CN105330698B

CN105330698B - Loop coil aryl phosphorous oxides and sulfide

Info

Publication number: CN105330698B
Application number: CN201410317076.7A
Authority: CN
Inventors: 丁照中; 张明会; 陈曙辉; 刘希乐; 朱屹东; 范传文; 赵保平; 张龙; 陈栋; 杨莹莹; 郑庆梅; 郑善松; 万海文; 胡金清
Original assignee: Qilu Pharmaceutical Co Ltd
Current assignee: Qilu Pharmaceutical Co Ltd
Priority date: 2014-07-04
Filing date: 2014-07-04
Publication date: 2019-05-28
Anticipated expiration: 2034-07-04
Also published as: CN105330698A

Abstract

The invention discloses a kind of loop coil aryl phosphorous oxides or sulfide as ALK inhibitor, specifically discloses compound shown in the formula (I) as ALK inhibitor or its pharmaceutically acceptable salt.

Description

Loop coil aryl phosphorous oxides and sulfide

Invention field

The present invention relates to a kind of loop coil aryl phosphorous oxides or sulfide as ALK inhibitor.In particular, the present invention relates to And the compound or its pharmaceutically acceptable salt of the formula (I) as ALK inhibitor.

Background of invention

Protein kinase almost plays leading regulating and controlling effect in all types of cell biological activities.They include proliferation, are withered It dies, cytoskeleton rearrangement, breaks up, develop, be immunoreacted, nervous function and conduction.In addition, many diseases and (or) function Disorder and the activity of one or more kinases are not normal, and abnormal or imbalance is related.

Anaplastic lymphoma kinase (ALK) is a part of tyrosine kinase (RTKs) receptor protein family.ALK gene mentions Instruction has been supplied so that the albumen of tyrosine kinase receptor transmits signal from cell surface by the process of a signal transduction To intracellular.This process is started from when the cell surface kinases is stimulated, and then dimerization occurs for kinases.After dimerization, Kinases is marked by phosphate, this process is known as phosphorylation.This process makes kinase activator.The kinases of activation can be by phosphate Group is transferred on another intracellular albumen, and continues for phosphorylation to be transmitted to a series of albumen in downstream.This signal passes It is extremely important to many cell processes to lead approach, as cell grows and divide (proliferation) or mature (differentiation).

Although the exceptional function to anaplastic lymphoma kinase is not clear, it is generally understood that in nerve cell early-stage development In, it can help to adjust the proliferation of nerve cell.

The mutation of anaplastic lymphoma kinase ALK gene is that basic unit-amino acid of protein changes.Some It is identified in neuroblastoma, and a kind of tumour patient being made of immature nerve cell (neuroblast) The ALK gene of at least 16 mutation out.Neuroblastoma and other cancers are since (these are crucial for some key genes Gene controls the proliferation and differentiation of cell) gene mutation occurs, so that cell is grown and is divided uncontrollable and form tumour.

The most common mutation of neuroblastoma is that arginine is replaced by glutamic acid (to be written as on position 1275 Arg1275Gln or R1275Q).Arg1275Gln mutation is found in the neuroblastoma of heredity and dispersibility, and It and is also the unique common ALK gene mutation found in both cases.

The anaplastic lymphoma kinase of mutation or overexpression is no longer needed from extracellular stimulus phosphorylation.Therefore, swash Enzyme is (constitutively activated) uninterruptedly connected with downstream signaling pathway.The composition activation of anaplastic lymphoma kinase can The proliferation for improving prematurity nerve cell, finally results in neuroblastoma.Rearrangement of the ALK gene on No. 2 chromosomes increases Risk with other cancers.These rearrangement be body cell mutation, that is, body cell mutation there are people in life, And it is only just displayed when canceration occurs for cell.

A type of reset is known as transposition, is the crossing between No. 2 chromosomes and other chromosomes.? In crowd with primary cutaneous type (ALCL), at least 15 kinds is identified and have been related to the transposition of ALK gene.Between be denaturalized Large celllymphoma is to occur to be a kind of rare cancer forms in the immunocyte of referred to as T cell.It is most common in ALCL Transposition occurs between chromosome 2 and No. 5 chromosome, referred to as t (2,5).This transposition makes ALK gene and NPM Gene Fusion, and shape At the fusion protein of NPM-ALK.In addition, having identified at least seven kinds of ALK genes in inflammatory myofibroblastic tumor (IMT) Transposition.IMT is a kind of rare cancer, it is characterized in that solid tumor is by inflammatory cell and a kind of pair of very important flesh of wound healing The composition of fibroblast.The crowd of about half IMT is related to ALK gene transposition.

Another type of rearrangement is known as inverting, and reversion occurs when No. 2 chromosome breakages are at two parts, gained segment DNA is squeezed, and is reinserted into chromosome.Non-small cell lung cancer is a kind of most common lung cancer, in sub-fraction patient, It is that No. 2 chromosomes are inverted.It is this to invert the Gene Fusion for making ALK gene be known as EML4 with another, form EML4- ALK fusion protein.There is pair of anaplastic lymphoma kinase and chaperone by the fusion protein that the gene that these are reset generates Weight function.

Recent ALK is always the popular target of antitumor research and development, and Mesatros summarizes the progress in this field (Expert Opin.Ther Patents 2014,24(4),1).Crizotinib is first ALK inhibitor of FDA approval, For treating ALK positive lung cancer.Although the initial response through Crizotinib is highly effective, most of patients is due to generating drug resistance Property and the First Year in treatment recurs.On April 29th, 2014, FDA approval Ceritinib is for treating anaplastic lymphoma The Metastatic Nsclc (NSCLC) of kinases (ALK) positive, including to crizotinib is effective and drug resistant patient. There are also some compounds to be just used for treating cancer, such as alectinib, AP-26113 etc. in clinical studies.Some heterocyclic compounds Object has also disclosed, the treatment for various cancers.Patent includes WO2014033136, WO2014025128, WO2014006554, WO2014002922, WO2013192512, WO2013177092, WO2013148857, WO2013138210, WO2012139499, WO2012140114.

However, the NSCLC patient in spite of more than half is good to Crizotinib curative effect, always drug resistance can be with medication Between and generate, so that drug loses its validity.Although in recent years, both at home and abroad all in Devoting Major Efforts To Developing for treating non-small cell The ALK inhibitor of lung cancer, but its curative effect and unsatisfactory.Therefore very there is an urgent need to develop novel, more efficient safety ALK inhibitor.

The present invention relates to the loop coil aryl phosphorous oxides and sulfide of a series of new, which is ALK and its The inhibitor of mutant, can be used for treating cancer and other diseases.Novel loop coil aryl phosphorous oxides of the invention and sulfide Unexpectedly to ALK, the mutant enzyme of ALK mutant and EGFR show the inhibitory activity better than AP26113；And these chemical combination It is also all shown on the NSCLC cell line PDX model and Crizotinib drug resistance PDX model that object obtains in ALK positive patients Than reference compound AP26113 preferably internal drug effect.Therefore, these compounds disease extremely caused to ALK enzyme, can It can provide significantly more efficient treatment.

Summary of the invention

The purpose of the present invention is to provide compound shown in formula (I) or its pharmaceutically acceptable salt,

Wherein,

T₁Selected from-N- or-C (R₀₁)-；

T₂Selected from-N (R₀₁)-, O, S (=O)₂Or-CH (NR₀₁R₀₂)-；

R₀₁Or R₀₂Separately it is selected from H, C_1-6Alkyl, C_1-6Halogenated alkyl and C_3-6Naphthenic base-(CH₂)_0-3, wherein H or C is optionally replaced by 1,2 or 3 hetero atom, and the hetero atom is selected from O, S, N, S (=O)₂And CN；

Optionally, T₂On R₀₁And R₀₂1 5~6 member ring of formation on the same N are interconnected to, are contained on the ring 1,2 or 3 hetero atoms, the hetero atom are selected from O, S and N；

D₁~D₄Separately selected from-(CR₁R₂)_1-3, O, S, C (=O), S (=O)₂With S (=O)；

D is selected from-N (R₀₁)-,-O- and-S-；

W is selected from=O ,=S ,=N (CN) and=N (OMe)；

R₃Selected from R₀₃、OR₀₃And SR₀₃；

R₀₃Selected from C_1-4Alkyl, C_1-4Halogenated alkyl and C_3-5Naphthenic base-(CH₂)_0-3-；

Z is selected from N and C (R₄)；

X₁Selected from C (R_x1) and N；

X₂Selected from C (R_x2) and N；

R_x1、R_x2、R₁、R₂And R₄Separately it is selected from H, F, Cl, Br, I, CN, OH, SH, NH₂、C_1-6Alkyl, C_1-6Miscellaneous alkane Base, C_1-6Halogenated alkyl, C_3-6Cyclic hydrocarbon radical-(CH₂)_0-3And C_3-6Heterocyclic hydrocarbyl-(CH₂)_0-3, wherein " miscellaneous " represent 1,2 or 3 hetero atoms, the hetero atom are selected from O, S and N；Optionally, R_x1And R_x2Be interconnected on the same atom formed 1 5~ 6 member rings, 1,2 or 3 hetero atom is contained on the ring, and the hetero atom is selected from O, S and N；

R_p1And R_p2Separately it is selected from H, C_1-4Alkyl and C_1-4Halogenated alkyl；

Optionally, R_p1And R_p21 5~6 member ring of formation on the same P are interconnected to, contain 1,2 or 3 on the ring A hetero atom, the hetero atom are selected from O, S, N and P；With

Optionally, Z andPosition can be interchanged.

In a scheme of the invention, above-mentioned R₀₁And R₀₂Separately it is selected from H, CH₃、CD₃、CF₃、CHF₂、CH₂CH₃、 CH(CH₃)₂、-CH₂CF₃、-CH₂CH₂CF₃、-CH₂CH₂F、-CH₂CH₂S (=O)₂CH₃、-CH₂CH₂CN、With-CH₂CH₂F。

In a scheme of the invention, above-mentioned R₀₃Selected from CH₃、CD₃、CF₃、CHF₂、CH₂CH₃、CH(CH₃)₂、-CH₂CF₃、- CH₂CH₂CF₃、-CH₂CH₂F and

In a scheme of the invention, above-mentioned R_p1And R_p2Separately it is selected from H, CH₃、CD₃、CF₃、CHF₂、CH₂CH₃、 CH(CH₃)₂、-CH₂CF₃、-CH₂CH₂CF₃With-CH₂CH₂F。

In a scheme of the invention, above-mentioned R_x1、R_x2、R₁、R₂And R₄Separately it is selected from H, F, Cl, Br, I, CH₃、 CD₃、CF₃、CHF₂、CH₂CH₃、CH(CH₃)₂、-CH₂CF₃、-CH₂CH₂CF₃、-CH₂CH₂F、-CH₂CH₂S (=O)₂CH₃、- CH₂CH₂CN、 With-CH₂CH₂F。

In a scheme of the invention, above-mentioned T₂On NR₀₁R₀₂Selected from NHCH₃、N(CH₃)₂、N(CH₂CH₃)₂、With

In a scheme of the invention, above-mentioned D, D_1-4Or T₂Separately it is selected from-NH- ,-NMe- and-O-；D_1-4And T₂ It is also selected from-CH (NCH₃CH₃)-。

In a scheme of the invention, above-mentioned spirane structure unitIt is selected from With

In a scheme of the invention, above compound or its pharmaceutically acceptable salt, with knot shown in formula (II) Structure:

Wherein each variable is as defined above.

In a scheme of the invention, above compound or its pharmaceutically acceptable salt, with knot shown in formula (III) Structure:

Wherein each variable is as defined above.

In a scheme of the invention, above compound or its pharmaceutically acceptable salt are selected from:

1) (((the chloro- 2- of 5- ((2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphine；

2) 2- (3- ((the chloro- 4- of 5- ((2- (solutions of dimethyl phosphoryl base) phenyl) amino) pyrimidine -2-base) amino) -4- methoxyl group Phenyl) -6- methyl -6- azaspiro [3.4] octyl- 7- ketone；

3) (((the chloro- 2- of 5- ((2- methoxyl group -4- (2,8- diaza spiro [4.5] decane -8- base) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphine；

4) (((the chloro- 2- of 5- ((2- methoxyl group -4- (2,7- diaza spiro [3.5] nonane -7- base) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphine；

5) (((the chloro- 2- of 5- ((2- methoxyl group -4- (3,9- diaza spiro [5.5] hendecane -3- base) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphine；

6) (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2,6- diaza spiro [3.4] octyl- 6- yl) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphine；

7) (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) Amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine；

8) (2- ((the chloro- 2- of 5- ((4- (9- isopropyl -3,9- diaza spiro [5.5] hendecane -3- base) -2- methoxybenzene Base) amino) pyrimidine-4-yl) amino base) phenyl) dimethyl phosphine；

9) (2- ((the chloro- 2- of 5- ((2- (difluoro-methoxy) -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- Base) phenyl) amino) pyrimidine-4-yl base) amino) phenyl) dimethyl phosphine；

10) (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (the 11 carbon -9- base of 3- methyl -3- azaspiro [5.5]) phenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine；

11) (2- ((2- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) ammonia Base) -7H- pyrrolo- [2,3-D d] pyrimidine-4-yl) amino) phenyl) dimethyl phosphine；

12) (2- ((2- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) ammonia Base) -5- (trifluoromethyl) pyrimidine-4-yl base) amino) phenyl) dimethyl phosphine；

13) (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) benzene Base) amino) pyrimidine-4-yl) (methyl) amino) phenyl) dimethyl phosphine；

14) (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) benzene Base) amino) pyrimidine-4-yl) oxygroup) phenyl) dimethyl phosphine；

15) (2- ((4- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) ammonia Base) -2 base of -1,3,5- triazine) amino) phenyl) dimethyl phosphine；

16) (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) benzene Base) amino) pyrimidine-4-yl) amino) -3- fluorophenyl) dimethyl phosphine；

17) (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (7- methyl -7- azaspiro [3.5] nonane -2- base) phenyl) amino) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphine；

18) (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) benzene Base) amino) pyrimidine-4-yl) amino) phenyl) dimethyl sulfide；

19) (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) benzene Base) amino) pyrimidine-4-yl) amino) -5- fluorophenyl) dimethyl phosphine；

20) (2- ((the chloro- 2- of 5- ((2- (difluoro-methoxy) -4- (the 11 carbon -9- base of 3- methyl -3- azaspiro [5.5]) benzene Base) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine；

21) (2- ((the chloro- 2- of 5- ((the fluoro- 2- methoxyl group -4- of 5- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- Base) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine；

22) (2- ((the chloro- 2- of 5- ((the chloro- 2- methoxyl group -4- of 5- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- Base) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine；

23) (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2- methyl -2,7- diaza spiro [3.5] nonyl- 7- yl) phenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine；

24) (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2- methyl -2,6- diaza spiro [3.4] octane -6- base) phenyl) Amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine；

25) (2- ((the chloro- 2- of 5- ((2- methoxyl group -5- methyl -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- Base) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine；

26) (2- ((2- ((the bromo- 2- methoxyl group -4- of 5- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) benzene Base) amino) -4 base of -5- chlorine pyrimidine) amino) phenyl) dimethyl phosphine；

27) the chloro- N2- of 5- (2- (difluoro-methoxy) -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) benzene Base)-N4- (2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamines；

28) (2- ((the chloro- 2- of 5- ((2- (difluoro-methoxy) -4- (the 11 carbon -9- base of 3- methyl -3- azaspiro [5.5]) benzene Base) (methyl) amino) -4 base of pyrimidine) amino) phenyl) dimethyl phosphine；

29) (2- ((the chloro- 2- of 5- ((4- methoxyl group -6- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) pyrrole Pyridine -3- base) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine；

30) (2- ((the chloro- 2- of 5- ((4- (2- (dimethylamino) -7- azaspiro [3.5] nonyl- 7- yl) -2- methoxybenzene Base) amino) pyrimidine-4-yl) amino base) phenyl) dimethyl phosphine；With

31) (2- ((the chloro- 2- of 5- ((4- (9- (dimethylamino) -3- azaspiro [5.5] hendecane -3- base) -2- methoxyl group Phenyl) amino) pyrimidine-4-yl) amino base) phenyl) dimethyl phosphine.

Another object of the present invention is to provide the method for preparation above compound, preparation route such as option A or C institute Show:

Option A

Scheme C

Wherein the preparation method of A5 is as shown in option b:

Option b

Another object of the invention be to provide above compound preparation treatment ALK and/or EGFR and they Non-small cell lung cancer and other cancers caused by being mutated, with ROS1, BRAF, c-MET, HER2, KRAS/MEK, PIK3CA, FDFR, The cancer of the inhibitor combination therapy such as DDR2 and/or VEGFR and with the combination therapies such as cytotoxin such as docetaxel or carboplatin Cancer drug in application.

Definition and explanation:

C_1-6Selected from by C₁, C₂, C₃, C₄, C₅And C₆The group of composition, the group of digital representation carbon atom number；C_3-6It is selected from In by C₃, C₄, C₅And C₆The group of composition.

C_1-6Alkyl, C_1-6Miscellaneous alkyl, C_3-6Naphthenic base, C_3-6Heterocyclylalkyl, C_1-6Alkyl is by C_3-6Naphthenic base or C_3-6Heterocycle alkane Base replaces and C_1-6Miscellaneous alkyl is by C_3-6Naphthenic base or C_3-6Heterocyclylalkyl replaces, including but not limited to: methyl, ethyl, n-propyl, Isopropyl ,-CH₂C(CH₃)(CH₃) (OH), cyclopropyl, cyclobutyl, propylmethylene, cyclopropyl acyl, benzyloxy, cyclopropyl alkene Base, trifluoromethyl, amino methyl, methylol, methoxyl group, methylacyl, methoxy acyl group, methyl sulphonyl, methylsulfinyl, Ethyoxyl, acetyl group, ethylsulfonyl, ethoxy acyl group, dimethylamino, diethylamino, dimethylamino and diethyl amino Base；N(CH₃)₂,NH(CH₃),-CH₂CF₃,-CH2CH₂CF₃,-CH₂CH₂F,-CH₂CH₂S (=O)₂CH₃,-CH₂CH₂CN,-CH₂CH₂F,-CH₂CF₃,- CH₂CH₂CF₃,-CH₂CH₂NH₂,-CH₂CH₂OH,-CH₂CH₂OCH₃,-CH₂CH₂CH₂OCH₃,-CH₂CH₂N(CH₃)₂,-S (=O)₂CH₃,-CH₂CH₂S (=O)₂CH₃, Here institute The term " pharmaceutically acceptable " of use is for those compounds, material, composition and/or dosage form, they are can Within the scope of the medical judgment leaned on, use is contacted suitable for the tissue with human and animal, without excessive toxicity, stimulation Property, allergic reaction or other problems or complication, match with reasonable interests/Hazard ratio.

Term " pharmaceutically acceptable salt " refers to the salt of the compounds of this invention, by present invention discover that have specific substitution It is prepared by the compound of base and the acid of relative nontoxic or alkali.It, can when in the compound of the present invention containing relatively acid functional group To pass through the side for using the alkali of sufficient amount to contact with the neutral form of this kind of compound in pure solution or suitable atent solvent Formula obtains base addition salts.Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt. It, can be by pure solution or suitable atent solvent when in the compound of the present invention containing relatively alkaline functional group Acid-addition salts are obtained with the mode that the acid of sufficient amount is contacted with the neutral form of this kind of compound.Pharmaceutically acceptable acid addition The example of salt includes inorganic acid salt, and the inorganic acid includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphorus A sour hydrogen radical, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc.；And acylate, the organic acid include As acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, Phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, the tartaric acid acid similar with methanesulfonic acid etc.；Further include amino acid (such as Arginine etc.) salt, and such as glucuronic acid organic acid salt (referring to Berge et al., " Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)).Certain specificization of the invention It closes object and contains alkalinity and acid functional group, so as to be converted into any alkali or acid-addition salts.

Preferably, it contacts salt with alkali or acid in a usual manner, then separates parent compound, thus again in raw compounds Property form.The forms of the parent fo of compound and its various salt is the difference is that certain physical properties, such as in polarity Different solubility in solvent.

" pharmaceutically acceptable salt " used herein belongs to the derivative of the compounds of this invention, wherein by with acid at Salt modifies the parent compound at the mode of salt with alkali.The example of pharmaceutically acceptable salt includes but is not limited to: base Such as the inorganic acid or acylate of amine, the alkali metal of acid group such as carboxylic acid or organic salt etc..Pharmaceutically acceptable salt packet The quaternary ammonium salt of conventional avirulent salt or parent compound is included, such as nontoxic inorganic acid or organic acid are formed by salt.Often The avirulent salt of rule includes but is not limited to the salt that those are derived from inorganic acid and organic acid, the inorganic acid or organic acid choosing From Aspirin, 2- ethylenehydrinsulfonic acid, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate radical, carbonic acid, lemon Lemon acid, edetic acid(EDTA), ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic, hydrobromic acid, salt Acid, hydriodate, hydroxyl, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, first Alkyl sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, poly galacturonic, propionic acid, salicylic acid, stearic acid, Asia Acetic acid, succinic acid, sulfamic acid, p-aminobenzene sulfonic acid, sulfuric acid, tannin, tartaric acid and p-methyl benzenesulfonic acid.

Pharmaceutically acceptable salt of the invention can pass through conventional chemical side by the parent compound containing acid group or base Method synthesis.Under normal circumstances, the preparation method of such salt is: in the mixture of water or organic solvent or both, via trip It reacts from acid or these compounds of alkali form with the alkali appropriate of stoichiometry or acid to prepare.It is generally preferable that ether, acetic acid The non-aqueous medias such as ethyl ester, ethyl alcohol, isopropanol or acetonitrile.

In addition to the form of salt, there is also prodrug forms for compound provided by the present invention.Compounds described herein Chemical change easily occurs in physiological conditions for prodrug to be converted to the compound of the present invention.In addition, pro-drug can be with The compound of the present invention is switched to by chemistry or biochemical method in environment in vivo.

Certain compounds of the invention can exist with nonsolvated forms or solvation form, including hydrate shape Formula.In general, solvation form is suitable with non-solvated form, it is intended to be included within the scope.Of the invention Certain compounds can exist with polycrystalline or amorphous form.

Certain compounds of the invention can have asymmetric carbon atom (optical centre) or double bond.It is racemic modification, non-right Isomers, geometric isomer and single isomers is reflected to be included within the scope of the present invention.

The diagrammatic representation of the compound of raceme, ambiscalemic and scalemic or enantiomer-pure herein is come From Maehr, J.Chem.Ed.1985,62:114-120.1985,62:114-120.Unless otherwise indicated, with wedge key and void Line key indicates the absolute configuration of a Stereocenter.When compound described herein contains in olefinic double bond or other geometry asymmetry The heart, unless otherwise prescribed, they include E, Z geometric isomer.Similarly, all tautomeric forms are included in the present invention Within the scope of.

The compound of the present invention may exist specific geometry or stereoisomer form.It is contemplated by the invention that all is this kind of Compound, including cis and trans isomer, (-)-and (+)-to enantiomer, (R)-and (S)-enantiomer, diastereoisomer, (D)-isomers, (L)-isomers and its racemic mixture and other mixtures, such as enantiomter or diastereomer richness The mixture of collection, all these mixtures are within the scope of the present invention.May be present in the substituent groups such as alkyl it is other not Symmetric carbon atom.All these isomers and their mixture, are included within the scope of the present invention.

