CN106467517A

CN106467517A - The Abemaciclib derivant that deuterium is modified

Info

Publication number: CN106467517A
Application number: CN201610659847.XA
Authority: CN
Inventors: 张寅生; 柳英帅; 李莉; 苗雷; 徐同杰; 刘海艳; 马雪琴; 俞森; 徐宏江
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2015-08-14
Filing date: 2016-08-12
Publication date: 2017-03-01
Anticipated expiration: 2036-08-12
Also published as: CN106467517B

Abstract

The invention belongs to medicinal chemistry art is and in particular to the Abemaciclib derivant of deuterium modification, its preparation method, the pharmaceutical composition of Abemaciclib derivant containing deuterium modification, the Abemaciclib derivant of deuterium modification and its pharmaceutical composition treat the purposes in cell proliferation disorders medicine in preparation.Compared with Abemaciclib, some compounds (especially embodiment compound) of the present invention have more excellent pharmacokinetic property, are expected to reduce Clinical practice dosage, thus reducing treatment cost to allow more patients to be benefited.

Description

The Abemaciclib derivant that deuterium is modified

Technical field

The invention belongs to medicinal chemistry art and in particular to the novel deuterium of a class modify Abemaciclib derivant, its Preparation method, containing deuterium modify the pharmaceutical composition of Abemaciclib derivant, deuterium modify Abemaciclib derivant and Purposes in the medicine of preparation treatment cell proliferation disorders for its pharmaceutical composition.

Background technology

Cyclin-dependent kinase (cyclin-dependent kinase, CDK) is a class serine/threonine kinase Enzyme, as intracellular important signal transducers, and the CDK-cyclin complex that cycle element (cyclin) is formed participates in carefully The growth of born of the same parents, propagation, dormancy or apoptosis.

CDK family includes 1-13, and cyclin is divided into A-L, different CDK to couple different cyclin respectively.Wherein, Cyclin D family started to express in the G1 phase, combines and activates CDK4 and CDK6, formation CDK4/6-cyclin D complex, made A series of substrate phosphorylations including Retinoblastoma Protein.The specific activation of CDK4/6 and the increasing of some tumors Grow closely related, therefore exploitation CDK4/6 inhibitor becomes a kind of effective means of targeting therapy on tumor.Just listing in 2015 New drug Palbociclib is exactly an orally active CDK4/6 inhibitor, is now used for the treatment of the women breast cancer in late period.

Abemaciclib (LY-2835219) is the New Target tropism breast cancer treatment medicine developed by Li Lai drugmaker Thing, it can Selective depression cell cycle protein dependent kinase 4 and 6 (CDK4/6) and Pim-1 kinases, recover cell week Phase controls, and blocks tumor cell proliferation, and clinical second phase effect is significant, is the new breast carcinoma of a class and lung cancer therapy medicine.

A lot of medicines are because poor absorption, distribution, metabolisming property are thus limit their making in some diseases With.Poor ADME property is also to lead to many drug candidates to fail by the reason clinical trial.Although with special system Agent technique or prodrug technologies can improve the ADME property of some medicines in some cases, but most of drug candidates are deposited ADME problem be still unable to effectively solving, especially for the tachymetabolism problem of medicine, lead to the many originally can be efficient The medicine for the treatment of disease is difficult to patent medicine due to too fast disposing from internal metabolism.

Deuterated modification is the very potential new drug development technology of one kind improving pharmacokinetic properties.In the method, Manage by one or more hydrogen atoms being carried out D-atom replacement thus slowing down the drug metabolism of CYP mediation or reducing undesirable Metabolite generation, result may significantly extend its drug metabolism circulation, reduce the generation of toxic metabolite and medicine Between interaction, improve safety and obtain more preferably curative effect.Even if however, D-atom is mixed with known metabolism position Put, the impact that deuterium is modified for the metabolisming property of medicine remain uncertain it is therefore necessary to reality through deuterated molecule Preparation and test, just can determine that deuterated medicine and difference in terms of metabolism for the non-deuterated medicine.

Content of the invention

One aspect of the present invention provide a kind of compound shown in formula I or its pharmaceutically acceptable salt, solvate or Prodrug：

Wherein R₁、R₂、R₄、R₅、R₆、R₇、R₈、R₉And R₁₁Separately it is selected from H (hydrogen) or D (deuterium), R₃、R₁₀、R₁₂Respectively Independently selected from CH₃、CH₂D、CHD₂Or CD₃, condition is that compound of formula I contains at least one D-atom and do not include following chemical combination Thing：

Preferably, wherein R₁、R₂、R₅、R₆、R₇、R₈Or R₁₁At least one is D.

It is further preferred that wherein R₁、R₂It is D simultaneously.

It is further preferred that wherein R₅、R₆It is D simultaneously.

It is further preferred that wherein R₇、R₈It is D simultaneously.

Still more preferably, wherein R₅、R₆、R₇、R₈It is D simultaneously.

In the certain preferred embodiments of the present invention, the example of compound shown in formula I is as follows：

In certain particularly preferred embodiments of the invention, the example of compound shown in formula I is as follows：

Term " pharmaceutically acceptable salt " refers to remain the biological efficacy of free bronsted lowry acids and bases bronsted lowry of specific compound and does not have There is the salt of ill effect biology.The example of pharmaceutically acceptable salt includes but is not limited to：(1) acid-addition salts, and mineral acid The salt of the such as formation such as hydrochloric acid, sulphuric acid, hydrobromic acid, nitric acid, phosphoric acid；Or and organic acids for example malic acid, fumaric acid, maleic acid, Benzoic acid, phenylacetic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ethyl sulfonic acid, hydroxyacetic acid, cinnamic acid, acetone acid, formic acid, The salt of the formation such as acetic acid, propanoic acid, oxalic acid, malonic acid, acrylic acid, mandelic acid；Or (2) base addition salts, and alkali metal such as lithium, The salt of the formation such as sodium, potassium；Salt with the alkaline-earth metal such as formation such as calcium, magnesium；With organic bases for example ammonium, choline, diethanolamine, rely Propylhomoserin, ethylenediamine, tert-butylamine, t-octanylamine, three (methylol) aminomethane, N- methyl glucose osamine, triethanolamine, dehydrogenated rosin The salt of the formation such as amine.For a person skilled in the art, other pharmaceutically acceptable salts are known.

Term " solvate " refers to send out by being coordinated this patent of the coordination compound forming solid-state or liquid with solvent molecule The form of bright compound..The example of such form is hydrate, alcohol adduct etc..

Term " prodrug " refers to change in vivo any medicament of parent drug.Prodrug is often useful, because, In some cases, they are easier to be administered than parent drug.For example, it is administered orally, they are bioavailable, and female Body medicine is not but.Prodrug also can improve the dissolubility in pharmaceutical composition with respect to parent drug.Prodrug can be via the side of enzyme The approach of method and metabolism hydrolysis is converted into parent drug.

If any atom of the compound of institute's labelled synthesis does not specify in the present invention, any of this atom can be represented A kind of stable isotope.Unless stated otherwise, when position a certain in structure is defined as H and is hydrogen (H-1), this position only contains Naturally occurring isotopic mass.Equally, unless stated otherwise, when position a certain in structure is defined as D and is deuterium (H-2), should Position contains at least bigger than naturally occurring isotopic mass (0.015%) 3340 times of isotopic mass (i.e. to I haven't seen you for ages the same position of 50.1% deuterium Element).

In the present invention, the deuterated rate of the compound of institute's labelled synthesis refers to the isotopic content of labelled synthesis and naturally occurs Isotopic mass ratio.In the present invention, the deuterated rate of each specified D-atom of the compound of institute's labelled synthesis can be at least 3500 times (52.5%), at least 4000 times (60%), at least 4500 times (67.5%), at least 5000 times (75%), extremely It is 5500 times (82.5%), at least 6000 times (90%) less, be at least 6333.3 times (95%), be at least 6466.7 times (97%), it is at least 6566.7 times (98.5%), at least 6600 times (99%), be at least 6633.3 times (99.5%).

Isotopic body (isotopologues) in the present invention refers to only have in isotopics not in terms of chemical constitution Same compound.In the present invention, the compound of institute's labelled synthesis has identical chemical constitution, only forms in the atom of its molecule In isotopic change.Therefore, in the present invention institute's labelled synthesis similarly can contain containing deuteride in ad-hoc location considerably less This position hydrogen isotope body, the measuring certainly of the hydrogen isotope body of certain position in the compound of institute's labelled synthesis in the present invention Many factors, including deuterated reagent (D₂O、D₂、NaBD₄、LiAlD₄Deng) deuterium isotopic purity and introduce deuterium isotope The effectiveness of synthetic method.However, the amount sum of the hydrogen isotope body of certain position this will be less than 49.9% as previously mentioned.This The amount sum of the hydrogen isotope body of certain position in the compound of bright middle institute labelled synthesis will less than 47.5%, 40%, 32.5%, 25%th, 17.5%, 10%, 5%, 3%, 1% or 0.5%.

Herein, any each atom being not designated as deuterium is existed with its natural isotopic abundance.

The present invention further provides being used for preparing the illustrative methods of compound and each intermediate shown in formula I.

Route 1 provides a kind of illustrative methods of the compound shown in formula I for preparation.

As shown in Scheme 1, in the presence of a catalyst, Formula II compound is reacted with double pinacol two boron and prepares formula III Compound, further under metallic catalyst effect, coupling reaction obtains formula IV compound.In the presence of a catalyst, formula finally IV compound and Formula V compound obtain compound of formula I using inorganic bases such as cesium carbonates as acid binding agent reaction.

Route 2 provides a kind of illustrative methods for the Formula II compound in syntheti c route 1.

As shown in Scheme 2, Formula VII compound can by Formula IV compound (wherein deuterated 2-aminopropane .-d1 and deuterated 2-aminopropane .- D7 can buy from Aldrich) prepare with acetic anhydride, further, Formula VII compound and formula compound VIII are in trichlorine oxygen In the presence of phosphorus, organic base, reaction generates Formula IX compound.Compounds X can by compound IX in the presence of the alkali such as potassium tert-butoxide warp Prepared by condensation reaction.Finally, with heavy water, deuterated methanol or deuterated ethanol etc. for deuterium source, in the basic conditions can through hydrogen-deuterium exchange Prepare Formula II compound.

Route 3 provides a kind of illustrative methods for the Formula V compound in syntheti c route 1.

As shown in Scheme 3, Formula X II compound can (can be from Aldrich by Formula X I and 5- bromopyridine -2- formaldehyde Buy) prepare in the presence of formic acid, trimethyl orthoformate.Further, compounds X II can be with hexamethyl two silicon substrate ammonia The reaction ammonification of base lithium obtains Formula V compound.

Route 4 provides another kind of illustrative methods for the Formula V compound in syntheti c route 1.

Formula V compound also can be prepared via route 4.With Formula X VII compound as initiation material, through 5- bromopyridine -2- first Aldehyde reduction amination accepted way of doing sth XXV compound, the latter can be reduced into Formula X II compound, and further ammonification becomes Formula V compound.

Route 5 provides another for the illustrative methods of the Formula V compound in syntheti c route 1.

Formula V compound also can be prepared via route 5.With Formula X VII compound as initiation material, (can through 6- amino-nicotinic acid Buy from Aldrich) reaction accepted way of doing sth XXVI compound, the latter can be in reducing agent (such as NaBD₄(H₄)) in the presence of by further also Former one-tenth Formula V compound.

Route 6 provides another kind of illustrative methods for preparing compound of formula I.

As shown in Scheme 6, Formula X I and 6- amino-nicotinic acid (can buy from Aldrich) are in dehydrant or activating agent In the presence of formula XIII compound.In the presence of a catalyst, there is C-N in the Formula X III compound of gained and formula IV compound Coupling reaction generates intermediate Formula X IV compound, and the Formula X IV compound of gained can be tried with go back original reagent or deuterated reduction further Agent such as lithium aluminium hydride reduction (LiAlH₄), deuterate aluminum lithium (LiAlD₄), sodium borohydride (NaBH₄)/lewis acid (AlCl₃,BF₃), boron deuterium Change sodium (NaBD₄)/lewis acid, borine (BH₃), deuterated borine (BD₃- THF), silane (PhSiH₃/ KOH) etc. reaction obtain Formulas I Compound.

For Formula X I, can be prepared by different methods for the deuterated compound of different loci.Route 7,8,9 carries Wherein three kinds different synthetic methods are supplied.

Route 7：The synthesis of Formula X I

As shown in Scheme 7, with piperazine as initiation material, N, N- dinitroso piperazine are prepared through nitrozation reaction first Piperazine.In the basic conditions, with heavy water, deuterated methanol or deuterated ethanol etc. for deuterium source, can formula XV further through hydrogen-deuterium exchange Compound.Under the conditions of alumel de- nitroso-group can formula XVI compound, then with quantitative acetic anhydride, chloroacetic chloride or Acetic acidreaction is prepared into Formula X VII compound.Last reducing agent for example lithium aluminium hydride reduction, deuterate aluminum lithium, sodium borohydride/lewis acid, The lower reaction of the effect such as boron deuterate sodium/lewis acid obtains Formula X I.

Route 8：The synthesis of Formula X I-a compound

As shown in Scheme 8, with NEP as initiation material, equally it is prepared into Formula X VIIIization through nitrozation reaction Compound.In the basic conditions, with heavy water, deuterated methanol or deuterated ethanol etc. for deuterium source, it is prepared into Formula X IXization through hydrogen-deuterium exchange Compound.Last nitroso-group de- under the conditions of alumel can be prepared into Formula X I-a compound.

Route 9：The synthesis of Formula X I-b compound

As shown in Scheme 9, (can buy from Aldrich) with N-benzyl piperazine as initiation material, anti-through nitrosylation Formula X X compound should be prepared into.In the basic conditions, with heavy water, deuterated methanol or deuterated ethanol etc. for deuterium source, through hydrogen-deuterium exchange It is prepared into Formula X XI compound.Then under the conditions of alumel, de- nitroso-group can be prepared into Formula X XII compound, then with quantitative Acetic anhydride, chloroacetic chloride or acetic acidreaction are prepared into Formula X XIII compound.Formula X XIII compound is in reducing agent such as lithium aluminium hydride reduction, deuterium Change the lower reaction of the effect such as aluminum lithium, sodium borohydride/lewis acid, boron deuterate sodium/lewis acid and obtain Formula X XIV compound.Last with The metals such as palladium are catalyst, in hydrogen environment reacting by heating debenzylation Formula X I-b compound.

