CN110467615A

CN110467615A - Azolopyrimidines include its pharmaceutical composition and its preparation method and application

Info

Publication number: CN110467615A
Application number: CN201910359257.9A
Authority: CN
Inventors: 刘金明; 何婷; 蔡家强; 陈强强; 康熙伟; 王利春; 王晶翼
Original assignee: Sichuan Kelun Botai Biological Pharmaceutical Ltd By Share Ltd
Current assignee: Sichuan Kelun Botai Biological Pharmaceutical Ltd By Share Ltd
Priority date: 2018-05-10
Filing date: 2019-04-30
Publication date: 2019-11-19

Description

Azolopyrimidines, comprising its pharmaceutical composition and preparation method thereof and Purposes

Technical field

The present invention relates to azolopyrimidines, the pharmaceutical composition comprising it, preparation method and its it is used for pre- Anti- or treatment Wee1 protein kinase related disorder purposes.

Background technique

Cell cycle is the process of a height adjustment and control, by a series of protein, metabolism and microenvironment The complex network that interaction is formed regulates and controls closely, it is therefore intended that carries out cell only according to specific stimulation and condition appropriate It is proliferated (S.Diaz-Moralli, M.Tarrado-Castellarnau, A.Miranda, M.Cascante, Pharmacology& Therapeutics,2013,138:255-271).The cell cycle of standard can successively undergo G1 phase, S phase (DNA synthesizes the phase), G2 Phase and M phase (cell division phase).There are several Cycle Arrest checkpoints during G1-S conversion, S phase, G2-M conversion etc., be used for The integrality of genome is maintained, and provides the time before entering mitosis to repair damaging DNA.As to DNA damage Response, cell cycle checkpoint can be in phase Activations such as G1/S phase, S phase and G2/M phases, and induction of cell cycle arrest, until It completes to repair；If reparation is unsuccessful, will driving cell ageing or Apoptosis (R.Visconti, M.R.Della, D.Grieco,Journal of Experimental&Clinical Cancer Research,2016,35:153)。

Wee1 protein kinase is the key element of the checkpoint cell cycle G2/M, and crucial work is played in fissional scheduling With (C.J.Matheson, D.S.Backos, P.Reigan, Trends in Pharmacological Sciences, 2016, 37:872).Phosphorylation state and cell cycle of the mitosis depending on CDK1 (also referred to as CDC2) are entered from the checkpoint G2/M The bonding state of plain B.Before mitosis, the site Tyr15 of Wee1 phosphorylation CDK1, then myelin transcription factor (MYT1) The site Thr14 of phosphorylation CDK1 maintains the inactive state of CDK1, and cell is inhibited to enter the M phase.It can be seen that Wee1 is thin Born of the same parents enter the negative regulation device of M phase from the G2 phase.

Therefore, inhibiting function of the Wee1 kinase activity to remove the checkpoint G2/M is a kind of potential strategy to drive Tumour cell enters unplanned mitosis, to undergo mitosis obstacle and lead to cell death.This cell is not It completes DNA replication dna and is forced into mitotic mode, it is very big to the toxicity of cell, represent a kind of novel induction tumour The mechanism of cell death.Therefore, Wee1 inhibitor has a good application prospect as drug.Patent WO2007126128 report Certain compounds show the activity of Wee1 kinases inhibitor.

Summary of the invention

The present invention provides azolopyrimidines, has good inhibiting effect to Wee1 protein kinase, thus With good antitumous effect；And it also has good physicochemical properties (such as solubility, physically and/or chemically Stability), improved pharmacokinetic profile (such as improved bioavilability, suitable half-life period and effect lasts Time), improved excellent properties such as safety (lower toxicity and/or less side effect, wider therapeutic window).

Some aspects of the invention provide compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, Polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, wherein the compound has The structure of formula (I):

Wherein:

Ring A is selected from phenyl ring and 5-6 member hetero-aromatic ring；

X is selected from N and CR⁴；

R¹Selected from hydrogen and fluorine；

R²Selected from hydrogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, halogenated C_1-6Alkyl ,-C_1-6Alkylidene-OH ,-C_1-6Alkylene Base-O-C_1-6Alkyl ,-C_1-6Alkylidene-cyano, C_3-6Cyclic hydrocarbon radical and 3-10 circle heterocyclic ring base；

R³Selected from-C_1-6Alkylidene-OH ,-C_1-6Alkylidene-O-C_1-6Alkyl ,-C_1-6Alkylidene-NR^3aR^3b,-C (=O) NR^3aR^3b,-N=S (=O) (R^3a)(R^3b) ,-P (=O) (R^3a)(R^3b) ,-NH-P (=O) (R^3a)(R^3b) and pyriconyl；

R⁴It is each independently selected from hydrogen, halogen, cyano, hydroxyl, C at each occurrence_1-6Alkyl, halogenated C_1-6Alkyl ,-O- C_1-6Alkyl and-NR^4aR^4b；

R⁵Selected from halogen, cyano, C_1-6Alkyl, halogenated C_1-6Alkyl ,-C_1-6Alkylidene-NR^5aR^5b,-C (=O) NR^5aR^5b、- O- (3-10 circle heterocyclic ring base) and 3-10 circle heterocyclic ring base；Preferably, R⁵Selected from halogen, cyano, C_1-6Alkyl, halogenated C_1-6Alkyl ,- C_1-6Alkylidene-NR^5aR^5b,-C (=O) NR^5aR^5b,-O- (3-10 circle heterocyclic ring base), 3-10 unit monocycle heterocycle, 7-10 member bridge heterocycle Base and 6-10 member condensed hetero ring base；

R⁶It is each independently selected from halogen, cyano, hydroxyl, C at each occurrence_1-6Alkyl, halogenated C_1-6Alkyl ,-C_1-6It is sub- Alkyl-OH and-O-C_1-6Alkyl；

Or R⁵With an adjacent R⁶3-10 circle heterocyclic ring base is collectively formed in the atom connected together with it or 7-12 member spiral shell is miscellaneous Ring group；

R^3aAnd R^3bIt is each independently selected from C_1-6Alkyl and C_3-6Cyclic hydrocarbon radical；Or R^3aAnd R^3bThe atom connected together with it 3-10 circle heterocyclic ring base is collectively formed；

R^4a、R^4b、R^5aAnd R^5bIt is each independently selected from hydrogen, C_1-6Alkyl, halogenated C_1-6Alkyl and C_3-6Cyclic hydrocarbon radical；Or R^4a With R^4bAnd/or R^5aWith R^5b3-10 circle heterocyclic ring base is collectively formed in the nitrogen-atoms connected together with it；

M is 1,2 or 3；

N is 0,1,2 or 3；And

Abovementioned alkyl, alkylidene, alkenyl, alkynyl, cyclic hydrocarbon radical, heterocycle, spiro heterocyclic radical, phenyl ring and hetero-aromatic ring are respectively optional Ground is replaced by 1,2,3 or 4 substituent group independently selected from the following: halogen, hydroxyl, oxo, cyano ,-NH₂, nitro, Sulfydryl ,-CO₂H、-CO₂C_1-6Alkyl, C_1-6Alkyl, halogenated C_1-6Alkyl ,-O-C_1-6The halogenated C of alkyl ,-O-_1-6Alkyl, C_3-6Cyclic hydrocarbon Base, halogenated C_3-6Cyclic hydrocarbon radical ,-NH-C_1-6Alkyl ,-N (C_1-6Alkyl)₂、-C_1-6Alkylidene-OH ,-C_1-6Alkylidene-CN ,-C_1-6It is sub- Alkyl-O-C_1-6Alkyl ,-C_1-6Alkylidene-CO₂-C_1-6Alkyl ,-S (=O)₂-C_1-6Alkyl, 3-10 circle heterocyclic ring base ,-(3-10 member is miscellaneous Ring group)-C_1-6Alkyl, C_6-10Aryl, 5-14 unit's heteroaryl and C_6-12Aralkyl；

Preferably, abovementioned alkyl, alkylidene, alkenyl, alkynyl, cyclic hydrocarbon radical, heterocycle, spiro heterocyclic radical, phenyl ring and hetero-aromatic ring Respectively optionally replaced by 1,2,3 or 4 substituent group independently selected from the following: halogen, hydroxyl, oxo, cyano ,- NH₂, nitro, sulfydryl ,-CO₂H、-CO₂C_1-6Alkyl, C_1-6Alkyl, halogenated C_1-6Alkyl ,-O-C_1-6The halogenated C of alkyl ,-O-_1-6Alkyl, C_3-6Cyclic hydrocarbon radical, halogenated C_3-6Cyclic hydrocarbon radical ,-NH-C_1-6Alkyl ,-N (C_1-6Alkyl)₂、-C_1-6Alkylidene-OH ,-C_1-6Alkylidene- CN、-C_1-6Alkylidene-O-C_1-6Alkyl ,-C_1-6Alkylidene-CO₂-C_1-6Alkyl, 3-10 circle heterocyclic ring base, C_6-10Aryl, 5-14 member are miscellaneous Aryl and C_6-12Aralkyl.

Another aspect of the present invention provides pharmaceutical composition, and it includes prevention or the compound of the present invention of therapeutically effective amount Or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N- oxide, isotope Compound, metabolin or the prodrug of label and one or more pharmaceutically acceptable carriers.

Another aspect of the present invention provides the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, mutually Tautomeric, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug or the present invention Pharmaceutical composition preparing the purposes in drug for preventing or treating Wee1 protein kinase related disorder.

Another aspect of the present invention provides the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, mutually Tautomeric, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug or the present invention Pharmaceutical composition, it is used to prevent or treat Wee1 protein kinase related disorders.

The method that another aspect of the present invention provides prevention or treatment Wee1 protein kinase related disorder, the method includes To needing its individual that a effective amount of the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, interconversion is administered Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug or of the invention Pharmaceutical composition.

Another aspect of the present invention provides the method for preparation the compound of the present invention.

Definition

Unless hereinafter defined otherwise, the meaning of all technical terms and scientific terms used herein is intended to and this Field technical staff is generally understood identical.It refers to that technology used herein is intended to refer to be generally understood in the art Technology, the replacement of variation or equivalence techniques including those technologies that will be apparent to those skilled in the art.While it is believed that with Lower term is for those skilled in the art it is well understood that but still illustrating defined below preferably to explain the present invention.

As used herein, the terms "include", "comprise", " having ", " containing " or " being related to " and its herein Other variant forms are the (inclusive) or open of inclusive, and are not excluded for other unlisted elements or method step Suddenly.

As used herein, term " alkyl " is defined as the saturated aliphatic hydrocarbons of linear chain or branched chain.In some implementations In scheme, alkyl has 1 to 12, such as 1 to 6 carbon atom.For example, as used herein, term " C_1-6Alkyl " refers to tool There is the group of the linear chain or branched chain of 1 to 6 carbon atom (such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, secondary Butyl, tert-butyl, n-pentyl or n-hexyl), substituent group such as halogen optionally suitable by one or more (such as 1 to 3) (group is referred to as " halogenated alkyl " at this time, such as CF for element substitution₃、C₂F₅、CHF₂、CH₂F、CH₂CF₃、CH₂Cl or-CH₂CH₂CF₃ Deng).Term " alkylidene " indicates corresponding bivalent group, including such as " C_1-6Alkylidene ", " C_1-4Alkylidene " etc., specific example Including but not limited to: methylene, ethylidene, propylidene, butylidene, pentylidene and hexylidene etc..

As used herein, term " alkenyl " means linear or branching univalence hydrocarbyl, and it includes a double bonds, and With 2-6 carbon atom (" C_2-6Alkenyl ").The alkenyl is such as vinyl, 1- acrylic, 2- acrylic, 2- cyclobutenyl, 3- Cyclobutenyl, 2- pentenyl, 3- pentenyl, 4- pentenyl, 2- hexenyl, 3- hexenyl, 4- hexenyl, 5- hexenyl, 2- methyl- 2- acrylic and 4- methyl-3-pentenyl.When the compound of the present invention contains alkenyl, the compound can be with pure E (heteropleural (entgegen)) form, pure Z (ipsilateral (zusammen)) form or its any mixture form exist.Term " alkenylene " is Corresponding bivalent group, including such as " C_2-6Alkenylene ", " C_2-4Alkenylene " etc., specific example include but is not limited to: sub- second Alkenyl, allylidene, butenylidene, inferior pentenyl, sub- hexenyl, cyclopentenylidene and cyclohexadienylidene etc..

As used herein, term " alkynyl " indicates the univalence hydrocarbyl comprising one or more three keys, preferably has 2,3,4,5 or 6 carbon atoms, such as acetenyl or propinyl.Term " alkynylene " is corresponding bivalent group, including for example “C_2-6Alkynylene ", " C_2-4Alkynylene " etc..The example includes but is not limited to: ethynylene, sub- propinyl, butynelene, Asia penta Alkynyl and sub- hexin base etc..

As used herein, term " cyclic hydrocarbon radical " refer to the unsaturated non-aromatic monocyclic of saturation or part or it is polycyclic (such as It is bicyclic) hydrocarbon ring (such as monocycle, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclononyl or double Ring, including loop coil, condensed or bridging system, such as bicyclic [1.1.1] amyl, bicyclic [2.2.1] heptyl, bicyclic [3.2.1] are pungent Base or bicyclic [5.2.0] nonyl, decahydronaphthalene naphthalene etc.), substitution optionally suitable by one or more (such as 1 to 3) Base replaces.The naphthenic base has 3 to 15, such as 3 to 6 carbon atoms.For example, term " C_3-6Naphthenic base " refers to 3 to 6 The unsaturated non-aromatic monocyclic of the saturation of a ring carbons or part or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, ring Butyl, cyclopenta or cyclohexyl), optionally replaced by one or more (such as 1 to 3) suitable substituent group, such as first The cyclopropyl that base replaces.

As used herein, term " halogenated " or " halogen " group definition be include fluorine, chlorine, bromine or iodine.

As used herein, term " heterocycle " refers to the unsaturated one or more cyclic groups of saturation or part, such as its There are 2,3,4,5,6,7,8 or 9 carbon atoms and one or more (such as 1,2,3 or 4) to be selected from nitrogen, oxygen in ring Or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), such as, but not limited to Oxyranyle, '-aziridino, azelidinyl (azetidinyl), oxetanylmethoxy (oxetanyl), tetrahydrofuran base, pyrrolidinyl, pyrrolidone-base, imidazolidinyl, pyrrole Oxazolidinyl, THP trtrahydropyranyl, piperidyl, morpholinyl, dithianyl (dithianyl), thiomorpholine base, piperazinyl, trithiane base (trithianyl) etc., correspondingly, term " condensed hetero ring base " refers to that the shared a pair adjoined of other rings in each ring and system is former The multiring heterocyclic of son, one or more of rings can be containing one or more double bonds, but none ring has completely The pi-electron system of conjugation, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe miscellaneous original of (wherein m is integer 0 to 2) Son, remaining annular atom are carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to a group cyclic number can be divided into it is bicyclic, Tricyclic, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero rings Base.

As used herein, term " bridge heterocycle " refers to 6 to 14 yuan, and any two ring shares two and is not directly connected The polycyclic heterocyclic group of atom, can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated System, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom For carbon.Such as the bridge heterocycle is 6 to 14 yuan or 7 to 10 yuan of bridge heterocycles.According to a group cyclic number can be divided into it is bicyclic, Tricyclic, Fourth Ring or polycyclic bridge heterocycle.

As used herein, term " spiro heterocyclic radical " means the ring system with the bi-cyclic form of 7-12 annular atom, Two of them ring shares 1 carbon atom (referred to as " spiro-atom ").

As used herein, term " aryl " or " aromatic ring " refer to the full carbon monocycle or condensed with conjugated pi electron system Ring polycyclic aromatic group.For example, as used herein, term " C_6-14Aryl " or " C_6-14Aromatic ring " refers to containing 6 to 14 carbon originals The aromatic group of son, term " C_6-10Aryl " or " C_6-10Aromatic ring " refers to the aromatic group containing 6 to 10 carbon atoms, such as phenyl (ring) or naphthalene (ring).Aryl optionally by 1 or multiple (such as 1 to 3) be suitble to substituent group (such as halogen ,-OH ,-CN ,- NO₂、C_1-6Alkyl etc.) replace.

As used herein, term " heteroaryl " or " hetero-aromatic ring " refer to the hetero atom that N, O and S are selected from containing at least one Monocyclic, bicyclic or tricyclic aromatics ring system, preferably there are 5,6,8,9,10,11,12,13 or 14 annular atoms, especially contain There is 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atom, also, at each occurrence can be in addition benzo-fused.For example, Heteroaryl or hetero-aromatic ring can be selected from thienyl (ring), furyl (ring), pyrrole radicals (ring), oxazolyl (ring), thiazolyl (ring), miaow Oxazolyl (ring), pyrazolyl (ring), isoxazolyl (ring), isothiazolyl (ring), oxadiazoles base (ring), triazolyl (ring), thiadiazoles Base (ring) etc. and their benzo derivative；Or pyridyl group (ring), pyridazinyl (ring), pyrimidine radicals (ring), pyrazinyl (ring), Triazine radical (ring) etc. and their benzo derivative.

As used herein, the preferred alkyl for indicating aryl or heteroaryl and replacing of term " aralkyl ", wherein the virtue Base, heteroaryl and alkyl are as defined herein.In general, the aryl can have 6-10 carbon atom, the heteroaryl can have There is 5-10 annular atom, and the alkyl there can be 1-6 carbon atom.Exemplary aralkyl includes but is not limited to benzyl, benzene Base ethyl, phenyl propyl, phenyl butyl.

Term " substitution " refers to one or more (such as 1,2, the 3 or 4) hydrogen on specified atom by from institute The selection of the group pointed out replaces, and condition is the normal atom valency being less than specified atom in the current situation and described Substitution forms stable compound.The combination of substituent group and/or variable only when this combination forms stable compound It is allowed.

If substituent group is described as " optionally by ... replaces ", substituent group can (1) it is unsubstituted or (2) are substituted. If the carbon of substituent group is described as being optionally substituted one or more substitutions in base list, the one or more on carbon The substituent group that hydrogen (to the degree of existing any hydrogen) can be independently selected individually and/or together optionally substitutes.If taken The nitrogen of Dai Ji be described as being optionally substituted in base list it is one or more replace, then one or more hydrogen on nitrogen are (extremely The degree of existing any hydrogen) substituent group that can respectively be independently selected optionally substitutes.

If substituent group is described as " independently selected from " one group of group, each substituent group is selected independently of another one. Therefore, each substituent group can be identical or different with another (other) substituent group.

As used herein, term " one or more " means 1 under reasonable terms or more than 1, such as 2 A, 3,4,5 or 10.

Unless indicated, otherwise as used herein, the tie point of substituent group may be from any suitable location of substituent group.

When the key of substituent group is shown as pass through the key for connecting two atoms in ring, then such substituent group can be bonded to this Any ring member nitrogen atoms in substitutive ring.

The invention also includes the compounds of all pharmaceutically acceptable isotope labellings, with the compound of the present invention phase Together, in addition to one or more atoms are by with same atoms ordinal number but atomic mass or mass number are different from being dominant in nature The atomic mass of gesture or the atom substitution of mass number.It is suitble to include that the example of isotope in the compound of the present invention includes (but being not limited to) hydrogen isotope (such as²H、³H)；Carbon isotope (such as¹¹C、¹³C and¹⁴C)；Chlorine isotope (such as³⁷Cl)；Fluorine isotope (such as¹⁸F)；Iodine isotope (such as¹²³I and¹²⁵I)；Nitrogen isotope (such as¹³N and¹⁵N)；Oxygen Isotope (such as¹⁵O、¹⁷O and¹⁸O)；Phosphorus isotope (such as³²P)；And sulphur isotope (such as³⁵S).Certain isotope marks The compound of the present invention (such as mix radioisotopic those) of note can be used for drug and/or substrate tissue distribution research In (such as analysis).Radioactive isotope tritium is (i.e.³H) and carbon-14 (i.e.¹⁴C) especially available because being easily incorporate into and being easy detection In the purpose.With Positron emitting isotopes (such as¹¹C、¹⁸F、¹⁵O and¹³N) carrying out substitution can be in positron emission tomography For examining substrate receptor occupancy in art (PET) research.The compound of the present invention being isotopically labeled can by with retouch Similar method is by using the examination appropriate being isotopically labeled those of in being set forth in accompanying route and/or embodiment and preparing Agent replaces the reagent of the non-marked used before to prepare.Pharmaceutically acceptable solvate of the invention includes wherein crystallizing Solvent those of can be replaced by isotope, for example, D₂O, acetone-d₆Or DMSO-d₆。

Term " stereoisomer " indicates the isomers formed due at least one asymmetric center.There is one or more In the compound of a (such as 1,2,3 or 4) asymmetric center, it is different to can produce racemic mixture, single mapping Structure body, non-enantiomer mixture and individual diastereoisomer.Specific individual molecules can also be (suitable with geometric isomer Formula/trans-) exist.Similarly, the different shape of the structure that the compound of the present invention can be in Fast-Balance with two or more The mixture (commonly referred to as tautomer) of formula exists.The representative example of tautomer includes ketoenol tautomerization Body, phenol -one tautomer, nitroso-oxime tautomer, imine-enamine tautomers etc..It is appreciated that the application Range cover it is all it is such with arbitrary proportion (such as 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof isomers.

Usable solid line hereinReal wedge shapeOr empty wedge shapeDescribe the compound of the present invention Chemical bond.It is bonded to the key of asymmetric carbon atom to describe using solid line and is intended to show include all possible at the carbon atom Stereoisomer (for example, specific enantiomter, racemic mixture etc.).It is bonded to not using real or imaginary wedge shape with describing The key of symmetric carbon atom be intended to show to exist shown in stereoisomer.When being present in racemic mixture, use is real and imaginary Wedge shape is to define relative stereochemistry, rather than absolute stereochemistry.Unless otherwise specified, be intended to can for the compound of the present invention With stereoisomer, (it includes cis- and transisomer, optical isomer (such as R and S enantiomter), diastereo-isomerism Body, geometric isomer, rotational isomer, conformer, atropisomer and its mixture) form exist.Of the invention Compound can express the isomerism of more than one types, and by its mixture (such as racemic mixture and diastereo-isomerism Body to) composition.

The present invention covers all possible crystal form or polymorph of the compound of the present invention, can be single polycrystalline The mixture of the arbitrary proportion of type object or more than one polymorph.

It is also understood that certain compounds of the invention can exist in a free form for treating, or where appropriate, with its medicine Acceptable derivates form exists on.In the present invention, pharmaceutically acceptable derivates include but is not limited to: pharmaceutically Acceptable salt, solvate, metabolin or prodrug, by they to need its patient administration after, can be direct or indirect The compound of the present invention or its metabolin or residue are provided.Therefore, when referenced herein " the compound of the present invention ", It is intended to the above-mentioned various derivative forms of compound.

The pharmaceutically acceptable salt of the compound of the present invention includes its acid-addition salts and base addition salts.

Suitable acid-addition salts are formed by the acid of formation pharmaceutically-acceptable salts.Example include acetate, adipate, Aspartate, benzoate, bicarbonate/carbonate, disulfate/sulfate, fumarate, gluceptate, Portugal Sugar lime, glucuronate, hexafluorophosphate, hydrobromate/bromide, hydriodate/iodide, maleate, third Diacid salt, Methylsulfate, naphthoate (naphthylate), nicotinate, nitrate, Orotate, oxalates, palmitinic acid Salt and other similar salt.

Suitable base addition salts are formed by the alkali of formation pharmaceutically-acceptable salts.Example includes aluminium salt, arginine salt, gallbladder Alkali salt, diethylamine salt, lysine salt, magnesium salts, meglumine salt, sylvite, sodium salt, amino butanetriol salt and other similar salt.

The summary of suitable salt referring to Stahl and Wermuth " Handbook of Pharmaceutical Salts: Properties,Selection,and Use"(Wiley-VCH,2002).It is for the preparation of the compounds of the present invention pharmaceutically The method of acceptable salt is well known by persons skilled in the art.

The compound of the present invention can exist in the form of solvate (preferably hydrate), wherein the compound of the present invention packet Polar solvent containing the structural element as the compound lattice, especially such as water, methanol or ethyl alcohol.Polar solvent is special The amount for being water can be with stoichiometric ratio or non-stoichiometric presence.

