CN104968664A - Bicyclic compound functioning as tyrosine kinase inhibitor - Google Patents

BICYCLIC COMPOUND FUNCTIONING AS TYROSINE KINASE INHIBITOR

As the dark inhibitor of tyrosine-kinase and cycle compound

1st, technical field

The invention belongs to pharmaceutical technology field, specifically related to as tyrosine kinase inhibitor and cycle compound, its deuterated thing, its pharmaceutically acceptable salt or its stereoisomer, the preparation method of the compound, pharmaceutical composition containing the compound, is prevented using the compound and/or treats the related leukemia of B cells in individual（Such as B Cell chronic lymphocytics cancer, NHL）, inflammatory and autoimmune disease are (such as rheumatoid arthritis, systemic loupus erythematosus）Method, and be confused compound is used to preventing and/or treating the related leukemia of B cells preparing（Such as B cell chronic lymphocytic cancer, NHL）, inflammatory and autoimmune disease（Such as rheumatoid arthritis, systemic loupus erythematosus）Medicine in application.

2nd, background technology

One of maximum family of protein kinase composition people's fermentoid, and adjust many different signal transduction process (T. Hunter, Cell 1,987 50 by adding phosphate group to protein: 823-829).Especially, hydroxylic moiety of the EGFR-TK phosphorylated protein shield in tyrosine residue.Family tyrosine kinase includes control cell growth, migration and the member of differentiation.Abnormal kinase activity has been directed to many human diseases, including cancer, autoimmune disease and inflammatory disease.Because protein kinase belongs to the key regulator of cellular signal transduction, their offers adjust the target of cell function with small molecule kinase inhibitors, and therefore become good drug design target.Except the treatment of kinase mediated lysis, the selectivity of kinase activity and effective inhibitor can be additionally used in research cell signaling processes and identify other cell targets with therapeutic potential.

There is good evidence on key effect of the B cell in the pathogenesis of autoimmunity and/or inflammatory disease.It is effective that therapeutic agent based on the protein such as Rituxan of B cell, which is consumed, for inflammatory disease such as rheumatoid arthritis caused by autoantibody（Rastetter etc., Annu Rev Med 2,004 55:477) therefore, the inhibitor of the protein kinase played a role in B cell activation should generate useful therapeutic agent for disease pathology cell-mediated B such as autoantibody to.

A series of B cell responses, including propagation and differentiation are controlled to arrive ripe antibody-producting cell by the signal transduction of B cell receptors (BCR).BCR is that the crucial point of adjustment and abnormal signal transduction of B cell activity can cause the B cells propagation and pathogenic autoantibodies of imbalance Formed, it causes various autoimmune disease and/or inflammatory disease.Bu Ludun (Bruton's) LCK (Btk) is in the BCR film near-end kinases related to the non-BCR in immediately downstream.Btk shortage has shown that blocking BCR signal transductions, and therefore Btk suppression can be the effective treatment method for the lysis for blocking B cell mediation.

Btk is the member of EGFR-TK Tec families, and shows the key regulator for being the formation of early stage B cell and mature B cell activation and survival（Khan etc., Immunity 1,995 3: 283;Ellmeier etc., J. Exp. Med. 2,000 192: 1611).The Btk mutation of people cause the chain gamma-globulins of illness X to lack mass formed by blood stasis (the XLA) (Immunol. such as Lindvall Rev. 2,005 203: 200).These patients are immunocompromised hosts, and show impaired B cell maturations, the immunoglobulin and periphery b cell level of reduction, the immune response and the calciokinesis in the post-stimulatory decreases of BCR independent of T cell of reduction.

Evidence on effects of the Btk in autoimmune disease and inflammatory disease is provided via Btk- deficient mices model.In the preclinical mouse model of systemic loupus erythematosus (SLE), Btk deficient mices show significantly improving for progression of disease.In addition, Btk- deficient mices (Jansson and Holmdahl Clin. Exp. Immunol. 1,993 94 resistant to Collagen-Induced Arthritis: 459).Dose dependent effect (Z. Pan etc., Chem. Med Chem. 2,007 2 of the verified selective Btk inhibitor in arthritis mouse model: 58) .

Btk also has the cell expression that lysis is may relate in addition to B cell.Threshing (the J. Biol. Chem. 2,005 280 Iwaki of impaired antigen induction are shown as mast cell-expressed and Btk deficiency derived from bone marrow mast cell such as Btk: 40261) .This display Btk can be used for treatment pathologic mast cells reaction such as allergy and asthma.In addition, the monocyte from XLA patient for wherein lacking Btk activity shows TNFa generations (the J Exp such as Horwood Med 2,003 197 of reduction after stimulation: 1603).Therefore, the inflammation of TNFa mediations can be adjusted by small molecule Btk inhibitor.Moreover it has been reported that Btk played a role in Apoptosis（Islam and Smith Immunol. Rev. 2,000 178:, and therefore 49) Btk inhibitor will be effective (the J. Exp. such as Feldhahn Med. 2,005 201 for treating some B cell lymphomas and leukaemia: 1837) .

The Dasatinib of listing in 2006 is Mutiple Targets inhibitor, has to Btk and is acted on compared with high inhibition, for treating chronic myelogenous leukemia；In addition, in November, 2013 is also Mutiple Targets inhibitor by the FDA PCI-32765 for ratifying listing, it is irreversibility to Btk inhibitory action, for treating lymthoma, leukaemia and autoimmune disease.

Not yet selective Btk inhibitor listing at present, it is CC-292 (also known as AVL-292) to study most fast medicine, is studied in by the end of October, 2013 into the clinic II phases, it is used as irreversible selective depression Bt

It is an object of the invention to provide excellent high selectivity Btk inhibitor, it can be used in preventing and/or treats B cell related leukemia, inflammatory and/or autoimmune disease.

3rd, the content of the invention

The invention provides as tyrosine kinase inhibitor and cycle compound, it is excellent Btk inhibitor to be confused compound, and can be used in preventing and/or treat B cells related leukemia, inflammatory and/or autoimmune disease.

The invention provides lower fan's formula（I compound, its deuterated thing, its pharmaceutically acceptable salt or its stereoisomer shown in)：

Wherein, the expression C-Ra of X and W independently, C=0 or N-Rb,

And X it is different with W when be C=0,

Ra represents hydrogen atom, halogen atom ,-CN ,-CF₃, by 1-2 it is identical or different (^ replaces or unsubstituted C_MAlkyl, d.₄Alkoxy QM alkylidenes, amino, C₃.₆Cycloalkyl Q alkylidenes, phenyl CCM alkylidenes, naphthyl CQ.₄Alkyl, 5-10 unit's heteroaryl QM alkylidenes or-OH, Rb is not present, or represents hydrogen atom, identical or different by 1-2（^ replaces or unsubstituted C₄Alkyl, alkoxy 0)-₄Alkylidene, C_3-6Cycloalkyl Co_₄Alkylidene, phenyl Q alkylidenes, naphthyl Q alkylidenes or 5-10 unit's heteroaryl QM alkylidenes,

Represent d-₄Alkoxy, alkoxy carbonyl group, carbamoyl, C_1-3Alkyl-carbamoyl, 3-8 members cycloalkyl or contains the heteroatomic 3-8 circle heterocycles base selected from N or 0；

R₂Represent hydrogen atom, halogen atom ,-CF₃, C_MAlkyl, alkoxy, amino or

-OH;

The expression phenyl of ring A and ring B independently, 3-8 member cycloalkyl, containing the heteroatomic 3-8 circle heterocycles alkyl for selecting N, 0 and S, 4-7 unit's heteroaryls or 6-12 member bicyclic ring structures；And L₂Expression covalent bond independently ,-NH- ,-N (C_1-3Alkyl) -, -0-,-S (0)_m-, -N(C_1-3Alkyl）C (O)-,-QC N Cw alkyl） - , -N(C_1-3Alkyl） S(0)₂- or-S (0)₂N(C_1-3Alkyl)-;

A represents covalent bond, or unsubstituted or by the alkyl-substituted imino groups of CM；

B represents-CO- or-S0₂-;

C represents the sub- allene bases of 1,3-, 1,1- or 1 unsubstituted or replaced by one or two methyl or trifluoromethyl, 2- ethenylidenes, ethynylene, or it is unsubstituted or replaced by one to four methyl or trifluoromethyl 1,3- butadiene -1,4- subunits；

D represents covalent bond or C_1-6Alkylidene；

E represents hydrogen atom,._1-4Alkoxy, amino, 3-7 member cycloalkyl, 6-12 member bicyclic ring structures, d.₄Alkyl amino or two-(Cw alkyl）Amino, wherein moieties may be the same or different；1^ and R₃Expression hydrogen atom independently, halogen atom, cyano group, nitro, C₄Alkenyl C2-4 blocks base or-- R45

L₃Represent covalent bond ,-NH- ,-N (Ci_-3Alkyl) -, -0-,-O-Ci.3 alkylidenes -,-S-C_1-3Alkylidene-,-S (0)_m- ,-C (0)-,-NHC (O)-,-N (C_1-3Alkyl) C (0)-,-C (0) NH-,-C (0) N (C,₃Alkyl）- ,-NHS (0)₂- , -N(Ci_-3Alkyl） S(0)₂- ,-S (0)₂NH-,-S (0)₂N(Ci.₃Alkyl)-,-OC (O)-or-C (0) 0-,

R₄Represent hydrogen atom, d-₄Alkyl ,-N (C_{1 -3}Alkyl) 2,-NHC C^CKCM alkyl),-OH, -0 (C_1-4Alkyl）,-S (0)₂(Cw alkyl）, 3-7 member cycloalkyl, phenyl or 5-6 unit's heteroaryls；

Above-mentioned c_1-3Alkyl and c_1-4Moieties, cycloalkyl, heteroaryl in alkyl can be further by 1-4 identical or different Q₂Substitution,

(^ represents plain atom, d.₃Alkyl, amino, d_₃Alkyl amino, two-(Cw alkyl） Amino, hydroxyl, d.₃Alkoxy, d_₃Alkoxy carbonyl group, carbamoyl, alkyl-carbamoyl, two-(C_{I -3}Alkyl）Carbamoyl or 3-6 member cycloalkyl, wherein Q₂Can be with identical or different；

The upper carbon atom of the cycloalkyl and bicyclic ring structures can be by 1-4 identical or different N, NH, N (C_1-3Alkyl）、 0、 S(0)_m, C (O) replace；

The heteroaryl can be independently selected from N, 0 or S containing 1-4 hetero atom, described hetero atom;

Represent singly-bound or double bond；

M represents 0,1 or 2;

The expression 0,1,2,3 or 4 of p and q independently.

In a preferred embodiment, the invention provides above-mentioned formula（I compound, its deuterated thing, its pharmaceutically acceptable salt or its stereoisomer shown in), wherein：

X represents C-Ra or N-Rb,

Ra represents hydrogen atom, halogen atom ,-CF₃, methyl, ethyl, methoxyl group, Yue epoxide ethyls, amino, cyclopropyl, phenyl, benzyl, naphthyl, pyrrole radicals, furyl or pyridine radicals, Rb is not present, or represents hydrogen atom, identical or different by 1-2（^ replaces or unsubstituted d_₃Alkyl, C_1-3Alkoxy C o.3 alkylidene, C_3-6Cycloalkyl C_Q-3Alkylidene, phenyl, benzyl, naphthyl, pyrrole radicals, THP trtrahydropyranyl, furyl or pyridine radicals,

Represent d.₃Alkoxy, alkoxy carbonyl group or contains the heteroatomic 5-7 circle heterocycles base selected from N or 0；

W represents C=0;

R₂Represent hydrogen atom or amino；

The expression phenyl of ring A and ring B independently, 5-6 member cycloalkyl, containing the heteroatomic 5-6 circle heterocycles alkyl selected from N, 0 and S, 5-6 unit's heteroaryls or 8-10 member bicyclic ring structures；1^ and₂Expression covalent bond independently ,-NH- ,-N (CH₃) -, -0-,-S (0)_m-,

-N(CH₃)C(0)-, -C(0)N(CH₃)-,-N (CH₃)S(0)₂- or-S (0)₂N(CH₃)

A represents covalent bond, or imino group that is unsubstituted or being replaced by C；

B represents-CO- or-S0₂-;

C represents unsubstituted or by one or two methyl substituted 1,2- ethenylidenes or ethynylene；

D represents covalent bond or Asia Yue bases；

E represents hydrogen atom, methoxyl group, amino, piperidyl, morpholinyl, 6-9 member spirane structures, 6-8 members and ring structure, 6-8 member caged scaffolds, methylamino, piperazine, pyrrolidinyl or two-(methyl）Amino；

1^ and 1₃Expression hydrogen atom independently, halogen atom, nitro or-L₃-R₄,

L₃Represent covalent bond,-NH-,-N Cw alkyl) -, -0-,-O-Cw alkylidenes -,-S-C_1-3Alkylidene-,-S (0)_m- ,-C (O)-,-NHC (O)-,-C (0) NH-,-NHS (0)₂- ,-S (0)₂NH-,

- OC (O)-or-C (0) 0-,

R₄Represent hydrogen atom, C_1-4Alkyl ,-N Cw alkyl)₂, -NHC(0)0-(C_MAlkyl),

- OH ,-O CM alkyl）,-S OWCw alkyl）, 5-6 member cycloalkyl, phenyl or 5-6 unit's heteroaryls；

Above-mentioned C_1-3Moieties, cycloalkyl, heteroaryl, spirane structure and ring structure and caged scaffold in alkyl can be further by 1-4 identical or different Q₂Substitution,

Q₂Represent！Plain atom, C_1-3Alkyl, amino, d.₃Alkyl amino, two-(d.₃Alkyl）Amino, hydroxyl, d_₃Alkoxy, alkoxy carbonyl group, carbamoyl, C₃Alkyl-carbamoyl, two-alkyl）Carbamoyl or 5-6 member cycloalkyl, wherein Q₂Can be with identical or different；

Carbon atom in the cycloalkyl and bicyclic ring structures can be by 4 identical or different N, NH, N (C_1-3Alkyl）、 0、 S(0)_m, C (O) replace；

Be confused spirane structure and ring structure and caged scaffold can be containing 1-4 hetero atoms, and described hetero atom is separately selected from N or S;

^ represents singly-bound or double bond；

M represents 0,1 or 2;

The expression 0,1,2,3 or 4 of p and q independently.

In a preferred embodiment, the invention provides above-mentioned formula（I compound, its deuterated thing, its pharmaceutically acceptable salt or its stereoisomer shown in), wherein：

X represents CH or N-Rb,

Rb is not present, or represents hydrogen atom, identical or different by 1-2（^ replaces or unsubstituted methyl, ethyl, cyclopropane base, pentamethylene base or THP trtrahydropyranyl,

Q represents alkoxy or containing the heteroatomic 5-6 circle heterocycles base selected from N or 0；

W represents c=o;

R₂Represent hydrogen atom or amino；

The expression phenyl of ring A and ring B independently, contains the heteroatomic 5-6 circle heterocycles alkyl of N or 5-6 unit's heteroaryls； 1^ and L₂Expression covalent bond independently ,-NH- or-N (CH₃)-;

A represents covalent bond or imino group；

B represents-CO-;

C represents 1,2- ethenylidenes；

D represents Gong Jia Key or methylene；

E represents hydrogen atom, piperidyl, morpholinyl, piperazine, pyrrolidinyl or two-(methyl) amino；Represent hydrogen atom, halogen atom, methyl, methoxyl group unsubstituted or replaced by 1-4 identical or different halogen atoms, Yue bases amino or two-(methyl）Amino；

R₃Represent hydrogen atom, halogen atom or-L₃-R₄,

L₃Represent covalent bond ,-NH- ,-N (C_1-3Alkyl) -, -0-, -0-C_MAlkylidene-,-S-d-3 alkylidenes ,-S (0)_m- ,-C (O)-,-NHC (O)-,-C (0) NH- ,-OC (O)-or-C (0) 0-,

R₄Represent hydrogen atom, methyl, ethyl ,-N (C_1-3Alkyl)₂, -NHC(0)0-C₃H₇, -0(CH₃), -0(CH₂CH₃), -0(C(C¾)₃) ,-S (0)₂-C₃H₇, pentamethylene base, cyclohexyl, pyrrolidinyl, tetrahydrofuran base, piperidyl, morpholinyl, piperazinyl, phenyl, pyrrole radicals, imidazole radicals, thiazolyl , oxazolyls, thiadiazolyl group, pyridine radicals or pyrimidine radicals；

The pentamethylene base, cyclohexyl, pyrrolidinyl, tetrahydrofuran base, piperidyl, morpholinyl, piperazinyl, phenyl, pyrrole radicals, imidazole radicals, thiazolyl, oxazolyls, thiadiazolyl group, pyridine radicals, pyrimidine radicals can be further by 1-2 identical or different Q₂Substitution,

Q₂Represent plain atom, methyl, amino, methylamino, two Yue bases amino, hydroxyl, Yue epoxides, Yue oxygen carbonyls, carbamoyl, Yue bases carbamoyl or two-(methyl）Carbamoyl；

- ^ represents singly-bound or double bond；

M represents 0,1 or 2;

The expression 0,1 or 2 of p and q independently.

In a preferred embodiment, the invention provides above-mentioned formula（I compound, its deuterated thing, its pharmaceutically acceptable salt or its stereoisomer shown in), wherein：

X represents CH or N-Rb,

Rb is not present, or represents hydrogen atom, cyclopropane base, THP trtrahydropyranyl, by 1（^ replaces or unsubstituted methyl or ethyl,

Represent Yue epoxides, pyrrolidone-base or pyrrolidinyl；

W represents 00;

R₂Represent hydrogen atom； The expression phenyl of ring A and ring B independently, pyrazolyl, imidazole radicals , isoxazolyl , oxazolyls, pyridine radicals or piperidyl；

1^ and L₂Expression covalent bond independently ,-NH- or-N (CH₃);

A represents covalent bond or imino group；

B represents-CO-;

C represents 1,2- ethenylidenes；

D represents covalent bond or methylene；

E represents hydrogen atom, piperidyl, morpholinyl, piperazine, pyrrolidinyl or two-(methyl）Amino；

R!Represent hydrogen atom, fluorine atom, chlorine atom, trifluoromethyl, methoxyl group or trifluoro Yue epoxides；

R₃Represent hydrogen atom, fluorine atom, chlorine atom or-L₃-R₄,

L₃Represent covalent bond ,-NH- ,-N (C₃H₇) -, -0-, -0-CH₂CH₂- or-S (0)_m-, R₄Represent hydrogen atom, Yue bases, ethyl, dimethylamino ,-NHC (0) 0-C₃H₇ ,

-0(CH₃), -0 (C (C)₃), -S(0)₂-C₃H₇, morpholinyl, phenyl, pyrrole radicals, imidazole radicals, thiazolyl , oxazolyls, thiadiazolyl group or pyridine radicals,

The phenyl, pyrrole radicals, imidazole radicals, thiazolyl, oxazolyls, thiadiazolyl group, pyridine radicals can be further by 1-2 identical or different Q₂Substitution,

Q₂Represent carbamoyl, methylcarbamoyl or two-(methyl）Amino Yue acyl groups；：Singly-bound or double bond are represented,

M represents 0,1 or 2;

The expression 0 or 1 of p and q independently.

