78(s,1H), 8.16 (d, J=8.9Hz, 1H), 8.03 (d, J=2.8Hz, 1H), 7.90 (s, 1H), 7.68-7.62 (m, 4H), 7.33 (dd, J =9.0,2.8Hz, 1H), 5.99-5.93 (m, 1H), 3.17-3.15 (m, 4H), 3.09-3.07 (m, 4H), 2.67 (s, 3H), 2.37(s,2H),2.11(s,2H),1.89(s,2H),1.70(s,2H)。

The preparation (being prepared according to five circuit of scheme) of 32 compound 48 of embodiment

4- tributyl tin ethyl-acetylene base benzylamino t-butyl formates (tert-butyl (4- ((tributylstannyl) Ethynyl) benzyl) carbamate) (compound 502-48) preparation：By 4- bromobenzenes methylamine hydrochloride (3 grams, 13.5 mmoles You, 1 equivalent) it is dissolved in (50 milliliters) addition sodium bicarbonates (2.27 grams, 27 mMs, 2 equivalents) of tetrahydrofuran and two carbonic acid two The tert-butyl ester (3.24 grams, 14.9 mMs, 1.1 equivalents), reaction mixture stirs 16 hours at normal temperatures.Extracted with dichloromethane It takes, the washing of organic phase salt, after anhydrous sodium sulfate drying, reduced under vacuum obtains the 4- bromobenzyl amidocarbonic acids tert-butyl ester, and (3.68 grams, receive Rate：95%), LCMS (ESI):m/z286[M+1]⁺。

The anti-of the tetrahydrofuran solution of the 4- bromobenzyl amidocarbonic acids tert-butyl ester (2 grams, 7.02 mMs, 1 equivalent) will be housed It answers bottle to be placed under subzero 60 degrees Celsius and is slowly dropped into holding during (5.6 milliliters, 14 mMs, 2 equivalents) of n-BuLi is added dropwise Temperature of reaction system at subzero 60 degrees Celsius hereinafter, stirring 30 minutes after, will dissolved with iodine element (1.78 grams, 7.02 mMs, 1 works as Amount) tetrahydrofuran (10 milliliters) be slowly dropped into reaction system.It drips off and is stirred 6 hours under 0 degree Celsius.A small amount of water is added It is quenched, water and ethyl acetate extracting and demixing is added, organic phase is washed three times with salt, and anhydrous sodium sulfate drying, decompression is spin-dried for obtaining 4- Iodine benzylamino t-butyl formate (1.52 grams, yield：65%).LCMS(ESI):m/z334[M+1]⁺。

Under nitrogen protection, by triphenyl phosphorus (16 milligrams, 0.06 mM, 0.018 equivalent), bi triphenyl phosphorus dichloride Palladium (84 milligrams, 0.121 mM, 0.05 equivalent), cuprous iodide (6 milligrams, 0.03 mM, 0.09 equivalent), above-mentioned preparation Obtain 4- iodine benzylaminos t-butyl formate (0.8 gram, 2.42 mMs, 1 equivalent) and triethylamine (366 milligrams, 3.63 mmoles You, 1.5 equivalents) reaction bulb equipped with DMF (5 milliliters) is added, by trimethylsilyl acetylene, (356 milligrams, 3.63 mMs, 1.5 work as Amount) it is added in reaction bulb, it stirs 16 hours at 60 c.Water is added and drinks ethyl acetate extracting and demixing, organic phase brine Anhydrous sodium sulfate is dried after washing, is concentrated to give crude product, 4- trimethylsilyl acetylene base benzyls are obtained by silica gel column chromatography separating purification The amidocarbonic acid tert-butyl ester (0.61 gram, yield：85%).LCMS(ESI):m/z304[M+1]⁺.This 4- trimethyl being prepared Silico acetylene base benzylamino t-butyl formate (1.16 grams, 3.83 mMs) trimethyl silicane potassium alcoholate (490 milligrams, 3.83 mMs) It is dissolved in tetrahydrofuran (50 milliliters), tributyltin oxide (2.82 grams, 3.83 mMs) is added in system, is stirred 3 hours.Add Enter water and ethyl acetate extracting and demixing, organic phase is washed with brine rear anhydrous sodium sulfate drying, and reduced under vacuum obtains crude product, passes through Silica gel column chromatography separating purification obtain 4- tributyl tin ethyl-acetylene base benzylaminos t-butyl formate (1.57 grams, yield：78.6%).

6- (4- amine methyl phenylacetylene base) -8- cyclopenta -5- methyl -2- [5- (piperazine -1- bases) pyridine -2- amidos] -8H- Pyrido [2,3-D] pyrimidin-7-ones (6- ((4- (aminomethyl) phenyl) ethynyl) -8-cyclopentyl-5- methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)- One) the preparation of (compound 48)：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-48.

Target product characterize data：LCMS(ESI):m/z 535[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.06 (s, 1H), 8.94 (s, 1H), 8.04 (d, J=2.8Hz, 1H), 7.87 (d, J=8.9Hz, 1H), 7.53 (d, J=8.2Hz, 2H), 7.44 (t, J=6.7Hz, 3H), 5.94-5.84 (m, 1H), 3.86 (s, 2H), 3.08 (d, J=5.0Hz, 4H), 2.88 (d, J=4.6Hz, 4H), 2.65 (s, 3H), 2.24 (s, 2H), 1.93 (s, 2H), 1.79 (s, 2H), 1.61 (s, 2H).

The preparation (being prepared according to five circuit of scheme) of 33 compound 49 of embodiment

(4- trifluoromethyls-phenylacetylene base)-tributyl stannane Tributyl- (4-trifluoromethyl- Phenylethynyl) the preparation of-stannane (compound 502-49)：Under nitrogen protection, by bi triphenyl phosphorus palladium chloride (0.33 gram, 0.47 mM, 0.1 equivalent), cuprous iodide (0.046 gram, 0.235 mM, 5 equivalents), the iodo- 4- fluoroforms of 1- Base-benzene (1.28 grams, 4.7 mMs, 1 equivalent) and n,N-Dimethylformamide (10 milliliters) are mixed in there-necked flask.Then will Trimethylsilyl acetylene (0.6 gram, 6.11 mMs, 1.3 equivalents) and triethylamine (1.42 grams, 14.1 mMs, 3 equivalents) are added dropwise to Mixed system.Reaction is stirred to react 4 hours at ambient temperature.After reaction, water is added, is extracted with ethyl acetate.It is organic It is mutually washed with salt, anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure, and residue is purified with silica gel column chromatography, obtains brown oil (4- trifluoromethyls-phenylacetylene base)-trimethyl silane (1.2 grams, crude product).

The compound 4- trifluoromethyls-phenylacetylene base that will be obtained)-trimethyl silane (1.2 grams, 4.59 mMs, 1 equivalent) It is dissolved in tetrahydrofuran (12 milliliters).Then tributyltin oxide (2.95 grams, 4.95 mMs, 1 equivalent) and front three is added Base silanol potassium (635.1 milligrams, 4.95 mMs, 1 equivalent).Reaction system is reacted 2 hours at ambient temperature.Reaction terminates Afterwards, mixed system is concentrated under reduced pressure, and silica gel column chromatography purifying obtains yellow oil (4- trifluoromethyls-phenylacetylene base)-tributyl Stannane (3.5 grams, crude product).

8- cyclopenta -5- methyl -2- [5- (piperazine -1- bases) pyridine -2- amidos] -6- (4- trifluoromethyls-phenylacetylene base) - 8H- pyridos [2,3-D] pyrimidin-7-ones (8-Cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin- 2-ylamino)-6-(4-trifluoromethyl-phenylethynyl)-8H-pyrido[2,3-d]pyrimidin-7- One) the preparation of (compound 49)：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-49.

Target product characterize data：LCMS(ESI)m/z574[M+1]⁺.1H NMR(500MHz,DMSO-D6)δ10.11 (s, 1H), 8.96 (s, 1H), 8.04 (d, J=3.0Hz, 1H), 7.86 (d, J=9.1Hz, 1H), 7.78 (q, J=8.4Hz, 4H), 7.44 (dd, J=9.1,3.0Hz, 1H), 5.88 (m, 1H), 3.07 (m, 4H), 2.86 (m, 4H), 2.67 (s, 3H), 2.24 (s, 2H), 1.92 (s, 2H), 1.80 (s, 2H), 1.60 (d, J=5.3Hz, 2H).