Can by chiral synthesis or chiral reagent or other routine techniques prepare optically active (R)-and (S)- Isomers and D and L isomers.If expecting a kind of enantiomer of certain compound of the invention, asymmetric syntheses can be passed through Or prepared by the derivatization with chiral auxiliary, wherein gained non-enantiomer mixture is separated, and auxiliary group is split It opens to provide pure required enantiomter.Alternatively, when containing basic functionality (such as amino) or acidic functionality (such as in molecule Carboxyl) when, the salt of diastereoisomer is formed with optically active acid appropriate or alkali, then passes through known in the field point One step crystallizing or chromatography carry out diastereoisomer fractionation, and then recycling obtains pure enantiomer.In addition, enantiomter and The separation of diastereoisomer is usually to be completed by using chromatography, and the chromatography uses chiral stationary phase, and optionally Ground combines (such as generating carbaminate by amine) with chemical derivatization.

The compound of the present invention can include the original of unnatural proportions on one or more atoms for constituting the compound Daughter isotope.For example, radioisotope labeled compound can be used, such as tritium (³H), iodine-125 (¹²⁵I) or C-14 (¹⁴C).This The transformation of all isotopics of the compound of invention, no matter radioactivity whether, be included within the scope of the present invention.

Term " pharmaceutically acceptable carrier " is to refer to deliver effective quantity active material of the present invention, do not interfere active matter The bioactivity of the matter and any preparation having no toxic side effect to host or patient or the representative carrier of mounting medium include Water, oil, vegetables and minerals, cream base, lotion base, ointment bases etc..These matrix include suspending agent, tackifier, transdermal rush Into agent etc..Their preparation is well known to the technical staff in cosmetic field or topical remedy field.Other letters about carrier Breath can refer to Remington:The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams&Wilkins (2005), the content of the document are incorporated herein by reference.

Term " excipient " typically refers to carrier, diluent and/or medium required for preparing drug composition effective.

For drug or pharmacologically active agents, term " effective quantity " or " therapeutically effective amount " refer to nontoxic but can reach To the drug of desired effect or enough dosages of medicament.For the peroral dosage form in the present invention, a kind of active material in composition " effective quantity " refer to when being combined with active material another in the composition for the required dosage that achieves the desired results.Have The determination of effect amount varies with each individual, and age and ordinary circumstance depending on receptor also depend on specific active material, close in case Suitable effective quantity can be determined by those skilled in the art according to routine test.

Term " active constituent ", " therapeutic agent ", " active material " or " activating agent " refers to a kind of chemical entities, it can have The therapeutic purpose disorder of effect ground, disease or illness.

Term " substituted " refers to that any one or more hydrogen atoms in specific atoms are substituted with a substituent, including weight The variant of hydrogen and hydrogen, as long as the compound after the valence state of specific atoms is normal and substitution is stable.When substituent group is When ketone group (i.e.=O), it is meant that two hydrogen atoms are substituted.Ketone substitution does not occur on aromatic radical.Term " is optionally substituted " refer to and can be substituted, can not also be substituted, unless otherwise prescribed, the type and number of substituent group in chemistry can be with It can be arbitrary on the basis of realization.

When any variable (such as R) occurs more than once in the composition of compound or structure, in every case Under definition be all independent.Thus, for example, the group can be optionally if a group is replaced 0-2 R At most replaced two R, and R in each case has independent option.In addition, the group of substituent group and/or its variant Conjunction is only just allowed in the case where such group of credit union generates stable compound.

When the key of a substituent group can be cross connected to two atomic time on a ring, this substituent group can be with this Arbitrary atom on a ring is mutually bonded.When not indicating it is connected to chemical knot by which atom in cited substituent group Include in structure general formula but be not specifically mentioned compound when, this substituent group can be mutually bonded by its any atom.Substituent group And/or the combination of its variant is only just allowed in the case where such group of credit union generates stable compound.

Alkyl and miscellaneous alkyl atomic group (including be commonly known as alkylidene, alkenyl, sub- miscellaneous alkyl, miscellaneous thiazolinyl, alkynyl, Those of naphthenic base, Heterocyclylalkyl, cycloalkenyl and heterocycloalkenyl group) substituent group be commonly referred to as " alkyl substituent ", it Can be one or more of selected from but not limited to following groups :-R ' ,-OR ' ,=O ,=NR ' ,=N-OR ' ,-NR ' R " ,- SR ', halogen ,-SiR ' R " R " ', OC (O) R ' ,-C (O) R ' ,-CO₂R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、 NR’C(O)NR”R”’、-NR”C(O)₂R ' ,-NR " " '-C (NR ' R " R ' ")=NR " ", NR " " C (NR ' R ")=NR ' " ,-S (O) R’、-S(O)₂R’、-S(O)₂NR’R”、NR”SO₂R’、-CN、–NO₂、-N₃、-CH(Ph)₂With fluoro (C₁-C₄) alkyl, substituent group Number is 0~(2m '+1), and wherein m ' is the sum of carbon atom in this kind of atomic group.R', R ", R " ', R " " and R " " ' it is respectively independent The preferred hydrogen in ground, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted aryl (such as are replaced by 1~3 halogen Aryl), substituted or unsubstituted alkyl, alkoxy, thio alkoxy group or aralkyl.When the compound of the present invention packet When including more than one R group, for example, each R group is independently to be subject to selection, as when there are more than one R', R ", R " ', R " " and R " " ' group when each of these groups.When R' and R " is attached to the same nitrogen-atoms, they can be with The nitrogen-atoms combines and forms 5-, 6- or 7- member ring.For example,-NR'R " is intended to include but are not limited to 1- pyrrolidinyl and 4- morpholine Base.According in the above-mentioned discussion about substituent group, it will be understood by those skilled in the art that term " alkyl " is intended to include carbon atom It is bonded to the group that non-hydrogen group is constituted, such as halogenated alkyl (such as-CF₃、-CH₂CF₃) and acyl group (such as-C (O) CH₃、-C (O)CF₃、-C(O)CH₂OCH₃Deng).Similar to substituent group described in alkyl radicals, aryl and heteroaryl substituent are commonly referred to collectively as " aryl substituent ", is selected from such as-R ' ,-OR ' ,-NR ' R " ,-SR ' ,-halogen ,-SiR ' R " R " ', OC (O) R ' ,-C (O) R ' ,- CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’ R " R ' ")=NR " ", NR " " C (NR ' R ")=NR ' " ,-S (O) R ' ,-S (O)₂R’、-S(O)₂NR’R”、NR”SO₂R’、-CN、– NO₂、-N₃、-CH(Ph)₂, fluorine (C₁-C₄) alkoxy and fluorine (C₁-C₄) alkyl etc., the quantity of substituent group is 0 to open on aromatic rings Between the sum of chemical valence；Wherein R ', R ", R " ', R " " and R " " ' preferably independently be selected from hydrogen, substituted or unsubstituted alkane Base, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When the compound of the present invention includes more than one R group, for example, each R group is independently to be subject to selection, as worked as There are more than one R ', R ", R " ', R " " and R " " ' group when each of these groups.

Two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally-T-C (O)-by general formula Replaced the substituent group of (CRR ') q-U-, wherein T and U is independently selected from-NR- ,-O-, CRR'- or singly-bound, q be 0 to 3 it is whole Number.Alternatively, two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally-A by general formula (CH2) replaced the substituent group of r B-, wherein A and B is independent is selected from-CRR '-,-O- ,-NR- ,-S- ,-S (O)-, S (O)₂-、- S(O)₂NR '-or singly-bound, r are 1~4 integers.Optionally, a singly-bound on the new ring being consequently formed could alternatively be double Key.Alternatively, two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally-A by general formula (CH2) replaced the substituent group of r B-, wherein s and d is independently selected from 0~3 integer, and X is-O- ,-NR ' ,-S- ,-S (O)-、-S(O)₂Or-S (O)₂NR'-.Substituent R, R ', R " and R " ' preferably separately are selected from hydrogen and are substituted or are not taken (the C in generation₁-C₆) alkyl.

Unless otherwise prescribed, term " halogenated element " or " halogen " itself or a part as another substituent group indicate fluorine, Chlorine, bromine or iodine atom.In addition, term " halogenated alkyl " is intended to include monohaloalkyl alkyl and multi-haloalkyl.For example, term " halogen Generation (C₁-C₄) alkyl " be intended to include but are not limited to trifluoromethyl, 2,2,2- trifluoroethyls, 4- chlorobutyl and 3- bromopropyl etc. Deng.

The example of halogenated alkyl includes but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl group and five chloroethyls. " alkoxy " represents the abovementioned alkyl with given number carbon atom connected by oxygen bridge.C_1-6Alkoxy includes C₁、C₂、C₃、 C₄、C₅And C₆Alkoxy.The example of alkoxy includes but is not limited to: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, just Butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- amoxy." naphthenic base " includes saturation ring group, such as cyclopropyl, ring Butyl or cyclopenta.3-7 naphthenic base includes C₃、C₄、C₅、C₆And C₇Naphthenic base." alkenyl " includes the hydrocarbon of straight chain or branched chain Wherein there are one or more carbon-to-carbon double bonds, such as vinyl and acrylic on stabilization site any on the chain in chain.

Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.

Terms used herein " hetero atom " includes the atom other than carbon (C) and hydrogen (H), for example including oxygen (O), nitrogen (N), sulphur (S), silicon (Si), germanium (Ge), aluminium (Al) and boron (B) etc..

Unless otherwise indicated, term " miscellaneous ", " hetero atom " or " miscellaneous free radical " (i.e. free radical contains hetero atom), including remove carbon It (C) and the outer atom of hydrogen (H) also include, above-mentioned heteroatomic free radical.For example including oxygen (O), nitrogen (N), sulphur (S), silicon (Si), Germanium (Ge), aluminium (Al) and boron (B) etc. further include any substituted-C (=O) N (H)-,-N (H)-,-C (=NH)-,-S (=O) 2N (H)-, or-S (=O) N (H)-.

" ring " indicate substituted or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, be substituted or Unsubstituted aryl or substituted or unsubstituted heteroaryl.So-called ring includes condensed ring.The number of ring atom is usual It is defined as first number of ring, for example, " 5~7 member ring " refers to around 5~7 atoms of arrangement.Unless otherwise prescribed, the ring is optional Ground includes 1~3 hetero atom.Therefore, " 5~7 member ring " includes such as phenylpyridine and piperidyl；On the other hand, term " 5~7 Membered heterocycloalkyl ring " includes pyridyl group and piperidyl, but does not include phenyl.Term " ring " further includes the ring containing at least one ring System, each of these " ring " independently conforms to above-mentioned definition.

Term " heterocycle " or " heterocycle " mean stable monocycle or bicyclic or bicyclic heterocycle, they can be saturation, Part is unsaturated or unsaturated (aromatics), they include carbon atom and 1,2,3 or 4 ring independently selected from N, O and S Hetero atom, wherein above-mentioned any heterocycle can be fused on a phenyl ring formed it is bicyclic.Nitrogen and sulfur heteroatom can be optionally oxidized (i.e. NO and S (O) p).Nitrogen-atoms can be that substituted or unsubstituted (i.e. N or NR, wherein R is H or defined mistake herein Other substituent groups).The heterocycle can be attached in the side group of any hetero atom or carbon atom to form stable structure.Such as Fruit generate compound be it is stable, the substitution on carbon potential or nitrogen position can occur for heterocycle as described herein.Miscellaneous nuclear nitrogen is former Son is optionally quaternized.One preferred embodiment is that, when the sum of S in heterocycle and O atom is more than 1, these hetero atoms are each other It is non-conterminous.Another preferred embodiment is that the sum of S and O atom is no more than 1 in heterocycle.As used herein, term " aromatic heterocycle Group " or " heteroaryl " mean stable 5,6,7 unit monocycles or bicyclic or 7,8,9 or 10 membered bicyclic heterocycles aromatic rings, it Include carbon atom and 1,2,3 or 4 ring hetero atom independently selected from N, O and S.Nitrogen-atoms can be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituent groups of defined mistake herein).Nitrogen and sulfur heteroatom can be optionally oxidized (i.e. NO and S (O) p).It is worth noting that, the sum of S and O atom is no more than 1 on aromatic heterocycle.Bridged ring is also contained in determining for heterocycle In justice.Bridged ring is formed when one or more atoms (i.e. C, O, N or S) connects two non-conterminous carbon atoms or nitrogen-atoms.It is excellent The bridged ring of choosing includes but is not limited to: a carbon atom, two carbon atoms, a nitrogen-atoms, two nitrogen-atoms and a carbon-to-nitrogen Base.It is worth noting that, monocycle is always converted into tricyclic by a bridge.In bridged ring, the substituent group on ring can also appear in bridge On.

The example of heterocyclic compound includes but is not limited to: acridinyl, azocine base, benzimidazolyl, benzofuranyl, benzene And sulfydryl furyl, benzo mercaptophenyl, benzoxazolyl, benzoxazoles quinoline base, benzothiazolyl, benzotriazole base, benzo Tetrazole radical, benzo isoxazolyl, benzisothia oxazolyl, benzimidazoline base, carbazyl, 4aH- carbazyl, carboline base, benzo two Hydrogen pyranose, chromene, cinnoline base decahydroquinolyl, 2H, 6H-1,5,2- dithiazine base, dihydrofuran simultaneously [2,3-b] tetrahydrofuran Base, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazole radicals, 1H- indazolyl, indoles alkenyl, indolinyl, middle nitrogen Indenyl, indyl, 3H- indyl, isatino base, isobenzofuran-base, pyrans, isoindolyl, iso-dihydro-indole-group, different Yin Diindyl base, indyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridines base, octahydro isoquinoline Quinoline base, 1,2,3- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,5- oxadiazoles base, 1,3,4- oxadiazoles base, is disliked at oxadiazoles base Oxazolidinyl, oxazolyl, isoxazolyl, hydroxyindole base, pyrimidine radicals, phenanthridinyl, phenanthroline, azophenlyene, phenthazine, benzo xanthine Base, phenol oxazines base, phthalazinyl, piperazinyl, piperidyl, piperidone base, 4- piperidone base, piperonyl, pteridyl, purine radicals, pyrrole Mutter base, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido oxazole, pyridine-imidazole, pyridothiazole, Pyridyl group, pyrimidine radicals, pyrrolidinyl, pyrrolinyl, 2H- pyrrole radicals, pyrrole radicals, pyrazolyl, quinazolyl, quinolyl, 4H- quinoline Piperazine base, quinoxalinyl, quininuclidinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazole radical, 6H-1,2,5- thiophenes Diazine, 1,2,3- thiadiazolyl group, 1,2,4- thiadiazolyl group, 1,2,5- thiadiazolyl group, 1,3,4- thiadiazolyl group, thianthrene group, thiophene Oxazolyl, isothiazolyl thienyl, thienyl, thieno oxazolyl, thiophene benzothiazolyl, Thienoimidazole base, thienyl, triazine Base, 1,2,3- triazolyl, 1,2,4- triazolyl, 1,2,5- triazolyl, 1,3,4- triazolyl and xanthyl.It further include condensed ring and spiral shell Cycle compound.

Unless otherwise prescribed, term " alkyl " or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl etc.) sheet Body indicates straight chain, branch or cricoid hydrocarbon atomic group or combinations thereof as a part of of another substituent group, can be Fully saturated, unit or polynary unsaturated, can be it is monosubstituted, two replace or polysubstituted, may include divalent or more Valence atomic group, carbon atom (such as C with specified quantity₁-C₁₀Indicate 1 to 10 carbon)." alkyl " includes but is not limited to aliphatic hydrocarbon Base and aryl radical, the aliphatic group include chain and ring-type, are specifically including but not limited to alkyl, alkenyl, alkynyl, the virtue Fragrant alkyl includes but is not limited to aryl radical of 6-12 member, such as benzene, naphthalene etc..In some embodiments, term " alkyl " indicates Straight chain or branch atomic group or their combination can be fully saturated, unit or polynary unsaturated, may include Divalent and polyad group.The example of saturated hydrocarbons atomic group includes but is not limited to methyl, ethyl, n-propyl, isopropyl, positive fourth Base, tert-butyl, isobutyl group, sec-butyl, isobutyl group, cyclohexyl, (cyclohexyl) methyl, Cvclopropvlmethvl and n-pentyl, just oneself The homologue or isomers of the atomic groups such as base, n-heptyl, n-octyl.Unsaturated alkyl has one or more double or triple bonds, The example includes but is not limited to vinyl, 2- acrylic, cyclobutenyl, crotyl, 2- isopentene group, 2- (butadienyl), 2,4- Pentadienyl, 3- (Isosorbide-5-Nitrae-pentadienyl), acetenyl, 1- and 3- propinyl, 3- butynyl and more advanced homologue and different Structure body.

Unless otherwise prescribed, term " miscellaneous alkyl " or its subordinate concept (such as miscellaneous alkyl, miscellaneous thiazolinyl, miscellaneous alkynyl, heteroaryl Base etc.) itself or combine the stable straight chain of expression, branch or cricoid hydrocarbon atomic group with another term or combinations thereof, It is made of the carbon atom and at least one hetero atom of certain amount.In some embodiments, term " miscellaneous alkyl " itself or with Another term joint indicates stable straight chain, branch hydrocarbon atomic group or combinations thereof object, there is the carbon atom and extremely of certain amount Few hetero atom composition.In an exemplary embodiment, hetero atom is selected from B, O, N and S, wherein nitrogen and sulphur atom optionally by Oxidation, nitrogen heteroatom are optionally quaternized.Any interior location that hetero atom B, O, N and S can be located at miscellaneous alkyl (removes the hydrocarbon Ji Ji is attached to except the position of molecule rest part).Example includes but is not limited to-CH₂-CH₂-O-CH₃、-CH₂-CH₂-NH- CH₃、-CH₂-CH₂-N(CH₃)-CH₃、-CH₂-S-CH₂-CH₃、-CH₂-CH₂、-S(O)-CH₃、-CH₂-CH₂-S(O)₂-CH₃,-CH= CH-O-CH₃、-CH₂- CH=N-OCH₃With-CH=CH-N (CH₃)-CH₃.At most two hetero atoms can be continuously, such as- CH₂-NH-OCH₃。

Term " alkoxy ", " alkylamino " and " alkylthio group " (or thio alkoxy) belongs to idiomatic expression, refers to and leads to respectively It crosses an oxygen atom, amino or sulphur atom and is connected to those of rest part of molecule alkyl group.

Unless otherwise prescribed, term " cyclic hydrocarbon radical ", " heterocyclic hydrocarbyl ", " the miscellaneous base of cyclic hydrocarbon " or its subordinate concept (such as virtue It is the miscellaneous base of base, heteroaryl, heterocyclic base, naphthenic base, Heterocyclylalkyl, cycloalkanes, cycloalkenyl, heterocycloalkenyl, the miscellaneous base of cyclenes, cycloalkynyl radical, miscellaneous Miscellaneous base of cycloalkynyl radical, cycloalkyne etc.) itself or combine " alkyl " for respectively indicating cyclisation, " miscellaneous alkyl " with other terms or " hydrocarbon is miscellaneous Base ".In addition, hetero atom can take up heterocycle attachment for miscellaneous alkyl or heterocyclic hydrocarbyl (such as miscellaneous alkyl, Heterocyclylalkyl) In the position of molecule rest part.The example of naphthenic base includes but is not limited to cyclopenta, cyclohexyl, 1- cyclohexenyl group, 3- hexamethylene Alkenyl, suberyl etc..The non-limiting example of heterocycle includes 1- (1,2,5,6- tetrahydro pyridyl), 1- piperidyl, 2- piperidines Base, 3- piperidyl, 4- morpholinyl, morpholinyl, tetrahydrofuran -2- base, tetrahydrofuran indol-3-yl, thiophane -2- base, Thiophane -3- base, 1- piperazinyl and 2- piperazinyl.

Unless otherwise prescribed, term " aryl " indicates the aromatics hydrocarbon substituent of how unsaturated, can be monosubstituted, two substitutions Or it is polysubstituted, it can be monocycle or polycyclic (preferably 1 to 3 ring), they are fused together or are covalently attached.Term is " miscellaneous Aryl " refers to containing one to four heteroatomic aryl (or ring).In an exemplary embodiment, hetero atom be selected from B, N, O and S, wherein nitrogen and sulphur atom are optionally oxidized, and nitrogen-atoms is optionally quaternized.Heteroaryl can be connected to point by hetero atom The rest part of son.The non-limiting embodiment of aryl or heteroaryl includes phenyl, 1- naphthalene, 2- naphthalene, 4- xenyl, 1- pyrrole Cough up base, 2- pyrrole radicals, 3- pyrrole radicals, 3- pyrazolyl, 2- imidazole radicals, 4- imidazole radicals, pyrazinyl, 2- oxazolyl, 4- oxazolyl, 2- Phenyl -4- oxazolyl, 5- oxazolyl, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- thiazolyl, 4- thiazolyl, 5- Thiazolyl, 2- furyl, 3- furyl, 2- thienyl, 3- thienyl, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine Base, 4- pyrimidine radicals, 5- benzothiazolyl, purine radicals, 2- benzimidazolyl, 5- indyl, 1- isoquinolyl, 5- isoquinolyl, 2- quinoxalinyl, 5- quinoxalinyl, 3- quinolyl and 6- quinolyl.The substituent group of above-mentioned any one aryl and heteroaryl ring system Selected from acceptable substituent group described below.

For simplicity, aryl when being used in combination with other terms (such as aryloxy group, arylthio, aralkyl) includes such as The aryl and heteroaryl ring of upper definition.Therefore, term " aralkyl " is intended to include that aryl is attached to those of alkyl atomic group (example Such as benzyl, phenethyl, pyridylmethyl), including wherein carbon atom (such as methylene) by such as oxygen atom replace that A little alkyl, such as phenoxymethyl, 2- pyridine oxygen methyl 3- (1- naphthoxy) propyl etc..

Term " leaving group " refer to can by another functional group or atom by substitution reaction (such as it is affine replace it is anti- Answer) replaced functional group or atom.For example, representative leaving group includes triflate；Chlorine, bromine, iodine；Sulphonic acid ester Base, such as methanesulfonates, tosylate, brosylate, p-methyl benzenesulfonic acid ester；Acyloxy, such as acetoxyl group, trifluoro second Acyloxy etc..

Term " protecting group " includes but is not limited to " amino protecting group ", " hydroxyl protection base " or " sulfhydryl protected base ".Term " amino protecting group " refers to suitable for the blocking group for preventing side reaction on ammonia nitrogen position.Representative amino protecting group includes But it is not limited to: formoxyl；Acyl group, such as alkanoyl (such as acetyl group, trichloroacetyl or trifluoroacetyl group)；Alkoxy carbonyl Base, such as tert-butoxycarbonyl (Boc)；Arylmethoxycarbonyl groups, such as benzyloxycarbonyl group (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc)；Aryl Methyl, such as benzyl (Bn), trityl (Tr), 1,1- bis--(4'- methoxyphenyl) methyl；Silicyl, such as trimethyl first silicon Alkyl (TMS) and t-butyldimethylsilyl (TBS) etc..Term " hydroxyl protection base " refers to suitable for prevention hydroxyl The protecting group of side reaction.Representative hydroxyl protection base includes but is not limited to: alkyl, such as methyl, ethyl and tert-butyl；Acyl group, example Such as alkanoyl (such as acetyl group)；Aryl methyl, such as benzyl (Bn), to methoxy-benzyl (PMB), 9- fluorenyl methyl (Fm) and two Phenyl methyl (benzhydryl, DPM)；Silicyl, such as trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS) etc..

General formula preparation example:

In some embodiments, the compound with formula (I) can be prepared according to the synthetic method described in option A.