In a preferred embodiment, the invention provides above-mentioned formula（I compound, its deuterated thing, its pharmaceutically acceptable salt or its stereoisomer shown in), wherein：

X represents N-Rb,

Rb is not present, hydrogen atom, methyl, cyclopropane base, THP trtrahydropyranyl, C OCH₂CH₂-, ^ H;

W represents c=o;

R₂Represent hydrogen atom；

Ring A represents phenyl； Ring B represents phenyl, pyridine radicals, pyrazolyl, imidazole radicals , isoxazolyl Huo oxazolyls；Represent covalent bond；

L₂Expression covalent bond independently ,-NH- or-N (C);

A represents imino group；

B represents-CO-;

C represents 1,2- ethenylidenes；

D represents covalent bond or methylene；

E represents hydrogen atom, piperidyl, morpholinyl, piperazine, pyrrolidinyl or two-(methyl）Amino；

Represent hydrogen atom；

R₃Expression-L₃-R₄, L₃Represent covalent bond, 0 or -0-CH₂CH₂-, R₄Represent -0 (CH₃), dimethylamino, morpholinyl or pyridine radicals, the pyridine radicals can be further by 1-2 identical or different Q₂Substitution, Q₂Represent carbamoyl, methylcarbamoyl or two-(methyl）Amino Yue acyl groups；

Represent singly-bound；

P represents 0;

Q represents 1.Detailed description of the invention

Unless otherwise stated, otherwise, it should be appreciated that the term used in this application has following meanings.

" C^ alkyl " of the present invention refers to the alkyl of the straight or branched containing 1-6 carbon atom, including " d_₄Alkyl ", " d_₃Alkyl " etc., the example includes but is not limited to such as Yue bases, ethyl, n-propyl, isopropyl, normal-butyl, 2- methyl-propyls, 1- Yue bases propyl group, 1,1- dimethyl ethyls etc..Term " (：_1-4Alkyl ", " Ci.₃Alkyl " refers to the instantiation containing 1 to 4,1 to 3 carbon atom in examples detailed above.

" the Ox alkylidenes " that the present invention is confused refers to covalent bond（ C_QAlkylidene）Or contain 1-6 carbon atom（〇^₆Alkylidene）The alkyl of straight or branched remove the structure after a hydrogen atom, including " QM alkylidenes ", " Co_-3Alkylidene,, " C_1-4Alkylidene ", " C_{1 -3}Alkylidene " etc., the example includes but is not limited to such as Asia Yue bases（-CH₂-), ethylidene（ -CH₂CH₂-), propylidene（ -CH₂CH₂C -), butylidene (- CH2CH2CH2CH2-) etc..Term " C_MAlkylidene ", " Ci-3 alkylidenes " refer to the tool containing 1 to 4,1 to 3 carbon atom in examples detailed above Body example.

" C of the present invention₂₄Alkenyl " refers to the straight or branched alkenyl that the carbon number containing key is 2-4；The example includes but is not limited to such as vinyl, 1-acrylic, 2- acrylic, 1-methyl ethylene, 1-cyclobutenyl, 2- cyclobutenyls, 3- cyclobutenyls, 1-methyl-1-acrylic ,-1-acrylic of 2- Yue bases, 1-Yue base-2- acrylic, 2- methyl-2- acrylic.

" C of the present invention₂-₄Alkynyl " refers to the alkynyl for the straight or branched that the carbon number containing three key is 2-4；The example includes but is not limited to such as acetenyl, 2-propynyl, 2- butynyls, 3- butynyls, 1-methyl-2-propynyl.

" C of the present invention_MAlkoxy ", " C_{1 -4}Alkylamino ", " two (C_MAlkyl) amino ", " C!.₄Alkoxy carbonyl ", " C_MAlkyl sulfenyl ", " CM alkyl sulphonyls ", " C_MAlkyl sulphinyl ", " CM alkyl amino sulfonyls ", " (alkyl amino sulfinyl ", refer respectively to " Ci_-4Alkyl -0- " group, " C_1-4Alkyl-NH- " group, " (C_MAlkyl)₂N-, group, " C_1-4Alkyl-O-C (O)-" group, " C_{1 -4}Alkyl-S- " group, " C_{1 -4}Alkyl-S0₂-, group, " C_1-4Alkyl-SO- " group, " C_{1 -4}Alkyl-S0₂-NH -"、 "C_MAlkyl-SO-NH- " groups, wherein " CM alkyl " is as defined hereinabove.

Alkoxy " referring to term " alkyl " group being connected by oxygen atom with other structures, such as Yue epoxides, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, amoxy, neopentyl oxygen, hexyloxy of the present invention.It is preferred that alkoxy, more preferably alkoxy.Term " d_₄Alkoxy ", " d_₃Alkoxy " referring to term " CM alkyl ", " C_{1 -3}The group that alkyl " is connected by oxygen atom with other structures.

" alkyl amido " of the present invention refers to " C_{1 -6}The group that alkyl " is connected by acylamino- with other structures.

" 1 element " of the present invention refers to fluorine atom, chlorine atom, bromine atoms or iodine atom etc.." d- of the present invention₄Alkoxy Q alkylidenes, C_3-6Ring protective embankment base QM alkylidenes, phenyl C () _₄Alkylidene, naphthyl Q alkylidenes, the unit's heteroaryl CQ- of 5- 10₄Alkylidene " refers to C_1-4Alkoxy, cycloalkyl, phenyl, naphthyl, the unit's heteroaryls of 5- 10 pass through Co_₄The group that alkylidene is connected with other structures, wherein " C (M alkylidenes " as defined hereinabove.

" 3-8 members cycloalkyl " of the present invention refers to all carbon atoms of annular atom, remove cyclic alkyl radical derived from a hydrogen atom, including such as " 3-7 members cycloalkyl ", " 3-6 members cycloalkyl ", " 4-6 members cycloalkyl " " 5-7 members cycloalkyl ", " 5-6 members cycloalkyl ", the example includes but is not limited to：Cyclopropane base, cyclobutane base, pentamethylene base, cyclohexyl, cycloheptyl alkyl, cyclooctane base etc.. " 3-8 circle heterocycles alkyl " of the present invention refers to that, containing one or more heteroatomic 3-8 cyclic group, " hetero atom " refers to nitrogen-atoms, oxygen atom, sulphur atom etc..It is preferred that 3-7 circle heterocycles base, 3-6 circle heterocycles bases, more preferably 5-7 circle heterocycles base, 5-6 circle heterocycles bases.Instantiation includes but are not limited to 2,5- dihydro-thiophenes base, 4,5- pyrazolines base, 3, -2-pyranose of 4- dihydros, 5,6- dihydros-4/-1,3- oxazinyls, aziridine base, azetidinyl, Thietane base, tetrahydrofuran base, nafoxidine base, imidazolidinyl, pyrazolidinyl, tetrahydrofuran base, Isosorbide-5-Nitrae-dioxane base, 1,3- dioxanes base, 1,3- dithians base, morpholinyl, piperazinyl etc..

" 4-7 unit's heteroaryls " refers to containing 4-7 annular atom（Wherein at least contains a hetero atom）The aromatic radical of composition, including " 5-7 unit's heteroaryls ", " 5-6 unit's heteroaryls ", its instantiation include but is not limited to such as furans, pyrroles, thiophene, imidazoles, oxazole, isoxazoles, thiazole, pyridine, pyrrole.The Qin, it is phonetic to sting, reach.Qin etc..

" 6-12 members bicyclic ring structures " refer to the bicyclic groups constituted containing 12 annular atoms of 6-（It can not contain or containing one and more than one hetero atom）, including " 7-10 members bicyclic ring structures ", " 8-10 members bicyclic ring structures ", " 6-9 members spirane structure ", " 6-8 members and ring structure ", " 6-8 members caged scaffold " etc..Its instantiation includes but is not limited to two rings [3. 1.0] hexyl, two rings [4.1.0] heptane base, two rings [2.2.0] hexyl, two rings [3.2.0] heptane base, two rings [4.2.0] octyl, octahydro pentalene base, octahydro indenyl, decahydronaphthalene naphthyl, ten tetrahydrochysene phenanthryl, bicyclic [3.1.0] hex- 2- Women bases, bicyclic [4.1.0] hept- 3- alkenyls, bicyclic [3.2.0] hept- 3- alkenyls, bicyclic [4.2.0] octyl- 3- alkenyls, l, 2, 3, 3a- tetrahydrochysene pentalene bases, 2, 3, 3a, 4, 7, 7a- hexahydro -1/7- indenyls, 1, 2, 3, 4, 4 α, 5, 6, 8 α-octahydro naphthyl, 1, 2, 4 α, 5, 6, 8-hexahydro naphthyl, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10- decahydro phenanthryl, cyclobutane and nafoxidine base, pentamethylene and nafoxidine base, azetidine and imidazolidinyl, 3- oxabicyclos simultaneously [3.1.0] hexyl, hexahydro furyl

[3,4-b] [l, 4] bioxin bases, hexahydro -2/-pentamethylene simultaneously [b] [l, 4] bioxin bases,

,ΝΗ ΗΝ、 ,ΝΗ ΗΝ ΗΝ、 ΗΝ、

And the bicyclic ring structures of armaticity, including but not limited to benzofuranyl, benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl, indazolyl, BTA base, quinolyl, isoquinolyl, acridinyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridines base, 1,3- dihydro benzo furyl, benzo [[1.3] dioxa cyclopentenyl, isoindoline base, Chromanyl, 1,2,3,4- nafoxidine simultaneously [3,4-c] pyrrole radicals, 5,6- glyoxalidine [1.2-] pyrazine -7 (8 Λ bases, 5,6- dihydros -1,7- naphthyridines -7 (8)-base, 5//- pyrroles [3.4-b] pyridine -6 (7)-base, 7,8- dihydropyridines [4. pyrimidines -6 (5/)-base, 2,3,6,7- tetrahydro-pyrazoles [4.3-cj pyridines -5 (4 /)-base, 6,7- thiazolines [5.4-c] pyridine -5 (4/ /)-base etc..

Term " 7-10 members bicyclic ring structures ", " 8-10 members bicyclic ring structures " refer to the instantiation containing 7 to 10,8 to 10 carbon atoms in examples detailed above.

" 6-9 member loop coils base " of the present invention refers to the 6-9 member condensed cyclic structures of the shared atom formation of at least two rings of a class.Its specific embodiment is included but are not limited to：Spiral shell [3.3] heptane base, spiral shell [3.4] octyl, spiral shell [3.5] nonyl, spiral shell [4.4] nonyl, spiral shell [3.4] oct-6-ene base, spiral shell [3.5] nonyl- 6- alkenyls, spiral shell [4.4] nonyl- 6- alkenyls, spiral shell [4.4] nonyl- 2,7- dialkylenes, 2- oxa- spiroheptane bases, 6- oxaspiros [2.5] octyl, 4- oxa-s -7- amino spiral shell [2.5] octyl, 2- amino spiral shell [3.3] heptane base, 2- oxa-s -6- amino spiral shell [3.3] heptane base, 2- amino spiral shell [3.4] octyl, 6- oxa-s -2- amino spiral shell [3.4] octyl, 2- oxa-s -6- amino spiral shell [3.4] octyl, 2- oxaspiros [3.4] octyl, 5- oxaspiros [3.5] nonyl, 7- amino spiral shell [3.5] nonyl, 2- amino spiral shell [4.4] nonyl, 2- oxa-s -7- amino spiral shell [4.4] nonyl, 2- oxaspiros [4.4] nonyl, 1,7- dioxo spiro [4.4] nonyl, 1,4,7- trioxa spiral shell [4.4] nonyl, 6- amino spiral shell [3.4] octyl- 7- alkenyls, 2- oxa-s -6- amino spiral shell [3.4] octyl- 7- alkenyls, 7- amino spiral shell [3.5] nonyl- 5- alkenyls, 2- amino spiral shell [4.4] nonyl- 7- alkenyls etc..

" 6-8 yuan and ring structure " of the present invention refers to share the 6-8 cyclic groups that two adjacent atoms are formed each other by two or more cyclic structures, and its specific embodiment is included but are not limited to：Two rings [3.1.0] hexyl, two rings [4.1.0] heptane base, two rings [2.2.0] hexyl, two rings [3.2.0] heptane base, two rings [4.2.0] octyl, bicyclic [3. 1.0] hex- 2- alkenyls, Chinese ring [4. 1.0] hept- 3- alkenyls, bicyclic [3.2.0] hept- 3- alkenyls, bicyclic [4.2.0] octyl- 3- alkenyls, benzofuranyl, benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl, Yin Oxazolyl, BTA base, quinolyl, isoquinolyl, acridinyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, thieno [2, 3-b] thienyl, thieno [3, 2-b] thienyl, benzo [b] thienyl, benzo [0] thiazolyl, cyclobutane and nafoxidine base, pentamethylene and nafoxidine base, azetidine and imidazolidinyl, the joyous ring of 3- oxa-s simultaneously [3.1.0] hexyl, hexahydro furyl [3, 4-b] [l, 4] bioxin bases, hexahydro-2-pentamethylene simultaneously [b] [l, 4] bioxin bases etc..

" 6-8 members caged scaffold " of the present invention refers to share the 6-8 yuan of rings that two non-conterminous atoms are formed each other by two or more cyclic structures

Compound specifically preferred according to the invention includes:

o/u/〇 ssssosld 26680ΗοίM

The method and/or other methods known to persons of ordinary skill in the art of fan is retouched in following reaction schemes to synthesize, but is not limited only to following methods.

For convenience, the present invention represents a variety of chemical compounds using well-known abbreviation, includes but is not limited to

DMF:N, V- dimethylformamide； THF:Tetrahydrofuran； DIEA:TV, Y-diisopropylethylamine； DMA:Dimethylamine； m-CPBA:Metachloroperbenzoic acid； LAH:Lithium Aluminium Hydride etc..

Reaction scheme 1:

Reactions steps：

Step 1:The preparation of intermediate 1

In dry reaction bulb, (1 equivalent of raw material 1 is added）, add polar solvent（Such as DMF, DMA) dissolving, add (1 equivalent of raw material 2）, alkali（Such as potassium carbonate）（2 equivalents）, heating response a few hours, room temperature is cooled to, reaction solution is poured into water water, filtered, filter cake is washed with frozen water, is dried in vacuo to obtain intermediate 1.

Step 2:The preparation of intermediate 2

In dry reaction bulb, (1 equivalent of intermediate 1 is added）, add under tetrahydrofuran dissolving, -78 °C and Lithium Aluminium Hydride be added portionwise（3-5 equivalents）, treat that temperature is warmed to room temperature after completion of dropping, add the aqueous ammonium chloride solution of saturation, stir at room temperature half an hour, filter, filtrate adds water, extraction concentrates organic phase, and column chromatography obtains intermediate 2.

Step 3:The preparation of intermediate 3

In dry reaction bulb, (1 equivalent of intermediate 2 is added）, dichloromethane dissolving, addition Manganese dioxide（20-40 equivalents）, at room temperature stirring reaction stay overnight, filter, use organic solvent washing filter cake, be spin-dried for organic phase, obtain intermediate 3, be directly used in next step reaction.

Step 4:The preparation of intermediate 4

In dry reaction bottle, (1 equivalent of intermediate 3）Use polar solvent（Such as Yue alcohol）Dissolving, adds (the 1.5-3 equivalents of raw material 3）, acetic acid（Minimum 1.5 equivalent）, at room temperature stirring reaction a few hours, add sodium borohydride（2-5 equivalents）, a few hours are reacted, are quenched, organic solvent extraction concentrates organic phase, column chromatography obtains intermediate 4.Tetrahydrofuran is dissolved in after can also imines be post-processed, is reduced with tetrahydrochysene lithium aluminium.

The preparation of step 5. intermediate 5

In dry reactor, (1 equivalent of intermediate 4 is added）, add appropriate solvent（Such as tetrahydrofuran, dichloromethane）Dissolving, adds alkali（Such as DIEA) (3 equivalents）, (the 0.5-1.5 equivalents of raw material 4 are added under ice-water bath）, continue after completion of dropping to react, be then quenched, extracted with organic solvent, column chromatography obtains intermediate 5.

Step 6:The preparation of intermediate 6

In dry reaction bulb, (1 equivalent of intermediate 5 is added）, add appropriate solvent（Such as dichloro Yue alkane）Under dissolving, ice-water bath, metachloroperbenzoic acid is added（1.5-3 equivalent）, it is warmed to room temperature continuation and reacts, be quenched, extracted with organic solvent, is concentrated to give intermediate 6 and is directly used in next step reaction.

Step 7:The preparation of intermediate 7

In dry reaction bulb, (1 equivalent of intermediate 6 is added）, add appropriate solvent（Such as tert-pentyl alcohol）Dissolving, adds (the 1-1.5 equivalents of raw material 5）, concentrated hydrochloric acid or trifluoracetic acid（0.5-1.5 equivalents）, back flow reaction is cooled to after room temperature and is quenched, extracted with organic solvent, concentrates, and column chromatography obtains intermediate 7.

Step 8:The preparation of intermediate 8

Intermediate 7 (1 equivalent) is added into appropriate solvent（Such as dichloro Yue alkane）Dissolving, adds quantity of solvent trifluoroacetic acid, or is passed through hydrogen chloride gas, and room temperature or lower stirring reaction to the intermediate 7 of cooling disappear.Concentration, obtains intermediate 8, is directly used in the next step.