The preparation (being prepared according to five circuit of scheme) of 34 compound 50 of embodiment

(4- acetamidos phenylacetylene base)-tributyl stannane (N- (4- ((tributylstannyl) ethynyl) Phenyl) acetamide) (compound 502-50) preparation：By compound 4- acetylene aniline (400 milligrams, 3.42 mMs, 1.0 equivalents) and triethylamine (1 milliliter) be dissolved in dichloromethane (40 milliliters), then under condition of ice bath into solution plus second Acyl chlorides (0.3 milliliter, 4.10 mMs, 1.2 equivalents) is simultaneously stirred at room temperature overnight.Filtering, solvent in vacuo is spin-dried for.Residue Cross column purification obtain orange target compound 4- acetamidos phenylacetylene (412 milligrams, yield：75.7%).LCMS(ESI):m/ z160[M+1]⁺。

By above-mentioned reaction product 4- acetamidos phenylacetylene (200 milligrams, 1.25 mMs, 1.0 equivalents) and trimethyl silicane Potassium alcoholate (161 milligrams, 1.25 mMs, 1.0 equivalents) is dissolved in tetrahydrofuran (50 milliliters), and normal-butyl is then added into solution Tin oxide (745 milligrams, 1.25 mMs, 1.0 equivalents) is simultaneously stirred at room temperature overnight.Reaction dissolvent vacuum is spin-dried for.Residual Object cross column purification obtain yellow oily target compound (4- acetamidos phenylacetylene base)-tributyl stannane (687 milligrams, slightly Product).

N- (4- ((8- cyclopenta -5- methyl -7- oxos -2- (5- (piperazine -1- bases) pyridine -2- amidos) -7,8- dihydro pyrroles Pyridine simultaneously [2,3-d] pyrimidine -6- bases) ethynyl phenyl) acetamide (N- (4- ((8-cyclopentyl-5-methyl-7-oxo-2- ((5-(piperazin-1-yl)pyridin-2-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidin-6- Yl) ethynyl) phenyl) acetamide) and (compound 50) preparation：Synthetic method such as embodiment 13, being only will be therein 502-29 replaces with 502-50.

Target product characterize data：LCMS(ESI):m/z 563[M+1]⁺.1H NMR(500MHz,DMSO-D6)δ10.13 (s, 1H), 10.07 (s, 1H), 8.93 (s, 1H), 8.06 (d, J=2.8Hz, 1H), 7.89 (d, J=9.0Hz, 1H), 7.65 (d, J=8.5Hz, 2H), 7.47 (d, J=8.6Hz, 3H), 5.88 (m, 1H), 3.17 (m, 4H), 2.99 (m, 4H), 2.63 (s, 3H), 2.23 (d, J=7.7Hz, 2H), 2.07 (s, 3H), 1.93 (s, 2H), 1.79 (m, 2H), 1.61 (m, 2H).

The preparation (being prepared according to five circuit of scheme) of 35 compound 51 of embodiment

4- tributyl tins acetenyl benzyloxy-tert-butyl-dimethylsilane (tert-butyldimethyl ((4- ((tributylstannyl) ethynyl) benzyl) oxy) silane) and (compound 502-51) preparation：It will be to bromobenzyl alcohol (3 Gram, 16 mMs, 1 equivalent), cuprous iodide (0.3 gram, 1.6 mMs, 0.1 equivalent) and two triphenyl phosphorus palladium (0.57 of dichloro Gram, 0.8 mM, 0.05 equivalent) it is dissolved in tetrahydrofuran (50 milliliters) solution, under the conditions of nitrogen protection, front three is added inward Base silico acetylene (7.8 grams, 80 mMs, 5 equivalents).After mixed system reacts 16 hours under the conditions of 50 degree, decompression is spin-dried for solvent, Residue silica gel column chromatography purifies to obtain brown solid 4- trimethylsilyl acetylene bases benzylalcohol (1.5 grams, crude product).By above compound (1.5 grams, 7.3 mMs, 1 equivalent), potassium carbonate (2 grams, 14.6 mMs, 2 equivalents) and methanol (5 milliliters) are dissolved in tetrahydrochysene furan It mutters in (50 milliliters).Mixed system stirs 1 hour at room temperature.Reaction is quenched with water, and is extracted with ethyl acetate, organic phase salt Washing, anhydrous sodium sulfate drying, concentration.Residue silica gel column chromatography purify to obtain brown liquid 4- acetenyls benzylalcohol (0.8 gram, Crude product).4- acetenyls benzylalcohol (0.8 gram, 6 mMs, 1 equivalent) obtained by reacting, tert-butyl chloro-silicane (1.4 grams, 9 mMs, 1.5 equivalents) and imidazoles (0.4 gram, 6 mMs, 1 equivalent) be dissolved in DMF (20 milliliters).Mixed system stirs at room temperature It mixes 3 hours, reaction is quenched with water, and be extracted with ethyl acetate, organic phase is washed with salt, anhydrous sodium sulfate drying, concentration.Residual Object silica gel column chromatography purify to obtain greenish liquid 4- acetenyls benzyloxy-tert-butyl-dimethylsilane (0.3 gram, yield： 20%).

4- acetenyls benzyloxy-tert-butyl-dimethylsilane (240 milligrams, 1 mM, 1 equivalent) of reaction gained is molten In tetrahydrofuran (10 milliliters), under nitrogen protection, dry ice acetone bath cool to -60 degree inward be added dropwise n-BuLi (0.8 milliliter, 2 MM, 2 equivalents).It drips after reacting half an hour again, tributyltin chloride is added dropwise inward, and (0.65 gram, 2 mMs, 2 work as Amount).React that obtain within 1 hour 4- tributyl tins acetenyl benzyloxy-tert-butyl-dimethylsilane tetrahydrofuran molten after dripping again Liquid need not be handled to be directly used in and be reacted in next step.

8- cyclopenta -6- (4- methylols phenylacetylene base) -5- methyl -2- (5- (piperazine -1- bases) pyridine -2- amidos) -7, 8- dihydro pyridos [2,3-d] pyrimidin-7-ones hydrochloride (8-cyclopentyl-6- ((4- (hydroxymethyl) phenyl) ethynyl)-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d] Pyrimidin-7 (8H)-one hydrochloride) (compound 51) preparation：Synthetic method such as embodiment 13, be only by 502-29 therein replaces with 502-51.

Target product characterize data：LCMS(ESI):m/z536[M+1]⁺.1H NMR(500MHz,DMSO-D6)δ10.55 (s, 1H), 8.97 (m, 3H), 8.10 (d, J=3.0Hz, 1H), 7.90 (d, J=3.0Hz, 1H), 7.69 (s, 1H), 7.51 (d, J =8Hz, 2H), 7.38 (d, J=8Hz, 2H), 5.90 (t, J=9Hz, 1H), 4.54 (s, 2H), 3.39-3.41 (m, 4H), 3.26 (m,4H),2.67(s,3H),2.21(m,2H),1.95(m,2H),1.80(m,2H),1.61(m,2H)。

The preparation (being prepared according to five circuit of scheme) of 36 compound 52 of embodiment

N- (4- tributyl tins acetenyl-phenyl)-Methanesulfonamide (N- (4- ((tributylstannyl) ethynyl) Phenyl) methanesulfonamide) (compound 502-52) preparation：Will to amido phenylacetylene (400 milligrams, 3.42 milli Mole, 1.0 equivalents) and triethylamine (1 milliliter) be dissolved in dichloromethane (50 milliliters), then under condition of ice bath into solution Add mesyl chloride (584 milligrams, 5.13 mMs, 1.5 equivalents) and is stirred at room temperature overnight.Filtering, solvent in vacuo is spin-dried for. Residue cross column purification obtain orange target compound N- (4- ethynyl phenyls) Methanesulfonamide (350 milligrams, yield： 52.5%).

By compound N-(4- ethynyl phenyls) Methanesulfonamide (170 milligrams, 0.87 mM, 1.0 equivalents) and front three Base silanol potassium (112 milligrams, 0.87 mM, 1.0 equivalents) is dissolved in tetrahydrofuran (50 milliliters), then into solution plus just Butyl tin oxide (518 milligrams, 0.87 mM, 1.0 equivalents) is simultaneously stirred at room temperature overnight.Reaction dissolvent vacuum is spin-dried for. Residue cross column purification obtain target compound N- (4- tributyl tins acetenyl-phenyl)-Methanesulfonamide (1.23 grams, slightly Product).