Option A

Phosphonate ester (A1) is reacted with Grignard Reagent, such as is reacted in solvents tetrahydrofurane or ether with methyl-magnesium-bromide, Obtain phosphorous oxide (A2).Coupling reaction is under palladium chtalyst in a solvent as, such as potassium carbonate, obtained virtue in the presence of DMF and alkali Base phosphoric-oxygenic compound A3；A3 can be converted into phosphorus sulphur compound by the effect of lawesson reagent.Aryl phosphorous oxides or vulcanization Object is reacted with dichloro pyrimidine derivative or other dichloro heterocyclic compounds, obtains compound A4, it can be with arylamine A7 in acid It is coupled under the conditions of property, such as in the presence of Loprazolam, obtains the compounds of this invention A8 using the tert-butyl alcohol as solvent reaction, or can be with Further reaction, such as reduction amination obtain the compound of formula (I).Loop coil amine compound A5 can chemically suppliers be purchased It buys, such as Aldrich Chemical, or can be prepared by option b below.Loop coil amino-compound A5 by Substitution reaction occurs in solvent (such as DMF), obtains compound A6, arylamine A7 is obtained by further hydrogenating reduction.

Option b

Option b is the general synthetic method of loop coil aminated compounds B5 (A5), and ketone B1 is reacted with cyan-acetic ester, obtains spiral shell Cycle compound B2, hydrolysis obtain B3, then B4, with reducing agent such as lithium aluminium hydride reduction, restore B4 and obtain B5；B5 can in option A Aryl chloride A4 be coupled to obtain A6.

Scheme C

Scheme C is the general synthetic method for preparing formula (I) compound, and wherein T1 is CH.C1 compound aldehyde and ethylene methacrylic Base ketone reacts under alkali such as KOH effect, obtains ketone C2, and hydrogenation obtains C3, triflated generation C4；Then with amino Aryl or nitro virtue boric acid are coupled to obtain C5, and reduction obtains compound C6；Then it is coupled with compound A4, obtains chemical combination of the present invention Object C7 can further react, such as reduction amination, obtain the compound of formula (I).

The present invention is further described by embodiment now.Example given below is for illustration purposes only, rather than It is only limitted to the range of the invention.The compound of the present invention can be prepared with known methods many in organic synthesis field.This The embodiment of invention method as described below can be used synthesize and synthetic organic chemical art in known synthesis side Method, or pass through improved method on its basis.Preferred method includes, but are not limited to that method is described below.

All solvents used in the present invention are commercially available, and can be used without being further purified.Reaction is usually lazy Under property nitrogen, carried out in anhydrous solvent.Proton magnetic resonance (PMR) data are recorded in Bruker Avance III 400 (400MHz) On spectroscope, chemical shift is indicated with (ppm) at tetramethylsilane low field.Mass spectrum is in 1200 series of Agilent plus 6110 (& It is measured on 1956A).LC/MS or Shimadzu MS includes a DAD:SPD-M20A (LC) and Shimadzu Micromass 2020 detectors.Mass spectrograph is equipped with the electric spray ion source (ESI) operated under a positive or negative mode.

The present invention uses following initialisms: aq represents water；DCM represents methylene chloride；PE represents petroleum ether；DMF represents N, Dinethylformamide；DMSO represents dimethyl sulfoxide；EtOAc represents ethyl acetate；EtOH represents ethyl alcohol；MeOH represents first Alcohol；Cbz represents benzyloxycarbonyl group, a kind of amine protecting group；Boc represents tertiary butyl oxycarbonyl, a kind of amine protecting group；HOAc represents second Acid；NaBH(OAc)₃Represent sodium triacetoxy borohydride；R.t represents room temperature；THF represents tetrahydrofuran；Boc₂O represents two uncles Butyl dicarbonate；TFA represents trifluoroacetic acid；DIPEA represents diisopropylethylamine；Pd(dppf)Cl₂Represent [1,1'- bis- (two Phenyl phosphino-) ferrocene] palladium chloride (II)；POCl₃Represent phosphorus oxychloride；NaH represents sodium hydride；LAH represents lithium aluminium hydride reduction； Pd(OAc)₂Represent palladium (II) acetate；Pd₂(dba)₃Represent tris(dibenzylideneacetone) dipalladium；Pd(PPh₃)₄Represent four (triphens Base phosphine) palladium；Et₃SiH represents triethylsilane；PPh₃Represent triphenylphosphine；Xantphos represents 4,5- bis- (diphenylphosphinos)- 9,9- dimethyl；MeSO₃H represents methanesulfonic acid；Xphos represents 2- dicyclohexyl phosphino- -2', 4', 6'- tri isopropyl biphenyl；Labor Gloomy reagent represents 2,4- bis- (4- methoxyphenyl) -1,3- dithia -2,4- diphosphane -2,4- disulphide；NBS represents N- bromine For succimide；T-BuOK represents potassium tert-butoxide.

Compound manually orSoftware name, commercial compound use supplier's directory name.

With the Shimadzu equipped with Shimadzu SIL-20A autosampler and Japanese Shimadzu DAD:SPD-M20A detector LC20AB system carries out efficient liquid phase chromatographic analysis, using Xtimate C18 (3m filler, specification are 2.1x 300mm) chromatography Column.0-60AB_6 minutes methods: applying linear gradient, starts to elute with 100%A (aqueous solution that A is 0.0675%TFA), And elution is terminated with 60%B (the MeCN solution that B is 0.0625%TFA), whole process is 4.2 minutes, is then eluted with 60%B 1 minute.Reached 100:0 for chromatographic column rebalancing 0.8 minute, total run time is 6 minutes.10-80AB_6 minutes methods: it answers With linear gradient, start to elute with 90%A (aqueous solution that A is 0.0675%TFA), and (B is 0.0625%TFA's with 80%B Acetonitrile solution) terminate elution, whole process is 4.2 minutes, then with 80%B elution 1 minute.Chromatographic column rebalancing 0.8 is divided Clock reaches 90:10, and total run time is 6 minutes.Column temperature is 50 DEG C, flow velocity 0.8mL/min.Diode array detector scanning Wavelength is 200-400nm.

Thin-layer chromatographic analysis (TLC) is carried out on the silica GF254 of Sanpont-group, commonly uses ultraviolet lamp irradiation inspection Spotting out also inspects spot using other methods in some cases, in these cases, (about 1g is added in 10g silica gel with iodine Iodine is simultaneously thoroughly mixed), vanillic aldehyde (dissolution about 1g vanillic aldehyde in 100mL 10%H₂SO₄In be made), ninhydrin (from Aldrich is bought) or special color developing agent (be thoroughly mixed (NH₄)₆Mo₇O₂₄·4H₂O、5g(NH₄)₂Ce(IV)(NO₃)₆、450mL H₂The dense H2SO of O and 50mL₄And be made) expansion lamellae, inspect compound.Using Still, W.C.；Kahn,M.；and Mitra, M.Journal of Organic Chemistry, the similar approach of technology disclosed in 1978,43,2923-2925., Flash column chromatography is carried out on 40-63 μm of (230-400 mesh) silica gel of Silicycle.Flash column chromatography or thin-layer chromatography it is common Solvent is the mixture of methylene chloride/methanol, ethyl acetate/methanol and hexane/ethyl acetate.

Preparation chromatography point is carried out using the gloomy UV/VIS-156 detector of gill in 322 system of Gilson-281Prep LC Analysis, used chromatographic column is Agella Venusil ASB Prep C18,5m, 150x 21.2mm；Phenomenex Gemini C18,5m,150x 30mm；Boston Symmetrix C18,5m,150x 30mm；Or Phenomenex Synergi C18,4m,150x 30mm.When flow velocity is about 25mL/min, with the acetonitrile/water eluting compounds of low gradient, Contain 0.05%HCl, 0.25%HCOOH or 0.5%NH in middle water₃·H₂O, total run time are 8-15 minutes.

Specific embodiment

In order to which the present invention is described in more detail, following Examples are provided, but the scope of the present invention is not limited to this.

Process A

Embodiment 1

(2- ((the chloro- 2- of 5- ((2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphine oxide

Embodiment 1A

1- methoxyl group -4- vinyl benzene

The bromo- 4- methoxybenzene of 1- (8.15 grams, 43.6 mMs), and vinyl potassium trifluoborate (7.08 grams, 52.8 mmoles You), Pd (dppf) Cl₂(1.6 grams, 2.20 mMs) and cesium carbonate (28.7 grams, 88.1 mMs) are in 1,4- dioxane The mixture of (120mL) and water (25mL) is heated to 110 DEG C, and stirs 16 hours.TLC display reaction is completed, and reaction is mixed Object filtering, filtrate are concentrated to dryness, and obtain crude product；Crude product obtains title compound by isolating and purifying by column chromatography (PE) Object (yellow oily, 3.45 grams, yield 59%).

Embodiment 1B

2,2- bis- chloro- 3- (4- methoxyphenyl) cyclobutanone

Embodiment 1A (3.45 grams, 9.33 mMs) and copper-zincon (3.18 grams, 64.3 mMs) are in anhydrous THF The mixture of (25.0mL) is heated to flow back, and phosphorus oxychloride (7.78 grams, 50.7 mMs) and 2 successively then are added dropwise, and 2,2- tri- Anhydrous THF (25.0mL) solution of chloracetyl chloride (8.75 grams, 48.1 mMs), after being added dropwise 1 hour.Reaction mixture is flowed back Lower stirring 12 hours.TLC (PE) display reaction is completed, and mixture is filtered, and filtrate decompression concentration obtains brown oil compound (6.0 grams, crude product) are directly used in and react in next step.

Embodiment 1C

3- (4- methoxyphenyl) cyclobutanone

Under stiring, into the mixture of the HOAc (25.0mL) of Zn powder (6.4 grams, 98.4 mMs), embodiment is added dropwise HOAc (25.0mL) solution of 1B (6.0 grams, 24.6 mMs).Reaction mixture is heated to 70 DEG C, and stirs 4 hours.It will be anti- It answers mixture to filter, is concentrated to dryness, obtain crude product, isolated and purified by preparing HPLC, obtain pale yellowish oil compounds (1.02 grams, yield 24%).¹H NMR(400MHz,CDCl₃): δ, 7.23 (dd, J=6.8,1.6Hz, 2H), 6.91 (dd, J= 9.6,2.8Hz,2H),3.82(s,3H),3.70-3.55(m,1H),3.54-3.40(m,2H),3.70-3.55(m,2H).

Embodiment 1D

Methyl 2- (3- (4- methoxyphenyl) cyclobutyl) second

At 0 DEG C, to sodium hydride (278 milligrams, 6.96 mMs, 60%) in the suspension of anhydrous THF (20.0mL), It is added dropwise methyl 2- (diethoxy phosphoryl) ethyl acetate (1.46 grams, 6.96 mMs), reaction mixture stirs 0.5 at 0 DEG C Hour.Then embodiment 1C (1.02 grams, 5.80 mMs) is dissolved in anhydrous THF (10mL), is then added dropwise to above-mentioned anti- Answer mixture.Mixture is warming up to 23 DEG C, stirs 16h at 23 DEG C.TLC (PE: ethyl acetate=10:1) display has been reacted At.Reaction mixture is cooled to 0 DEG C, is slowly added into water (20mL) quenching reaction, and the mixture is extracted with EtOAc (20mL) It takes.Organic layer is washed with water (10mL) and salt water (10mL) respectively, then dry with anhydrous sodium sulfate, and is concentrated to dryness, and is obtained It is purified (PE: ethyl acetate=10:1) by column chromatography, obtains (0.99 gram, 73%) of title compound as nothing by crude product Color grease.¹H NMR(400MHz,CDCl₃): δ, 7.21 (d, J=8.8Hz, 2H), 6.90 (d, J=8.8Hz, 2H), 5.80- 5.68(m,1H),3.83(s,3H),3.73(s,3H),3.58-3.48(m,2H),3.33-3.16(m,2H),2.98-2.90(m, 1H).

Embodiment 1E

Methyl 2- (3- (4- methoxyphenyl) -1- (nitromethyla) cyclobutyl) second

Nitromethane is added in the mixture of anhydrous THF (25.0mL) to embodiment 1D (0.99 gram, 4.27 mMs) (521 milligrams, 8.54 mMs) and TBAF (1.67 grams, 6.41 mMs).Reaction mixture is heated to 70 DEG C, and stirs 16 Hour.Mixture is cooled to 18 DEG C, and is concentrated to dryness, crude product is obtained, by its by column chromatography (PE: ethyl acetate=9: 1) it purifies, obtains title compound (1.15g, yield 92%), be light yellow oil.¹H NMR(400MHz,CDCl₃):δ, 7.18-7.08(m,2H),6.94-6.88(m,2H),4.89(s,1H),4.71(s,1H),3.82(s,3H),3.75(s, 1.5H),3.71(s,1.5H),3.65-3.47(m,1H),2.90(s,1H),2.75(s,1H),2.65-2.57(m,1H), 2.52-2.44(m,1H),2.32-2.26(m,1H),2.20-2.10(m,1H).

Embodiment 1F

2- (4- methoxyphenyl) -6- azaspiro [3.4] octyl- 7- ketone

Under 18 DEG C of nitrogen protections, into methanol (15.0mL) solution of embodiment 1E (1.15 grams, 3.92 mMs), add Enter Raney-Ni (0.20g).Reaction mixture is heated to 50 DEG C, and (pressure: 50Psi) stirs 16 hours in hydrogen.LCMS is aobvious Show that reaction is completed.Reaction mixture is filtered by diatomite, filtrate decompression concentration, obtaining title compound, (0.77 gram, slightly produce Product) it is white solid.LCMS(ESI)(10-80CD):m/z:232.2[M+1].

Embodiment 1G

2- (4- methoxyphenyl) -6- methyl -6- azaspiro [3.4] octyl- 7- ketone

At 0 DEG C, into anhydrous DMF (5.0mL) mixture of NaH (60 milligrams, 1.5 mMs, 60%), it is added and implements Example 1F (230 milligrams, 1.0 mMs)；Reaction mixture is stirred 1 hour at 0 DEG C.Then be added MeI (213 milligrams, 1.5 MM, it is dissolved in the anhydrous THF of dry 5mL) it is added dropwise in said mixture.Mixture is warming up to 16 DEG C and is stirred It mixes 16 hours.LCMS shows fully reacting, water (20mL) quenching reaction is added into reaction solution, and extracted with ethyl acetate (20mL) It takes.Organic layer is washed with water (10mL) and salt water (10mL) respectively, dry with anhydrous sodium sulfate, is concentrated to dryness, is obtained titled Closing (0.24 gram, crude product) of object is yellow oil.LCMS(ESI)(5-95AB):m/z:246.3[M+1].

Embodiment 1H

2- (4- methoxyl group -3- nitrobenzophenone) -6- methyl -6- azaspiro [3.4] octyl- 7- ketone

Acetic anhydride (5.0mL) solution of embodiment 1G (240 milligrams, 1.0 mMs) is cooled to 0 DEG C, concentrated nitric acid (1.0mL) is slowly added in reaction mixture；Reaction mixture is warming up to 18 DEG C, and stirs 2h.LCMS display has been reacted Entirely.Mixture is filtered, filtrate is concentrated at reduced pressure conditions, obtains title compound (202 milligrams, crude product), is yellow oily Object.LCMS(ESI)(5-95AB):m/z:291.2[M+1].

Embodiment 1I

2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline

At 0 DEG C, into THF (10.0mL) solution of embodiment 1H (202 milligrams, 0.70 mM), LAH (106 is added Milligram, 2.80 mMs)；Reaction mixture is heated to 70 DEG C and is stirred 12 hours.LCMS shows fully reacting.Reaction is mixed It closes object and is cooled to 0 DEG C, ethyl acetate (20.0mL) quenching reaction is added dropwise, water (2.0mL) then is added；Mixture is filtered, is filtered Liquid is concentrated under reduced pressure, and obtaining title compound (120mg, crude product) is brown oil.LCMS(ESI)(10-80CD):m/ z:247.2[M+1].

Embodiment 1J

Dimethyl phosphine oxide

THF (800mL) solution of MeMgBr (1.30 moles, 434.46mL) is cooled to 0 DEG C, in N₂Under protection, diethyl Phosphonate ester (60.0 grams, 434.46 mMs, be dissolved in 40mL THF) is added dropwise in reaction mixture, and 2h is added dropwise and protects Internal temperature is held not higher than 0 DEG C.After adding, reaction mixture is warming up to 20 DEG C and is stirred 14 hours.Solution of potassium carbonate (177 Gram, it is dissolved in 250mL water) it is added to quenching reaction in reaction mixture.There is white solid appearance, mixture is filtered, filters Cake is washed with ethyl alcohol (100mL), and filtrate is concentrated, and the solid occurred during filtering and concentrating.Toluene (200mL) is added to filter It in liquid, and is concentrated to dryness and removes excessive moisture, obtain title compound (30.11 grams, 385.78 mMs, 88.79% yield) For the grease of colorless viscous.¹HNMR(400MHz,CDCl₃):δ,7.74-7.67(m,0.5H),6.57-6.52(m,0.5H), 1.56 (d, J=3.6Hz, 3H), 1.53 (d, J=3.6Hz, 3H)

Embodiment 1K

(2- aminophenyl) dimethyl phosphine

By 2- iodobenzene amine aqueous solution (12.50 grams, 57.07 mMs) and embodiment 1J (5.35 grams, 68.49 mMs), K₃PO₄(14.54 grams, 68.49 mMs), Xantphos (660.44 milligrams, 1.14 mMs) and palladium acetate (256.26 milligrams, 1.14 mMs) it is placed in DMF (80mL), reaction mixture under nitrogen protection, is heated to 100 DEG C and stirs 16 hours. LCMS (DCM: methanol=10:1) display reaction is completed.Mixture is filtered and is concentrated, by gained residue HCL aqueous solution (1N, 80mL) dilution adjusts pH value to about 2, gained mixture is filtered.Filtrate is extracted with DCM (100mL × 2), by water layer It separates, and pH value is adjusted to about 9 with sodium bicarbonate aqueous solution, then extracted with DCM (200mL × 2).Organic layer is used Anhydrous sodium sulfate is dried and concentrated to dry.By crude product by recrystallization (PE: ethyl acetate=5:1) purifying, obtain titled Closing (6.00 grams, 35.47 mMs, 62.15% yield) of object is white solid.¹H NMR(400MHz,CDCl₃):δ,7.20(t,J =7.6Hz, 1H), 7.04 (dd, J=13.6,7.6Hz, 1H), 6.69-6.58 (m, 2H), 5.35 (br s, 2H), 1.75 (s, 3H),1.71(s,3H).LCMS(ESI)(10-80CD):m/z:170.1[M+1].

Embodiment 1L

(2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine

At 16 DEG C, to embodiment 1K (2.50 grams, 14.8 mMs) and 2, (2.85 grams, 15.5 in the least for 4,5- trichloropyrimidines Mole) DMF (20mL) mixture in, be added DIPEA (3.82 grams, 29.6 mMs).Then reaction mixture is heated to 70 DEG C and stirring 16 hours.TLC display reaction is completed.By reaction mixture with water (50mL) dilute, and with EtOAc (40mL × 3) it extracts.Combined organic phase is washed with saturated brine (20mL × 2), anhydrous sodium sulfate is dried, filtered and is concentrated in vacuo.Slightly Product recrystallizes in ethanol, obtains (3.20 grams, 10.1 mMs, 68.4% yield) of title compound as white solid.¹H NMR(400MHz,CD₃OD): δ, 8.50 (dd, J=8.0,4.0Hz, 1H), 8.35-8.28 (m, 1H), 7.69-7.59 (m, 2H), 7.36-7.28(m,1H),1.91(s,3H),1.88(s,3H).LCMS(ESI)(5-95AB):m/z:315.9[M+1].

Embodiment 1M

To embodiment 1I (120 milligrams, 0.49 mM), embodiment 1L (154 milligrams, 0.49 mM) is in the tert-butyl alcohol In the mixture of (5.0mL), MeSO is added₃H (141 milligrams, 1.47 mMs)；Reaction mixture is heated under nitrogen protection It is reacted 12 hours to 90 DEG C.LCMS shows fully reacting, after reduced pressure, obtains crude product, it is passed through preparation HPLC separation Purifying obtains (52.2 milligrams, yield 20%) of title compound as brown oil.¹H NMR(400MHz,CD₃OD):δ,8.45 (s,1H),8.31-8.27(m,1H),8.10(s,1H),7.82(s,1H),7.70-7.64(m,1H),7.57-7.51(m,1H), 7.34-7.30(m,1H),6.95-6.89(m,2H),3.86(s,3H),3.53(s,1H),3.44(s,1H),3.35-3.32(m, 1.5H),3.28-3.22(m,1.5H),2.96(s,1.5H),2.88(s,1.5H),2.44-2.39(m,1H),2.36-2.27 (m,2H),2.21-2.14(m,2H),2.12-2.08(m,1H),1.87(s,3H),1.84(s,3H).LCMS(ESI)(5- 95AB):m/z:526.2[M+1].

Embodiment 2

2- (3- ((the chloro- 4- of 5- ((2- (dimethyl phosphine acyl group) phenyl) amino) pyrimidine -2-base) amino) -4- methoxybenzene Base) -6- methyl -6- azaspiro [3.4] octane 7- ketone

Embodiment 2A

2- (3- amino-4-methoxyl phenyl) -6- methyl -6- azaspiro [3.4] octane-7-ketone

Under protection of argon gas, it into MeOH (5.0mL) solution of embodiment 1H (701 milligrams, 2: 42 mMs), is added Pd/C (150 milligrams)；Reaction mixture is in H₂It is reacted 16 hours under (pressure: 15psi) in 22 DEG C.LCMS display reacts complete At reaction mixture is filtered by diatomite, filtrate decompression concentration, and it is white solid for obtaining (596 milligrams, crude product) of title compound Body.LCMS(ESI)(10-80CD):m/z:261.2[M+1].

Embodiment 2B

The present embodiment preparation method is consistent with method described in embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- nitrogen Miscellaneous spiral shell [3.4] octane -2- base) aniline 2- (3- amino-4-methoxyl phenyl) -6- methyl -6- azaspiro [3.4] octane -7- Ketone replaces.Obtained title compound is brown oil (32% yield).LCMS(ESI)(5-95AB):m/z:540.1[M+ 1].

Process B

Embodiment 3

(2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2,8- diaza spiro [4.5] decane -8- base) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphine

Embodiment 3A

Tert-butyl 4- (2- ethyoxyl -2- oxo ethylidene) piperidines -1- t-butyl formate

At 0 DEG C, the anhydrous THF of Xiang Yiji 2- (diethoxy phosphoryl) ethyl acetate (6.18 grams, 27.6 mMs) In (100mL) solution, NaH (1.2 grams, 30.1 mMs, 60%) are slowly added portionwise, it is small which stirs 1 at 0 DEG C When, then tert-butyl -4- oxo-piperidine -1- t-butyl formate (5 grams, 25.1 mMs) is slowly added into reaction mixture. Reaction mixture stirs 12 hours at 0 DEG C.TLC (petroleum ether: ethyl acetate=3:1) display reaction is completed.Into reaction solution Water (50mL) quenching reaction is added, is extracted with EtOAc (100mL), the dry organic layer of anhydrous sodium sulfate, and be concentrated to dryness, it obtains (4.95 grams, yield 73%) of title compound are white solid.¹H NMR(400MHz,CDCl₃):δ,5.73(s,1H),4.23- 4.14(m,2H),3.53-3.47(m,4H),2.96-2.93(m,2H),2.31-2.28(m,2H),1.48(s,9H),1.28- 1.32(m,3H).