It will be appreciated by those skilled in the art that since nitrogen needs available lone pair electrons to be oxidized to oxide, not All nitrogen-containing heterocycles can form N- oxide；Those skilled in the art can identify the nitrogen-containing hetero for being capable of forming N- oxide Ring.Skilled persons will also appreciate that tertiary amine is capable of forming N- oxide.It is used to prepare the N- oxide of heterocycle and tertiary amine Synthetic method be well known to those skilled in the art, including with peroxy acid such as Peracetic acid and metachloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxide such as tert-butyl hydroperoxide, sodium perborate and bisoxirane (dioxirane) As dimethyldioxirane comes oxygenated heterocyclic and tertiary amine.These methods for being used to prepare N- oxide have obtained extensively in the literature General description and summary, see, for example: T.L.Gilchrist, Comprehensive Organic Synthesis, vol.7, pp 748-750；A.R.Katritzky and A.J.Boulton, Eds., Academic Press；And G.W.H.Cheeseman and E.S.G.Werstiuk, Advances in Heterocyclic Chemistry, vol.22, pp 390-392, A.R.Katritzky and A.J.Boulton, Eds., Academic Press.

It within the scope of the invention further include the metabolin of the compound of the present invention, i.e., when the compound of the present invention is administered The substance formed in vivo.Such product can be by the oxidation for the compound being for example administered, reduction, hydrolysis, amidation, deamidation Change, esterification, enzymatic hydrolysis etc. generate.Therefore, the present invention includes the metabolin of the compound of the present invention, including by making change of the invention It closes object and mammalian animal is enough to generate compound made from the method for the time of its metabolite.

The present invention further comprises the prodrug of the compound of the present invention within its scope, for that itself can have smaller pharmacology Certain derivatives of activity or the compound of the present invention without pharmacological activity are learned when being administered in body or Shi Ketong thereon It crosses such as hydrolytic rupture and is converted to have and it is expected active the compound of the present invention.Usually such prodrug can be the compound Functional group derivant, be easy to be converted to desired therapeutical active compound in vivo.Other letters used about prodrug Breath can be found in " Pro-drugs as Novel Delivery Systems ", and volume 14, ACS Symposium Series (T.Higuchi and V.Stella) and " Bioreversible Carriers in Drug Design, " Pergamon Press, 1987 (E.B.Roche is edited, American Pharmaceutical Association).Prodrug of the invention can Such as it is known to those skilled in the art as " preceding-part (pro-moiety) (such as " Design of by using Described in Prodrugs ", H.Bundgaard (Elsevier, 1985)) " certain parts substitute in the compound of the present invention and deposit Appropriate functional group prepare.

Present invention also contemplates that the compound of the present invention containing protecting group.In any process of preparation the compound of the present invention In, protection may be necessary and/or desired in any sensitive group in relation on molecule or reactive group, be consequently formed The form of the chemoproection of the compound of invention.This can be realized by conventional protecting group, for example, in Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；And T.W.Greene& P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley&Sons, described in 1991 Those of protecting group, these bibliography by quotes addition herein.Using methods known in the art, in subsequent stages appropriate Section can remove protecting group.

Term " about " refers in ± 10% range of the numerical value, in preferably ± 5% range, more preferable ± 2% range It is interior.

Compound

In some embodiments, the present invention provides compound or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, wherein describedization Close the structure that object has formula (I):

Wherein:

Ring A is selected from phenyl ring and 5-6 member hetero-aromatic ring；

X is selected from N and CR⁴；

R¹Selected from hydrogen and fluorine；

R⁶It is each independently selected from halogen, cyano, hydroxyl, C at each occurrence_1-6Alkyl, halogenated C_1-6Alkyl ,-C_1-6It is sub- Alkyl-OH and-O-C_1-6Alkyl；Preferably, R⁶It is each independently selected from F, Cl, Br, methyl ,-CH at each occurrence₂OH and- OCH₃；

M is 1,2 or 3；

N is 0,1,2 or 3；And

In some embodiments, the present invention provides compound or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, in which:

R²Selected from hydrogen, C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, halogenated C_1-4Alkyl ,-C_1-4Alkylidene-OH ,-C_1-4Alkylene Base-O-C_1-4Alkyl ,-C_1-4Alkylidene-cyano, C_3-6Cyclic hydrocarbon radical and 4-6 circle heterocyclic ring base；

Preferably, R²Selected from hydrogen, methyl, ethyl, propyl, isopropyl, acrylic, propinyl, trifluoromethyl, fluoro ethyl, Trifluoroethyl ,-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CH₂OCH₂CH₃、-CH₂CN、-CH₂CH₂CN, cyclopropyl Base, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base and THP trtrahydropyranyl；

It is highly preferred that R²For hydrogen.

R³Selected from-C_1-4Alkylidene-OH ,-C_1-4Alkylidene-O-C_1-4Alkyl ,-C_1-4Alkylidene-NR^3aR^3b,-C (=O) NR^3aR^3b、

- N=S (=O) (R^3a)(R^3b) ,-P (=O) (R^3a)(R^3b) ,-NH-P (=O) (R^3a)(R^3b) and pyriconyl；And And

R^3aAnd R^3bIt is each independently selected from C_1-4Alkyl and C_3-6Cyclic hydrocarbon radical；Or R^3aAnd R^3bThe atom connected together with it 4-6 circle heterocyclic ring base is collectively formed, the heterocycle is optionally by 1,2,3 or 4 independently selected from C_1-4Alkyl and C_3-6 The substituent group of cyclic hydrocarbon radical replaces.

In some embodiments, R³Selected from-CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-C(CH₃)₂OCH₃、-CH₂N (CH₃)₂,-C (=O) N (CH₃)₂,-N=S (=O) (CH₃)₂,-N=S (=O) (C₂H₅)₂,-P (=O) (CH₃)₂,-NH-P (=O) (CH₃)₂、And pyriconyl.

In some embodiments, R³Selected from-CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-C(CH₃)₂OCH₃、-CH₂N (CH₃)₂,-C (=O) N (CH₃)₂,-N=S (=O) (CH₃)₂,-P (=O) (CH₃)₂,-NH-P (=O) (CH₃)₂、 And pyriconyl；

In some embodiments, R³Selected from-C (CH₃)₂OH、-CH₂N(CH₃)₂,-C (=O) N (CH₃)₂,-N=S (=O) (CH₃)₂,-N=S (=O) (C₂H₅)₂,-P (=O) (CH₃)₂、

In some embodiments, R³Selected from-C (CH₃)₂OH、-CH₂N(CH₃)₂,-C (=O) N (CH₃)₂,-N=S (=O) (CH₃)₂,-P (=O) (CH₃)₂、

In some embodiments, the present invention provides compound or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, whereinIt is selected from:

In some embodiments,It is selected from:

Ring A is selected from phenyl ring and 5-6 member hetero-aromatic ring, and the phenyl ring and hetero-aromatic ring are optionally selected from ring by one or more Butyl, cyclopenta, cyclohexyl and-N (CH₃)₂Substituent group replace.

In some embodiments, ring A is selected from phenyl ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring, thiazole ring and pyrazoles Ring.

In some embodiments, ring A is selected from phenyl ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring and pyrazole ring.

In some embodiments, ring A is selected from phenyl ring, pyridine ring, thiazole ring and pyrazole ring.

In some embodiments, ring A is selected from phenyl ring, pyridine ring and pyrazole ring.

In some embodiments, the present invention provides compound or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, in which: R⁵It is selected from Halogen, cyano, C_1-6Alkyl, halogenated C_1-6Alkyl ,-C_1-6Alkylidene-NR^5aR^5b,-C (=O) NR^5aR^5bWith 3-10 circle heterocyclic ring base.

R⁵Selected from halogen, cyano, C_1-4Alkyl, halogenated C_1-4Alkyl ,-C_1-4Alkylidene-NR^5aR^5b,-C (=O) NR^5aR^5b、- O- (3-10 circle heterocyclic ring base) (preferably-O- THP trtrahydropyranyl), pyrrolidinyl, THP trtrahydropyranyl, piperazinyl, morpholinyl, Thiomorpholine base, piperidyl and tetrahydro pyridyl, the pyrrolidinyl, oxinane Base, piperazinyl, morpholinyl, Thiomorpholine base, piperidyl and tetrahydro pyridyl are optional Ground is by 1,2,3 or 4 independently selected from F, Cl, Br, hydroxyl, oxo, cyano, C_1-4Alkyl (preferably methyl, isopropyl Base), halogenated C_1-4Alkyl ,-O-C_1-4Alkyl (preferably methoxyl group), C_3-6Cyclic hydrocarbon radical ,-C_1-4Alkylidene-O-C_1-4Alkyl ,-N (C_1-4 Alkyl)₂、-C_1-6Alkylidene-OH is (preferably), 3-10 circle heterocyclic ring base (preferably) and-S (=O)₂-C_1-4Alkyl Substituent group replace.

In some embodiments, R⁵Selected from halogen, cyano, C_1-4Alkyl, halogenated C_1-4Alkyl ,-C_1-4Alkylidene- NR^5aR^5b,-C (=O) NR^5aR^5b, piperazinyl, morpholinyl, piperidyl and tetrahydro pyridyl, the piperazinyl, morpholinyl, piperidyl With tetrahydro pyridyl optionally by 1,2,3 or 4 independently selected from C_1-4Alkyl, halogenated C_1-4Alkyl, C_3-6Cyclic hydrocarbon radical ,- C_1-4Alkylidene-O-C_1-4Alkyl and-N (C_1-4Alkyl)₂Substituent group replace.

In some embodiments, R^5aAnd R^5bIt is each independently selected from hydrogen, C_1-4Alkyl, halogenated C_1-4Alkyl and C_3-6Cyclic hydrocarbon Base；Or R^5aWith R^5b4-6 circle heterocyclic ring base is collectively formed in the nitrogen-atoms connected together with it, and the heterocycle is optionally by 1,2 A, 3 or 4 are independently selected from C_1-4Alkyl and C_3-6The substituent group of cyclic hydrocarbon radical replaces.

In some embodiments, R⁵Selected from fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, fluoro ethyl, three Fluoro ethyl ,-CH₂N(CH₃)₂、-C₂H₄N(CH₃)₂,-C (=O) N (CH₃)₂,-O- THP trtrahydropyranyl, pyrrolidinyl, oxinane Base, thiomorpholine base, piperazinyl, 4- methyl piperazine base, 4- isopropyl piperazinyl, morpholinyl, 4- methyl piperidine base, 4- dimethylamino Phenylpiperidines base, 1- methyl tetrahydro pyridyl and 1- isopropyl tetrahydro pyridyl.

In some embodiments, R⁵Selected from fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, fluoro ethyl, three Fluoro ethyl ,-CH₂N(CH₃)₂、-C₂H₄N(CH₃)₂,-C (=O) N (CH₃)₂, piperazinyl, 4- methyl piperazine base, 4- isopropyl piperazine Base, morpholinyl, 4- methyl piperidine base, 4- dimethylaminopyridine base, 1- methyl tetrahydro pyridyl and 1- isopropyl tetrahydropyridine Base.

In some embodiments, R⁵Selected from cyano, methyl, isopropyl, trifluoroethyl ,-C₂H₄N(CH₃)₂,-C (=O) N (CH₃)₂、

In some embodiments, R⁵Selected from cyano, isopropyl ,-C₂H₄N(CH₃)₂,-C (=O) N (CH₃)₂、

R⁵With an adjacent R⁶5- or 6-membered heterocycle or 8 yuan of spiroheterocyclics are collectively formed in the atom connected together with it Base, the heterocycle and spiro heterocyclic radical are optionally by 1,2,3 or 4 independently selected from methyl, ethyl, isopropyl, ring Propyl, fluoro ethyl and-CH₂CH₂OCH₃Substituent group replace.

In some embodiments, R⁵With an adjacent R⁶The atom connected together with it be collectively formed 6 circle heterocyclic ring bases or 8 yuan of spiro heterocyclic radicals, the heterocycle and spiro heterocyclic radical optionally by 1,2,3 or 4 independently selected from methyl, ethyl, Isopropyl, cyclopropyl, fluoro ethyl and-CH₂CH₂OCH₃Substituent group replace.

In some embodiments, the present invention provides compound or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, whereinIt is selected from

In some embodiments,It is selected from

In some embodiments, the present invention provides compound or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, wherein describedization Close the structure that object has formula (II), formula (III) or formula (IV):

Preferably, the compound have formula (II) -1, formula (II) -2, formula (III) -1, formula (III) -2, formula (IV) -1 or The structure of formula (IV) -2:

The present invention, which covers, carries out the resulting compound of any combination to each embodiment.

In some embodiments, the present invention provides compound or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, wherein describedization Object is closed to be selected from:

Preparation method

In some embodiments, the present invention provides the method for the compound of preparation formula (I), and the method includes following steps It is rapid:

Wherein:

Y is halogen, boric acid base group or borate group, preferably Cl, Br, I ,-B (OH)₂Or

Z is halogen, such as Cl or Br；

Remaining each group is as hereinbefore defined；

It the described method comprises the following steps:

(1) react compound IN-1 with compound IN-2 to obtain compound IN-3；

Preferably, make compound IN-1 and compound IN-2 that coupling reaction occur to obtain compound IN-3.The coupling Reaction preferably carries out in the presence of metallic catalyst and alkali.Preferably, the metallic catalyst is copper salt catalyst, preferably Cuprous iodide, cuprous bromide, copper acetate or cuprous oxide etc..The alkali is selected from potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, 2, 2- bipyridyl, triethylamine and pyridine, preferably potassium carbonate or pyridine.The coupling reaction preferably carries out in the presence of ligand, institute State ligand be selected from (1S, 2S)-N, N '-dimethyl hexamethylene -1,2- diamines and N, N '-dimethyl ethylenediamine, preferably (1S, 2S)-N, N '-dimethyl -1,2- cyclohexanediamine.The solvent of the coupling reaction is selected from benzene, toluene, 1,4- dioxane, N, N- dimethyl Formamide, glycol dimethyl ether, methanol, tetrahydrofuran, methylene chloride etc. and its mixed solvent, preferably Isosorbide-5-Nitrae-dioxane, N, Dinethylformamide or methanol.The temperature of the coupling reaction is preferably 80-110 DEG C or room temperature.Reaction time is preferably 2- 80 hours.

(2) react compound IN-3 with compound IN-4 to obtain the compound of formula (I)；

Preferably, make compound IN-3 and compound IN-4 that coupling reaction occur to obtain the compound of formula (I).The idol Connection reaction preferably carries out in the presence of metallic catalyst and alkali.Preferably, the metallic catalyst is palladium metal catalyst, example Such as Pd₂(dba)₃, tetrakis triphenylphosphine palladium, [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride, two (triphenylphosphines) two Palladium chloride, palladium acetate, preferably Pd₂(dba)₃.The alkali is preferably inorganic base, such as potassium carbonate, cesium carbonate, sodium carbonate, bicarbonate Sodium or saleratus, more preferable cesium carbonate.The coupling reaction preferably carries out in the presence of ligand, and the ligand is selected from 2- bis- Cyclohexyl phosphine -2 ', 4 ', 6 '-tri isopropyl biphenyls, 2- (dicyclohexylphosphontetrafluoroborate) 3,6- dimethoxy -2 ', 4 ', 6 '-triisopropyls - 1,1 '-biphenyl and 1,1 '-dinaphthalene -2,2 '-bis- diphenylphosphines, preferably 1,1 '-dinaphthalene -2,2 '-bis- diphenylphosphines.The coupling is anti- The solvent answered is selected from benzene, toluene, Isosorbide-5-Nitrae-dioxane, n,N-Dimethylformamide, glycol dimethyl ether etc. and its mixed solvent, It is preferred that 1,4- dioxane.The coupling reaction temperature is preferably 80-110 DEG C or room temperature.Reaction time is preferably 2-6 hours.

When preparing the compound of formula (I), it may be necessary to protect the distal end functional group (such as hydroxyl or amino) of intermediate. The needs of this protection can be changed with the property of distal end functional group and the condition of preparation method.About the general of protecting group The purposes for addressing them, referring to T.W.Greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991。

Pharmaceutical composition

In some embodiments, the present invention provides pharmaceutical composition, and it includes prevention or the present invention of therapeutically effective amount Compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N- oxidation Object, the compound of isotope labelling, metabolin or prodrug and one or more pharmaceutically acceptable carriers.

" pharmaceutically acceptable carrier " refers to the diluent, adjuvant, excipient being administered together with therapeutic agent in the present invention Or medium, and its tissue that the mankind and/or other animals are adapted for contact in the range of reasonable medical judgment without Excessive toxicity, stimulation, allergic reaction or with reasonable benefit/risk than corresponding other problems or complication.

Workable pharmaceutically acceptable carrier includes but is not limited to sterile liquid in pharmaceutical composition of the invention, Such as water and oil, the oil including those petroleum, animal, plant or synthesis source, such as peanut oil, soybean oil, mineral oil, sesame Oil etc..When described pharmaceutical composition is administered intravenously (IV, water is exemplary carrier.Physiological saline and grape can also be used Sugar and glycerine water solution are especially used for injection as liquid-carrier.Suitable drug excipient include starch, glucose, Lactose, sucrose, gelatin, maltose, chalk, silica gel, odium stearate, glycerin monostearate, talcum, sodium chloride, skimmed milk power, Glycerol, propylene glycol, water, ethyl alcohol etc..The composition can also optionally include a small amount of wetting agent, emulsifier or pH buffering Agent.Oral preparation may include standard vector, such as the mannitol of pharmaceutical grade, lactose, starch, magnesium stearate, saccharin sodium, fiber Element, magnesium carbonate etc..The example of suitable pharmaceutically acceptable carrier is such as in Remington ' s Pharmaceutical Described in Sciences (1990).

Pharmaceutical composition of the invention can be acted on systematically and/or locally be acted on.For this purpose, they can be suitble to Approach administration, such as by injection (as in intravenous, intra-arterial, subcutaneous, peritonaeum, intramuscular injection, including instil) or it is percutaneous Administration；Or oral, buccal, intranasal, it is transmucosal, local, in the form of eye-drops preparations or pass through inhalation.

For these administration routes, pharmaceutical composition of the invention is administered in the dosage form that can be suitble to.The dosage form include but It is not limited to tablet, capsule, pastille, hard candy agent, powder, spray, cream, ointment, suppository, gelling agent, paste, washes Agent, ointment, aqueous suspension, injectable solutions, elixir, syrup etc..

Content or dosage of the compound of the present invention in pharmaceutical composition can be about 0.01mg to about 1000mg.

In some embodiments, the present invention provides the method for preparing pharmaceutical composition of the invention, the method includes By the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug are combined with one or more pharmaceutically acceptable carriers.

Treatment method and purposes

In some embodiments, the present invention provides the compound of the present invention or its pharmaceutically acceptable salt, solid are different Structure body, tautomer, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug or Person's pharmaceutical composition of the invention is preparing the purposes in the drug for preventing or treating Wee1 protein kinase related disorder.

In some embodiments, the present invention provides the compound of the present invention or its pharmaceutically acceptable salt, solid are different Structure body, tautomer, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug or Person's pharmaceutical composition of the invention, it is used to prevent or treat Wee1 protein kinase related disorders.

In some embodiments, the method that the present invention provides prevention or treatment Wee1 protein kinase related disorder, it is described Method includes to needing its individual that a effective amount of the compound of the present invention or its pharmaceutically acceptable salt, alloisomerism is administered Body, tautomer, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug or Pharmaceutical composition of the invention.

In some embodiments, the Wee1 protein kinase related disorder is cancer.

In some embodiments, the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, mutually variation Structure body, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug or medicine of the invention Compositions can be preferred for treating cancer with other antitumor agent drug combinations.Other described antitumor agents refer to have Treating cancer and its active substance of associated disease.

" drug combination " includes simultaneously, sequence, alternately uses two or more drugs, particularly includes by two Kind or more drug, which is made, to be present in one or more dosage units, obtains the drug products of suitable drug combination, and will The drug products are administered to needing the mammal of drug combination.

" effective quantity " refers to as used herein, the term be administered after can alleviate treated illness to a certain extent The amount of the compound of one or more symptoms.

Dosage regimen be can adjust to provide optimal required response.For example, single bolus can be administered, can be administered at any time several Divided dose, or dosage can be proportionally reduced or increased as indicated in the urgent need for the treatment of condition.It should be noted that dose value can be with will subtract The type and seriousness of the light patient's condition and change, and may include single or multiple dosage.It further understands, for any specific Individual, specific dosage regimen should be sentenced according to the profession of individual need and administration composition or the personnel for the administration for supervising composition Break to adjust at any time.

The amount of the compound of the present invention being administered can depend on individual treated, the seriousness of illness or the patient's condition, to The rate of medicine, the disposition of compound and the judgement of prescriber.In general, effective dose is in per kg body weight per day about 0.0001 To about 50mg, for example, about 0.01 to about 10mg/kg/ days (single or divided doses).For the people of 70kg, this can be added up to about 0.007mg/ to about 3500mg/, for example, about 0.7mg/ to about 700mg/.In some cases, it is not higher than aforementioned model The dosage level of the lower limit enclosed can be it is enough, and in other cases, still can be in the feelings for not causing any harmful side effect Larger dose is used under condition, condition is that the larger dose is divided into several smaller doses to be administered throughout the day first.

Unless otherwise stated, otherwise as used herein, term " treatment " means to reverse, mitigates, inhibits such art The progress of one or more symptoms of illness or the patient's condition applied by language or such illness or the patient's condition, or prevent such illness Or one or more symptoms of the patient's condition or such illness or the patient's condition.

" individual " includes people or non-human animal as used herein.Exemplary individual human include with disease (such as this Disease described in text) individual human (referred to as patient) or normal individual." non-human animal " includes all vertebrates in the present invention, Such as nonmammalian (such as birds, amphibian, reptile) and mammal, such as non-human primates, domestic animal and/or Domesticated animal (such as sheep, dog, cat, milk cow, pig etc.).

Specific embodiment

Embodiment

In order to keep the purpose of the present invention and technical solution clearer, this hair is further described below in conjunction with specific embodiment It is bright.It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.Also, the following example In unmentioned specific experiment method, according to routine experiment method carry out.

Abbreviation herein has following meanings:

The structure for the compound recorded in following embodiment passes through¹H-NMR or MS is confirmed.¹The determining instrument of H-NMR makes With Bruker400MHz Nuclear Magnetic Resonance, measurement solvent is CD₃OD、CDCl₃Or DMSO-d₆, internal standard substance TMS, whole δ values It is indicated with ppm value.The determining instrument of mass spectrum (MS) uses Agilent (ESI) mass spectrograph, model Agilent 6120B.

The aluminium sheet (20 × 20cm) that thin-layer chromatography silica gel plate (TLC) uses Merck to produce, thin-layered chromatography isolates and purifies use Be GF 254 (0.4~0.5mm).

The monitoring of reaction uses thin-layered chromatography (TLC) or LC-MS, and the solvent system used has: methylene chloride and first Alcohol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system.According to the polarity different adjustment solvent of compound Volume ratio, a small amount of triethylamine etc. can also be added and be adjusted.

Microwave reaction usesInitiator+ (400W, RT~300 DEG C) microwave reactor.

It is carrier that column chromatography, which generally uses 200~300 mesh silica gel,.The system of eluant, eluent includes: methylene chloride and methanol System, petroleum ether and ethyl acetate system.According to the volume ratio of the polarity different adjustment solvent of compound, can also be added a small amount of Triethylamine etc. be adjusted.

Instrument model used in preparative high performance liquid chromatography: Agilent 1260, chromatographic column: Waters XBridge Prep C₁₈OBD(19mm×150mm×5.0μm)；Chromatographic column temperature: 25 DEG C；Flow velocity: 20.0mL/min；Detection wavelength: 214nm； Gradient: (0min:10%A, 90%B；16.0min:90%A, 10%B)；Mobile phase A: 100% acetonitrile；Mobile phase B: 0.05% ammonium bicarbonate aqueous solution.

Unless otherwise indicated, reaction temperature is room temperature (20 DEG C~30 DEG C).

Reagent used in the present invention is purchased from Acros Organics, Aldrich Chemical Company, Shang Haite Chemical Science and Technology Ltd. of uncle etc..

The preparation of intermediate

Intermediate Preparation 1:2- (6- (chloro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of 2-) pyridine -2- base) propan-2-ol (Int-1) preparation

Step 1: the preparation of 2- (6- bromopyridine -2- base) propan-2-ol (Int-1-b)

The dissolution in ether (100mL) by 6- Bromopicolinic acid methyl esters (Int-1-a) (5g, 23.1mmol), is protected in nitrogen Shield is lower to be added methylpyridinium iodide magnesium (17mL, 50.8mmol), is stirred at room temperature 0.5 hour.Water and 2N salt are added into reaction solution Acid is extracted with ethyl acetate 3 times, and saturated sodium bicarbonate aqueous solution and saturated common salt water washing are successively used after organic layer is merged, It is dried, filtered with anhydrous sodium sulfate, concentration filtrate obtains title compound (5g, the yield: 100%) of this step.