Above-mentioned route illustrates the synthetic method constituting the present invention, is for describing applicableization by specific embodiment Method, rather than represent the scope of the present invention or be intended to limit.Regardless of by identical variable name (that is, R¹、R²、R³ Deng) be identified, the chemical constitution in illustrating herein depicts the chemical group definition with relevant position in compounds herein formula The variable that here is suitably limited.In the chemical structural formula for synthesizing another kind of compound, the appropriateness of chemical group exists Within the ken of those of ordinary skill in the art.

Another aspect of the invention provides a kind of pharmaceutical composition, its comprise therapeutically effective amount shown in formula I Compound or its pharmaceutically acceptable salt, solvate or prodrug and one or more pharmaceutically acceptable carrier or figuration Agent.

The pharmaceutical composition of the present invention can be given by number of ways, this depend on whether locally or systemically to treat and The region treated.Can local (for example, transdermal, skin, eye and mucosa include intranasal, vagina and rectum pass medicine), lung (for example, By sucking or being blown into powder or aerosol, including by aerosol apparatus；Tracheal strips, intranasal), oral and parenteral administration.The intestines and stomach External administration includes intravenouss, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion；Or intracranial such as intrathecal or Intraventricular give Medicine.

Some examples of acceptable carrier or excipient include Lactose, glucose, sucrose, Sorbitol, Mannitol, shallow lake Powder, arabic gum, calcium phosphate, alginate, Tragacanth, gelatin, calcium silicates, Microcrystalline Cellulose, Polyvinylpyrrolidone, fiber Element, water, syrup and methylcellulose etc..Pharmaceutical composition also can contain：Lubricant such as Pulvis Talci, magnesium stearate and mineral Oil；Wetting agent；Emulsifying agent and suspending agent；Preservative such as essence of Niobe and benzoic acid hydroxy propyl ester；Sweeting agent and correctivess. Can by using method as known in the art prepare the present invention pharmaceutical composition so that after giving patient provide rapid release, Slow release or the effect of delayed release of active elements.

Can be by unit dosage forms compositions formulated, every dose contains about 5～1000mg, and more typically from about 100～500mg activity becomes Point.Term " unit dosage forms " refer to physically separated suitable as the single dose list for people patient and other mammals Position, constituent parts are contained being computed of being mixed with suitable drug excipient and can produce the active substance of the scheduled volume of required curative effect.

The scope of the effective dose of reactive compound can be very big, generally presses medicinal effective dose administration.However, it is to be understood that it is real The amount of the compound that border gives generally is determined by physician in view correlation circumstance, they include treated disease, selected to Medicine approach, the actual compound being given；The age of individual patients, weight and reaction；Order of severity of patients symptomatic etc..

The therapeutic dose of the compounds of this invention can be according to depending on for example following：Treatment particular use, give compound Mode, the health of patient and state, and sign the judgement of prescriber.Ratio in Pharmaceutical composition for the compounds of this invention or Concentration can not be fixed, and depending on many factors, they include dosage, chemical characteristic (such as hydrophobicity) and route of administration.For example The compounds of this invention can be provided by the physiological buffer aqueous solution containing this compound of about 0.1～10%w/v, give for parenteral Medicine.Some exemplary dosage ranges are about 1 μ g/kg～about 1g/kg body weight/day.In certain embodiments, dosage range is about 0.01mg/kg～about 100mg/kg body weight/day.Dosage will likely depend on this class variable, such as the species of disease or disease and sending out Exhibition degree, the general health status of concrete patient, the relative biological efficacy of selected compound, excipient preparation and its give Medicine approach.Effective dose can be obtained by the dose-response curve extrapolation derived by external or animal model test system.

Another aspect of the present invention provides compound or its pharmaceutically acceptable salt, solvate or front shown in formula I Purposes in the medicine of preparation treating cancer for the medicine.Preferably, described cancer is selected from colorectal carcinoma, breast carcinoma, pulmonary carcinoma (especially NSCLC), carcinoma of prostate, glioblastoma multiforme, lymphoma mantle cell, chronic myelocytic leukemia and the white blood of acute myelogenous Disease.

Another aspect of the invention provides a kind of method treating cancer in mammal, and described cancer is selected from colorectum Cancer, breast carcinoma, pulmonary carcinoma (particularly NSCLC), carcinoma of prostate, glioblastoma multiforme, lymphoma mantle cell, the white blood of chronic granulocyte Disease and acute myeloblastic leukemia, the method include to mammal in need apply therapeutically effective amount shown in formula I Compound or its pharmaceutically acceptable salt, solvate or prodrug.

Embodiments of the invention compound has significant CDK4 and CDK6 inhibitory activity.For example, as herein described one In kind or many measure, there is the CDK4 inhibitory activity less than 50nM, preferably have less than the CDK4 inhibitory activity of 20nM, more excellent Choosing has the CDK4 inhibitor activity less than 8nM, most preferably has the CDK4 inhibitory activity less than 2nM.For example, described herein One or more mensure in, there is the CDK6 inhibitory activity less than 50nM, preferably have less than the CDK6 inhibitory activity of 20nM, The more preferably less than CDK6 inhibitor activity of 8nM, most preferably has the CDK6 inhibitory activity less than 2nM.

Compared with Abemaciclib, some compounds (especially embodiment compound) of the present invention are in people's hepatomicrosome In there is more preferably stability, and more excellent pharmacokinetic property, be expected to reduce clinical using dosage, thus reducing Treatment cost is benefited with allowing more patients.

Specific embodiment：

The following examples can illustrate in greater detail the present invention, but the invention is not limited in any way.

The preparation of embodiment 1 compound I-1

Step 1) N- isopropyl-acetamide

Under ice bath, 2- 2-aminopropane. (20g, 338.4mmol), triethylamine (34.6g, 341.8mmol) are dissolved in dichloromethane successively Alkane (150mL), acetic anhydride (35.2g, 345.1mmol) is slowly dropped in reaction bulb by constant pressure funnel, controls interior Temperature is less than 5 DEG C.Finish, reaction bulb is transferred to and is stirred overnight at room temperature.Solvent is removed by concentrating under reduced pressure, uses methyl tertiary butyl ether(MTBE) (200mL) add potassium carbonate (50g) after diluting, stir 1 hour under room temperature.Decompression sucking filtration, filtrate reduced in volume obtains Formula VII -1 and changes Compound (27.8g), is weak yellow liquid.

¹H-NMR(CDCl₃,300MHz)：δ 5.71 (s, 1H), 4.06 (dt, 1H), 1.94 (s, 3H), 1.14 (d, J= 6.5Hz,6H).

HRMS(M+H)m/z：102.0908.

Step 2) N- (4- bromo- 2,6- difluorophenyl)-N '-isopropyl-second narrows

By bromo- for 4- 2,6- difluoroaniline (31.05g, 0.15mol), N- isopropyl yl acetamide (30.3g, 0.30mmol), three Chlorethoxyfos (20.9mL, 0.225mol) are added sequentially in dry toluene.Under ice bath by triethylamine (31.3mL, 0.225mol) in It is slowly dropped to reaction bulb in constant pressure funnel, keep interior temperature to be less than 60 DEG C.Reaction bulb is transferred in oil bath pan and is heated to solvent and returns Stream.After 2 hours, reaction bulb is cooled to room temperature, is poured slowly in 300g mixture of ice and water, adds 300 milliliters of ethyl acetate, fills Divide point liquid after mixing, water layer is extracted with 200 milliliters of ethyl acetate again, merges organic layer, anhydrous sulfur after saturated common salt water washing Sour sodium is dried, and obtains faint yellow solid after concentrating under reduced pressure, adds 100 milliliters of petroleum ether to pull an oar 10 minutes, and decompression sucking filtration obtains Formula IX -1 Compound (28.0g), is off-white powder (yield 92.3%).

¹H-NMR(CDCl₃,300MHz)：δ 7.01～7.03 (m, 2H), 4.17 (s, 1H), 1.76 (s, 3H), 1.23 (d, J =5.6Hz, 6H).

¹³C-NMR(DMSO,300MHz)：δ157.48,156.65,153.41,115.09,114.72,110.03,41.62, 21.79,17.62.

HRMS(M+H)m/z：291.0088.

Step 3) the bromo- 4- of 6- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole

N- (4- bromo- 2,6- difluorophenyl)-N '-isopropyl-second is narrowed (27.2g, 93.47mmol) and is dissolved in anhydrous N, N- bis- Methylformamide (200mL), adds potassium tert-butoxide (13.11g, 116.83mmol), is heated to 110 DEG C under nitrogen protection.4 hours Reaction bulb is cooled to room temperature afterwards, adds 500 milliliters of ethyl acetate, 800 milliliters of water, point liquid after fully mixing, water layer continues to use 500 Milliliter ethyl acetate extraction, point liquid.Merge organic layer, first use 200 milliliters of water washings 5 times, then with 200 milliliters of saturated common salts washings Wash 3 times, after organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure obtains Light brown solid, after adding 100 milliliters of petroleum ether making beating twice Obtain Formula II -1 compound (21.0g), be faint yellow solid.

¹H-NMR(CDCl₃,300MHz)：δ 7.41 (d, J=1.2Hz, 1H), 7.07 (dd, J₁=1.4Hz, J₂=9.6Hz, 1H), 4.62 (heptet, 1H), 2.62 (s, 3H), 1.62 (d, J=7.0Hz, 6H).

¹³C-NMR(CDCl₃,300MHz)：δ154.75,151.91,151.35,137.11,130.90,111.14, 110.27,48.39,21.17,14.79.

HRMS(M+H)m/z：271.0251.

Step 4) the bromo- 4- of 6- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H [5,7-D₂] benzimidazole

Heavy water (15mL), the heavy aqueous solution (2mL) of 40% content NaOD, anhydrous tetrahydro furan (5mL) are added sequentially to In microwave reaction bottle, it is subsequently adding the bromo- 4- of 6- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole (2.76g, 10mmoL).Open Microwave heating reacts, and setting reaction temperature is 145 DEG C, and the response time is 15 hours.Reaction finishes, and product is sunken to reaction bulb bottom Portion, after removing solvent, adds heavy water (15mL), the heavy aqueous solution (2mL) of 40% content NaOD, anhydrous tetrahydro furan again (5mL), continue microwave reaction under same reaction conditions (145 DEG C of reaction temperature, 15 hours response time), repeat deuterated 4 times.Can Obtain Formula II -2 compound (2.30g).

¹H-NMR(DMSO,300MHz)：δ 4.76 (heptet, 1H), 1.54 (d, J=6.9Hz, 6H).

MS(M+H)：276.0553.

¹³C-NMR(DMSO,300MHz)：δ153.91,152.79,150.55,137.34,130.51,112.48, 110.68,47.87,20.63.

HRMS(M+H)m/z：276.0557.

Step 5) 4- fluoro- 1- isopropyl -2- [D₃] methyl -6- (4,4,5,5- tetramethyl-[1,3,2] dioxa bora ring Pentane -2- base) -1H- [5,7-D₂] benzimidazole

DMSO (100mL) is added in 500 milliliters of single-necked flasks, sequentially adds the bromo- 4- of 6- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole (20.7g, 73.80mmoL), double (pinacol) two boron (27.6g, 108.69mmol), tricyclohexyl phosphine (3.53g, 12.61mmol), potassium acetate (21.3g, 217.38mmol).Nitrogen displacement is reacted Acid chloride (1.5g) is rapidly joined, the lower unlatching of nitrogen protection is heated to 90 DEG C after air in bottle.After 3 hours, reaction bulb is cooled to room Temperature, reactant liquor is poured in 700 milliliters of water, and reduce pressure after being sufficiently mixed sucking filtration, and filter cake is lightly dry afterwards twice with 100 milliliters of water washings Brown solid.Crude product adds 50mL petroleum ether, 10mL ethyl acetate making beating 10min, and decompression sucking filtration obtains formula III -1 compound (18.8g), it is off-white powder.

¹H-NMR(DMSO,300MHz)：δ 4.82 (heptet, 1H), 1.56 (d, J=6.9Hz, 6H), 1.32 (s, 12H).

¹³C-NMR(DMSO,300MHz)：δ154.08,153.12,150.76,136.62,133.79,113.61, 110.99,83.74,47.68,24.59,22.90,21.00.

HRMS(M+H)m/z：324.2311.

Step 6) 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzo Imidazoles

Chloro- for 2,4- bis- 5-FU (9.95g, 59.60mmol) is dissolved in glycol dimethyl ether (210mL), sequentially adds 2M aqueous sodium carbonate (140mL), 4- fluoro- 1- isopropyl -2- [D₃] methyl -6- (4,4,5,5- tetramethyl-[1,3,2] dioxy Miscellaneous bora Pentamethylene. -2- base) -1H- [5,7-D₂] benzimidazole (17.5g, 54.18mmol), double (triphenylphosphine) Palladous chloride. (1.0g).Air in nitrogen displacement reaction bulb, opens oil bath heating, stirring reaction 1h at 85 DEG C.Reaction bulb is cooled to room temperature, instead Answer liquid to pour in 300mL water, a large amount of solids separate out, reduce pressure after being sufficiently stirred for sucking filtration, after filtration cakes torrefaction, obtain formula IV -1 compound (13.18g), it is pale solid.

¹H-NMR(DMSO,300MHz)：δ 8.94 (d, J=3.4Hz, 1H), 4.86 (heptet, 1H), 1.60 (d, J= 6.9Hz,6H).

¹³C-NMR(CDCl₃,300MHz)：δ156.45,154.81,153.85,152.95,150.54,149.58, 149.22,136.35,124.50,109.15,106.98,47.93,20.77,14.50(m,CD₃).

HRMS(M+H)m/z：328.1184.

Step 7) 1- (6- bromo- pyridin-3-yl methyl) -4- ethyl-piperazin

NEP (1.59g, 13.95mmol), 2- bromo- 5- pyridine carboxaldehyde (3.14g, 16.88mmol) are added successively Enter in acetonitrile, add formic acid (2.10mL, 55.80mmol), trimethyl orthoformate (3.07mL, 27.90mmol).Nitrogen is protected Under be heated to reflux, after 4 hours, reactant liquor is cooled to room temperature, adds 30mL water, 15mL ethyl acetate, point liquid.Organic layer is residue 2- bromo- 5- pyridine carboxaldehyde.Water layer adds saturation sodium hydroxide to adjust pH to 10, adds 30mL ethyl acetate, point liquid, and water layer is again Add 30mL ethyl acetate, merge organic layer, after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains product crude product.Column chromatography purification obtains formula XII-1 compound (1.48g), is colourless liquid.