N- (4- (8- cyclopenta -5- methyl -7- oxos -2- (5- (piperazine -1- bases) pyridine -2- amidos) -7,8- dihydro pyrroles Pyridine simultaneously [2,3-d] pyrimidine -6- acetenyls) phenyl) Methanesulfomide (N- (4- ((8-cyclopentyl-5-methyl-7-oxo-2- ((5-(piperazin-1-yl)pyridin-2-yl)amino)-7,8-dihydropyrido[2,3-d]p yrimidin-6- Yl) ethynyl) phenyl) methanesulfonamide) and (compound 52) preparation：Synthetic method such as embodiment 13 is only 502-29 therein is replaced with into 502-52.

Target product characterize data：LCMS(ESI):m/z 599[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.11 (s, 1H), 8.94 (s, 1H), 8.08 (d, J=2.9Hz, 1H), 7.92 (d, J=9.0Hz, 1H), 7.51 (dd, J=14.0, 5.7Hz, 3H), 7.26 (d, J=8.6Hz, 2H), 5.89 (p, J=8.9Hz, 1H), 3.26 (m, 4H), 3.09 (m, 4H), 3.06 (s,3H),2.64(s,3H),2.24(s,2H),1.94(s,2H),1.79(m,2H),1.62(m,2H)。

The preparation (being prepared according to five circuit of scheme) of 37 compound 53 of embodiment

4- tributyl tin acetylenylbenzene formamide (4-Tributylstannanylethynyl-benzamide) (compound Preparation 502-53)：Under nitrogen protection, 4- brombenzamides (597 milligrams, 3 mMs, 1.0 equivalents) are dissolved in 25 milliliters In triethylamine, then add trimethylsilyl acetylene (2.94 grams, 30 mMs, 10 equivalents), bis-triphenylphosphipalladium palladium dichloride (421 millis Gram, 0.6 mM, 0.2 equivalent), cuprous iodide (228 milligrams, 1.2 mMs, 0.4 equivalent).Reaction mixture is heated to 50 DEG C stirring.Reaction system is diluted with ethyl acetate, is filtered by diatomite, then is washed twice with ethyl acetate, and filtrate is under vacuum Concentration, residue purify to obtain brown oil target compound 4- trimethylsilyl acetylenes base-benzamide (780 by column chromatography Milligram, crude product).LCMS(ESI):m/z 218[M+1]⁺。

By the 4- trimethylsilyl acetylenes base-benzamide (780 milligrams, crude product) and trimethyl silicane potassium alcoholate (385 of reaction gained Milligram, 3 mMs, 1.0 equivalents) it is dissolved in tetrahydrofuran (50 milliliters), normal-butyl tin oxide is then added into solution (1.788 grams, 3 mMs, 1.0 equivalents) are simultaneously stirred at room temperature overnight.Reaction dissolvent vacuum is spin-dried for.Residue crosses column purification Obtain target compound 4- tributyl tin acetylenylbenzenes formamide (1.04 grams, crude product).

4- (8- cyclopenta -5- methyl -7- oxos -2- (5- (piperazine -1- bases) pyridine -2- amidos) -7,8- dihydro pyridos [2,3-d] pyrimidine -6- acetenyls) benzamide (4- ((8-cyclopentyl-5-methyl-7-oxo-2- ((5- (piperazin-1-yl)pyridin-2-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl) Ethynyl) benzamide) (compound 53) preparation：Synthetic method such as embodiment 13, is only to replace 502-29 therein For 502-53.

Target product characterize data：LCMS(ESI):m/z549[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.14 (s, 1H), 8.96 (s, 1H), 8.06 (m, 2H), 7.91 (m, 3H), 7.62 (d, J=8.3Hz, 2H), 7.49 (dd, J=9.1, 3.0Hz, 1H), 7.42 (s, 1H), 5.89 (p, J=8.9Hz, 1H), 3.23 (m, 4H), 3.06 (m, 4H), 2.67 (s, 3H), 2.23 (d, J=8.0Hz, 2H), 1.93 (s, 2H), 1.78 (s, 2H), 1.61 (m, 2H).

The preparation (being prepared according to five circuit of scheme) of 38 compound 54 of embodiment

Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-43, and 111-29 replaces with 111-34, Obtain compound 6- (3- amidos phenylacetylene base) -8- cyclopenta -5- methyl -2- (5- (piperazine -1- methyl) pyridine -2- amidos) -8H- Pyrido [2,3-d] pyrimidin-7-ones (6- ((3-aminophenyl) ethynyl) -8-cyclopentyl-5-methyl-2- ((5-(piperazin-1-ylmethyl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)- One) (compound 54)

Target product characterize data：LCMS(ESI):m/z535[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.28 (s, 1H), 8.98 (s, 1H), 8.23 (d, J=1.9Hz, 1H), 8.04 (d, J=8.4Hz, 1H), 7.73 (dd, J=8.5, 2.2Hz, 1H), 7.06 (t, J=7.8Hz, 1H), 6.75 (s, 1H), 6.68 (d, J=7.5Hz, 1H), 6.61 (d, J=8.1Hz, 1H), 5.90 (t, J=8.7Hz, 1H), 5.24 (s, 2H), 3.43 (s, 2H), 2.70 (t, J=4.7Hz, 4H), 2.64 (s, 3H), 2.28 (d, J=23.9Hz, 6H), 1.95 (s, 2H), 1.79 (s, 2H), 1.61 (d, J=4.8Hz, 2H).

The preparation (being prepared according to five circuit of scheme) of 39 compound 55 of embodiment

Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-42, and 111-29 replaces with 111-34, Compound 6- (4- amidos phenylacetylene)-8- cyclopenta-5- methyl-2- (5-(piperazine-1- methyl)-pyridine-2- amidos]-8H- Pyrido [2,3-D] pyrimidin-7-ones (6- ((4-aminophenyl) ethynyl) -8-cyclopentyl-5-methyl-2- ((5-(piperazin-1-ylmethyl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)- One) (compound 55).

Target product characterize data：LCMS(ESI):m/z535[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.22 (s, 1H), 8.94 (s, 1H), 8.22 (d, J=1.5Hz, 1H), 8.05 (d, J=8.5Hz, 1H), 7.72 (dd, J=8.5, 2.0Hz, 1H), 7.21 (d, J=8.4Hz, 2H), 6.58 (d, J=8.5Hz, 2H), 5.90 (m, 1H), 5.58 (s, 2H), 3.42 (s, 2H), 2.69 (t, J=4.5Hz, 4H), 2.61 (d, J=9.1Hz, 3H), 2.26 (m, 6H), 1.95 (s, 2H), 1.80 (m, 2H),1.61(m,2H).

The preparation (being prepared according to five circuit of scheme) of 40 compound 56 of embodiment

3- ((tributyl tinbase) acetenyl) pyridine (3- ((tributylstannyl) ethynyl) pyridine) (chemical combination Object 502-56) preparation：3- ethynyl pyridines (0.2 gram, 1.94 mMs, 1.0 equivalents) are dissolved in 10 milliliters of dry tetrahydrochysenes In furans, nitrogen is replaced 3 times, and after being cooled to -60 degree, n-BuLi (1.0 milliliters, 2.5 mMs, 1.3 equivalents) is added dropwise inward, It is warming up to 0 degree of stirring half an hour after stirring half an hour at this temperature, this buff reaction solution is then cooled to -60 once again Degree.Tributyltin chloride (0.548 gram, 1.97 mMs, 1.01 equivalents) is added drop-wise in reaction solution, then is stirred under -60 degree Half an hour is warming up to and is stirred at room temperature 3 hours.Reaction is quenched with water, ethyl acetate is added and is extracted, the organic phase of extraction is used Saturated common salt water washing, anhydrous sodium sulfate drying, then concentrated and done with Rotary Evaporators.Product after concentration is after silica gel column chromatography Obtain colorless oil 4- ((tributyl tinbase) acetenyl) pyridine (0.677 gram, yield：59%).

8- cyclopenta -5- methyl -2- (5- (piperazine -1- bases) pyridine -2- amidos) -6- (pyridine -3- acetenyls) -8H- pyrroles Pyridine simultaneously [2,3-D] pyrimidin-7-ones (8-cyclopentyl-5-methyl-2- ((5- (piperazin-1-yl) pyridin-2- Yl) amino) -6- (pyridin-3-ylethynyl) pyrido [2,3-d] pyrimidin-7 (8H)-one) (compound 56) Preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-56.