MS m/z(ESI):216.0[M+H]⁺。

Step 2: 2- (6- (chloro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of 2-) pyridine -2- base) propan-2-ol (Int-1) Preparation

Chloro- 7H- pyrrolo- [2,3-d] pyrimidine (Reg-1) (100mg, 0.65mmol) of 2- is dissolved in 1,4- dioxane (5mL) sequentially adds compound (Int-1-a) (183mg, 0.85mmol), cuprous iodide (124mg, 0.65mmol), potassium carbonate (126mg, 0.91mmol) and (1S, 2S)-N, N '-dimethyl hexamethylene -1,2- diamines (102mg, 0.72mmol), under nitrogen protection 95 DEG C are reacted 3 hours.Reaction solution is concentrated, residue is separated into (eluant, eluent: petrol ether/ethyl acetate by silica gel column chromatography =3/1) title compound (100mg, yield: 53.2%), are obtained.

MS m/z(ESI):289.1[M+H]⁺。

Intermediate Preparation 2:2- (6- (fluoro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of the chloro- 5- of 2-) pyridine -2- base) propyl- The preparation of 2- alcohol (Int-2)

Step 1: the preparation of fluoro- 7H- pyrrolo- [2,3-d] pyrimidine (Int-2-a) of the chloro- 5- of 2-

Acetonitrile (250mL) and acetic acid (50mL) is added in chloro- 7H- pyrrolo- [2,3-d] pyrimidine (5g, 32.56mmol) of 2- In the mixed solvent, then be added fluoro- Isosorbide-5-Nitrae-diazabicyclo [2.2.2] octane two (tetrafluoro boric acid) salt of 1- chloromethyl -4- (57.7g, 162.8mmol), lower 70 DEG C of nitrogen protection are reacted 4 hours.Reaction solution is cooling, saturated sodium bicarbonate solution is added, It is extracted with ethyl acetate, water and saturated common salt water washing is successively used after organic phase is merged, is dried, filtered with anhydrous sodium sulfate, Concentration filtrate obtains title compound (2.5g, the yield: 44.8%) of this step.

MS m/z(ESI):172.0[M+H]⁺。

Step 2: 2- (6- (fluoro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of the chloro- 5- of 2-) pyridine -2- base) propan-2-ol (Int-2) preparation

Compound (Int-2-a) (2.2g, 12.82mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (60mL), is then successively added Enter compound (Int-1-b) (3.05g, 14.11mmol), cuprous iodide (1.22g, 6.41mmol), potassium carbonate (2.66g, 19.24mmol) and (1S, 2S)-N, N '-dimethyl hexamethylene -1,2- diamines (910.47mg, 6.41mmol), 95 under nitrogen protection DEG C reaction overnight.Reaction solution is concentrated, residue is separated into (eluant, eluent: petrol ether/ethyl acetate=3/ by silica gel column chromatography 1) title compound (2g, yield: 50.9%), are obtained.

MS m/z(ESI):307.1[M+H]⁺。

The preparation of intermediate Preparation 3:4- (4- isopropyl piperazine -1- base) aniline (Int-3)

Step 1: the preparation of 4- (4- nitrobenzophenone) piperazine -1- t-butyl formate (Int-3-b)

By the fluoro- 4- nitrobenzene (2g, 14.17mmol) of 1-, piperazine -1- t-butyl formate (2.64g, 14.17mmol) and carbon Sour potassium (5.88g, 42.52mmol) is added in DMF (10mL), and 50 DEG C are reacted 16 hours.Reaction solution is cooled down in falling back, mistake Filter, drying solid obtain title compound (4g, the yield: 91.8%) of this step.

MS m/z(ESI):308.2[M+H]⁺。

Step 2: the preparation of 1- (4- nitrobenzophenone) piperazine hydrochloride (Int-3-c)

By compound (Int-3-b) (2g, 6.51mmol) be dissolved in 4N hydrogen chloride 1,4- dioxane solution (16mL, In 65.1mmol), it is stirred at room temperature 2 hours.Obtained after reaction solution is concentrated this step title compound (1.59g, yield: 100%).

MS m/z(ESI):208.1[M+H]⁺。

Step 3: the preparation of 1- isopropyl -4- (4- nitrobenzophenone) piperazine (Int-3-d)

By compound (Int-3-c) (1g, 4.10mmol), 2- iodopropane (906.8mg, 5.33mmol) and sodium carbonate (1.3g, 12.31mmol) is added in DMF (20mL), and 50 DEG C are reacted 16 hours.Reaction solution is cooled down in falling back, uses acetic acid Ethyl ester extraction, organic phase is merged, and is successively used water and saturated common salt water washing, is dried, filtered with anhydrous sodium sulfate.Filtrate is dense Residue is separated (eluant, eluent: methylene chloride/methanol=10/1) by silica gel column chromatography, obtains the title compound of this step by contracting Object (356mg, yield: 34.8%).

MS m/z(ESI):250.1[M+H]⁺。

Step 4: the preparation of 4- (4- isopropyl piperazine -1- base) aniline (Int-3)

Compound (Int-3-d) (356mg, 1.43mmol) is dissolved in methanol (15mL), palladium/carbon is added, hydrogen is replaced, It is stirred at room temperature 2 hours.By reaction solution by Celite pad filter, by filtrate be concentrated to get title compound (110mg, yield: 35.1%).

MS m/z(ESI):220.2[M+H]⁺。

The preparation of intermediate Preparation 4:4- (1- isopropyl -1,2,3,6- tetrahydropyridine -4- base) aniline (Int-4)

Step 1: the preparation of 4- (4- nitrobenzophenone) -5,6- dihydropyridine -1 (2H)-t-butyl formate (Int-4-b)

By the bromo- 4- nitrobenzene (500mg, 2.48mmol) of 1-, 4- (4,4,5,5- tetramethyl -1,3,2- dioxa boron heterocycle Pentane -2- base) -5,6- dihydropyridine -1 (2H)-t-butyl formate (921mg, 2.98mmol), Pd (dppf) Cl₂(204mg, It 0.25mmol) is added in Isosorbide-5-Nitrae-dioxane (12mL) and water (4mL) with potassium carbonate (1.0g, 7.44mmol), nitrogen displacement, 100 DEG C are reacted 2 hours.Reaction solution is cooled to room temperature, it is filtered by Celite pad, filtrate is concentrated, residue is passed through into system Standby thin layer chromatography (eluant, eluent: petrol ether/ethyl acetate=3/1) obtain this step title compound (781mg, yield: 100%).

MS m/z(ESI):305.1[M+H]⁺。

Step 2: the preparation of 4- (4- nitrobenzophenone) -1,2,3,6- tetrahydropyridine hydrochloride (Int-4-c)

To the 1,4- dioxane solution that 4N hydrogen chloride is added in compound (Int-4-b) (360mg, 1.18mmol) (3mL, 11.8mmol) is stirred at room temperature 1 hour, vacuum distillation remove solvent obtain this step title compound (285mg, yield: 100%).

MS m/z(ESI):205.1[M+H]⁺。

Step 3: the preparation of 1- isopropyl -4- (4- nitrobenzophenone) -1,2,3,6- tetrahydropyridine (Int-4-d)

By compound (Int-4-c) (520mg, 1.22mmol), 2- iodopropane (1.1g, 6.48mmol) and triethylamine (655.9mg, 6.48mmol) is dissolved in acetonitrile (5mL), and 70 DEG C are reacted 10 hours.Reaction solution is cooling, and concentration passes through residue Preparative thin layer chromatography purifying (eluant, eluent: petrol ether/ethyl acetate=1/3) obtains title compound (220mg, the receipts of this step Rate: 41.3%).

MS m/z(ESI):247.1[M+H]⁺。

Step 4: the preparation of 4- (1- isopropyl -1,2,3,6- tetrahydropyridine -4- base) aniline (Int-4)

Compound (Int-4-d) (220mg, 0.89mmol) is dissolved in methanol (8mL), Raney Ni is added, then instills water It closes hydrazine (222mg, 4.45mmol), is stirred at room temperature 2 hours.Reaction solution to be filtered by Celite pad, vacuum distillation removes methanol, Water and methylene chloride is added to extract 3 times.It by organic layer saturated common salt water washing, is dried, filtered with anhydrous sodium sulfate, filtrate is concentrated Obtain title compound (133mg, yield: 61.6%).

MS m/z(ESI):217.2[M+H]⁺。

Intermediate Preparation 5:(5- amino -2- (4- methylpiperazine-1-yl) phenyl) methanol (Int-5) preparation

Step 1: the preparation of 2- (4- methylpiperazine-1-yl) -5- nitrobenzaldehyde (Int-5-b)

By the fluoro- 5- nitrobenzaldehyde (1g, 5.91mmol) of 2-, 1- methyl piperazine (592.3mg, 5.91mmol) and potassium carbonate (1.23g, 8.87mmol) is added in DMF (5mL), and 50 DEG C of reactions are overnight.Reaction solution is cooled down in falling back, is filtered, it is dry Solid obtains title compound (1.4g, the yield: 95.0%) of this step.

MS m/z(ESI):250.1[M+H]⁺。

Step 2: the preparation of 2- (4- methylpiperazine-1-yl) -5- nitrobenzophenone methanol (Int-5-c)

Compound (Int-5-b) (1.52g, 6.10mmol) is dissolved in dry tetrahydrofuran (15mL), boron is added under ice bath Sodium hydride (230.7mg, 6.10mmol), 0 DEG C is reacted 1.5 hours.Reaction plus water quenching are gone out, are extracted with dichloromethane, it will be organic Saturated common salt water washing is used after mutually merging, is dried, filtered with anhydrous sodium sulfate, and concentration filtrate obtains the title compound of this step (1.25g, yield: 81.6%).

MS m/z(ESI):252.1[M+H]⁺。

Step 3: the preparation of (5- amino -2- (4- methylpiperazine-1-yl) phenyl) methanol (Int-5)

Compound (Int-5-c) (1.25g, 4.97mmol) is dissolved in ethyl alcohol (20mL), palladium/carbon, hydrogen displacement, room is added Temperature reaction 2 hours.By reaction solution by Celite pad filter, by filtrate be concentrated to get title compound (1g, yield: 90.8%).

MS m/z(ESI):222.2[M+H]⁺。

The preparation of intermediate Preparation 6:4- (4- amino -2- methoxyphenyl) piperazine -1- t-butyl formate (Int-6)

Step 1: the preparation of 4- (2- methoxyl group -4- nitrobenzophenone) piperazine -1- t-butyl formate (Int-6-b)

By the fluoro- 2- methoxyl group -4- nitrobenzene (1g, 5.84mmol) of 1-, piperazine -1- t-butyl formate (1.2g, It 6.43mmol) is added in DMF (10mL) with potassium carbonate (2.42g, 17.53mmol), 95 DEG C are reacted 20 hours.Reaction solution is cooling In falling back, filtering, drying solid obtains title compound (1.9g, the yield: 96.4%) of this step.

MS m/z(ESI):338.2[M+H]⁺。

Step 2: the preparation of 4- (4- amino -2- methoxyphenyl) piperazine -1- t-butyl formate (Int-6)

Compound (Int-6-b) (1.9g, 5.63mmol) is dissolved in methanol (40mL), palladium/carbon is added, hydrogen is replaced, It is stirred at room temperature 2 hours.By reaction solution by Celite pad filter, by filtrate be concentrated to get title compound (1.65g, yield: 95.3%).

MS m/z(ESI):308.2[M+H]⁺。

The preparation of intermediate Preparation 7:4- (4- amino -2- (methylol) phenyl) piperazine -1- t-butyl formate (Int-7)

Step 1: the preparation of 4- (2- formoxyl -4- nitrobenzophenone) piperazine -1- t-butyl formate (Int-7-a)

By the fluoro- 5- nitrobenzaldehyde (1g, 5.91mmol) of 2-, piperazine -1- t-butyl formate (1.1g, 5.91mmol) and carbon Sour potassium (1.23g, 8.87mmol) is added in DMF (5mL), and 50 DEG C of reactions are overnight.Reaction solution is cooled down in falling back, filtering, Drying solid obtains title compound (1.88g, the yield: 94.8%) of this step.

MS m/z(ESI):336.1[M+H]⁺。

Step 2: the preparation of 4- (2- (methylol) -4- nitrobenzophenone) piperazine -1- t-butyl formate (Int-7-b)

Compound (Int-7-a) (1.88g, 5.61mmol) is dissolved in dry tetrahydrofuran (15mL), boron is added under ice bath Sodium hydride (212.1mg, 5.61mmol), 0 DEG C is reacted 1.5 hours.Reaction plus water quenching are gone out, are extracted with dichloromethane, it will be organic Saturated common salt water washing is used after mutually merging, is dried, filtered with anhydrous sodium sulfate, and concentration filtrate obtains the title compound of this step (1.89g, yield: 100%).

MS m/z(ESI):338.2[M+H]⁺。

Step 3: the preparation of 4- (4- amino -2- (methylol) phenyl) piperazine -1- t-butyl formate (Int-7)

Compound (Int-7-b) (1.89g, 5.60mmol) is dissolved in ethyl alcohol (20mL), palladium/carbon, hydrogen displacement, room is added Temperature reaction 2 hours.By reaction solution by Celite pad filter, by filtrate be concentrated to get title compound (1.66g, yield: 96.4%).

MS m/z(ESI):308.2[M+H]⁺。

The preparation of intermediate Preparation 8:2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- amine (Int-8)

Step 1: the preparation of -1,3 (2H, 4H)-diketone (Int-8-b) of 2,4,4- trimethyl isoquinolin

By isoquinolin -1,3 (2H, 4H)-diketone (5g, 31.03mmol), potassium carbonate (14.15g, 102.38mmol), four fourths Base ammonium hydrogen sulfate (1.05g, 3.10mmol) and iodomethane (14.53g, 102.38mmol) are added in DMF (50mL), 70 DEG C of heating Overnight, then iodomethane (14.53g, 102.38mmol) is added, 70 DEG C are heated 4 hours.Reaction solution is cooled down in falling back, is used Ethyl acetate extraction, merges organic phase, successively uses water and saturated common salt water washing, and organic phase is concentrated, obtained residue is passed through Silica gel column chromatography separates (eluant, eluent: petrol ether/ethyl acetate=3/1), obtains title compound (5.36g, the receipts of this step Rate: 85.0%).

MS m/z(ESI):204.1[M+H]⁺。

Step 2: the preparation of -1,3 (2H, 4H)-diketone (Int-8-c) of 2,4,4- trimethyl -7- nitroisoquinoline

Compound (Int-8-b) (5.36g, 26.37mmol) is dissolved in the concentrated sulfuric acid (50mL), is slowly dropped under ice bath dense Nitric acid (25mL), temperature are controlled at 0-5 DEG C, and after being added dropwise to complete, the reaction was continued 0.5 hour.Reaction solution is poured slowly into ice water, The solid filtered out, is dried to obtain title compound (6.42g, the yield: 98.1%) of this step by filtering.

MS m/z(ESI):249.1[M+H]⁺。

Step 3: the preparation of 2,4,4- trimethyl -7- nitro -1,2,3,4- tetrahydroisoquinoline (Int-8-d)

Compound (Int-8-c) (6.42g, 25.86mmol) is dissolved in tetrahydrofuran (150mL), borine diformazan is added Thioether (103.45mmol, 52mL), 70 DEG C are flowed back 24 hours.It is concentrated after reaction solution is cooling, methanol and dilute hydrochloric acid is added in residue Reaction solution, is concentrated to get title compound (5.6g, the yield: 98.3%) of this step by reflux 1 hour.

MS m/z(ESI):221.1[M+H]⁺。

Step 4: the preparation of 2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- amine (Int-8)

Compound (Int-8-d) (1g, 4.55mmol) is dissolved in ethyl alcohol (10mL), palladium/carbon, hydrogen displacement, room temperature is added Reaction 2 hours.By reaction solution by Celite pad filter, by filtrate be concentrated to get title compound (810mg, yield: 93.6%).

MS m/z(ESI):191.1[M+H]⁺。

Intermediate Preparation 9:2 '-methyl -2 ', the 3 '-H- of dihydro -1 ' spiral shell [cyclopropane -1,4 '-isoquinolin] -7 '-amine (Int-9) preparation

Step 1: the preparation of 1- (2- cyano-phenyl) cyclopropanecarboxylate (Int-9-b)

2- (2- cyano-phenyl) methyl acetate is dissolved in toluene (5mL), addition tetrabutylammonium bromide (184mg, 0.57mmol), 1,2- Bromofume (807mg, 4.29mmol) and 50% sodium hydrate aqueous solution (2.5mL), it is small to be stirred at room temperature 1 When.Reaction solution water and ethyl acetate are extracted, organic phase is merged, it is used into saturated common salt water washing.Organic phase is concentrated, it will Residue obtains the title compound of this step by preparative thin layer chromatography purifying (eluant, eluent: petrol ether/ethyl acetate=3/1) (282mg, yield: 49%).

MS m/z(ESI):202.1[M+H]⁺。

Step 2: the preparation of 1- (2- (amino methyl) phenyl) cyclopropanecarboxylate (Int-9-c)

Compound (Int-9-b) (570mg, 2.82mmol) is dissolved in ethyl alcohol (15mL), dilute hydrochloric acid and palladium/carbon, hydrogen is added Gas displacement, reacts at room temperature 3 hours.Reaction solution is filtered by Celite pad, filtrate is concentrated to get to the title compound of this step (706mg, yield: 100%).

MS m/z(ESI):206.1[M+H]⁺。

Step 3: the preparation of -3 ' (2 ' H) -one (Int-9-d) of 1 ' H- spiral shell [cyclopropane -1,4 '-isoquinolin]

Compound (Int-9-c) (706mg, 2.92mmol) is dissolved in methanol (5mL), 5N sodium hydroxide solution is added (1mL) is stirred at room temperature 0.5 hour.Reaction solution 1N hydrochloric acid is neutralized, concentration, adds water and ethyl acetate to extract, be harmonious organic And saturated common salt water washing is used afterwards, it is dried, filtered with anhydrous sodium sulfate, concentration filtrate obtains the title compound of this step (438mg, yield: 86.6%).

MS m/z(ESI):174.1[M+H]⁺。

Step 4: the preparation of -3 ' (2 ' H) -one (Int-9-e) of the 7 '-H- of nitro -1 ' spiral shell [cyclopropane -1,4 '-isoquinolin]

Compound (Int-9-d) (438mg, 2.53mmol) is dissolved in the concentrated sulfuric acid (12mL), is slowly added into nitre under ice bath Sour potassium (281mg, 2.78mmol) is stirred 5 minutes, and stirring 10 minutes is warmed to room temperature.Reaction solution is poured into ice water, is filtered, is done Dry title compound (556mg, the yield: 100%) for obtaining this step.

MS m/z(ESI):219.1[M+H]⁺。

Step 5: 7 '-nitros -2 ', the preparation of the 3 '-H- of dihydro -1 ' spiral shells [cyclopropane -1,4 '-isoquinolin] (Int-9-f)

Boron trifluoride ether (260.30mg, 1.83mmol) is added to the tetrahydro of sodium borohydride (52.24mg, 1.37mmol) It in furans suspension, stirs 1 hour, the tetrahydrofuran (8mL) that compound (Int-9-e) (100mg, 0.46mmol) is added is molten Liquid, 70 DEG C are flowed back 2 hours.Reaction solution is neutralized with saturated sodium bicarbonate, is concentrated, residue is added into ethyl alcohol and 5N hydrochloric acid, Reflux 1 hour, concentrated solvent.Reaction solution is neutralized with saturated potassium carbonate, is extracted with ethyl acetate, with full after organic layer is merged And brine It, dried, filtered with anhydrous sodium sulfate, concentration filtrate obtain this step title compound (282mg, yield: 91.3%).

MS m/z(ESI):205.1[M+H]⁺。

Step 6: 2 '-methyl -7 '-nitro -2 ', the 3 '-H- of dihydro -1 ' spiral shells [cyclopropane -1,4 '-isoquinolin] (Int-9-g) Preparation

Compound (Int-9-f) (300mg, 1.47mmol) is dissolved in methanol (15mL), formalin is added (1.10g, 14.69mmol) and sodium triacetoxy borohydride (1.56g, 7.34mmol), is stirred at room temperature 4 hours.To reaction solution Middle addition saturated sodium carbonate solution, is extracted with dichloromethane, is dried, filtered after organic phase is merged with anhydrous sodium sulfate, concentration Filtrate obtains title compound (294mg, the yield: 91.7%) of this step.

MS m/z(ESI):219.1[M+H]⁺。

Step 7: 2 '-methyl -2 ', the system of the 3 '-H- of dihydro -1 ' spiral shell [cyclopropane -1,4 '-isoquinolin] -7 '-amine (Int-9) It is standby

Compound (Int-9-g) (294mg, 1.35mmol) is dissolved in methanol (15mL), Raney Ni and hydrazine hydrate is added (420.96mg, 6.74mmol) is stirred at room temperature 2 hours.Reaction solution is filtered by Celite pad, filtrate is concentrated, with water and two Chloromethanes extraction merges organic phase and is dried, filtered with saturated common salt water washing with anhydrous sodium sulfate, and concentration filtrate obtains title Compound (219mg, yield: 86.4%).

MS m/z(ESI):189.1[M+H]⁺。

Intermediate Preparation 10:((6- (chloro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of 2-) pyridine -2- base) imino group) Dimethyl-λ⁶The preparation of sulfane ketone (sulfanone) (Int-10)

Step 1: ((6- bromopyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (Int-10-b)

By 2,6- dibromo pyridine (100mg, 0.42mmol), dimethyl sulfenimide (42mg, 0.45mmol), Pd₂ (dba)₃Bis- diphenylphosphine -9,9- the xanthphos (24mg, 0.045mmol) of (38mg, 0.042mmol), 4,5- and carbonic acid Caesium (195mg, 0.60mmol) sequentially adds in 1,4- dioxane (5mL).After nitrogen is replaced 3 times, keep rising under nitrogen protection Temperature to 80 DEG C react 2 hours.Reaction solution is cooled down in falling back, is extracted with ethyl acetate.Organic layer is merged, with anhydrous sulphur Sour sodium dries, filters, concentration filtrate obtain crude product, by preparative thin layer chromatography purifying (eluant, eluent: petrol ether/ethyl acetate= 1/1) title compound (50.0mg, the yield: 47.8%) of this step, are obtained.

MS m/z(ESI):251.0[M+H]⁺。

Step 2: ((6- (chloro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of 2-) pyridine -2- base) imino group) dimethyl - λ⁶The preparation of sulfane ketone (Int-10)

By compound (Int-10-b) (50mg, 0.20mmol), chloro- 7H- pyrrolo- [2,3-d] pyrimidine of 2- (30mg, 0.20mmol), cuprous iodide (40mg, 0.21mmol), potassium carbonate (55mg, 0.4mmol) and (1S, 2S)-N, N '-dimethyl ring Hex- 1,2- diamines (30mg, 0.21mmol) sequentially adds in 1,4- dioxane (5mL).After nitrogen is replaced 3 times, nitrogen is kept 100 DEG C are warming up under protection to react 2 hours.Reaction solution is cooled down in falling back, is extracted with ethyl acetate.It will be organic laminated And dried, filtered with anhydrous sodium sulfate, concentration filtrate obtains crude product, by preparing thin layer chromatography (eluant, eluent: acetic acid second Ester), obtain title compound (35mg, yield: 54.5%).

MS m/z(ESI):322.0[M+H]⁺。

The preparation of intermediate Preparation 11:4- amino-N, N- dimethyl benzamide (Int-11)

Step 1: the preparation of N, N- dimethyl -4- nitrobenzamide (Int-11-b)

At 0 DEG C, to the tetrahydro furan of 4- nitrobenzoic acid (5g, 29.92mmol) and DIPEA (7.73g, 49.84mmol) It mutters and HATU (12.51g, 32.91mmol) is added in batches in (50mL) solution.Reaction mixture is stirred at room temperature 30 points Clock.The tetrahydrofuran solution (30mL, 2.0M) of dimethylamine is added thereto.Reaction mixture is stirred at room temperature 11 hours. Water quenching reaction is added, evaporating solvent under reduced pressure separates (eluant, eluent: petroleum ether/acetic acid by silica gel column chromatography for residue obtained Ethyl ester=1/1), to obtain title compound (5.6g, the yield: 96.4%) of this step.