Step 9:The preparation of compound of formula I

Intermediate 8 (1 equivalent) is dissolved in appropriate solvent（Such as tetrahydrofuran, dichloromethane, acetone, DMF, or be mixed solvent）, the alkali (such as DIEA) of 2-3 equivalents is added, under cooling（- 20 degree to -10 degree), Slow instills (0.9-1.1 equivalents) stirring reaction of raw material 4 to intermediate 8 and disappeared slowly.Reaction is quenched, concentrates, column chromatography or mesolow prepare liquid phase and purify to obtain compound of formula I. Reaction scheme 2:

Step 1:The preparation of intermediate 1

In dry reaction bulb, (1 equivalent of raw material 1 is added）, add appropriate solvent（Such as dichloromethane）Dissolving, adds (1.5 equivalents of raw material 2）, no ice copper acetate（2 equivalents）, pyridine（2 equivalents）, react stay overnight at room temperature, filter, silica gel column chromatography obtains intermediate 1 after filtrate concentration.

Step 2:The preparation of compound of formula I

Intermediate 1 (1 equivalent) is dissolved in appropriate solvent（Such as tert-pentyl alcohol）, add (the 1-1.5 equivalents of raw material 3）, few drops of concentrated hydrochloric acids are eventually adding, are heated to reflux to intermediate 2 disappearing.Cooling, concentration prepares liquid phase and purifies to obtain compound of formula I.

X, W in reaction scheme, R₂、 R₃、 L₂、 a、 b、 c、 d、 e、 p、 q、 ^：, ring A and ring B as mentioned before.Formula（I) compound, its deuterated thing or its stereoisomer can in a free form or the form of its pharmaceutically acceptable salt is used.Formula（I) the aobvious alkalescence of compound, can be with inorganic acid or organic acid formation acid salt.Such as hydrochloride, hydrofluoride, hydrochloride, hydrobromate, hydriodate, sulfate, trifluoroacetate, benzene sulfonate, mesylate, trifluoro Yue sulfonate, esilate, carbonate, nitrate, phosphate, phosphite, maleate, tartrate, citrate, acetate, benzoate, esilate, fumarate, oxalates, gluconate, hydroxyl acetate, isethionic acid, lactate, Lactobionate, Lactobionate, malate, Yue sulfonate, succinate, tosilate, glycinate, trimethylglycine salt, arginine salt, ornithine salt, glutamate, aspartate etc..

Formula（I) compound or its deuterated thing, its pharmaceutically acceptable salt can exist, therefore, present invention additionally comprises these optical isomers and its mixture due to there is asymmetric carbon atom with a kind of optical isomeric form.

Formula（I) compound, its deuterated thing, its pharmaceutically acceptable salt or its stereoisomer can constitute pharmaceutical composition with one or more pharmaceutical acceptable carrier.In an implementation In scheme, the invention provides pharmaceutical composition, the composition contains such as preceding the compounds of this invention, its deuterated thing, its pharmaceutically acceptable salt or its stereoisomer and pharmaceutical acceptable carrier being confused.In another embodiment, the invention provides pharmaceutical composition, the composition contains foregoing the compounds of this invention, its deuterated thing, its pharmaceutically acceptable salt or its stereoisomer, and the second therapeutic agent selected from antitumor agent, immunodepressant and/or anti-inflammatory agent.The conventional formulation clinically used can be made in described pharmaceutical composition, and can be applied in modes such as oral and parenteral administrations needs the patient of this treatment.Such as tablet, particle, glue Nang, powder, injection, inhalant, sublingual administration preparation, syrup, gel, ointment, suppository, lotion, nasal cavity drop, spray, preparation capable of permeating skin.These preparations can be added pharmaceutical acceptable carrier such as excipient, adhesive, humidizer, disintegrant, thickener etc. and be prepared from by conventional method.

Formula（I) compound, its deuterated thing, its pharmaceutically acceptable salt or its stereoisomer have preferable BTK kinase inhibitory activities, are the medicines that preferably there are excellent antitumor action and treating autoimmune diseases to act on.While formula（I) compound, its deuterated thing, its pharmaceutically acceptable salt or its stereoisomer are preparing the related leukemia for the treatment of B cells（Such as B Cell chronic lymphocytics cancer, NHL）, and autoimmune disease（Such as rheumatoid arthritis, systemic loupus erythematosus）In play an important role.

Formula（I) compound, its deuterated thing, its pharmaceutically acceptable salt or its stereoisomer are a kind of kinase inhibitors, particularly Btk inhibitor.The disease for one or more response kinase inhibitions that these inhibitor can be used for treating in mammal, includes the disease of response Btk suppression and/or the suppression of B cell proliferation.Shu Tied are not intended in any specific theory, it is believed that the compounds of this invention and Btk interaction cause the suppression of Btk activity, and therefore obtain these compound pharmaceutical applications.Therefore, the present invention includes being used to treat the mammal for having the suppression of response Btk activity and/or suppressing the disease of B cell proliferation, and the method for such as people, this method includes：At least one the compounds of this invention being described herein of effective dose is administered to the mammal with such disease.For example valid density can be determined on real danger by calculating bioavilability by determining the haemoconcentration of compound, or in theory.In addition to Btk, it is also possible to which affected other kinases include but is not limited to, other EGFR-TKs and serine/threonine kinase.

Kinases is in control elementary cell process such as propagation, differentiation and death（Apoptosis）Signal transduction path in terms of play obvious action.Abnormal kinase activity has been implied in various diseases In disease, described disease includes kinds cancer, autoimmunity and/or inflammatory disease and acute inflammatory response.Versatility effect of the kinases in key cells signal transduction path provides the notable chance of the novel drugs in identification targeting kinases and signal transduction path.

The method that one embodiment of the invention has the patient of the acute inflammatory response of the suppression of autoimmunity and/or inflammatory disease or response Btk activity and/or B cell proliferation including the use of the compounds of this invention or medicine composite for curing.

The autoimmunity and/or inflammatory disease that can be influenceed using the compound and composition according to the present invention are included but is not limited to：Psoriasis, allergy, regional enteritis, IBS, sjogren disease, tissue graft rejection reaction and the hyperacute rejection of transplant organ, asthma, systemic loupus erythematosus（With related glomerulonephritis）, dermatomyositis, multiple sclerosis, chorionitis, vasculitis（ANCA- correlations and other vasculitises）, autoimmune haemolytic and thrombocytopenic symptom, Gourde(G) Paasche syndrome（With related glomerulonephritis and empsyxis）, atherosclerosis, rheumatoid arthritis, chronic ITP (ITP), Addison disease, Parkinson's, Alzheimer disease, diabetes, septic shock and severe are several powerless.

, can be by least one the compounds of this invention provided herein and anti-inflammatory agent combination medicine-feeding in subject treatment method.Anti-inflammatory agent includes but is not limited to：The specific cyclooxygenase enzyme inhibitor of NSAID, non-specific and COX-2, gold compound, cortical steroid, methotrexate (MTX), Tumor Necrosis Factor Receptors（TNF) receptor antagonist, immunodepressant and methotrexate (MTX).

NSAID example includes but is not limited to, brufen, Flurbiprofen, the combination of naproxen and naproxen sodium, Diclofenac, C14H10Cl2NNaO2 and Misoprostol, sulindac, benzene daybreak propionic acid, Diflunisal, piroxicam, Indomethacin, Etodolac, fenoprofen calcium, Ketoprofen, Nabumetone sodium, SASP, tolmetin sodium and HCQ.NSAID example also includes COX-2 specific inhibitors such as celecoxib, valdecoxib, Lu meter Kao former times and/or etoricoxib.

In one embodiment, anti-inflammatory agent is salicylate or salt.Salicylate or salt include but is not limited to acetylsalicylic acid or aspirin, sodium salicylate and Choline Salicylate and magnesium salicylate.

Anti-inflammatory agent can also be cortical steroid.For example, cortical steroid can be cortisone, and dexamethasone, methylprednisolone, prednisolone, Inflamase, or metacortandracin.

In a further embodiment, anti-inflammatory agent is gold compound such as sodium aurothiomalate or Anranofin.It is metabolic poison such as dihydrofolate reductase inhibitor present invention additionally comprises wherein anti-inflammatory agent Such as the embodiment of Yue aminopterins or dihydrooratic acid salt dehydrogenase inhibitor such as leflunomide.

In other embodiments of the present invention, at least one anti-inflammatory compound is anti-monoclonal antibody（Such as according to storehouse pearl monoclonal antibody or training gram pearl monoclonal antibody）, TNF antagonists such as Etanercept (entanercept) or infliximab, the infliximab is a kind of anti-TNFa monoclonal antibodies.

In other embodiments of the present invention, at least one anti-inflammatory agent is immunosuppressant compounds as being selected from methotrexate (MTX), leflunomide, ring born of the same parents element, tacrolimus, imuran and the combination that the immunosuppressant compounds expected in ester are examined for wheat.

The B cell and B cell precursor for expressing Btk have implied that in the pernicious pathology of B cell B cell is pernicious to include but is not limited to B cell lymphoma, lymthoma（Including Huo Qijin and NHL）, hairy cell lymphoma, Huppert's disease, chronic and acute myelogene leukemia and chronic and acute lymphocytic leukemia.

It is the inhibitor of Fas/APO-l (CD-95) the death inducement signal conducting composites (DISC) in B- systems lymphoid cell to have shown that Btk.The destiny of leukaemia/lymphoma cell may is that by the reverse proapoptosis effect of the DISC Caspases activated and including balance (Vassilev etc. between Btk and/or the upstream anti-apoptotic regulation mechanism of its substrate, Biol. Chem. 1998,274,1646-1656).

It has also been found that Btk inhibitor may be used as chemical sensitizer, therefore can be used for combining with other chemotherapeutic drugs, the medicine of described chemotherapeutic drug particularly inducing cell apoptosis, such as antitumor agent, immunodepressant.The example for the other chemotherapeutic drugs that can be applied in combination with chemical sensitization inhibitor includes but are not limited to topoisomerase I inhibitor（Camptothecine or Hycamtin）, topoisermerase I I inhibitor（Such as daunomycin and Etoposide）, alkylating agent（Such as endoxan, melphalan and BCNU), the medicament that tubulin is oriented to（Such as PTX and vincaleukoblastinum）And biological agent（Such as antibody such as anti-CD 20 antibodies, IDEC8, immunotoxin and cell factor）.

Btk activity is related to some expression leukaemia of bcr-abl fusions caused by the transposition of chromosome dyad 9 and 22.This exception is generally observed in chronic myelogenous leukemia.Btk is substantially by bcr-abl tyrosine phosphorylations, and this initiation prevents the downstream survival signaling of Apoptosis in bcr-abl cells（N.Feldhahn etc., J. Exp. Med. 2005,201 (11), 1837-1852).

The compounds of this invention is compared with immediate prior art, with advantages below：

(1) formula（I) compound, its pharmaceutically acceptable salt or its deuterated thing have preferable BTK kinase inhibitory activities； (2) formula（I) compound, its pharmaceutically acceptable salt or its deuterated thing Small side effects, security window are big；

(3) the compounds of this invention preparation technology is simple, steady quality, it is easy to carry out large-scale industrial production.

The compounds of this invention beneficial effect, which is expanded on further, below by way of pharmacological evaluation, but this should not be interpreted as to the compounds of this invention only has following beneficial effect.

The pharmacological activity test of test example the compounds of this invention

The external anti-bruton's tyrosine of I the compounds of this invention swashs dark Β Τ Κ) determination of activity

Test sample：

The compounds of this invention：Self-control, its chemical name and structural formula are shown in the preparation embodiment of each compound with preparation method.

Control compound：CC-292, is made according to WO2009158571A1.

Real face method：

1. test material

HTRFR KinEASE™ -TK:Purchased from Cisbio, lot number 62TK0PEB; BTK:Purchased from Carna, Cat.No.08-080; ATP :Purchased from Sigma, Cat. No. A7699, CAS No.34369-07-8; MgCl₂：Purchased from Sigma, CAS No. 7786-30-3, Lot. No. 101M8701 V； DMSO：Purchased from Sigma, CAS No.67-68-5, Lot. No. STBC0365V;96 orifice plates:Purchased from Thermo, Cat. No. 249944, Lot. No. 1057825;384 orifice plates:Purchased from Greiner, Cat. No. 784075, the Υ of 1 12 Φ of Lot. No. El 6

2. experiment preparation of reagents

① 1 χ Kinase buffer ( 5 mM MgCl₂, lmM DTT, 50nM SEB );2. that DTT stostes are diluted into l OOmM with sterilized water for injection is standby as storing solution by DTT；3. the storing solution that ATP prepares 5mM with sterilized water for injection is standby；4. 10mM compound solutions：The compound stock solution that compound dissolving is configured into 10mM using 100% DMSO is standby.

3. the enzyme reaction stage

1. 10mM compound solution is diluted 20 times with 100%DMSO, then dilutes a series of 3 times of dilutions are carried out after 2 times, totally 10 concentration gradients, then with 1 X kinases Slow fliud flushings（Kinase buffer) it regard 100 times of the solution dilution of each concentration as experiment compound concentration, the holes of 4 μ 17.2. 5 χ enzyme solutions (Enzyme solution) are prepared：By enzyme add 1 χ kinases Slow fliud flushings, 2 xLI holes.3. 30min is incubated under the conditions of 25 °C.4. 5 χ Τ Κ substrates-biotin (Substrate-biotin) is prepared：TK substrates-biotin is added in l x kinases Slow fliud flushings, 2 μ!7 holes； 5. 5 χ Α Τ Ρ are prepared:ATP is added into the basic Slow fliud flushings of 1 χ kinases（Kinase base buffer) in, the holes of 2 μ Ι 7；6. it is incubated 40min under the conditions of 25 °C.

4. detect the stage of reaction

1. 4 χ streptavidins are prepared（ Streptavidin ) -XL665 :Streptavidin-XL665 is added into HTRF detection Slow fliud flushings（Detection buffer) in, the holes of 5 μ 17.2. 5 μ TK Antibody-Cryptate are added per hole.3. 60 min are incubated under the conditions of 25 °C.

5. digital independent

Detect after the completion of the stage of reaction, detect fluorescent value of the sample at 615nm and 665nm respectively with ELIASA.

6. curve matching draws IC₅₀

Carried out curve fitting using the softwares of GraphPad 5.0, fit equation is Y=Bottom+(Top-Bottom)/(l+10^A((LogIC50-X) * HillSlope)), draw IC₅₀Value.

Experimental result：The compounds of this invention（Compound 1-24) to the external IC for suppressing bruton's tyrosine kinase (BTK)₅₀< 0.2μΜ.The IC of part of compounds₅₀As follows, '：Table 1

Compound

CC-292 16.0

Compound 1 2.5

Compound 2 1.35

Compound 3 0.91

Compound 4 2.46

Compound 5 1.05

Compound 6 0.62

Compound 7 0.52

Compound 8 1.26

Compound 11 1.06

Compound 12 0.97

Compound 13 13.05

Compound 14 1.72

Compound 16 11.83

Compound 18 1.09

Compound 19 7.34

Compound 20 1.96

Experiment conclusion： There is stronger inhibitory activity to BTK kinases by the visible the compounds of this invention of table 1.

Π the compounds of this invention is to rat spleen cells BTK enzyme occupation rate determination experiments

In order to determine the amount for not taken BTK in cell or tissue lysate by compound, use ELISA schemes, it is not taken BTK biotinylated probe compound using a kind of combination by compound, compound is evaluated under various concentrations, to the occupation rate situation of BTK enzymes in splenocyte, calculate⁰/ oBTK occupation rates（ BTK Occupancy ).

1st, experiment material

The anti-BTK antibody of mouse (Becton Dickinson);Goat anti-mouse HRP antibody (Becton Dickinson);Cell pyrolysis liquid (Cell Signaling);Bruton's tyrosine kinase（ BTK ) (Carna);Coated 96 orifice plate (Thermo) of Streptavidin;Rat lymphocyte separating kit (LTS 1083PK, Tianjin Hao ocean biological products science and technology limited Company）；ELIASA (victor4, PE)；Centrifuge (5804R, Eppendorf);Microscope (CX31RTSF, Olympus）；MACS sorters (midiMACS separation unit, MACS).

2nd, real long-mouth dog step

(1) preparation of reagents

Probe compound solution（Probe ):Sample compound lmg is weighed, compound concentration is ImM storing solution, is diluted when using with Yang Pin Xi Feng liquid；Sample diluting liquid（ Sample diluents )：PBS containing 1 % bovine serum albumin(BSA)s and 0.1 % Tween-20;Cleaning solution（Washing solution ):PBS containing 0.05 % Tween-20.

(2) Rats Spleen is unicellular prepares

Spleen is rinsed with lmL PBS Slow fliud flushings（An osculum is cut in one end of spleen, 1ml precoolings PBS is injected in the spleen other end with syringe and rinses）, the sterile filter screen of 200 mesh is then transferred to, is shredded with operating scissors, then ground with syringe, note adding the PBS Slow fliud flushings of precooling to rinse in grinding, rinsed altogether with 5ml PBS Slow fliud flushings.4 °C, 400g centrifugation 3min remove supernatant, add 20ml cell washing solutions PBS, 4 °C, 600Rpm centrifuges lOmin, washs 3 times.

(3) compound and cytosis

After cell count, cell concentration is diluted to 3 l07Cells/ml, the holes of 90 μ 1/ with PBS.Add compound Ι Ο μ Ι/hole, 37 °C of incubation lh. 20.C, 400g centrifuge 20min, discard supernatant.

(4) cell lysis

Protease inhibitors PMSF is added to cell pyrolysis liquid（Cell lysis buffer) in（Note The PMSF that anticipates uses preceding addition in lysate；).Lysate is added and mixed in the cell of often pipe enrichment, is operated according to lysate specification, 5min, 14000g centrifugations 10min are cracked on ice.Supernatant Ι Ο Ο μ Ι are taken to add in 96 orifice plates.