Target product characterize data：LCMS(ESI):m/z507[M+1]⁺.¹H NMR(500MHz,CDCl₃)¹H NMR (500MHz,CDCl₃) δ 8.82 (d, J=1.4Hz, 1H), 8.78 (s, 1H), 8.55 (dd, J=4.9,1.6Hz, 1H), 8.17 (d, J=9.1Hz, 1H), 8.03 (d, J=2.9Hz, 1H), 7.91-7.89 (m, 2H), 7.30-7.27 (m, 2H), 6.06-5.86 (m,1H),3.16(m,4H),3.11–3.02(m,4H),2.68(s,3H),2.38(s,2H),2.12(s,2H),1.89(m, 2H),1.70(m,2H).

The preparation (being prepared according to five circuit of scheme) of 41 compound 57 of embodiment

2- ((tributyl tinbase) acetenyl) pyridine 2- (tributylstannyl) ethynyl) pyridine (compounds Preparation 502-57)：2- ethynyl pyridines (1.0 grams, 14.7 mMs, 1.0 equivalents) are dissolved in 10 milliliters of dry tetrahydrochysene furans In muttering, nitrogen is replaced 3 times, and after being cooled to -60 degree, n-BuLi (6.7 milliliters, 16.2 mMs, 1.1 equivalents) is added dropwise inward, It is warming up to 0 degree of stirring half an hour after stirring half an hour at this temperature, this buff reaction solution is then cooled to -60 once again Degree.Tributyltin chloride (5.26 grams, 16.2 mMs, 1.1 equivalents) is added drop-wise in reaction solution, then the stirring half under -60 degree Hour, it is warming up to and is stirred at room temperature 3 hours.Reaction is quenched with water, ethyl acetate is added and is extracted, the organic phase of extraction, which is used, satisfies And brine It, anhydrous sodium sulfate drying, then concentrated and done with Rotary Evaporators.Product after concentration obtains after silica gel column chromatography To colorless oil 2- ((tributyl tinbase) acetenyl) pyridine (3.0 grams, yield：79%).

8- cyclopenta -5- methyl -2- (5- (piperazine -1- bases) pyridine -2- amidos) -6- (pyridine -2- acetenyls) -8H- pyrroles Pyridine simultaneously [2,3-D] pyrimidin-7-ones 8-cyclopentyl-5-methyl-2- (5- (piperazin-1-yl) pyridin-2- Ylamino) -6- (pyridin-2-ylethynyl) pyrido [2,3-d] pyrimidin-7 (8H)-one (compound 57) It prepares：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-57.

Target product characterize data：LCMS(ESI):m/z 507[M+1]⁺.¹H NMR(500MHz,CDCl3)δ8.78(s, 1H), 8.62 (d, J=4.6Hz, 1H), 8.17 (d, J=9.1Hz, 1H), 8.03 (d, J=2.8Hz, 2H), 7.70-7.61 (m, 2H), 7.33 (dd, J=9.0,2.9Hz, 1H), 7.23 (d, J=6.0Hz, 1H), 5.94 (m, 1H), 3.19-3.14 (m, 4H), 3.07 (d, J=5.0Hz, 4H), 2.71 (s, 3H), 2.38 (m, 2H), 2.07 (m, 2H), 1.91-1.86 (m, 2H), 1.68 (m, 2H)。

The preparation (being prepared according to five circuit of scheme) of 42 compound 58 of embodiment

4- (tributyl tinbase) ethynyl pyridine (4- (tributylstannyl) ethynyl) pyridine) (compound Preparation 502-58)：By 4- bromopyridines (3.0 grams, 15.5 mMs, 1.0 equivalents), bi triphenyl phosphorus palladium chloride (1.0 grams, 1.4 mMs, 0.09 equivalent) and cuprous iodide (88.4 milligrams, 0.47 mM, 0.03 equivalent), triethylamine (3.1 grams, 30.7 MM, 2.0 equivalents) it is added in 20 milliliters of nitrogen nitrogen diformamides.Reaction solution is placed under nitrogen protection, then adds three Methyl silico acetylene (2.3 grams, 23.4 mMs, 1.5 equivalents).After reaction overnight at normal temperatures, by reaction solution ethyl acetate and Water extracts, obtained organic phase saturated common salt water washing, anhydrous sodium sulfate drying, then is concentrated and done with Rotary Evaporators.Concentration Product afterwards obtains brown solid 4- trimethyl silicanes ethyl-acetylene base-pyridine (2.0 grams, yield 74%) after silica gel column chromatography. LCMS(ESI):m/z176[M+1]⁺。

By 4- trimethyl silicanes ethyl-acetylene base-pyridine (1.0 grams, 6.0 mMs, 1.0 equivalents) of reaction gained, tributyl oxygen Change tin (3.4 grams, 6.0 mMs, 1.0 equivalents), trimethyl silicane potassium alcoholate (0.77 gram, 6.0 mMs, 1.0 equivalents) is dissolved in 100 In milliliter tetrahydrofuran, after reacting 2 hours at normal temperatures, reaction solution ethyl acetate and water are extracted, obtained organic phase is used Saturated common salt water washing, anhydrous sodium sulfate drying, then concentrated and done with Rotary Evaporators.Product after concentration is after silica gel column chromatography Obtain colorless oil 4- (tributyl tinbase) ethynyl pyridine (2.0 grams, yield：89%).

8- cyclopenta -5- methyl -2- (5- (piperazine -1- bases) pyridine -2- amidos) -6- (pyridine -4- acetenyls) -8H- pyrroles Pyridine simultaneously [2,3-D] pyrimidin-7-ones (8-cyclopentyl-5-methyl-2- (5- (piperazin-1-yl) pyridin-2- Ylamino) -6- (pyridin-4-ylethynyl) pyrido [2,3-d] pyrimidin-7 (8H)-one) (compound 58) It prepares：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-58.

Target product characterize data：LCMS(ESI):m/z507[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.25 (s, 1H), 8.99 (s, 1H), 8.64-8.60 (m, 2H), 8.12 (d, J=2.9Hz, 1H), 7.93 (d, J=9.0Hz, 1H), 7.57-7.48 (m, 3H), 5.92-5.81 (m, 1H), 3.42 (s, 4H), 3.22 (s, 4H), 3.17 (s, 3H), 2.65 (d, J= 19.6Hz,2H),1.92(m,2H),1.80(s,2H),1.61(s,2H)。

The preparation (being prepared according to five circuit of scheme) of 43 compound 59 of embodiment

- 2 tert-butoxycarbonylamino pyrimidine (5-Tributylstannanylethynyl- of 5- tributyl tins acetenyl Pyrimidin-2-yl)-carbamic acid tert-butyl ester) (compound 502-59) preparation：By 2- amidos Pyrimidine (2.4 grams, 25 mMs, 1.0 equivalents) and elemental iodine (2.7 grams, 10.7 mMs, 0.43 equivalent) are added to 60 milliliters of ice In acetic acid, periodic acid (0.86 gram, 3.76 mMs, 0.15 equivalent) and 0.5 milliliter of concentrated sulfuric acid dissolution are then added in 3 milliliters The sulfuric acid solution of water.Reaction system is placed under condition of nitrogen gas, 80 degree is heated to and reacts 24 hours.Then reaction solution is poured into full It is extracted to solution with dichloromethane (200 milliliters × 3), mixed organic phase to clarify in the sodium thiosulfate solution of sum It is dried, is filtered with anhydrous sodium sulfate, is concentrated under reduced pressure, the iodo- 2- amine pyrimidines of white solid 5- (1.4 are obtained after silica gel column chromatography Gram, yield 22.2%).LCMS(ESI):m/z222[M+1]⁺。

By the iodo- 2- amidos-pyrimidines of 5- obtained (1.4 grams, 6.33 mMs, 1.0 equivalents) and triethylamine, (1.9 grams, 19 in the least Mole, 3.0 equivalents) be dissolved in 25 milliliters of tetrahydrofurans, then be added dimethylamino pyridine (DMAP) (0.3 gram, 3.2 mmoles You, 0.5 equivalent) and dimethyl dicarbonate butyl ester (2.77 grams, 12.7 mMs, 2.0 equivalents).Reaction solution is heated to 60 degree of reactions 12 Hour.Brown solid 5- iodo- 2 (tertbutyloxycarbonyl) amine pyrimidine is obtained after reaction solution is concentrated under reduced pressure, after silica gel column chromatography (1.35 grams, yield：51%).LCMS(ESI):m/z322[M+1]⁺。