MS m/z(ESI):195.1[M+H]⁺。

Step 2: the preparation of 4- amino-N, N- dimethyl benzamide (Int-11)

Compound (Int-11-b) (5.6g, 28.84mmol) is dissolved in ethyl alcohol (50mL), is added palladium/carbon (500mg), hydrogen Gas displacement, reacts 8 hours at room temperature.Reaction solution is filtered by Celite pad, filtrate is concentrated, by obtained solid through petroleum Ether mashing, filtering obtain title compound (4.5g, yield: 95%).

MS m/z(ESI):165.1[M+H]⁺。

The preparation of intermediate Preparation 12:1- isopropyl -1H- pyrazoles -4- amine (Int-12)

Step 1: the preparation of 1- isopropyl -4- nitro -1H- pyrazoles (Int-12-b)

Into DMF (50mL) solution of 4- nitropyrazole (5g, 44.22mmol) be added potassium carbonate (12.20g, 88.44mmol) and Iso-Propyl iodide (11.28g, 66.33mmol).Reaction mixture is heated to 50 DEG C, is stirred to react 30 points Clock.It by reaction mixture sat, is cooled to room temperature, filters, gained filtrate is poured into water, be extracted with ethyl acetate three times, close And organic phase, three times with saturated common salt water washing organic phase.Gained organic phase is dried, filtered with anhydrous sodium sulfate, by filtrate Concentration separates (eluant, eluent: petrol ether/ethyl acetate=3/1) by silica gel column chromatography for residue obtained, obtains the mark of this step Inscribe compound (6.2g, yield: 90.0%).

MS m/z(ESI):156.1[M+H]⁺。

Step 2: the preparation of 1- isopropyl -1H- pyrazoles -4- amine (Int-12)

Compound (Int-12-b) (6g, 38.67mmol) is dissolved in ethyl alcohol (50mL), is added palladium/carbon (600mg), hydrogen Displacement is reacted 8 hours at room temperature.Reaction solution is filtered by Celite pad, filtrate is concentrated, title compound is obtained (4.5g, yield: 93%).

MS m/z(ESI):126.1[M+H]⁺。

Intermediate Preparation 13:((6- (fluoro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of the chloro- 5- of 2-) pyridine -2- base) it is sub- Amino) dimethyl-λ⁶The preparation of sulfane ketone (Int-13)

Replace the compound (Int-1-b) in intermediate 2 second step of Preparation with compound (Int-10-b), with centre Similar method described in 2 second step of Preparation, synthesis obtain title compound (190mg, yield: 83.9%).

MS m/z(ESI):340.0[M+H]⁺。

Intermediate Preparation 14:6- (8- oxa- -3- azabicyclo [3.2.1] oct-3-yl) pyridine -3- amine (Int-14) Preparation

Step 1: the system of 3- (5- nitropyridine -2- base) -8- oxa- -3- azabicyclo [3.2.1] octane (Int-14-b) It is standby

By 2- chloro-5-nitropyridine (300mg, 1.879mmol) and 8- oxa- -3- azabicyclo [3.2.1] octane (257mg, 2.27mmol) is placed in 100mL single port bottle, and acetonitrile (40mL) and DMSO (4mL) is added, is stirred overnight at room temperature, and is reacted Liquid concentration, residue add water (60mL), and stirring is filtered after 30 minutes, and filtration cakes torrefaction obtains title compound (420mg, the receipts of this step Rate: 81.7%).

MS m/z(ESI):236.1[M+H]⁺。

Step 2: the preparation of 6- (8- oxa- -3- azabicyclo [3.2.1] oct-3-yl) pyridine -3- amine (Int-14)

Compound (Int-14-b) (420mg, 1.79mmol) is dissolved in methanol (20mL), is added Raney's nickel (0.3g), room Temperature is slowly added to hydrazine hydrate (5mL), is stirred at room temperature 1 hour, and reaction fluid cushion diatomite filtering, filtrate is concentrated to get title compound (340mg, yield: 92.8%).

MS m/z(ESI):206.1[M+H]⁺。

The preparation of intermediate Preparation 15:1- (2- (dimethylamino) ethyl) -1H- pyrazoles -4- amine (Int-15)

The Iso-Propyl iodide in intermediate 12 first step of Preparation is replaced with compound (Int-15-a), is prepared with intermediate Similar method described in example 12, synthesis obtain title compound (250mg, yield: 85.2%).

MS m/z(ESI):155.1[M+H]⁺。

The preparation of intermediate Preparation 16:4- (4- methoxy piperide -1- base) aniline (Int-16)

The fluoro- 2- methoxyl group -4- nitrobenzene of 1- in intermediate 6 first step of Preparation is replaced with compound (Int-3-a), is used Compound (Int-16-a) replaces the piperazine -1- t-butyl formate in intermediate 6 first step of Preparation, with intermediate Preparation 6 The similar method, synthesis obtain title compound (230mg, yield: 80.6%).

MS m/z(ESI):207.1[M+H]⁺。

The preparation of intermediate Preparation 17:4- (5- aminopyridine -2- base) thiomorpholine 1,1- dioxide (Int-17)

8- oxa- -3- the azabicyclo in intermediate 14 first step of Preparation is replaced with compound (Int-17-a) [3.2.1] octane, in method similar described in intermediate Preparation 14, synthesis obtain title compound (320mg, yield: 75.2%).

MS m/z(ESI):228.1[M+H]⁺。

The preparation of intermediate Preparation 18:6- (4- (methyl sulphonyl) piperidin-1-yl) pyridine -3- amine (Int-18)

8- oxa- -3- the azabicyclo in intermediate 14 first step of Preparation is replaced with compound (Int-18-a) [3.2.1] octane, in method similar described in intermediate Preparation 14, synthesis obtain title compound (210mg, yield: 65.3%).

MS m/z(ESI):256.1[M+H]⁺。

The preparation of the intermediate fluoro- 6- morpholino pyridine -3- amine (Int-19) of Preparation 19:5-

The 2- chloro-5-nitropyridine in intermediate 14 first step of Preparation is replaced with compound (Int-19-a), uses morpholine Instead of 8- oxa- -3- azabicyclo [3.2.1] octane in intermediate 14 first step of Preparation, described in intermediate Preparation 14 Similar method, synthesis obtain title compound (270mg, yield: 78.3%).

MS m/z(ESI):198.1[M+H]⁺。

The preparation of the intermediate chloro- 4- morpholino aniline (Int-20) of Preparation 20:3-

The fluoro- 2- methoxyl group -4- nitrobenzene of 1- in intermediate 6 first step of Preparation is replaced with compound (Int-20-a), With morpholino for the piperazine -1- t-butyl formate in intermediate 6 first step of Preparation, with similar described in intermediate Preparation 6 Method, synthesis obtain title compound (180mg, yield: 73.2%).

MS m/z(ESI):213.1[M+H]⁺。

The preparation of intermediate Preparation 21:4- (2- oxa- -5- azabicyclo [2.2.1] hept- 5- yl) aniline (Int-21)

The fluoro- 2- methoxyl group -4- nitrobenzene of 1- in intermediate 6 first step of Preparation is replaced with compound (Int-3-a), is used Compound (Int-21-a) replaces the piperazine -1- t-butyl formate in intermediate 6 first step of Preparation, with intermediate Preparation 6 The similar method, synthesis obtain title compound (160mg, yield: 79.2%).

MS m/z(ESI):191.1[M+H]⁺。

The preparation of intermediate Preparation 22:4- (8- oxa- -3- azabicyclo [3.2.1] oct-3-yl) aniline (Int-22)

The fluoro- 2- methoxyl group -4- nitrobenzene of 1- in intermediate 6 first step of Preparation is replaced with compound (Int-3-a), is used Compound (Int-22-a) replaces the piperazine -1- t-butyl formate in intermediate 6 first step of Preparation, with intermediate Preparation 6 The similar method, synthesis obtain title compound (120mg, yield: 83.2%).

MS m/z(ESI):205.1[M+H]⁺。

The preparation of intermediate Preparation 23:5- methyl -6- morpholino pyridine -3- amine (Int-23)

The 2- chloro-5-nitropyridine in intermediate 14 first step of Preparation is replaced with compound (Int-23-a), uses morpholine Instead of 8- oxa- -3- azabicyclo [3.2.1] octane in intermediate 14 first step of Preparation, described in intermediate Preparation 14 Similar method, synthesis obtain title compound (160mg, yield: 68.3%).

MS m/z(ESI):194.1[M+H]⁺。

The preparation of intermediate Preparation 24:4- (3- oxa- -8- azabicyclo [3.2.1] octyl- 8- yl) aniline (Int-24)

The fluoro- 2- methoxyl group -4- nitrobenzene of 1- in intermediate 6 first step of Preparation is replaced with compound (Int-3-a), is used Compound (Int-24-a) replaces the piperazine -1- t-butyl formate in intermediate 6 first step of Preparation, with intermediate Preparation 6 The similar method, synthesis obtain title compound (140mg, yield: 81.2%).

MS m/z(ESI):205.1[M+H]⁺。

The preparation of intermediate Preparation 25:5- methoxyl group -6- morpholino pyridine -3- amine (Int-25)

The 2- chloro-5-nitropyridine in intermediate 14 first step of Preparation is replaced with compound (Int-25-a), uses morpholine Instead of 8- oxa- -3- azabicyclo [3.2.1] octane in intermediate 14 first step of Preparation, described in intermediate Preparation 14 Similar method, synthesis obtain title compound (140mg, yield: 76.3%).

MS m/z(ESI):210.1[M+H]⁺。

The preparation of intermediate Preparation 26:2- (1- (5- aminopyridine -2- base) piperidin-4-yl) propan-2-ol (Int-26)

8- oxa- -3- the azabicyclo in intermediate 14 first step of Preparation is replaced with compound (Int-26-a) [3.2.1] octane, in method similar described in intermediate Preparation 14, synthesis obtain title compound (160mg, yield: 74.5%).

MS m/z(ESI):236.2[M+H]⁺。

The preparation of intermediate Preparation 27:1- (5- aminopyridine -2- base) piperidines -4- formonitrile HCN (Int-27)

8- oxa- -3- the azabicyclo in intermediate 14 first step of Preparation is replaced with compound (Int-27-a) [3.2.1] octane, in method similar described in intermediate Preparation 14, synthesis obtain title compound (210mg, yield: 81.5%).

MS m/z(ESI):203.2[M+H]⁺。

The preparation of intermediate Preparation 28:6- (4,4- difluoropiperdin -1- base) pyridine -3- amine (Int-28)

8- oxa- -3- the azabicyclo in intermediate 14 first step of Preparation is replaced with compound (Int-28-a) [3.2.1] octane, in method similar described in intermediate Preparation 14, synthesis obtain title compound (190mg, yield: 85.3%).

MS m/z(ESI):214.1[M+H]⁺。

The preparation of intermediate Preparation 29:1- (5- aminopyridine -2- base) -4- methyl piperidine -4- alcohol (Int-29)

The fluoro- 2- methoxyl group -4- nitrobenzene of 1- in intermediate 6 first step of Preparation is replaced with compound (Int-3-a), is used Compound (Int-29-a) replaces the piperazine -1- t-butyl formate in intermediate 6 first step of Preparation, with intermediate Preparation 6 The similar method, synthesis obtain title compound (170mg, yield: 83.2%).

MS m/z(ESI):208.2[M+H]⁺。

Intermediate Preparation 30:6- (3- oxa- -8- azabicyclo [3.2.1] octyl- 8- yl) pyridine -3- amine (Int-30) Preparation

8- oxa- -3- the azabicyclo in intermediate 14 first step of Preparation is replaced with compound (Int-24-a) [3.2.1] octane, in method similar described in intermediate Preparation 14, synthesis obtain title compound (190mg, yield: 85.3%).

MS m/z(ESI):206.2[M+H]⁺。

Intermediate Preparation 31:(R) -6- (2- methyl morpholine generation) pyridine -3- amine (Int-31) preparation

The fluoro- 2- methoxyl group -4- nitrobenzene of 1- in intermediate 6 first step of Preparation is replaced with compound (Int-3-a), is used Compound (Int-31-a) replaces the piperazine -1- t-butyl formate in intermediate 6 first step of Preparation, with intermediate Preparation 6 The similar method, synthesis obtain title compound (120mg, yield: 86.2%).

MS m/z(ESI):194.2[M+H]⁺。

Intermediate Preparation 32 and intermediate Preparation 33:2- (2- fluoro ethyl) -4,4- dimethyl -1,2,3,4- tetrahydro are different Quinoline -7- amine (Int-32) and 2- (2- fluoro ethyl) -4,4- dimethyl -1,2,3,4- tetrahydroisoquinoline -6- amine (Int-33) Preparation

Step 1: -3 (2H) -one of 4,4- dimethyl -6- nitro -1,4- dihydro-isoquinoline and 4,4- dimethyl -7- nitro - The preparation of 1,4- dihydro-isoquinoline -3 (2H) -one (Int-32-b)

By compound (Int-32-a) (1g, 5.71mmol, using Journal of the American Chemical Society, 2018,140 (21), the method recorded in 6668-6684 are prepared) it is dissolved in the concentrated sulfuric acid (14mL), ice bath is cold But it is slowly added to down potassium nitrate (0.69g, 6.85mmol), keeps ice bath and stirs 1 hour.Reaction solution is poured into ice water, mistake Filter, is dried to obtain title compound (0.9g, the yield: 72%) of this step.

MS m/z(ESI):221.1[M+H]⁺。

Step 2: 4,4- dimethyl -6- nitro -1,2,3,4- tetrahydroisoquinoline and nitro -1,2,3 4,4- dimethyl -7-, The preparation of 4- tetrahydroisoquinoline (Int-32-c)

Compound (Int-32-b) (0.9g, 4.09mmol) is dissolved in anhydrous tetrahydro furan (15mL), boron is slowly added dropwise Alkane dimethyl sulphide solution (2M, 6.1mL, 12.3mmol) then flows back 4 hours for 70 DEG C.Reaction solution is cooled to room temperature, 5N is added Hydrochloric acid is adjusted to highly acid, flows back 1 hour, concentrated solvent.Reaction solution is neutralized with saturated potassium carbonate, is extracted with ethyl acetate, it will Organic layer uses saturated common salt water washing after merging, and is dried, filtered with anhydrous sodium sulfate, and concentration filtrate obtains the title compound of this step Object (720mg, yield: 85.7%).

MS m/z(ESI):207.1[M+H]⁺。

Step 3: 2- (2- fluoro ethyl) -4,4- dimethyl -6- nitro -1,2,3,4- tetrahydroisoquinoline and 2- (2- fluorine second Base) -4,4- dimethyl -7- nitro -1,2,3,4- tetrahydroisoquinoline (Int-32-d) preparation

Compound (Int-32-c) (0.7g, 3.39mmol) is dissolved in acetonitrile (10mL), fluorine bromine second is then sequentially added Alkane (0.47g, 3.72mmol), potassium carbonate (0.7g, 5.08mmol) and potassium iodide (56mg, 0.34mmol), it is small to be stirred at room temperature 20 When.Water dilution is added into reaction solution, is extracted with ethyl acetate, is dried, filtered after organic phase is merged with anhydrous sodium sulfate, it is dense Contracting filtrate obtains title compound (0.7g, the yield: 81.7%) of this step.

MS m/z(ESI):253.2[M+H]⁺。

Step 4: 2- (2- fluoro ethyl) -4,4- dimethyl -1,2,3,4- tetrahydroisoquinoline -7- amine (Int-32) and 2- (2- Fluoro ethyl) -4,4- dimethyl -1,2,3,4- tetrahydroisoquinoline -6- amine (Int-33) preparation

Compound (Int-32-d) (0.7g, 2.78mmol) is dissolved in methanol (15mL), Raney Ni and hydrazine hydrate is added (0.45g, 13.9mmol) is stirred at room temperature 2 hours.Reaction solution is filtered by Celite pad, filtrate is concentrated, with water and acetic acid second Ester extraction merges organic phase and is dried, filtered with saturated common salt water washing with anhydrous sodium sulfate, and concentration filtrate obtains crude product, so Afterwards through preparation chromatographic isolation obtain title compound Int-32 (140mg, yield: 22.7%) and Int-33 (160mg, yield: 25.9%)

MS m/z(ESI):223.2[M+H]⁺。

Intermediate Preparation 34:2- (2- methoxy ethyl) -4,4- dimethyl -1,2,3,4- tetrahydroisoquinoline -7- amine (Int-34) preparation

The fluorine bromoethane in intermediate 32 third step of Preparation is replaced with bromo-ethyl-methyl ether, with intermediate 32 institute of Preparation Similar method is stated, synthesis obtains title compound (120mg, yield: 21.2%).

MS m/z(ESI):235.2[M+H]⁺。

Intermediate Preparation 35:3- methoxyl group -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) aniline (Int-35) Preparation

The fluoro- 2- methoxyl group -4- nitrobenzene of 1- in intermediate 6 first step of Preparation is replaced with compound (Int-35-a), Piperazine -1- the t-butyl formate in intermediate 6 first step of Preparation is replaced with compound (Int-35-b), with intermediate Preparation The 6 similar methods, synthesis obtain title compound (170mg, yield: 74.2%).

MS m/z(ESI):305.3[M+H]⁺。

The preparation of intermediate Preparation 36:1- (tetrahydro -2H- pyrans -4- base) -1H- pyrazoles -4- amine (Int-36)

The Iso-Propyl iodide in intermediate 12 first step of Preparation is replaced with compound (Int-36-a), is prepared with intermediate Similar method described in example 12, synthesis obtain title compound (230mg, yield: 77.6%).

MS m/z(ESI):168.2[M+H]⁺。

The preparation of intermediate Preparation 37:6- (4- methylpiperazine-1-yl) pyridine -3- amine (Int-37)

8- oxa- -3- the azabicyclo in intermediate 14 first step of Preparation is replaced with compound (Int-37-a) [3.2.1] octane, in method similar described in intermediate Preparation 14, synthesis obtain title compound (190mg, yield: 85.3%).

MS m/z(ESI):193.2[M+H]⁺。

The preparation of intermediate Preparation 38:1- (2,2,2- trifluoroethyl) -1H- pyrazoles -4- amine (Int-38)

The Iso-Propyl iodide in intermediate 12 first step of Preparation is replaced with compound (Int-38-a), is prepared with intermediate Similar method described in example 12, synthesis obtain title compound (210mg, yield: 81.1%).

MS m/z(ESI):166.1[M+H]⁺。

The preparation of intermediate Preparation 39:6- (4- (dimethylamino) piperidin-1-yl) pyridine -3- amine (Int-39)

8- oxa- -3- the azabicyclo in intermediate 14 first step of Preparation is replaced with compound (Int-39-a) [3.2.1] octane, in method similar described in intermediate Preparation 14, synthesis obtain title compound (130mg, yield: 72.3%).

MS m/z(ESI):221.3[M+H]⁺。

The preparation of the fluoro- 4- morpholino aniline (Int-40) of intermediate Preparation 40:3,5- bis-

The fluoro- 2- methoxyl group -4- nitrobenzene of 1- in intermediate 6 first step of Preparation is replaced with compound (Int-40-a), With morpholino for the piperazine -1- t-butyl formate in intermediate 6 first step of Preparation, with similar described in intermediate Preparation 6 Method, synthesis obtain title compound (180mg, yield: 79.4%).

MS m/z(ESI):215.1[M+H]⁺。

The preparation of the intermediate fluoro- 4- morpholino aniline (Int-41) of Preparation 41:3-

The fluoro- 2- methoxyl group -4- nitrobenzene of 1- in intermediate 6 first step of Preparation is replaced with compound (Int-41-a), With morpholino for the piperazine -1- t-butyl formate in intermediate 6 first step of Preparation, with similar described in intermediate Preparation 6 Method, synthesis obtain title compound (220mg, yield: 83.3%).

MS m/z(ESI):197.2[M+H]⁺。

The preparation of intermediate Preparation 42:4- ((2S, 6R) -2,6- thebaine generation) aniline (Int-42)

The fluoro- 2- methoxyl group -4- nitrobenzene of 1- in intermediate 6 first step of Preparation is replaced with compound (Int-3-a), is used Compound (Int-42-a) replaces the piperazine -1- t-butyl formate in intermediate 6 first step of Preparation, with intermediate Preparation 6 The similar method, synthesis obtain title compound (150mg, yield: 86.5%).

MS m/z(ESI):207.2[M+H]⁺。

The preparation of intermediate Preparation 43:1- (4- aminophenyl) -4- methyl piperidine -4- alcohol (Int-43)

The fluoro- 2- methoxyl group -4- nitrobenzene of 1- in intermediate 6 first step of Preparation is replaced with compound (Int-3-a), is used Compound (Int-29-a) replaces the piperazine -1- t-butyl formate in intermediate 6 first step of Preparation, with intermediate Preparation 6 The similar method, synthesis obtain title compound (240mg, yield: 78.5%).

MS m/z(ESI):207.1[M+H]⁺。

The preparation of intermediate Preparation 44:6- ((2S, 6R) -2,6- thebaine generation) pyridine -3- amine (Int-44)

8- oxa- -3- the azabicyclo in intermediate 14 first step of Preparation is replaced with compound (Int-42-a) [3.2.1] octane, in method similar described in intermediate Preparation 14, synthesis obtain title compound (130mg, yield: 72.3%).

MS m/z(ESI):208.1[M+H]⁺。

Intermediate Preparation 45:6- ((1S, 4S) -2- oxa- -5- azabicyclo [2.2.1] hept- 5- yl) pyridine -3- amine (Int-45) preparation

8- oxa- -3- the azabicyclo in intermediate 14 first step of Preparation is replaced with compound (Int-45-a) [3.2.1] octane, in method similar described in intermediate Preparation 14, synthesis obtain title compound (140mg, yield: 81.3%).

MS m/z(ESI):192.2[M+H]⁺。

Intermediate Preparation 46:6- ((1R, 4R) -2- oxa- -5- azabicyclo [2.2.1] hept- 5- yl) pyridine -3- amine (Int-46) preparation

8- oxa- -3- the azabicyclo in intermediate 14 first step of Preparation is replaced with compound (Int-46-a) [3.2.1] octane, in method similar described in intermediate Preparation 14, synthesis obtain title compound (120mg, yield: 84.3%).

MS m/z(ESI):192.1[M+H]⁺。

Intermediate Preparation 47:(S) -6- (2- methyl morpholine generation) pyridine -3- amine (Int-47) preparation

8- oxa- -3- the azabicyclo in intermediate 14 first step of Preparation is replaced with compound (Int-47-a) [3.2.1] octane, in method similar described in intermediate Preparation 14, synthesis obtain title compound (130mg, yield: 80.7%).

MS m/z(ESI):194.1[M+H]⁺。

The preparation of intermediate Preparation 48:6- ((tetrahydro -2H- pyrans -4- base) oxygroup) pyridine -3- amine (Int-48)

Step 1: the preparation of 5- nitro -2- ((tetrahydro -2H- pyrans -4- base) oxygroup) pyridine (Int-48-b)

Compound (Int-48-a) (300mg, 1.339mmol) is dissolved in anhydrous THF (10mL), is cooled to 0 DEG C, is added Sodium hydride (59mg, 1.473mmol, content 60%) then stirs 30 minutes at 0 DEG C, by 2- chloro-5-nitropyridine (210mg, 1.339mmol) is added in reaction system, is stirred overnight at room temperature.Reaction solution is cooled down in falling back, with acetic acid second Ester extraction.Organic layer is merged, is dried, filtered with anhydrous sodium sulfate, concentration filtrate obtains crude product, pure by preparative thin layer chromatography Change (eluant, eluent: petrol ether/ethyl acetate=2/1), obtains title compound (180mg, the yield: 60.2%) of this step.

MS m/z(ESI):225.0[M+H]⁺。

Step 2: the preparation of 6- ((tetrahydro -2H- pyrans -4- base) oxygroup) pyridine -3- amine (Int-48)

In method similar described in intermediate 14 second step of Preparation, synthesis obtain title compound (140mg, yield: 90.3%).

MS m/z(ESI):195.1[M+H]⁺。

The preparation of intermediate Preparation 49:1- cyclopenta -1H- pyrazoles -4- amine (Int-49)

The Iso-Propyl iodide in intermediate 12 first step of Preparation is replaced with compound (Int-49-a), is prepared with intermediate Similar method described in example 12, synthesis obtain title compound (180mg, yield: 83.1%).