¹H-NMR(300MHz,CDCl₃)：δ 8.29 (1H, d, J=1.74Hz, Py), 7.53-7.55 (1H, dd, J= 1.98Hz, 8.10Hz, Py), 7.43 (1H, d, J=8.10Hz, Py), 3.47 (2H, s, CH₂),2.38-2.48(10H,m, piper-CH₃ CH ₂), 1.08 (3H, t, J=7.14Hz,CH ₃CH₂).

¹³C-NMR(300MHz,CDCl₃)：δ150.59,140.71,139.29,133.18,127.72,59.25,52.61, 52.21,11.84.

HRMS(M+H)m/z：284.0757.

Step 8) 5- (4- ethyl-piperazin -1- ylmethyl)-pyridine -2- base amine

1- (6- bromo- pyridin-3-yl methyl) -4- ethyl-piperazin (960mg, 3.38mmol) is dissolved in anhydrous tetrahydro furan (8mL), add 2- (dicyclohexyl phosphino-) biphenyl (120mg, 0.338mmol), three (dibenzalacetone) two palladium (154mg, 0.169mmol).It is slowly added to lithium hexamethyldisilazide (4.06mL, 1M, 4.06mmol) under nitrogen protection.Reaction bulb oil Bath is heated to 65 DEG C, and after 20 minutes, reaction bulb is cooled to room temperature, adds 50mL ethyl acetate, 30mL water, point liquid, water layer after mixing Add 30mL ethyl acetate again, point liquid, merge organic layer, after anhydrous sodium sulfate drying, revolving obtains Light brown solid.Column chromatography Purification obtains Formula V -1 compound (670mg), is faint yellow solid.

¹H-NMR(300MHz,CDCl₃)：δ 7.75 (1H, d, J=1.65Hz, Py), 7.24-7.28 (1H, dd, J= 2.16Hz, 8.37Hz, Py), 6.40 (1H, d, J=8.37Hz, Py), 5.77 (2H, s, NH₂),3.24(2H,s,CH₂),2.25- 2.32(10H,m,piper-CH₃ CH ₂), 0.96 (3H, t, J=7.11Hz,CH ₃CH₂).

¹³C-NMR(300MHz,CDCl₃)：δ157.64,148.54,139.12,123.18,108.27,59.74,52.64, 52.20,11.84.

HRMS(ESI)m/z：220.1688.

Step 9) [5- (4- ethyl piperazidine -1- ylmethyl)-pyridine -2- base]-[5 fluoro- 4- (7- fluoro- 3- isopropyl -2- [D₃] methyl -3H- [5,7-D₂] benzimidazole -5 base)-pyrimidine -2-base]-amine

By 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole (788mg, 2.41mmol), 5- (4- ethyl piperazidine -1- ylmethyl)-pyridine -2- base amine (530mg, 2.41mmol), cesium carbonate (1.57g, 4.82mmol) is added sequentially in dioxane (20mL), and air in nitrogen displacement reaction bulb rapidly joins three (two BENZYLIDENE ACETONE) two palladiums (50mg), the double diphenylphosphine xanthene (80mg) of 9,9- dimethyl -4,5-.It is heated under nitrogen protection Reactant liquor flows back.After 2 hours, reactant liquor is cooled to room temperature, adds 30mL ethyl acetate, and reduce pressure sucking filtration.Filtrate adds 20mL water, Divide liquid, during water layer, enter 20mL ethyl acetate, point liquid, merge organic layer, after anhydrous sodium sulfate drying, concentrating under reduced pressure removes solvent and obtains Light brown solid.Crude product adds 9mL petroleum ether, 3mL ethyl acetate, is stirred at room temperature 30 minutes, and reduce pressure sucking filtration, obtains Formulas I -1 chemical combination Thing 858mg, is off-white powder (yield 69.8%).

¹H-NMR(DMSO,300MHz)：δ 10.08 (s, 1H), 8.67 (s, 1H), 8.20～8.22 (m, 1H), 7.65 (d, J =7.7Hz, 1H), 4.81～4.85 (m, 1H), 3.42 (s, 2H), 2.27～2.36 (m, 10H), 1.62 (d, J=6.4Hz, 6H), 0.96 (t, J=6.6Hz, 3H).

¹³C-NMR(DMSO,300MHz)：δ155.34,154.46,153.85,152.11,150.55,148.73, 148.07,147.77,147.41,138.17,136.36,133.38,126.97,126.40,111.69,108.81,58.77, 52.44,51.52,48.03,20.88,11.96, (deuterated methyl carbon multiplet bag is in noise).

HRMS(M+H)m/z：512.3103.

The preparation of embodiment 2 compound I-10

Step 1) 4- fluoro- 1- isopropyl -2- methyl -6- (4,4,5,5- tetramethyl-[1,3,2] dioxaborolan alkane - 2- yl) -1H- benzimidazole

Replace the bromo- 4- of 6- fluoro- 1- isopropyl -2- [D with the bromo- 4- of 6- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole₃] Methyl isophthalic acid H [5,7-D₂] benzimidazole, and with reference to embodiment 1 step 5) shown in method preparation formula III-2 compound.

¹H-NMR(CDCl₃,300MHz)：δ 7.69 (s, 1H), 7.33 (d, J=10.7Hz, 1H), 4.65～4.74 (m, 1H), 2.65 (s, 3H), 1.65 (d, J=7.0Hz, 6H), 1.36 (s, 12H).

¹³C-NMR(CDCl₃,300MHz)：δ154.89,152.20,151.55,136.67,134.27,113.46, 112.51,83.88,48.28,24.81,21.43,15.12.

HRMS(M+H)m/z：319.1987.

Step 2) 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole

With 4- fluoro- 1- isopropyl -2- methyl -6- (4,4,5,5- tetramethyl-[1,3,2] dioxaborolan alkane -2- Base) -1H- benzimidazole replacement 4- fluoro- 1- isopropyl -2- [D₃] methyl -6- (4,4,5,5- tetramethyl-[1,3,2] dioxa boron Heterocycle pentane -2- base) -1H- [5,7-D₂] benzimidazole, and with reference to embodiment 1 step 6) shown in method formula IV-2 chemical combination Thing.

¹H-NMR(DMSO,300MHz)：δ 8.95 (d, J=3.3Hz, 1H), 8.15 (s, 1H), 7.62 (d, J=11.9Hz, 1H), 4.86 (heptet, 1H), 2.65 (s, 3H), 1.60 (d, J=6.9Hz, 6H).

¹³C-NMR(DMSO,300MHz)：δ156.60,155.03,153.96,153.10,150.66,149.78, 149.42,136.49,124.66,109.36,107.08,48.05,20.88,14.63.

HRMS(M+H)m/z：323.0870.

Step 3) N- benzyl-N- nitroso-group piperazine

N-benzyl piperazine (50.0g, 0.284mol) is added in reaction bulb, 0 DEG C about Deca 2M HCl (160ml, 0.318mol), the reactant liquor obtaining stirs 10 minutes at 0 DEG C, then to Deca NaNO in reaction₂Aqueous solution [NaNO₂, (24.50g, 0.335mol) adds the solution that water (58mL) is made into], maintain temperature at 0～10 DEG C, drip off within 40 minutes.Reaction is mixed Compound is stirred at room temperature overnight.Next day, reaction is heated to 35 DEG C about 1 hour (a large amount of insoluble solids generations), then by reaction bulb Put in cryostat, cooling at 0 DEG C separates out, and isolates solid product finally by sucking filtration, washing, and water layer is extracted with DCM again, has Machine phase merges, and anhydrous magnesium sulfate is dried, and removes desiccant by sucking filtration, and rotary evaporation removes solvent and obtains solid product.Finally Obtain Formula X X-1 compound (56.71g) after 50 DEG C of dryings of baking oven of reducing pressure, be faint yellow solid (yield 97.30%).

¹H-NMR(300MHz,CDCl₃):7.26～7.34 (m, 5H), 4.23～4.27 (t, J=10.4Hz, 2H), 3.81 ～3.85 (t, J=10.7Hz, 2H), 3.60 (s, 2H), 2.66～2.70 (t, J=10.3Hz, 2H), 2.43～2.46 (t, J= 10.7Hz,2H).

MS(M+H)m/z：206.1.

Step 4) N- benzyl-N- nitroso-group-[3,3,5,5-D₄] piperazine

Addition N- benzyl-N- nitroso-group piperazine (20.0g, 97.43mmol) in reaction bulb, Feldalat NM (15.79g, 292.29mmol), under nitrogen, in reaction bulb, heavy water (150ml), deuterated ethanol (d1,100ml) are slowly added.Then heat To 80 DEG C, reaction is molten clear.After 24 hours stop heating, to be cooled put in cryostat to after room temperature, at 0 DEG C cooling separate out.3 After hour, solid product is isolated by sucking filtration.It is dried to obtain Formula X XI-1 compound finally by 50 DEG C of baking oven of decompression (17.735g), it is faint yellow solid.

¹H-NMR(300MHz,CDCl₃)：7.25～7.33 (m, 5H), 3.56 (s, 2H), 2.64 (s, 2H), 2.41 (s, 2H).

MS ESI,(M+Na)m/z：232.2.

Step 5) N- benzyl-[3,3,5,5-D₄] piperazine

Addition Formula X XI-1 compound (10.0g, 47.78mmol) in reaction bulb, Feldalat NM (7.74g, 143.34mmol), under nitrogen, slowly in reaction, heavy water (75mL) and deuterated ethanol (d1,75mL) are added.It is then heated to 70 ℃.Reaction stopped heating after 24 hours, after being cooled to room temperature, several times to addition Al-Ni alloy (30.0g) in reaction, about 2 Hour adds, and reactant mixture is stirred at room temperature overnight.Next day, solid metal is removed by sucking filtration, collect containing product Filtrate.Extracted with DCM again, organic faciess merge, anhydrous magnesium sulfate is dried, desiccant is removed by sucking filtration, rotary evaporation removes molten Agent obtains solid product.Finally by obtaining Formula X XII-1 compound (7.13g) after drying under reduced pressure, it is that faint yellow oily body (produces Rate 82.81%).

¹H-NMR(300MHz,CD₃OD)：7.20～7.31 (m, 5H), 3.47 (s, 2H), 2.39 (s, 4H).

HRMS(ESI,M+H)m/z：181.2.

Step 6) N- benzyl-N '-acetyl group-[3,3,5,5-D₄] piperazine

By N- benzyl-[3,3,5,5-D₄] piperazine (5.40g, 30mmol) is dissolved in dichloromethane (30mL), under condition of ice bath It is slowly added to acetic anhydride (3.4mL, 36mmol), is stirred at room temperature 10 minutes, in reactant liquor, add 20mL saturated sodium carbonate solution, point Liquid, water layer adds 30mL dichloromethane, merges organic faciess, after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains Formula X XIII-1 after point liquid Compound (6.20g), is light brown liquid.

Step 7) N- benzyl-N '-[1,1-D₂] ethyl-[3,3,5,5-D₄] piperazine

By N- benzyl-N '-acetyl group-[3,3,5,5-D₄] piperazine (3.33g, 15.0mmol) is dissolved in anhydrous tetrahydro furan (30mL), sequentially add [D4] boron deuterate sodium (1.23g, 30mmol), aluminum chloride (4.01g, 30mmol), open and be heated to reacting Liquid flows back.After 3 hours, reactant liquor is cooled to room temperature, pours in 50g mixture of ice and water, adds saturation sodium hydroxide solution to adjust pH To 10 about.Add 50mL ethyl acetate, point liquid after mixing, water layer adds 50mL ethyl acetate again, and point liquid merges organic Layer, after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains Formula X XIV-1 compound (2.85g), is colourless liquid.

¹H-NMR(DMSO,300MHz)：δ 7.21～7.33 (m, 5H), 3.43 (s, 2H), 2.33 (s, 4H), 0.95 (s, 3H).

¹³C-NMR(DMSO,300MHz)：δ138.27,128.67,128.02,126.74,69.66,62.13,52.47, 11.70.

HRMS(M+H)m/z：211.1454.

Step 8) N- [1,1-D₂] ethyl-[2,2,6,6-D₄] piperazine

By N- benzyl-N '-[1,1-D₂] ethyl-[3,3,5,5-D₄] piperazine (2.75g, 13.10mmol) is dissolved in methanol, plus Enter 10% content palladium carbon (0.28g).It is heated to 60 DEG C in hydrogen environment.Reactant liquor decompression sucking filtration after 10 hours, filtrate revolving obtains Formula X I-2 compound (1.80g), is colourless liquid.

¹H-NMR(DMSO,300MHz)：δ2.74(s,4H),0.95(s,3H).

¹³C-NMR(DMSO,300MHz)：δ69.76,52.59,44.56,26.06,11.70.

HRMS(M+H)m/z：121.1282.

Step 9) 1- (6- bromo- pyridin-3-yl methyl) -4- [1,1-D₂] ethyl-[3,3,5,5--D₄] piperazine

With N- [1,1-D₂] ethyl-[2,2,6,6-D₄] piperazine XI-2 replaces NEP, and reference embodiment 1 step 7) compound of method formula XII-2 shown in.

¹H-NMR(DMSO,300MHz)：δ 8.29 (s, 1H), 7.65～7.68 (m, 1H), 7.58～7.61 (m, 1H), 3.46(s,2H),2.36(s,4H),0.96(s,3H).

¹³C-NMR(DMSO,300MHz)：δ150.51,139.94,139.77,133.67,127.62,69.66,58.08, 52.09,11.51.

MS(M+H)m/z：290.1127.

Step 10) 5- (4- [1,1-D₂] ethyl-[3,3,5,5-D₄] piperazine -1- ylmethyl)-pyridine -2- base amine

With 1- (6- bromo- pyridin-3-yl methyl) -4- [1,1-D₂] ethyl-[3,3,5,5-D₄] piperazine replacement 1- (the bromo- pyrrole of 6- Pyridine -3- ylmethyl) -4- ethyl-piperazin, and with reference to embodiment 1 step 8) shown in method formula V-2 compound.