Embodiment 3B

Tert-butyl 4- (2- ethyoxyl -2- oxoethyl) -4- (nitromethyla) piperidines -1- t-butyl formate

At 30 DEG C, into MeCN (100mL) reaction mixture of embodiment 3A (5 grams, 18.6 mMs), DBU is added (5.62 grams, 37.0 mMs) and nitromethane (2.3 grams, 37 mMs), reaction mixture is heated to 80 DEG C and stirring 12 is small When, TLC (PE: ethyl acetate=3:1) display reaction is completed.Reaction mixture is concentrated to remove solvent；Obtained residue It is diluted with EtOAc (50mL), and successively uses water (30mL), be saturated NaHCO 3 (20mL) and salt water (20mL) washing；Anhydrous slufuric acid Sodium dries organic layer, and is concentrated to get brown oil, is isolated and purified, is obtained with column chromatography (PE: ethyl acetate=10:1,8:1) It is colorless oil to (3.2 grams, yield 52.4%) of title compound.1H NMR(400MHz,CDCl3):δ,4.76(s,2H), 4.24-4.16 (q, J=7.2Hz, 2H), 3.57-3.52 (m, 2H), 3.44-3.39 (m, 2H), 2.64 (s, 2H), 1.68-1.63 (m, 4H), 1.48 (s, 9H), 1.30 (t, J=7.2Hz, 3H) .LCMS (ESI) (5-95AB): m/z:353.1 [M+Na⁺].

Embodiment 3C

Tert-butyl -3- oxo -2,8- diaza spiro [4.5] decane -8- carboxylic acid, ethyl ester

Methanol (50mL) solution of embodiment 3B (1.5 grams, 4.54 mMs) stirs 10 minutes, then protects under argon gas Under, it is added Raney Ni (150 milligrams, 10%).Reaction mixture is heated to 50 DEG C of stirrings 12 under hydrogen (pressure: 50psi) Hour.TLC (PE: ethyl acetate=10:1) display reaction is completed.Reaction mixture is filtered and is concentrated, and obtains title compound (920 milligrams, yield 80%) are white solid.LCMS(ESI)(5-95AB):m/z:509.4[2M+1].

Embodiment 3D

2,8- diaza spiro [4.5] decane -3- ketone

It is small to stir 12 at 30 DEG C for DCM/TFA (5mL/5mL) mixture of embodiment 3C (920 milligrams, 3.62 mMs) When, TLC (PE: ethyl acetate=1:1) display is completed.Reaction mixture is concentrated under reduced pressure to obtain crude product, and the crude product is molten In Xie Shui (30mL), pH is adjusted to 10 with sodium hydroxide solution (1N)；(15mL × 4) are extracted with dichloromethane in the mixture. Combined organic layer is dried and concentrated with anhydrous sodium sulfate, and obtaining title compound (550mg, yield 98%) is yellow oily Object.

Embodiment 3E

8- (3- methoxyl group -4- nitrobenzophenone) -2,8- diaza spiro [4.5] decane -3- ketone

Into DMF (15mL) solution of embodiment 3D (550 milligrams, 3.57 mMs), and addition potassium carbonate (1.5 grams, 10.7 MM) and (855 milligrams, 5.0 mMs of the fluoro- 2- methoxyl group -1- nitrobenzene of 4-；Then, reaction mixture is heated to 90 DEG C simultaneously Stirring 12 hours.TLC (DCM: methanol=20:1) display reaction is completed.Reaction mixture is diluted with EtOAc (50mL), is successively used Water (20mL) is saturated NaHCO₃(20mL), salt water (20mL) washing, organic phase anhydrous Na₂SO₄It is dry, it then filters and is concentrated Obtain brown oil, crude product is isolated and purified by column chromatography (DCM: methanol=20:1), obtain title compound (1.02 grams, Yield 95%) it is yellow solid.¹H NMR (400MHz, DMSO-d6): δ, 7.89 (d, J=9.6Hz, 1H), 7.59 (s, 1H), 6.60 (dd, J=2.4Hz, 9.6Hz, 1H), 6.51 (d, J=2.4Hz, 1H), 3.90 (s, 3H), 3.59-3.56 (m, 2H), 3.44-3.42 (m, 2H), 3.17 (d, J=5.2Hz, 2H), 3.10 (s, 2H), 1.64-1.61 (t, J=5.6Hz, 4H) .LCMS (ESI)(5-95AB):m/z:306.3[M+1].

Embodiment 3F

8- (4- amino -3- methoxyphenyl) -2,8- diaza spiro [4.5] decane -3- ketone

At 30 DEG C, to the EtOH (10mL) of embodiment 3E (500 milligrams, 1.64 mMs) and the mixture of water (10mL) In, iron powder (367 milligrams, 6.56 mMs) and ammonium chloride (260 milligrams, 4.92 mMs) are added.Reaction mixture heating It is stirred 5 hours to 80 DEG C, TLC (DCM: methanol=20:1) display reaction is completed.Reaction mixture filtering, filtrate are dense under vacuum Contracting obtains (450 milligrams, yield 99%) of title compound as dark oil object.

Embodiment 3G

2- methoxyl group -4- (2,8- diaza spiro [4.5] decane -8- base) aniline

Anhydrous THF (10mL) solution of embodiment 3F (400 milligrams, 1.45 mMs) stirs 0.5 hour at 0 DEG C, LiAlH₄(58 milligrams 1.53 mMs) are added in said mixture in batches.After adding, 80 DEG C are heated the mixture to instead It answers 12 hours.TLC (DCM: methanol=6:1) display reaction is completed.Water (10mL) is added into reaction mixture to be quenched, is used in combination DCM extracts (10mL × 3), and organic phase separation is dried and concentrated, and obtaining crude product is dark oil object, and crude product passes through preparation HPLC is isolated and purified, and obtaining title compound (80mg, yield 20%) is white solid.

Embodiment 3H

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with 2- methoxyl group -4- (2,8- diaza spiro [4.5] decane -8- base) aniline.It is white for obtaining title compound Color solid (yield 20%).LCMS(ESI)(5-95AB):m/z:541.1[M+1].

Embodiment 4

(2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2,7- diaza spiro [3.5] nonane -7- base) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphine

Embodiment 4A

Tert-butyl ester 7- (4- methoxyl group -3- nitrobenzophenone) -2,7- diaza spiro [3.5] nonane -2- carboxylate methyl ester

2,7- diaza spiros [3.5] nonane -2- carboxylic acid tert-butyl ester (100 milligrams, 0.44 mM), the fluoro- 2- methoxyl group-of 4- DMSO (3mL) mixture of 1- nitrobenzene (113 milligrams, 0.66 mM) and potassium carbonate (152 milligrams, 1.1 mMs), heating To 90 DEG C and stir 12 hours.LCMS display reaction is completed, and water (20mL) is added to reaction mixture, and with DCM (25mL × 2) Extraction.Organic layer is washed with brine, is dried, filtered and concentrated with anhydrous sodium sulfate, residue is obtained, crude product preparation TLC isolates and purifies (PE: ethyl acetate=1:1) and obtains (150 milligrams, yield 90%) of title compound as yellow oil. LCMS(ESI)(5-95AB):m/z:378.1[M+1].

Embodiment 4B

Tert-butyl ester 7- (3- amino-4-methoxyl phenyl) -2,7- diaza spiro [3.5] nonane -2- carboxylate methyl ester

The present embodiment is prepared according to the method for embodiment 3F, by 8- (3- methoxyl group -4- nitrobenzophenone) -2,8- diaza spiro [4.5] decane -3- ketone replaces with tert-butyl ester 7- (4- methoxyl group -3- nitrobenzophenone) -2,7- diaza spiro [3.5] nonane -2- carboxylic Sour methyl esters.Title compound is obtained, is green oil object (crude product), is directly used in next step.LCMS(ESI)(5-95AB): m/z:348.2[M+1].

Embodiment 4C

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with tert-butyl ester 7- (3- amino-4-methoxyl phenyl) -2,7- diaza spiro [3.5] nonane -2- carboxylic acid first Ester.Obtaining title compound is colorless oil compound (yield 16%).LCMS(ESI)(5-95AB):m/z:527.1[M+1].

Embodiment 5

(2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2- methyl -2,7- diaza spiro [3.5] nonane -7- base) phenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide

Embodiment 5A

1- tert-butyl -4- methyl -4- (chloromethyl) piperidines -1,4- dicarboxylic ester

In N₂Protection, at -78 DEG C, to 1- tert-butyl -4- methyl piperidine-Isosorbide-5-Nitrae-dicarboxylic ester (4.60 grams, 18.91 mmoles You, 1.00 equivalents) tetrahydrofuran (100mL) solution in, LDA (2M, 18.91mL) solution is added dropwise.After being added dropwise to complete, mix Object is closed in -78 DEG C and stirred under nitrogen atmosphere 2 hours.Then at -78 DEG C, by a syringe by chloroiodomethane (10 grams, 56.72 mMs) it is added dropwise in reaction mixture.Then, acquired solution is slowly ramped to 20 DEG C and stirring 12 is small When.Reaction system is quenched with aqueous ammonium chloride solution, and ethyl acetate and water are added into reaction system.By organic layer separation and it is dense Contracting, crude product isolates and purifies through column chromatography (petroleum ether: ethyl acetate=100:1 to 25:1), obtain title compound (2.39 grams, 8.19 mMs, 43.32% yield) it is yellow oil.¹H NMR(400MHz,CDCl₃):3.86(br.s.,2H)3.76(s, 3H) 3.59 (br.s., 2H) 3.00 (br.s., 2H), 2.16 (d, J=13.2Hz, 2H) 1.45 (m, 9H)

Embodiment 5B

Tert-butyl 4- (chloromethyl) -4- (methylol) piperidines -1- t-butyl formate

The anhydrous tetrahydrofuran solution (150mL) of embodiment 5A (14.4 grams, 49.35 mMs) is cooled to 0 DEG C, LAH (2.25 grams, 59.22 mMs) are slowly added into solution in batches, and the mixed liquor is stirred 25 minutes at 0 DEG C.TLC Show fully reacting, mixture is quenched at 0-10 DEG C with water (2.25mL), be then added sodium hydroxide solution (1N, 2.25mL), mixture filters；Filter cake washs (30mL × 2) with ethyl acetate, then filtrate water (150mL) and salt water (150mL) washing, anhydrous sodium sulfate is dry, concentration, and obtaining title compound, (9.79 grams, 37.12 mMs, 75.21% produces Rate) it is light yellow oil.¹H NMR(400MHz,CDCl₃):3.69-3.56(m,4H),3.47-3.37(m,4H),1.60- 1.51(m,4H),1.50-1.43(m,9H).

Embodiment 5C

Tert-butyl 4- (chloromethyl) -4- formyl piperidine -1- t-butyl formate

At -65 DEG C, diformazan is added into the dichloromethane solution (90mL) of oxalyl chloride (5.34 grams, 42.07 mMs) Methylene chloride (20mL) solution of base sulfoxide (6.57 grams, 84.15 mMs).Then, embodiment 5B (9.79 grams, 37.12 mmoles You) dichloromethane solution (20mL) be added dropwise in said mixture, and keep internal temperature lower than -60 DEG C.Reaction is mixed Object is closed to stir 15 minutes at -65 DEG C to -60 DEG C.Then at -60 DEG C, triethylamine (18.77 is added into reaction mixture Gram, 185.49 mMs).After adding, reaction mixture is warming up to room temperature (20 DEG C), uses saturated sodium bicarbonate aqueous solution (50mL) is quenched.Organic layer is separated, and is washed with salt water (30mL), it is dry with anhydrous sodium sulfate, and pass through column chromatography (dichloro Methane: methanol=50:1 to 10:1) is isolated and purified, and obtains (10.50 grams, crude product) of title compound as light yellow oil.¹H NMR (400MHz,CDCl₃): 9.59 (s, 1H), 3.92-3.67 (m, 2H), 3.62 (s, 2H), 3.10 (t, J=10.4Hz, 2H), 2.08 (dt, J=13.6,4.0Hz, 2H), 1.60-1.52 (m, 2H), 1.47 (s, 9H)

Embodiment 5D

Tert-butyl -2- methyl -2,7- diaza spiro [3.5] nonane -7- carboxylic acid, ethyl ester

At 15 DEG C, to embodiment 5C (10.50 grams, 40.12 mMs) and methylamine hydrochloride (10.51 grams, 155.65 millis Mole) methanol (100mL) mixed liquor in be added sodium cyanoborohydride (14.50 grams, 230.7 mMs), then, mixture exists It is stirred 16 hours at 100 DEG C.TLC shows fully reacting.Mixture is concentrated to dryness, obtained residue ethyl acetate (100mL) dilution, is washed with water (100mL) and salt water (100mL), is dried and concentrated with anhydrous sodium sulfate.Crude product is through column color Spectrum (methylene chloride: methanol=100:1 to 10:1) is isolated and purified, obtain title compound (4.20 grams, 17.48 mMs, 43.56% yield) it is yellow oil.¹H NMR(400MHz,CDCl₃):3.97(br.s.,4H),3.42-3.36(m,4H), 2.99(s,3H),1.94-1.84(m,4H),1.45(s,9H).

Embodiment 5E

2- methyl -2,7- diaza spiro [3.5] nonane

At 15 DEG C, hydrochloric acid/methanol (30mL) solution stirring 0.5 of embodiment 5D (4.20 grams, 17.48 mMs) is small When.TLC shows fully reacting.Mixture is concentrated, obtains (3.62 grams, hydrochloride) of title compound as white solid.¹H NMR(400MHz,CD₃OD): 4.24 (d, J=15.6Hz, 2H), 4.00 (d, J=15.2Hz, 2H), 3.29-3.15 (m, 4H), 2.99(s,3H),2.32-2.07(m,4H).

Embodiment 5F

7- (3- methoxyl group -4- nitrobenzophenone) -2- methyl -2,7- diaza spiro [3.5] nonane

The present embodiment is prepared according to the method for embodiment 4A, by the tert-butyl ester 2,7- diaza spiro [3.5] nonane -2- carboxylic acid first Ester replaces with 2- methyl -2,7- diaza spiro [3.5] nonane.Obtaining title compound is yellow solid, yield 92%.LCMS (ESI)(10-80CD):m/z:292.2[M+1].

Embodiment 5G

2- methoxyl group -4- (2- methyl -2,7- diaza spiro [3.5] nonyl- 7- yl) aniline

At 15 DEG C, to embodiment 5F (1.20 grams, 4.12 mMs) and ammonium chloride (1.40 grams, 26.17 mMs) Middle addition zinc powder (2.00 grams, 30.59 mMs) in the mixed liquor of methanol (20mL) and methylene chloride (2mL), then, reaction are mixed Liquid is closed to stir 10 minutes at 35 DEG C.TLC display reaction is completed.Mixture is filtered, filtrate is concentrated.Concentrated residues object is molten Solution in the solution of potassium carbonate (20mL) of saturation, and with the mixture of methylene chloride and methanol extraction (methylene chloride: methanol= 20:1,20mL*2).Combined organic layer is dried and concentrated with anhydrous sodium sulfate, obtain title compound (920 milligrams, 3.52 MM, 85.44% yield) it is bottle green grease.¹H NMR(400MHz,CDCl₃): 6.64 (d, J=8.4Hz, 1H), 6.53 (d, J=2.4Hz, 1H), 6.42 (dd, J=8.4,2.4Hz, 1H), 3.85 (s, 3H), 3.07 (s, 4H), 2.97-2.92 (m,4H),2.37(s,3H),1.95-1.85(m,4H).

Embodiment 5H

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with 2- methoxyl group -4- (2- methyl -2,7- diaza spiro [3.5] nonyl- 7- yl) aniline.Obtain title compound Object is yellow solid, yield 23%.¹H NMR(400MHz,CD₃OD):8.22(s,2H),7.87-7.61(m,3H),7.57- 7.45 (m, 1H), 7.38 (br.s., 1H), 7.12 (d, J=8.0Hz, 1H), 4.34 (d, J=10.4Hz, 2H), 4.06 (d, J= 11.2Hz, 2H), 3.99 (s, 3H), 3.74-3.49 (m, 4H), 3.03 (s, 3H), 2.51-2.30 (m, 4H), 1.89 (d, J= 13.6Hz,6H)；LCMS(ESI)(0-60AB):m/z:541.2[M+1].

Embodiment 6

(2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2,6- diaza spiro [3.4] octyl- 6- yl) phenyl) amino) pyrimidine -4- Base) amino) phenyl) dimethyl phosphine

Embodiment 6A

Tert-butyl 6- (4- methoxyl group -3- nitrobenzophenone) -2,6- diaza spiro [3.4] octane -2- t-butyl formate

The present embodiment is prepared according to the method for embodiment 4A, by the tert-butyl ester 2,7- diaza spiro [3.5] nonane -2- carboxylic acid first Ester replaces with tert-butyl ester 2,6- diaza spiro [3.4] octane -2- carboxylic acid tert-butyl ester.Obtaining title compound is colorless oil chemical combination Object, yield 92%.LCMS(ESI)(5-95AB):m/z:364.1[M+1].

Embodiment 6B

Tert-butyl 6- (3- amino-4-methoxyl phenyl) -2,6- diaza spiro [3.4] octane -2- carboxylic acid tert-butyl ester

The present embodiment is prepared according to the method for embodiment 3F, by 8- (3- methoxyl group -4- nitrobenzophenone) -2,8- diaza spiro [4.5] decane -3- ketone replaces with tert-butyl 6- (4- methoxyl group -3- nitrobenzophenone) -2,6- diaza spiro [3.4] octane -2- first Tert-butyl acrylate.Obtaining title compound is green oil object (crude product).LCMS(ESI)(5-95AB):m/z:334.2[M+1].

Embodiment 6C

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with the tertiary fourth of tert-butyl 6- (3- amino-4-methoxyl phenyl) -2,6- diaza spiro [3.4] octane -2- carboxylic acid Ester.Obtaining title compound is colorless oil, yield 19%.LCMS(ESI)(5-95AB):m/z:513.0[M+1].

Embodiment 7

(2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2- methyl -2,6- diaza spiro [3.4] octane -6- base) phenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide

Formalin (9.5 is added into the tetrahydrofuran solution (5mL) of embodiment 6C (50 milligrams, 0.039 mM) Milligram, 37%, 0.117 mM)；Reaction mixture stirs 30 minutes at 16 DEG C, and vinegar is then added into reaction mixture Sour sodium borohydride (25 milligrams, 0.117 mM), and stirred 12 hours at 16 DEG C.LCMS display reaction is completed.Reaction is mixed Object filtering is closed, by preparation HPLC purifying, obtains (9.6 milligrams, yield 46%) of title compound as white solid.LCMS (ESI)(5-95AB):m/z:527.2[M+1].

Embodiment 8

(((the chloro- 2- of 5- ((2- methoxyl group -4- (3,9- diaza spiro [5.5] hendecane -3- base) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphine

Embodiment 8A

9- benzyl -2,4- dioxo -3,9- diaza spiro [5.5] hendecane -1,5- dintrile

At 5-8 DEG C, ammonium acetate (2.04 grams, 26.42 mMs, 0.10 equivalent) be added to cyan-acetic ester (90 grams, 796 mMs, 3.00 equivalents) methanol solution (100mL) in；Then (50 grams, 0.264 mole) of 1-benzyl piepridine 4- ketone additions Into above-mentioned reaction mixture；Then, at 10 DEG C hereinafter, ammonium hydroxide (46.3 grams, 370 mMs, 1.40 equivalents) is added to reaction In mixture, which is stirred 1 hour at 0-5 DEG C.Then reaction mixture is warming up to 20 DEG C (room temperatures), and stirs 20 Hour.LCMS display generates product.Water (100mL) is added in mixture, and is heated to 55 DEG C.Concentrated hydrochloric acid (12M) is added will PH is adjusted to 4, and temperature is kept to be no more than 70 DEG C.Then reaction solution is cooled to 10 DEG C, stirring is filtered after 30 minutes.Filter cake water Air drying is placed in washing, obtains (66 grams, 77% yield) of title compound as white solid.LCMS(ESI)(0- 30AB):m/z:323.0[M+1].

Embodiment 8B

1'- benzyl -3,7- diaza spiro [two rings [3.3.1] nonane -9,4'- piperidines] -2,4,6,8- tetrones

Sulfuric acid (88%, the 4mL) mixed liquor of embodiment 8A (1.00 grams, 3.10 mMs, 1.00 equivalents) stirs at 60 DEG C It mixes 4 hours.Then water (1.4mL) is added into reaction solution, and is heated to 100 DEG C and stirs 1 hour.Add again into reaction mixture Enter water (5mL), and be cooled to 10 DEG C, and stirred 30 minutes at 10 DEG C, is then filtered.Filter cake is washed and is done with cold water (5mL) It is dry, (1.11 grams, crude product) of title compound are obtained as white solid.¹H NMR(400MHz,CDCl₃):11.87(s,2H),9.56 (br.s., 1H), 7.47 (s, 5H), 4.34 (d, J=4.4Hz, 2H), 3.75 (br.s., 1H), 3.22 (br.s., 4H), 1.88 (br.s.,4H).

Embodiment 8C

9- benzyl -3,9- diaza spiro [5.5] hendecane -2,4- diketone

At 15 DEG C, NaOH aqueous solution is added into the flask of embodiment 8B (1.10 grams, 3.22 mMs, 1.00 equivalents) Then mixture is warming up to 70 DEG C and stirred 4 hours by (5N, 5mL).Mixed liquor is cooled to 45 DEG C, then by concentrated hydrochloric acid (12N ,~1.5mL) is slowly added, until the pH value of solution is 7 or so.70-75 DEG C is heated the mixture to again, then will Dense HCl (12N ,~1mL) is added dropwise, to control the speed of carbon dioxide release, until pH value is adjusted to 3-4 or so.It will mixing Object is heated to 70-75 DEG C and goes forward side by side single step reaction 1 hour.Gained suspension is cooled to 10 DEG C and is stirred 0.5 hour.By solid mistake It filters and is washed with water in (25mL).Solid is dry, obtain title compound (380 milligrams, 1.40 mMs, 2 step yields It 45%) is white solid.¹H NMR(400MHz,CDCl₃):10.89(s,1H),10.60(br.s,1H),7.57(br.s., 2H),7.44(br.s.,3H),4.28(br.s.,2H),3.11(br.s.,4H),2.76(br.s.,2H),2.42(br.s., 2H),2.00-1.48(m,4H).

Embodiment 8D

3- benzyl -3,9- diaza spiro [5.5] hendecane

At 0-10 DEG C, to the tetrahydrofuran solution of embodiment 8C (10.6 grams, 38.92 mMs, 1.00 equivalents) Lithium aluminium hydride reduction (5.17 grams, 136.22 mMs, 3.50 equivalents) are added in (120mL), then stir mixed liquor at 65 DEG C Lower 3 hours.TLC display reaction is completed.Mixed liquor is cooled to 10 DEG C, and water (5.2mL) quenching reaction is added, is subsequently added into hydrogen Aqueous solution of sodium oxide (1N, 5.2mL).Mixture is filtered, filtrate concentration, obtain title compound (7.40 grams, 30.28 mmoles You, 77.81% yield) it is light yellow oil.¹H NMR(400MHz,CDCl₃):7.34-7.27(m,5H),3.52(s,2H), 2.88-2.73(m,4H),2.46-2.35(m,4H),1.58-1.51(m,4H),1.48-1.39(m,4H).