By 5- obtained iodo- 2 (tertbutyloxycarbonyl) amine pyrimidine (1.35 grams, 4.2 mMs, 1.0 equivalents), triethylamine (0.85 gram, 8.4 mMs, 2.0 equivalents), bi triphenyl phosphorus palladium chloride (0.15 gram, 0.21 mM, 0.05 equivalent) and iodine Change cuprous (40 milligrams, 0.21 mM, 0.05 equivalent) to be added in 15 milliliters of acetonitriles.Reaction solution is placed under nitrogen protection, Then trimethylsilyl acetylene (0.45 gram, 4.6 mMs, 1.1 equivalents) is added.After reacting 24 hours at normal temperatures, reaction Liquid is concentrated under reduced pressure, and -2 tert-butoxycarbonylamino pyrimidine (1.2 of brown solid 5- trimethylsilyl acetylenes base is obtained after silica gel column chromatography Gram, yield 100%).LCMS(ESI):m/z292[M+1]⁺。

By -2 tert-butoxycarbonylamino pyrimidine of 5- trimethylsilyl acetylenes base obtained (1.2 grams, 3.3 mMs, 1.0 equivalents) It is dissolved in 20 ml methanols, potassium hydroxide (0.58 gram, 10 mMs, 3.0 equivalents) is then added.Reaction solution is at normal temperatures It after stirring 4 hours, is concentrated under reduced pressure, is spin-dried for after silica gel column chromatography, product is then dissolved in 20 milliliters of dry tetrahydrochysene furans In muttering, under nitrogen protection, temperature is down to minus 70 octave, be then added dropwise 1M n-BuLis/tetrahydrofuran (3.75 milliliters, 1.1 equivalents), after a hour, tributyltin chloride (1.1 grams, 3.3 mMs, 1.0 equivalents) is added, is reacted at -78 degrees Celsius After one hour, stirring at normal temperature is moved to 16 hours.After reduced pressure, silica gel column chromatography obtains yellow solid 5- tributyl tin acetylene - 2 tert-butoxycarbonylamino pyrimidine of base (0.47 gram, yield：22%).

6- (2- amidos-pyrimidine -5- acetenyls) -8- cyclopenta -5- methyl -2- (5- (piperazine -1- bases) pyridine -2- amine Base) -8H- pyridines [2,3-d] pyrimidin-7-ones (6- ((2-aminopyrimidin-5-yl) ethynyl) -8-cyclopentyl- 5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7 (8H)-one) (compound 59) preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-59.

Target product characterize data：LCMS(ESI):m/z523[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.08 (s,1H),8.93(s,1H),8.42(s,2H),8.06(s,1H),7.90(m,1H),7.48(m,1H),7.13(s,2H), 5.91–5.86(m,1H),3.19(s,4H),3.02(s,4H),2.62(s,3H),2.22(m,2H),1.93(m,2H),1.77 (m,2H),1.60(m,2H)。

The preparation (being prepared according to five circuit of scheme) of 44 compound 60 of embodiment

4- (tributyl tin acetenyl) -2- amido pyridines 5- ((tributylstannyl) ethynyl) -2-amino The preparation of pyridine (compound 502-60)：By -5 iodo- pyridine of 2- amidos (1 gram, 4.52 mMs, 1.0 equivalents) and CuI (0.08 gram, 0.41 mM, 0.09 equivalent) is scattered in 50 milliliters of N,N-dimethylformamides.Under nitrogen protection, respectively Addition bi triphenyl phosphorus palladium chloride (0.3 gram, 0.41 mM, 0.09 equivalent), and triethylamine (2 milliliters, 14.3 mMs, 3.0 Equivalent) and trimethylsilyl acetylene (1.34 milliliters, 9.6 mMs, 2.1 equivalents), it is stirred to react at room temperature 1 hour.With acetic acid second Ester extracts, organic phase saturated common salt water washing, and anhydrous sodium sulfate drying, decompression is spin-dried for.Finally purified with silica gel column chromatography To brown solid 5- (trimethylsilyl acetylene base) -2- amidos pyridine (867 milligrams, yield：95%).LCMS(ESI):m/z 191 [M+1]⁺。

By 5- obtained (trimethylsilyl acetylene base) -2- amidos pyridine (0.8 gram, 4.188 mMs, 1.0 equivalents) and three Methyl silanol potassium (0.536 gram, 4.188 mMs, 1.0 equivalents) is dissolved in 50 milliliters of tetrahydrofurans.Then tributyl is added Tin oxide (2.136 milliliters, 4.188 mMs, 1.0 equivalents), is heated to 45 DEG C, is stirred to react 4 hours.Naturally cool to room Temperature, decompression are spin-dried for.Finally purified to obtain yellow solid 4- (tributyl tin acetenyl) -2- amido pyridines with silica gel column chromatography (1.32 grams).

4- (6- (2- amidos pyridinylethynyl) -8- cyclopenta -5- methyl -7- oxo -7,8- dihydro pyridos [2,3-d] Pyrimidine -2- amidos) pyridin-3-yl) piperazine (4- ((8-cyclopentyl-5-methyl-7-oxo-2- (5- (piperazin- 1-yl)pyridin-2-ylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)ethynyl)-2- Amino pyridine) (compound 60) preparation：Synthetic method such as embodiment 13, is only to replace with 502-29 therein 502-60。

Target product characterize data：LCMS(ESI):m/z 522[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.08 (s, 1H), 8.91 (s, 1H), 8.11 (d, J=2.0Hz, 1H), 8.02 (d, J=2.8Hz, 1H), 7.87 (d, J=9.0Hz, 1H), 7.451-7.49 (m, 2H), 6.46 (d, J=7.5Hz, 3H), 5.93-5.80 (m, 1H), 3.11-2.99 (m, 4H), 2.90–2.78(m,4H),2.60(s,3H),2.21(s,2H),1.92(s,2H),1.81–1.73(m,2H),1.64–1.53(m, 2H)。

The preparation (being prepared according to five circuit of scheme) of 45 compound 61 of embodiment

2- tributyl tins acetenyl-furans (tributyl (furan-2-ylethynyl) stannane) (compound 502- 61).Compound furans (3 milliliters, 41.25 mMs, 1.0 equivalents) is dissolved in 30 milliliters of dry tetrahydrofurans, nitrogen Under protection, by syringe dropwise addition n-butyllithium solution, (2.4M, 17.2 milliliters, 41.25 mMs, 1.0 work as after being down to -60 DEG C Amount).It is reacted at this temperature after dripping off 5 hours, then is warmed to room temperature reaction 2 hours.Add elemental iodine solid after being down to -60 DEG C (10.45 grams, 41.25 mMs, 1.0 equivalents), are sufficiently stirred slowly to be warmed to room temperature and are stirred overnight.Reaction solution is with freshly prepared Hypo solution and sodium bicarbonate solution are quenched, and liquid separation, organic phase is dried with anhydrous sodium sulfate, are concentrated in vacuo to obtain reddish oil Shape product 2- iodofurans (3.24 grams, crude product).Target product characterize data：¹H NMR (500MHz, CDCl3) δ 7.53 (dd, J= 1.9,0.8Hz, 1H), 6.54 (dd, J=3.3,0.7Hz, 1H), 6.32 (dd, J=3.3,2.0Hz, 1H).

Under nitrogen protection, compound 2- iodofurans obtained (1.5 grams, 7.73 mMs, 1.0 equivalents) are dissolved in 50 millis It rises in triethylamine, then adds trimethylsilyl acetylene (834 milligrams, 8.5 mMs, 1.1 equivalents), bis-triphenylphosphipalladium palladium dichloride (161 milligrams, 0.23 mM, 0.03 equivalent), cuprous iodide (96.8 milligrams, 0.51 mM, 0.06 equivalent).Reaction mixing Object is protected from light 16 hours in room temperature.Reaction system is diluted with n-hexane, is filtered by diatomite, then is washed twice with n-hexane, Filtrate is concentrated under vacuum, and residue purifies to obtain yellow oily target compound 2- trimethylsilyl acetylene base furans by column chromatography Mutter (1.25 grams, yield：98.4%).Target product characterize data：¹H NMR (500MHz, CDCl3) δ 7.16 (dd, J=1.8, 0.6Hz, 1H), 6.40 (dd, J=3.4,0.6Hz, 1H), 6.17 (dd, J=3.4,1.9Hz, 1H), 0.06 (s, 9H).