¹H-NMR(DMSO,300MHz)：δ 7.75 (d, J=1.6Hz, 1H), 7.26 (dd, J₁=2.1Hz, J₁=8.4Hz 1H), 6.39 (d, J=8.4Hz, 1H), 5.77 (s, 2H), 3.23 (s, 2H), 2.29 (s, 4H), 0.94 (s, 3H).

¹³C-NMR(DMSO,300MHz)：δ158.93,147.95,138.05,120.78,107.50,59.14,52.14, 11.70.

HRMS(M+H)m/z：227.2136.

Step 11) [5- (4- [1,1-D₂] ethyl-[3,3,5,5-D₄] piperazine -1- ylmethyl)-pyridine -2- base]-[5 is fluoro- 4- (7- fluoro- 3- isopropyl -2- methyl -3H- benzimidazole -5 base)-pyrimidine -2-base]-amine

Replace 6-- (2- with 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole Chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole, with 5- (4- [1,1-D₂] Ethyl-[3,3,5,5-D₄] piperazine -1- ylmethyl)-pyridine -2- base amine replacement 5- (4- ethyl piperazidine -1- ylmethyl)-pyridine - 2- base amine, and with reference to method formula I-10 compound shown in embodiment 1 step 9.

¹H-NMR(DMSO,300MHz)：δ 10.12 (s, 1H), 8.69 (d, J=2.9Hz, 1H), 8.29 (s, 1H), 8.20 ～8.22 (m, 2H), 7.66～7.70 (m, 2H), 4.80～4.89 (m, 1H), 3.43 (s, 2H), 2.64 (s, 3H), 2.36 (s, 4H), 1.63 (d, J=6.5Hz, 6H), 0.95 (s, 3H).

¹³C-NMR(DMSO,300MHz)：δ155.33,154.52,153.89,152.12,150.59,148.75, 148.09,147.79,147.43,138.19,136.37,133.36,127.00,126.56,111.72,108.88,58.81, 52.29,51.45,48.05,20.89,14.50,11.72.

HRMS(M+H)m/z：513.3152.

The preparation of embodiment 3 compound I-9

Step 1) N- benzyl-N '-ethyl-[3,3,5,5-D₄] piperazine

Replace boron deuterate sodium with lithium aluminium hydride, and with reference to embodiment 2 step 7) shown in method formula XXIV-2 compound.

¹H-NMR(DMSO,300MHz)：δ 7.20～7.33 (m, 5H), 3.43 (s, 2H), 2.26～2.34 (m, 6H), 0.97 (t, J=7.2Hz, 3H).

¹³C-NMR(DMSO,300MHz)：δ138.25,128.70,128.04,126.77,62.10,52.41,51.44, 11.92.

MS(M+H)：209.1346.

Step 2) N- ethyl-[2,2,6,6-D₄] piperazine

With N- benzyl-N '-ethyl-[3,3,5,5-D₄] piperazine replacement N- benzyl-N '-[1,1-D₂] ethyl-[3,3,5,5- D₄] piperazine, and with reference to method formula XI-3 compound shown in embodiment 2 step 8.

¹H-NMR(DMSO,300MHz)：δ 2.73 (s, 4H), 2.28 (q, J=7.2Hz, 2H), 0.97 (t, J=7.2Hz, 3H).

¹³C-NMR(DMSO,300MHz)：δ169.76,51.96,44.73,26.06,11.71.

HRMS(M+H)m/z：119.1475.

Step 3) 1- (6- bromo- pyridin-3-yl methyl) -4- ethyl-[3,3,5,5-D₄] piperazine

With N- ethyl-[2,2,6,6-D₄] piperazine replacement N- [1,1-D₂] ethyl-[2,2,6,6-D₄] piperazine, and with reference to real Apply example 2 step 9) shown in method formula XII-3 compound.

¹H-NMR(DMSO,300MHz)：δ 8.28 (1H, s, Py), 7.64-7.68 (1H, m, Py), 7.59 (1H, d, J= 8.10Hz,Py),3.46(2H,s,CH₂-Py),2.35(4H,s,CD2CH₂- piper), 2.28 (2H, q, J=7.20Hz, CH₃CH₂- piper), 0.96 (3H, t, J=7.20Hz, CH₃CH₂).

¹³C-NMR(DMSO,300MHz)：δ150.47,139.89,139.73,133.70,127.59,58.12,52.28, 51.37,26.02,11.91.

HRMS(M+H)m/z：288.0843,290.0825.

Step 4) 5- (4- ethyl-[3,3,5,5-D₄] piperazine -1- ylmethyl)-pyridine -2- base amine

With 1- (6- bromo- pyridin-3-yl methyl) -4- ethyl-[3,3,5,5-D₄] piperazine replacement 1- (the bromo- pyridin-3-yl of 6- Methyl) -4- [1,1-D₂] ethyl-[3,3,5,5-D₄] piperazine, and with reference to method formula V-3 chemical combination shown in embodiment 2 step 10 Thing.

¹H-NMR(DMSO,300MHz)：δ 7.74 (1H, s, Py), 7.25 (1H, d, J=8.34HzPy), 6.38 (1H, d, J =8.37Hz, Py), 3.23 (2H, s, CH₂-Py),2.30(4H,s,CD2CH₂- piper), 2.26 (2H, q, J=7.20Hz, CH₃CH₂- piper), 0.96 (3H, t, J=7.14Hz, CH₃CH₂).

¹³C-NMR(DMSO,300MHz)：δ158.90,147.93,138.03,120.81,107.48,59.13,52.16, 51.41,11.95.

HRMS(M+H)m/z：225.1881.

Step 5) [5- (4- ethyl-[3,3,5,5-D₄] piperazine -1- ylmethyl)-pyridine -2- base]-[(7- is fluoro- for 5 fluoro- 4- 3- isopropyl -2- methyl -3H- benzimidazole -5 base)-pyrimidine -2-base]-amine

With 5- (4- ethyl-[3,3,5,5-D₄] piperazine -1- ylmethyl)-pyridine -2- base amine replacement 5- (4- [1,1-D₂] second Base-[3,3,5,5-D₄] piperazine -1- ylmethyl)-pyridine -2- base amine, and with reference to embodiment 2 step 11) shown in method formula I-9 compound.

¹H-NMR(DMSO,300MHz)：δ 10.08 (s, 1H), 8.68 (d, J=2.6Hz, 1H), 8.29 (s, 1H), 8.20 ～8.22 (m, 2H), 7.65～7.70 (m, 2H), 4.80～4.89 (m, 1H), 3.45 (s, 2H), 2.64 (s, 3H), 2.35～ 2.55 (m, 6H), 1.63 (d, J=6.4Hz, 6H), 0.99 (t, J=6.7Hz, 3H).

¹³C-NMR(DMSO,300MHz)：δ155.35,154.51,153.89,152.15,150.59,148.75, 148.13,147.76,147.41,138.22,136.38,133.35,126.82,126.47,111.71,108.87,58.65, 51.82,51.29,48.05,30.36,20.88,14.48,11.50.

HRMS(M+H)m/z:511.3017.

The preparation of embodiment 4 compound I-4

Step 1) N, N- dinitrosopiperazine

Addition piperazine (8.0g, 93.0mmol) in reaction bulb, 0 DEG C about Deca 2M HCl (104ml, 208mmol), 0 Deca NaNO after stirring 10min at DEG C₂Aqueous solution (NaNO₂, 15.2g, water 36ml), 30 minutes about completion of dropping, room temperature is anti- Should overnight.It is heated to 35 DEG C of reaction about 1-2 hours, 0 DEG C of cooling separates out, sucking filtration obtains faint yellow solid, 45 DEG C of bakings of vacuum drying oven N, N- dinitrosopiperazine (12.32g), yield 92% is obtained after dry.

¹H-NMR(400MHz,CDCl₃)：δ 4.60 (s, 1.7H), 4.46 (t, J=5.4Hz, 2.3H), 4.21 (t, 2.3H), 3.88 (s, 1.7H) (form inseparable two isomers ,-N-N=O by nitroso-group on nitrogen two different orientation).

¹³C-NMR(400MHz,CDCl₃)：δ 49.58,47.09,40.50,37.75 (inseparable two isomers ,- N-N=O)

HRMS(ESI)m/z：144.0647.

Step 2) N, N- dinitroso-[D₈] piperazine

Dinitrosopiperazine (10.0g, 69.4mmol), Feldalat NM (15.0g, 277.7mmol), nitrogen is added in reaction bulb It is slowly added to heavy water (300mL, 15.0mol), 80 DEG C are reacted 10 hours under gas.At 0 DEG C, cooling separates out, sucking filtration, vacuum drying oven Dry to obtain Formula X V-1 compound (8.56g) for 45 DEG C, be faint yellow solid, yield 82%.

¹H-NMR(300MHz,CDCl₃) (paranitroanisole does internal standard)：δ 8.20 (2H, d, J=9.21Hz, Ph), 6.96 (2H, d, J=9.21Hz, Ph), 3.91 (3H, s, CH₃) (in addition to internal standard molecular hydrogen peak, no other hydrogen peaks, hydrogen all quilts on piperazine Deuterium replaces).

HRMS(M+H)m/z：153.1212.

Step 3) [D₈] piperazine dihydrochloride

Dinitroso-D is added in reaction bulb₈- piperazine (3.0g, 19.74mmol), Feldalat NM (5.99g, 0.11mol), It is slowly added to heavy water (30mL, 15.0mol) and the deuterated ethanol of D1- (30mL), after being cooled to room temperature, add Al-Ni alloy several times (24.0g), react overnight under room temperature.Sucking filtration, filtrate air-distillation (130 DEG C), after liquid all steams, it is slowly added dropwise dense salt Sour (4mL).Revolving removes solvent and obtains white solid, and 45 DEG C of vacuum drying oven dries to obtain XVI-1 compound (2.86g), yield 82%.

¹H-NMR(300MHz,CDCl₃) (paranitroanisole does internal standard)：δ 8.20 (2H, d, J=9.27Hz, Ph), 7.07 (2H, d, J=9.27Hz, Ph), 3.91 (3H, s, CH₃) (in addition to internal standard molecular hydrogen peak, no other hydrogen peaks, hydrogen all quilts on piperazine Deuterium replaces).

HRMS(M+H)m/z：95.1417.

Step 4) N- acetyl group-[D₈] piperazine

Formula X VI-1 compound (0.5g, 2.99mmol) is added in single neck bottle of 25ml, water (5mL), then plus Na₂CO₃ Adjust pH to 8 about, under ice bath, be slowly added dropwise acetic anhydride (0.34mL, 3.59mmol), stir 10 minutes under room temperature.DCM extraction removes Decontamination, aqueous phase adjusts pH to alkalescence with the NaOH of 2M, is spin-dried for obtaining white solid, and DCM pulls an oar, and merges organic faciess after filtration, concentrates Obtain Formula X VII-1 compound (0.23g), be white solid, yield 56.5%.

¹H-NMR(300MHz,CDCl₃)：δ2.02(3H,s,CH₃).

HRMS(M+H)m/z：137.1526.

Step 5) 1- (6- bromo- pyridin-3-yl methyl) -4- acetyl group-[D₈] piperazine

With N- acetyl group-[D₈] piperazine replaces NEP, and method formula shown in reference embodiment 1 step 7 XXV-1 compound.

¹H-NMR(300MHz,CDCl₃)：δ 8.29 (1H, d, J=1.65Hz, Py), 7.62-7.66 (1H, dd, J= 2.40Hz, 8.16Hz, Py), 7.43 (1H, d, J=8.10Hz, Py), 3.48 (2H, s, CH₂),2.09(3H,s,CH₃).

HRMS(M+H)m/z：306.1057.

Step 6) 1- (6- bromo- pyridin-3-yl methyl) -4- ethyl-[D₈] piperazine

Formula X XV-1 compound (3.07g, 10.03mmol), anhydrous THF (35mL), NaBH is added in 100ml mono- neck bottle₄ (1.52g, 40.10mmol), is dividedly in some parts AlCl₃(5.35g, 40.10mmol), room temperature reaction is overnight.Add 2M hydrochloric acid extremely molten Clearly, 70 DEG C of backflow 1h, 2M sodium hydroxide solution adjusts pH to alkalescence, and DCM extracts, anhydrous sodium sulfate drying.Column chromatographic isolation and purification (DCM:MeOH=5:1) obtain Formula X II-4 compound (1.91g), be yellow liquid, yield 72%.

¹H-NMR(300MHz,CDCl₃)：δ 8.29 (1H, d, J=1.74Hz, Py), 7.62-7.66 (1H, dd, J= 2.40Hz, 8.10Hz, Py), 7.42 (1H, d, J=8.10Hz, Py), 3.48 (2H, s, CH₂), 2.40-2.47 (2H, q, J= 7.23Hz,CH₃ CH ₂), 1.09 (3H, t, J=7.23Hz,CH ₃CH₂).

HRMS(M+H)m/z：292.1245.

Step 7) 5- (4- ethyl-[D₈] piperazine -1- ylmethyl)-pyridine -2- amine

With 1- (6- bromo- pyridin-3-yl methyl) -4- ethyl-[D₈] piperazine replacement 1- (6- bromo- pyridin-3-yl methyl) -4- Ethyl-piperazin, and with reference to embodiment 1 step 8) shown in method formula V-4 compound.

¹H-NMR(300MHz,CDCl₃)：δ 7.95 (1H, d, J=1.65Hz, Py), 7.39-7.43 (1H, dd, J= 2.04Hz, 8.34Hz, Py), 6.47 (1H, d, J=8.34Hz, Py), 4.44 (2H, s, NH₂),3.37(2H,s,CH₂),2.37- 2.45 (2H, q, J=7.20Hz, CH₃ CH ₂), 1.07 (3H, t, J=7.20Hz,CH ₃CH₂).

HRMS(M+H)m/z：229.2268.

Step 8) [5- (4- ethyl-[D₈] piperazine -1- ylmethyl)-pyridine -2- base]-[5 fluoro- 4- (7- fluoro- 3- isopropyl - 2- methyl -3H- benzimidazole -5 base)-pyrimidine -2-base]-amine

(2- is chloro- to replace 6- with 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole 5-FU -4- base) -4- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole, with 5- (4- ethyl-[D₈] piperazine Piperazine -1- ylmethyl)-pyridine -2- amine replaces 5- (4- ethyl piperazidine -1- ylmethyl)-pyridine -2- base amine, and reference embodiment 1 step Method formula I-4 compound shown in rapid 9.