MS m/z(ESI):152.1[M+H]⁺。

The preparation of intermediate Preparation 50:1- cyclohexyl -1H- pyrazoles -4- amine (Int-50)

The Iso-Propyl iodide in intermediate 12 first step of Preparation is replaced with compound (Int-50-a), is prepared with intermediate Similar method described in example 12, synthesis obtain title compound (170mg, yield: 78.1%).

MS m/z(ESI):166.2[M+H]⁺。

Intermediate Preparation 51:((6- (fluoro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of the chloro- 5- of 2-) pyridine -2- base) it is sub- Amino) diethyl-λ⁶The preparation of sulfane ketone (Int-51)

The dimethyl sulfenimide in intermediate 10 first step of Preparation is replaced with compound (Int-51-a), uses chemical combination Object (Int-2-a) replaces chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine of 2- in intermediate 10 second step of Preparation, is prepared with intermediate Similar method described in example 10, synthesis obtain title compound (130mg, yield: 52.3%).

MS m/z(ESI):368.1[M+H]⁺。

Compound prepares embodiment

Embodiment 1:2- (6- (2- ((2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- base) amino) -7H- pyrroles And [2,3-d] pyrimidin-7-yl) pyridine -2- base) propan-2-ol (compound 1) preparation

Compound (Int-1) (50mg, 0.17mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (5mL), sequentially adds compound (Int-8)(40mg,0.21mmol)、Pd₂(dba)₃(8mg, 0.009mmol), 1,1 '-dinaphthalenes -2,2 '-bis- diphenylphosphines (6mg, 0.009mmol) and cesium carbonate (169mg, 0.52mmol), 95 DEG C are heated under nitrogen protection to react 4 hours.Reaction solution is dense Contracting, residue is purified by preparative high-performance liquid chromatographic instrument, obtains title compound (8mg, yield: 9.9%).

MS m/z(ESI):443.3[M+H]⁺。

¹H-NMR(400MHz,CDCl₃) δ: 8.64-8.61 (m, 2H), 8.00 (d, J=4.0Hz, 1H), 7.84 (t, J= 8.0Hz, 1H), 7.48 (s, 1H), 7.31-7.28 (m, 1H), 7.23 (t, J=8.0Hz, 2H), 7.09 (s, 1H), 6.52 (d, J =4.0Hz, 1H), 4.27 (s, 1H), 3.59 (s, 2H), 2.44 (s, 5H), 1.54 (s, 6H), 1.29 (s, 6H).

Embodiment 2:2- (6- (2- ((4- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) the fluoro- 7H- pyrroles of -5- And [2,3-d] pyrimidin-7-yl) pyridine -2- base) propan-2-ol (compound 2) preparation

By compound (Int-2) (100mg, 0.33mmol) and 1- (4- aminophenyl)-N, N- lupetidine -4- amine (71mg, 0.33mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (5mL), sequentially adds Pd₂(dba)₃(15mg,0.02mmol)、1,1’- Dinaphthalene -2,2 '-bis- diphenylphosphines (13mg, 0.02mmol) and cesium carbonate (200mg, 0.66mmol), then with nitrogen displacement three It is secondary, it reacts 3 hours at 110 DEG C under nitrogen protection.Diatomite filtering and collecting filter liquid, it is after concentration that residue is efficient by preparation Liquid chromatograph purifying, obtains title compound (2mg, yield: 1.2%).

MS m/z(ESI):490.3[M+H]⁺。

¹H-NMR(400MHz,CDCl₃) δ: 8.63-8.56 (m, 2H), 7.78-7.71 (m, 2H), 7.46 (d, J=8.4Hz, 2H), 7.07 (s, 1H), 6.91 (d, J=8.8Hz, 2H), 3.64 (d, J=12.0Hz, 2H), 2.66 (t, J=12.0Hz, 2H), 2.34 (s, 7H), 1.95 (d, J=11.6Hz, 2H), 1.68-1.65 (m, 2H), 1.53 (s, 6H).

((2- ((4- (4- isopropyl piperazine -1- base) phenyl) amino) -7H- pyrrolo- [2,3-d] is phonetic by 6- by embodiment 3:2- Pyridine -7- base) pyridine -2- base) propan-2-ol (compound 3) preparation

The compound (Int-8) in embodiment 1 is replaced with compound (Int-3), with the side similar with described in embodiment 1 Method, synthesis obtain title compound (4.0mg, yield: 4.7%).

MS m/z(ESI):472.3[M+H]⁺。

¹H-NMR(400MHz,CDCl₃) δ: 8.69 (d, J=7.6Hz, 2H), 8.10 (d, J=3.6Hz, 1H), 7.93 (t, J =7.6Hz, 1H), 7.65 (d, J=8.8Hz, 2H), 7.47 (s, 1H), 7.01 (d, J=8.8Hz, 2H), 6.63 (d, J= 3.6Hz,1H),3.47(s,4H),3.35-3.30(m,1H),3.15(s,4H),1.65(s,6H),1.37-1.30(m,8H)。

Embodiment 4:2- (6- (2- ((4- (1- isopropyl -1,2,3,6- tetrahydropyridine -4- base) phenyl) amino) -7H- pyrrole Cough up simultaneously [2,3-d] pyrimidin-7-yl) pyridine -2- base) propan-2-ol (compound 4) preparation

The compound (Int-8) in embodiment 1 is replaced with compound (Int-4), with the side similar with described in embodiment 1 Method, synthesis obtain title compound (15.0mg, yield: 16%).

MS m/z(ESI):469.3[M+H]⁺。

¹H-NMR(400MHz,CDCl₃) δ: 8.62-8.57 (m, 2H), 8.46 (s, 1H), 8.00 (d, J=3.6Hz, 1H), 7.84 (t, J=7.6Hz, 1H), 7.60 (d, J=8.4Hz, 2H), 7.41 (s, 1H), 7.31-7.24 (m, 3H), 6.52 (s, 1H), 5.94 (s, 1H), 3.54 (s, 2H), 3.31 (d, J=5.2Hz, 1H), 3.07 (s, 2H), 1.55 (s, 6H), 1.26-1.13 (m,6H)。

((2- ((4- (2- (dimethylamino) ethyl) phenyl) amino) -7H- pyrrolo- [2,3-d] is phonetic by 6- by embodiment 5:2- Pyridine -7- base) pyridine -2- base) propan-2-ol (compound 5) preparation

Replace the compound (Int-8) in embodiment 1 with 4- (2- (dimethylamino) ethyl) aniline, with embodiment 1 Described in similar method, synthesis obtains title compound (20.0mg, yield: 23.7%).

MS m/z(ESI):417.2[M+H]⁺。

¹H-NMR(400MHz,CDCl₃) δ: 8.74-8.62 (m, 2H), 8.11 (d, J=3.6Hz, 1H), 7.95 (t, J= 8.0Hz, 1H), 7.69 (d, J=8.4Hz, 2H), 7.38-7.24 (m, 4H), 6.64 (d, J=4.0Hz, 1H), 2.99 (s, 4H), 2.65(s,6H),1.66(s,6H)。

Embodiment 6:2- (6- (2- ((3- (methylol) -4- (4- methylpiperazine-1-yl) phenyl) amino) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) propan-2-ol (compound 6) preparation

The compound (Int-8) in embodiment 1 is replaced with compound (Int-5), with the side similar with described in embodiment 1 Method, synthesis obtain title compound (25.0mg, yield: 29%).

MS m/z(ESI):474.3[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆) δ: 8.62-8.58 (m, 2H), 8.00 (d, J=4.0Hz, 1H), 7.85 (t, J= 8.0Hz, 1H), 7.66 (d, J=2.4Hz, 1H), 7.35-7.33 (m, 1H), 7.25-7.15 (m, 2H), 6.53 (d, J= 2.8Hz, 1H), 4.77 (s, 2H), 2.98 (t, J=4.8Hz, 4H), 2.57-2.50 (m, 4H), 2.32 (s, 3H), 1.54 (s, 6H)。

((2- ((3- methoxyl group -4- (piperazine -1- base) phenyl) amino) -7H- pyrrolo- [2,3-d] is phonetic by 6- by embodiment 7:2- Pyridine -7- base) pyridine -2- base) propan-2-ol (compound 7) preparation

Step 1: 4- (4- ((7- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -7H- pyrrolo- [2,3-d] pyrimidine -2- Base) amino) -2- methoxyphenylpiperazderivatives -1- t-butyl formate (7-a) preparation

The compound (Int-8) in embodiment 1 is replaced with compound (Int-6), with the side similar with described in embodiment 1 Method, synthesis obtain title compound (20.0mg, the yield: 10.3%) of this step.

MS m/z(ESI):560.3[M+H]⁺。

Step 2: ((2- ((3- methoxyl group -4- (piperazine -1- base) phenyl) amino) -7H- pyrrolo- [2,3-d] is phonetic by 6- by 2- Pyridine -7- base) pyridine -2- base) propan-2-ol (7) preparation

Compound (7-a) (20mg, 0.036mmol) is dissolved in Isosorbide-5-Nitrae-dioxane solution (5mL) of 4N hydrogen chloride, It is stirred to react at room temperature 3 hours, title compound (10mg, yield: 53.6%) is obtained after concentration.

MS m/z(ESI):460.2[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆) δ: 10.79 (s, 1H), 9.88 (s, 1H), 9.06 (s, 1H), 8.33 (t, J= 8.8Hz, 1H), 8.02 (t, J=7.6Hz, 1H), 7.68 (d, J=7.6Hz, 2H), 7.48 (s, 1H), 7.32-7.23 (m, 2H), 6.91 (d, J=3.6Hz, 1H), 3.82 (s, 3H), 3.74-3.67 (m, 4H), 3.44-3.41 (m, 4H), 1.51 (s, 6H).

Embodiment 8:2- (6- (2- ((3- (methylol) -4- (piperazine -1- base) phenyl) amino) -7H- pyrrolo- [2,3-d] Pyrimidin-7-yl) pyridine -2- base) propan-2-ol (compound 8) preparation

Step 1: 4- (2- (methylol) -4- ((7- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -7H- pyrrolo- [2, 3-d] pyrimidine -2-base) amino) and phenylpiperazine -1- t-butyl formate (8-a) preparation

The compound (Int-8) in embodiment 1 is replaced with compound (Int-7), with the side similar with described in embodiment 1 Method, synthesis obtain title compound (20.0mg, the yield: 10.3%) of this step.

MS m/z(ESI):560.3[M+H]⁺。

Step 2: 2- (6- (2- ((3- (methylol) -4- (piperazine -1- base) phenyl) amino) -7H- pyrrolo- [2,3-d] Pyrimidin-7-yl) pyridine -2- base) propan-2-ol (8) preparation

Compound (8-a) (20mg, 0.036mmol) is dissolved in Isosorbide-5-Nitrae-dioxane solution (5mL) of 4N hydrogen chloride, It is stirred to react at room temperature 3 hours, title compound (15mg, yield: 80.4%) is obtained after concentration.

MS m/z(ESI):460.2[M+H]⁺。

¹H-NMR(400MHz,CDCl₃) δ: 10.58 (s, 1H), 9.43 (s, 2H), 9.01 (s, 1H), 8.44 (d, J= 8.4Hz, 1H), 8.32 (d, J=3.6Hz, 1H), 8.07 (t, J=8.0Hz, 1H), 7.95 (d, J=2.4Hz, 1H), 7.65 (d, J=7.6Hz, 1H), 7.52-7.50 (m, 1H), 7.15 (d, J=8.4Hz, 1H), 6.88-6.83 (m, 1H), 4.63 (s, 2H), 3.72-3.39 (m, 4H), 3.11 (d, J=4.4Hz, 4H), 1.51 (s, 6H).

Embodiment 9:2- (6- (the fluoro- 2- of 5- ((2 '-methyl -2 ', the 3 '-H- of dihydro -1 ' spiral shells [cyclopropane -1,4 '-isoquinolin] - 7 '-yls) amino) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) propan-2-ol (compound 9) preparation

Replace 1- (4- aminophenyl)-N, N- lupetidine -4- amine in embodiment 2 with compound (Int-9), with Similar method described in embodiment 2, synthesis obtain title compound (10.0mg, yield: 12.7%).

MS m/z(ESI):459.2[M+H]⁺。

¹H-NMR(400MHz,CDCl₃) δ: 8.65 (s, 1H), 8.57 (d, J=8.4Hz, 1H), 7.79-7.73 (m, 2H), 7.48 (s, 1H), 7.24-7.17 (m, 2H), 6.61 (d, J=8.8Hz, 1H), 3.72 (s, 2H), 2.55 (s, 2H), 2.45 (s, 3H),1.54(s,6H)。

Embodiment 10:N- (7- (3- ((dimethylamino) methyl) phenyl) -7H- pyrrolo- [2,3-d] pyrimidine -2-base) - The preparation of 2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- amine (compound 10)

Step 1: 1- (3- (chloro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of 2-) phenyl)-N, N- dimethyl methylamine (10- A) preparation

By chloro- 7H- pyrrolo- [2,3-d] pyrimidine (200mg, 1.33mmol) of 2- and 3- ((dimethylamino) methyl) phenyl Boric acid (561mg, 2.60mmol) is dissolved in methanol (10mL), and copper acetate (787.92mg, 3.91mmol) and pyridine is added (420.47mg, 5.21mmol), 25 DEG C of lower open mouths react 80 hours.Reaction solution is poured into water, is extracted with ethyl acetate, is merged Organic phase is dried, filtered with saturated common salt water washing with anhydrous sodium sulfate.Filtrate is concentrated, by residue by preparing thin layer color Spectrometry purifies (eluant, eluent: petrol ether/ethyl acetate=1/2), obtains title compound (50mg, the yield: 6.0%) of this step.

MS m/z(ESI):287.1[M+H]⁺。

Step 2: N- (7- (3- ((dimethylamino) methyl) phenyl) -7H- pyrrolo- [2,3-d] pyrimidine -2-base) -2, The preparation of 4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- amine (10)

1,4- is added in compound (Int-8) (33.2mg, 0.17mmol) and compound (10-a) (50mg, 0.17mmol) In dioxane (5mL), 1,1 '-dinaphthalene -2,2 '-bis- diphenylphosphines (10.8mg, 0.017mmol), carbonic acid are then sequentially added Caesium (56.8mg, 0.17mmol) and Pd₂(dba)₃(10.0mg, 0.017mmol), then nitrogen displacement three times, is warming up to 110 DEG C Reaction 3 hours.Reaction solution is cooling, it is then filtered by Celite pad, filtrate is concentrated, residue is passed through into preparation efficient liquid phase Chromatography purifying, obtains title compound (13mg, yield: 16.9%).

MS m/z(ESI):441.3[M+H]⁺。

¹H-NMR(400MHz,CDCl₃)δ:8.73(s,1H),7.86-7.84(m,1H),7.72(s,1H),7.56-7.48 (m, 3H), 7.38-7.21 (m, 4H), 6.60 (d, J=3.6Hz, 1H), 3.60 (s, 2H), 3.56 (s, 2H), 2.67 (s, 3H), 2.43(s,2H),2.35(s,6H),1.34(s,6H)。

Embodiment 11:N, N- dimethyl -3- (2- ((2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- base) ammonia Base) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) benzamide (compound 11) preparation

Step 1: 3- (chloro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of 2-)-N, N- dimethyl benzamide (11-a) Preparation

With N, N- dimethyl -3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- base) benzamide generation For 3- ((dimethylamino) methyl) phenylboric acid in 10 first step of embodiment, with similar with described in 10 first step of embodiment Method, synthesis obtain title compound (100mg, yield: 20.4%).

MS m/z(ESI):301.1[M+H]⁺。

Step 2: N, N- dimethyl -3- (2- ((2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- base) amino) - 7H- pyrrolo- [2,3-d] pyrimidin-7-yl) benzamide (11) preparation

Replace the compound (10-a) in 10 second step of embodiment with compound (11-a), with in 10 second step of embodiment The similar method, synthesis obtain title compound (18mg, yield: 22.8%).

MS m/z(ESI):455.2[M+H]⁺。

¹H-NMR(400MHz,CDCl₃) δ: 8.70 (s, 1H), 7.99 (d, J=7.6Hz, 1H), 7.75 (s, 1H), 7.59 (t, J=8.0Hz, 1H), 7.44-7.39 (m, 3H), 7.28-7.23 (m, 1H), 7.12 (s, 1H), 6.59 (d, J=3.6Hz, 1H),3.62(s,2H),3.15(s,3H),3.03(s,3H),2.51(s,5H),1.34(s,6H)。

Embodiment 12:((6- (2- ((2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- base) amino) -7H- pyrroles And [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 12)

Replace the compound (10-a) in 10 second step of embodiment with compound (Int-10), with 10 second step of embodiment Described in similar method, synthesis obtains title compound (3mg, yield: 5.7%).

MS m/z(ESI):476.2[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆) δ: 9.46 (s, 1H), 8.78 (s, 1H), 8.12 (d, J=8.0Hz, 1H), 7.92 (d, J=3.6Hz, 1H), 7.76 (t, J=8.0Hz, 1H), 7.67 (s, 1H), 7.42 (d, J=8.0Hz, 1H), 7.25 (d, J= 8.0Hz, 1H), 6.69 (d, J=3.6Hz, 1H), 6.61 (d, J=8.0Hz, 1H), 3.46 (s, 2H), 3.43 (s, 6H), 2.34 (s,5H),1.24(s,6H)。

Embodiment 13:6 '-(2- ((2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- base) amino) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) -2H- [1,2 '-bipyridyl] -2- ketone (compound 13) preparation

Step 1: the preparation of 6 '-bromo- 2H- [1,2 '-bipyridyl] -2- ketone (13-b)

By 2,6- dibromo pyridine (236mg, 1.00mmol), pyridine -2 (1H) -one (95mg, 1.00mmol) and potassium carbonate (207mg, 1.50mmol) is sequentially added in N-Methyl pyrrolidone (5mL), is warming up to 120 DEG C and is reacted 24 hours.By reaction solution Cooling is extracted with ethyl acetate in falling back, organic phase is merged, dried, filtered with anhydrous sodium sulfate, and concentration filtrate obtains slightly Product obtain the title compound of this step with thin layer chromatography (eluant, eluent: petrol ether/ethyl acetate=1/1) is prepared (120mg, yield: 48.0%).

MS m/z(ESI):251.0[M+H]⁺。

Step 2: 6 '-(chloro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of 2-) -2H- [1,2 '-bipyridyl] -2- ketone (13- C) preparation

By compound (13-b) (100mg, 0.40mmol), chloro- 7H- pyrrolo- [2,3-d] pyrimidine of 2- (60mg, 0.40mmol), cuprous iodide (75mg, 0.40mmol), potassium carbonate (82mg, 0.60mmol) and (1S, 2S)-N, N '-dimethyl Hexamethylene -1,2- diamines (56mg, 0.40mmol) sequentially adds in 1,4- dioxane (5mL).After nitrogen is replaced 3 times, nitrogen is kept 100 DEG C are warming up under gas shielded to react 2 hours.Reaction solution is cooled down in falling back, is extracted with ethyl acetate, is harmonious organic And dried, filtered with anhydrous sodium sulfate, filtrate is concentrated to give crude product, with preparing thin layer chromatography (eluant, eluent: acetic acid second Ester), obtain title compound (80mg, the yield: 62.0%) of this step.

MS m/z(ESI):324.1[M+H]⁺。

Step 3: 6 '-(2- ((2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- base) amino) -7H- pyrrolo-es [2,3-d] pyrimidin-7-yl) -2H- [1,2 '-bipyridyl] -2- ketone (13) preparation

Replace the compound (10-a) in 10 second step of embodiment with compound (13-c), with in 10 second step of embodiment The similar method, synthesis obtain title compound (8mg, yield: 6.7%).

MS m/z(ESI):478.2[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆) δ: 9.55 (s, 1H), 8.81 (s, 1H), 8.77 (d, J=8.0Hz, 1H), 8.21 (t, J=3.6Hz, 1H), 8.09 (d, J=8.0Hz, 1H), 8.03 (d, J=4.0Hz, 1H), 7.76 (d, J=8.0Hz, 1H), 7.61 (s, 1H), 7.56 (t, J=8.0Hz, 1H), 7.48 (d, J=8.0Hz, 1H), 7.28 (d, J=8.0Hz, 1H), 6.71 (d, J=3.6Hz, 1H), 6.55 (d, J=9.2Hz, 1H), 6.41 (t, J=6.4Hz, 1H), 3.48 (s, 2H), 3.43 (s, 6H),2.35(s,5H),1.25(s,6H)。

Embodiment 14:((6- (the fluoro- 2- of 5- ((4- morphlinophenyl) amino) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) Pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 14)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and replaces implementing with 4- morpholino aniline 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is synthesized in the method similar with described in embodiment 2 To title compound (3mg, yield: 3.8%).

MS m/z(ESI):482.2[M+H]⁺。

¹H-NMR(400MHz,CDCl₃) δ: 8.67 (s, 1H), 8.16 (d, J=8.0Hz, 1H), 7.73-7.57 (m, 4H), 7.38 (s, 1H), 6.99 (t, J=7.6Hz, 2H), 6.62 (d, J=7.6Hz, 1H), 3.91 (t, J=4.4Hz, 4H), 3.39 (s,6H),3.17(s,4H)。

Embodiment 15:((6- (2- ((4- morphlinophenyl) amino) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine - 2- yl) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 15)

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with 4- morpholino aniline It is synthesized instead of the compound (Int-8) in 10 second step of embodiment in the method similar with described in 10 second step of embodiment To title compound (20mg, yield: 16.0%).

MS m/z(ESI):464.2[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆) δ: 9.36 (s, 1H), 8.75 (s, 1H), 8.16 (d, J=8.0Hz, 1H), 7.90 (d, J=4.0Hz, 1H), 7.80 (t, J=8.0Hz, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 6.96 (s, 1H), 6.93 (s, 1H), 6.67 (d, J=4.0Hz, 1H), 6.58 (d, J=8.0Hz, 1H), 3.75 (t, J=4.8Hz, 4H), 3.06 (t, J= 4.8Hz,4H)。

Embodiment 16: dimethyl (6- (2- ((2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- base) amino) -7H- Pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) phosphine oxide (compound 16) preparation

Step 1: the preparation of (6- bromopyridine -2- base) dimethyl phosphine (16-a)

Palladium acetate (94.6mg, 0.42mmol) and bis- (diphenylphosphine) propane (174.9mg, 0.42mmol) of 1,3- are dissolved in It in DMF (5ml), is stirred at room temperature 15 minutes, then sequentially adds 2,6- dibromo pyridine (1g, 4.22mmol), dimethyl phosphine The DMF solution (20ml) of (329.5mg, 4.22mmol) and DIPEA (2.72g, 21.11mmol), finish and are warming up to 120 DEG C, instead It answers 5 hours.Reaction solution is concentrated, residue is purified to obtain the title compound of this step by preparative high performance liquid chromatography (210mg, yield: 21.3%).

MS m/z(ESI):234.0[M+H]⁺。

Step 2: (6- (chloro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of 2-) pyridine -2- base) dimethyl phosphine (16- B) preparation

By compound (16-a) (210mg, 897.32 μm of ol), chloro- 7H- pyrrolo- [2,3-d] pyrimidine of 2- (137.80mg, 0.90mmol), potassium carbonate (186.03mg, 1.35mmol) and cuprous iodide (170.89mg, 0.90mmol) are dissolved in 1,4- dioxy In six rings (10mL), (1S, 2S)-N is added, N '-dimethyl hexamethylene -1,2- diamines (191.13mg, 1.35mmol), 100 DEG C anti- It answers 6 hours.Be concentrated after reaction solution is cooled to room temperature, by residue by silica gel column chromatography purifying (eluant, eluent: methylene chloride/ Methanol=13/1), obtain title compound (250mg, the yield: 90.9%) of this step.

MS m/z(ESI):307.0[M+H]⁺。

Step 3: dimethyl (6- (2- ((2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- base) amino) -7H- pyrrole Cough up simultaneously [2,3-d] pyrimidin-7-yl) pyridine -2- base) phosphine oxide (16) preparation

Replace the compound (10-a) in 10 second step of embodiment with compound (16-b), with in 10 second step of embodiment The similar method, synthesis obtain title compound (70mg, yield: 18.7%).