Embodiment 8E

Tert-butyl ester 3,9- diaza spiro [5.5] hendecane -3- carboxylate methyl ester

To embodiment 8D (500 milligrams, 2.05 mMs) and Boc₂The methyl alcohol mixed liquor of O (450 milligrams, 2.06 mMs) Middle addition triethylamine (311 milligrams, 3.08 mMs), then stirs mixture 16 hours at 20-30 DEG C.Reaction is mixed Object concentration, residue is diluted with ethyl acetate (20mL), and is washed with water (15mL × 2) and salt water (20mL), and organic layer is used Anhydrous sodium sulfate is dry, concentration.Crude intermediate is dissolved in ethyl alcohol (15mL) and acetic acid (2mL), palladium dydroxide/carbon is then added (0.1 gram), and the mixture is reacted 20 hours at hydrogen (50Psi).Mixture is filtered, filtrate concentration obtains title The acetate (320 milligrams, 1.26 mMs, 61.37% yield) of compound.

Embodiment 8F

Tert-butyl ester 9- (3- methoxyl group -4- nitrobenzophenone) -3,9- diaza spiro [5.5] hendecane -3- carboxylate methyl ester

The present embodiment is prepared according to the method for embodiment 4A, by tert-butyl 2,7- diaza spiro [3.5] nonane -2- carboxylic acid first Ester replaces with tert-butyl 3,9- diaza spiro [5.5] hendecane -3- t-butyl formate.Obtaining title compound is yellow oily Object, yield 62%.¹H NMR(400MHz,CD₃OD): δ, 7.95 (d, J=9.2Hz, 1H), 6.55 (dd, J=9.6,2.4Hz, 1H), 6.48 (d, J=2.4Hz, 1H), 3.95 (s, 3H), 3.56-3.41 (m, 8H), 1.72-1.65 (m, 4H), 1.58-1.50 (m,4H),1.48(s,9H).

Embodiment 8G

Tert-butyl ester 9- (4- amino -3- methoxyphenyl) -3,9- diaza spiro [5.5] hendecane -3- carboxylate methyl ester

The present embodiment is prepared according to the method for embodiment 3F, by 8- (3- methoxyl group -4- nitrobenzophenone -2,8- diaza spiro [4.5] decane -3- ketone replaces with tert-butyl ester 9- (3- methoxyl group -4- nitrobenzophenone) -3,9- diaza spiro [5.5] hendecane -3- Carboxylic acid, ethyl ester.Obtaining title compound is brown oil, yield 36%.LCMS(ESI)(5-95AB):m/z:376.2[M+1].

Embodiment 8H

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with tert-butyl ester 9- (4- amino -3- methoxyphenyl) -3,9- diaza spiro [5.5] hendecane -3- carboxylic acid first Ester.Obtaining title compound is yellow solid, yield 21%.LCMS(ESI)(5-95AB):m/z:555.2[M+1].

Embodiment 9

(2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide

The present embodiment is prepared according to the method for embodiment 7, by (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2,6- diazas Spiral shell [3.4] octyl- 6- yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine replaces with (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (3,9- diaza spiro [5.5] hendecane -3- base) phenyl) amino) pyrimidine-4-yl) amino) phenyl) diformazan Base phosphine oxide.Obtaining title compound is yellow solid, yield 57%.¹H NMR(400MHz,CD₃OD):δ,8.28(s,1H), 8.12 (br.s., 1H), 7.81-7.68 (m, 3H), 7.65 (d, J=2.0Hz, 1H), 7.56-7.49 (m, 1H), 7.37 (d, J= 8.8Hz, 1H), 4.02 (s, 3H), 3.74 (br.s., 4H), 3.47 (d, J=12.8Hz, 2H), 3.24 (t, J=12.8Hz, 2H),2.93(s,3H),2.42-1.97(m,5H),1.93-1.75(m,9H).LCMS(ESI)(0-60AB):m/z:569.2[M+ 1].

Embodiment 10

(2- ((the chloro- 2- of 5- ((4- (9- isopropyl -3,9- diaza spiro [5.5] hendecane -3- base) -2- methoxyphenyl) Amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide

Embodiment 8C (100 milligrams, 0.18 mM), acetic acid sodium borohydride (114 milligrams, 0.54 mM), acetic acid Tetrahydrofuran (5.0mL) mixture of (21.6 milligrams, 0.36 mM) and acetone (20.9 milligrams, 0.36 mM), 18 It is stirred 16 hours at DEG C.LCMS shows fully reacting.It is concentrated under reduced pressure and removes solvent, obtain crude product, it is passed through into preparation HPLC Purifying, obtaining title compound (50mg, yield 47%) is brown solid.LCMS(ESI)(10-80AB):m/z:597.3[M+ 1].

Embodiment 11

(2- ((the chloro- 2- of 5- ((2- (difluoro-methoxy) -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) Phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine

Embodiment 11A

The fluoro- 2- nitrophenol of 5-

At 0 DEG C, to the methylene chloride (30mL) of the fluoro- 2- methoxy nitrobenzene of 4- (3 grams, 17.53 mMs) of stirring Solution in Boron tribromide is added dropwise.Reaction solution stirs 1.5 hours at 0 DEG C.TLC (petroleum ether: ethyl acetate=10:1) display The fluoro- 2- methoxy nitrobenzene of 4- disappears.Solution is slowly added into ice water (100mL), and is extracted with methylene chloride (50mL × 3) It takes.Organic phase is dried and concentrated, obtaining title compound (2.5g, yield 90.8%) is yellow oil.¹H NMR (400MHz,CDCl₃): δ, 10.80 (s, 1H), 8.16 (dd, J=9.6,5.6Hz, 1H), 6.84 (dd, J=9.6,2.4Hz, 1H),6.77-6.67(m,1H).

Embodiment 11B

The fluoro- 1- nitrobenzene of 2- (difluoro-methoxy) -4-

Under constant stirring, molten to the n,N-Dimethylformamide (20mL) of embodiment 11A (2.0 grams, 12.73 mMs) ClCF is added in liquid₂COONa (6.9 grams, 44.56 mMs) and sodium carbonate (1.62 grams, 15.28 mMs).Reaction is mixed Liquid is heated to 90 DEG C and stirs 16 hours.TLC (petroleum ether: ethyl acetate=10:1) shows that the fluoro- 2- nitrophenol of 5- disappears.It will Reaction solution dilutes (100mL) with ethyl acetate, and is washed with water (20mL × 2).Organic layer is dried and concentrated, and obtains crude product, By it by silica gel column purification (petroleum ether: ethyl acetate=10:1), title compound (1.4g, yield 53.1%) is obtained as Huang Color grease.¹H NMR(400MHz,CDCl₃): δ, 8.07-7.98 (m, 1H), 7.17-7.05 (m, 2H), 6.65 (t, J= 72.0Hz,1H).

Embodiment 11C

Tert-butyl ester 9- (3- (difluoro-methoxy) -4- nitrobenzophenone) -3,9- diaza spiro [5.5] hendecane -3- carboxylic acid first Ester

The present embodiment is prepared according to the method for embodiment 4A, by the tert-butyl ester 2,7- diaza spiro [3.5] nonane -2- carboxylic acid first Ester replaces with the tert-butyl ester 3,9- diaza spiro [5.5] hendecane -3- t-butyl formate, and by the fluoro- 2- methoxyl group -1- nitro of 4- Benzene replaces with the fluoro- 1- nitrobenzene of 2- (difluoro-methoxy) -4-.Obtaining title compound is yellow oil, yield 77%.

Embodiment 11D

Tert-butyl ester 9- (4- amino -3- (difluoro-methoxy) phenyl) -3,9- diaza spiro [5.5] hendecane -3- carboxylic acid first Ester

The present embodiment is prepared according to the method for embodiment 3F, by 8- (3- methoxyl group -4- nitrobenzophenone -2,8- diaza spiro [4.5] decane -3- ketone replaces with tert-butyl ester 9- (3- (difluoro-methoxy) base -4- nitrobenzophenone) -3,9- diaza spiro [5.5] ten One alkane -3- carboxylic acid, ethyl ester.Obtaining title compound is green solid, yield 95%.LCMS(ESI)(5-95AB):m/z:412.2 [M+1].

Embodiment 11E

(2- ((the chloro- 2- of 5- ((2- (difluoro-methoxy) -4- (3,9- diaza spiro [5.5] hendecane -3- base) phenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with tert-butyl ester 9- (4- amino -3- (difluoro-methoxy) phenyl) -3,9- diaza spiro [5.5] hendecane -3- Carboxylate methyl ester.Title compound is white solid, yield 22%.LCMS(ESI)(0-60AB):m/z:591.2[M+1].

Embodiment 11F

The present embodiment is prepared according to the method for embodiment 7, by (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2,6- diazas Spiral shell [3.4] octyl- 6- yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine replaces with (2- ((the chloro- 2- of 5- ((2- (difluoro-methoxy) -4- (3,9- diaza spiro [5.5] hendecane -3- base) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) dimethyl phosphine oxide.Obtaining title compound is colorless oil, yield 22%.¹H NMR(400MHz,CD₃OD):δ,8.31(s, 1H),8.12(m,1H),7.86-7.84(m,1H),7.79-7.65(m,3H),7.62-7.55(m,1H),7.54-7.48(m, 1H), 7.08 (t, J=72.0Hz, 1H), 3.75-3.62 (m, 4H), 3.52-3.45 (m, 2H), 3.29-3.21 (m, 2H), 2.94 (s, 3H), 2.34-2.13 (m, 4H), 2.11-1.98 (m, 2H), 1.89 (d, J=13.6Hz, 6H), 1.88-1.79 (m, 2H) .LCMS(ESI)(5-95AB):m/z:605.2[M+1].

Embodiment 12

(2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) dimethyl sulfide

Embodiment 12A

(2- aminophenyl) dimethyl sulfide

(2- aminophenyl) dimethyl phosphine oxide (1.00 grams, 5.91 mMs) and lawesson reagent (4.78 grams, 11.82 mmoles You) it is placed in toluene (60mL), reaction mixture is heated to 110 DEG C and stirs 4 hours.TLC (petroleum ether: ethyl acetate=3: 1) display reaction is completed.Mixture is filtered and is concentrated, crude product obtains title compound by preparation HPLC (alkalinity) purifying (600 milligrams, 3.24 mMs, yield 54.81%) are colorless oil.¹H NMR(400MHz,CDCl₃):δ,7.31-7.27 (m,1H),7.22-7.15(m,1H),6.81-6.75(m,1H),6.68-6.60(m,1H),2.08(s,3H),2.05(s,3H)

Embodiment 12B

(2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl sulfide

Embodiment 12A (50.0 milligrams, 269.94 micromoles), (148.54 milligrams, 809.82 micro- rub 2,4,5- trichloropyrimidines You) and potassium carbonate (111.93 milligrams, 809.82 micromoles) be placed in n,N-Dimethylformamide (3mL), reaction mixture exists It is stirred 12 hours at 60 DEG C.TLC (petroleum ether: ethyl acetate=3:1) shows that product generates.Water is added into the reaction mixture (10mL), and extracted with ethyl acetate (10mL × 3).Combined organic layer is dried and concentrated, yellow oil is obtained.The oil Shape object by prepare TLC (petroleum ether: ethyl acetate=3:1) isolate and purify, obtain title compound (25.00 milligrams, 75.26 Micromole, 27.88% yield) it is yellow solid.¹H NMR(400MHz,CDCl₃):δ,10.12(br.s.,1H),8.28(s, 1H), 8.10 (dd, J=8.0,4.8Hz, 1H), 7.61 (dd, J=8.0,8.0Hz, 1H), 7.46 (dd, J=13.8,7.6Hz, 1H),7.33-7.28(m,1H),2.07(s,3H),2.04(s,3H).

Embodiment 12C

3- (3- methoxyl group -4- nitrobenzophenone) -3,9- diaza spiro [5.5] hendecane

Embodiment 8A (0.7 gram, 1.73 mMs) in the mixed solution of trifluoroacetic acid (4mL) and methylene chloride (4mL), It is stirred 1 hour at 16 DEG C.LCMS display reaction is completed.Aqueous sodium carbonate (50mL) is added into mixture, and uses dichloromethane Alkane (50mL × 2) extraction.Organic layer is dried, filtered and concentrated with anhydrous sodium sulfate, obtains title compound (0.7 gram, crude product) For yellow solid.LCMS(ESI)(0-60AB):m/z:306.0[M+1].

Embodiment 12D

3- (3- methoxyl group -4- nitrobenzophenone) -9- methyl -3,9- diaza spiro [5.5] hendecane

At 16 DEG C, it is water-soluble that formaldehyde is added into tetrahydrofuran (10mL) solution of example 12C (0.7 gram, 2.3 mMs) Liquid (207 milligrams, 6.9 mMs, 37%), and stirred 0.5 hour at 16 DEG C.Then be added acetic acid sodium borohydride (1.5 grams, 6.9 mMs), and stirred 12 hours at 16 DEG C.LCMS display reaction is completed.Mixture is dilute with methylene chloride (60mL) It releases, filter and is concentrated, obtain (0.6 gram, yield 82%) of title compound as yellow oil.LCMS(ESI)(0-60AB):m/ z:320.2[M+1].

Embodiment 12E

2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) aniline

To the EtOH/H of embodiment 12D (0.6 gram, 1.9 mMs)₂In O (12mL) mixed liquor be added iron powder (1.1 grams, 18.8 mMs) and ammonium chloride (1.1 grams, 18.8 mMs).Mixture is stirred 2 hours at 80 DEG C.TLC (DCM: methanol =6:1) show that reaction is completed.Reaction mixture is filtered and is concentrated.Obtained residue is passed through into preparation TLC purifying (DCM: methanol=6:1) obtains (400 milligrams, yield 74%) of title compound as green solid.¹H NMR(400MHz, CD₃OD): δ, 6.72 (d, J=8.4Hz, 1H), 6.64 (d, J=2.0Hz, 1H), 6.51 (d, J=8.4Hz, 1H), 3.86 (s, 3H),3.08-2.96(m,4H),2.58-2.45(m,4H),2.32(s,3H),1.75-1.52(m,8H).

Embodiment 12F

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with 2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) aniline, and by (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine replaces with (2- ((2,5- dichloro pyrimidine -4- base) amino) Phenyl) dimethyl sulfide.Obtaining title compound is brown solid, yield 36%.¹H NMR(400MHz,CD₃OD):δ,8.35 (s, 1H), 7.89 (dd, J=13.6,8.0Hz, 1H), 7.75-7.80 (m, 2H), 7.71 (d, J=8.8Hz, 1H), 7.57- 7.66 (m, 2H), 7.22 (d, J=8.4Hz, 1H), 4.02 (s, 3H), 3.69 (br.s., 4H), 3.47 (d, J=12.8Hz, 2H),3.18-3.29(m,2H),2.92(s,3H),2.19-2.38(m,2H),2.15-1.94(m,10H),1.75-1.91(m, 2H).LCMS(ESI)(0-60AB):m/z:585.2[M+1].

Process C

Embodiment 13

(2- ((the chloro- 2- of 5- ((4- (2- (dimethylamino) -7- azaspiro [3.5] nonyl- 7- yl) -2- methoxyphenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide

Embodiment 13A

Tert-butyl 2- (dimethylamino) -7- azaspiro [3.5] nonane -7- carboxylic acid, ethyl ester

At room temperature, N₂Under protection, to tert-butyl -2- oxo -7- azaspiro [3.5] nonane -7- carboxylic acid, ethyl ester (200 millis Gram, 0.835 mM) MeOH (10mL) mixture in be added dimethylamine hydrochloride (340.73 milligrams, 4.18 mMs) and Triethylamine (507.41 milligrams, 5.01 mMs).Reaction mixture is stirred at room temperature 30 minutes, acetic acid boron hydrogen is then added Change sodium (531.38 milligrams, 2.51 mMs).Reaction mixture is stirred 6 hours at 30 DEG C.LCMS display reaction is completed.It will Mixture is concentrated under reduced pressure, and obtains residue, is diluted with water in (30mL) and is extracted with DCM (50mL × 2).Organic phase is saturated Salt water (50mL) washing, anhydrous sodium sulfate are dried, filtered and are concentrated in vacuo, and obtain title compound (200mg, yield It 89.16%) is white solid.LCMS(ESI)(5-95AB):m/z:269.3[M+1].

Embodiment 13B

N, N- dimethyl -7- azaspiro [3.5] nonane -2- amine

TFA (10mL) mixture of embodiment 13A (400.00 milligrams, 1.49 mMs), is stirred 12 hours at 30 DEG C. TLC display reaction is completed.Mixture is concentrated under reduced pressure, obtains (251 milligrams, crude product) of title compound as yellow oil.

Embodiment 13C

7- (3- methoxyl group -4- nitrobenzophenone)-N, N- dimethyl -7- azaspiro [3.5] nonane -2- amine

Under nitrogen protection, to embodiment 13B (251.00 milligrams, 1.49 mMs) and the fluoro- 2- methoxyl group -1- nitro of 4- In the solution of the dimethyl sulfoxide (10mL) of benzene (305.98 milligrams, 1.79 mMs) be added potassium carbonate (617.80 milligrams, 4.47 MM), mixture is stirred 12 hours at 90 DEG C.TLC display reaction is completed.It pours the mixture into water (25mL) and is used in combination Methylene chloride (50mL × 2) extraction.Organic phase is washed with saturated brine (50ml × 2), is dried, filtered with anhydrous sodium sulfate and dense Contracting, obtains residue, by silica gel chromatography (methylene chloride: methanol=80:1,60:1), obtains title compound (310 millis Gram, yield 65.14%) it is yellow solid.LCMS(ESI)(5-95AB):m/z:320.3[M+1].

Embodiment 13D

7- (4- amino -3- methoxyphenyl)-N, N- dimethyl -7- azaspiro [3.5] nonane -2- amine

Into methanol (10mL) solution of embodiment 13C (310 milligrams, 0.97 mM) be added zinc powder (317.33 milligrams, 4.85 mMs) and ammonium chloride (207.66 milligrams, 3.88 mMs).This suspension is stirred 0.5 hour at 30 DEG C.TLC Display starting material completely consumes.Reaction mixture is filtered, be concentrated, obtain title compound (185 milligrams, yield It 65.86%) is white solid.

Embodiment 13E

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with 7- (4- amino -3- methoxyphenyl)-N, N- dimethyl -7- azaspiro [3.5] nonane -2- amine.It obtains Title compound is white solid, yield 16%.¹H NMR(400MHz,CD₃OD):δ,8.29(s,1H),8.14(br.s,1H), 7.68-7.82 (m, 3H), 7.60 (d, J=2.0Hz, 1H), 7.54 (t, J=6.8Hz, 1H), 7.31 (dd, J=8.8,2.0Hz, 1H), 4.04 (s, 3H), 3.85 (t, J=8.4Hz, 1H), 3.65-3.77 (m, 4H), 2.86 (s, 6H), 2.60 (br.s., 2H), 2.22-2.34(m,6H),1.85-1.92(m,6H).LCMS(ESI)(5-95AB):m/z:569.2[M+1].

Embodiment 14

(2- ((the chloro- 2- of 5- ((4- (9- (dimethylamino) -3- azaspiro [5.5] hendecane -3- base) -2- methoxybenzene Base) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide

Embodiment 14A

Tert-butyl 10- (dimethylamino) -3- azaspiro [5.5] hendecane -3- carboxylate methyl ester

The present embodiment is prepared according to the method for embodiment 13A, by tert-butyl 2- oxo -7- azaspiro [3.5] nonane -7- carboxylic Acetoacetic ester replaces with tert-butyl -9- oxo -3- azaspiro [5.5] hendecane -3- carboxylate methyl ester.Obtaining title compound is yellow Grease, yield 79.37%.

Embodiment 14B

The 11 carbon -9- amine of N, N- dimethyl -3- azaspiro [5.5]

The present embodiment is prepared according to the method for embodiment 13B, by tert-butyl 2- (dimethylamino) -7- azaspiro [3.5] Nonane -7- carboxylic acid, ethyl ester replaces with tert-butyl 10- (dimethylamino) -3- azaspiro [5.5] hendecane -3- carboxylate methyl ester.? To title compound, it is yellow oil (crude product), is directly used in next step without being further purified.

Embodiment 14C

3- (3- methoxyl group -4- nitrobenzophenone)-N, the 11 carbon -9- amine of N- dimethyl -3- azaspiro [5.5]

The present embodiment is prepared according to the method for embodiment 13C, and by N, N- dimethyl -7- azaspiro [3.5] nonane -2- amine is replaced It is changed to N, the 11 carbon -9- amine of N- dimethyl -3- azaspiro [5.5].Obtaining title compound is dark solid, yield 55%. LCMS(ESI)(5-95AB):m/z:348.1[M+1].

Embodiment 14D

3- (4- amino -3- methoxyphenyl)-N, the 11 carbon -9- amine of N- dimethyl -3- azaspiro [5.5]

The present embodiment is prepared according to the method for embodiment 13D, by 7- (3- methoxyl group -4- nitrobenzophenone)-N, N- dimethyl - 7- azaspiro [3.5] nonane -2- amine replaces with 3- (3- methoxyl group -4- nitrobenzophenone)-N, N- dimethyl -3- azaspiro [5.5] 11 carbon -9- amine.Obtaining title compound is dark solid, yield 82%.LCMS(ESI)(5-95AB):m/z:318.2[M+ 1].

Embodiment 14E

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with 3- (4- amino -3- methoxyphenyl)-N, the 11 carbon -9- amine of N- dimethyl -3- azaspiro [5.5].? It is yellow solid, yield 11% to title compound.¹H NMR(400MHz,CD₃OD):δ,8.29(s,1H),8.11-8.20(m, 1H), 7.70-7.80 (m, 3H), 7.64 (d, J=2.8Hz, 1H), 7.52-7.56 (m, 1H), 7.36 (dd, J=8.8,2.0Hz, 1H),4.04(s,3H),3.58-3.86(m,4H),3.26-3.29(m,1H),2.91(s,6H),1.97-2.22(m 8H), 1.91(s,3H),1.88(s,3H),1.73-1.82(m,2H),1.44-1.56(m,2H).LCMS(ESI)(0-60AB):m/z: 597.3[M+1].

Process D

Embodiment 15

(2- ((2- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) amino) - 5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine

Embodiment 15A

(2- ((2- chloro- 5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine

The present embodiment is prepared according to the method for embodiment 1L, and 2,4,5- trichloropyrimidines are replaced with the chloro- 5- (trifluoro of 2,4- bis- Methyl) pyrimidine.Obtaining title compound is white solid, yield 23%.LCMS(ESI)(5-95AB):m/z:350.0[M+1].

Embodiment 15B

2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline and 2- methoxyl group -4- (9- methyl -3,9- Diaza spiro [5.5] hendecane -3- base) aniline

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with 2- methoxyl group -4- (9- methyl -3-1,9- diaza spiro [5.5] hendecane -3- base) aniline, and (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine replaces with (2- ((2- chloro- 5- (trifluoromethyl) pyrimidine -4- Base) amino) phenyl) dimethyl phosphine.Obtaining title compound is colourless oil yield 20%.LCMS(ESI)(5-95AB):m/ z:603.3[M+1].

Embodiment 16

(2- ((4- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) amino) - 1,3,5- triazine -2- base base) amino) phenyl) dimethyl phosphine

Embodiment 16A

(2- ((the chloro- 1,3,5- triazine -2- base of 4-) amino) phenyl) dimethyl phosphine

Into MeCN (3.0mL) solution of 2,4-, bis- chloro-1,3,5-triazines (50 milligrams, 0.33 mM), DIPEA is added (52 milligrams, 0.40 mM) and (2- aminophenyl) dimethyl phosphine oxide (85 milligrams, 0.50 mM).Reaction mixture is existed It is stirred 2 hours at 20 DEG C.TLC (DCM: methanol=20:1) display reaction is completed.Mixture is concentrated, residue is obtained, uses water Solution is acidified with HCL aqueous solution (1N) to adjust pH value to 7 by (10mL) dilution, and with DCM (20mL × 2) extraction.It will be organic Layer is dried and concentrated with anhydrous sodium sulfate, and obtaining title compound (50mg, yield 53.05%) is yellow oil.LCMS (ESI)(0-30AB):m/z:282.9[M+1].