(5) Β Τ Κ determination experiment steps

LOOul standard items or sample and Ι Ο μ Ι probe compound solution are added per hole（It is final concentration of

Ι μ Μ) mixing, 28 °C of concussion incubation lh.After incubation, Ι Ο Ο μ Ι are taken to be added on the coated ELISA plates of Streptavidin (Streptavidin-coatd ELISA plate), 28 °C of concussions are incubated lh.Use cleaning solution（Washing sol ution) board-washing 5 times.The mouse anti human Β Τ Κ antibody (Purified mouse anti-human BTK antibody) (1 of Ι Ο Ο μ Ι purifying is added into every hole:1000 times of dilutions）.28 °C of concussions are incubated lh.With cleaning solution board-washing 5 times.The goat anti-mouse antibody of Ι Ο Ο μ Ι HRP marks is added into every hole（HRP goat anti-mouse Ig)( 1:1000 dilutions）.28 °C of concussions are incubated lh.With 5 backward addition Ι Ο Ο μ Ι substrate Τ Μ Β solution per hole of cleaning solution board-washing, 28 °C of incubation 15min.50 μ 11M S0 are added per hole₄Terminating reaction.

3rd, Testing index and detection method

After reaction terminating, the OD values at detection 450nm.According to OD values, the amount of BTK in each sample is calculated using A4 parameter logistic curves in ELIASA.

4th, data processing and result

* %BTK occupation rates=(control group BTK amounts-compound group BTK amounts）/ control group BTK amounts χ 100%

* coefficient of variation CV=S/x 100%

Experimental result is as shown in table 2：

The compounds of this invention of table 2 is to rat spleen cells BTK occupation rate experimental results

%BTK occupation rates

Compound

50nM 200nM

The experiment conclusion of 22 54.57 84.64 compound of compound, 23 34.22 59.49 compound 24 25.59 68.09：From table 2, BTK occupation rate of the compounds of this invention in rat spleen cells is higher, embodies preferable drug effect.

4th, embodiment

The embodiment of form, is described in further detail to the above of the invention by the following examples.But this should not be interpreted as the scope of above-mentioned theme of the invention be only limitted to Lower embodiment.All technologies realized based on the above of the present invention belong to the scope of the present invention.

((8- (3- acrylamidos phenyl) -6- methyl -7- oxo -5,6,7,8- tetrahydropyrimidines are simultaneously by 4- by the 4- of embodiment 1【4,5- Α Π pyrimidine -2 --aminos) phenoxy group V- picoline-2- formamides (compound 1) preparation

(1) oc processed of 4- (3- (t-butoxycarbonyl amino) phenylamino) -2- (Yue sulfenyls) pyrimidine -5- Ethyl formates

In dry reaction bulb, 4- chloro- 2- (Yue sulfenyls) pyrimidine -5- Ethyl formates are added（6.99 g, 30.04 mmol), 100 mL DMF dissolvings are added, the tertiary fourth II (6.26 g, 30.05 mmol) of 3- aminophenyiaminos Yue acid, potassium carbonate is added（8.293 g, 60 mmol), react 16 hours under 75 °C, be cooled to room temperature, reaction solution is poured into the mL of water water 500, separate out solid, filtering, filter cake water water washing is dried in vacuo to obtain the g of white solid 11.7, yield is 96.3%.

(2) preparation of 3- (5- (hydroxyl Yue yls) -2- (Yue sulfenyls) pyrimidine-4-yl amino) phenyl amino Yue tert-butyl acrylates

In thousand dry reaction bulbs, 4- (3- (t-butoxycarbonyl amino) phenylamino) -2- (methyl mercapto) pyrimidine -5- Yue acetoacetic esters are added（7.0 g, 17.31 mmol), add the tetrahydrofuran solution for the Lithium Aluminium Hydride that 2.5 M are added dropwise under the mL of tetrahydrofuran 100 dissolvings, -78 °C（16.62 mL, 41.55 mmol), treat that temperature is warmed to room temperature after completion of dropping, the mL of aqueous ammonium chloride solution 30 for adding saturation is quenched, stir half an hour, filter at room temperature, filtrate adds water, and is extracted with dichloromethane, filtrate is concentrated, silicagel column, ethyl acetate is crossed：Petroleum ether=1:2, the g of white solid 4.3, yield is 68.5%.

(3) preparation of the tertiary fourth vinegar of 3- (5- formoxyls -2- (first dredges base) pyrimidine-4-yl amino) phenyl amino Yue acid

In dry reaction bulb, 3- (5- (methylol) -2- (methyl mercapto) pyrimidine-4-yls amino) phenyl amino Yue tert-butyl acrylates are added（4.3 g, 11.86 mmol), the dissolving of lOO mL dichloromethane adds manganese dioxide（10.31 g, 118.6 mmol), stirring reaction 18 hours, filtering, wash filter cake with dichloromethane, are spin-dried for organic phase, obtain the g of gray solid crude product 3.7 at room temperature, are directly used in next step reaction.

(4) preparation of 3- (5- ((methylamino) methyl) -2- (first bowl base) pyrimidine-4-yl amino) phenylcarbamate

In dry reaction bottle, the g of crude product 3.7 of 3- (5- formoxyls -2- (methyl mercapto) pyrimidine-4-yls amino) phenyl amino Yue tert-butyl acrylates is added, is dissolved with 100 mL methanol, while adding sodium acetate（4.1 g, 50 mmol), methylamine hydrochloride（3.376 g, 50 mmol), stirring reaction 16 at room temperature Hour, add sodium borohydride（0.757 g, 20 mmol), half an hour is reacted, the mL of the saturated sodium bicarbonate aqueous solution 50 and mL of dichloromethane 100 is added, point liquid, aqueous phase is extracted with dichloromethane, organic phase is concentrated, silicagel column is crossed（Pure ethyl acetate）The g of yellow solid 2.62 is obtained, the yield of two steps is 58.9%.

(5) system of 3- (3- Yue bases -7- (Yue sulfenyls) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2)-yl) phenyl amino Yue tert-butyl acrylates

In dry reactor, 3- (5- ((methylaminos are added）Yue yls) -2- (Yue sulfenyls) pyrimidine-4-yl amino) phenylcarbamate（2.62 g, 6.98 mmol), add the mL of tetrahydrofuran 100 dissolvings, add DIEA (4 mL, 23 mmol), the tetrahydrofuran solution (12 mL, 2.4 mmol) of 0.2 M triphosgene is added dropwise under water water-bath, 10 min are reacted after completion of dropping, saturated sodium bicarbonate solution is added, is extracted with dichloro Yue alkane, organic phase is concentrated, cross silicagel column, ethyl acetate：Petroleum ether=2:1, the g of white solid 1.9 is obtained, yield is 67.8%.

(6) 3- (3- Yue bases -7- (Yue sulfonyls）- 2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2/)-yl) the tertiary fourth of phenylcarbamic acid

In dry reaction bulb, add 3- (3- Yue bases -7- (methyl mercapto) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2)-yl) phenylcarbamate (1.9 g, 4.73 mmol), the mL of dichloromethane 50；Under water water-bath, 85% metachloroperbenzoic acid is added（2.89 g, 14.2 mmol), reaction is warmed to room temperature, and is reacted 4 hours at room temperature, adds sodium bicarbonate aqueous solution, extracted with dichloromethane, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, the g of crude white solid 2.3 is concentrated to give, next step reaction is directly used in.

(7) 3- (3- Yue bases -7- (4- (2- (Yue base amino Yue acyl groups) p is than pyridine -4- bases epoxide) phenylamino) -2- oxos -3; 4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2)-yl) phenyl amino Yue tert-butyl acrylates preparation

In dry reaction bulb; add 3- (3- methyl -7- (mesyl) -2- oxos -3; 4- dihydro-pyrimidins simultaneously [4; 5-d] pyrimidine -1 (2H)-yl) phenyl amino Yue tert-butyl acrylates the g of crude product 2.3; tertriary amylo alcohol 50 mL, 4- (4- amino-benzene oxygens)-N- Yue yl pyridines formamides（1.38 g, 5.67 mmol), trifluoracetic acid（0.539 g, 4.73 mmol), react 16 hours under 110 °C, be cooled to after room temperature, add saturated sodium bicarbonate aqueous solution, the extraction of dichloro Yue alkane concentrates organic phase, crosses silicagel column（Pure ethyl acetate）The g of yellow solid 1.13 is obtained, the yield of above-mentioned two step is 40.0%.

(8) preparation of 4- (4- (8- (3- aminophenyls)-6- methyl-7- oxos-5,6,7,8- tetrahydropyrimidines simultaneously [4,5-] pyrimidine -2 --amino) phenoxy group)-2- formamides

In dry reaction bulb; add 3-(3-Yue bases-7- (4- (2- (Yue base amino Yue acyl groups) pyridine-4- bases epoxide) phenylamino)-2- oxos-3; 4- dihydro-pyrimidins simultaneously [(2/ /)-yl of 4,5- pyrimidine-1) phenyl amino Yue tert-butyl acrylates（298 mg, 0.5 mmol), the mL of dichloro Yue alkane 5 and the mL of trifluoracetic acid 5 are stirred 3 hours under ice-water bath, concentration is spin-dried for, and are directly used in next step reaction.

(9) 4- (4- (8- (3- acrylamidos phenyl)-6- Yue base-7- oxos-5,6,7,8- tetrahydropyrimidines simultaneously [4,5-d] pyrimidine -2 --amino) phenoxy group)-N- methyl p than pyridine-2- formamides preparation

Previous step crude reaction, adds the mL of tetrahydrofuran 20, is adjusted with DIEA and is added dropwise to acryloyl chloride under pH to 9-10, -10 °C（45 mg, 0.5 mmol), react 2 hours after completion of dropping, stop after reaction, add Yue alcohol to be quenched, mix sample, prepare liquid phase and purify to obtain yellow powdery solid, washed with methanol, dry, obtain the mg of yellow powdery solid 56, two step yields are 20.4%.

Molecular formula： C₂₉H₂₆N₈0₄Molecular weight：550.21 mass spectrum (m/e): 551.3 ^-NMRC^-DMSO, 400 MHz, δρρπι):δ 10.26 (1 Η, s), 9.57 (1 Η, s), 8.75 (IH, q), 8.45 (IH, d), 8.19 (IH, s), 7.66-7.59 (2H, m), 7.42 (IH, t), 7.37 (2H, d), 7.28 (IH, d), 7.02 (IH, dd), 6.98 (IH, d), 6,77 (2H, d), 6.31 (IH, dd), 6.12 (IH, d), 5.63 (IH, d), 4.49 (2H, s), 2.96 (3H, s), 2.77 (3H, d)

The W3-r of embodiment 2-(4- (2- methoxy ethoxies）Stupid amino) -3- methyl -2- oxo -3,4- dihydro-pyrimidins are simultaneously【4,5-cH pyrimidines-1 (2-yl) phenyl) acrylamide (compound 2) preparation

(1) 4- (3- (t-butoxycarbonyl amino) stupid amino) -2- (methyl mercapto) pyrimidine -5- Ethyl formates

In dry reaction bulb, the chloro- 2- methylthiopyrimidines -5- Yue acetoacetic esters of 4- are added（35.0 g, 150 mmol), 500 mL DMA dissolvings are added, 3- aminophenyiamino Yue tert-butyl acrylates (31.2 g, 150 mmol), potassium carbonate is added（41.4 g, 300 mmol), react 16 hours under 75 °C, be cooled to room temperature, reaction solution is poured into the mL of frozen water 500, filter, filter cake is washed with frozen water, is dried in vacuo to obtain the g of white solid 40.0, yield is 66%.

(2) preparation of 3- (5- (methylol) -2- (methyl mercapto) pyrimidine-4-yls amino) phenylcarbamate

In dry reaction bulb, 4- (3- (t-butoxycarbonyl amino) phenylamino) -2- (Yue sulfenyls) pyrimidine -5- Yue acetoacetic esters are added（40.0 g, 99 mmol), add under the mL of tetrahydrofuran 300 dissolvings, -78 °C and Lithium Aluminium Hydride is added portionwise（11.4 g, 300 mmol), treat that temperature is warmed to room temperature after completion of dropping, add the aqueous ammonium chloride solution of saturation, stir at room temperature half an hour, filter, filtrate adds water, and is extracted with dichloro Yue alkane, silicagel column, PE:EA=2:1, the g of white solid 20.0 is obtained, yield is 55.8%.

(3) preparation of 3- (5- Yue acyl groups -2- (methyl mercapto) pyrimidine-4-yls amino) phenyl amino Yue tert-butyl acrylates

In dry reaction bulb, 3- (5- (hydroxyl Yue yls) -2- (Yue sulfenyls) pyrimidine-4-yl amino) phenyl amino Yue tert-butyl acrylates are added（20.0 g, 55.2 mmol), the dissolving of 800 mL dichloro Yue alkane adds manganese dioxide（144 g, 1.66 mol), stirring reaction 24 hours, filtering, wash filter cake with dichloromethane, are spin-dried for organic phase, obtain the g of gray solid crude product 17.0 at room temperature, are directly used in next step reaction.

(4) preparation of 3- (5- ((Yue amino) Yue yls) -2- (Yue sulfenyls) pyrimidine-4-yl amino) phenylcarbamate

In dry reaction bottle, 3- (5- formoxyls -2- (methyl mercapto) pyrimidine-4-yls amino) phenyl amino Yue tert-butyl acrylates are added（2.50 g, 6.94 mmol), dissolved, added simultaneously with 100 mL Yue alcohol Sodium acetate（1.39g, 16.9 mmol), Yue amine hydrochlorates（1.14g, 16.9 mmol), stirring reaction 12 hours, add sodium borohydride at room temperature（0.53 g, 14 mmol), react 12 hours, add the mL of saturated sodium bicarbonate aqueous solution 50 and dichloromethane, point liquid, aqueous phase is extracted with dichloromethane, concentrate organic phase, cross silicagel column (PE:EA=1:2) g of faint yellow solid 2.38 is obtained, yield is 91.4%.

(5) the tertiary fourth of 3- (3- methyl -7- (Yue sulfenyls) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- ^ pyrimidines -1 (2)-yl) phenyl amino Yue acid

In dry reactor, 3- (5- ((Yue amino is added）Yue yls) -2- (Yue sulfenyls) pyrimidine-4-yl amino) phenyl amino Yue tert-butyl acrylates（2.1 g, 5.59 mmol), tetrahydrofuran 40mL dissolvings are added, DIEA (2.17g, 16.8 mmol) is added, triphosgene is added dropwise under water water-bath（0.83 g, 2.80 mmol) tetrahydrofuran solution, continue after completion of dropping to react 2h, then add saturated sodium bicarbonate solution, extracted with dichloro Yue alkane, cross silicagel column（Ethyl acetate：Petroleum ether=2:1) g of white solid 1.85, is obtained, yield is 82.5%.

(6) 3- (3- methyl -7- (mesyl) -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5- pyrimidines

- 1 (2 /)-yl) the tertiary fourth of phenyl amino Yue acid

In dry reaction bulb, add 3- (3- Yue bases -7- (Yue sulfenyls) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-t] pyrimidine -1 (2)-yl) phenyl amino Yue tert-butyl acrylates (1.0 g, 2.49 mmol), dichloro Yue alkane 30mL, under water water-bath, add m-chloro peroxide benzene Yue acid（1.29 g, 7.47 mmol), reaction is warmed to room temperature, and is reacted 2 hours at room temperature, stops reaction, then saturated sodium bicarbonate aqueous solution is added, extracted with dichloromethane, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, is concentrated to give faint yellow solid and is directly used in next step reaction.

(7) 3- (preparations of 7- (4- (2- methoxy ethoxies) phenylamino -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5- pyrimidines -2 (1/ /)-yl) phenyl amino Yue tert-butyl acrylates

In dry reaction bulb; obtained 3- (3- methyl -7- (mesyl) -2- oxos -3 are walked in addition; 4- dihydro-pyrimidins simultaneously [4; the crude product of the stupid base amino Yue tert-butyl acrylates of 5- pyrimidines -1 (2H yls); tert-pentyl alcohol 40mL, 4- (2- Yue epoxides ethyoxyl) aniline（0.50g, 2.99 mmol), trifluoracetic acid (0.28 g, 2.46 mmol), back flow reaction 12 hours in 110 °C of oil baths, stops reaction, is cooled to after room temperature, saturated sodium bicarbonate aqueous solution is added, silicagel column (PE is crossed in dichloromethane extraction:EA=1:2) g of faint yellow solid 0.88 is obtained, the yield of above-mentioned two step is 67.9%.

(8) 1- (3- aminophenyls)-7- (4- (2- methoxy ethoxies) phenylamino)-3- methyl-3,4- the dihydro-pyrimidins simultaneously [(preparation of 1 -one of 4,5- pyrimidines-2

In thousand dry reaction bulbs, 3- (7- (4- (2- methoxy ethoxies) phenylamino -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5- pyrimidines -2 (1) _ yl) phenylcarbamates are added（0.88 mmol), dissolved with 30.0 mL dichloromethane, the mL of trifluoroacetic acid 15.0 is added dropwise under conditions of ice bath, completion of dropping, room temperature continues to stir, under TLC detections after raw material reaction completely, stop reaction, be then concentrated under reduced pressure, products therefrom is directly used in next step reaction.

(9) TV- (3- (7- (4- (2- methoxy ethoxies) phenylamino) -3- methyl -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2/ /)-yl) phenyl）The preparation of acrylamide

Obtained 1-(3- aminophenyls)-7- (4- (2- Yue epoxides ethyoxyl) phenylamino)-3- methyl-3 is walked on being added in dry reaction bulb, 4- dihydro-pyrimidins and pyrimidine-2 (1 /) -one, add tetrahydrofuran 30mL, adjusted with DIEA and be added dropwise to acryloyl chloride under pH to 9-10 ,-10 °C（0.31 g,

3.43 mmol), continue after completion of dropping to react 0.5 hour, stop after reaction, add Yue alcohol and be quenched, mix sample, prepare liquid phase purifying（Methanol/water=40%) obtain yellow powdery solid, is washed with methanol, obtains the mg of white solid 150, and two step yields are 18.7%.