MS m/z(ESI):461.2[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆)δ:9.56(s,1H),8.91(dd,J₁=1.2Hz, J₂=8.4Hz, 1H), 8.81 (s, 1H), 8.23-8.18 (m, 1H), 8.17 (d, J=4.0Hz, 1H), 7.91-7.88 (m, 1H), 7.60 (d, J= 2.0Hz,1H),7.46(dd,J₁=2.0Hz, J₂=8.4Hz, 1H), 7.29 (d, J=8.4Hz, 1H), 6.74 (d, J=4.0Hz, 1H),3.47(s,2H),2.35(s,5H),1.77(s,3H),1.73(s,3H),1.25(s,6H)。

Embodiment 17:2- (6- (the fluoro- 2- of 5- ((2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- base) amino) - 7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) propan-2-ol (compound 17) preparation

Replace 1- (4- aminophenyl)-N, N- lupetidine -4- amine in embodiment 2 with compound (Int-8), with Similar method described in embodiment 2, synthesis obtain title compound (3mg, yield: 3.8%).

MS m/z(ESI):461.2[M+H]⁺。

¹H-NMR(400MHz,CDCl₃) δ: 8.65 (s, 1H), 8.59 (d, J=8.0Hz, 1H), 7.82-7.73 (m, 2H), 7.44(s,1H),7.27-7.22(m,2H),7.15(s,1H),3.56(s,2H),2.42(s,5H),1.54(s,6H),1.28 (s,6H)。

Embodiment 18:4- ((7- (6- ((dimethyl (oxo)-λ⁶Sulfurous alkane (sulfanylidene)) amino) pyridine- 2- yl) -7H- pyrrolo- [2,3-d] pyrimidine -2-base) amino)-N, the preparation of N- dimethyl benzamide (compound 18)

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound (Int- 11) compound (Int-8) in 10 second step of embodiment is replaced, in the method similar with described in 10 second step of embodiment, is closed At obtaining title compound (18mg, yield: 14.7%).

MS m/z(ESI):450.2[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆) δ: 9.85 (s, 1H), 8.86 (s, 1H), 8.13 (d, J=4.0Hz, 1H), 7.97 (d, J=4.0Hz, 1H), 7.89 (d, J=8.0Hz, 2H), 6.82 (t, J=8.0Hz, 1H), 7.41 (d, J=8.0Hz, 2H), 6.75 (d, J=4.0Hz, 1H), 6.61 (d, J=8.0Hz, 1H), 3.44 (s, 6H), 2.99 (s, 6H).

Embodiment 19:4- ((6- (2- ((2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- base) amino) -7H- pyrrole Cough up simultaneously [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) -1,4 λ⁶Thioxane 4- oxide (compound 19) Preparation

Step 1: 4- ((6- bromopyridine -2- base) imino group) -1,4 λ⁶The system of thioxane 4- oxide (19-a) It is standby

By 2,6- dibromo pyridine (400mg, 1.69mmol), -1,4 λ of 4- imino group⁶Thioxane 4- oxide (228mg,1.69mmol)、Pd₂(dba)₃Bis- diphenylphosphine -9,9- the xanthphos of (77mg, 0.077mmol), 4,5- (97mg, 0.169mmol) and cesium carbonate (1.1g, 3.38mmol) sequentially add in 1,4- dioxane (5mL).Nitrogen displacement 3 After secondary, keep being warming up to 80 DEG C of reactions 2 hours under nitrogen protection.Reaction solution is cooled down in falling back, is extracted with ethyl acetate, Organic layer is merged, is dried, filtered with anhydrous sodium sulfate, concentration filtrate obtains crude product, passes through preparative thin layer chromatography purifying (elution Agent: petrol ether/ethyl acetate=1/1), obtain title compound (400mg, the yield: 81%) of this step.

MS m/z(ESI):293.0[M+H]⁺。

Step 2: 4- ((6- (chloro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of 2-) pyridine -2- base) imino group) -1,4 λ⁶- The preparation of thioxane 4- oxide (19-b)

By compound (19-a) (370mg, 1.27mmol), chloro- 7H- pyrrolo- [2,3-d] pyrimidine of 2- (195mg, 1.27mmol), cuprous iodide (242mg, 1.27mmol), potassium carbonate (350mg, 2.54mmol) and (1S, 2S)-N, N '-diformazan Basic ring hex- 1,2- diamines (180mg, 1.27mmol) sequentially adds in 1,4- dioxane (10mL).After nitrogen is replaced 3 times, protect It holds and is warming up to 100 DEG C of reactions 2 hours under nitrogen protection.Reaction solution is cooled down in falling back, is extracted with ethyl acetate, it will be organic Laminated simultaneously to be dried, filtered with anhydrous sodium sulfate, concentration filtrate obtains crude product, purifies (eluant, eluent: second by preparative thin layer chromatography Acetoacetic ester), obtain title compound (200mg, the yield: 43%) of this step.

MS m/z(ESI):364.1[M+H]⁺。

Step 3: 4- ((6- (2- ((2,4,4- trimethyl -1,2,3,4- tetrahydroisoquinoline -7- base) amino) -7H- pyrroles And [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) -1,4 λ⁶The preparation of thioxane 4- oxide (19)

Replace the compound (10-a) in 10 second step of embodiment with compound (19-b), with in 10 second step of embodiment The similar method, synthesis obtain title compound (30mg, yield: 20%).

MS m/z(ESI):518.2[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆) δ: 9.51 (s, 1H), 8.79 (s, 1H), 8.17 (d, J=8.0Hz, 1H), 7.88 (d, J=4.0Hz, 1H), 7.80 (t, J=8.0Hz, 2H), 7.76 (s, 1H), 7.73 (d, J=8.0Hz, 1H), 7.27 (d, J= 8.0Hz,1H),6.73-6.69(m,2H),4.41-4.09(m,2H),3.98-3.94(m,2H),3.84-3.81(m,2H), 3.61-3.56(m,2H),3.46(s,2H),3.32(s,1H),2.34(s,4H),1.25(s,6H)。

Embodiment 20:4- ((7- (6- ((dimethyl (oxo)-λ⁶Sulfurous alkane) amino) pyridine -2- base) -7H- pyrrolo- [2,3-d] pyrimidine -2-base) amino) benzonitrile (compound 20) preparation

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound 4- amino Benzonitrile replaces the compound (Int-8) in 10 second step of embodiment, in the method similar with described in 10 second step of embodiment, Synthesis obtains title compound (8mg, yield: 12%).

MS m/z(ESI):404.1[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆)δ:10.20(s,1H),8.92(s,1H),8.08-8.00(m,4H),7.87(t, J=8.0Hz, 1H), 7.77 (d, J=8.0Hz, 2H), 6.79 (d, J=4.0Hz, 1H), 6.63 (d, J=8.0Hz, 1H), 3.44 (s,6H)。

Embodiment 21:((6- (2- ((1- (1- methyl piperidine -4- base) -1H- pyrazoles -4- base) amino) -7H- pyrrolo- [2, 3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 21)

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound 1- (1- Methyl piperidine -4- base) -1H- pyrazoles -4- amine replaces the compound (Int-8) in 10 second step of embodiment, with embodiment 10 the Similar method described in two steps, synthesis obtain title compound (8mg, yield: 12%).

MS m/z(ESI):466.2[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆)δ:9.40(s,1H),8.74(s,1H),8.06-8.03(m,2H),7.84(d,J =4.0Hz, 1H), 7.77 (t, J=8.0Hz, 1H), 7.53 (s, 1H), 6.67 (d, J=4.0Hz, 1H), 6.61 (d, J= 8.0Hz, 1H), 4.10-4.03 (m, 1H), 3.44 (s, 6H), 2.87 (d, J=12.0Hz, 2H), 2.22 (s, 3H), 2.08- 1.86(m,6H)。

Embodiment 22:((6- (2- ((1- isopropyl -1H- pyrazoles -4- base) amino) -7H- pyrrolo- [2,3-d] pyrimidine -7- Base) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 22)

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound (Int- 12) compound (Int-8) in 10 second step of embodiment is replaced, in the method similar with described in 10 second step of embodiment, is closed At obtaining title compound (14mg, yield: 20.8%).

MS m/z(ESI):411.2[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆)δ:9.40(s,1H),8.74(s,1H),8.07-8.03(m,2H),7.84(d,J =4.0Hz, 1H), 7.80 (t, J=8.0Hz, 1H), 7.51 (s, 1H), 6.67 (d, J=4.0Hz, 1H), 6.61 (d, J= 8.0Hz, 1H), 4.49-4.42 (m, 1H), 3.44 (s, 6H), 1.43 (d, J=8.0Hz, 6H).

Embodiment 23:((6- (2- ((4- (1- methyl-1,2,5,6- tetrahydropyridine -3- base) phenyl) amino) -7H- pyrroles And [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 23)

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound 4- (1- Methyl-1,2,5,6- tetrahydropyridine -3- bases) aniline replace 10 second step of embodiment in compound (Int-8), with embodiment Similar method described in 10 second steps, synthesis obtain title compound (10mg, yield: 12.9%).

MS m/z(ESI):474.2[M+H]⁺。

¹H-NMR(400MHz,CDCl₃) δ: 8.68 (s, 1H), 8.21 (d, J=7.6Hz, 1H), 8.00 (s, 1H), 7.74- 7.67 (m, 3H), 7.34 (s, 1H), 7.32 (s, 1H), 6.70 (d, J=8.0Hz, 1H), 6.54 (d, J=8.0Hz, 1H), 6.14 (s, 1H), 3.48 (s, 2H), 3.40 (s, 6H), 2.77 (t, J=7.2Hz, 2H), 2.60 (s, 3H), 2.50 (s, 2H).

Embodiment 24:((6- (2- ((4- (1- methyl-1,2,3,6- tetrahydropyridine -4- base) phenyl) amino) -7H- pyrroles And [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 24)

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound 4- (1- Methyl-1,2,3,6- tetrahydropyridine -4- bases) aniline replace 10 second step of embodiment in compound (Int-8), with embodiment Similar method described in 10 second steps, synthesis obtain title compound (9mg, yield: 11.6%).

MS m/z(ESI):474.2[M+H]⁺。

¹H-NMR(400MHz,CDCl₃) δ: 8.68 (s, 1H), 8.21 (d, J=7.6Hz, 1H), 8.00 (s, 1H), 7.74- 7.67 (m, 3H), 7.34 (s, 1H), 7.32 (s, 1H), 6.70 (d, J=8.0Hz, 1H), 6.54 (d, J=8.0Hz, 1H), 6.02 (s,1H),3.40(s,6H),3.37(s,2H),2.93(s,2H),2.74(s,2H),2.59(s,3H)。

Embodiment 25:((6- (2- ((6- (4- methylpiperazine-1-yl) pyridin-3-yl) amino) -7H- pyrrolo- [2,3-d] Pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 25)

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with 6- (4- methyl piperazine Piperazine -1- base) pyridine -3- amine replace 10 second step of embodiment in compound (Int-8), with described in 10 second step of embodiment Similar method, synthesis obtain title compound (18mg, yield: 14.7%).

MS m/z(ESI):478.2[M+H]⁺。

Embodiment 26:((6- (2- ((4- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) -7H- pyrrolo- [2, 3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 26)

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with 4- (N, N- diformazan Base amino piperidine base) aniline is instead of the compound (Int-8) in 10 second step of embodiment, with the side similar with described in embodiment 10 Method, synthesis obtain title compound (15mg, yield: 9%).

MS m/z(ESI):505.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.33 (s, 1H), 8.75 (s, 1H), 8.17 (d, J=8Hz, 1H), 7.90 (d, J=4Hz, 1H), 7.79 (t, J=8Hz, 1H), 7.63 (d, J=8.8Hz, 2H), 6.94 (d, J=8.8Hz, 2H), 6.67 (d, J=4Hz, 1H), 6.59 (d, J=8Hz, 1H), 3.63 (d, J=12Hz, 2H), 3.44 (s, 6H), 2.60 (t, J=12Hz, 2H), 2.24 (s, 6H), 1.85 (d, J=12Hz, 2H), 1.55-1.47 (m, 2H).

Embodiment 27:((6- (2- ((1- (2- (dimethylamino) ethyl) -1H- pyrazoles -4- base) amino) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 27)

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound (Int- 15) compound (Int-8) in 10 second step of embodiment is replaced, in the method similar with described in embodiment 10, synthesis is marked Inscribe compound (40mg, yield: 39%).

MS m/z(ESI):440.1[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ: 8.65 (s, 1H), 8.13 (d, J=7.6Hz, 1H), 7.97-7.93 (m, 2H), 7.71 (t, J=8Hz, 1H), 7.62 (s, 1H), 6.94 (s, 1H), 6.68 (d, J=8Hz, 1H), 6.52 (d, J=4Hz, 1H), 4.28 (t, J=6.8Hz, 2H), 3.40 (s, 6H), 2.88 (t, J=6.8Hz, 2H), 2.33 (s, 6H).

Embodiment 28:((6- (2- ((6- (8- oxa- -3- azabicyclo [3.2.1] oct-3-yl) pyridin-3-yl) amino) - 7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 28)

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound (Int- 14) compound (Int-8) in 10 second step of embodiment is replaced, in the method similar with described in embodiment 10, synthesis is marked Inscribe compound (55mg, yield: 15.6%).

MS m/z(ESI):491.2[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆)δ:9.59(s,1H),8.81(s,1H),8.53(s,1H),8.13(brs,1H), 8.06 (d, J=0.8Hz, 1H), 7.95 (d, J=0.4Hz, 1H), 7.79 (t, J=0.8Hz, 1H), 7.08 (brs, 1H), 6.72 (d, J=0.4Hz, 1H), 6.61 (d, J=0.8Hz, 1H), 4.49 (s, 2H), 3.77 (d, J=1.2Hz, 2H), 3.44 (s, 6H),3.09(brs,2H),1.88-1.80(m,4H)。

Embodiment 29:((6- (the fluoro- 2- of 5- ((4- (4- methoxy piperide -1- base) phenyl) amino) -7H- pyrrolo- [2,3- D] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 29)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-16) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (90mg, yield: 36.4%).

MS m/z(ESI):510.2[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆) δ: 9.53 (s, 1H), 8.84 (s, 1H), 8.11 (d, J=0.8Hz, 1H), 7.78 (t, J=0.8Hz, 1H), 7.70 (s, 1H), 7.61 (d, J=1.2Hz, 2H), 6.95 (d, J=0.8Hz, 2H), 6.57 (d, J= 0.8Hz,1H),3.43(s,7H),3.33(s,3H),3.33-3.30(m,2H),2.85-2.79(m,2H),1.97-1.92(m, 2H)1.58-1.51(m,2H)。

Embodiment 30:((6- (2- ((6- (1,1- sulfur dioxide morpholino) pyridin-3-yl) amino) the fluoro- 7H- pyrroles of -5- And [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 30)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-17) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (38mg, yield: 11.1%).

MS m/z(ESI):531.1[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆)δ:9.61(s,1H),8.86(s,1H),8.48(s,1H),8.07-8.04(m, 2H), 7.75-7.72 (m, 2H), 7.08 (d, J=1.2Hz, 1H), 6.58 (d, J=0.8Hz, 1H), 4.04 (s, 4H), 3.43 (s,6H),3.11(s,4H)。

Embodiment 31:((6- (the fluoro- 2- of 5- ((6- (4- (methyl sulphonyl) piperidin-1-yl) pyridin-3-yl) amino) -7H- Pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 31)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-18) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (32mg, yield: 13.3%).

MS m/z(ESI):559.1[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆) δ: 9.53 (s, 1H), 8.84 (s, 1H), 8.42 (s, 1H), 8.04 (d, J= 0.8Hz, 1H), 7.98 (d, J=0.8Hz, 1H), 7.74-7.70 (m, 2H), 6.96 (d, J=1.2Hz, 1H), 6.57 (d, J= 0.8Hz, 1H), 4.41 (d, J=1.2Hz, 2H), 3.43 (s, 6H), 3.39-3.36 (m, 1H), 2.95 (s, 3H), 2.84 (t, J =1.2Hz, 2H) 2.07 (d, J=1.2Hz, 2H), 1.65-1.56 (m, 2H).

Embodiment 32:((6- (the fluoro- 2- of 5- ((the fluoro- 6- morpholino pyridin-3-yl of 5-) amino) -7H- pyrrolo- [2,3-d] Pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 32)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-19) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (58mg, yield: 20.4%).

MS m/z(ESI):501.1[M+H]⁺。

¹H-NMR(400MHz,DMSO-d₆) δ: 9.91 (s, 1H), 8.92 (s, 1H), 8.34 (s, 1H), 8.20 (d, J= 1.2Hz, 1H), 8.00 (d, J=0.8Hz, 1H), 7.75-7.69 (m, 2H), 6.60 (d, J=0.8Hz, 1H), 3.74 (t, J= 0.4Hz, 4H), 3.44 (s, 6H), 3.27 (t, J=0.4Hz, 4H).

Embodiment 33:((6- (2- ((the chloro- 4- morphlinophenyl of 3-) amino) fluoro- 7H- pyrrolo- [2,3-d] pyrimidine-of -5- 7- yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 33)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-20) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (40mg, yield: 17.6%).

MS m/z(ESI):516.1[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.88 (s, 1H), 8.92 (s, 1H), 8.19 (d, J=2.4Hz, 1H), 8.06 (d, J=8.0Hz, 1H), 7.84-7.70 (m, 2H), 7.54 (dd, J=8.8,2.4Hz, 1H), 7.17 (d, J=8.8Hz, 1H), 6.61 (d, J=8.0Hz, 1H), 3.83-3.65 (m, 4H), 3.44 (s, 6H), 3.02-2.88 (m, 4H).

(2- ((4- (2- oxa- -5- azabicyclo [2.2.1] hept- 5- yl) phenyl) amino) -5- is fluoro- by embodiment 34:((6- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 34)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-21) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (45mg, yield: 31.0%).

MS m/z(ESI):494.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.42 (s, 1H), 8.81 (s, 1H), 8.12 (d, J=8.0Hz, 1H), 7.74 (t, J=8.0Hz, 1H), 7.68 (d, J=1.6Hz, 1H), 7.55 (d, J=8.8Hz, 2H), 6.64 (d, J=8.8Hz, 2H), 6.57 (d, J=8.0Hz, 1H), 4.60 (s, 1H), 4.52 (s, 1H), 3.75 (d, J=7.2Hz, 1H), 3.70 (d, J= 7.2Hz, 1H), 3.51 (d, J=9.2Hz, 1H), 3.43 (s, 6H), 2.95 (d, J=9.2Hz, 1H), 2.00-1.90 (m, 1H), 1.89-1.76(m,1H)。

(2- ((4- (8- oxa- -3- azabicyclo [3.2.1] oct-3-yl) phenyl) amino) -5- is fluoro- by embodiment 35:((6- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 35)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-22) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (45mg, yield: 23.2%).

MS m/z(ESI):508.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.42 (s, 1H), 8.81 (s, 1H), 8.12 (d, J=8.0Hz, 1H), 7.74 (t, J=8.0Hz, 1H), 7.68 (d, J=1.6Hz, 1H), 7.55 (d, J=8.8Hz, 2H), 6.64 (d, J=8.8Hz, 2H), 6.57 (d, J=8.0Hz, 1H), 4.60 (s, 1H), 4.52 (s, 1H), 3.75 (d, J=7.2Hz, 1H), 3.70 (d, J= 7.2Hz, 1H), 3.51 (d, J=9.2Hz, 1H), 3.43 (s, 6H), 2.95 (d, J=9.2Hz, 1H), 2.00-1.90 (m, 2H), 1.89-1.76(m,2H)。

Embodiment 36:((6- (the fluoro- 2- of 5- ((5- methyl -6- morpholino pyridin-3-yl) amino) -7H- pyrrolo- [2,3- D] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 36)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-23) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (80mg, yield: 36.5%).

MS m/z(ESI):497.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.73 (s, 1H), 8.88 (s, 1H), 8.35 (d, J=1.6Hz, 1H), 8.14 (s, 1H), 8.03 (d, J=7.8Hz, 1H), 7.75-7.71 (m, 2H), 6.59 (d, J=7.8Hz, 1H), 3.76-3.74 (m, 4H),3.43(s,6H),3.01-2.99(m,4H),2.29(s,3H)。

(2- ((4- (3- oxa- -8- azabicyclo [3.2.1] octyl- 8- yl) phenyl) amino) -5- is fluoro- by embodiment 37:((6- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 37)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-24) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (80mg, yield: 41.2%).

MS m/z(ESI):508.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.49 (s, 1H), 8.84 (s, 1H), 8.13 (d, J=8.0Hz, 1H), 7.77 (t, J=8.0Hz, 1H), 7.71-7.70 (m, 1H), 7.60 (d, J=9.0Hz, 2H), 6.89 (d, J=9.0Hz, 2H), 6.58 (d, J=8.0Hz, 1H), 4.13 (s, 2H), 3.77 (s, 1H), 3.75 (s, 1H), 3.48 (s, 1H), 3.44 (s, 6H), 1.94- 1.87(m,5H)。

Embodiment 38:((6- (the fluoro- 2- of 5- ((5- methoxyl group -6- morpholino pyridin-3-yl) amino) -7H- pyrrolo- [2, 3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 38)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-25) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (35mg, yield: 11.6%).

MS m/z(ESI):513.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.69 (s, 1H), 8.89 (s, 1H), 8.13 (d, J=2.0Hz, 1H), 8.02 (d, J=8.0Hz, 1H), 7.82 (d, J=2.0Hz, 1H), 7.73 (d, J=2.0Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 6.58 (d, J=8.0Hz, 1H), 3.78 (s, 3H), 3.75-3.69 (m, 4H), 3.43 (s, 6H), 3.26-3.16 (m, 4H).

Embodiment 39:((6- (the fluoro- 2- of 5- ((6- (4- (2- hydroxyl propyl- 2- yl) piperidin-1-yl) pyridin-3-yl) amino)- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 39)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-26) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (60mg, yield: 37.9%).

MS m/z(ESI):539.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.47 (s, 1H), 8.83 (s, 1H), 8.37 (d, J=2.4Hz, 1H), 8.05 (d, J=8.0Hz, 1H), 7.93 (dd, J=9.2,2.4Hz, 1H), 7.74-7.70 (m, 2H), 6.87 (d, J=9.2Hz, 1H), 6.57 (d, J=8.0Hz, 1H), 4.33 (s, 1H), 4.30 (s, 1H), 3.46 (s, 1H), 3.43 (s, 6H), 2.63 (t, J= 12.0Hz, 2H), 1.76 (d, J=12.0Hz, 2H), 1.40 (t, J=12.0Hz, 1H), 1.29-1.19 (m, 2H), 1.05 (s, 6H)。

Embodiment 40:1- (5- ((7- (6- ((dimethyl (oxo)-λ⁶Sulfurous alkyl) amino) pyridine -2- base) -5- is fluoro- 7H- pyrrolo- [2,3-d] pyrimidine -2-base) amino) pyridine -2- base) and piperidines -4- formonitrile HCN (compound 40) preparation

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-27) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (50mg, yield: 33.6%).

MS m/z(ESI):494.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.53 (s, 1H), 8.84 (s, 1H), 8.42 (d, J=2.4Hz, 1H), 8.04 (d, J=8.0Hz, 1H), 7.98 (dd, J=9.2,2.4Hz, 1H), 7.73 (d, J=8.0Hz, 1H), 7.71 (s, 1H), 6.93 (d, J=9.2Hz, 1H), 6.57 (d, J=8.0Hz, 1H), 3.78-3.72 (m, 2H), 3.40 (s, 6H), 3.32-3.27 (m, 2H),3.15-3.02(m,1H),2.01-1.89(m,2H),1.83-1.70(m,2H)。

Embodiment 41:((6- (2- ((6- (8- oxa- -3- azabicyclo [3.2.1] oct-3-yl) pyridin-3-yl) amino) - Fluoro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of 5-) pyridine -2- base) imino group) dimethyl-λ⁶Sulfane ketone (compound 41) Preparation

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-14) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (30mg, yield: 20.0%).

MS m/z(ESI):509.6[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.52 (s, 1H), 8.85 (s, 1H), 8.41 (d, J=2.4Hz, 1H), 8.06 (d, J=8.0Hz, 1H), 7.97 (dd, J=9.2,2.4Hz, 1H), 7.75-7.71 (m, 2H), 6.78 (d, J=9.2Hz, 1H), 6.59 (d, J=8.0Hz, 1H), 4.45 (s, 2H), 3.78 (d, J=12.0Hz, 2H), 3.44 (s, 6H), 2.92 (d, J= 12.0,2H),1.86-1.78(m,4H)。

Embodiment 42:((6- (2- ((6- (4,4- difluoropiperdin -1- base) pyridin-3-yl) amino) fluoro- 7H- pyrrolo- of -5- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 42)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-28) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (25mg, yield: 16.4%).