Under condition of ice bath and nitrogen protection, compound 2- trimethylsilyl acetylene bases furans (1.25 grams, 7.6 mMs, 1.0 equivalents) it is dissolved in methanol (50 milliliters), then add potassium carbonate (2.41 grams, 17.48 mMs, 2.3 equivalents).Reaction Mixture is stirred at room temperature 18 hours.It is extracted with 300 milliliters of water diluting reactions, then with dichloromethane, organic phase water and full It arrives three times with salt washing two, then is dried with anhydrous sodium sulfate, vacuum is spin-dried for solvent and obtains compound 2- acetenyls-furans (693 Milligram, yield：98.9%).Target product characterize data：¹H NMR (500MHz, CDCl3) δ 7.38 (dd, J=1.8,0.6Hz, 1H), 6.65 (d, J=3.4Hz, 1H), 6.38 (dd, J=3.4,1.9Hz, 1H), 3.38 (s, 1H).

Under nitrogen protection, 2- acetenyls-furans (690 milligrams, 7.49 mMs, 1.0 equivalents) is dissolved in dry four In hydrogen furans (30 milliliters), -60 DEG C are then cooled to, n-BuLi (4.1 milliliters, 9.74 mMs, 1.3 equivalents) is added dropwise, so It stirs at this temperature afterwards half an hour, half an hour is then stirred at 0 DEG C.Then it reacts and is down to -60 DEG C again, tributyl chlorination is added dropwise Tin (2.44 grams, 7.49 mMs, 1.0 equivalents) is stirred for being warmed to room temperature after half an hour being stirred overnight.Reaction is quenched with water, then It is extracted with ethyl acetate.Organic phase is cleaned with saturated salt solution, then is dried with anhydrous sodium sulfate, concentration.Residue is quick to cross column Purifying obtain brown oil compound 2- tributyl tins acetenyl-furans (926 milligrams, yield：32.5%).

8- cyclopenta -6- (furans -2- acetenyls) -5- methyl -2- [5- (piperazine -1- bases) pyridine -2- amidos] -8H- pyrroles Pyridine simultaneously [2,3-D] pyrimidin-7-ones (8-cyclopentyl-6- (furan-2-ylethynyl) -5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d] pyrimidin-7 (8H)-one) (compound 61) preparation：Synthetic method such as embodiment 13, is only that 502-29 therein is replaced with 502-61.

Target product characterize data：LCMS(ESI):m/z 496[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ10.20 (s, 1H), 9.19 (s, 1H), 8.95 (s, 1H), 8.11 (s, 1H), 7.93 (d, J=9.0Hz, 1H), 7.79 (s, 1H), 7.54 (dd, J=9.1,3.0Hz, 1H), 6.91 (d, J=3.4Hz, 1H), 6.62 (dd, J=3.4,1.9Hz, 1H), 5.93-5.81 (m,1H),3.46–3.36(m,4H),3.26-3.24(m,4H),2.62(s,3H),2.25-2.21(m,2H),1.92(s,2H), 1.85–1.72(m,2H),1.66–1.54(m,2H)。

The preparation (being prepared according to four route of scheme) of 46 compound 25 of embodiment

Step 46a：Chloro- 3- methvl-pyridiniums (the 4-bromo-2-chloro-3-methylpyridine) (chemical combination of the bromo- 2- of 4- Object 402-25) preparation：Bromo- 2 chloropyridines of 4- (5 grams, 26.19 mMs, 1.0 equivalents) are dissolved in 30 milliliters of dry tetrahydrochysene furans In muttering, then under the conditions of minus 70 degree, being slowly added drop-wise to freshly prepared lithium diisopropyl amido solution, (50 milliliters, 28.8 in the least Mole, 1.1 equivalents) it is inner.It is maintained under the conditions of minus 70 degree, after reacting one hour, dropwise addition iodomethane (4.087 grams, 28.8 mmoles You, 1.1 equivalents).After low-temp reaction 50 minutes, reaction is quenched with saturated sodium bicarbonate solution, is extracted with ethyl acetate, organic phase Dried with anhydrous sodium sulfate, then be concentrated to give the chloro- 3- methvl-pyridiniums of the bromo- 2- of solid chemical compound 4- (5.22 grams, yield： 97.2%).LCMS(ESI):m/z 208/206[M+1]⁺.

Step 46b：The chloro- 3- methyl -4- cyclopentamines yl pyridines 2-chloro-N-cyclopentyl-3- of 2- The preparation of methylpyridin-4-amine (compound 403-25)：Under nitrogen protection, by compound 402-25 (4.80 grams, 23.4 mMs, 1.0 equivalents), cyclopentamine (2.988 grams, 35.1 mMs, 1.5 equivalents), tris(dibenzylideneacetone) dipalladium (1.07 grams, 1.17 mMs, 0.05 equivalent), and 4,5- bis- diphenylphosphine -9,9- xanthphos (1.22 grams, 2.1 mmoles You, 0.09 equivalent) and cesium carbonate (15.24 grams, 46.8 mMs, 2.0 equivalents) be dissolved in dry toluene (100 milliliters), Then oil bath heating flows back 5 hours.Then it reacts and is down to room temperature again, filter, be concentrated in vacuo.Obtained residue passes through column layer Analysis purifying obtain the chloro- 3- methyl -4- cyclopentamines yl pyridines of brown oil compound 2- (4.52 grams, yield：91.9%).LCMS (ESI):m/z 211[M+1]⁺.

Step 46c：The chloro- 3- methyl -4- cyclopentamines yl pyridines 2-chloro-N-cyclopentyl-5-iodo- of the iodo- 2- of 5- The preparation of 3-methylpyridin-4-amine (compound 404-25)：By compound 403-25 (1.0 grams, 4.76 mMs, 1.0 equivalents), it is dissolved in the system solution (10 milliliters) that toluene is 5 to 1 than acetic acid, N- iodine is then added under nitrogen protection For succimide (2.14 grams, 9.52 mMs, 2.0 equivalents).90 degree are heated to be stirred overnight.Reaction mixture is cooled to room Then temperature is slowly poured into sodium sulfite solution, with the pH value of saturated sodium carbonate solution tune reaction solution to 8-9, use ethyl acetate Extraction.Organic phase is cleaned with saline solution, and anhydrous sodium sulfate drying is spin-dried for solvent and obtains brown oil residue, pure by column chromatography Change obtain the chloro- 3- methyl -4- cyclopentamines yl pyridines of the iodo- 2- of yellow oily compound 5- (848 milligrams, yield：53%).LCMS (ESI):m/z 337[M+1]⁺.

Step 46d：(E) -3- (the chloro- 4- cyclopenta amidos of 6--picoline -3- bases) -2- butenoic acid ethyls (ethyl (E) -3- (6-chloro-4- (cyclopentylamino) -5-methylpyridin-3-yl) but-2-enoate) (chemical combination Object 405-25) preparation：Under nitrogen protection, compound 404-25 (848 milligrams, 2.52 mMs, 1.0 equivalents) is dissolved in N, In the solution system (50 milliliters) of dinethylformamide and water 10 to 1, then plus bi triphenyl palladium chloride (177 milligrams, 0.252 mM, 0.1 equivalent), sodium carbonate (534 milligrams, 5.04 mMs, 2.0 equivalents) and 3- (4,4,5,5- tetramethyls- Penta ring -2- bases of [1,3,2] dioxy boron)-but-2-ene acetoacetic ester (727 milligrams, 3.03 mMs, 1.2 equivalents), it then heats to 90 degree are stirred to react 1 hour.After dropping to room temperature, reaction is quenched with water, is then extracted with ethyl acetate.Organic phase water and food Brine cleans two to three times, and anhydrous sodium sulfate drying is spin-dried for solvent and obtains brown oil residue, purifies to obtain Huang by column chromatography (733 milligrams, receive color oily compound (E) -3- (the chloro- 4- cyclopenta amidos of 6--picoline -3- bases) -2- butenoic acid ethyls Rate：90.3%).LCMS(ESI):m/z 323[M+1]⁺。

Step 46e：Chloro- -2 (1H) -one (7-chloro-1- of 1- cyclopenta -4,8- dimethyl -1,6- naphthyridines of 7- Cyclopentyl-4,8-dimethyl-1,6-naphthyridin-2 (1H)-one) (compound 406-25) preparation：It will change It closes object 405-25 (733 milligrams, 2.27 mMs, 1.0 equivalents) to be dissolved in dry tetrahydrofuran (50 milliliters), then heat up Cesium carbonate (1.48 grams, 4.55 mMs, 2.0 equivalents) is added after to 80 degree, stirs 1 hour.Filtering, concentration, obtained residual Object purifies to obtain chloro- -2 (1H) -one of 1- cyclopenta -4,8- dimethyl -1,6- naphthyridines of waxy solid 7- (513 millis by column chromatography Gram, yield：81.9%).LCMS(ESI):m/z 277[M+1]⁺。