Molecular formula： C₂₅H₂₆N₆0₄Molecular weight：474.20 matter (m/e): 474.9 ^JH-NMR(^-DMSO, 400 ΜΗζ,δρριη):δ 10.29 (IH, s), 9.23 (IH, s), 8.13 (IH, s), 7.74 (IH, d), 7.62 (IH, s), 7.43 (IH, t), 7.15 (2H, d), 6.96 (IH d), 6.51 (2H, d), 6.42 (IH, dd), 6.23 (IH, dd), 5.74 (IH, dd), 4.45 (2H, s), 3.92 (2H, t), 3.58 (2H, t), 3.28 (3H, s), 2.96 (3H, s)

Embodiment 3 4--f8- (3- acrylamidos) -6- cyclopropyl -7- oxo -5,6,7,8- tetrahydropyrimidines simultaneously " 4,5-</] pyrimidine -2 --amino) and phenoxy group WV- picoline-2- formamides (compound 3) preparation

(1) 3- (5- ((cyclopropyl imino groups）Methyl) -2- (methyl mercapto) pyrimidine-4-yls amino) phenyl amino Yue tert-butyl acrylates preparation

In thousand dry reaction bulbs, 3- (5- formoxyls -2- (methyl mercapto) pyrimidine-4-yls amino) phenylcarbamate (7.2 g, 20.0 mmol) is added, is added:100 mL Yue alcohol dissolve, while adding cyclopropylamine (5.71 g, 0.1 mol) and 1 mL water acetic acid, stirring reaction 16 hours, revolve thousand solvents and be directly used in next step at room temperature.

(2) 3- (5- ((cyclopropylaminos）Yue yls) -2- (methyl mercapto) pyrimidine-4-yls amino) phenylcarbamate preparation

The tetrahydrofuran of 200 mL dryings, -78 are added in reaction system one step up.Tetrahydrochysene lithium aluminium powder (3.8 g are added portionwise under C, 0.1 mol), treat that temperature is warmed to room temperature continuation and reacted 5 hours after completion of dropping, the aqueous ammonium chloride solution for adding saturation is quenched, and stirs at room temperature half an hour, filters, filtrate adds water, and extracted with dichloro Yue alkane, filtrate is concentrated, the silicagel column (petroleum ether of petroleum ether one is crossed：Ethyl acetate=1:1) g of light yellow solid 4.2, is obtained, two steps add up to yield 52.5%.

(3) the tertiary fourth of 3- (3- cyclopropyl -7- (methyl mercapto) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5-^] pyrimidine -1 (2/)-yl) phenyl amino Yue acid

In dry reactor, add 3- (5- ((cyclopropylamino) methyl) -2- (methyl mercapto) pyrimidine -4- bases amino) phenylcarbamate (4.02 g, 10.0 mmol), add the mL of tetrahydrofuran 100 dissolvings, add DIEA (4.96 mL, 28.5 mmol), triphosgene is added dropwise under ice-water bath（1.04 g, 3.5 mmol) the mL of tetrahydrofuran solution 10, react 1 hour after completion of dropping, add saturated sodium bicarbonate solution, the silicagel column (petroleum ether of petroleum ether one is crossed in dichloro Yue alkane extraction, organic phase concentration：Ethyl acetate=1.5:1) g of white solid 3.03, is obtained, yield is 70.9%.

(4) 3- (3- cyclopropyl -7- (mesyl) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2 /)-yl) the tertiary fourth of phenylcarbamic acid

In dry reaction bulb, add 3- (3- cyclopropyl -7- (methyl mercapto) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2/ /)-yl) phenyl amino Yue tert-butyl acrylates (2.13 g, 4.98 mmol), the mL of dichloromethane 30, under water water-bath, add metachloroperbenzoic acid (2.59 g, 15.0 mmol) Reaction is warmed to room temperature, and is reacted 0.5 hour at room temperature, adds saturated sodium bicarbonate aqueous solution, dichloromethane is extracted, and is merged organic phase, is used saturated common salt water washing, anhydrous sodium sulfate drying, is concentrated to give the g of crude white solid 2.3, is directly used in next step reaction.

(5) (((2- (Yue base amino Yue acyl groups) p is than pyridine -4- base epoxides by 4- by 3- cyclopropyl -7- by 3-）Phenylamino) -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5- pyrimidines -1 (2)-yl) phenyl amino Yue tert-butyl acrylates preparation

In dry reaction bulb, 3- (3- cyclopropyl -7- (Yue sulfonyls) -2- oxos -3, 4- dihydro-pyrimidins simultaneously [4, 5- /] pyrimidine -1 (2)-yl) phenyl amino Yue tert-butyl acrylates the g of crude product 2.3, the mL of tert-pentyl alcohol 50, 4- (4- amino-benzene oxygens)-TV- Yue yl pyridines -2- Yue acid amides (1.34 g, 5.5 mmol), trifluoracetic acid (0.57 g, 5.0 mmol), reacted 24 hours under 110 °C, concentration, cross silicagel column (ethyl acetate of petroleum ether one) and obtain the g of yellow solid 1.42, the yield of above-mentioned two step is 45.8%.

(6) 4- (4- (8- (3- aminophenyls）- 6- cyclopropyl-7- oxo-5,6,7,8- tetrahydropyrimidines simultaneously [4,5-] pyrimidine -2 --amino) benzene)-Yue yl pyridines-2- Yue acid amides preparation

In dry reaction bulb; add 3- (3- cyclopropyl -7- (4- (2- (methylcarbamoyl) pyridin-4-yls epoxide) phenylamino) -2- oxos -3; 4- dihydro-pyrimidins simultaneously [4; 5-^] pyrimidine -1 (2/ /)-yl) phenyl amino Yue tert-butyl acrylates (0.311 g; 0.5 mmol); the mL of the dichloro Yue alkane 5 and mL of trifluoracetic acid 5; stirred 1 hour under water water-bath; concentration is spin-dried for, and is directly used in next step reaction.

(7) preparation of 4- (4- (8- (3- acrylamidos)-6- cyclopropyl-7- oxo-5,6,7,8- tetrahydropyrimidines simultaneously [4,5-] pyrimidine -2 --amino) benzene Yue yl pyridines-2- formamides

The mL of tetrahydrofuran 20 is added in previous step reaction system, pH is adjusted to 9-10 with DIEA, It is added dropwise to after acryloyl chloride (45 mg, 0.5 mmol), completion of dropping and reacts 2 hours under -10 °C, stop after reaction, add methanol and be quenched, prepares liquid phase purifying（Yue alcohol/water=60%) obtain yellow powdery solid, is washed with methanol, is dried, and obtains the mg of yellow powdery solid 71, and two step yields are 24.6%.

Molecular formula： C₃₁H₂₈N_s0₄Molecular weight：576.22 mass spectrum (m/e): 576.9 ^-NMR^-DMSO, 400 MHz, Sppm):(the IH of δ 10.25, s), 9.59 (IH, s), 8.76 (1H, q), 8.45 (IH, d), 8.21 (IH, s), 7.67-7.60 (2H, m), 7.49-7.35 (3H, m), 7.28 (IH, d), 7.03 (IH, dd), 6.98 (IH, dt), 6.78 (2H, d), 6.32 (IH, dd), 6.13 (IH, dd), 5.64 (IH, dd), 4.46 (2H, s), 2.77 (3H, d), 2.72-2.63 (IH, m), 0.80-0.73 (2H, m), 0.72-0.66 (2H, m)

The 4-f4- of embodiment 4 (8- (3- acrylamidos phenyl)-6- (2- methoxy ethyls)-7- oxos-5,6,7,8- tetrahydropyrimidines and i4,5- pyrimidine -2 --aminos) phenoxy group WV- Yue yl pyridines-2- first barefoots (compound 4) preparation

(1) preparation of 4- (3- (t-butoxycarbonyl amino) phenylamino) -2- (Yue sulfenyls) pyrimidine -5- Yue acetoacetic esters

In dry reaction bulb, the chloro- 2- Yue sulfenyls pyrimidine -5- Yue acetoacetic esters of 4- are added（35.0 g, 150 mmol), 500 mL DMA dissolvings are added, 3- aminophenyiamino Yue tert-butyl acrylates (31.2 g, 150 mmol), potassium carbonate is added（41.4 g, 300 mmol), react 16 hours under 75 °C, be cooled to room temperature, reaction solution is poured into the mL of frozen water 500, filter, filter cake is washed with frozen water, is dried in vacuo to obtain the g of white solid 40.0, yield is 66%.

(2) preparation of 3- (5- (hydroxyl Yue yls) -2- (methyl mercapto) pyrimidine-4-yls amino) phenyl amino Yue tert-butyl acrylates

In dry reaction bulb, 4- (3- (t-butoxycarbonyl amino) phenylamino) -2- (Yue sulfenyls) pyrimidine -5- Yue acetoacetic esters are added（40.0 g, 99 mmol), add under the mL of tetrahydrofuran 300 dissolvings, -78 °C and Lithium Aluminium Hydride is added portionwise（11.4 g, 300 mmol), treat that temperature is warmed to room temperature after completion of dropping, add the aqueous ammonium chloride solution of saturation, stir at room temperature half an hour, filter, filtrate adds water, and is extracted with dichloromethane, crosses silicagel column, PE:EA=2:1, the g of white solid 20.0 is obtained, yield is 55.8%.

(3) preparation of 3- (5- Yue acyl groups -2- (Yue sulfenyls) pyrimidine-4-yl amino) phenyl amino Yue tert-butyl acrylates

In dry reaction bulb, 3- (5- (hydroxyl Yue yls) -2- (Yue sulfenyls) pyrimidine-4-yl amino) phenyl amino Yue tert-butyl acrylates are added（20.0 g, 55.2 mmol), the dissolving of 800 mL dichloromethane adds manganese dioxide（144 g, 1.66 mol), stirring reaction 24 hours, filtering, wash filter cake with dichloromethane, are spin-dried for organic phase, obtain the g of gray solid crude product 17.0, be directly used in next step at room temperature Reaction.

(4) 3- (5- ((2- methoxyethylaminos）Methyl) -2- (methyl mercapto) pyrimidine-4-yls amino) phenylcarbamate preparation

In dry reaction bottle, 3- (5- Yue acyl groups -2- (Yue sulfenyls) pyrimidine-4-yl amino) phenyl amino Yue tert-butyl acrylates are added（2.50 g, 6.94 mmol), dissolved, dripped while adding acetic acid 8, Yue epoxide ethamine with 80 mL methanol（2.09 g, 27.8 mmol), stirring reaction 12 hours, add sodium borohydride at room temperature（1.06 g, 28 mmol), react 48 hours, add saturated sodium bicarbonate aqueous solution and dichloromethane, point liquid, aqueous phase is extracted with dichloromethane, concentrate organic phase, cross silicagel column (PE:EA=2:1) g of faint yellow solid 1.74 is obtained, yield is 59.8 %.

(5) 3- (3- (2- methoxy ethyls) -7- (Yue sulfenyls) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2)-yl) phenyl amino Yue acid

In dry reactor, 3- (5- ((2- Yue epoxides ethylamino) methyl) -2- (methyl mercapto) pyrimidine-4-yls amino) phenylcarbamate is added（1.40 g, 3.34 mmol), the mL of tetrahydrofuran 40 dissolvings are added, DIEA (1.30 g, 10.1 mmol) is added, triphosgene is added dropwise under water water-bath（0.50 g, 1.68 mmol) tetrahydrofuran solution, continue after completion of dropping to react 1.5 h, then add saturated sodium bicarbonate solution, extracted with dichloromethane, cross silicagel column, ethyl acetate：Petroleum ether=2:1, the g of white solid 0.95 is obtained, yield is 63.8%.

(6) preparation of 3- (3- (2- Yue epoxides ethyl) -7- (Yue sulfonyls) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2)-yl) phenyl amino Yue tert-butyl acrylates

In dry reaction bulb, add 3-(3-(2- methoxy ethyls)-7- (first dredges base)-2- oxos-3,4- dihydro-pyrimidins simultaneously [4,5-^] pyrimidine-1 (2)-yl) phenylcarbamate (0.95 g, 2.13 mmol), the mL of dichloromethane 30；Under water water-bath, m-chloro peroxide benzene Yue acid is added（1.10 g, 6.37 mmol), reaction is warmed to room temperature, and is reacted 3 hours at room temperature, stop reaction, then add saturated sodium bicarbonate aqueous solution, extracted with dichloro Yue alkane, merge organic phase, saturated common salt water washing is used, anhydrous sodium sulfate drying is concentrated to give faint yellow solid（Crude product）1 g is directly used in next step reaction.

(7) 3- (3- (2- methoxy ethyls) -7- (4- (2- (Yue base amino Yue acyl groups) pyridin-4-yl epoxide) phenylamino) -2- oxos -3; 4- dihydro-pyrimidins simultaneously [(2 /)-yl of 4,5 ^ pyrimidines -1) phenylcarbamate preparation

In dry reaction bulb; add 3- (3- (2- methoxy ethyls) -7- (Yue sulfonyls) -2- oxos -3; 4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2H)-yl) stupid carbamate crude product（1.0 g), tert-pentyl alcohol 40 mL, 4- (4- amino-benzene oxygens) picoline -2- formamides（0.56 g, 2.30 mmol), trifluoracetic acid（0.24 g, 2.1 1 mmol), back flow reaction 24 hours in 110 °C of oil baths stops reaction, is cooled to after room temperature, adds saturated sodium bicarbonate aqueous solution, and dichloromethane extraction concentrates organic phase, crosses silicagel column（100% ethyl acetate）Obtain faint yellow solid 0.38_g, the yield of above-mentioned two step is 27.7%.

(8) 4- (4- (preparations of 8- (3- aminophenyls) -6- (2- methoxy ethyls) -7- oxo -5,6,7,8- tetrahydropyrimidines simultaneously [4,5-] pyrimidine -2-base ammonia -2- formamides

In dry reaction bulb, add 3- (3- (2- methoxy ethyls) -7- (4- (2- (methylcarbamoyl) p are than pyridine -4- bases epoxide) phenylamino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2)-yl) phenylcarbamate（0.38 g, 0.59 mmol), dissolved with 30.0 mL dichloromethane, the mL of trifluoroacetic acid 15.0, completion of dropping are added dropwise under conditions of ice bath, room temperature continues to stir, under TLC detections after raw material reaction completely, stop reaction, be then concentrated under reduced pressure, products therefrom is directly used in next step reaction.

(9) 4- (4- (8- (3- acrylamidos phenyl)-6- (2- Yue epoxides ethyl)-7- oxos-5,6,7,8- tetrahydropyrimidines simultaneously [4,5-d] pyrimidine -2 --amino）Phenoxy group) picoline -2- formyls

Obtained 4- (4- (8- (3- aminophenyls)-6- (2- methoxy ethyls)-7- oxos-5 are walked on being added in dry reaction bulb, 6,7,8- tetrahydropyrimidines simultaneously [4,5- pyrimidine -2 --aminos) stupid epoxide) picoline-2- Yue acid amides, the mL of tetrahydrofuran 30 is added, is adjusted with DIEA and is added dropwise to acryloyl chloride under PH to 9-10 ,-10 °C（0.1 1 g, 1.22 mmol), continue after completion of dropping to react 0.5 hour, stop after reaction, add methanol and be quenched, mix sample, prepare chromatogram purification（Methanol/water=55%) obtain yellow powdery solid, is washed with methanol, obtains the mg of white solid 105, and two step yields are 30.5%.

Molecular formula： C₃₁H₃₀N₈O₅Molecular weight：594.23 mass spectrum (m/e): 594.9 'H-NMR^-DMSO, 400 MHz, 5ppm):(the IH of δ 10.24, s), 9.60 (IH, s), 8.75 (I H, q), 8.45 (1H, d), 8.20 (1H, s), 7.68-7.61 (2H, m), 7.43 (1H, t), 7.39 (2H, d), 7.29 (IH, d), 7.02 (IH, dd), 6.99 (IH, d), 6.79 (2H, d), 6.32 (IH, dd), 6.13 (IH, d), 5.64 (IH, d), 4.58 (2H, s), 3.57 (4H, s), 3.29 (3H, s), 2.77 (3H, d)

The 4- of embodiment 5 (4- 8--acrylamido)-7- oxos-6- (pyrans-4- of tetrahydrochysene-2 bases)-5,6,7,8- tetrahydropyrimidines simultaneously " 4,5-^] pyrimidine -2 --amino) phenoxy group WV- picoline-2- first barefoot amine (compound 5) preparation

(1) 3- (2- (methyl mercapto) -5- ((tetrahydrochysenes -2//- pyrans -4- base imino groups）Methyl) pyrimidine-4-yl amino) phenylcarbamate

In dry reaction bottle; add 3- (5- formoxyls -2- (Yue sulfenyls) pyrimidine-4-yl amino) phenylcarbamate (7.2 g; 20.0 mmol); the dissolving of 100 mL methanol is added, while adding tetrahydrochysene -2/- pyrans -4- amine hydrochlorates（13.76 g, 0.1 mol) and sodium acetate (8.2 g, 0.1 mol), stirring reaction 24 hours, revolve thousand solvents and are directly used in next step at room temperature.

(2) 3- (2- (methyl mercapto) -5- ((tetrahydrochysenes -2/-pyrans -4- base amino）Methyl) pyrimidine-4-yl amino) phenylcarbamate preparation

The tetrahydrofuran of 200 mL dryings is added in reaction system one step up, tetrahydrochysene lithium aluminium solid (3.8 g are added portionwise under -78 °C, 0.1 mol), treat that temperature is warmed to room temperature continuation and reacted 5 hours after completion of dropping, the aqueous ammonium chloride solution for adding saturation is quenched, half an hour is stirred at room temperature, filtering, filtrate adds water, and is extracted with dichloromethane, filtrate is concentrated, the silicagel column (petroleum ether of petroleum ether one is crossed：Ethyl acetate=1:1) g of light yellow solid 4.2, is obtained, two steps add up to yield 47.2%. (3) (simultaneously [4,5- pyrimidines-1 (2/yl) phenylamino is standby for 7- (Yue sulfenyls)-2- oxos-3- (tetrahydrochysene-2-pyrans-4- bases)-3,4- dihydro-pyrimidins by 3-

In dry reactor, add 3- (2- (Yue sulfenyls) -5- ((tetrahydrochysene -2//- pyrans -4- bases amino) methyl) pyrimidine-4-yl amino) phenylcarbamate (4.46 g, 10.0 mmol), add tetrahydrofuran lOO mL dissolvings, power mouthful enters DIEA (4.96 mL, 28.5 mmol)；Triphosgene is added dropwise under water water-bath（1.04 g, 3.5 mmol) the mL of tetrahydrofuran solution 10, react 1 hour after completion of dropping, add saturated sodium bicarbonate solution, the silicagel column (petroleum ether of petroleum ether one is crossed in dichloro Yue alkane extraction, organic phase concentration：Ethyl acetate=1:1) g of white solid 2.97, is obtained, yield is 63%.