MS m/z(ESI):509.6[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.56 (s, 1H), 8.85 (s, 1H), 8.44 (d, J=2.8Hz, 1H), 8.04 (d, J=8.0Hz, 1H), 8.01 (dd, J=9.2,2.8Hz, 1H), 7.75-7.71 (m, 2H), 7.01 (d, J=9.2Hz, 1H), 6.58 (d, J=8.0Hz, 1H), 3.67-3.64 (m, 4H), 3.43 (s, 6H), 2.05-1.95 (m, 4H).

Embodiment 43:((6- (the fluoro- 2- of 5- ((6- (4- hydroxy-4-methyl piperidin-1-yl) pyridin-3-yl) amino) -7H- Pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 43)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-29) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (70mg, yield: 35.8%).

MS m/z(ESI):511.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.47 (s, 1H), 8.83 (s, 1H), 8.37 (d, J=2.8Hz, 1H), 8.05 (d, J=8.0Hz, 1H), 7.92 (dd, J=9.2,2.8Hz, 1H), 7.73-7.70 (m, 2H), 6.88 (d, J=9.2Hz, 1H), 6.57 (d, J=8.0Hz, 1H), 4.32 (s, 1H), 3.75 (t, J=4.4Hz, 1H), 3.71 (t, J=4.4Hz, 1H), 3.43 (s,6H),3.32-3.28(m,2H),1.54-1.46(m,4H),1.15(s,3H)。

Embodiment 44:((6- (2- ((6- (3- oxa- -8- azabicyclo [3.2.1] octyl- 8- yl) pyridin-3-yl) amino) - Fluoro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of 5-) pyridine -2- base) imino group) dimethyl-λ⁶Sulfane ketone (compound 44) Preparation

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-30) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (15mg, yield: 6.7%).

MS m/z(ESI):509.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.51 (s, 1H), 8.84 (s, 1H), 8.40 (d, J=2.8Hz, 2H), 8.04 (d, J=8.0Hz, 1H), 7.96 (dd, J=9.0,2.8Hz, 1H), 7.72-7.68 (m, 2H), 6.88 (d, J=9.0Hz, 1H), 4.42 (s, 2H), 3.69 (d, J=10.8Hz, 2H), 3.52 (d, J=10.8Hz, 2H), 3.43 (s, 6H), 1.95-1.83 (m, 4H)。

Embodiment 45:(R)-((6- (the fluoro- 2- of 5- ((6- (2- methyl morpholine generation) pyridin-3-yl) amino) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 45)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-31) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (60mg, yield: 27.3%).

MS m/z(ESI):494.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.54 (s, 1H), 8.84 (s, 1H), 8.43 (d, J=2.8Hz, 1H), 8.04 (d, J=8.0Hz, 1H), 8.01 (dd, J=9.2,2.8Hz, 1H), 7.75-7.71 (m, 2H), 6.89 (d, J=9.2Hz, 1H), 6.58 (d, J=8.0Hz, 1H), 4.06 (d, J=12.4Hz, 1H), 3.97-3.90 (m, 2H), 3.61-3.58 (m, 2H), 3.43 (s, 6H), 2.75 (td, J=12.4,3.2Hz, 1H), 2.42 (dd, J=12.4,10.4Hz, 1H), 1.17 (d, J=6.0Hz, 3H)。

Embodiment 46:((6- (the fluoro- 2- of 5- ((3- methyl-isothiazol -5- base) amino) -7H- pyrrolo- [2,3-d] pyrimidine - 7- yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 46)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and with 3- methyl-isothiazol -5- amine generation For 1- (4- aminophenyl)-N, N- lupetidine -4- amine in embodiment 2, in the method similar with described in embodiment 2, Synthesis obtains title compound (50mg, yield: 20.4%).

MS m/z(ESI):417.1[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 11.55 (s, 1H), 9.07 (s, 1H), 8.07 (d, J=7.6Hz, 1H), 7.83 (s, 2H), 6.72 (s, 1H), 6.64 (d, J=7.6Hz, 1H), 3.44 (s, 6H), 2.31 (s, 3H).

Embodiment 47:((6- (2- ((1,3- dihydroisobenzofuran -5- base) amino) fluoro- 7H- pyrrolo- [2,3-d] of -5- Pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 47)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and with 1,3- dihydroisobenzofuran- 5- amine replaces 1- (4- aminophenyl)-N, N- lupetidine -4- amine in embodiment 2, with similar with described in embodiment 2 Method, synthesis obtain title compound (65mg, yield: 50.4%).

MS m/z(ESI):494.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.86 (s, 1H), 8.90 (s, 1H), 8.06 (d, J=8.0Hz, 1H), 7.92 (s, 1H), 7.79-7.74 (m, 2H), 7.57 (d, J=8.0Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 6.59 (d, J= 8.0Hz,1H),5.03(s,2H),4.99(s,2H),3.44(s,6H)。

Embodiment 48:((6- (2- ((2- (2- fluoro ethyl) -4,4- dimethyl -1,2,3,4- tetrahydroisoquinoline -7- base) ammonia Base) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The system of sulfane ketone (compound 48) It is standby

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound (Int- 32) compound (Int-8) in 10 second step of embodiment is replaced, in the method similar with described in embodiment 10, synthesis is marked Inscribe compound (10mg, yield: 12.04%).

MS m/z(ESI):508.2[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ: 8.65 (s, 1H), 8.19 (s, 1H), 7.98 (d, J=3.6Hz, 1H), 7.71 (s, 2H), 7.43-7.15 (m, 2H), 6.69 (d, J=8.0Hz, 1H), 6.53 (d, J=3.6Hz, 1H), 4.80-4.65 (m, 2H),3.79(s,2H),3.40(s,6H),2.96-2.90(m,2H),2.60(s,2H),1.34(s,6H)。

Embodiment 49:((6- (2- ((2- (2- fluoro ethyl) -4,4- dimethyl -1,2,3,4- tetrahydroisoquinoline -6- base) ammonia Base) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The system of sulfane ketone (compound 49) It is standby

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound (Int- 33) compound (Int-8) in 10 second step of embodiment is replaced, in the method similar with described in embodiment 10, synthesis is marked Inscribe compound (9mg, yield: 11.41%).

MS m/z(ESI):508.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.44 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.93 (d, J= 4.0Hz, 1H), 7.76-7.72 (m, 3H), 7.53 (d, J=7.9Hz, 1H), 6.95 (d, J=8.0Hz, 1H), 6.65 (d, J= 3.6,1H),4.68-4.57(m,2H),3.59(s,2H),3.43(s,6H),2.73(s,2H),2.47(s,2H),1.25(s, 6H)。

Embodiment 50:((6- (2- ((2- (2- methoxy ethyl) -4,4- dimethyl -1,2,3,4- tetrahydroisoquinoline -7- Base) amino) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶Sulfane ketone (compound 50) preparation

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound (Int- 34) compound (Int-8) in 10 second step of embodiment is replaced, in the method similar with described in embodiment 10, synthesis is marked Inscribe compound (23mg, yield: 28.5%).

MS m/z(ESI):520.3[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.49 (s, 1H), 8.79 (s, 1H), 8.14 (d, J=7.6Hz, 1H), 7.92 (d, J=4.0Hz, 1H), 7.85-7.65 (m, 2H), 7.71-7.70 (m, 1H), 7.25 (d, J=7.6Hz, 1H), 6.70-6.61 (m, 2H), 3.60-3.54 (m, 4H), 3.44 (s, 6H), 3.29 (s, 3H), 2.65 (t, J=5.6Hz, 2H), 2.44 (s, 2H), 1.24(s,6H)。

Embodiment 51:((6- (2- ((3- methoxyl group -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) ammonia Base) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The system of sulfane ketone (compound 51) It is standby

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound (Int- 35) compound (Int-8) in 10 second step of embodiment is replaced, in the method similar with described in embodiment 10, synthesis is marked Inscribe compound (14mg, yield: 14.5%).

MS m/z(ESI):590.3[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ: 8.66 (s, 1H), 8.19 (d, J=8.0Hz, 1H), 7.97 (d, J=4.0Hz, 1H), 7.65 (s, 1H), 7.43 (d, J=2.0Hz, 1H), 7.14 (s, 1H), 7.15-7.03 (m, 1H), 6.92 (d, J= 8.8Hz, 1H), 6.67 (d, J=8.0Hz, 1H), 6.54 (s, 1H), 3.85 (s, 3H), 3.52 (d, J=11.6Hz, 2H), 3.40 (s,5H),2.82(s,11H),2.38(s,3H),2.06-1.76(m,4H)。

Embodiment 52: dimethyl ((6- (2- ((4- (1- methyl-1,2,3,6- tetrahydropyridine -4- base) phenyl) amino) - 7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group)-λ⁶The preparation of sulfane ketone (compound 52)

Replace the compound (10-a) in 10 second step of embodiment with compound (Int-10), and with 4- (1- methyl-1, 2,3,6- tetrahydropyridine -4- bases) aniline replace 10 second step of embodiment in compound (Int-8), with described in embodiment 10 Similar method, synthesis obtain title compound (25mg, yield: 32.8%).

MS m/z(ESI):474.2[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ: 8.72 (s, 1H), 8.18 (d, J=8.0Hz, 1H), 7.77-7.61 (m, 4H), 7.40 (d, J=8.8Hz, 2H), 7.34 (s, 1H), 6.66 (d, J=8.0Hz, 1H), 6.04 (d, J=3.6Hz, 1H), 3.38 (s, 6H), 3.21 (d, J=2.8Hz, 2H), 2.77 (t, J=5.2Hz, 2H), 2.65 (d, J=1.6Hz, 2H), 2.47 (s, 3H)。

Embodiment 53: dimethyl ((6- (2- ((1- (tetrahydro -2H- pyrans -4- base) -1H- pyrazoles -4- base) amino) -7H- Pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group)-λ⁶The preparation of sulfane ketone (compound 53)

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound (Int- 36) compound (Int-8) in 10 second step of embodiment is replaced, in the method similar with described in embodiment 10, synthesis is marked Inscribe compound (72mg, yield: 33.1%).

MS m/z(ESI):453.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆)δ:9.42(s,1H),8.74(s,1H),8.22-7.94(m,2H),7.95- 7.69(m,2H),7.55(s,1H),6.67-6.61(m,2H),4.47-4.24(m,1H),3.99-3.96(m,4H),3.57- 3.39(m,8H),2.09-1.79(m,2H)。

Embodiment 54:((6- (the fluoro- 2- of 5- ((4- (1- methyl-1,2,5,6- tetrahydropyridine -3- base) phenyl) amino) -7H- Pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 54)

Replace compound (Int-2) in embodiment 2 with compound (Int-13), and with 4- (1- methyl-1,2,5,6- tetra- Pyridinium hydroxide -3- base) aniline replace embodiment 2 in 1- (4- aminophenyl)-N, N- lupetidine -4- amine, with embodiment 2 Described in similar method, synthesis obtains title compound (24mg, yield: 33.1%).

MS m/z(ESI):492.6[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ: 8.72 (s, 1H), 8.18 (d, J=8.0Hz, 1H), 7.79-7.60 (m, 4H), 7.42-7.31 (m, 2H), 6.67 (d, J=7.6Hz, 1H), 6.19-6.05 (m, 1H), 3.38 (s, 8H), 2.68 (t, J= 5.6Hz, 2H), 2.54 (s, 3H), 2.45 (d, J=3.6Hz, 2H).

Embodiment 55:((6- (2- ((4- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) the fluoro- 7H- pyrroles of -5- And [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 55)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), with the side similar with described in embodiment 2 Method, synthesis obtain title compound (28mg, yield: 34.6%).

MS m/z(ESI):523.2[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ: 8.68 (s, 1H), 8.19 (d, J=8.0Hz, 1H), 7.76-7.46 (m, 4H), 7.18 (s, 1H), 6.97 (d, J=8.8Hz, 2H), 6.64 (d, J=8.0Hz, 1H), 3.69 (d, J=12.4Hz, 2H), 3.38 (m, 6H), 2.71 (t, J=10.4Hz, 2H), 2.36 (s, 6H), 1.99 (d, J=10.4Hz, 2H), 1.76-1.66 (m, 2H).

Embodiment 56:((6- (the fluoro- 2- of 5- ((3- methoxyl group -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) Amino) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶Sulfane ketone (compound 56) Preparation

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-35) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (36mg, yield: 38.2%).

MS m/z(ESI):608.7[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ: 8.70 (s, 1H), 8.17 (d, J=8.0Hz, 1H), 7.71 (d, J=2.0Hz, 1H), 7.62 (t, J=8.0Hz, 1H), 7.37 (d, J=2.4Hz, 1H), 7.06-7.04 (m, 1H), 6.93 (d, J=8.4Hz, 1H), 6.64 (d, J=8.0Hz, 1H), 3.85 (s, 3H), 3.53-3.50 (m, 2H), 3.39 (s, 6H), 2.88-2.39 (m, 7H),2.33-2.30(m,3H),2.19-1.61(m,8H)。

Embodiment 57:((6- (the fluoro- 2- of 5- ((6- (4- methylpiperazine-1-yl) pyridin-3-yl) amino) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 57)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-37) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (33mg, yield: 43.0%).

MS m/z(ESI):496.4[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ: 8.68 (s, 1H), 8.35 (d, J=2.4Hz, 1H), 8.10 (d, J=8.0Hz, 1H), 7.97-7.94 (m, 1H), 7.79-7.56 (m, 1H), 7.07 (s, 1H), 6.72 (d, J=9.2Hz, 1H), 6.64 (d, J= 7.6Hz, 1H), 3.70-3.53 (m, 4H), 3.40 (d, J=9.2Hz, 6H), 2.75-2.53 (m, 4H), 2.42 (s, 3H).

Embodiment 58:((6- (the fluoro- 2- of 5- ((1- (tetrahydro -2H- pyrans -4- base) -1H- pyrazoles -4- base) amino) -7H- pyrrole Cough up simultaneously [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 58)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-36) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (66mg, yield: 23.1%).

MS m/z(ESI):471.5[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ: 8.68 (s, 1H), 8.07 (d, J=8.0Hz, 1H), 8.01 (s, 1H), 7.78- 7.55 (m, 2H), 7.37 (s, 1H), 6.67 (d, J=8.0Hz, 1H), 4.47-4.26 (m, 1H), 4.15-4.12 (m, 2H), 3.60-3.54(m,2H),3.40(s,6H),2.22-1.94(m,4H)。

(the fluoro- 2- of 5- ((1- methyl-1 H- pyrazoles -4- base) amino) -7H- pyrrolo- [2,3-d] is phonetic by embodiment 59:((6- Pyridine -7- base) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 59)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and with 1- methyl-1 H- pyrazoles -4- amine Instead of 1- (4- aminophenyl)-N, N- lupetidine -4- amine in embodiment 2, with the side similar with described in embodiment 2 Method, synthesis obtain title compound (70mg, yield: 28.8%).

MS m/z(ESI):401.4[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ: 8.67 (s, 1H), 8.09 (d, J=8.0Hz, 1H), 7.84 (s, 1H), 7.75- 7.58 (m, 3H), 6.67 (d, J=7.6Hz, 1H), 3.92 (s, 3H), 3.47-3.32 (m, 6H).

Embodiment 60:((6- (the fluoro- 2- of 5- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -4- base) amino) -7H- pyrroles And [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 60)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-38) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (81mg, yield: 28.5%).

MS m/z(ESI):469.4[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ: 8.60 (s, 1H), 8.01 (s, 1H), 7.92 (d, J=8.0Hz, 1H), 7.70- 7.50 (m, 3H), 6.62 (d, J=8.0Hz, 1H), 4.67-4.60 (m, 2H), 3.33 (s, 6H).

(the fluoro- 2- of 5- ((1- isopropyl -1H- pyrazoles -4- base) amino) -7H- pyrrolo- [2,3-d] is phonetic by embodiment 61:((6- Pyridine -7- base) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 61)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-12) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (48mg, yield: 19.0%).

MS m/z(ESI):429.4[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ: 8.66 (s, 1H), 8.08 (d, J=8.0Hz, 1H), 7.95 (s, 1H), 7.78- 7.56 (m, 3H), 6.67 (d, J=7.6Hz, 1H), 4.55-4.48 (m, 1H), 3.40 (s, 6H), 1.54 (t, J=8.8Hz, 6H)。

Embodiment 62:((6- (the fluoro- 2- of 5- ((1- (1- methyl piperidine -4- base) -1H- pyrazoles -4- base) amino) -7H- pyrroles And [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 62)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and with 1- (1- methyl piperidine -4- base) - 1H- pyrazoles -4- amine replace embodiment 2 in 1- (4- aminophenyl)-N, N- lupetidine -4- amine, with institute in embodiment 2 Similar method is stated, synthesis obtains title compound (23mg, yield: 30.7%).

MS m/z(ESI):484.5[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ: 8.68 (s, 1H), 8.09 (d, J=8.0Hz, 1H), 7.98 (s, 1H), 7.73- 7.54 (m, 3H), 6.66 (d, J=7.6Hz, 1H), 3.40 (s, 6H), 3.04 (s, 3H), 2.48-2.00 (m, 5H), 1.25 (d, J =6.4Hz, 5H).

Embodiment 63:((6- (2- ((6- (4- (dimethylamino) piperidin-1-yl) pyridin-3-yl) amino) -7H- pyrroles And [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 63)

The compound (10-a) in 10 second step of embodiment is replaced with compound (Int-10), and with compound (Int- 39) compound (Int-8) in 10 second step of embodiment is replaced, in the method similar with described in embodiment 10, synthesis is marked Inscribe compound (45mg, yield: 22.1%).

MS m/z(ESI):523.4[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.32 (s, 1H), 8.75 (s, 1H), 8.44 (d, J=2.8Hz, 1H), 8.10 (d, J=8.0Hz, 1H), 8.00 (dd, J=9.2,2.8Hz, 1H), 7.90 (d, J=3.6Hz, 1H), 7.76-7.72 (m, 1H), 6.92 (d, J=9.2Hz, 1H), 6.68 (d, J=4.0Hz, 1H), 6.59 (d, J=8.0Hz, 1H), 4.32 (d, J=13.2Hz, 2H), 3.44 (s, 6H), 2.89 (t, J=11.6Hz, 1H), 2.75-2.72 (m, 2H), 2.50 (s, 6H), 1.98-1.95 (m, 2H),1.52-1.49(m,2H)。

(2- ((the fluoro- 4- morphlinophenyl of 3,5- bis-) amino) fluoro- 7H- pyrrolo- [2,3-d] of -5- is phonetic by embodiment 64:((6- Pyridine -7- base) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 64)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-40) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (40mg, yield: 25.1%).

MS m/z(ESI):518.4[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 10.07 (s, 1H), 8.96 (s, 1H), 7.98 (d, J=7.6Hz, 1H), 7.80-7.71 (m, 2H), 7.58 (d, J=12.4Hz, 2H), 6.63 (d, J=8.0Hz, 1H), 3.72-3.66 (m, 4H), 3.44 (s,6H),3.05(s,4H)。

Embodiment 65:((6- (the fluoro- 2- of 5- ((the fluoro- 4- morphlinophenyl of 3-) amino) -7H- pyrrolo- [2,3-d] pyrimidine - 7- yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 65)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-41) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (45mg, yield: 29.4%).

MS m/z(ESI):500.3[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.84 (s, 1H), 8.91 (s, 1H), 8.05 (d, J=7.6Hz, 1H), 7.79 (m, 3H), 7.43 (dd, J=8.8,2.0Hz, 1H), 7.10-6.98 (m, 1H), 6.60 (d, J=8.0Hz, 1H), 3.84-3.69 (m,4H),3.43(s,6H),3.05-2.92(m,4H)。

Embodiment 66:((6- (2- ((4- ((2R, 6S) -2,6- thebaine generation) phenyl) amino) the fluoro- 7H- pyrroles of -5- And [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 66)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-42) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (8mg, yield: 5.2%).

MS m/z(ESI):510.6[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.54 (s, 1H), 8.84 (s, 1H), 8.11 (d, J=8.0Hz, 1H), 7.79 (t, J=8.0Hz, 1H), 7.70 (d, J=1.6Hz, 1H), 7.63 (d, J=9.2Hz, 2H), 6.95 (d, J=9.2Hz, 2H), 6.58 (d, J=8.0Hz, 1H), 3.75-3.71 (m, 1H), 3.53-3.52 (m, 1H), 3.43 (s, 6H), 2.24-2.19 (m, 2H),2.02-1.97(m,2H),1.17(s,3H),1.15(s,3H)。

Embodiment 67:((6- (the fluoro- 2- of 5- ((4- (4- hydroxy-4-methyl piperidin-1-yl) phenyl) amino) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 67)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-43) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (260mg, yield: 11.2%).

MS m/z(ESI):510.4[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.51 (s, 1H), 8.83 (s, 1H), 8.11 (d, J=8.0Hz, 1H), 7.78 (t, J=8.0Hz, 1H), 7.70 (d, J=1.6Hz, 1H), 7.59 (d, J=9.2Hz, 2H), 6.94 (d, J=9.2Hz, 2H), 6.57 (d, J=8.0Hz, 1H), 4.27 (s, 1H), 3.43 (s, 6H), 3.28-3.16 (m, 2H), 3.14-3.03 (m, 2H), 1.59-1.57(m,4H),1.11(s,3H)。

Embodiment 68:((6- (the fluoro- 2- of 5- ((6- morpholino pyridin-3-yl) amino) -7H- pyrrolo- [2,3-d] pyrimidine - 7- yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 68)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and with 6- morpholino pyridine -3- amine generation For 1- (4- aminophenyl)-N, N- lupetidine -4- amine in embodiment 2, in the method similar with described in embodiment 2, Synthesis obtains title compound (38mg, yield: 17.3%).

MS m/z(ESI):483.4[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.56 (s, 1H), 8.85 (s, 1H), 8.45 (d, J=2.8Hz, 1H), 8.12-7.97 (m, 2H), 7.72 (dd, J=11.2,4.8Hz, 2H), 6.90 (d, J=9.2Hz, 1H), 6.57 (d, J= 8.0Hz,1H),3.77-3.69(m,4H),3.43(s,6H),2.24-2.02(m,4H)。

(2- ((6- ((2R, 6S) -2,6- thebaine generation) pyridin-3-yl) amino) -5- is fluoro- by embodiment 69:((6- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 69)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-44) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (35mg, yield: 22.5%).

MS m/z(ESI):511.4[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.53 (s, 1H), 8.84 (s, 1H), 8.40 (d, J=2.8Hz, 1H), 8.11-7.97 (m, 2H), 7.73 (dd, J=13.6,4.8Hz, 2H), 6.89 (d, J=9.2Hz, 1H), 6.57 (d, J= 8.0Hz,1H),3.75-3.71(m,1H),3.53-3.52(m,1H),3.42(s,6H),2.24-2.19(m,2H),2.02- 1.97(m,2H),1.18(s,3H),1.16(s,3H)。

Embodiment 70:((6- (2- ((6- ((1S, 4S) -2- oxa- -5- azabicyclo [2.2.1] hept- 5- yl) pyridine -3- Base) amino) fluoro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of -5-) pyridine -2- base) imino group) dimethyl-λ⁶Sulfane ketone (is changed Close object 70) preparation

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-45) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (30mg, yield: 17.5%).

MS m/z(ESI):495.5[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.44 (s, 1H), 8.82 (s, 1H), 8.34 (d, J=2.4Hz, 1H), 8.04 (d, J=7.6Hz, 1H), 7.91 (dd, J=8.8,2.4Hz, 1H), 7.75-7.66 (m, 2H), 6.58 (dd, J=14.2, 8.4Hz, 2H), 4.80 (s, 1H), 4.65 (s, 1H), 3.79 (d, J=6.8Hz, 1H), 3.68 (d, J=6.8Hz, 1H), 3.48 (d, J=6.8Hz, 1H), 3.40 (s, 6H), 3.23 (d, J=8.0Hz, 1H), 1.93-1.83 (m, 2H).

Embodiment 71:((6- (2- ((6- ((1R, 4R) -2- oxa- -5- azabicyclo [2.2.1] hept- 5- yl) pyridine -3- Base) amino) fluoro- 7H- pyrrolo- [2,3-d] pyrimidin-7-yl of -5-) pyridine -2- base) imino group) dimethyl-λ⁶Sulfane ketone (is changed Close object 70) preparation

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-46) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (30mg, yield: 17.5%).