Embodiment 16B

Tert-butyl ester 9- (4- ((4- ((2- (dimethyl phosphine acyl group) phenyl) amino) -1,3,5- triazine -2- base) amino) -3- Methoxyphenyl) -3,9- diaza spiro [5.5] hendecane -3- carboxylate methyl ester

Into MeCN (3.0mL) solution of embodiment 16A (40 milligrams, 0.14 mM) be added DIPEA (27 milligrams, 0.21 mM) and embodiment 8B (53 milligrams, 0.14 mM).The mixture is stirred 2 hours at 20 DEG C.TLC (DCM: Methanol=20:1) display reaction completion.Mixture is concentrated, residue is obtained, mixture is used in itself plus water (10mL) dilution HCL aqueous solution (1N) adjusts pH value to 7, and with DCM (20mL × 2) extraction.Organic layer is dried and concentrated, title compound is obtained Object (50mg, yield 56.8%) is yellow oil.LCMS(ESI)(5-95AB):m/z:622.3[M+1].

Embodiment 16C

(2- ((4- ((2- methoxyl group -4- (3,9- diaza spiro [5.5] hendecane -3- base) phenyl) amino) -1,3,5- three Piperazine -2- base) amino) phenyl) dimethyl phosphine oxide

Embodiment 16B (50 milligrams, 0.08 mM) is dissolved in TFA (3.0mL), and reaction mixture stirs at 20 DEG C 2 hours.It in solution methylene chloride (5mL) and will be concentrated to dryness, obtaining title compound (40mg, crude product) is yellow oily Object.

Embodiment 16D

The present embodiment is prepared according to the method for embodiment 7, by (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2,6- diazas Spiral shell [3.4] octyl- 6- yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine replaces with (2- ((4- ((2- first Oxygroup -4- (3,9- diaza spiro [5.5] hendecane -3- base) phenyl) amino) -1,3,5- triazine -2- base) amino) phenyl) two Dimethyl phosphine oxide.Obtaining title compound is white solid, yield 15%.LCMS(ESI)(0-60AB):m/z:536.3[M+1].

Embodiment 17

(2- ((2- (amino) -7H- pyrrolo- [2,3-D] (2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] ten One alkane -3- base) phenyl) pyrimidine azoles -4- base) amino) phenyl) dimethyl phosphine

Embodiment 17A

(2- ((the chloro- 7- of 2- ((2- (trimethyl silyl) ethyoxyl) methyl) -7H- pyrrolo- [2,3-d] pyrimidine -4- Base) amino) phenyl) dimethyl phosphine

At 0 DEG C, NaH (106 millis are added into DMF (5.0mL) solution of embodiment 1K (300 milligrams, 1.77 mMs) Gram, 2.66 mMs), the chloro- 7- of 2,4- bis- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -7H- pyrrolo- is then added portionwise Into reaction mixture, which stirs 5 hours [2,3-d] pyrimidine (677 milligrams, 2.13 mMs) at 20 DEG C.TLC (methanol: DCM=20:1) display reaction is completed.Mixture is diluted with EtOAc (20mL), and (10mL) is washed with water.To have Machine layer is dried and concentrated.By crude product by preparation TLC (DCM: methanol=10:1) purifying, obtain title compound (270mg, Yield 33.8%) it is yellow oil.LCMS(ESI)(5-95AB):m/z:451.2[M+1].

Embodiment 17B

(2- ((2- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) amino) - 7- ((2- (trimethyl silyl) ethyoxyl) methyl) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl) amino) phenyl) dimethyl Phosphine oxide

Embodiment 12E is added into dioxane (5.0mL) solution of embodiment 17A (187 milligrams, 0.41 mM) (100 milligrams, 0.34 mM), Xphos (32 milligrams, 0.07 mM), Pd₂(dba)₃(32 milligrams, 0.03 mM) and carbon Sour potassium (95 milligrams, 0.69 mM).Reaction mixture is stirred 16 hours at 90 DEG C.TLC (PE: ethyl acetate=3:1) is aobvious Show that reaction is completed.Reaction suspension ethyl acetate (20mL) is diluted and filtered.Organic layer is washed simultaneously with water (50mL) It is dry, then it is concentrated.By crude product by preparation TLC (DCM: methanol=10:1) purifying, obtain title compound (100 milligrams, Yield 41.1%) it is yellow oil.LCMS(ESI)(5-95AB):m/z:704.2[M+1].

Embodiment 17C

Embodiment 17B (100 milligrams, 0.14 mM) is dissolved in TFA (3.0mL), and reaction mixture stirs at 20 DEG C 30 minutes.TLC (DCM: methanol=10:1) shows disappearance of starting material.By reaction mixture with DCM (10mL) dilute in and it is dense Contracting, obtains crude intermediate (59 milligrams, crude product)；The crude intermediate is dissolved in methanol (5.0mL), NaOH is then added and adjusts PH value stirs 30 minutes to 12, and by the mixture at 20 DEG C.LCMS shows to obtain product.Reaction mixture HCl/water is molten Liquid (1N) neutralizes, and by preparation HPLC purifying, obtains (10.58 milligrams, 12.98%) of title compound as white solid. LCMS(ESI)(0-60AB):m/z:574.3[M+1].

Process E

Embodiment 18

(2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) ammonia Base) pyrimidine-4-yl) (methyl base) amino) phenyl) dimethyl phosphine

Embodiment 18A

(2- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) phenyl) dimethyl phosphine

To embodiment 1L (100 milligrams, 0.32 mM), K₂CO₃The MeCN (2mL) of (87.44 milligrams, 0.63 mM) MeI (0.1mL, 1.58 mMs) is added in solution.Reaction mixture is stirred 8 hours at 70 DEG C.TLC (DCM: methanol= 20:1) display reaction is completed.Ethyl acetate (50mL) is added into the mixture and is washed with salt water (30mL), it is dry and dense Contracting, obtains yellow oil.By the residue by preparation TLC (DCM: methanol=20:1) purifying, title compound (50 is obtained Milligram, yield 47.88%) it is yellow oil.¹H NMR(400MHz,CDCl3):δ,8.05(s,1H),7.90-7.80(m, 1H), 7.60-7.48 (m, 2H), 7.14-7.20 (m, 1H), 3.55 (s, 3H), 1.79 (dd, J=19.2,12.8Hz, 6H)

Embodiment 18B

(((the chloro- 2- of 5- ((2- methoxyl group -4- (3,9- diaza spiro [5.5] hendecane -3- base) phenyl) amino) is phonetic by 2- Pyridine -4- base) (methyl) amino) phenyl) dimethyl phosphine oxide

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with tert-butyl 3,9- diaza spiro [5.5] hendecane -3- carboxylate methyl ester, and will (((2,5- dichloros are phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphine replaces with (2- ((2,5- dichloro pyrimidine -4- base) (methyl) amino) phenyl) two Methyl oxidation phosphine.Obtain title compound be yellow oil, the 33% of yield.LCMS(ESI)(0-60AB):m/z:569.2 [M+1].

Embodiment 18C

The present embodiment is prepared according to the method for embodiment 7, by (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2,6- diazas Spiral shell [3.4] octyl- 6- yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine replaces with (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (3,9- diaza spiro [5.5] hendecane -3- base) phenyl) amino) pyrimidine-4-yl) (methyl) amino) benzene Base) dimethyl phosphine oxide.Obtaining title compound is white solid, yield 32%.LCMS(ESI)(0-60AB):m/z:583.2[M +1].

Embodiment 19

(2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) ammonia Base) pyrimidine-4-yl) oxygen) phenyl) dimethyl phosphine oxide

Embodiment 12E (60 milligrams, 0.2 mM), (2- ((2,5- dichloro pyrimidine -4- base) oxygroup) phenyl) dimethyl oxygen Phosphine (66 milligrams, 0.2 mM), Xantphos (12 milligrams, 0.02 mM), palladium acetate (5 milligrams, 0.02 mM), carbon Dioxane (10mL) mixture of sour caesium (205 milligrams, 0.6 mM), in N₂It is heated to 100 DEG C under protection and stirring 12 is small When.LCMS display reaction is completed.Reaction mixture is concentrated, and by preparation HPLC purifying, obtains title compound (10.78 Milligram, yield 9%) it is white solid.LCMS(ESI)(5-95AB):m/z:570.2[M+1].

Process F

Embodiment 20

(2- ((the chloro- 2- of 5- ((the fluoro- 2- methoxyl group -4- of 5- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) benzene Base) amino) pyrimidine-4-yl base) amino) phenyl) dimethyl phosphine

Embodiment 20A

The fluoro- 5- methoxyl group -4- nitrobenzene of the bromo- 2- of 1-

Into methanol (100mL) solution of the fluoro- 4- nitrobenzene of bromo- 2, the 5- bis- of 1- (5 grams, 21.01 mMs), methanol is added Sodium (4.56 grams, 84.43 mMs).Mixed liquor is stirred 12 hours at 60 DEG C.TLC (petroleum ether: ethyl acetate=6:1) inspection Display reaction is surveyed to be completed.Reaction solution is cooled to room temperature, is concentrated under reduced pressure.Residue is diluted with water (30mL), and with acetic acid second Ester (50mL × 2) extraction.Organic phase is washed with saturated brine (20mL × 2), dries, filters concentration with anhydrous sodium sulfate.Residual Object is purified with silicagel column (petroleum ether: ethyl acetate=50:1,30:1,20:1), and obtaining title compound, (3.86 grams, 15.44 in the least Mole, 73.48% yield) it is yellow solid.¹H NMR(400MHz,CDCl₃): δ, 7.72 (d, J=7.6Hz, 1H), 7.31 (d, ), J=5.6Hz 3.96 (s, 3H)

Embodiment 20B

Tert-butyl ester 9- (the fluoro- 5- methoxyl group -4- nitrobenzophenone of 2-) -3,9- diaza spiro [5.5] hendecane -3- carboxylate methyl ester

To embodiment 20A (120 milligrams, 0.48 mM) in the solution of dioxane (10mL), tert-butyl -3 is added, 9- diaza spiro [5.5] hendecane -3- t-butyl formate (139.59 milligrams, 0.48 mM), Pd₂(dba)₃(43.95 milligrams, 0.048 mM), Xantphos (22.85 milligrams, 0.048 mM) and cesium carbonate (469.14 milligrams, 1.44 mMs)； Reaction mixture is stirred 12 hours at 100 DEG C.TLC (PE: ethyl acetate=2:1) display reaction is completed.By mixture It is diluted with EtOAc (20mL), successively uses water (20mL), salt water (20mL) washing, anhydrous Na₂SO₄It is dried, filtered and concentrated, obtains It is isolated and purified by column chromatography (PE: ethyl acetate=30:1,20:1), obtains title compound (148 by dark oil object Milligram, yield 72.82%) it is yellow solid.LCMS(ESI)(5-95AB):m/z:424.3[M+1].

Embodiment 20C

The present embodiment is prepared according to the method for embodiment 12C, by tert-butyl ester 9- (3- methoxyl group -4- nitrobenzophenone) -3,9- Diaza spiro [5.5] hendecane -3- carboxylic acid replaces with tert-butyl ester 9- (the fluoro- 5- methoxyl group -4- nitrobenzophenone of 2-) -3,9- diaza Spiral shell [5.5] hendecane -3- carboxylic acid, ethyl ester.Obtaining title compound is yellow oil (crude product), is directly used in next step Reaction.

Embodiment 20D

3- (the fluoro- 5- methoxyl group -4- nitrobenzophenone of 2-) -9- methyl -3,9- diaza spiro [5.5] hendecane

The present embodiment is prepared according to the method for embodiment 12D, by 3- (3- methoxyl group -4- nitrobenzophenone) -3,9- diaza Spiral shell [5.5] hendecane replaces with tert-butyl ester 9- (the fluoro- 5- methoxyl group -4- nitrobenzophenone of 2-) -3,9- diaza spiro [5.5] 11 Alkane -3- carboxylate methyl ester.Obtaining title compound is yellow solid (crude product), is used for next without being further purified.LCMS (ESI)(5-95AB):m/z:338.2[M+1].

Embodiment 20E

The fluoro- 2- methoxyl group -4- of 5- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) aniline

In N₂Under protection, zinc powder is added into MeOH (10mL) solution of embodiment 20D (90 milligrams, 0.267 mM) (87.21 milligrams, 1.33 mMs), ammonium chloride (57.07 milligrams, 1.07 mMs).Reaction mixture stirs 0.5 at 25 DEG C Hour.TLC (DCM: methanol=10:1) shows that raw material completely consumes.Reaction mixture is filtered, is concentrated, obtains title compound (80mg, crude product) is yellow solid.

Embodiment 20F

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with the fluoro- 2- methoxyl group -4- of 5- (the 11 carbon -3- base of 9- methyl -3,9- diaza spiro [5.5]) aniline.It obtains Title compound is white solid, yield 20%.¹H NMR(400MHz,CD₃OD)δ,8.34(s,1H),8.10(br.s.,1H), 7.69-7.86 (m, 3H) 7.51-7.59 (m, 1H), 7.42 (d, J=6.8Hz, 1H), 4.02 (s, 3H), 3.58-3.69 (m, 4H) 3.47 (d, J=12.8Hz, 2H), 3.24 (t, J=12.8Hz, 2H), 2.93 (s, 3H), 2.14-2.23 (m, 4H) 1.96 (br.s., 2H), 1.90 (d, J=13.2Hz, 6H), 1.76-1.86 (m, 2H) .LCMS (ESI) (5-95AB): m/z:587.3 [M +1].

Embodiment 21

(2- ((2- ((the bromo- 2- methoxyl group -4- of 5- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) ammonia Base) -5- chlorine pyrimidine-4-yl base) amino) phenyl) dimethyl phosphine

Embodiment 21A

The fluoro- 4- methoxyl group -5- nitrobenzene of the bromo- 2- of 1-

At 0 DEG C, to sulfuric acid (20.0mL) solution of the fluoro- 4- methoxybenzene of the bromo- 2- of 1- (5.00 grams, 24.39 mMs) In, it is added portionwise potassium nitrate (2.47 grams, 24.39 mMs), reaction mixture stirs 0.5 hour at 0 DEG C.TLC (petroleum ether: Ethyl acetate=3:1) show that reaction is complete.Reaction mixture is added in ice water (50.0mL) and is quenched, and uses EtOAc (100mL × 2) extraction.Organic layer anhydrous sodium sulfate is dry and filters, and is concentrated to dryness, obtains title compound (5.55 Gram, yield 90%) it is white solid.¹H NMR(400MHz,CDCl₃): δ, 8.20 (d.J=6.8Hz, 1H), 6.91 (d, J= 10Hz,1H),3.99(s,3H).

Embodiment 21B

9- (the bromo- 5- methoxyl group -4- nitrobenzophenone of 2-) -3,9- diaza spiro [5.5] hendecane -3- carboxylic acid tert-butyl ester

The present embodiment is prepared according to the method for embodiment 4A, by the tert-butyl ester 2,7- diaza spiro [3.5] nonane -2- carboxylic acid first Ester replaces with the tert-butyl ester 3,9- diaza spiro [5.5] hendecane -3- t-butyl formate, and by the fluoro- 2- methoxyl group -1- nitro of 4- Benzene replaces with the fluoro- 4- methoxyl group -5- nitrobenzene of the bromo- 2- of 1-.Obtaining title compound is yellow oil, yield 92%. LCMS(ESI)(0-60AB):m/z:484.2[M+1].

Embodiment 21C

3- (the bromo- 5- methoxyl group -4- nitrobenzophenone of 2-) -3,9- diaza spiro [5.5] hendecane

The present embodiment is prepared according to the method for embodiment 12C, by 9- (3- methoxyl group -4- nitrobenzophenone) -3,9- diaza Spiral shell [5.5] hendecane -3- carboxylic acid replaces with tert-butyl ester 9- (the bromo- 5- methoxyl group -4- nitrobenzophenone of 2-) -3,9- diaza spiro [5.5] hendecane -3- carboxylic acid tert-butyl ester.Obtaining title compound is yellow solid (crude product), is directly used in and reacts in next step. LCMS(ESI)(0-60AB):m/z:384.1[M+1].

Embodiment 21D

3- (the bromo- 5- methoxyl group -4- nitrobenzophenone of 2-) -9- methyl -3,9- diaza spiro [5.5] hendecane

The present embodiment is prepared according to the method for embodiment 12D, by 3- (3- methoxyl group -4- nitrobenzophenone) -3,9- diaza Spiral shell [5.5] hendecane replaces with 3- (the bromo- 5- methoxyl group -4- nitrobenzophenone of 2-) -3,9- diaza spiro [5.5] hendecane.It obtains Title compound is yellow oil, yield 48%.LCMS(ESI)(0-60AB):m/z:398.1[M+1].

Embodiment 21E

The bromo- 2- methoxyl group -4- of 5- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) aniline

The present embodiment is prepared according to the method for embodiment 13D, by 7- (3- methoxyl group -4- nitrobenzophenone)-N, N- dimethyl - 7- azaspiro [3.5] nonane -2- amine replaces with 3- (2- bromine 5- methoxyl group -4- nitrobenzophenone) -9- methyl -3,9- diaza spiro [5.5] hendecane.Obtaining title compound is green solid, yield 72%.LCMS(ESI)(10-80CD):m/z:368.2 [M+1].

Embodiment 21F

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with the bromo- 2- methoxyl group -4- of 5- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) benzene Amine.Obtaining title compound is colorless oil, yield 12%.LCMS(ESI)(5-95AB):m/z:649.1[M+1]

Embodiment 22

(2- ((the chloro- 2- of 5- ((the chloro- 2- methoxyl group -4- of 5- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) benzene Base) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine

Embodiment 22A

The fluoro- 4- methoxybenzene of the chloro- 2- of 1-

Potassium carbonate is added into acetone (10mL) solution of the chloro- 3- fluorophenol of 4- (500 milligrams, 3.41 mMs) (942.59 milligrams, 6.82 mMs) and iodomethane (1.94 grams, 13.64 mMs).Reaction mixture is stirred 16 at 60 DEG C Hour.TLC (petroleum ether: ethyl acetate=20:1) display reaction is completed.Mixture is concentrated to remove solvent, to residue plus Enter water (20mL) and is extracted with ethyl acetate (20mL × 3).Organic layer is dried and concentrated, title compound (470 millis are obtained Gram, 2.93 mMs, 85.84% yield) it is colorless oil.¹H NMR(400MHz,CDCl₃):δ,7.24-7.31(m,2H), 6.71 (dd, J=10.8,2.8Hz, 1H), 6.65 (dt, J=8.8,1.4Hz, 1H), 3.80 (s, 3H)

Embodiment 22B

The fluoro- 4- methoxyl group -5- nitrobenzene of the chloro- 2- of 1-

The present embodiment is prepared according to the method for embodiment 21A, and the fluoro- 4- methoxybenzene of the bromo- 2- of 1- is replaced with the chloro- 2- of 1- Fluoro- 4- methoxybenzene.Obtaining title compound is yellow oil, yield 51%.¹H NMR(400MHz,CDCl₃):δ, 8.06 (d, J=7.6Hz, 1H), 6.92 (d, J=10.4Hz, 1H), 3.98 (s, 3H)

Embodiment 22C

9- (2- chloro-5-methoxyl -4- nitrobenzophenone) -3,9- diaza spiro [5.5] hendecane -3- carboxylic acid tert-butyl ester

The present embodiment is prepared according to the method for embodiment 4A, by the tert-butyl ester 2,7- diaza spiro [3.5] nonane -2- carboxylic acid first Ester replaces with 3,9- diaza spiro [5.5] hendecane -3- carboxylic acid tert-butyl ester, and the fluoro- 2- methoxyl group -1- nitrobenzene of 4- is replaced For the fluoro- 4- methoxyl group -5- nitrobenzene of the chloro- 2- of 1-.Obtaining title compound is yellow oil, yield 93%.¹H NMR (400MHz,CDCl₃):δ,8.04(s,1H),6.57(s,1H),3.96(s,3H),3.38-3.47(m,4H),3.16(br.s., 4H),1.69-1.73(m,4H),1.53(br.s.,4H),1.47(s,9H).

Embodiment 22D

9- (4- amino -2- chloro-5-methoxyl phenyl) -3,9- diaza spiro [5.5] hendecane -3- carboxylic acid tert-butyl ester

The present embodiment is prepared according to the method for embodiment 13D, by 7- (3- methoxyl group -4- nitrobenzophenone)-N, N- dimethyl - 7- azaspiro [3.5] nonane -2- amine replaces with 9- (2- chloro-5-methoxyl -4- nitrobenzophenone) -3,9- diaza spiro [5.5] ten One alkane -3- carboxylic acid tert-butyl ester.Obtaining title compound is brown oil, yield 60%.LCMS(ESI)(10-80CD):m/ z:310.2[M-100+1].

Embodiment 22E

(2- ((the chloro- 2- of 5- ((the chloro- 2- methoxyl group -4- of 5- (3,9- diaza [5.5] hendecane -3- base) phenyl) amino) Pyridin-4-yl) amino) phenyl) dimethyl phosphine oxide

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with 9- (4- amino -2- chloro-5-methoxyl phenyl) -3,9- diaza spiro [5.5] hendecane -3- carboxylic acid uncle Butyl ester.Obtaining title compound is brown oil, yield 35%.LCMS(ESI)(5-95AB):m/z:589.2[M+1].

Embodiment 22F

The present embodiment is prepared according to the method for embodiment 7, by (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2,6- diazas Spiral shell [3.4] octyl- 6- yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine replaces with (2- ((the chloro- 2- of 5- ((the chloro- 2- methoxyl group -4- of 5- (3,9- diaza spiro [5.5] hendecane -3- base) phenyl) amino) pyridin-4-yl) amino) benzene Base) dimethyl phosphine oxide.Obtaining title compound is white solid, yield 40%.¹H NMR(400MHz,CDCl₃):δ,8.35 (s, 1H), 8.06 (dd, J=7.6,3.6Hz, 1H), 7.97 (s, 1H), 7.80 (dd, J=13.2,7.2Hz, 1H), 7.73 (t, J =8.0Hz, 1H), 7.58 (s, 1H), 7.50-7.57 (m, 1H), 4.06 (s, 3H), 3.74-3.78 (m, 4H), 3.44-3.47 (m, 2H), 3.24 (t, J=12.4Hz, 2H), 2.92 (s, 3H), 2.15-2.30 (m, 4H), 2.01 (br.s., 2H), 1.90 (s, 3H),1.87(s,3H),1.77-1.86(m,2H).LCMS(ESI)(5-95AB):m/z:603.2[M+1].

Embodiment 23

(2- ((the chloro- 2- of 5- ((2- methoxyl group -5- methyl -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) Phenyl) amino) pyrimidine-4-yl base) amino) phenyl) dimethyl phosphine

Embodiment 23A

9- methyl -3,9- diaza spiro [5.5] hendecane -3- carboxylic acid tert-butyl ester

At 0 DEG C, to 3,9- diaza spiro [5.5] hendecane -3- t-butyl formate (120 milligrams, 0.47 mM) 37% formalin (71 milligrams, 2.36 mMs) are added in methanol (5mL) solution, reaction mixture stirs 0.5 at 16 DEG C Hour.Then sodium triacetoxy borohydride (299 milligrams, 1.42 mMs) is added in reaction mixture, and at 16 DEG C Lower stirring 12 hours.LCMS display reaction is completed.Mixture is concentrated to remove solvent, obtained residue is dilute with water (10mL) It is extracted after releasing with methylene chloride (60mL), will filter and be concentrated after organic layer anhydrous sodium sulfate drying, obtain title compound For colorless oil (100 milligrams, yield 79%).