¹H-NMR(DMSO,300MHz)：δ 10.08 (s, 1H), 8.68 (d, J=3.7Hz, 1H), 8.29 (s, 1H), 8.19 ～8.22 (m, 2H), 7.64～7.70 (m, 2H), 4.80～4.89 (m, 1H), 3.43 (s, 2H), 2.64 (s, 3H), 2.30 (q, J =7.1Hz, 2H), 1.63 (d, J=6.7Hz, 6H), 0.96 (t, J=7.1Hz, 3H).

¹³C-NMR(DMSO,300MHz)：δ155.34,154.51,153.89,152.11,150.59,148.73, 148.08,147.78,147.42,138.17,136.36,133.35,127.01,126.47,111.69,108.90,58.71, 52.12,51.47,48.05,20.88,14.49,11.98.

HRMS(M+H)m/z：515.3274.

The preparation of embodiment 5 compound I-3

Step 1) N- ethyl-N- nitroso-group piperazine

Replace N-benzyl piperazine with NEP, and with reference to method formula XVIII-1ization shown in embodiment 2 step 3 Compound.

¹H-NMR(300MHz,CDCl₃)：δ 4.28 (2H, t, J=5.13Hz, piper), 3.86 (2H, t, J=5.28Hz, ), piper 2.67 (2H, t, J=5.22Hz, piper), 2.47-2.54 (2H, q, J=7.20Hz, CH₃ CH ₂),2.43(2H,t,J =5.40Hz, piper), 1.12 (3H, t, J=7.20Hz,CH ₃CH₂).

HRMS(ESI)m/z：148.1383.

Step 2) 4- ethyl -1- nitroso-group-[2,2,6,6-D₄] piperazine

Replace N- benzyl-N- nitroso-group piperazine with N- ethyl-N- nitroso-group piperazine, and with reference to side shown in embodiment 2 step 4 Legal system prepares standby Formula X IX-1 compound.

¹H-NMR(300MHz,CDCl₃)：δ 2.64 (2H, s, piper), 2.45-2.52 (2H, q, J=7.20Hz, CH₃ CH ₂), 2.40 (2H, s, piper), 1.11 (3H, t, J=7.20Hz,CH ₃CH₂).

HRMS(ESI)m/z：147.1310.

Step 3) 1- ethyl-[3,3,5,5-D₄] piperazine hydrochloride

With N- ethyl-N- nitroso-group [2,2,6,6-D₄] piperazine replacement N- benzyl-N- nitroso-group [2,2,6,6-D₄] piperazine, And with reference to the preparation formula XI-a-1 compound of method shown in embodiment 2 step 5

¹H-NMR(300MHz,CDCl₃)：δ 3.06 (4H, s, piper), 2.81-2.88 (2H, q, J=7.23Hz, CH₃ CH ₂), 1.23 (3H, t, J=7.23Hz,CH ₃CH₂).

HRMS(M+H)m/z：119.1479.

Step 4) 1- (6- bromo- pyridin-3-yl methyl) -4- ethyl-[2,2,6,6-D₄] piperazine

Addition Formula X I-a-1 compound (1.6g, 10.34mmol) in single neck bottle, sodium hydroxide (0.41g, 10.34mmol), 15mL methanol, 65 DEG C are flowed back 3 hours.It is cooled to room temperature after vulcanization acid magnesium to stir 0.5 hour, sucking filtration, filtrate is spin-dried for obtaining milky Solid.Above-mentioned Off-white solid (1.22g, 10.32mmol) is added in single neck bottle, 6- bromo- 3- pyridine carboxaldehyde (2.30g, 12.38mmol), trimethyl orthoformate (2.26mL, 20.64mmol), formic acid (1.56mL, 41.28mmol), acetonitrile (5mL), 80 DEG C reaction overnight.2M sodium hydroxide solution adjusts pH to alkalescence, and DCM extracts, anhydrous sodium sulfate drying.Column chromatographic isolation and purification (DCM:MeOH=5:1) obtain Formula X II-5 compound (1.16g), be yellow liquid.

¹H-NMR(300MHz,CDCl₃)：δ 8.29 (1H, d, J=1.65Hz, Py), 7.52-7.56 (1H, dd, J= 2.40Hz, 8.16Hz, Py), 7.43 (1H, d, J=8.10Hz, Py), 3.48 (2H, s, CH₂-Py),2.40-2.51(8H,m, CH₃CH₂- piper), 1.11 (3H, t, J=7.2Hz, CH₃CH₂).

¹³C-NMR(CDCl₃, 300MHz)：δ160.64,150.59,139.27,133.11,127.73,59.09,52.99, 52.34,51.77,11.85,11.64.

HRMS(M+H)m/z：288.1055.

Step 5) 5- (4- ethyl-[2,2,6,6-D₄] piperazine -1- ylmethyl)-pyridine -2- amine

With 1- (6- bromo- pyridin-3-yl methyl) -4- ethyl-[2,2,6,6-D₄] piperazine replacement 1- (the bromo- pyridin-3-yl of 6- Methyl) -4- ethyl-piperazin, and with reference to embodiment 1 step 8) shown in method formula V-5 compound.

¹H-NMR(300MHz,CDCl₃)：δ 7.94 (1H, d, J=1.65Hz, Py), 7.39-7.42 (1H, dd, J= 1.50Hz, 8.31Hz, Py), 6.47 (1H, d, J=8.34Hz, Py), 4.47 (2H, s, NH₂),3.40(2H,s,CH₂-Py), 2.51-2.60(6H,m,CH₃CH₂- piper), 1.15 (3H, t, J=7.2Hz, CH₃CH₂).

¹³C-NMR(CDCl₃, 300MHz)：δ157.73,148.50,139.20,122.76,108.39,59.43,52.20, 52.15,11.31.

HRMS(M+H)m/z：225.2004.

Step 6) [5- (4- ethyl-[2,2,6,6-D₄] piperazine -1- ylmethyl)-pyridine -2- base]-[(7- is fluoro- for 5 fluoro- 4- 3- isopropyl -2- methyl -3H- benzimidazole -5 base)-pyrimidine -2-base]-amine

(2- is chloro- to replace 6- with 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole 5-FU -4- base) -4- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole, with 5- (4- ethyl-[2,2, 6,6-D₄] piperazine -1- ylmethyl)-pyridine -2- amine replaces 5- (4- ethyl piperazidine -1- ylmethyl)-pyridine -2- base amine, and reference Embodiment 1 step 9) shown in method formula I-3 compound.

¹H-NMR(DMSO,300MHz)：δ 10.12 (s, 1H), 8.68 (d, J=3.4Hz, 1H), 8.29 (s, 1H), 8.20 ～8.22 (m, 2H), 7.66～7.70 (m, 2H), 4.81～4.89 (m, 1H), 3.43 (s, 2H), 2.64 (s, 3H), 2.29～ (2.34 m, 6H), 1.62 (d, J=6.4Hz, 6H), 0.96 (t, J=6.7Hz, 3H).

¹³C-NMR(DMSO,300MHz)：δ155.37,154.54,153.89,152.14,150.60,148.76, 148.10,147.70,147.44,138.20,136.38,133.36,126.98,126.49,111.72,108.89,58.64, 52.12,51.55,48.06,20.89,14.51,11.90.

HRMS(M+H)m/z：511.3027.

The preparation of embodiment 6 compound I-6

Method one

Step 1) (6- aminopyridine -3- base) (4- ethyl piperazidine -1- base) ketone

Addition 6- amino-nicotinic acid (1.0g, 7.24mmol) in single neck bottle, DMF (20mL), CDI (1.41g, 8.68mmol), stir 10min at 70 DEG C, under room temperature, after stirring 1h, add NEP (1.84mL, 14.48mmol), room temperature Lower reaction is overnight.Revolving removes solvent, column chromatographic isolation and purification (DCM:MeOH=5:1) obtain Formula X III-1 compound, for white Solid (1.44g), yield 85%.

¹H-NMR(300MHz,CDCl₃)：δ 8.18 (1H, s, Py), 7.53-7.57 (1H, dd, J=2.19Hz, 8.49Hz, ), Py 6.49 (1H, d, J=8.49Hz, Py), 4.77 (2H, s, NH₂),3.66(4H,s,piper),2.42-2.47(6H,m, piper-CH ₂CH₃), 1.10 (3H, t, J=7.17Hz,CH ₃CH₂).

¹³C-NMR(CDCl₃, 300MHz)：δ168.58,159.25,147.91,137.72,121.23,107.70, 52.73,52.19,29.62,11.81.

HRMS(ESI)m/z：235.1550.

Step 2) 5- (4- ethyl piperazidine -1- base-[D₂] methyl)-pyridine -2- amine

Replace N- benzyl-N '-acetyl group-with (6- aminopyridine -3- base) (4- ethyl piperazidine -1- base) ketone XIII-1 [3,3,5,5-D₄] piperazine, and with reference to embodiment 2 step 7) shown in method formula V-7 compound.

¹H-NMR(300MHz,CDCl₃)：δ 7.95 (1H, s, Py), 7.39-7.42 (1H, dd, J=1.50Hz, 8.34Hz, ), Py 6.47 (1H, d, J=8.34Hz, Py), 4.42 (2H, s, NH₂),2.39-2.48(10H,m,piper-CH ₂CH₃),1.08 (3H, t, J=7.20Hz,CH ₃CH₂).

¹³C-NMR(CDCl₃, 300MHz)：δ157.67,148.59,139.10,123.07,108.26,52.58,11.81.

HRMS(ESI)m/z：223.1243.

Step 3) [5- (4- ethyl piperazidine -1- base [D₂] methyl)-pyridine -2- base]-[5 fluoro- 4- (7- fluoro- 3- isopropyl - 2- methyl -3H- benzimidazole -5 base)-pyrimidine -2-base]-amine

(2- is chloro- to replace 6- with 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole 5-FU -4- base) -4- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole, with 5- (4- ethyl piperazidine -1- Base-[D₂] methyl)-pyridine -2- amine replaces 5- (4- ethyl piperazidine -1- ylmethyl)-pyridine -2- base amine, and reference embodiment 1 step Method formula I-6 compound shown in rapid 9).

¹H-NMR(DMSO,300MHz)：δ 10.08 (s, 1H), 8.68 (d, J=3.4Hz, 1H), 8.29 (s, 1H), 8.20 ～8.23 (m, 2H), 7.66～7.70 (m, 2H), 4.81～4.89 (m, 1H), 2.64 (s, 3H), 2.35～2.50 (m, 10H), 1.63 (d, J=6.0Hz, 6H), 0.99 (t, J=6.6Hz, 3H).

¹³C-NMR(DMSO,300MHz)：δ155.32,154.53,153.90,152.16,150.60,148.75, 148.14,147.78,147.43,138.24,136.37,133.36,126.81,126.56,111.70,108.88,52.16, 51.46,48.06,20.89,14.50,11.73.

HRMS(M+H)m/z：509.2907.

Method two

Step 1) (4- ethyl piperazidine -1- base) (6- (the fluoro- 4- of 5- (4- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole - 6- yl)-pyrimidin-3-yl) ketone

By formula IV -2 compound (428mg, 1.33mmol), Formula X III-1 compound (314mg, 1.33mmol), cesium carbonate (532mg, 2.66mmol) is added sequentially in dioxane (15mL), air in nitrogen displacement reaction bulb, adds three (two benzal Benzylacetone) two palladiums (30mg), the double diphenylphosphine xanthene (50mg) of 9,9- dimethyl -4,5-.It is heated to reacting under nitrogen protection Liquid flows back.After 3 hours, reactant liquor is cooled to room temperature, adds 30mL ethyl acetate, and decompression sucking filtration removes inorganic salt and metal etc. no Molten thing.Filtrate adds 20mL water, point liquid, and water layer adds 20mL ethyl acetate, and point liquid merges organic layer, anhydrous sodium sulfate drying Concentrating under reduced pressure removes solvent and obtains off-white powder afterwards.Column chromatography purification obtains Formula X IV-1 compound (395mg), is white solid.

¹H-NMR(DMSO,300MHz)：δ 10.42 (s, 1H), 8.72 (d, 1H), 8.38 (s, 1H), 8.33～8.29 (m, 2H), 7.80 (d, 1H), 7.68 (d, 1H), 4.89～4.81 (m, 1H), 3.40-3.32 (m, 4H), 2.64 (s, 3H), 2.39～ 2.33(m,6H),1.63(d,6H),1.01(t,3H).

¹³C-NMR(DMSO,300MHz)：δ166.88,155.05,154.60,153.90,152.39,150.34, 149.02,147.60,147.00,136.96,136.42,133.35,126.30,124.78,110.89,109.0,107.26, 52.25,51.42,48.09,20.91,14.54,11.83.

HRMS(M+H)m/z：521.2474.

Step 2) [5- (4- ethyl piperazidine -1- base [D₂] methyl)-pyridine -2- base]-[5 fluoro- 4- (7- fluoro- 3- isopropyl - 2- methyl -3H- benzimidazole -5 base)-pyrimidine -2-base]-amine

Formula X IV-1 compound (260mg, 0.5mmol) is dissolved in anhydrous tetrahydro furan (5mL), sequentially adds boron deuterate sodium (41mg, 1.0mmol), aluminum chloride (134mg, 1.0mmol), reaction bulb is added boron deuterate sodium (21mg), is continued after being heated to reflux 2h It is cooled to room temperature after continuous reacting by heating 1h.Add 2M hydrochloric acid molten clear to reactant liquor, 70 DEG C be heated to reflux 1h after be cooled to room temperature, use 2M sodium hydroxide solution adjusts pH to alkalescence, and ethyl acetate extracts, anhydrous sodium sulfate drying.Column chromatographic isolation and purification (DCM: MeOH=5:1) obtain Formulas I -6 compound (220mg), be white solid.

HRMS(M+H)m/z：509.2907.

The preparation of embodiment 7 compound I-5

Step 1) (6- aminopyridine -3- base) (4- Acetylpiperazine -1- base) ketone

Replace NEP with N- Acetylpiperazine, and with reference to embodiment 7 step 1) shown in method formula XXVI-1 Compound.

¹H-NMR(300MHz,CDCl₃)：δ 8.18 (1H, s, Py), 7.54-7.57 (1H, dd, J=1.65Hz, 8.52Hz, ), Py 6.51 (1H, d, J=8.52Hz, Py), 4.92 (2H, s, NH₂),3.51-3.66(8H,m,piper),2.13(3H,s, CH₃).