(4) prepared by 3- (7- (mesyl) -2- oxos -3- (tetrahydrochysene -2//- pyrans -4- bases) -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2 /)-yl) phenyl

In dry reaction bulb, add 3- (7- (methyl mercapto) -2- oxos -3- (tetrahydrochysene -2/-pyrans -4- bases) -3, 4- dihydro-pyrimidins simultaneously [4, 5-c] pyrimidine -1 (2/)-yl) phenyl amino Yue tert-butyl acrylates (2.36 g, 5.0 mmol), the mL of dichloromethane 30, under ice-water bath, add metachloroperbenzoic acid (2.59 g, 15.0 mmol), reaction is warmed to room temperature, react 0.5 hour at room temperature, add saturated sodium bicarbonate aqueous solution, dichloromethane is extracted, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, it is concentrated to give the g of crude white solid 2.5, it is directly used in next step reaction.

(5) 3- (7- (4- (2- (Yue bases carbamoyl) pyridin-4-yl epoxide) phenylamino) -2- oxos -3- (tetrahydrochysene -2/-pyrans -4- bases) -3; 4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2/ /)-yl) phenyl amino Yue tert-butyl acrylates preparation

In dry reaction bulb, 3- (7- (Yue sulfonyls）- 2- oxos-3- (tetrahydrochysene-2-pyrans-4- bases)-3,4- dihydro-pyrimidins simultaneously [4,5-t] pyrimidine-1 (2/)-base）The crude product of phenyl amino Yue tert-butyl acrylates 2.5 g, tert-pentyl alcohol 50 mL, 4- (4- amino-benzene oxygens)-N- Yue yl pyridines -2- formamides（1.34 g, 5.5 mmol), trifluoracetic acid (0.57 g, 5.0 mmol), 110.Reacted 48 hours under C, silicagel column is crossed in concentration（The ethyl acetate of 100% petroleum acids one 100%) the g of yellow solid 1.8, the yield of above-mentioned two step for 54 °/..

(6) 4- (4- (8- (3- aminophenyls) -7- oxos -6- (tetrahydrochysene -2/-pyrans -4- bases) -5, the simultaneously [preparation of 4,5- pyrimidine -2- pyridine -2- formamides of 6,7,8- tetrahydropyrimidines

In dry reaction bulb, 3- (7- (4- (2- (methylamino Yue acyl groups) pyridin-4-yl epoxide) phenylaminos are added）- 2- oxos -3- (tetrahydrochysene -2H- pyrans -4- bases）- 3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2)-yl) phenyl amino Yue tert-butyl acrylates (0.333 g, 0.5 mmol), the mL of the dichloromethane 5 and mL of trifluoracetic acid 5, stirred 1 hour under ice-water bath, concentration is spin-dried for, be directly used in next step reaction.

(7) 4- (4- (8- (3- acrylamidos)-7- oxos-6- (tetrahydrochysene-2-pyrans-4- bases)-5, the preparation of 6,7,8- tetrahydropyrimidines simultaneously [4,5-] pyrimidine-2- pyridine-2- formamides

The mL of tetrahydrofuran 20 is added in previous step reaction system, pH is adjusted to 9-10, -10 with DIEA.It is added dropwise to after the third Xi acyl chlorides (45 mg, 0.5 mmol), completion of dropping and reacts 2 hours under C, stop after reaction, add methanol and be quenched, prepares liquid phase purifying（Methanol：Water=65%) obtain yellow powder solid, is washed with methanol, is dried, is obtained the mg of yellow powdery solid 62, two step yields are

Molecular formula： C₃₃H₃₂N₈0₅Molecular weight：620.25 mass spectrum (m/e): 620.9 ^-NMRC^-DMSO, 400 MHz, 5ppm): δ 10.24 (1H, s), 9.60 (1H, s), 8.76 ( 1H, q), 8.46 (1H, m), 8.23 ( 1 H, s), 7.72-7.57 (2H, m), 7.50-7.22 (4H, m), 7.03 (2H, m), 6.88-6.74 (2H, m), 6.32 (1H, dd), 6.13 (1 H, d), 5.64 (1H, d), 4.52-4.33 (3H, m), 3.95 (2H, m), 3.46-3.36 (2H, m), 2.78 (3H, d), 2.03-1.82 (2H, m), 1.68-1.58 (2H, m).

The iV- of embodiment 6 (3-i3- cyclopropyl -7- (6- (2- methoxy ethoxies）Pyridin-3-yl ammonia Base) -2- oxo -3,4- dihydro-pyrimidins simultaneously " 4,5- pyrimidines -1 (2^-yl) phenyl）The preparation of acrylamide (compound 6)

(1) 3- (3- cyclopropyl -7- (6- (2- Yue epoxide ethyoxyls）Pyridin-3-yl amino) -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5-d] pyrimidine -1 (2H)-yl) phenylcarbamate preparation

In thousand dry reaction bulbs; add 3- (3- cyclopropyl -7- (Yue sulfonyls) -2- oxos -3; 4- dihydro-pyrimidins simultaneously [4; 5-] pyrimidine -1 (2H yls) phenyl amino Yue tert-butyl acrylates (0.919 g; 2.0 mmol); the mL of tert-pentyl alcohol 30; 6- (2- Yue epoxides ethyoxyl) pyridine -3- amine (0.37 g; 2.2 mmol); trifluoracetic acid (0.228 g, 2.0 mmol), reacts 12 hours under 110 °C; concentration, crosses the silicagel column (petroleum ether of petroleum ether one：Ethyl acetate=1:2) g of yellow solid 0.67 is obtained, yield is 61%.

(2) 1- (3- aminophenyls) -3- cyclopropyl -7- (6- (2- Yue epoxide ethyoxyls）Pyridin-3-yl amino) -3,4- dihydro-pyrimidins simultaneously [4,5-c] -2 (1/ /) -one preparation

In dry reaction bulb, add 3- (3- cyclopropyl -7- (6- (2- methoxy ethoxies) pyridine -3- bases amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2/ /)-yl) phenylcarbamate (0.67 g, 1.22 mmol), the mL of dichloromethane 5 and the mL of trifluoracetic acid 5 are stirred 1 hour under water water-bath, concentration is spin-dried for, and is directly used in next step reaction.

(3) N- (3- (3- cyclopropyl -7- (6- (2- methoxy ethoxies) pyridin-3-yl amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2/ /)-yl) phenyl）The preparation of acrylamide

Crude product obtained in the previous step is dissolved in the dissolving of 15 mL tetrahydrofurans, pH to 9-10 is adjusted with DIEA, acryloyl chloride (110 mg is added dropwise under water water-bath, 1.22 mmol), react 1 hour after completion of dropping, stop after reaction, add Yue alcohol to be quenched, cross silicagel column（100% ethyl acetate) yellow powdery solid is obtained, washed, dried with methanol, obtain the mg of yellow powdery solid 210, two step yields are 34.4%.

Molecular formula： C₂₆H₂₇N₇0₄Molecular weight：501.21 mass spectrum（m/e ): 501.9 !H-NMR -DMSO, 400 MHz, Sppm):10.31 (IH, s), 9.31 (IH, s), 8.15 (IH, s), 7.97 (IH, s), 7.70-7.56 (3H, m), 7.41 (1H, t), 6.95 (IH, d), 6.41 (IH, dd), 6.38-6.28 (IH, m), 6.23 (IH, dd), 5.74 (IH, dd), 4.42 (2H, s) 4.20 (2H, t), 3.57 (2H, t), 3.25 (3H, s), 2.70-2.61 (IH, m), 0.80-0.71 (2H, m), 0.70-0.63 (2H, m)

The preparation of the iV- of embodiment 7 (3- (3- cyclopropyl -7- 6- Yue epoxide pyridin-3-yls amino) -2- oxo -3,4- dihydros -1 (2^-yl) phenyl) acrylamide (compound 7)

(1) 3- (3- cyclopropyl -7- (6- Yue epoxide pyridin-3-yls amino) -2- oxos -3,4- dihydro-pyrimidin simultaneously [(2 /)-yl of 4,5- pyrimidine -1) phenyl is standby

In dry reaction bottle; add 3- (3- cyclopropyl -7- (Yue bases sulfonyl) -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5-] pyrimidine -1 (2/)-yl) phenyl amino Yue tert-butyl acrylates (0.919 g; 2.0 mmol) Tert-pentyl alcohol 30 mL, 6- methoxyl group -3- aminopyridines (0.273 g, 2.2 mmol), trifluoracetic acid (0.228 g, 2.0 mmol), reacts 12 hours under 110 °C, concentration, crosses the silicagel column (petroleum ether of petroleum ether one：Ethyl acetate=1:1) g of yellow solid 0.4 is obtained, yield is 39.7%.

(2) 1- (3- aminophenyls) -3- cyclopropyl -7- (6- methoxypyridine -3- bases amino) -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -2 (1/ /) -one

In dry reaction bulb, add 3- (3- cyclopropyl -7- (6- methoxypyridine -3- bases amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-c] pyrimidine -1 (2/ /)-yl) phenylcarbamate (0.4 g, 0.794 mmol), the mL of the dichloromethane 5 and mL of trifluoracetic acid 5；Stirred 1 hour under water water-bath, concentration is spin-dried for, be directly used in next step reaction.

(3) N- (3- (and 3- cyclopropyl -7- (6- methoxypyridine -3- bases amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2/>Base) benzene

Crude product obtained in the previous step is dissolved with 15 mL tetrahydrofurans, is adjusted with DIEA and is added dropwise to acryloyl chloride (72 mg under pH to 9-10, ice-water bath, 0.794 mmol), react 1 hour after completion of dropping, stop after reaction, add methanol to be quenched, cross silicagel column（The Shi You Mi of 100% petroleum ether one：Ethyl acetate=1:2) off-white powder shape solid is obtained, is washed with methanol, is dried, the mg of off-white powder shape solid 1 12 is obtained, two step yields are 30.9%.

Molecular formula： C₂₄H₂₃N₇0₃Molecular weight：457. 19 mass spectrums（m/e ): 457.9 ^-NMR^-DMSO, 400 MHz, 5ppm):10.31 (1H, s), 9.29 (IH, s),

8.15 (IH, s), 7.99 (IH, s), 7.70-7.56 (3H, m), 7.41 (IH, t), 6.94 (IH, d), 6.41 (IH, dd), 6.37-6.28 (IH, m), 6.23 (1H, d), 5.74 (IH, d), 4.42 (2H, s), 3.70 (3H, s), 2.69-2.61 (I H, m), 0.80-0.71 (2H, m), 0.70-0.63 (2H, m)

V-i3-i3- cyclopropyl (dimethylamino) the pyridin-3-yl amino of embodiment 8) -2- oxo -3,4- dihydro-pyrimidins are simultaneously【4,5-^] pyrimidine-Ii2 bases) phenyl) and acrylamide (compound 8) preparation

(1) preparation at 4- (3- (t-butoxycarbonyl amino) stupid amino) -2- (mesyl) pyrimidine -5- formic acid second tenth of the twelve Earthly Branches

In dry reaction bulb, add 4- (3- (t-butoxycarbonyl amino) phenylamino) -2- (Yue sulfenyls) pyrimidine -5- Ethyl formates (6 g, 14.8 mmol), the mL of dichloromethane 300, under water water-bath, add metachloroperbenzoic acid (7.66 g, 44.4 mmol), reaction is warmed to room temperature, react 1 hour at room temperature, saturated sodium bicarbonate aqueous solution is added to be quenched, dichloromethane is extracted, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, it is concentrated to give the g of crude white solid 6.3, it is directly used in next step reaction.

(2) preparation of 4- (3- (t-butoxycarbonyl amino) stupid amino) -2- (6- (dimethylamino) p are than pyridine -3- bases amino) pyrimidine -5- Ethyl formates

In dry reaction bulb, the g of crude product 6.3, tert-pentyl alcohol 200 mL, N of 4- (3- (t-butoxycarbonyl amino) phenylamino) -2- (mesyl) pyrimidine -5- Ethyl formates are added²,Yue yl pyridines-the 2,5- of ^- bis- Diamines (2.23 g, 16.3 mmol), trifluoracetic acid（1.69 g, 14.8 mmol), react 16 hours under 110 °C, the silicagel column (petroleum ether of petroleum ether one is crossed in concentration：Ethyl acetate=2:1) g of yellow solid 3.1 is obtained, the yield of above-mentioned two step is 42.4%.

(3) preparation of 3- (2- (6- (two Yue amino) p are than pyridine -3- bases amino) -5- (hydroxyl Yue yls) pyrimidine-4-yl amino) phenyl amino Yue tert-butyl acrylates

In dry reaction bulb, add 4- (3- (t-butoxycarbonyl amino) phenylamino) -2- (6- (dimethylamino) pyridin-3-yls amino) pyrimidine -5- Ethyl formates (3.1 g, 6.28 mmol), add under tetrahydrofuran lOO mL dissolvings, -78 and tetrahydrochysene lithium aluminium solid is added portionwise（1.19 g, 31.3 mmol), temperature Slow continues to react 5 hours after being warmed to room temperature slowly, add sal glauberi solid to be quenched, filtered after being sufficiently stirred for, filter cake is washed with ethyl acetate, filtrate is concentrated, silicagel column (the Shi You Mi of petroleum ether one are crossed：Ethyl acetate=1.5:1) g of light yellow solid 2.4, yield 84.7%, are obtained.

(4) preparation of 3- (2- (6- (two Yue amino) p are than pyridine -3- bases amino) -5- Yue acyl -4- bases amino) stupid carbamate

In dry reaction bulb, add 3- (2- (6- (two Yue amino) pyridin-3-yl amino) -5- (methylol) pyrimidine-4-yls amino) phenylcarbamate (2.4 g, 5.32 mmol), 100 mL dichloromethane dissolve, add manganese dioxide (9.26 g, 107 mmol), 35 °C are warming up to react 18 hours, filtering, filter cake is washed with dichloromethane, organic phase is spin-dried for, the g of yellow crude 2.4 is obtained, next step reaction is directly used in.

(5) 3- (5- ((cyclopropyl Asia atmosphere bases）Yue yls) -2- (6- (two Yue amino) p are than pyridine -3- bases amino) pyrimidine-4-yl amino) the sour uncles of phenyl amino Yue

In dry reaction bottle, the g of crude product 2.4 of 3- (2- (6- (dimethylamino) pyridin-3-yls amino) -5- formylpyrimidin -4- bases amino) phenylcarbamate is added, the dissolving of 100 mL Yue alcohol is added, Cyclopropylamine is added simultaneously（1.43 g, 25 mmol) and few drops of glacial acetic acids, stirring reaction 48 hours, are spin-dried for solvent and are directly used in next step at room temperature.

(6) 3- (5- ((cyclopropylaminos）Yue yls) -2- (6- (two Yue amino) p are than pyridine -3- bases amino) pyrimidine-4-yl amino) phenylcarbamic acid

The tetrahydrofuran of 100 mL dryings, -78 are added in reaction system one step up.Tetrahydrochysene lithium aluminium solid is added portionwise under C（1.01 g, 26.6 mmol), treat that temperature is warmed to room temperature continuation and reacted 6 hours after completion of dropping, add the sour sodium solid of ten water stones gram and be quenched, filter, filter cake is washed with ethyl acetate, concentrate filtrate, cross the silicagel column (petroleum ether of petroleum ether one：Ethyl acetate=1:3) g of light yellow solid 1.4, is obtained, the step of the above three adds up to yield 53.6%.

(7) preparation of 3- (3- cyclopropyl -7- (6- (dimethylamino) pyridin-3-yls amino) -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5- pyrimidines -1 (2)-yl) benzene

In dry reactor, 3- (5- ((cyclopropylaminos are added）Methyl) -2- (6- (dimethylamino) pyridin-3-yls amino) pyrimidine-4-yl amino) phenyl amino Yue tert-butyl acrylates（1.4 g, 2.85 mmol), the mL of tetrahydrofuran 20 dissolvings are added, DIEA (1.5 mL are added, 8.6 mmol), reacted 1 hour after the mL of tetrahydrofuran solution 5 of triphosgene (0.423 g, 1.43 mmol), completion of dropping are added dropwise under ice-water bath, add saturated sodium bicarbonate solution, dichloromethane is extracted, organic phase concentration, crosses the silicagel column (petroleum ether of petroleum ether one：Ethyl acetate=1:5) g of white solid 0.83, is obtained, yield is 56.5%.

The simultaneously [(preparation of 1 -one of 4,5- pyrimidines-2 of (8) 1-(3- aminophenyls)-3- cyclopropyl-7- (6- (dimethylamino) p are than pyridine-3- bases amino)-3,4- dihydro-pyrimidins

In dry reaction bulb, 3- (3- cyclopropyl -7- (6- (dimethylaminos are added）Pyridin-3-yl amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-^] pyrimidine -1 (2/ /)-yl) phenylcarbamate (0.83 g, 1.61 mmol), stirred under the mL of the dichloro Yue alkane 10 and mL of trifluoracetic acid 10, ice-water bath Mix 1 hour, concentration is spin-dried for, be directly used in next step reaction.

(9) N- (3- (3- cyclopropyl -7- (6- (dimethylaminos）Pyridin-3-yl amino) simultaneously [4,5-t] pyrimidine -1 (2/ /)-preparation of -2- oxo -3,4- dihydro-pyrimidins

The crude product that upper step is obtained is dissolved with 20 mL tetrahydrofurans, adjusts pH to 9-10 with DIEA, acryloyl chloride is added dropwise under water water-bath（146 mg, 1.61 mmol), react 0.5 hour after completion of dropping, stop after reaction, add Yue alcohol and be quenched, mix sample and cross silicagel column（Ethyl acetate) mg of crude yellow powder 330 is obtained, prepare liquid phase purifying（Yue alcohol：Water=70%) obtain yellow powdery solid, is recrystallized with ethylacetate/ether mixed solvent, obtains the mg of yellow solid 91, and two step yields are 11.8%.