Embodiment 23B

3- methyl -3,9- diaza spiro [5.5] hendecane

Example 23A (100 milligrams, 0.37 mM) is in the mixture solution of trifluoroacetic acid (2mL) and methylene chloride (2mL) It is stirred 1 hour at 16 DEG C.LCMS display reaction is completed.Mixture is alkalized with sodium carbonate liquor (50mL) and uses methylene chloride (50mL × 2) extraction.Organic layer is dried, filtered and concentrated with sodium sulphate, and obtaining title compound is brown oil (70mg).

Embodiment 23C

3- (5- methoxyl group -2- methyl -4- nitrobenzophenone) -9- methyl -3,9- diaza spiro [5.5] hendecane

The present embodiment is prepared according to the method for embodiment 4A, by the tert-butyl ester 2,7- diaza spiro [3.5] nonane -2- carboxylic acid first Ester replaces with 3- methyl -3,9- diaza spiro [5.5] hendecane, and the fluoro- 2- methoxyl group -1- nitrobenzene of 4- is replaced with 1- Fluoro- 5- methoxyl group -2- methyl -4- nitrobenzene.Obtaining title compound is yellow oil, yield 40%.LCMS(ESI) (0-60AB):m/z:334.2[M+1].

Embodiment 23D

2- methoxyl group -5- methyl -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) aniline

The present embodiment is prepared according to the method for embodiment 13D, by 7- (3- methoxyl group -4- nitrobenzophenone)-N, N- dimethyl - 7- azaspiro [3.5] nonane -2- amine replaces with 3- (5- methoxyl group -2- methyl -4- nitrobenzophenone) -9- methyl -3,9- diaza Spiral shell [5.5] hendecane.Obtaining title compound is brown solid, yield 69%.LCMS(ESI)(10-80CD):m/z: 304.3[M+1].

Embodiment 23E

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with 2- methoxyl group -5- methyl -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) aniline.? It is white solid, yield 19% to title compound.¹H NMR(400MHz,CD3OD):δ,8.28(s,1H),8.17 (br.s,1H),7.75-7.84(m,1H),7.62-7.74(m,2H),7.48-7.57(m,1H),7.42(s,1H),4.04(s, 3H),3.56-3.84(m,4H),3.42-3.54(m,2H),3.18-3.27(m,2H),2.94(s,3H),2.21-2.44(m, 6H),2.01-2.13(m,2H),1.76-1.95(m,9H).LCMS(ESI)(5-95AB):m/z:583.3[M+1].

Embodiment 24

(2- ((the chloro- 2- of 5- ((4- methoxyl group -6- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) pyridine -3- Base) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine

Embodiment 24A

3- (4- methoxyl group -5- nitropyridine -2- base) -9- methyl -3,9- diaza spiro [5.5] hendecane

Under nitrogen protection, by embodiment 23B (70 milligrams, 0.42 mM), 2- chloro-4-methoxy -5- nitropyridine (94 milligrams, 0.5 mM), Pd₂(dba)₃(38 milligrams, 0.04 mM), Xantphos (24 milligrams, 0.04 mM) and The solution of cesium carbonate (271 milligrams, 0.83 mM) dioxane (5mL), is stirred 12 hours at 90 DEG C.LCMS display reaction Completely.Reaction mixture is extracted after adding water (40mL) to dilute with methylene chloride (50mL × 2).By organic layer with salt water (30mL × 2) it washs, anhydrous sodium sulfate is dried, filtered and concentrated.By gained residue cross silica gel column purification (petroleum ether: ethyl acetate=4: 1,3:1), obtaining title compound (50mg, yield 37.5%) is yellow oil.

Embodiment 24B

4- methoxyl group -6- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) pyridine -3- amine

The present embodiment is prepared according to the method for embodiment 13D, by 7- (3- methoxyl group -4- nitrobenzophenone)-N, N- dimethyl - 7- azaspiro [3.5] nonane -2- amine replaces with 3- (4- methoxyl group -5- nitropyridine -2- base) -9- methyl -3,9- diaza spiro [5.5] hendecane.Obtaining title compound is brown solid, yield 88%.

Embodiment 24C

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with 4- methoxyl group -6- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) pyridine -3- amine.It obtains Title compound is white solid, yield 15%.LCMS(ESI)(10-80CD):m/z:570.2[M+1].

Process G

Embodiment 25

(2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) ammonia Base) pyrimidine-4-yl) amino) base -3- fluorophenyl) dimethyl phosphine

Embodiment 25A

(2- amino -3- fluorophenyl) dimethyl phosphine

At 15 DEG C, to the fluoro- aniline of the bromo- 6- of 2- (1.00 grams, 5.26 mMs) and dimethyl phosphine oxide (451.84 milligrams, 5.79 mMs) potassium carbonate (2.91 grams, 21.05 mMs) and palladium/carbon (150 millis are added in the mixture in water (20mL) Gram), reaction mixture stirs 3 hours under 160 DEG C of microwave heatings.TLC (petroleum ether: ethyl acetate=10:1) display has been reacted At.Reaction mixture is extracted with methylene chloride (20mL × 4).After combined organic layer is filtered, filtrate is concentrated and is passed through It is yellow that column, which chromatographs (methylene chloride: methanol=1:0 to 10:1) isolated title compound (100mg, yield 10.16%), Solid.¹H NMR(400MHz,CDCl₃): 7.12-7.03 (m, 1H), 6.86 (dd, J=8.0,13.2Hz, 1H), 6.68-6.58 (m, 1H), 5.52 (br.s., 2H), 1.79 (d, J=13.2Hz, 6H)

Embodiment 25B

(2- ((2,5- dichloro pyrimidine -4- base) amino) -3- fluorophenyl) dimethyl phosphine

Mixing at 0 DEG C, to the n,N-Dimethylformamide (2mL) of embodiment 25A (100 milligrams, 0.534 mM) Sodium hydride (53.60 milligrams, 1.34 mMs, 60%) are added in object, then by reaction mixture after 0 DEG C is stirred 0.5 hour, 2,4,5- trichloropyrimidines (196 milligrams, 1.07 mMs) are added in reaction mixture, reaction mixture stirs at 15 DEG C 16 hours.LCMS shows fully reacting.Water (30mL) is added into the reaction mixture to extract afterwards and with ethyl acetate (15mL × 3) It takes.It is concentrated after combined organic layer is washed with salt water (20mL), by column chromatography, (methylene chloride: methanol=1:0 is arrived residue It 10:1) isolates and purifies, obtains (150 milligrams, yield 84.02%) of title compound as brown oil.¹H NMR (400MHz,CDCl₃):8.28(s,1H),7.53-7.33(m,3H),7.28-7.17(m,1H),5.54(br.s.,2H),1.85 (d, J=13.2Hz, 6H) .LCMS (ESI) (10-80CD): m/z:334.0 [M+1]

Embodiment 25C

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with 2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) aniline, and by (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine replaces with (2- ((- 4 base of 2,5- dichloro pyrimidine) amino) - 3- fluorophenyl) dimethyl phosphine.Obtaining title compound is brown solid, yield 17%.¹H NMR(400MHz, CDCl₃):8.36(s,1H),7.84-7.73(m,2H),7.71-7.62(m,2H),7.55-7.49(m,2H),7.16–7.09 (m,1H),4.02(s,3H),3.80–3.60(m,4H),3.54–3.50(m,2H),3.29–3.20(m,2H),2.94(s,3H), 2.47-1.90 (m, 6H), 1.83 (d, J=13.6Hz, 8H) .LCMS (ESI) (0-60AB): m/z:587.3 [M+1]

Embodiment 26

(2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) phenyl) ammonia Base) pyrimidine-4-yl) amino) base -5- fluorophenyl) dimethyl phosphine

Embodiment 26A

(2- amino-5-fluorine phenyl) dimethyl phosphine

The present embodiment is prepared according to the method for embodiment 1K, and 2- Iodoaniline is replaced with the fluoro- 2- Iodoaniline of 4-.Obtain title Compound is brown solid, yield 47%.¹H NMR(400MHz,CDCl₃):δ,6.96(m,1H),6.77(m,1H),6.60 (m, 1H), 5.21 (br s, 2H), 1.72-1.81 (d, J=22.8Hz, 6H) .LCMS (ESI) (10-80CD): m/z:188.1 [M +1].

Embodiment 26B

(2- ((2,5- dichloro pyrimidine -4- base) amino) -5- fluorophenyl) dimethyl phosphine

The present embodiment is prepared according to the method for embodiment 1L, and (2- aminophenyl) dimethyl phosphine is replaced with (2- ammonia Base -5- fluorophenyl) dimethyl phosphine.Obtaining title compound is white solid, yield 50%.¹H NMR(400MHz, CDCl₃):δ,11.34(br.s.,1H),8.66(m,1H),8.19-8.28(m,1H),7.35-7.28(m,1H),6.98(m, 1H) 1.89-1.83 (d, J=13.2HZ, 6H) .LCMS (ESI) (5-95AB): m/z:334.1 [M+1]

Embodiment 26C

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with 2- methoxyl group -4- (9- methyl -3,9- diaza spiro [5.5] hendecane -3- base) aniline, and by (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine replaces with (2- ((- 4 base of 2,5- dichloro pyrimidine) amino) - 5- fluorophenyl) dimethyl phosphine.Obtaining title compound is white solid, yield 10%.LCMS(ESI)(5-95AB): m/z:587.2[M+1].

Process H

Embodiment 27

((2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (the 11 carbon -9- base of 3- methyl -3- azaspiro [5.5]) phenyl) amino) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide

Embodiment 27A

4- formyl piperidine -1- t-butyl formate

Under -70 DEG C, nitrogen protection, the methylene chloride (25mL) to dimethyl sulfoxide (4.37 grams, 46.52 mMs) is molten Methylene chloride (75mL) solution of oxalyl chloride (5.9 grams, 46.52 mMs) is added dropwise in liquid；Then by 4- (hydroxyl first at -70 DEG C Base) methylene chloride (40mL) solution of piperidines -1- t-butyl formate (5 grams, 23.26 mMs) is added dropwise to said mixture In.Reaction mixture stirs 15 minutes at -70 DEG C, is added dropwise (11.76 grams, 116.3 mMs) of triethylamine and mixes to reaction It closes in object.It adds rear reaction mixture to stir 1 hour at -70 DEG C, and is warming up to 15 DEG C.Reaction mixture is poured into water, And it is extracted with methylene chloride (200mL).After organic layer is washed with sodium bicarbonate solution (100mL), anhydrous sodium sulfate is dry, mistake It filters and is concentrated to dryness.By gained grease, by column chromatographic purifying, (petroleum ether: ethyl acetate=10:1 obtains title to 3:1) (2.4 grams, yield 48%) of compound are yellow oil.¹H NMR(400MHz,CDCl₃):δ,9.68(s,1H),3.98- 3.92(m,2H),2.96-2.91(m,2H),2.45-2.42(m,1H),1.89-1.60(m,2H),1.60-1.54(m,2H), 1.47(s,9H).

Embodiment 27B

The 11 carbon -7- alkene -3- carboxylic acid tert-butyl ester of 9- oxo -3- azaspiro [5.5]

Butyl- 3- alkene -2- ketone (0.658 gram, 9.39 mMs) is added to the tetrahydro of embodiment 27A (2 grams, 9.39 mMs) In furans (100mL) solution.Reaction mixture is cooled to -5 DEG C, by potassium hydroxide-ethanol (3 mol/Ls, 1.57mL, 4.7 MM) solution is added dropwise in reaction mixture in 5 minutes.Reaction mixture is warming up to 15 DEG C and stirs 16 hours. Petroleum ether (10mL) is added in reaction mixture, and the mixture is washed with salt water (100mL).Organic layer concentration, obtains To crude product, by silica gel column chromatography purifying, (petroleum ether: ethyl acetate=10:1 obtains title compound to 2:1) to crude product (1.12 grams, yield 45%) are yellow oil.¹H NMR(400MHz,CDCl₃): δ, 6.82 (d, J=10Hz, 1H), 5.97 (d, J=10Hz, 1H), 3.57-3.56 (m, 2H), 2.50-2.47 (m, 2H), 2.01-1.97 (m, 2H), 1.67-1.65 (m, 2H),1.61-1.59(m,2H),1.49(s,9H).

Embodiment 27C

9- oxo -3- azaspiro [5.5] hendecane -3- carboxylic acid tert-butyl ester

Into methanol (100mL) solution of embodiment 27B (5.00 grams, 18.84 mMs) be added palladium/carbon (200 milligrams, 1.88 mM).This suspension is vacuumized and is replaced several times with hydrogen.Reaction mixture keeps temperature at hydrogen (18psi) 10-25 DEG C of degree simultaneously stirs 5 hours.Reaction mixture is filtered, filtrate concentration.Crude product purifies (petroleum by silica gel column chromatography Ether: ethyl acetate=2:1), (4.78 grams, 17.88 mMs, yield 94.9%) of title compound are obtained as white solid.¹H NMR(400MHz,CDCl₃):δ,3.47-3.44(m,4H),2.38-2.35(m,4H),1.81-1.77(m,4H),1.58- 1.56(m,4H),1.49(s,9H).

Embodiment 27D

11 carbon -8- alkene -3- carboxylic acid tert-butyl ester of 9- (((trifluoromethyl) sulphonyl) oxygroup) -3- azaspiro [5.5]

Under -78 DEG C of nitrogen protections, into tetrahydrofuran (20mL) solution of embodiment 27C (2 grams, 7.5 mMs) by It is added dropwise to lithium diisopropylamine (2.5M, 1.22mL, 9 mM), after adding, reaction mixture is stirred 2 hours.Then by Being added dropwise to 1,1,1- tri- fluoro- N- phenyl-N- ((trifluoromethyl) sulfonyl) Methanesulfomide, (2.67 grams, be dissolved in by 7.48 mMs In the THF of 5mL) it is stirred 1.5 hours into reaction solution, and at -78 DEG C.Mixture is warming up to 10 DEG C of stirrings 2.5 hours, instead It answers mixture to be quenched with ammonium chloride solution (30mL), and is extracted with ethyl acetate (50mL × 2).By organic layer with salt water (50mL) Washing, uses Na₂SO₄Be dried and concentrated, obtain residue, by its by silica gel column chromatography purifying (petroleum ether: ethyl acetate=5: 1), obtaining title compound (2.3g, yield 77%) is brown oil.¹H NMR(400MHz,CDCl₃):δ,5.71(t,J =4.0Hz, 1H), 3.51-3.45 (m, 2H), 3.39-3.32 (m, 2H), 2.37-2.35 (m, 2H), 2.16-2.09 (m, 2H), 1.71-1.67(m,2H),1.48(s,9H).1.45-1.42(m,4H).

Embodiment 27E

The bromo- 2- aminoanisole of 4-

N- bromo-succinimide is added into acetonitrile (30mL) solution of 2- aminoanisole (3 grams, 24.36 mMs) (4.34 grams, 24.36 mMs) stir reaction mixture 15 minutes at 15 DEG C.Sulfurous acid is added into reaction mixture Sodium solution (40mL) quenching reaction extracts mixture with ethyl acetate (50ml)；Organic layer is dry with sodium sulphate, and concentration obtains To crude product, it by silica gel column chromatography purifying (petroleum ether: ethyl acetate=10:1) is obtained title compound, and (2.7 grams, produced Rate 55%) it is yellow solid.¹H NMR(400MHz,CDCl₃): δ, 6.93-6.91 (m, 2H), 6.62-6.59 (dd, J=1.6, 2.0Hz,1H),3.86(s,1H).

Embodiment 27F

2- methoxyl group -4- (penta ring -2- base of 4,4,5,5- tetramethyl -1,3,2- dioxy boron) aniline

Duplex pinacol borate is added into DMSO (5mL) solution of embodiment 27E (500 milligrams, 2.47 mMs) (628.4 milligrams, 2.47 mMs), tetra-triphenylphosphine palladium (150 milligrams, 0.13 mM) and potassium acetate (485 milligrams, 4.95 MM), reaction mixture is stirred 40 minutes under 150 DEG C of microwaves.By reaction mixture ethyl acetate (50mL) and water (30mL) dilution.Organic layer separation, is dried and concentrated, obtains crude product, it is purified (petroleum ether: acetic acid by silica gel column chromatography Ethyl ester=10:1) (160 milligrams, yield 26%) of title compound are obtained as yellow oil.¹H NMR(400MHz, CDCl₃): δ, 7.31 (d, J=8.0Hz, 1H), 7.22 (s, 1H), 6.71 (d, J=8.0Hz, 1H), 3.91 (s, 3H), 1.35 (s,12H).

Embodiment 27G

11 carbon -8- alkene -3- carboxylic acid tert-butyl ester of 9- (4- amino -3- methoxyphenyl) -3- azaspiro [5.5]

To embodiment 27D (300 milligrams, 0.75 mM), the dioxy six of embodiment 27F (187 milligrams, 0.75 mM) Pd (dppf) Cl is added in ring (10mL) solution₂(15 milligrams, 0.075 mM) and potassium carbonate (204 milligrams, 1.5 mMs), Reaction mixture is stirred 16 hours at 110 DEG C.Reaction mixture to be filtered by diatomite, filtrate concentration obtains crude product, It is purified into (petroleum ether: ethyl acetate=3:1) by silica gel column chromatography, obtains title compound (110mg, yield 39%) For yellow oil.LCMS(ESI)(5-95AB):m/z:373.2[M+1].

Embodiment 27H

9- (4- amino -3- methoxyphenyl) -3- azaspiro [5.5] hendecane -3- carboxylic acid tert-butyl ester

In N₂Under protection, palladium/carbon is added into methanol (5mL) solution of embodiment 27G (110 milligrams, 0.3 mM) (10 milligrams, 10%) stir 5 hours by reaction mixture at hydrogen (15PSI) in 16 DEG C.Reaction mixture is passed through into silicon Diatomaceous earth is filtered and concentrated in vacuo, and obtains (130 milligrams) of crude title compound as yellow oil.LCMS(ESI)(5-95AB): m/z:319.1[M-56+1].

Embodiment 27I

(2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (the 11 carbon -9- base of 3- azaspiro [5.5]) phenyl) amino) pyrimidine -4- Base) amino) phenyl) dimethyl phosphine

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with 9- (4- amino -3- methoxyphenyl) -3- azaspiro [5.5] hendecane -3- carboxylic acid tert-butyl ester.It obtains Title compound is colorless oil, yield 15%.LCMS(ESI)(5-95AB):m/z:554.2[M+1].

Embodiment 27J

The present embodiment is prepared according to the method for embodiment 7, by (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2,6- diazas Spiral shell [3.4] octyl- 6- yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine replaces with (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (3- azaspiro [5.5] hendecane -9- base) phenyl) amino) pyridin-4-yl) amino) phenyl) dimethyl oxygen Phosphine.Obtaining title compound is yellow solid, yield 27%.¹H NMR(400MHz,CDCl₃):δ,8.31-8.15(m,2H), 7.75-7.70(m,1H),7.57(s,1H),7.45-7.37(m,2H),7.06(s,1H),6.91(s,1H),3.90(s,3H), 3.44-3.36(m,2H),3.22-3.19(m,2H),2.91(s,3H),2.66-2.64(m 1H),2.44-1.93(m,2H), 1.93 (s, 3H), 1.92-1.88 (d, J=13.6Hz, 6H), 1.89 (s, 3H), 1.84-1.60 (m 9H), 1.33-1.31 (m, 1H).LCMS(ESI)(5-95AB):m/z:568.2[M+1].

Embodiment 28

(2- ((the chloro- 2- of 5- ((2- (difluoro-methoxy) -4- (the 11 carbon -9- base of 3- methyl -3- azaspiro [5.5]) phenyl) Amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide

Embodiment 28A

The chloro- 2- Nitro-phenol of 5-

The present embodiment is prepared according to the method for embodiment 11A, and the fluoro- 2- methoxyl group -1- nitrobenzene of 4- is replaced with the chloro- 2- of 4- Methoxyl group -1- nitrobenzene.Obtaining title compound is yellow oil, yield 93%.¹H NMR(400MHz,CDCl₃):δ, 10.67 (s, 2H), 8.07 (d, J=8.8Hz, 1H), 7.20 (d, J=2.4Hz, 1H), 6.99 (dd, J=9.2,2.0Hz, 1H)

Embodiment 28B

4- chloro- 2- (difluoro-methoxy) -1- nitrobenzene

The present embodiment is prepared according to the method for embodiment 11B, and the fluoro- 2- nitrophenol of 5- is replaced with the chloro- 2- nitrobenzene of 5- Phenol, obtaining title compound is yellow oil, yield 78%.¹H NMR(400MHz,CDCl₃): δ, 7.92 (d, J= 8.8Hz, 1H), 7.42-7.37 (m, 2H), 6.64 (t, J=72.4Hz, 1H)

Embodiment 28C

Penta ring of 2- (3- (difluoro-methoxy) -4- nitrobenzophenone) -4,4,5,5- tetramethyl -1,3,2- dioxy boron

Into dioxane (10mL) solution of embodiment 28C (223.56 milligrams, 1.00 mMs) be added duplex frequency that Alcohol borate (262 milligrams, 1.00 mMs), Pd (dppf) Cl₂(73.17 milligrams, 0.1 mM), triphenylphosphine (262.29 Milligram, 1.00 mMs) and potassium acetate (196.28 milligrams, 2.00 mMs), reaction mixture is taken a breath and is heated to 100 DEG C Stirring 16 hours.TLC (petroleum ether: ethyl acetate=10:1) shows that raw material completely consumes.Reaction mixture is poured into water It is extracted in (30mL) and with ethyl acetate (25mL × 2).Organic phase is washed with salt water (30mL), it is dry with anhydrous magnesium sulfate, Vacuum concentration, obtains residue, it is purified (petroleum ether: ethyl acetate=30:1,20:1) by silica gel column chromatography, is marked (300 milligrams, yield 95.21%) of compound of topic are yellow solid.

Embodiment 28D

11 carbon -8- alkene -3- carboxylic acid tert-butyl ester of 9- (3- (difluoro-methoxy) -4- nitrobenzophenone) -3- azaspiro [5.5]

Under nitrogen protection, to embodiment 27D (948 milligrams, 2.37 mMs), (500 milligrams, 1.58 in the least by embodiment 28C Mole) Pd (dppf) Cl is added in the mixed liquor of dioxane (4mL) and water (2mL)₂(116 milligrams, 0.16 mM) and Sodium carbonate (503 milligrams, 4.75 mMs) stirs reaction mixture 16 hours at 110 DEG C.The reaction mixture passes through silicon Diatomaceous earth filtering, concentration obtain crude product, it is purified (petroleum ether: ethyl acetate=5:1) by silica gel column chromatography, is marked (602 milligrams, yield 58%) of compound of topic are yellow solid.¹H NMR(400MHz,CDCl₃): δ, 7.92 (d, J=8.8Hz, 1H),7.38-7.34(m,2H),6.82-6.28(m,2H),3.54-3.47(m,2H),3.38-3.33(m,2H),2.41(s, 2H), 2.18 (d, J=9.6Hz, 1H), 1.70-1.65 (m, 2H), 1.46-1.42 (m, 5H)

Embodiment 28E

9- (4- amino -3- (difluoro-methoxy) phenyl) -3- azaspiro [5.5] hendecane -3- carboxylic acid tert-butyl ester

Palladium/carbon (20 millis are added into tetrahydrofuran (10mL) solution of embodiment 28D (200 milligrams, 0.46 mM) Gram)；Reaction mixture is in H₂(50psi) is stirred 5 hours in 16 DEG C.Reaction mixture is filtered and is concentrated by diatomite, is obtained It is brown solid to title compound (150mg, yield 80%).LCMS(ESI)(10-80CD):m/z:355.2[M+1- 56].