¹³C-NMR(CDCl₃, 300MHz)：δ169.17,159.46,147.87,137.90,120.48,107.95, 41.45,29.65,21.31.

HRMS(ESI)m/z：249.1532.

Step 2) 5- (4- [1,1-D₂] ethyl piperazidine -1- base-[D₂] methyl)-pyridine -2- amine

Replaced with (6- aminopyridine -3- base) (4- Acetylpiperazine -1- base) ketone N- benzyl-N '-acetyl group-[3,3, 5,5-D₄] piperazine, and with double amount [D₄] boron deuterate sodium, and with reference to embodiment 2 step 7) shown in method formula V-8 compound.

¹H-NMR(300MHz,CDCl₃)：δ 7.95 (1H, d, J=1.62Hz, Py), 7.39-7.42 (1H, dd, J= 2.07Hz, 8.34Hz, Py), 6.47 (1H, d, J=8.34Hz, Py), 4.44 (2H, s, NH₂),2.40-2.50(8H,m, piper),1.07(3H,s,CH₃).

¹³C-NMR(CDCl₃, 300MHz)：δ157.67,148.56,139.12,120.98,108.28,52.52,11.49.

HRMS(ESI)m/z：225.2022.

Step 3) [5- (4- [1,1-D₂] ethyl piperazidine -1- base-[D₂] methyl)-pyridine -2- base]-[5 fluoro- 4- (the fluoro- 3- of 7- Isopropyl -2- methyl -3H- benzimidazole -5 base)-pyrimidine -2-base]-amine

(2- is chloro- to replace 6- with 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole 5-FU -4- base) -4- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole, with 5- (4- [1,1-D₂] second Base piperazine -1- base-[D₂] methyl)-pyridine -2- amine replaces 5- (4- ethyl piperazidine -1- ylmethyl)-pyridine -2- base amine, and reference Embodiment 1 step 9) shown in method formula I-5 compound.

¹H-NMR(DMSO,300MHz)：δ 9.99 (s, 1H), 8.67 (d, J=2.7Hz, 1H), 8.29 (s, 1H), 8.18～ 8.21 (m, 2H), 7.66～7.70 (m, 2H), 4.81～4.89 (m, 1H), 2.64 (s, 3H), 2.35～2.50 (m, 8H), 1.63 (d, J=6.5Hz, 6H), 0.96 (s, 3H).

¹³C-NMR(DMSO,300MHz)：δ155.34,154.50,153.88,152.12,150.58,148.74, 148.10,147.76,147.40,138.19,136.37,133.34,126.82,126.55,111.71,108.86,52.17, 48.03,20.87,14.47,11.56.

HRMS(M+H)m/z：511.3033.

The preparation of embodiment 8 compound I-7

[5-(4-[1,1-D₂] ethyl piperazidine -1- ylmethyl)-pyridine -2- base]-[5 fluoro- 4- (7- fluoro- 3- isopropyl -2- [D₃] methyl -3H- [5,7-D₂] benzimidazole -5 base)-pyrimidine -2-base]-amine

With 5- (4- [1,1-D₂] ethyl piperazidine -1- ylmethyl)-pyridine -2- amine replacement 5- (4- ethyl piperazidine -1- Ji Jia Base)-pyridine -2- base amine, and with reference to embodiment 1 step 9) shown in method formula I-7 compound.

¹H-NMR(DMSO,300MHz)：δ 10.09 (s, 1H), 8.69 (d, J=3.7Hz, 1H), 8.20 (d, J=6.4Hz, 2H), 7.66 (d, J=8.4Hz, 2H), 4.80～4.89 (m, 1H), 3.44 (s, 2H), 2.40～2.55 (m, 8H), 1.63 (d, J =6.8Hz, 6H), 0.96 (s, 3H).

¹³C-NMR(DMSO,300MHz)：δ155.36,154.48,153.85,152.13,150.56,148.75, 148.09,147.78,147.43,138.19,136.28,133.40,126.95,126.32,111.71,58.74,52.36, 52.21,48.03,20.89,11.64.

HRMS(M+H)m/z：514.3224.

The preparation of embodiment 9 compound I-8

[5- (4- ethyl piperazidine -1- base-[D₂] methyl)-pyridine -2- base]-[5 fluoro- 4- (7- fluoro- 3- isopropyl -2- [D₃] Methyl -3H- [5,7-D₂] benzimidazole -5 base)-pyrimidine -2-base]-amine

With 5- (4- ethyl piperazidine -1- base-[D₂] methyl)-pyridine -2- amine replacement 5- (4- ethyl piperazidine -1- ylmethyl) - Pyridine -2- base amine, and with reference to embodiment 1 step 9) shown in method formula I-8 compound.

¹H-NMR(DMSO,300MHz)：δ 10.09 (s, 1H), 8.68 (d, J=3.7Hz, 1H), 8.20 (d, J=6.4Hz, 2H), 7.66 (d, J=8.4Hz, 2H), 4.80～4.89 (m, 1H), 2.40～2.55 (m, 10H), 1.63 (d, J=6.8Hz, 6H), 0.97 (t, J=6.7Hz, 3H).

HRMS(M+H)m/z：514.3212.

The preparation of embodiment 10 compound I-35

Step 1) 4- toluene sulfonic acide [D₅] ethyl ester

Sodium hydroxide (15.4g, 385mmol) is dissolved in water and is made into 26mL solution, under condition of ice bath, add D₆Ethanol.Will be right Toluene sulfochloride (15.8g, 84.49mmol) is dissolved in oxolane (26mL), is slowly dropped in above-mentioned solution, is stirred at room temperature anti- Answer 2 hours.Reactant liquor adds ethyl acetate 50mL, point liquid after being sufficiently stirred for, and water layer adds 50mL ethyl acetate again, point liquid, Merge organic layer, add anhydrous sodium sulfate drying, concentrating under reduced pressure obtains colourless viscous liquid 17.5g.

¹H-NMR(500MHz,DMSO)：δ 7.80 (2H, d, J=8.0Hz, Py), 7.35 (2H, d, J=8.0Hz, Py), 2.45(3H,s,CH₃).

¹³C-NMR(DMSO,500MHz)：144.73,133.24,129.86,127.84,21.63.

HRMS(ESI)m/z：171.0121.

M/z 171.0121 is [M-H] of p-methyl benzenesulfonic acid^-, ethyl p-toluenesulfonate is easy to be cracked in an ion source P-methyl benzenesulfonic acid, so do not collect the ion of toluenesulfonic acid ethyl ester.

Step 2) N- benzyl-N '-[D₅] ethyl piperazidine

Acetonitrile (10mL) is added in 25mL single-necked flask, sequentially adds 4- toluene sulfonic acide [D₅] ethyl ester (2.05g, 10mmol), benzyl diethylenediamine (1.76g, 10mmol), potassium carbonate (1.65g, 12mmol), open and be heated to reactant liquor backflow, 3 is little When after TLC display reaction substantially completely.Reactant liquor is extracted with ethyl acetate to water layer no product, organic layer anhydrous slufuric acid acid sodium After drying, revolving obtains colourless viscous liquid, and column chromatography purification obtains colourless viscous liquid 1.80g.

¹H-NMR(500MHz,DMSO)：δ7.25-7.33(5H,m,Py),3.54(2H,s,-CH₂),2.57(8H,s).

¹³C-NMR(DMSO,500MHz)：138.09,129.25,128.21,127.03,63.09,53.00,52.74.

HRMS(ESI)m/z：210.2116.

Step 3) N- [D₅] ethyl piperazidine

With N- benzyl-N '-[D₅] ethyl piperazidine replacement N- benzyl-N '-[1,1-D₂] ethyl-[3,3,5,5-D₄] piperazine, and With reference to method formula XI-4 compound shown in embodiment 2 step 8.

¹H-NMR(500MHz,DMSO)：δ 2.93 (4H, t, J=5.0Hz), 2.43-2.46 (4H, m).

¹³C-NMR(DMSO,500MHz)：52.77,45.25.

HRMS(ESI)m/z：120.1540.

Step 4) (6- aminopyridine -3- base) (4- [D₅] ethyl piperazidine -1- base) ketone

With N- [D₅] ethyl piperazidine replaces ethyl piperazidine, and with reference to embodiment 7, in method one prepared by method shown in step 1 Formula X III-2 compound.

¹H-NMR(300MHz,DMSO)：δ 7.74 (1H, d, J=3.00Hz, Py), 7.40-7.41 (1H, dd, J= 3.00Hz,Py),7.02(1H,s,Py),6.35(2H,s,NH₂), 3.49 (4H, t, J=9.00Hz, piper), 2.36 (4H, t, J=9.00Hz, piper).

¹³C-NMR(DMSO,300MHz)：167.94,160.49,147.87,136.76,121.62,118.87,106.77, 52.24,39.78.

HRMS(ESI)m/z：240.1872.

Step 5) 5- (4- [D₅] ethyl piperazidine -1- base-[D₂] methyl)-pyridine -2- amine

With (6- aminopyridine -3- base) (4- [D₅] ethyl piperazidine -1- base) ketone XIII-2 replacement N- benzyl-N '-acetyl Base-[3,3,5,5-D₄] piperazine, and with reference to embodiment 2 step 7) shown in method formula V-9 compound.

¹H-NMR(300MHz,DMSO)：δ 7.75 (1H, s, Py), 7.25-7.28 (1H, dd, J=9.00Hz, Py), 6.40 (1H, d, J=9.00Hz, Py), 5.80 (2H, s, NH₂),2.25-2.50(8H,m,piper).

¹³C-NMR (DMSO, 300MHz)：δ158.14,148.92,137.56,122.04,109.64,55.96,11.59.

HRMS(ESI)m/z：227.2127.

Step 6) [5- (4- [D₅] ethyl piperazidine -1- base-[D₂] methyl)-pyridine -2- base]-[5 fluoro- 4- (7- fluoro- 3- isopropyls Base -2- methyl -3H- benzimidazole -5 base)-pyrimidine -2-base]-amine

(2- is chloro- to replace 6- with 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole 5-FU -4- base) -4- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole, with 5- (4- [D₅] ethyl piperazine Piperazine -1- base-[D₂] methyl)-pyridine -2- amine replaces 5- (4- ethyl piperazidine -1- ylmethyl)-pyridine -2- base amine, and reference is implemented Example 1 step 9) shown in method formula I-35 compound.

¹H-NMR(DMSO,300MHz)：δ 10.10 (s, 1H), 8.69 (s, 1H), 8.30 (s, 1H), 8.19～8.22 (m, 2H), 7.66～7.70 (m, 2H), 4.81～4.89 (m, 1H), 2.64 (s, 3H), 2.35～2.50 (m, 8H), 1.63 (d, J= 5.2Hz,6H).

HRMS(M+H)m/z：514.3229.

The preparation of embodiment 11 compound I-36

Step 1) [5- (4- [D₅] ethyl piperazidine -1- base-[D₂] methyl)-pyridine -2- base]-[5 fluoro- 4- (7- fluoro- 3- isopropyls Base -2- [D₃] methyl -3H- [5,7-D₂] benzimidazole -5 base)-pyrimidine -2-base]-amine

With 5- (4- [D₅] ethyl piperazidine -1- base-[D₂] methyl)-pyridine -2- amine replacement 5- (4- ethyl piperazidine -1- Ji Jia Base)-pyridine -2- base amine, and with reference to embodiment 1 step 9) shown in method formula I-36 compound.

¹H-NMR(DMSO,300MHz)：δ 10.12 (s, 1H), 8.69 (d, J=3.8Hz, 1H), 8.20 (d, J=6.5Hz, 2H), 7.66 (d, J=8.9Hz, 1H), 4.80～4.89 (m, 1H), 2.40～2.55 (m, 8H), 1.63 (d, J=6.8Hz, 6H).

¹³C-NMR(DMSO,300MHz)：δ155.39,154.54,153.87,152.20,150.57,148.78, 148.18,147.84,147.49,138.28,136.29,126.80,126.34,111.75,52.20,48.08,20.93.

HRMS(M+H)m/z：519.3531.

The preparation of embodiment 12 compound I-37

Step 1) [5- (4- [1,1-D₂] ethyl piperazidine -1- base-[D₂] methyl)-pyridine -2- base]-[5 fluoro- 4- (the fluoro- 3- of 7- Isopropyl -2- [D₃] methyl -3H- [5,7-D₂] benzimidazole -5 base)-pyrimidine -2-base]-amine

With 5- (4- [1,1-D₂] ethyl piperazidine -1- base-[D₂] methyl)-pyridine -2- amine replacement 5- (4- ethyl piperazidine -1- base Methyl)-pyridine -2- base amine, and with reference to embodiment 1 step 9) shown in method formula I-37 compound.

¹H-NMR(DMSO,300MHz)：δ 10.10 (s, 1H), 8.69 (d, J=3.9Hz, 1H), 8.20 (d, J=5.2Hz, 2H),7.66(dd,J₁=2.1Hz, J₂=8.7Hz, 1H), 4.80～4.89 (m, 1H), 2.30～2.42 (m, 8H), 1.63 (d, J =6.9Hz, 6H), 0.95 (s, 3H).

¹³C-NMR(DMSO,300MHz)：δ155.37,154.54,153.86,152.17,150.57,148.97, 148.78,147.85,147.50,138.26,126.90,111.77,52.40,48.07,20.92,11.77.

HRMS(M+H)m/z：516.3344.

The preparation of embodiment 13 compound I-38

Step 1) (6- aminopyridine -3- base) (4- acetyl group-[D₈] piperazine -1- base) ketone

With N- acetyl group-[D₈] piperazine replaces NEP, and with reference to embodiment 8 step 1) shown in method formula XXVI-2 compound.

¹H-NMR(300MHz,DMSO)：δ 8.19 (1H, d, J=2.0Hz, Py), 7.56-7.58 (1H, dd, J₁=2.0Hz, J₂=8.5Hz, Py), 6.52 (1H, d, J=8.5Hz, Py), 4.90 (2H, s, NH₂),2.14(3H,s,CH₃).

¹³C-NMR(DMSO,300MHz)：δ169.28,159.58,148.07,137.88,120.46,107.91,21.40.

HRMS(ESI)m/z：257.1858.