Molecular formula： C₂₅H₂₆N₈0₂Molecular weight：470.22 mass spectrum（m/e ): 471.2 lH^MR(CDCl₃, 400 MHz, 5ppm):7.99 (IH, s), 7.94 (IH, s), 7.72 (IH, s), 7.61 (IH, s), 7.51-7.37 (3H, m), 7.00 (IH, d), 6.64 (IH, s), 6.39 (IH, dd), 6.32-6.24 (IH, m), 6.19 (I H, dd), 5.74 (I H, d), 4.41 (2H, s), 3.00 (6H, s), 2.74-2.65 (I H, m), 0.93-0.85 (2H, m), 0.79-0.72 (2H, m)

(- 5,6,7,8- tetrahydropyrimidines are simultaneously by 4- (8- (3- propylene barefoots aminophenyl) -7- oxos -6--(pyrrolidin-1-yl) ethyl) by the 4- of embodiment 9【4,5-^1 pyrimidine -2 --aminos) phenoxy group V- picoline-2- Yue acid amides (compound 9) preparation

(1) preparation of 4- (3- (t-butoxycarbonyl amino) phenylamino) -2- (Yue sulfonyls) pyrimidine -5- formic acid second

In dry reaction bulb, add 4- (3- (t-butoxycarbonyl amino) phenylamino) -2- (methyl mercapto) pyrimidine -5- Ethyl formates (6 g, 14.8 mmol), the mL of dichloromethane 300, under ice-water bath, add metachloroperbenzoic acid (7.66 g, 44.4 mmol), reaction is warmed to room temperature, react 1 hour at room temperature, saturated sodium bicarbonate aqueous solution is added to be quenched, dichloromethane is extracted, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, it is concentrated to give the g of crude white solid 6.3, it is directly used in next step reaction. (2) preparation of 4- (3- (t-butoxycarbonyl amino) phenylamino) -2- (4- (2- (Yue base amino Yue acyl groups) p is than pyridine -4- bases epoxide) phenylamino) pyrimidine-- Ethyl formate

In dry reaction bulb; add the g of crude product 6.3 of 4- (3- (t-butoxycarbonyl amino) phenylamino) -2- (Yue sulfonyls) pyrimidine -5- Yue acetoacetic esters; the mL of tert-pentyl alcohol 200; 4- (4- amino-benzene oxygens) picoline -2- formamides (3.97 g; 16.3 mmol), trifluoracetic acid（1.69 g, 14.8 mmol), react 12 hours under 110 °C, the silicagel column (petroleum ether of petroleum ether one is crossed in concentration：Ethyl acetate=1:2) g of yellow solid 3.85 is obtained, the yield of above-mentioned two step is 43.4%.

(3) 3- (5- (hydroxyl Yue yls) -2- (4- (2- (Yue bases carbamoyl) p are than pyridine -4- bases epoxide) stupid amino) pyrimidine-4-yl amino) phenyl

In dry reaction bulb, 4- (3- (t-butoxycarbonyl amino) phenylamino) -2- (4- (2- (methylcarbamoyls are added）Pyridin-4-yl epoxide）Stupid amino）Pyrimidine -5- Ethyl formates (3.85 g, 6.42 mmol), add under the mL of tetrahydrofuran 100 dissolvings, -78 °C and tetrahydrochysene lithium aluminium solid (1.22 g, 32.1 mmol) is added portionwise, temperature Slow continues to react 3 hours after being warmed to room temperature slowly, add sal glauberi solid to be quenched, filtered after being sufficiently stirred for, filter cake is washed with ethyl acetate, filtrate is concentrated, silicagel column is crossed（100% ethyl acetate）, obtain the g of off-white powder 2.8, yield 78.2%.

(4) 3- (5- Yue acyl groups -2- (4- (2- (Yue bases carbamoyl) pyridin-4-yl epoxide) phenylamino) pyrimidine-4-yl amino) phenyl amino

In dry reaction bulb; add 3- (5- (hydroxyl Yue yls) -2- (4- (2- (Yue base amino Yue acyl groups) pyridin-4-yl epoxide) phenylamino) pyrimidine-4-yl amino) phenyl amino Yue tert-butyl acrylates (2.8 g; 5.02 mmol); 100 mL dichloromethane dissolve; add manganese dioxide (8.73 g; 100.5 mmol) It is warming up to 35 °C to react 48 hours, filtering washs filter cake with dichloromethane, is spin-dried for organic phase, obtains the light yellow g of crude product 2.8, is directly used in next step reaction.

(5) ((((P ratios cough up alkane -1- bases to 2- to -5- to 2- (4- (2- (methylamino Yue acyl groups) pyridin-4-yl epoxide) phenylamino) to 3-）Ethylimino）Methyl) pyrimidine-4-yl amino) phenyl amino Yue tert-butyl acrylates preparation

In dry reaction bottle; add the g of crude product 2.8 of 3- (5- formoxyls -2- (4- (2- (methylcarbamoyl) pyridine -4- bases epoxide) phenylamino) pyrimidine-4-yl amino) phenylcarbamate; the dissolving of 100 mL methanol is added, while adding 2- (pyrrolidin-1-yls）Ethamine (2.86 g, 25 mmol) sum is dripped acetic acid, and stirring reaction 48 hours, are spin-dried for solvent and are directly used in next step at room temperature.

(6) 3- (2- (4- (2- (methylcarbamoyl) pyridin-4-yls epoxide) phenylamino)-5- ((2- (pyrrolidines-1-base）Ethylamino) Yue base -4- bases amino) phenylcarbamate preparation

The tetrahydrofuran of 100 mL dryings is added in reaction system one step up, tetrahydrochysene lithium aluminium solid (0.954 g is added portionwise under -78 °C, 25.1 mmol), treat that temperature is warmed to room temperature continuation and reacted 4 hours after completion of dropping, add sal glauberi solid to be quenched, filter, filter cake is washed with ethyl acetate, filtrate is concentrated, silicagel column is crossed（Ethyl acetate：Methanol=100:1) g of light yellow solid 1.1, is obtained, the step of the above three adds up to yield 33.5%.

(7) 3- (7- (4- (2- (methylcarbamoyl) pyridin-4-yls epoxide) phenylamino) -2- oxos -3- (2- (pyrrolidin-1-yls）Ethyl) -3,4- dihydro-pyrimidins simultaneously [4,5-if] pyrimidine -1 (2)-base）The preparation of phenylcarbamate

In dry reactor, 3- (2- (4- (2- (methylcarbamoyl) pyridin-4-yls epoxide) phenylamino) -5- ((2- (pyrrolidin-1-yls are added）Ethylamino）Methyl) pyrimidine-4-yl amino) phenylcarbamate（1.1 g, 1.68 mmol), the mL of tetrahydrofuran 15 dissolvings are added, DIEA (650 mg, 5.03 mmol) is added,；Reacted 1 hour after the mL of tetrahydrofuran solution 5 of triphosgene (0.249 g, 0.84 mmol), completion of dropping are added dropwise under water water-bath, add methanol, silicagel column is crossed in concentration（Ethyl acetate）, the g of white solid 0.33 is obtained, yield is 28.9%.

(8) 4- (4- (8- (3- aminophenyls) -7- oxos -6- (2- (the small bases of pyrrolidines）Ethyl)-5,6,7,8- tetrahydropyrimidines simultaneously [4,5-] pyrimidine -2 --amino) phenoxy group) and picoline-2- formamides preparation

In dry reaction bulb, adding 3-, (((P ratios cough up alkane-1-base to 2- to-2- oxos-3- to 7- (4- (2- (methylamino Yue acyl groups) pyridin-4-yl epoxide) phenylamino)）Ethyl) -3,4- dihydro-pyrimidins simultaneously [4,5-c] pyrimidine -1 (2/ /)-yl) phenylcarbamate (0.33 g, 0.485 mmol), the mL of dichloromethane 5 and trifluoracetic acid 5mL, stirred 2 hours under water water-bath, concentration thousand solvents of rotation are directly used in next step reaction.

(9) 4- (4- (8- (3- acrylamidos phenyl)-7- oxos-6- (2- (pyrrolidines-1-base）Ethyl)-5,6,7,8- tetrahydropyrimidines simultaneously [4,5- ^ pyrimidine -2 --aminos）Phenoxy group) picoline -2- formamides preparation

The crude product that upper step is obtained is dissolved with 5 mL tetrahydrofurans, and pH is adjusted to 9-10 with DIEA,；It is added dropwise to after acryloyl chloride (44 mg, 0.486 mmol), completion of dropping and reacts 0.5 hour under ice water-bath, stop after reaction, adds methanol and be quenched, high pressure prepares liquid phase Pureization（Acetonitrile：Water=60%) obtain the mg of yellow powdery solid 11, two step yields are 3.6%.

Molecular formula： C₃₄H₃₅N₉0₄Molecular weight：633.28 mass spectrum（M+H ): 634.3

^-NMRC^-DMSO, 400 MHz, 5ppm):(the IH of δ 10.25, s), 9.60 (IH, s), 8.76 (IH, q), 8.46 (1H, d), 8.20 (IH, s), 7.68 (IH, s), 7.62 (IH, d), 7.43 (IH, t), 7.41-7.35 (2H, m), 7.29 (IH, d), 7.03 (1H, dd), 6.99 (1H, d), 6.79 (2H, d), 6.33 (IH, dd), 6.13 (IH, dd), 5.64 (IH, dd), 4.58 (2H, s), 2.77 (3H, d), 2.69-2.62 (4H, m), 2.34-2.29 (4H, m), 1.76-1.68 (4H, m), 1.49-1.40 (4H m)

The 4- 4- of embodiment 10 (8- (3- acrylamido phenyl V7- oxo -6- 2- 2- oxo-pyrrolidine -1- bases）Ethyl)-5,6,7,8- tetrahydropyrimidines simultaneously " 4,5-rf] pyrimidine -2 --amino) phenoxy group)-V- Yue

The preparation of -2- formamides (compound 10)

(1) 2- (2- oxo-pyrrolidine -1- bases）It is standby In dry reaction bottle, 20 mL anhydrous acetonitriles are added, DMF (0.876 g, 12 mmol) maintains 0.C, into system, Slow adds POCl3 (1.69 g, 11 mmol) slowly, continues to stir 1 hour, 2- (the small bases of 2- oxo-pyrrolidines are added portionwise）Acetamide (1.42 g, 10 mmol), is warming up to 50 °C and reacts 3 hours, 0 °C is cooled to, Slow adds pyridine (1.74 g, 22 mmol) slowly, stirring adds l mL concentrated hydrochloric acids after 20 minutes, is added water into reaction solution, separates organic phase, aqueous phase dichloro Yue alkane is extracted three times, is merged organic phase, is used saturated common salt water washing, dry, concentration, obtains the g of yellow crude 1.4, is directly used in next step reaction.

(2) preparation of 1- (2- amino-ethyls) pyrroles's -2- keto hydrochlorides

10 mL methanol are added in the g of crude product 1.4 obtained one step up, add 1 g Raney's nickels, Slow is added dropwise slowly afterwards contains sodium borohydride (0.76 g, 20 mmol) 8 M sodium hydrate aqueous solutions (2.5 mL, 20 mmol), react 2 hours at room temperature, filtering, filter cake washed once with a little methanol, filtrate concentration, obtained white solid is added in 20 mL ether, the aqueous isopropanol of hydrochloric acid is added dropwise, pH to 5 or so, filtering is adjusted, filtration cakes torrefaction, obtained product is directly used in next step reaction.

(3) 3- (2- (methyl mercapto) -5- ((2- (2- oxo-pyrrolidine -1- bases）Ethylimino）Yue yls) pyrimidine-4-yl amino) phenyl formic acid uncle

In thousand dry reaction bulbs; add 3- (5- Yue acyl groups -2- (Yue sulfenyls) pyrimidine-4-yl amino) phenylcarbamate (3.6 g; 10.0 mmol); add the dissolving of 50 mL methanol; add crude product obtained in the previous step and sodium acetate (0.82 g simultaneously; 10.0 mmol), stirring reaction 48 hours, are spin-dried for solvent and are directly used in next step at room temperature.

(4) 3- (2- (Yue sulfenyls)-5- ((2- (2--1-bases of oxo-pyrrolidine）Ethylamino）Methyl) pyrimidine -4- bases amino) phenyl t-butyl formate preparation

The tetrahydrofuran of 50 mL dryings is added in reaction system one step up, sodium borohydride is added portionwise under water water-bath（1.9 g, 50 mmol), after room temperature reaction 12 hours, continue to add sodium borohydride (3.8 g, 0. 1 mol), continue to react 72 hours, add 50 mL methanol, silicagel column is crossed in concentration（100% ethyl acetate）, the g of light yellow solid 1.6 is obtained, four steps add up to yield 33.9%.

(5) (((2- oxos p ratios cough up alkane-1-base to 2- to 7- (methyl mercapto)-2- oxos-3- to 3-）Ethyl) -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2/ /)-yl) prepare

In dry reactor, 3- (2- (methyl mercapto) -5- ((2- (2- oxo-pyrrolidine -1- bases are added）Ethylamino）Methyl) pyrimidine-4-yl amino) phenyl t-butyl formate（1.6 g, 3.39 mmol), the mL of tetrahydrofuran 30 dissolvings are added, DIEA (1.31 g are added, 10.1 mmol), reacted 1 hour after the mL of tetrahydrofuran solution 10 of triphosgene (0.505 g, 1.7 mmol), completion of dropping are added dropwise under ice-water bath, add saturated sodium bicarbonate solution, dichloromethane is extracted, and concentrates organic phase, crosses silicagel column（100% ethyl acetate）, the g of light yellow solid 1.03 is obtained, yield is 61.1 %.

(6) 3- (7- (methyl sulphonyl) -2- oxos -3- (2- (2- oxo pyrroles's protective embankment -1- bases）Ethyl) -3, the 4- dihydro-pyrimidins simultaneously stupid base t-butyl formate of [4,5-d] pyrimidine -1 (2/-yl) preparation

In dry reaction bulb, 3- (7- (Yue sulfenyls) -2- oxos -3- (2- (2- oxo-pyrrolidine -1- bases are added）Ethyl) -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2A yls) phenyl t-butyl formate（1.03 g, 2.07 mmol), the mL of dichloromethane 20,；Under water water-bath, m-chloro peroxide benzene Yue acid (1.07 g, 6.2 mmol) is added, is reacted 2 hours, saturated sodium bicarbonate aqueous solution is added, the extraction of dichloro Yue alkane merges organic phase, saturated common salt water washing is used, anhydrous sodium sulfate drying is concentrated to give white solid The g of crude product 1.1, is directly used in next step reaction.

(7) 3- (7- (4- (2- (Yue bases carbamoyl) pyridin-4-yl epoxide) phenylamino) -2- oxos -3- (2- (2- oxo-pyrrolidine -1- bases）Ethyl) -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2/ /)-yl) phenylcarbamate

In thousand dry reaction bulbs, the obtained g of crude product 1.1 walked in addition, tert-pentyl alcohol 20 mL, 4- (4- amino-benzene oxygens;V- Yue yl pyridines -2- formamides (0.553 g, 2.27 mmol), trifluoracetic acid (0.236 g, 2.07 mmol) is reacted 12 hours under 110 °C, and silicagel column (dichloromethane is crossed in concentration:Methanol=30:1) g of yellow solid 0.35 is obtained, the yield of above-mentioned two step is 24.3%.

(8) 4- (4- (8- (3- aminophenyls) -7- oxos -6- (2- (2- oxo-pyrrolidine -1- bases）Ethyl)-5,6,7,8- tetrahydropyrimidines simultaneously [4,5-d] pyrimidine -2 --amino) phenoxy group) and Yue yl pyridines-2- formamides preparation

In thousand dry reaction bulbs, 3- (7- (4- (2- (Yue bases carbamoyl) pyridin-4-yl epoxide) phenylamino) -2- oxos -3- (2- (2- oxo-pyrrolidine -1- bases are added）Ethyl) -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2/)-yl) phenylcarbamate (0.35 g, 0.504 mmol), the mL of the dichloromethane 5 and mL of trifluoracetic acid 5, stirred 1 hour under water water-bath, concentration is spin-dried for, be directly used in next step reaction.

(9) 4- (4- (8- (3- acrylamidos phenyl)-7- oxos-6- (2- (2- oxo-pyrrolidine-1- bases) ethyl)-5,6,7,8- tetrahydropyrimidines simultaneously [4,5-d] pyrimidine -2 --amino）Phenoxy group) picoline -2- formamides preparation The crude product that upper step is obtained is dissolved in the mL of 1-METHYLPYRROLIDONE 10, and pH is adjusted to 9-10, -10 with DIEA.Acryloyl chloride (46 mg are added dropwise under C, 0.508 mmol), reacted 1 hour after completion of dropping, continue to add acryloyl chloride (46 mg, 0.508 mmol), after LC-MS display reactions completely, add methanol and be quenched, concentrate system, crosses silicagel column (dichloromethane:Methanol=30:1) yellow solid is obtained, is washed with methanol, is dried, the mg of yellow powdery solid 85 is obtained, two step yields are 26%.

Molecular formula： C₃₄H₃₃N₉0₅Molecular weight：647.26 mass spectrum（M+H): 648.3

^-NMRC^-DMSO, 400 MHz, 5ppm):(the IH of δ 10.25, s), 9.60 (IH, s), 8.76 (IH, q), 8.45 (IH, d), 8.21 (IH, s), 7.68-7.60 (2H, m), 7.43 (IH, t), 7.41-7.34 (2H, m), 7.29 (IH, d), 7.02 (IH, dd), 6.94 (IH, d), 6.78 (2H, d), 6.32 (IH, dd), 6.12 (IH, dd), 5.63 (IH, dd), 4.57 (2H, s), 3.56 (2H, t), 3.46 (2H, t), 3.39 (2H, t), 2.77 (3H, d), 2.16 (2H, t), 1.85 (2H, quintet)

Pyrazoles -4- bases the amino of 11 7 Υ -3- 3- Cvclopropvlmethvls of embodiment -1) -2- oxo -3,4- dihydro-pyrimidins are simultaneously【4,5-<F pyrimidines -1 (2^- yls) phenyl) acrylamide (compound 11) preparation

(1) preparation of 3- (3- cyclopropyl -7- (l- methyl-pyrazol-4-yls amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2/ /)-yl) phenyl amino Yue tert-butyl acrylates

In dry reaction bulb, 3- (3- cyclopropyl -7- (mesyl) -2- oxo -3,4- dihydros are added Pyrimido [4,5-d] pyrimidine -1 (2)-yl) phenylcarbamate（0.46 g, l.Ommol) and the amine of 1- methylpyrazoles -4（117mg, 1.20 mmol), dissolved with 20mL tert-pentyl alcohols, add trifluoracetic acid（0.114 g, l.Ommol), back flow reaction 4 hours in 100 °C of oil baths stops reaction, is cooled to after room temperature, be concentrated under reduced pressure column chromatography（PE:EA=1:2) 0.4 g faint yellow solids are obtained, yield is 83.9 %.