Embodiment 28F

(((the chloro- 2- of 5- ((2- (difluoro-methoxy) -4- (the 11 carbon -9- base of 3- azaspiro [5.5]) phenyl) amino) is phonetic by 2- Pyridine -4- base) amino) phenyl) dimethyl phosphine

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with 9- (4- amino -3- (difluoro-methoxy) phenyl) tertiary fourth of -3- azaspiro [5.5] hendecane -3- formic acid Ester.Obtaining title compound is brown oil, yield 37.2%.

Embodiment 28G

The present embodiment is prepared according to the method for embodiment 7, by (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2,6- diazas Spiral shell [3.4] octyl- 6- yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine replaces with (2- ((the chloro- 2- of 5- ((2- (difluoro-methoxy) -4- (the 11 carbon -9- base of 3- azaspiro [5.5]) phenyl) amino) pyrimidine-4-yl) amino) phenyl) two Methyl oxidation phosphine.Obtaining title compound is white solid, yield 24%.LCMS(ESI)(5-95AB):m/z:604.2[M+ 1].

Embodiment 29

(2- ((the chloro- 2- of 5- ((the fluoro- 2- methoxyl group -4- of 5- (7- methyl -7- azaspiro [3.5] nonane -2- base) phenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine

Embodiment 29A

4- methylenepiperidines -1- benzyl formate

In room temperature N₂Under protection, Xiang Jiaji (triphenyl) phosphonium bromide (16.14 grams, 45.17 mMs) and potassium tert-butoxide The tertiary fourth of 4- oxo-piperidine -1- carboxylic acid is added at one time in tetrahydrofuran (350mL) mixture of (5.58 grams, 49.69 mMs) Ester (9.00 grams, 45.17 mMs).Reaction mixture stirs 3 hours at 16 DEG C.TLC display reaction is completed.Residue is fallen Enter in water.Water phase is extracted with ethyl acetate (200mL × 3).Combined organic phase is washed with saturated brine (100mL), it is anhydrous Sodium sulphate is dried, filtered and is concentrated in vacuo.Residue purifies (petroleum ether: ethyl acetate=10:1,5:1) by silica gel column chromatography (8.40 grams, yield 80.4%) of title compound are obtained as colorless solid.¹H NMR(400MHz,CDCl₃):δ,7.41-7.34 (m,5H),5.17(s 2H),4.78(s,2H),3.55-3.52(m,4H),2.24-2.21(m,4H).

Embodiment 29B

1,1- bis- chloro-2-oxo -7- azaspiro [3.5] nonane -7- benzyl carboxylate

At 15-20 DEG C, to embodiment 29A (6.00 grams, 25.94 mMs) and zinc-copper (30.10 grams, 233.46 mmoles You) tetrahydrofuran (300mL) mixture in be added dropwise 2,2,2- trichloro-acetic chlorides (23.58 grams, 129.70 mMs), be added dropwise After 0.5 hour, reaction mixture is stirred 16 hours at 20-30 DEG C.Reaction solution is slowly quenched with ice, then uses acetic acid second Ester (250mL × 3) extraction.Combined organic phase is washed with salt water (100mL × 2), anhydrous sodium sulfate dries, filters and vacuum Concentration.Residue purifies (petroleum ether: ethyl acetate=10:1,5:1) by silica gel column chromatography, obtains title compound (3.81 Gram, yield 42.81%) it is white solid.¹H NMR(400MHz,CDCl₃):δ,7.42-7.36(m,5H),5.17(s 2H), 4.21-4.17(m,2H),3.13(s 2H),3.05-2.98(m,2H),2.02-1.96(m,2H),1.87-1.82(m,2H).

Embodiment 29C

2- oxo -7- azaspiro [3.5] nonane -7- benzyl carboxylate

Into methanol (50mL) mixture of embodiment 29B (3.00 grams, 8.77 mMs) be added zinc powder (1.72 grams, 26.31 mMs) and ammonium chloride (4.69 grams, 87.70 mMs).Reaction mixture stirs 0.5 hour at 10-20 DEG C.It will Reaction mixture pours into water (50mL), and stirs 20 minutes.Water phase is extracted with ethyl acetate (50mL × 3).By having for merging Machine is mutually washed with saturated salt solution (30mL), and anhydrous sodium sulfate is dried, filtered and is concentrated in vacuo.Residue passes through silica gel column chromatography It purifies (petroleum ether: ethyl acetate=30:1,20:1), it is solid for yellow to obtain title compound (2.12 grams, yield 88.44%) Body.¹H NMR(400MHz,CDCl₃):δ,7.40-7.35(m,5H),5.16(s 2H),3.54-3.51(m,4H),2.85(s, 4H),1.76-1.74(m,4H).

Embodiment 29D

2- (the fluoro- 5- methoxyphenyl of 2-) -2- hydroxyl -7- azaspiro [3.5] nonane -7- benzyl carboxylate

Under -60 DEG C of nitrogen protections, to the tetrahydro furan of the fluoro- 4- methoxyl group-benzene of the bromo- 1- of 2- (400 milligrams, 1.95 mMs) It mutters and n-BuLi (249.83 milligrams, 3.90 mMs) is added in (15mL) mixture solution.Mixture is stirred at -60 DEG C 1 hour.Then embodiment 29C (399.75 milligrams, 1.46 mMs) was added to reaction mixture with 20 minutes at -60 DEG C In.Reaction mixture stirs 2 hours at this temperature, and reaction mixture is poured into water (50mL), and stirs 20 minutes.Water phase It is extracted with ethyl acetate (50mL × 3), combined organic phase is washed with saturated brine (50mL × 2), and anhydrous sodium sulfate is dry, mistake It filters and is concentrated in vacuo.Residue purifies (petroleum ether: ethyl acetate=10:1,1:1) by silica gel column chromatography, obtains title compound (340 milligrams, yield 43.65%) of object are colorless oil.

Embodiment 29E

2- (the fluoro- 5- methoxyphenyl of 2-) -7- azaspiro [3.5] nonane -7- benzyl carboxylate

Under room temperature under nitrogen protection, mixed to the methylene chloride (10mL) of embodiment 29D (380 milligrams, 0.951 mM) Triethyl group silicon hydrogen (221.24 milligrams, 1.90 mMs) are added in object.Reaction mixture stirs 1 hour at 18 DEG C.It will reaction Mixture pours into water (20mL), and stirs 20 minutes.Water phase is extracted with ethyl acetate (30mL × 3).By combined organic phase It is washed with saturated salt solution (20mL), anhydrous sodium sulfate is dried, filtered and is concentrated in vacuo.Residue is purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1,3:1) purifying obtains (160 milligrams, yield 43.86%) of title compound as yellow oil Shape object.LCMS(ESI)(5-95AB):m/z:384.2[M+1].

Embodiment 29F

2- (the fluoro- 5- methoxyl group -4- nitrobenzophenone of 2-) -7- azaspiro [3.5] nonane -7- benzyl carboxylate

At 0-10 DEG C, into AcOH (4mL) mixture of embodiment 29E (160 milligrams, 0.417 mM), disposably It is added nitric acid (268.28 milligrams, 4.17 mMs).Reaction mixture is stirred 2 hours at 18 DEG C.Reaction mixing is poured into In ice water (20mL), and stir 20 minutes.Water phase is extracted with ethyl acetate (40mL × 3).By combined organic phase saturation food Salt water (20mL) washing, anhydrous sodium sulfate are dried, filtered and are concentrated in vacuo.Residue by silica gel column chromatography purify (petroleum ether: Ethyl acetate=2:1), (145 milligrams, yield 81.10%) of title compound are obtained as yellow oil.LCMS(ESI)(5- 95AB):m/z:451.1[M+Na].

Embodiment 29G

The fluoro- 2- methoxyl group -4- of 5- (7- azaspiro [3.5] nonane -2- base) aniline

Under nitrogen protection, it is mixed to the tetrahydrofuran (10mL) of embodiment 29F (148.00 milligrams, 345.43 micromoles) Palladium/carbon (40 milligrams, 10%) are added in object.Reaction solution is vacuumized and uses H₂Displacement, by reaction mixture at hydrogen (16psi) Under conditions of in 10-25 DEG C stir 3 hours.Reaction mixture is filtered, filtrate is concentrated.Crude product is pure by silica gel column chromatography Change (methylene chloride: methanol=20:1) and obtains (50 milligrams, yield 54.76%) of title compound as yellow oil.LCMS (ESI)(5-95AB):m/z:265.2[M+1].

Embodiment 29H

(2- ((the chloro- 2- of 5- ((the fluoro- 2- methoxyl group -4- of 5- (7- azaspiro [3.5] nonane -2- base) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) dimethyl phosphine oxide

The present embodiment is prepared according to the method for embodiment 1M, by 2- methoxyl group -5- (6- methyl -6- azaspiro [3.4] octyl- 2- yl) aniline replaces with the fluoro- 2- methoxyl group -4- of 5- (7- azaspiro [3.5] nonane -2- base) aniline.Obtaining title compound is Yellow oil, yield 27.21%.LCMS(ESI)(5-95AB):m/z:544.2[M+1].

Embodiment 29I

(2- ((the chloro- 2- of 5- ((the fluoro- 2- methoxyl group -4- of 5- (7 methyl -7- azaspiro [3.5] nonyl- 2- yl) phenyl) amino) Pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide

The present embodiment is prepared according to the method for embodiment 7, by (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- (2,6- diazas Spiral shell [3.4] octyl- 6- yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine replaces with (2- ((the chloro- 2- of 5- ((the fluoro- 2- methoxyl group -4- of 5- (7- azaspiro [3.5] nonane -2- base) phenyl) amino) pyrimidine-4-yl) amino) phenyl) diformazan Base phosphine oxide.Obtaining title compound is yellow solid, yield 42%.¹H NMR(400MHz,CD₃OD):δ,8.28(s,1H), 8.25-8.19 (m, 1H), 7.79-7.73 (m, 1H), 7.63-7.61 (m, 1H), 7.50-7.41 (m, 2H), 6.98 (d, J= 6.8,1H),3.93(s,3H),3.81-3.72(m,1H),3.52-3.39(m,2H),3.17-3.11(m,1H),3.01(m, 1H),2.89(s,3H),2.56-2.51(m 1H),2.33-2.30(m,2H),2.19-2.06(m,2H),1.91-1.88(m, 8H).LCMS(ESI)(5-95AB):m/z:558.2[M+1].

Biochemical test

Experimental material

Enzyme: ALK wild type, ALK C1156Y and ALK L1196M are purchased from Carna Biosciences (Japan), EGFR T790M/L858R is purchased from Life technology (Madison, WI).

HTRF kit: being purchased from Cis-Bio International, includes Eu label TK1 antibody, XL665 and biotin The TK1 peptide substrate of label.

Detecting instrument: Envision (PerkinElmer).

Experimental method

3 times of gradient dilutions of compound will be tested, final concentration 11 dosage from 1uM to 0.017nM is obtained.

10ul wild type ALK enzyme reaction mixture system: 0.5nM wild type ALK, 1uM biotin-TK1 peptide, 30uM ATP.Reaction buffer: 50mM Hepes (pH7.5), 10mM MgCl2,0.01mM NaV3VO4. reaction plate are white Proxiplate 384-Plus plate (PerkinElmer) is reacted at room temperature 90 minutes.

10ul ALK C1156Y enzyme reaction mixture system: 0.15nM ALK C1156Y, 1uM biotin-TK1 peptide,30uM ATP.Reaction buffer: 50mM Hepes (pH7.5), 10mM MgCl2,0.01mM NaV3VO4. reaction Plate is white Proxiplate 384-Plus plate (PerkinElmer).Room temperature reaction 60 minutes.

10ul ALK L1196M enzyme reaction mixture system: 0.15nM ALK L1196M, 1uM biotin-TK1 peptide,30uM ATP.Reaction buffer: 50mM Hepes (pH7.5), 10mM MgCl2,0.01mM NaV3VO4. reaction Plate is white Proxiplate 384-Plus plate (PerkinElmer), is reacted at room temperature 60 minutes.

10ul EGFR T790M/L858R enzyme reaction mixture system: 0.08nM EGFR T790M/L858R, 1uM biotin-TK1peptide,20uM ATP.Reaction buffer: 50mM Hepes (pH7.5), 10mM MgCl2,0.01mM NaV3VO4. reaction plate is white Proxiplate 384-Plus plate (PerkinElmer).Room temperature reaction 60 minutes.

Detection reaction: add 10ul detection reagent into reaction plate, Antibody final concentration of 2nM, XL665 62.5nM. Incubation at room temperature 60 minutes.Envision read plate.

Data analysis

Reading is converted to inhibiting rate (%) (Min-Ratio)/(Max-Min) * 100% by following equation.4 parameters are bent Line fitting (Model 205in XLFIT5, iDBS) measures IC50 data.

Cell experiment

Experimental material

RPMI1640, fetal calf serum, penicillin/streptomycin solution, be purchased from Life Technology (Madison, WI).Cell Titer-Glo luminescent cell viability reagents purchased from Promega (Madison, WI).Karpas299cell line is purchased from European Collection of Cell Cultures (ECACC).Plate reader Device: Envision (PerkinElmer).

Experimental method

384 orifice plates, 2500 Karpas-299 cells of every hole kind, 45ul volume.37 DEG C of trainings overnight in 2 incubator of CO It supports.Untested compound does 3 times of gradient dilutions, obtains concentration 10 dose concentrations from 2.5mM to 0.127uM, two multiple holes.It is intermediate The every hole of plate adds 49ul culture medium.1ul compound is shifted to intermediate plate from gradient dilution compound plate, and mixing is abundant.Again from centre Plate takes 5ul liquid to go to cell plates.Cell continuation is cultivated 72 hours in CO2 incubator.After 72 hours, 25ul detection examination is added Agent.Incubation at room temperature 10 minutes, Envision read plate.

Data analysis

Reading is converted to inhibiting rate (%) by following equation(Max-Sample)/(Max-Min) * 100%.4 parameters Curve matching (Model 205 in XLFIT5, iDBS) measures 50 data of IC.

The ALK enzyme of the compounds of this invention inhibits IC 50, and ALK L1196M enzyme inhibits IC 50, and ALK C1156Y enzyme inhibits IC 50, EGFR T790M/L858R enzymes inhibit the data of the ALK IC50 of IC 50 and Karpas-299 cell to open up in following table Show.Compound of the IC 50 between 1-100nM is used +++ it indicates；Compound of the IC 50 between 101-1000nm is used ++ it indicates, The IC50 of compound is greater than 1000nm compound use+indicate.

Internal drug efficacy study

Internal efficacy data shows the compound of the present invention in the different of wild type LU-01-0015 patients with lung cancer source below Kind transplanting (PDX) model (BALB/c nude mice) and LU-01-0319Crizotinib resistant models (BALB/c nude mice) both moulds Anti-tumor activity more unexpected than reference compound AP26113 is all shown in type and reduces gross tumor volume.For example, Representative compounds 9,12,22,27 etc. are after administration (25 mgs/kg) 16 days, about 277mm of the gross tumor volume since most³ It is decreased to 34-50mm³, and AP26133 is only reduced to 119mm³。

1. carrying out body on heterograft (PDX) the BALB/c nude mouse for being subcutaneously implanted LU-01-0015 patients with lung cancer source Interior effect experiment

BALB/c nude mice, female, 6-8 weeks, about 18-22 grams of weight, is maintained at a special pathogen-free domestic for mouse In environment, and in single ventilated cage (5 every cages of mouse).All cages, place mat and water carry out disinfection before use.It is all Animal can freely obtain the commercial laboratory diet of standard authentication.It shares 80 and is purchased from Shanghai BK Laboratory The mouse of Animal Co., LTD are for studying.Every mouse is subcutaneously implanted tumor tissues (20-30 cubic millimeters) in right flank abdomen, Growth for tumour.Start to test when mean tumour volume reaches about 250-300 cubic millimeters.Test compound is daily Oral administration, 25 mgs/kg.The two-dimentional calliper to measure of every 3 days of gross tumor volume, volume is measured with cubic millimeter, by following Formula calculates: V=V=0.5a x b2, wherein a and b is the major diameter and minor axis of tumour respectively.Antitumor drug effect is by with change The average tumor for closing the processed animal of object increases volume and increases volume divided by the average tumor of untreated animal to determine.

2. in subcutaneous transplantation LU-01-0319 xenograft tumor, and to resisting on Crizotinib drug resistance BALB/c nude mice Effect experiment in tumour body

It is initially the LU-01-0319 xenograft tumor models obtained from the clinical sample of operation excision, and is implanted into naked Mouse, this is defined as batch P0 (LU-01-0319-P0).Next a batch is defined as batch P1 (LU- from the implantation of the tumour of P0 01-0319-P1).FP3 is regained from P2, and next batch is defined as batch FP4 from the implantation of FP3 tumour.Implantation is swollen About 2-3 weeks after tumor, when tumor size reaches about 300mm3, treated with mice with tumor with Crizotinib.What is continued to increase is swollen Tumor is defined as LU-01-0319 antitumor model.BALB/c nude mice, female, 6~8 weeks, about 18~22 grams of weight, totally 75 mouse It for studying, is bought from Shanghai BK Laboratory Animal Co., LTD.Every mouse right flank is subcutaneously implanted LU-01- Tumor biopsy (the about 30mm of 0319R FP6³), the growth for tumour.About 2-3 weeks after implantation tumour, tumor size reaches about 300mm³When, the mouse with tumour is handled with Crizotinib (10/25/50/75 mg/kg).According to tumor size The dosage of Crizotinib can suitably change.When mean tumour volume reaches about 200-400mm³When start experimental study.Examination Compound is tested to be administered orally once a day.Tumor size measures weekly twice, with two dimensions of slide calliper rule, and uses following formula Volume: V=0.5a x b2 is calculated, wherein a and b is the major diameter and minor axis of tumour respectively.Antitumor drug effect is by with compound The average tumor of processed animal increases volume and increases volume divided by the average tumor of untreated animal to determine.

ALK inhibitor of the invention, can be used for treating various cancers includes primary cutaneous type, non-small cell lung Cancer, the big B- cell lymphoma of diffusion, Inflammatory myofibroblastic tumor, neuroblastoma, anaplastic thyroid carcinoma and cross Line muscle tumor.ALK inhibitor can be used as monotherapy or use with other chemotherapeutic agents.

Claims

1. compound shown in formula (I) or its pharmaceutically acceptable salt,

Wherein,

T₁Selected from-N- or-C (R₀₁)-；

T₂Selected from-N (R₀₁)-, O, S (=O)₂Or-CH (NR₀₁R₀₂)-；

R₀₁Or R₀₂Separately it is selected from H, CD₃、C_1-6Alkyl, C_1-6Halogenated alkyl and C_3-6Ring Alkyl-(CH₂)_0-3, wherein H or C is optionally replaced by 1,2 or 3 hetero atom, and the hetero atom is selected from O, S, N, S (=O)₂With CN；

Optionally, T₂On R₀₁And R₀₂Be interconnected on the same N 1 5~6 member ring of formation, on the ring containing 1,2 or 3 hetero atoms, the hetero atom are selected from O, S and N；

D₁~D₄Separately selected from-(CR₁R₂)_1-3-,；

D is selected from-N (R₀₁)-,-O- and-S-；

W is selected from=O ,=S ,=N (CN) and=N (OMe)；

R₃Selected from R₀₃、OR₀₃And SR₀₃；

R₀₃Selected from C_1-4Alkyl, CD₃、C_1-4Halogenated alkyl and C_3-5Naphthenic base-(CH₂)_0-3-；

Z is selected from N and C (R₄)；

X₁Selected from C (R_x1)；

X₂Selected from CH；

R_x1Selected from H, F, Cl, Br, I, OH, NH₂；

R₁、R₂And R₄Separately it is selected from H, F, Cl, Br, I, CN, OH, SH, NH₂、C_1-6Alkyl, CD₃、C_1-6Miscellaneous alkyl, C_1-6Halogen Substituted alkyl, C_3-6Cyclic hydrocarbon radical-(CH₂)_0-3And C_3-6Heterocyclic hydrocarbyl-(CH₂)_0-3-、-CH₂CH₂S (=O)₂CH₃、-CH₂CH₂CN、

Wherein " miscellaneous " represents 1,2 or 3 hetero atom, and the hetero atom is selected from O, S and N；

R_p1And R_p2Separately it is selected from H, C_1-4Alkyl, CD₃And C_1-4Halogenated alkyl；

With

Optionally, Z andPosition can be interchanged.

2. compound or its pharmaceutically acceptable salt according to claim 1, wherein the R₀₁And R₀₂Separately select From H, CH₃、CD₃、CF₃、CHF₂、CH₂CH₃、CH(CH₃)₂、-CH₂CF₃、-CH₂CH₂CF₃、-CH₂CH₂F、-CH₂CH₂S (=O)₂CH₃、-CH₂CH₂CN、 With- CH₂CH₂F。

3. compound or its pharmaceutically acceptable salt according to claim 1, wherein the R₀₃Selected from CH₃、CD₃、CF₃、 CHF₂、CH₂CH₃、CH(CH₃)₂、-CH₂CF₃、-CH₂CH₂CF₃、-CH₂CH₂F and

4. compound or its pharmaceutically acceptable salt according to claim 1, wherein the R_p1And R_p2Separately select From H, CH₃、CD₃、CF₃、CHF₂、CH₂CH₃、CH(CH₃)₂、-CH₂CF₃、-CH₂CH₂CF₃With-CH₂CH₂F。

5. compound or its pharmaceutically acceptable salt according to claim 1, wherein the R₁、R₂And R₄Separately Selected from H, F, Cl, Br, I, CH₃、CD₃、CF₃、CHF₂、CH₂CH₃、CH(CH₃)₂、-CH₂CF₃、-CH₂CH₂CF₃、-CH₂CH₂F、- CH₂CH₂S (=O)₂CH₃、-CH₂CH₂CN、 With-CH₂CH₂F。

6. compound or its pharmaceutically acceptable salt according to claim 1, wherein T₂On NR₀₁R₀₂Selected from NHCH₃、N (CH₃)₂、N(CH₂CH₃)₂And

7. compound or its pharmaceutically acceptable salt according to claim 1, wherein D or T₂Separately be selected from- NH- ,-NMe- and-O-；D_1-4And T₂It is also selected from-CH (NCH₃CH₃)-。

8. compound or its pharmaceutically acceptable salt according to claim 1, wherein spirane structure unitChoosing From

9. compound or its pharmaceutically acceptable salt that one kind has structure shown in formula (II):

Wherein each variable such as claim 1~8 is defined.

10. compound or its pharmaceutically acceptable salt according to claim 1, with structure shown in formula (III):

Wherein each variable such as claim 1~8 is defined.

11. compound or its pharmaceutically acceptable salt, are selected from:

12. the preparation method of compound according to claim 1, preparation route is as shown in option A or C:

Option A

Scheme C

13. the preparation method of compound according to claim 12, wherein the preparation method of A5 is as shown in option b:

Option b

14. compound or its pharmaceutically acceptable salt described in any one are in preparation treatment and ALK according to claim 1~11 And/or EGFR and the relevant cancer of their mutation, with ROS1, BRAF, c-MET, HER2, KRAS/MEK, PIK3CA, The cancer of FDFR, DDR2 and/or VEGFR inhibitor combination therapy or in the drug of the cancer of cytotoxin combination therapy Using.