Step 2) 5- (4- [1,1-D₂] ethyl-[D₈] piperazine -1- base-[D₂] methyl)-pyridine -2- amine

With (6- aminopyridine -3- base) (4- acetyl group-[D₈] piperazine -1- base) ketone replacement N- benzyl-N '-acetyl group - [3,3,5,5-D₄] piperazine, and with double amount [D₄] boron deuterate sodium, and with reference to embodiment 2 step 7) shown in method formula V-10 Compound.

¹H-NMR(300MHz,DMSO)：δ 7.74 (1H, s, Py), 7.24-7.27 (1H, dd, J=9.00Hz, Py), 6.38 (1H, d, J=9.00Hz, Py), 5.78 (2H, s, NH₂),0.94(3H,s,CH₃).

¹³C-NMR(DMSO,300MHz)：δ158.52,148.36,137.48,122.10,109.14,61.82,10.65.

HRMS(ESI)m/z：232.2441.

Step 3) [5- (4- [1,1-D₂] ethyl-[D₈] piperazine -1- base-[D₂] methyl)-pyridine -2- base]-[5 fluoro- 4- (7- Fluoro- 3- isopropyl -2- [D₃] methyl -3H- [5,7-D₂] benzimidazole -5 base)-pyrimidine -2-base]-amine

With 5- (4- [1,1-D₂] ethyl [D₈] piperazine -1- base-[D₂] methyl)-pyridine -2- amine replacement 5- (4- ethyl piperazidine - 1- ylmethyl)-pyridine -2- base amine, and with reference to embodiment 1 step 9) shown in method formula I-38 compound.

¹H-NMR(DMSO,300MHz)：δ 10.10 (s, 1H), 8.69 (d, J=3.9Hz, 1H), 8.20 (d, J=5.0Hz, 2H),7.66(dd,J₁=2.1Hz, J₂=8.7Hz, 1H), 4.80～4.89 (m, 1H), 1.63 (d, J=6.9Hz, 6H), 0.96 (s,3H).

¹³C-NMR(DMSO,300MHz)：δ155.42,154.56,153.87,152.19,148.79,148.18, 147.86,147.51,138.29,126.86,111.78,48.08,20.93,11.61.

HRMS(M+H)m/z：524.3854.

The preparation of embodiment 14 compound I-24

Step 1) N- [D₇] isopropyl-acetamide

By D₈Isopropanol (5.7g, 83.2mmol) is dissolved in acetonitrile (85.38g, 2.1mol), is heated to 60 DEG C, disposably Add 10ml concentrated sulphuric acid, reaction system very exothermic, close heating, reflux flows back, water flow increases；Treat that temperature is down to 50 DEG C, open heating, repeat aforesaid operations, continue enriching sulphuric acid, add concentrated sulphuric acid 30ml (0.56mol) altogether.TLC follows the tracks of, and treats anti- Should be complete, reaction system is poured in frozen water, with NaOH aqueous solution neutralization reaction system.It is extracted twice with DCM, use NaCl aqueous solution Wash twice, be dried, vacuum distillation removes solvent, ether dilutes, and adds 10g K₂CO₃, room temperature making beating 2h.Filter, decompression is dense Contracting obtains 8.7g pale yellow oil.Yield：96%.

¹H-NMR(CDCl₃,300MHz)：δ1.95(s,3H).

¹³C-NMR(CDCl₃,300MHz)：δ171.81,77.0,24.72,23.17.

HRMS(M+H)m/z：109.1349.

Step 2) N- (4- bromo- 2,6- difluorophenyl)-N '-[D₇] isopropyl-second narrows

With N- [D₇] isopropyl-acetamide replaces N- isopropyl-acetamide, and with reference to embodiment 1 step 2) shown in method Formula IX-2 compound.

¹H-NMR(CDCl₃,300MHz)：δ 7.03 (d, J=6.12Hz, 2H), 4.45 (s, 1H), 1.76 (s, 3H).

¹³C-NMR(CDCl₃,300MHz)：δ157.19,153.98,115.32,115.17,115.09,114.95, 77.42,77.00,76.57,18.72,18.66.

HRMS(M+H)m/z：298.0751.

Step 3) the bromo- 4- of 6- fluoro- 1- [D₇] isopropyl -2- methyl isophthalic acid H- benzimidazole

With N- (4- bromo- 2,6- difluorophenyl)-N '-[D₇] isopropyl-second narrow replacement N- (4- bromo- 2,6- difluorophenyl)- N '-isopropyl-second is narrowed, and with reference to embodiment 1 step 3) shown in method formula II-3 compound.

¹H-NMR(CDCl₃,300MHz)：δ 7.41 (d, J=1.17Hz, 1H), 7.08 (dd, J₁=1.26Hz, J₂= 9.6Hz,1H),2.63(s,3H).

¹³C-NMR(CDCl₃,300MHz)：δ154.76,151.94,111.45,111.17,110.34,110.28, 77.42,77.00,76.57,14.78.

HRMS(M+H)m/z：278.0684.

Step 4) 4- fluoro- 1- [D₇] isopropyl -2- methyl -6- (4,4,5,5- tetramethyl-[1,3,2] dioxa bora ring Pentane -2- base) -1H- benzimidazole

With the fluoro- 1- [D of the bromo- 4- of 6-₇] isopropyl -2- methyl isophthalic acid H- benzimidazole replacement bromo- 4- of 6- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole, and with reference to embodiment 1 step 5) shown in method formula III-3 compound.

¹H-NMR(CDCl₃,300MHz)：δ7.69(s,1H),7.37(m,1H),2.68(s,3H),1.36(s,12H).

¹³C-NMR(DMSO,300MHz)：δ152.03,113.60,113.56,113.18,112.97,84.03,77.41, 76.99,76.57,24.87,14.84.

HRMS(M+H)m/z：326.2423.

Step 5) 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- [D₇] isopropyl -2- methyl isophthalic acid H- benzimidazole

With 4- fluoro- 1- [D₇] isopropyl -2- methyl -6- (4,4,5,5- tetramethyl-[1,3,2] dioxaborolan alkane - 2- yl) -1H- benzimidazole replacement 4- fluoro- 1- isopropyl -2- [D₃] methyl -6- (4,4,5,5- tetramethyl-[1,3,2] dioxa Bora Pentamethylene. -2- base) -1H- [5,7-D₂] benzimidazole, and with reference to embodiment 1 step 6) shown in method formula IV-3ization Compound.

¹H-NMR(CDCl₃,300MHz)：δ 8.51 (d, J=3.42Hz, 1H), 8.15 (s, 1H), 7.80 (d, J= 11.49Hz),2.70(s,3H).

¹³C-NMR(CDCl₃,300MHz)：δ156.63,154.22,151.66,148.57,148.21,108.88, 108.76,108.51,108.40,108.24,108.13,15.17.

HRMS(M+H)m/z：330.1079.

Step 6) [5- (4- ethyl-piperazin -1- ylmethyl)-pyridine -2- base]-[5 fluoro- 4- (7- fluoro- 3- [D₇] isopropyl- 2- methyl -3H- benzimidazole -5 base)-pyrimidine -2-base]-amine

With 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- [D₇] isopropyl -2- methyl isophthalic acid H- benzimidazole replacement 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole, and with reference to embodiment 1 step 9) shown in method formula I-24 compound.

¹H-NMR(CDCl₃,300MHz)：δ 8.41 (m, 2H), 8.26 (s, 1H), 8.18 (s, 1H), 7.79 (d, J= 11.64Hz, 1H), 7.68 (m, 1H), 3.53 (s, 2H), 2.69～2.64 (m, 5H), 2.56 (t, J=7.29Hz, 8H), 1.18 (t, J=7.14Hz, 3H).

¹³C-NMR(CDCl₃,300MHz)：δ154.69,153.11,151.64,148.84,146.81,146.45, 138.48,135.90,127.65,126.89,126.41,108.23,108.12,108.08,107.79,107.52,107.42, 76.93,59.07,51.91,51.73,51.53,14.51,10.78.

HRMS(M+H)m/z：514.3225.

The preparation of embodiment 15 compound I-39

Step 1) [5- (4- [D₅] ethyl piperazidine -1- ylmethyl)-pyridine -2- base]-[5 fluoro- 4- (7- fluoro- 3- [D₇] isopropyl Base -2- methyl -3H- benzimidazole -5 base)-pyrimidine -2-base]-amine

With 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- [D₇] isopropyl -2- methyl isophthalic acid H- benzimidazole replacement 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole, with 5- (4- [D₅] Ethyl piperazidine -1- base-methyl)-pyridine -2- amine replaces 5- (4- ethyl piperazidine -1- ylmethyl)-pyridine -2- base amine, and reference is real Apply example 1 step 9) shown in method formula I-39 compound.

¹H-NMR(DMSO,500MHz):δ 10.08 (s, 1H), 8.68 (d, J=3.5Hz, 1H), 8.29 (s, 1H), 8.20 ～8.21 (m, 2H), 7.65～7.69 (m, 2H), 3.44 (s, 2H), 2.64 (s, 3H), 2.34～2.49 (m, 8H).

¹³C-NMR(DMSO,500MHz):155.86,153.74,152.66,151.97,150.55,149.55,148.63, 138.74,136.82,133.69,127.47,112.26,109.33,107.49,59.25,52.85,15.01.

HRMS(M+H)m/z：519.3573.

The preparation of embodiment 16 compound I-17

Step 1) N- benzyl-N '-[D₅] ethyl [3,3,5,5-D₄] piperazine

With N- benzyl-[3,3,5,5-D₄] piperazine replaces benzyl diethylenediamine, and prepare with reference to method shown in embodiment 11 step 2 Formula X XIV-4 compound.

Step 2) N- [1,1,2,2,2-D₅] ethyl-[2,2,6,6-D₄] piperazine

With N- benzyl-N '-[D₅] ethyl-[3,3,5,5-D₄] piperazine replacement N- benzyl-N '-[1,1-D₂] ethyl-[3,3, 5,5-D₄] piperazine, and with reference to method formula XI-5 compound shown in embodiment 2 step 8.

¹H-NMR(CDCl₃,500MHz)：δ2.86(s,4H).

¹³C-NMR(CDCl₃,500MHz)：δ45.74.

HRMS(M+H)m/z：124.1788.

Step 3) 1- (6- bromo- pyridin-3-yl methyl) -4- [1,1,2,2,2-D₅] ethyl-[3,3,5,5-D₄] piperazine

With N- [D₅] ethyl-[2,2,6,6-D₄] piperazine replacement N- [1,1-D₂] ethyl-[2,2,6,6-D₄] piperazine, and join According to embodiment 2 step 9) shown in method formula XII-7 compound.

¹H-NMR(CDCl₃,500MHz)：δ 8.33 (d, J=2Hz, 1H), 7.47 (d, J=8.2Hz, 1H), 7.50 (dd, J =8.2Hz, 2.0Hz, 1H), 3.6 (s, 2H), 3.03 (s, 2H), 2.90 (s, 2H).

¹³C-NMR(CDCl₃,500MHz)：δ150.7,141.5,139.2,131.9,128.0,58.4,50.6,49.0, 49.0,37.0.

HRMS(M+H)m/z：293.1619.

Step 4) 5- (4- [1,1,2,2,2-D₅] ethyl-[3,3,5,5--D₄] piperazine -1- ylmethyl)-pyridine -2- base amine

With 1- (6- bromo- pyridin-3-yl methyl) -4- [D₅] ethyl-[3,3,5,5-D₄] piperazine replacement 1- (the bromo- pyridine of 6-- 3- ylmethyl) -4- [1,1-D₂] ethyl-[3,3,5,5-D₄] piperazine, and with reference to method formula V- shown in embodiment 2 step 10 12 compounds.

¹H-NMR(CDCl₃,500MHz):δ 7.97 (d, J=2.2Hz, 1H), 7.43 (dd, J=8.4Hz, 2.2Hz, 1H), 6.49 (d, J=8.4Hz, 1H), 4.43 (s, 2H), 3.40 (s, 2H), 2.50 (s, 4H).

¹³C-NMR(CDCl₃,500MHz)：δ157.7,148.6,139.2,123.2,108.4,59.8,52.4.

HRMS(ESI)m/z：230.2323.

Step 5) [5- (4- [1,1,2,2,2-D₅] ethyl-[3,3,5,5--D₄] piperazine -1- base-methyl)-pyridine -2- Base]-[5 fluoro- 4- (7- fluoro- 3- isopropyl -2- methyl -3H- benzimidazole -5 base)-pyrimidine -2-base]-amine

(2- is chloro- to replace 6- with 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole 5-FU -4- base) -4- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole, with 5- (4- [D₅] ethyl [2, 2,6,6-D₄] piperazine -1- base-methyl)-pyridine -2- amine replacement 5- (4- ethyl piperazidine -1- ylmethyl)-pyridine -2- base amine, and With reference to embodiment 1 step 9) shown in method formula I-17 compound.

¹H-NMR(CDCl₃,500MHz)：δ 8.48 (m, 1H), 8.41 (d, J=8.25Hz, 1H), 8.29 (d, J=1.5Hz, 1H), 8.21 (d, J=1.0Hz, 1H), 7.81 (d, J=11.5Hz, 1H), 7.71 (m, 1H), 4.76 (quintet, J=7Hz, 1H), 3.53 (s, 2H), 2.71 (s, 3H), 2.65 (s, 4H), 1.73 (d, J=7Hz, 6H).

¹³C-NMR(CDCl₃,500MHz)：154.32,153.62,152.08,150.00,148.72,136.47, 136.39,134.18,134.05,127.42,111.42,108.75,108.24,108.18,108.02,59.77,52.40, 48.66,21.48,15.07.

HRMS(M+H)m/z：516.3403.

The preparation of reference implementation example 1 compound I-2

Step 1) 1- (6- bromo- pyridin-3-yl methyl) -4- acetyl group-piperazine

Replace NEP with N- Acetylpiperazine, and with reference to embodiment 1 step 7) shown in method formula XXV-2ization Compound.

¹H-NMR(300MHz,CDCl₃)：δ 8.29 (1H, d, J=1.65Hz, Py), 7.55-7.58 (1H, dd, J= 1.74Hz, 8.10Hz, Py), 7.46 (1H, d, J=8.10Hz, Py), 3.62 (2H, t, J=4.77Hz, piper), 3.49 (2H, s,CH₂- Py), 3.46 (2H, t, J=4.86Hz, piper), 2.40-2.44 (4H, m, piper), 2.08 (3H, s, CH₃).