MS m/z(ESI):495.5[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.44 (s, 1H), 8.82 (s, 1H), 8.33 (d, J=2.4Hz, 1H), 8.04 (d, J=7.6Hz, 1H), 7.91 (dd, J=9.2,2.8Hz, 1H), 7.74-7.67 (m, 2H), 6.58 (dd, J=14.2, 8.4Hz, 2H), 4.80 (s, 1H), 4.64 (s, 1H), 3.79 (d, J=6.8Hz, 1H), 3.67 (d, J=7.2Hz, 1H), 3.50- 3.40 (m, 6H), 3.23 (d, J=8.4Hz, 1H), 1.95-1.82 (m, 2H).

Embodiment 72:(S)-((6- (the fluoro- 2- of 5- ((6- (2- methyl morpholine generation) pyridin-3-yl) amino) -7H- pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 70)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-47) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (30mg, yield: 19.9%).

MS m/z(ESI):497.4[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.55 (s, 1H), 8.85 (s, 1H), 8.42 (d, J=2.6Hz, 1H), 8.10-7.98 (m, 2H), 7.72 (dd, J=12.4,4.8Hz, 2H), 6.90 (d, J=9.2Hz, 1H), 6.57 (d, J= 7.6Hz, 1H), 4.06 (d, J=12.0Hz, 1H), 3.97-3.90 (m, 2H), 3.61-3.58 (m, 2H), 3.43 (s, 6H), 2.75 (td, J=12.4,3.2Hz, 1H), 2.42 (dd, J=12.4,10.4Hz, 1H), 1.17 (d, J=6.0Hz, 3H).

Embodiment 73:((6- (2- ((6- (4- (dimethylamino) piperidin-1-yl) pyridin-3-yl) amino) fluoro- 7H- of -5- Pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 70)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-39) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (38mg, yield: 11.3%).

MS m/z(ESI):524.3[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.49 (s, 1H), 8.83 (s, 1H), 8.38 (d, J=2.8Hz, 1H), 8.04 (d, J=8.0Hz, 1H), 7.94 (dd, J=9.2,2.8Hz, 1H), 7.71 (dd, J=10.8,4.8Hz, 2H), 6.89 (d, J= 9.2Hz, 1H), 6.57 (d, J=8.0Hz, 1H), 4.23 (d, J=12.8Hz, 2H), 3.43 (s, 6H), 2.75 (t, J= 11.6Hz,2H),2.19(s,6H),2.04-2.01(m,1H),1.83-1.81(m,2H),1.43-1.32(m,2H)。

Embodiment 74:((6- (2- ((6- (dimethylamino) pyridin-3-yl) amino) fluoro- 7H- pyrrolo- [2,3-d] of -5- Pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 70)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and uses N²,N²Lutidines -2,5- Diamines replaces 1- (4- aminophenyl)-N, N- lupetidine -4- amine in embodiment 2, with similar with described in embodiment 2 Method, synthesis obtain title compound (45mg, yield: 22.4%).

MS m/z(ESI):441.4[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.36 (s, 1H), 8.74 (s, 1H), 8.28 (d, J=2.8Hz, 1H), 7.99 (d, J=7.6Hz, 1H), 7.84 (dd, J=9.2,2.8Hz, 1H), 7.64 (dd, J=9.6,4.8Hz, 2H), 6.63 (d, J= 9.2Hz, 1H), 6.50 (d, J=8.0Hz, 1H), 3.36 (s, 6H), 2.94 (s, 6H).

Embodiment 75:((6- (the fluoro- 2- of 5- ((6- picoline -3- base) amino) -7H- pyrrolo- [2,3-d] pyrimidine -7- Base) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 75)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced with 6- picoline -3- amine 1- (4- aminophenyl)-N, N- lupetidine -4- amine in embodiment 2 is closed in the method similar with described in embodiment 2 At obtaining title compound (33mg, yield: 17.4%).

MS m/z(ESI):412.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.84 (s, 1H), 8.92 (s, 1H), 8.79 (d, J=2.8Hz, 1H), 8.14 (dd, J=8.4,2.8Hz, 1H), 8.02 (d, J=8.0Hz, 1H), 7.76 (dd, J=9.2,6.8Hz, 2H), 7.23 (d, J= 8.4Hz, 1H), 6.59 (d, J=8.0Hz, 1H), 3.43 (s, 6H), 2.43 (s, 3H).

Embodiment 76:((6- (the fluoro- 2- of 5- ((6- ((tetrahydro -2H- pyrans -4- base) oxygroup) pyridin-3-yl) amino) -7H- Pyrrolo- [2,3-d] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 76)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-48) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (45mg, yield: 29.8%).

MS m/z(ESI):498.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.68 (s, 1H), 8.88 (s, 1H), 8.43 (d, J=2.8Hz, 1H), 8.11 (dd, J=8.8,2.8Hz, 1H), 8.02 (d, J=7.6Hz, 1H), 7.76-7.69 (m, 2H), 6.84 (d, J=8.8Hz, 1H), 6.58 (d, J=7.6Hz, 1H), 5.25-5.08 (m, 1H), 3.89-3.83 (m, 2H), 3.59-3.47 (m, 2H), 3.43 (s, 6H),2.00-2.05(m,2H),1.73-1.57(m,2H)。

Embodiment 77: diethyl ((6- (the fluoro- 2- of 5- ((6- morpholino pyridin-3-yl) amino) -7H- pyrrolo- [2,3-d] Pyrimidin-7-yl) pyridine -2- base) imino group)-λ⁶The preparation of sulfane ketone (compound 77)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-51), and with 6- morpholino pyridine -3- amine generation For 1- (4- aminophenyl)-N, N- lupetidine -4- amine in embodiment 2, in the method similar with described in embodiment 2, Synthesis obtains title compound (18mg, yield: 12.3%).

MS m/z(ESI):511.4[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.57 (d, J=8.4Hz, 1H), 8.85 (s, 1H), 8.45 (d, J= 2.8Hz, 1H), 8.12-7.97 (m, 2H), 7.72 (t, J=8.0Hz, 1H), 7.66 (d, J=1.6Hz, 1H), 6.90 (d, J= 9.2Hz,1H),6.79-6.50(m,1H),3.80-3.66(m,4H),3.52-3.57(m,4H),3.44-3.37(m,4H), 1.29 (t, J=7.2Hz, 6H).

(2- ((1- cyclobutyl -1H- pyrazoles -4- base) amino) fluoro- 7H- pyrrolo- [2,3-d] of -5- is phonetic by embodiment 78:((6- Pyridine -7- base) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 78)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and with 1- cyclobutyl -1H- pyrazoles -4- Amine replaces 1- (4- aminophenyl)-N, N- lupetidine -4- amine in embodiment 2, with the side similar with described in embodiment 2 Method, synthesis obtain title compound (40mg, yield: 27.3%).

MS m/z(ESI):441.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.66 (s, 1H), 8.84 (s, 1H), 8.03 (s, 2H), 7.77 (t, J= 8.0Hz, 1H), 7.66 (s, 1H), 7.55 (s, 1H), 6.61 (d, J=8.0Hz, 1H), 4.80 (d, J=8.4Hz, 1H), 3.43 (s,6H),2.47-2.36(m,4H),1.82-1.78(m,2H)。

(2- ((1- cyclopenta -1H- pyrazoles -4- base) amino) fluoro- 7H- pyrrolo- [2,3-d] of -5- is phonetic by embodiment 79:((6- Pyridine -7- base) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 79)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-49) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (47mg, yield: 22.3%).

MS m/z(ESI):455.3[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.62 (s, 1H), 8.83 (s, 1H), 8.01 (s, 2H), 7.74 (t, J= 7.6Hz, 1H), 7.65 (s, 1H), 7.52 (s, 1H), 6.61 (d, J=8.0Hz, 1H), 4.76-4.56 (m, 1H), 3.43 (s, 6H),2.05-2.10(m,2H),1.90-1.95(m,2H),1.73-1.78(m,2H),1.72-1.58(m,2H)。

(2- ((1- cyclohexyl -1H- pyrazoles -4- base) amino) fluoro- 7H- pyrrolo- [2,3-d] of -5- is phonetic by embodiment 80:((6- Pyridine -7- base) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 80)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and is replaced in fact with compound (Int-50) 1- (4- aminophenyl)-N, N- lupetidine -4- amine in example 2 is applied, with the method similar with described in embodiment 2, synthesis Obtain title compound (47mg, yield: 22.3%).

MS m/z(ESI):469.4[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.62 (s, 1H), 8.82 (s, 1H), 8.02 (s, 2H), 7.73 (t, J= 7.6Hz, 1H), 7.65 (s, 1H), 7.51 (s, 1H), 6.61 (d, J=8.0Hz, 1H), 4.10-4.05 (m, 1H), 3.43 (s, 6H),2.05-2.04(m,2H),1.85-1.83(m,2H),1.68-1.63(m,4H),1.40-1.20(m,2H)。

Embodiment 81:((6- (the fluoro- 2- of 5- ((6- (pyrrolidin-1-yl) pyridin-3-yl) amino) -7H- pyrrolo- [2,3- D] pyrimidin-7-yl) pyridine -2- base) imino group) dimethyl-λ⁶The preparation of sulfane ketone (compound 81)

Compound (Int-2) in embodiment 2 is replaced with compound (Int-13), and with 6- (pyrrolidin-1-yl) pyridine- 3- amine replaces 1- (4- aminophenyl)-N, N- lupetidine -4- amine in embodiment 2, with similar with described in embodiment 2 Method, synthesis obtain title compound (25mg, yield: 23.8%).

MS m/z(ESI):467.4[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆) δ: 9.68 (s, 1H), 8.88 (s, 1H), 8.43 (d, J=2.8Hz, 1H), 8.11 (m 1H), 8.02 (d, J=7.6Hz, 1H), 7.76-7.69 (m, 2H), 6.84 (d, J=8.4Hz, 1H), 6.58 (d, J= 7.6Hz,1H),3.89-3.83(m,2H),3.59-3.47(m,2H),2.00-2.05(m,2H),1.73-1.57(m,2H)。

Biology test

The Inhibition test of experimental example 1:Wee1 kinases

It is each embodiment compound of test to the external inhibitory activity of Wee1 kinases, is tested in accordance with the following steps:

1) by the untested compound of Wee1 albumen (Carna Biosciences) and various concentration preincubate 15 at room temperature Minute, substrate (Poly (Lys, Tyr), Sigma) and 10 μM of ATP starting reactions are then added, are reacted 90 minutes in 30 DEG C；

2) addition and the isometric ADP-Glo reagent (Promega) of reaction system, be incubated for 40 minutes makes to react at room temperature It terminates；

3) kinase assay reagent is added, is incubated for 30 minutes at room temperature.Detect the spontaneous optical signal of product.With solvent group (DMSO) be negative control, reaction buffer group (without enzyme and compound) be blank control, it is nearest from 50% with residual activity Concentration calculation compound half-inhibitory concentration (IC₅₀), as a result as shown in table 1.

1. compound of table is to Wee1 activity suppression data

As seen from Table 1, each embodiment compound significantly inhibits Wee1 kinases.

Experimental example 2: cell growth inhibition assay

The compounds of this invention is tested to the proliferation inhibiting effect of NCI-H1299 cell according to following experimental procedure.

With complete medium (RPMI-1640 culture medium (Hyclone)+10%FBS (Gibco)) by NCI-H1299 cell It is inoculated in 96 orifice plates, so that 2500 cells of each Kong Zhonghan.After 24 hours, the culture medium in 96 orifice plates is discarded, is added and uses Complete medium (RPMI-1640 culture medium (Hyclone)+10%FBS (Gibco)) diluted compound working solutions culture 72 is small When.Then the pastille culture medium in 96 orifice plates is discarded, basal medium (RPMI-1640 culture medium is added with 100 holes μ L/ (Hyclone)) 10 hole μ L/ MTS (promega), is added, 96 orifice plates are placed in cell incubator and are incubated for 3-4 hours, enzyme is passed through Mark instrument reading (OD 490nm).It is calculated by the following formula inhibiting rate: with solvent group (DMSO) for control group, inhibiting rate=(1- Administration group absorbance/control group absorbance) × 100%.Using 12.5 matched curve of SigmaPlot, measured by multipoint method IC₅₀Value, the results are shown in Table 2.

Proliferation Ability data of 2. compound of table to NCI-H1299 cell

As can be seen from Table 2, tested compound there is apparent inhibition to make the proliferation of NCI-H1299 cell With.

In addition to those described herein, according to foregoing description, a variety of modifications of the invention to those skilled in the art and Speech can be obvious.Such modification is also intended to fall within the scope of the appended claims.Cited in the application Each bibliography (including all patents, patent application, journal of writings, books and any other disclosure), which is quoted with its entirety, to be added Enter herein.

Claims

1. compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N- oxygen Compound, the compound of isotope labelling, metabolin or prodrug, wherein the compound has the structure of formula (I):

Wherein:

Ring A is selected from phenyl ring and 5-6 member hetero-aromatic ring；

X is selected from N and CR⁴；

R¹Selected from hydrogen and fluorine；

R²Selected from hydrogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, halogenated C_1-6Alkyl ,-C_1-6Alkylidene-OH ,-C_1-6Alkylidene-O- C_1-6Alkyl ,-C_1-6Alkylidene-cyano, C_3-6Cyclic hydrocarbon radical and 3-10 circle heterocyclic ring base；

R³Selected from-C_1-6Alkylidene-OH ,-C_1-6Alkylidene-O-C_1-6Alkyl ,-C_1-6Alkylidene-NR^3aR^3b,-C (=O) NR^3aR^3b、- N=S (=O) (R^3a)(R^3b) ,-P (=O) (R^3a)(R^3b) ,-NH-P (=O) (R^3a)(R^3b) and pyriconyl；

R⁴It is each independently selected from hydrogen, halogen, cyano, hydroxyl, C at each occurrence_1-6Alkyl, halogenated C_1-6Alkyl ,-O-C_1-6Alkane Base and-NR^4aR^4b；

R⁵Selected from halogen, cyano, C_1-6Alkyl, halogenated C_1-6Alkyl ,-C_1-6Alkylidene-NR^5aR^5b,-C (=O) NR^5aR^5b、-O-(3- 10 circle heterocyclic ring bases) and 3-10 circle heterocyclic ring base；Preferably, R⁵Selected from halogen, cyano, C_1-6Alkyl, halogenated C_1-6Alkyl ,-C_1-6Alkylene Base-NR^5aR^5b,-C (=O) NR^5aR^5b,-O- (3-10 circle heterocyclic ring base), 3-10 unit monocycle heterocycle, 7-10 member bridge heterocycle and 6- 10 yuan of condensed hetero ring bases；

R⁶It is each independently selected from halogen, cyano, hydroxyl, C at each occurrence_1-6Alkyl, halogenated C_1-6Alkyl ,-C_1-6Alkylidene- OH and-O-C_1-6Alkyl；Preferably, R⁶It is each independently selected from F, Cl, Br, methyl ,-CH at each occurrence₂OH and-OCH₃；

Or R⁵With an adjacent R⁶3-10 circle heterocyclic ring base or 7-12 member spiroheterocyclic is collectively formed in the atom connected together with it Base；

R^3aAnd R^3bIt is each independently selected from C_1-6Alkyl and C_3-6Cyclic hydrocarbon radical；Or R^3aAnd R^3bThe atom connected together with it is common Form 3-10 circle heterocyclic ring base；

R^4a、R^4b、R^5aAnd R^5bIt is each independently selected from hydrogen, C_1-6Alkyl, halogenated C_1-6Alkyl and C_3-6Cyclic hydrocarbon radical；Or R^4aWith R^4b And/or R^5aWith R^5b3-10 circle heterocyclic ring base is collectively formed in the nitrogen-atoms connected together with it；

M is 1,2 or 3；

N is 0,1,2 or 3；And

Abovementioned alkyl, alkylidene, alkenyl, alkynyl, cyclic hydrocarbon radical, heterocycle, spiro heterocyclic radical, phenyl ring and hetero-aromatic ring respectively optionally by 1,2,3 or 4 substituent group independently selected from the following replaces: halogen, hydroxyl, oxo, cyano ,-NH₂, nitro, mercapto Base ,-CO₂H、-CO₂C_1-6Alkyl, C_1-6Alkyl, halogenated C_1-6Alkyl ,-O-C_1-6The halogenated C of alkyl ,-O-_1-6Alkyl, C_3-6Cyclic hydrocarbon radical, Halogenated C_3-6Cyclic hydrocarbon radical ,-NH-C_1-6Alkyl ,-N (C_1-6Alkyl)₂、-C_1-6Alkylidene-OH ,-C_1-6Alkylidene-CN ,-C_1-6Alkylene Base-O-C_1-6Alkyl ,-C_1-6Alkylidene-CO₂-C_1-6Alkyl ,-S (=O)₂-C_1-6Alkyl, 3-10 circle heterocyclic ring base ,-(3-10 circle heterocyclic ring Base)-C_1-6Alkyl, C_6-10Aryl, 5-14 unit's heteroaryl and C_6-12Aralkyl.

2. compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, more Crystal form object, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, in which:

R²Selected from hydrogen, C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, halogenated C_1-4Alkyl ,-C_1-4Alkylidene-OH ,-C_1-4Alkylidene-O- C_1-4Alkyl ,-C_1-4Alkylidene-cyano, C_3-6Cyclic hydrocarbon radical and 4-6 circle heterocyclic ring base；

Preferably, R²Selected from hydrogen, methyl, ethyl, propyl, isopropyl, acrylic, propinyl, trifluoromethyl, fluoro ethyl, trifluoro second Base ,-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CH₂OCH₂CH₃、-CH₂CN、-CH₂CH₂CN, cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, tetrahydrofuran base and THP trtrahydropyranyl；

It is highly preferred that R²For hydrogen.

3. compound according to claim 1 or 2 or its pharmaceutically acceptable salt, stereoisomer, tautomer, Polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, in which:

R³Selected from-C_1-4Alkylidene-OH ,-C_1-4Alkylidene-O-C_1-4Alkyl ,-C_1-4Alkylidene-NR^3aR^3b,-C (=O) NR^3aR^3b、- N=S (=O) (R^3a)(R^3b) ,-P (=O) (R^3a)(R^3b) ,-NH-P (=O) (R^3a)(R^3b) and pyriconyl；And

R^3aAnd R^3bIt is each independently selected from C_1-4Alkyl and C_3-6Cyclic hydrocarbon radical；Or R^3aAnd R^3bThe atom connected together with it is common 4-6 circle heterocyclic ring base is formed, the heterocycle is optionally by 1,2,3 or 4 independently selected from C_1-4Alkyl and C_3-6Cyclic hydrocarbon The substituent group of base replaces；

Preferably, R³Selected from-CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-C(CH₃)₂OCH₃、-CH₂N(CH₃)₂,-C (=O) N (CH₃)₂,-N=S (=O) (CH₃)₂,-N=S (=O) (C₂H₅)₂,-P (=O) (CH₃)₂,-NH-P (=O) (CH₃)₂、And pyriconyl；

It is highly preferred that R³Selected from-C (CH₃)₂OH、-CH₂N(CH₃)₂,-C (=O) N (CH₃)₂,-N=S (=O) (CH₃)₂,-N=S (=O) (C₂H₅)₂,-P (=O) (CH₃)₂、

4. compound according to any one of claim 1-3 or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, whereinIt is selected from:

5. compound described in any one of -4 or its pharmaceutically acceptable salt, stereoisomer, interconversion according to claim 1 Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, in which:

Ring A is selected from phenyl ring and 5-6 member hetero-aromatic ring, and the phenyl ring and hetero-aromatic ring are optionally selected from ring fourth by one or more Base, cyclopenta, cyclohexyl and-N (CH₃)₂Substituent group replace；

Preferably, ring A is selected from phenyl ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring, thiazole ring and pyrazole ring；

It is highly preferred that ring A is selected from phenyl ring, pyridine ring, thiazole ring and pyrazole ring.

6. compound according to any one of claims 1-5 or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, in which:

R⁵Selected from halogen, cyano, C_1-4Alkyl, halogenated C_1-4Alkyl ,-C_1-4Alkylidene-NR^5aR^5b,-C (=O) NR^5aR^5b、-O-(3- 10 circle heterocyclic ring bases) (preferably-O- THP trtrahydropyranyl), pyrrolidinyl, THP trtrahydropyranyl, piperazinyl, morpholinyl, Thiomorpholine base, piperidyl and tetrahydro pyridyl, the pyrrolidinyl, oxinane Base, piperazinyl, morpholinyl, Thiomorpholine base, piperidyl and tetrahydro pyridyl are optional Ground is by 1,2,3 or 4 independently selected from F, Cl, Br, hydroxyl, oxo, cyano, C_1-4Alkyl (preferably methyl, isopropyl Base), halogenated C_1-4Alkyl ,-O-C_1-4Alkyl (preferably methoxyl group), C_3-6Cyclic hydrocarbon radical ,-C_1-4Alkylidene-O-C_1-4Alkyl ,-N (C_1-4 Alkyl)₂、-C_1-6Alkylidene-OH is (preferably), 3-10 circle heterocyclic ring base (preferably) and-S (=O)₂-C_1-4Alkane The substituent group of base replaces；

R^5aAnd R^5bIt is each independently selected from hydrogen, C_1-4Alkyl, halogenated C_1-4Alkyl and C_3-6Cyclic hydrocarbon radical；Or R^5aWith R^5bTogether with its institute The nitrogen-atoms of connection is collectively formed 4-6 circle heterocyclic ring base, the heterocycle optionally by 1,2,3 or 4 independently selected from C_1-4Alkyl and C_3-6The substituent group of cyclic hydrocarbon radical replaces；

Preferably, R⁵Selected from fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, fluoro ethyl, trifluoroethyl ,-CH₂N (CH₃)₂、-C₂H₄N(CH₃)₂,-C (=O) N (CH₃)₂,-O- THP trtrahydropyranyl, pyrrolidinyl, THP trtrahydropyranyl, thiomorpholine base, piperazine Piperazine base, 4- methyl piperazine base, 4- isopropyl piperazinyl, morpholinyl, 4- methyl piperidine base, 4- dimethylaminopyridine base, 1- first Base tetrahydro pyridyl and 1- isopropyl tetrahydro pyridyl；

It is highly preferred that R⁵Selected from cyano, methyl, isopropyl, trifluoroethyl ,-C₂H₄N(CH₃)₂,-C (=O) N (CH₃)₂、

7. compound according to any one of claims 1-5 or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, in which:

R⁵With an adjacent R⁶5- or 6-membered heterocycle or 8 yuan of spiro heterocyclic radicals, institute is collectively formed in the atom connected together with it State heterocycle and spiro heterocyclic radical optionally by 1,2,3 or 4 independently selected from methyl, ethyl, isopropyl, cyclopropyl, Fluoro ethyl and-CH₂CH₂OCH₃Substituent group replace.

8. compound described in any one of -7 or its pharmaceutically acceptable salt, stereoisomer, interconversion according to claim 1 Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, whereinIt is selected from

9. compound according to claim 1 to 8 or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, wherein describedization Close the structure that object has formula (II), formula (III) or formula (IV):

Preferably, the compound has formula (II) -1, formula (II) -2, formula (III) -1, formula (III) -2, formula (IV) -1 or formula (IV) -2 structure:

10. compound according to claim 1 to 9 or its pharmaceutically acceptable salt, stereoisomer, mutually Tautomeric, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, wherein described Compound is selected from:

11. pharmaceutical composition, it includes prevention or the chemical combination according to claim 1 to 10 of therapeutically effective amount Object or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N- oxide, same to position Compound, metabolin or the prodrug of element label and one or more pharmaceutically acceptable carriers.

12. compound according to claim 1 to 10 or its pharmaceutically acceptable salt, stereoisomer, mutually Tautomeric, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug or according to power Benefit require 11 described in pharmaceutical composition preparing the use in drug for preventing or treating Wee1 protein kinase related disorder On the way, wherein the drug preferably by oral, intravenous, intra-arterial, subcutaneous, peritonaeum is interior, intramuscular or transdermal routes of administration, wherein The Wee1 protein kinase related disorder is preferably cancer.

13. purposes according to claim 12, wherein the drug also includes other antitumor agents.

14. the method for preparing the compound of formula according to claim 1 to 10 (I), the method includes following Step:

Wherein:

Z is halogen, such as Cl or Br；

Any one of remaining each group such as claim 1-10 is defined；

It the described method comprises the following steps:

Step 1: react compound IN-1 with compound IN-2 to obtain compound IN-3；And

Step 2: react compound IN-3 with compound IN-4 to obtain the compound of formula (I).