Step 46f：Chloro- -2 (1H) the -one 3-bromo-7- of 1- cyclopenta -4,8- dimethyl -1,6- naphthyridines of the bromo- 7- of 3- The preparation of chloro-1-cyclopentyl-4,8-dimethyl-1,6-naphthyridin--one (compound 407-25)： In closed single port bottle, compound 406-25 (513 milligrams, 1.86 mMs, 1.0 equivalents) and sodium acetate (305 millis is added Gram, 3.72 mMs, 2.0 equivalents), add 50 milliliters of glacial acetic acid (3.4 grams, 10.6 mMs, 1.0 equivalents), stirring condition Lower addition bromine (2 milliliters, 39.5 mMs, 20.1 equivalents), is then warming up to 60 degree and is stirred overnight.After dropping to room temperature, with full Reaction is quenched with sodium sulfite solution, is then extracted with ethyl acetate.Organic phase is washed twice with saturated sodium bicarbonate solution, then is used Anhydrous sodium sulfate is dried, and is concentrated to give brown oil residue, is purified to obtain White waxy target compound 3- by column chromatography Bromo- chloro- -2 (1H) -one of 1- cyclopenta -4,8- dimethyl -1,6- naphthyridines of 7- (500 milligrams, yield：76%).LCMS(ESI):m/ z 357/355[M+1]⁺。

Step 46g：Chloro- -2 (1H) -one of -3 (1- ethoxy ethylenes base) -4,8- dimethyl -1,6- naphthyridines of 1- cyclopenta of 7- (7-chloro-1-cyclopentyl-3-(1-ethoxyvinyl)-4,8-dimethyl-1,6-naphthyridin-2 (1H)-one) (compound 408-25) preparation：By compound 407-25 (250 milligrams, 0.7 mM, 1.0 equivalents), four or three (383 milligrams, 1.06 in the least for Phenylphosphine palladium (81 milligrams, 0.07 mM, 0.1 equivalent) and tributyl (1- ethoxy ethylenes base) tin Mole, 1.5 equivalents) it is dispersed in toluene (20 milliliters), it is then heated to reflux under nitrogen protection 4.5 hours.Reaction mixture It is cooled to room temperature, concentrates, obtained residue purifies to obtain the chloro- 1- cyclopenta of yellow waxy compound 7- -3 by column chromatography (1- ethoxy ethylenes base) -4,8- dimethyl -1,6- naphthyridines -2 (1H) -one (120 milligrams, yield：49.6%).LCMS(ESI): m/z 347[M+1]⁺。

Step 46h：4- { 6- [1- cyclopenta -3- (1- ethoxy ethylenes base) -4,8- dimethyl -2- oxo -1,2- dihydros - 1,6- naphthyridines -7- amidos] pyridin-3-yl } piperazine -1- carboxylates (tert-butyl 4- (6- ((1- cyclopentyl-3-(1-ethoxyvinyl)-4,8-dimethyl-2-oxo-1,2-dihydro-1,6- Naphthyridin-7-yl) amino) pyridin-3-yl) piperazine-1-carboxylate) (compound 409-25) Preparation：Under nitrogen protection, by compound 408-25 (120 milligrams, 0.35 mM, 1.0 equivalents), 4- (6- amidos-pyrrole Pyridine -3- bases) piperazine -1- carboxylates (compound 1-1-A12) (116.8 milligrams, 0.42 mM, 1.2 equivalents), three (dibenzalacetone) two palladium (16 milligrams, 0.017 mM, 0.05 equivalent), 4,5- bis- diphenylphosphine -9,9- dimethyl oxa-s Anthracene (18 milligrams, 0.031 mM, 0.09 equivalent) and cesium carbonate (228 milligrams, 0.7 mM, 2.0 equivalents) are dissolved in drying Toluene (20 milliliters) in, then oil bath heating is refluxed overnight.Reaction mixture is down to room temperature, filters, and is concentrated in vacuo.It obtains Residue purifies to obtain yellow waxy compound 4- { 6- [1- cyclopenta -3- (1- ethoxy ethylenes base) -4,8- by column chromatography Dimethyl -2- oxo -1,2- dihydro -1,6- naphthyridines -7- amidos] pyridin-3-yl } piperazine -1- carboxylates (187 milligrams, Yield：90.8%).

Step 46i：3- acetyl group -1- cyclopenta -4,8- dimethyl -7- (5- (piperazine -1- bases)-pyridine -2- amidos) -1, 6- naphthyridines -2 (1H) -one (3-acetyl-1-cyclopentyl-4,8-dimethyl-7- ((5- (piperazin-1-yl) Pyridin-2-yl) amino) -1,6-naphthyridin-2 (1H)-one) (compound 25) preparation：Compound 409-25 (187 milligrams, 0.317 mM, 1.0 equivalents) are dissolved in dichloromethane (50 milliliters), and then ice bath cools down.To reaction drop Add methanol hydrochloride solution (3 milliliters), is then stirred at room temperature 1 hour.100 milliliters of dichloromethane dilutions are added, then use saturated carbon The pH value of acid sodium solution tune reaction solution is to 8-9, liquid separation.Organic phase is dried with anhydrous sodium sulfate, and being spin-dried for solvent, to obtain yellow waxy residual Object is stayed, purifies to obtain yellow solid compound 3- acetyl group -1- cyclopenta -4,8- dimethyl -7- (5- (piperazines-by column chromatography 1- yls)-pyridine -2- amidos) -1,6- naphthyridines -2 (1H) -one (104 milligrams, yield：71.3%).

Target product characterize data：LCMS(ESI):m/z 461[M+1]⁺.¹H NMR(500MHz,DMSO-D6)δ8.56 (m, 2H), 7.95 (d, J=2.8Hz, 1H), 7.71 (d, J=9.0Hz, 1H), 7.37 (d, J=9.1Hz, 1H), 4.50 (m, 1H), 3.02 (d, J=3.8Hz, 4H), 2.85 (s, 4H), 2.42 (d, J=11.0Hz, 3H), 2.38 (s, 3H), 2.32 (d, J= 15.0Hz, 3H), 2.21 (s, 2H), 1.91 (s, 4H), 1.52 (d, J=21.4Hz, 2H)

47 biological activity test of embodiment

One, inhibition of enzyme activity is tested

1, experimental method

(1), CDK2 activity suppressions are tested

CDK2 eggs are measured using Caliper mobility shiftings detection technique (Caliper mobility shift assay) White kinase activity is (referring to J Biomol Screen 14:31,2009).With sharp after compound obtained above is dissolved with DMSO Enzyme buffer liquid (20mM HEPES-pH 7.5,0.01%Triton X-100,10mM MgCl₂, 2mM DTT) and dilution, in 384 holes The compound of 5 times of reaction final concentrations of the 10%DMSO dissolvings of 5 μ l is added in plate, no compound control hole is the 10% of 5 μ l DMSO, non-enzymatic activity control wells are 5 μ l kinase buffer liquids.Be added the CDK2 enzyme solutions after 2.5 times of the dilution of 10 μ l (Carna, Cat.No04-103 it is incubated at room temperature after) 10 minutes, adds the substrate solution Peptide after 2.5 times of the dilution of 10 μ l FAM-P18(GL Biochem,Cat.No.114202).It is incubated at 28 DEG C after sixty minutes plus 25 μ l terminate liquids terminates reaction. Reading and converting rate data on Caliper EZ Reader II (Caliper Life Sciences).Conversion at suppression Rate data processed.Wherein max refers to conversion ratios of the DMSO without compound control hole, and min refers to the conversion ratio of no enzyme activity control.To change It is transverse and longitudinal coordinate to close object concentration and inhibiting rate, draws curve, uses XLFit excel add-in version 4.3.1 softwares Matched curve simultaneously calculates IC50.Inhibiting rate %=(max- conversion ratios)/(max-min) × 100.

(2), CDK4 activity suppressions are tested

CDK4 eggs are measured using Caliper mobility shiftings detection technique (Caliper mobility shift assay) White kinase activity is (referring to J Biomol Screen 14:31,2009).With sharp after compound obtained above is dissolved with DMSO Enzyme buffer liquid (20mM HEPES-pH 7.5,0.01%Triton X-100,10mM MgCl2,2mM DTT) dilutes, in 384 holes The compound of 5 times of reaction final concentrations of the 10%DMSO dissolvings of 5 μ l is added in plate, no compound control hole is the 10% of 5 μ l DMSO, non-enzymatic activity control wells are the kinase buffer liquids of 5 μ l.10 μ l are added and dilute the CDK4 enzyme solutions (GST-CDK4 after 2.5 times (1-303end)/GST-CycD3(1-292end；Carna, Cat.No 04-105)) after be incubated at room temperature 10 minutes, then add Enter the substrate solution Peptide FAM-P8 (GL Biochem, Cat.No.112396) after 2.5 times of the dilution of 10 μ l.At 28 DEG C After being incubated for 3 hours plus 25 μ l terminate liquids terminate reaction.On Caliper EZ Reader II (Caliper Life Sciences) Reading and converting rate data.According to the method described above conversion at inhibiting rate data.Wherein, (max- turns inhibiting rate %= Change)/(max-min) × 100.