¹³C-NMR(CDCl₃, 300MHz)：δ150.48,141.03,139.20,132.61,127.88,59.10,52.93, 52.65,46.10,41.24,21.24.

HRMS(M+H)m/z：298.0549.

Step 2) 1- (6- bromo- pyridin-3-yl methyl) -4- [1,1-D₂] ethyl piperazidine

Replace N- benzyl-N '-acetyl group-[3,3,5,5- with 1- (6- bromo- pyridin-3-yl methyl) -4- acetyl group-piperazine D₄] piperazine, and with reference to embodiment 2 step 7) shown in method formula XII-6 compound.

¹H-NMR(300MHz,CDCl₃)：δ 8.29 (1H, d, J=1.74Hz, Py), 7.52-7.56 (1H, dd, J= 1.98Hz, 8.10Hz, Py), 7.43 (1H, d, J=8.10Hz, Py), 3.47 (2H, s, CH₂),2.50(8H,s,piper), 1.08(3H,s,CH ₃CD₂).

¹³C-NMR(CDCl₃, 300MHz)：δ150.59,140.73,139.28,133.18,127.73,59.25,52.84, 52.54,11.56.

HRMS(M+H)m/z：286.0879.

Step 3) 5- (4- [1,1-D₂] ethyl piperazidine -1- ylmethyl)-pyridine -2- amine

With 1- (6- bromo- pyridin-3-yl methyl) -4- [1,1-D₂] ethyl piperazidine replacement 1- (6- bromo- pyridin-3-yl first Base) -4- ethyl-piperazin, and with reference to embodiment 1 step 8) shown in method formula V-6 compound.

¹H-NMR(300MHz,CDCl₃)：δ 7.95 (1H, d, J=1.65Hz, Py), 7.39-7.42 (1H, dd, J= 1.50Hz, 8.31Hz, Py), 6.47 (1H, d, J=8.31Hz, Py), 4.42 (2H, s, NH₂),3.37(2H,s,CH₂),2.47 (8H,s,piper),1.05(3H,s,CH ₃CD₂).

¹³C-NMR(CDCl₃, 300MHz)：δ157.63,148.58,139.11,123.27,108.26,59.79,52.77, 52.63,11.65.

HRMS(ESI)m/z：223.1890.

Step 4) [5- (4- [1,1-D₂] ethyl piperazidine -1- ylmethyl)-pyridine -2- base]-[5 fluoro- 4- (7- fluoro- 3- isopropyls Base -2- methyl -3H- benzimidazole -5 base)-pyrimidine -2-base]-amine

Replace 6- (2- with 6-- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole Chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole, with 5- (4- [1,1-D₂] Ethyl piperazidine -1- ylmethyl)-pyridine -2- amine replaces 5- (4- ethyl piperazidine -1- ylmethyl)-pyridine -2- base amine, and reference is real Apply example 1 step 9) shown in method formula I-2 compound.

¹H-NMR(DMSO,300MHz)：δ 10.06 (s, 1H), 8.69 (d, J=3.4Hz, 1H), 8.29 (s, 1H), 8.20 ～8.22 (m, 2H), 7.65～7.69 (m, 2H), 4.81～4.89 (m, 1H), 3.47 (s, 2H), 2.65 (s, 3H), 2.40～ 2.55 (m, 8H), 1.63 (d, J=6.4Hz, 6H), 0.84 (s, 3H).

HRMS(M+H)m/z：509.2899.

The preparation of reference implementation example 2 compound I-16

Step 1) 5- (4- [D₅] ethyl piperazidine -1- ylmethyl)-pyridine -2- amine

With (6- aminopyridine -3- base) (4- [D₅] ethyl piperazidine -1- base) ketone XIII-2 replacement N- benzyl-N '-acetyl Base-[3,3,5,5-D₄] piperazine, and with reference to embodiment 2 step 7) shown in method formula V-11 compound.

¹H-NMR(300MHz,DMSO):δ 7.74 (1H, s, Py), 7.24-7.27 (1H, dd, J=9.00Hz, Py), 6.39 (1H, d, J=9.00Hz, Py), 5.76 (2H, s, NH₂),3.23(2H,s,-CH₂),2.32-2.50(8H,m,piper).

¹³C-NMR(DMSO,300MHz):158.95,147.97,138.07,120.75,107.52,59.09,39.52.

HRMS(ESI)m/z：226.2084.

Step 2) [5- (4- [D₅] ethyl piperazidine -1- ylmethyl)-pyridine -2- base]-[5 fluoro- 4- (7- fluoro- 3- isopropyl - 2- methyl -3H- benzimidazole -5 base)-pyrimidine -2-base]-amine

(2- is chloro- to replace 6- with 6- (2- chloro- 5-FU -4- base) -4- fluoro- 1- isopropyl -2- methyl isophthalic acid H- benzimidazole 5-FU -4- base) -4- fluoro- 1- isopropyl -2- [D₃] methyl isophthalic acid H- [5,7-D₂] benzimidazole, with 5- (4- [D₅] ethyl piperazine Piperazine -1- base-methyl)-pyridine -2- amine replaces 5- (4- ethyl piperazidine -1- ylmethyl)-pyridine -2- base amine, and reference embodiment 1 Step 9) shown in method formula I-16 compound.

¹H-NMR(DMSO,500MHz)：δ 10.09 (s, 1H), 8.68 (d, J=4.0Hz, 1H), 8.29 (s, 1H), 8.20 ～8.21 (m, 2H), 7.66～7.69 (m, 2H), 4.82～4.87 (m, 1H), 3.45 (s, 2H), 2.64 (s, 3H), 2.35～ 2.48 (m, 8H), 1.63 (d, J=7.0Hz, 6H).

¹³C-NMR(DMSO,500MHz):δ155.88,153.75,152.71,151.77,150.62,149.96, 148.26,138.78,136.79,133.82,127.30,112.27,107.59,59.13,52.52,48.59,21.42, 15.03.

HRMS(M+H)m/z：512.3152.

Embodiment 17CDK4 inhibitory activity is analyzed

Experimental procedure

Preparation ATP and peptide substrate Ulight-4E-BP1 (Thr37/46) (PerkinElmer company Cat NO.TRF0128-D) solution, obtains being diluted in 50mM HEPES, 10mM MgCl₂, 10mM EGTA, 2mM DTT, 0.01% Final concentration of 70 μM of ATP and 50nM Ulight-4E-BP1 (Thr37/46) in the kinase buffer liquid of Tween 20.Prepare enzyme Solution, obtains CDK4 enzyme (the CARNA Biosciences company being diluted in final concentration of 0.5ng/ μ L in above-mentioned kinase buffer liquid Cat NO.04-105).By test compound in 0.02%DMSO for the 2 μ L, 4 μ L ATP and peptide substrate Ulight-4E-BP1 (Thr37/46) solution and 4 μ L enzymatic solution mix in low volume 384 orifice plate.By test compound with 1:3 are serially diluted In 0.02%DMSO, produce the curve of 8 points, initial concentration is 400nM, without the independent 0.02%DMSO of test compound Buffer control, kinase buffer liquid, as the background signal not existed during enzyme activity, reagent is mixed, centrifugation 1 minute (2500 turns/ Minute) and sealer after 25 DEG C incubate 60 minutes, by adding 5 μ L 40mM EDTA terminating reaction (final concentration 10mM), after Add 5 μ L 8nM (final concentration 2nM) Eu-anti-P-4E-BP1 (Thr37/46) (PerkinElmer company Cat NO.TRF0216-D) in detection plate, mix, centrifugation continues after (2500 revs/min) sealer to incubate 60 points at 25 DEG C for 1 minute Clock, after put into multi-functional plate reader (Molecular Devices company model Paradigm) adopt HTRF module detect numerical value.

Experimental result

Table 1. compound suppresses IC to CDK4₅₀Value (nM)

Using four parameter fitting modes, the suppression ratio matched curve to testing result calculates IC₅₀Value, sees the above table 1, is screened I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9 and I-10 and positive compound LY-2835219 result close, all Less than 2nM.Experimental result confirms that above compound is excellent CDK4 inhibitor.

Embodiment 18 CDK6 inhibitory activity is analyzed

Experimental procedure

Preparation ATP and peptide substrate Ulight-4E-BP1 (Thr37/46) (PerkinElmer company Cat NO.TRF0128-D) solution, obtains being diluted in 50mMHEPES, 10mM MgCl₂, 10mM EGTA, 2mM DTT, 0.01% Final concentration of 70 μM of ATP and 50nMUlight-4E-BP1 (Thr37/46) in the kinase buffer liquid of Tween 20.Prepare enzyme molten Liquid, obtains CDK6 enzyme (the CARNA Biosciences company being diluted in final concentration of 0.5ng/ μ L in above-mentioned kinase buffer liquid Cat NO.04-107).By test compound in 0.02%DMSO for the 2 μ L, 4 μ L ATP and peptide substrate Ulight-4E-BP1 (Thr37/46) solution and 4 μ L enzymatic solution mix in low volume 384 orifice plate.By test compound with 1:3 are serially diluted In 0.02%DMSO, produce the curve of 7 points, initial concentration is 100nM, without the independent 0.02%DMSO of test compound Buffer control, kinase buffer liquid, as the background signal not existed during enzyme activity, reagent is mixed, centrifugation 1 minute (2500 turns/ Minute) and sealer after 25 DEG C incubate 60 minutes, by adding 5 μ L 40mM EDTA terminating reaction (final concentration 10mM), after Add 5 μ L 8nM (final concentration 2nM) Eu-anti-P-4E-BP1 (Thr37/46) (PerkinElmer company Cat NO.TRF0216-D) in detection plate, mix, centrifugation continues after (2500 revs/min) sealer to incubate 60 points at 25 DEG C for 1 minute Clock, after put into multi-functional plate reader (Molecular Devices company model Paradigm) adopt HTRF module detect numerical value.

Experimental result

Table 2. compound suppresses IC to CDK6₅₀Value (nM)

Using four parameter fitting modes, the suppression ratio matched curve to testing result calculates IC₅₀Value, sees the above table 2, is screened I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10 and tester LY-2835219 compound suppression CDK6 live Similar temperament, respectively less than 5nM.Result confirms that above compound is excellent CDK6 inhibitor.

Embodiment 19 stability study in people's hepatomicrosome

The final temperature of 300 μ L is incubated in system, containing 30 μ L hepatomicrosome (protein concentrations：0.15mg/mL), 30 μ L NADPH+ MgCl₂, 3 μ L substrates, 237 μ L PBS.The ratio of wherein organic solvent (acetonitrile) is 1%.Each kind does 2 parts, often Part 0.3mL.Often pipe first prepares the mixing liquid of the substrate that cumulative volume is 270 μ L and enzyme, and NADPH incubates 5min in 37 DEG C of pre-temperatures respectively Afterwards, 30 μ L NADPH+MgCl are added₂Mixing, respectively at 0,15,30,60,120min take out the ice acetonitrile of 50 μ L containing the internal standard 300 μ L terminating reactions.In addition it is 3 parts of blank (KB) each 300 μ L, respectively KB1 respectively：It is not added with NADPH；KB2：It is not added with substrate； KB3：Not enzyme-added.

Draw 50 μ L temperature and incubate sample, add the ice acetonitrile precipitation of 300 μ L containing the internal standard, after the concussion 5min that is vortexed, centrifugation (8800rpm, 4 DEG C) 10min.Aspirate supernatant 100 μ L to sample injection bottle, analyze by 0.5 μ L sample introduction.Related compound is micro- in people liver Eliminate parameter in plastochondria and be shown in Table 3.

Table 3 related compound external people hepatomicrosome metabolic stability

Pharmacokinetic Evaluation in embodiment 20 rat

SD rat, body weight 200～220g, after adapting to 3-5 days, it is randomly divided into 7 groups, every group 3, gives 10mg/kg respectively The compound of dosage:Abemaciclib、I-4、I-5、I-8、I-9、I-10.

Animal subject (SD rat) administration before fasting 12h, after administration 4h to food, before and after experiment and experimentation in all from By drinking water.

After gastric infusion, take blood in 0min, 15min, 30min, 1h, 3h, 4h, 5h, 6h, 8h, 10h, 24h in eye socket 0.10mL about, EDTA-K2 anticoagulant, immediately blood sample is placed in ice, transfer to 4 DEG C in 30min, 4000rpm, 10min condition Lower centrifugal separation plasma.Collect to be measured in -20 DEG C of preservations immediately after whole blood plasma.

Draw 40 μ L test plasma sample and mark song sample, add the methanol solution of 200 μ L containing the internal standard, vibration mixes 5min, 13000rpm are centrifuged 10min, take supernatant 80 μ L, draw 1 μ L and are used for LC/MS/MS mensure, record chromatogram.

Oral administration biaavailability by Rats pharmacokinetics experimental evaluation the compounds of this invention.Some are representative The medicine of compound is as shown in the table for parameter.

The medicine of table 4 related compound is for parameter

Claims

1. a kind of compound shown in formula I or its pharmaceutically acceptable salt, solvate or prodrug：

Wherein R₁、R₂、R₄、R₅、R₆、R₇、R₈、R₉And R₁₁Separately it is selected from H or D, R₃、R₁₀、R₁₂Separately it is selected from CH₃、 CH₂D、CHD₂Or CD₃, condition is that compound of formula I contains at least one D-atom and do not include following compound：

2. the compound of claim 1, wherein R₁、R₂、R₅、R₆、R₇、R₈Or R₁₁At least one is D.

3. the compound of claim 2, wherein R₁、R₂It is D simultaneously.

4. the compound of claim 2, wherein R₅、R₆It is D simultaneously.

5. the compound of claim 2, wherein R₇、R₈It is D simultaneously.

6. the compound of claim 2, wherein R₅、R₆、R₇、R₈It is D simultaneously.

7. the compound of claim 1, it is selected from following compound：

8. the compound of claim 1, it is selected from following compound：

9. a kind of pharmaceutical composition, it comprises the compound of any one of claim 1-8 or its pharmaceutically acceptable salt, with And one or more pharmaceutically acceptable carrier or excipient.

10. the compound of any one of claim 1-8 or the pharmaceutical composition of claim 9 are in preparation treating cancer medicine Purposes.

The purposes of 11. claim 10, wherein said cancer is selected from colorectal carcinoma, breast carcinoma, pulmonary carcinoma, carcinoma of prostate, glue Matter blastoma, lymphoma mantle cell, chronic myelocytic leukemia or acute myeloblastic leukemia.