(3), CDK6 activity suppressions are tested

CDK6 eggs are measured using Caliper mobility shiftings detection technique (Caliper mobility shift assay) White kinase activity is (referring to J Biomol Screen 14:31,2009).With sharp after compound obtained above is dissolved with DMSO Enzyme buffer liquid (20mM HEPES-pH 7.5,0.01%Triton X-100,10mM MgCl2,2mM DTT) dilutes, in 384 holes The compound of 5 times of reaction final concentrations of the 10%DMSO dissolvings of 5 μ l is added in plate, no compound control hole is the 10% of 5 μ l DMSO, non-enzymatic activity control control wells are the kinase buffer liquids of 5 μ l.The CDK6 enzyme solutions after 2.5 times of the dilution of 10 μ l are added (GST-CDK6(1-326end)；Carna, Cat.No 04-107) after be incubated at room temperature 10 minutes, add the dilution of 10 μ l Substrate solution Peptide FAM-P8 (GL Biochem, Cat.No.112396) after 2.5 times.It is incubated after forty minutes at 28 DEG C 25 μ l terminate liquids are added to terminate reaction.Reading and converting rate on Caliper EZ Reader II (Caliper Life Sciences) Data.Conversion at inhibiting rate data.Wherein max refers to the conversion ratio of DMSO controls (no compound), and min refers to nothing The conversion ratio of enzyme activity control.According to the method described above conversion at inhibiting rate data.Wherein, (max- turns inhibiting rate %= Change)/(max-min) × 100.

2, experimental result

It is above-mentioned that the experimental results are shown inthe following table.

1 inhibition of enzyme activity result of table

Compound

CDK6

CDK4

CDK2

Compound

CDK6

CDK4

CDK2

1

V

I

2

III

3

IV

V

II

4

IV

V

I

5

IV

V

I

6

II

7

V

I

16

IV

V

II

17

III

18

IV

19

IV

21

IV

29

IV

V

I

30

IV

31

II

32

IV

33

IV

34

IV

35

IV

36

II

37

III

39

III

IV

I

40

III

II

42

IV

43

V

44

IV

45

III

50

IV

51

III

52

II

53

II

54

IV

55

IV

56

II

57

III

59

II

60

III

61

IV

PD-0332991

V

I

LY2835219

IV

V

IV

LEE011

III

Note：I indicates IC₅₀＞ 500nM, II indicate 500nM >=IC₅₀＞ 100nM, III indicate 100nM >=IC₅₀＞ 50nM, IV indicates 50nM >=IC₅₀＞ 10nM, V indicate IC₅₀≤10nM。

From the above it will be seen that the IC that compound provided by the invention inhibits CDK2₅₀For I or II, i.e., extremely Few ＞ 100nM, and to the IC of CDK4 or CDK6 inhibition₅₀Mostly 100nM is hereinafter, such i.e. compound can be with selective depression CDK4 And CDK6, compound 1,4,5,7,29,39 especially therein etc., the IC that CDK2 is inhibited₅₀More than 500nM, almost unrestraint Activity, and have higher inhibitory activity to CDK4 and CDK6,50nM can be reached hereinafter, with highly selective and high activity spy Point.

Two, Cytostatic to tumor cell is tested

1, experimental method

Three phosphorus are measured using CellTiter-Glo luminescent cell viability detection kit methods (Promega, Madison, WI) The content of adenosine monophosphate (ATP) assesses cell viability.Tumor cell line (SW620, ZR-75-1, MDA-MB-231) is bought from upper Extra large Fudan University IBS cell resource centers and American Type Culture Collecti (ATCC).Pancreatin is digested cell from cell culture It is close with Scepter automated cells calculating instrument (Millipore#PHCC00000) counting measurement cell after being resuspended with DPBS culture mediums Degree.Cell is diluted to every milliliter of solution for containing 44,000 cells.The cell solution after density is adjusted with every hole to add for 90 microlitres Enter in cell experiment plate.Orifice plate is placed in 37 DEG C, 5%CO₂The compound to be tried of various concentration is added in incubator culture after 24 hours. Cell is cultivated 72 hours in the presence of 10% fetal calf serum together with compound.It usesLuminescent Cell Viability Assay kit (see shop instruction) measure the content of ATP to assess cell growth inhibition.Briefly come It says, 30 μ l is added in each holeReagent, rocker 10 minutes, inducing cell lysis uses Fluoroskan Ascent FL (Thermo) detection record Fluorescent signals.Maximum signal is obtained from 72 hours cells of dmso treatment Value.Minimum signal value is obtained from individual culture medium (cell number zero).Inhibiting rate %=(maximum signal levels-compound signal Value)/(maximum signal level-minimum signal value) X100.Use GraphPad Prism V5.0 (GraphPad Software, San Diego, CA) software data processing.Pass through S-shaped dose-response curve the Fitting Calculation IC50 values.

2, experimental result

2 Cytostatic to tumor cell result of table

Compound	SW620	ZR-75-1	MDA-MB-231
				1	IV	III	I
3	III	III	II
				4	V	V	IV
5	IV	IV	IV
				7	IV	IV	III
16	IV	IV	IV
				17	IV	IV	II
18	IV	III	III
				19	IV	III	II
21	III	III	II
				29	II	IV	II
30	IV		II

32	I	III	II
				33	II	II
34	II	III	II
				35	II	III
43	III	III	II
				44	II	III	II
50	II	III
				54	III	III	II
55	III	III
				PD-0332991	IV	IV	IV
LY2835219	IV	V	IV
				LEE011	III	V	II

Note：I indicates IC₅₀5 μM of ＞, II indicate 5 μM >=IC₅₀1 μM of ＞, III indicate 1 μM >=IC₅₀0.5 μM of ＞, IV are indicated 0.5μM≥IC₅₀0.1 μM of ＞, V indicate IC₅₀≤0.1μM。

From the above it will be seen that compound provided by the invention is swollen to SW620, ZR-75-1, MDA-MB-231 Tumor cell strain has inhibitory activity, and part of compounds activity is higher.

Several embodiments of the invention above described embodiment only expresses, the description thereof is more specific and detailed, but simultaneously Cannot the limitation to the scope of the claims of the present invention therefore be interpreted as.It should be pointed out that for those of ordinary skill in the art For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the guarantor of the present invention Protect range.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.

Claims

1. pyrimidine or pyridopyridine ketone compounds or its pharmaceutically acceptable salt, which is characterized in that the pyrimidine Or pyridopyridine ketone compounds are selected from following compound：

2. the preparation method of pyrimidine described in claim 1 or pyridopyridine ketone compounds, which is characterized in that including following Step：

(1) compound 501 uses the end proton exchange of organolithium reagent and alkynes first, and generation is then reacted with tributyltin chloride Compound 502；

Reaction route is as follows：

Wherein, R₁、R₄、R₉With with pyrimidine described in claim 1 or pyridopyridine ketone compounds corresponding position substituent group phase Same definition.

3. pyrimidine described in claim 1 or pyridopyridine ketone compounds or its pharmaceutically acceptable salt are anti-in preparation Application in curing oncoma drug.

4. application according to claim 3, it is characterised in that：The tumour is entity tumor and neoplastic hematologic disorder.

5. application according to claim 4, it is characterised in that：The entity tumor and neoplastic hematologic disorder include breast cancer, fat Fat sarcoma, non-small cell lung cancer, liver cancer, oophoroma, glioblastoma, melanoma, Huppert's disease and jacket cell lymph Tumor.

6. application according to claim 5, it is characterised in that：The breast cancer includes：Postmenopausal women estrogen by The Locally Advanced or metastatic breast cancer of the body positive and/or human epidermal growth factor receptor 2's feminine gender.

7. a kind of pharmaceutical composition of anti-curing oncoma, which is characterized in that include as the described in claim 1 phonetic of active ingredient Pyridine or pyridopyridine ketone compounds or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.