(2) 1- (3- aminophenyls) -3- cyclopropyl -7- (1- Yue base pyrazoles -4- bases amino) -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -2 (preparation of 1/ -one

In dry reaction bulb, add 3- (3- cyclopropyl -7- (1- Yue base pyrazoles -4- bases amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2 /)-yl) phenylcarbamate (0.40g, 0.839 mmol), dissolved with 20.0 mL dichloromethane, the mL of trifluoroacetic acid 10.0 is added dropwise under ice bath, completion of dropping, room temperature continues to stir, and under TLC detections after raw material reaction completely, stops reaction, then it is concentrated under reduced pressure, gained grease is directly used in next step reaction.

(3) (3- (3- cyclopropyl -7- (1- Yue base pyrazoles -4- bases amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2)-yl) is standby by V-

Obtained crude product is walked on being added in dry reaction bulb, the mL of tetrahydrofuran 15 is added, is adjusted with DIEA and is added dropwise to acryloyl chloride under pH to 9-10,0 °C（152 mg, 1.678 mmol), continue after completion of dropping to react 15 min, stop after reaction, add methanol and be quenched, silica gel column chromatography（100%EA), pale yellow powder shape solid is obtained, solid is washed with Yue alcohol and ether and obtains white solid 120mg, two step yields are 33.2%.

Molecular formula： C₂₂H₂₂N₈0₂Molecular weight：430.2 mass spectrum（M+H): 431.2 ^-NMR^-DMSO, 400 MHz, 5ppm):δ 10.34 (IH, s), 9.36 (IH, s), 8.12 (IH, s), 7.78 (IH, d), 7.62 (IH, s), 7.50 (IH, t), 7.05-6.95 (2H, m), 6.61 (IH, br), 6.42 (IH, dd), 6.24 (IH, dd), 5.75 (IH, dd), 4.42 (2H, s) 3.46 (3H, s), 2.67 (1H, m), 0.79-0.72 (2H, m), 0.72-0.64 (2H, m).

(- 2- oxos-- dihydro-pyrimidin is simultaneously by 3- cyclopropyl 7- (1- methyl isophthalic acid pyrazoles -5- bases amino) by the iV-i3- of embodiment 12【4,5-^1 pyrimidines-lG-yl) phenyl) acrylamide f compounds 12) and preparation

(1) preparation of 3- (3- cyclopropyl -7- (1- Yue base pyrazoles -5- bases amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2/)-yl) ester

In dry reaction bulb, 1- Yue base -5- amino-pyrazols are added（117 mg, 1.20 mmol), dissolved with 20 mL tetrahydrofurans, add sodium hydrogen（80 mg; 2.0 mmol) stirred 1 hour in 50 °C of oil baths; add 3- (3- cyclopropyl -7- (mesyl) -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5-d] pyrimidine -1 (2)-yl) phenylcarbamate（0.46 g, l.Ommol) back flow reaction 4 hours in 100 °C of oil baths, stop reaction, be cooled to after room temperature, be concentrated under reduced pressure column chromatography (PE:EA=1:3) 102 mg faint yellow solids are obtained, yield is 21.4 %.

(2) 1- (3- aminophenyls) -3- cyclopropyl -7- (1- Yue base pyrazoles -5- bases amino) -3,4- dihydro-pyrimidins simultaneously [4,5- /] pyrimidine -2 (1/

In dry reaction bulb, add 3- (3- cyclopropyl -7- (1- methylpyrazole -5- bases amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2 /)-yl) phenyl amino Yue tert-butyl acrylates (102 mg, 0.214 mmol), dissolved with 10.0 mL dichloromethane, under conditions of ice bath The mL of trifluoroacetic acid 5.0, completion of dropping is added dropwise, room temperature continues to stir, and under TLC detections after raw material reaction completely, stops reaction, is then concentrated under reduced pressure, and gained grease is directly used in next step reaction.

(3) prepared by N- (3- (3- cyclopropyl -7- (1- methylpyrazole -5- bases amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2/ /)-yl)

Obtained crude product is walked on being added in dry reaction bulb, the mL of tetrahydrofuran 8 is added, is adjusted with DIEA and is added dropwise to acryloyl chloride under pH to 9-10,0 °C（39 mg, 0.428 mmol), continue after completion of dropping to react 15 mm, stop after reaction, add Yue alcohol and be quenched, silica gel column chromatography（The mg of white powdery solids 20 100%EA) is obtained, two step yields are 21.7 %.

Molecular formula： C₂₂H₂₂N₈0₂Molecular weight：430.2 mass spectrum（M+H ): 431.2 400 MHz, 5ppm): δ 10.25 (IH, s), 9.18 (IH, br), 8.16 (IH, s), 7.66-7.56 (2H, m), 7.37 (IH, t), 7.00 (IH, br), 6.93 (IH, d), 6.42 (IH, dd), 6.23 (IH, d), 5.75 (IH, d), 5.66 (IH, s), 4.43 (2H, s), 3.53 (3H, s), 2.66 (IH, m), 0.79-0.72 (2H, m), 0.70-0.62 (2H, m).

((- 2- oxo -3,4- dihydro-pyrimidins are simultaneously by 3- cyclopropyl -7- (isothiazole -5- bases amino) by 3- by the jV- of embodiment 13【4,5- pyrimidines-K2^-yl) phenyl) acrylamide compound 13) and preparation

(1) preparation of 3- (3- cyclopropyl -7- (isothiazole -5- bases amino) -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5- pyrimidines -1 (2/)-yl) phenylcarbamate

In dry reaction bottle; add 5- An isoxazoles (0; 504 g; 6.0 mmol); the dry mL of tetrahydrofuran 10; sodium hydride (60% is added at room temperature; 0.48 g; 12.0 mmol), nitrogen protection, after stirring ten minutes; 50 °C are warming up to react 1 hour; add 3- (3- cyclopropyl -7- (methyl sulphonyl) -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5-] pyrimidine -1 (2)-yl) phenyl amino Yue tert-butyl acrylates（1.38 g, 3.0 mmol), react 2 hours under 80 °C, silicagel column (the dichloro Yue alkane of dichloromethane one is crossed in concentration：Methanol=50:1) g of yellow solid 0.483 is obtained, yield is 34.8%.

(2) system of 1- (3- aminophenyls) -3- cyclopropyl -7- (isothiazole -5- bases amino) -3,4- dihydro-pyrimidins simultaneously [4,5-c] pyrimidine -2 (1) -one

In dry reaction bulb, 3- (3- cyclopropyl -7- (isothiazole -5- bases amino) -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5-c] pyrimidine -1 (2)-bases are added）Phenylcarbamate (0.483 g, 1.04 mmol), the mL of dichloromethane 5 and the mL of trifluoracetic acid 5,；Stir 1 hour, be spin-dried under water water-bath, be directly used in next step reaction.

(3) N- (3- (3- cyclopropyl -7- (isothiazole -5- bases amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- α] pyrimidine -1 (2/)-yl) phenyl）Third

Crude product obtained in the previous step is dissolved with 5 mL tetrahydrofurans, pH to 9-10 is adjusted with DIEA, acryloyl chloride is added dropwise under water water-bath（113 mg, 1.25 mmol), react 10 minutes after completion of dropping, stop after reaction, add methanol and be quenched, prepare liquid phase purifying（Methanol：Water=50%) obtain the mg of white solid 75, two step yields are 17.3%.

Molecular formula： C₂₁H₁₉N₇0₃Molecular weight：417.2 mass spectrum（M+H ): 472.2 ^-NM^^-DMSO, 400 MHz, 5ppm):δ 11.13 (1H, s), 10.27 (1H, s), 8.28 (IH, s), 7.99 (IH, d), 7.67 (IH, d), 7.62 (IH, m), 7.44 (IH, t), 6.99 (IH, d), 6.41 (1H, dd), 6.23 (IH, dd), 5.75 (IH, dd), 5.12 (IH, s), 4.49 (2H, s), 2.72-2.62 (IH, m), 0.80-0.73 (2H, m), 0.72-0.63 (2H, m)

- 2- oxo -3,4- dihydro-pyrimidins are simultaneously by the 7V-i3- of embodiment 14 (3- cyclopropyl 1-7- (isoxazole -4-bases amino)【4,5- ^ pyrimidines-U2^-yl) phenyl) acrylamide f compounds 14) and preparation

The preparation of 4- nitro isoxazoles

In dry reaction bulb, isoxazole is added（5.01 g, 72.5 mmol) and TFAA (53.3 g, 253.8 mmol), ammonium nitrate is slowly added into batches under water-bath（8.99 g, 112.4 mmol), add and 4h is stirred at room temperature, then add water to system, organic phase column chromatography (PE is dried and concentrated in dichloromethane aqueous phase extracted:EA=5:1) Pureization obtains the g of faint yellow solid 1.05, and yield is 12.7%.

(the preparation of 2) isoxazole -4- amine

In dry reaction bulb, 4- nitro isoxazoles are added（1.05 g, 9.20 mmol) and ammonium chloride（9.84 g, 184 mmol) mL of water 70 is added, zinc powder is slowly added under ice bath（5.98 g, 91.4 mmol), add complete latter 0 °C and be stirred overnight, filter out zinc powder, extract ice phase with EA, organic phase is dried and concentrated and obtains 0.4 g dark red oils, yield is 51.7%.

(3) preparation of 3- (3- cyclopropyl -7- (methyl sulphonyl) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2)-yl) stupid base amino Yue tert-butyl acrylates P T/CN2013/001555

In dry reaction bulb, add 3- (3- cyclopropyl -7- (methyl mercapto) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2 /)-yl) phenyl amino Yue tert-butyl acrylates (5.0 g, 11.7 mmol), dichloromethane and each 50 mL of Yue alcohol, metachloroperbenzoic acid is added under water water-bath（6.04 g, 35.1 mmol), add and be warmed to room temperature reaction 2 hours, stop reaction, be concentrated under reduced pressure, column chromatography (PE:EA=1:2) 4.01 g faint yellow solids are obtained, yield is 74.6%.

(4) -2- oxos -3,4- dihydro-pyrimidin is simultaneously by 3- (3- cyclopropyl -7- (isoxazole -4-bases amino)

[4,5- pyrimidines -1 (2)-yl) phenylamino is standby

In dry reaction bulb, 3- (3- cyclopropyl -7- (methyl sulphonyl) -2- oxos -3,4- dihydro-pyrimidin simultaneously [(2 /)-yl of 4,5- pyrimidine -1) phenylcarbamate is added（0.46 g, l.Ommol) are He isoxazole -4- amine（101 mg, 1.20 mmol), dissolved with 20 mL tert-pentyl alcohols, then add trifluoracetic acid（0.114 g, l.Ommol), back flow reaction 12 hours in 100 °C of oil baths stops reaction, is cooled to after room temperature, be concentrated under reduced pressure column chromatography（PE:EA=1:2) 0.24g faint yellow solids are obtained, yield is 51.8%.

(5) 1- (3- aminophenyls) -3- cyclopropyl -7- (isoxazole -4-bases amino) -3,4- dihydro-pyrimidins simultaneously [4,5-c] pyrimidine -2 (1/) -one preparation

In thousand dry reaction bulbs, add 3- (3- cyclopropyl -7- (isoxazole -4-bases amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2/ /)-yl) phenyl amino Yue tert-butyl acrylates (0.24 g, 0.518 mmol), dissolved with 20.0 mL dichloromethane,;The mL of trifluoroacetic acid 10.0 is added dropwise under conditions of water-bath, completion of dropping is stirred at room temperature, under TLC detections after raw material reaction completely, stops reaction, be then concentrated under reduced pressure, gained grease is directly used in next step reaction.

(6) (- 2- oxo -3,4- dihydro-pyrimidins are simultaneously by 3- (3- cyclopropyl 1-7- (isoxazole -4-bases amino) by N- [4,5-c] pyrimidine -1 (2/ /)-yl) phenyl）Third

Obtained crude product is walked on being added in dry reaction bulb, the mL of tetrahydrofuran 20 is added, is adjusted with DIEA and is added dropwise to acryloyl chloride under pH to 9-10,0 °C（94 mg, 1.04 mmol), continue after completion of dropping to react 15 min, stop after reaction, add methanol and be quenched, mix sample, prepare liquid phase purifying（Methanol/water=45%) obtain the mg of pale yellow powder shape solid 120, two step yields are 55.4%.

Molecular formula： C₂₁H₁₉N₇0₃Molecular weight：417.2 mass spectrum（M+H ): 418.2 ^-NMRC^-DMSO, 400 MHz, : δ 10.33 (IH, s), 9.60 (IH, br), 8.30-8.15 (2H, m), 7.72 (IH, br), 7.67 (IH, d), 7.60-7.51 (IH, m), 7.48 (IH t), 7.00 (IH, d), 6.41 (IH, dd), 6.23 (IH, dd), 5.75 (IH, dd), 4.45 (2H, s),

2.67 (IH, m), 0.80-0.71 (2H, m), 0.71-0.65 (2H, m)

The A^3- of embodiment 15 (3- cyclopropyl -7- 6- Yue epoxides pyridin-3-yl)（Methyl) amino) -2- oxo -3,4- dihydro-pyrimidins and i4,5-dl pyrimidines-K2iy)-yl) phenyl）The preparation of Bing Xi Fu amine (compound 15)

(1) preparation of 6- methoxyl groups-N- Yue yl pyridines -3- amine

In dry reaction bottle, 10 mL anhydrous tetrahydro furans and diisopropylamine are added（1.01 g, 10.0 mmol), -78.The hexane solution of n-BuLi is added dropwise under C（2.4 M, 4.16 mL, 10.0 mmol), after stirring ten minutes, ice-water bath continues to stir 20 minutes, and -78 are cooled to again.C, adds 6- Yue epoxide -3- aminopyridines（1.24 g, 10.0 mmol) the mL of tetrahydrofuran solution 10, It is warming up to 0.C is reacted 1 hour, and -78 are cooled to again.C, is added dropwise iodine Yue alkane（1.42 g, 10.0 mmol), kept for -78 °C react 2 hours, Slow is warmed to room temperature continuation and reacted 18 hours slowly afterwards, adds saturated ammonium chloride solution and reaction is quenched, ethyl acetate is extracted three times, merge organic phase, dry, the silicagel column (petroleum ether of petroleum ether one is crossed in concentration：Ethyl acetate=10:1) g of large-leaved dogwood red oil 0.31 is obtained, yield is 22.5%.

(2) 3- (3- cyclopropyl -7- ((6- methoxypyridine -3- bases) (methyl) amino) -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5-d] pyrimidine -1 (preparations of 2 butyl esters

In dry reaction bottle; add 3- (3- cyclopropyl -7- (Yue bases sulfonyl) -2- oxos -3; 4- dihydro-pyrimidins simultaneously [4; 5-] pyrimidine -1 (2/ /)-yl) phenylcarbamate (0.937 g; 2.04 mmol); the mL of tert-pentyl alcohol 20; 6- methoxyl group Yue yl pyridines -3- amine (0.31 g; 2.25 mmol); trifluoracetic acid (0.233 g, 2.04 mmol), reacts 12 hours under 110 °C; concentration, crosses the silicagel column (petroleum ether of petroleum ether one：Ethyl acetate=1:2) g of dark red oil 0.39 is obtained, yield is 37%.

(3) 1-(3- aminophenyls)-3- cyclopropyl-7- ((6- methoxypyridine-3- bases)（Methyl) amino) -3,4- dihydro-pyrimidins simultaneously [4,5-d] -2 (1) -one preparation

In dry reaction bulb, 3- (3- cyclopropyl -7- ((6- methoxypyridine -3- bases) are added（Yue yls) amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2/)-yl) phenyl amino Yue tert-butyl acrylates (0.39 g, 0.754 mmol), the mL of the dichloro Yue alkane 5 and mL of trifluoracetic acid 5, stirred 1 hour under ice-water bath, concentration is spin-dried for, be directly used in next step reaction.

() Λ Κ 3- (3- cyclopropyl -7- ((6- methoxypyridine -3- bases)（Yue yls) amino) -2- oxos

- 3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine-- yl) stupid base）The preparation of acrylamide

Crude product obtained in the previous step is dissolved with 10 mL tetrahydrofurans, pH is adjusted extremely with DIEA 9-10, is added dropwise to after acryloyl chloride (82 mg, 0.905 mmol), completion of dropping under water water-bath and reacts 1 hour, stop after reaction, adds methanol and is quenched, crosses silicagel column（The petroleum ether of 100% petroleum ether one：Ethyl acetate=1:3) mg of light yellow solid 70 is obtained, two step yields are 19.6%.

Molecular formula： C₂₅H₂₅N₇0₃Molecular weight：471.2 mass spectrum（M+H ): 472.2 ^-NMR^-DMSO, 400 MHz, 6ppm):δ 10.19 (IH, s), 8.09 (IH, s), 7.92 (IH, d), 7.57 (1H, t), 7.53 (IH, d), 7.46 (IH, dd), 7.29 (IH, t), 6.85 (IH, d), 6.53 (IH, d), 6.42 (IH, dd), 6.23 (IH, dd), 5.75 (IH, dd), 4.39 (2H s), 3.77 (3H, s), 3.16 (3H, s), 2.70-2.61 (IH, m), 0.78-0.71 (2H, m), 0.68-0.61 (2H, m)

- 2- oxo -3,4- dihydro-pyrimidins are simultaneously by 16 V-O- of embodiment-cyclopropyl -7- (5- methoxypyridine -2- bases amino)【4,5-rfl pyrimidines -1 (2^)-yl) phenyl) acrylamide compound 16) and preparation

(1) preparation of 3- (3- cyclopropyl -7- (5- methoxypyridine -2- bases amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2)-yl) phenylcarbamate

In dry reaction bottle, 5- Yue epoxide pyridine -2- amine (0.149 g, 1.2 mmol) is added, the dry mL of tetrahydrofuran 10 adds sodium hydride at room temperature（60%, 96 mg, 2.4 mmol), nitrogen protection is warming up to 60.C reacts 1 hour; add 3- (3- cyclopropyl -7- (methyl sulphonyl) -2- oxos -3; 4- dihydro-pyrimidins simultaneously [4; 5-] pyrimidine -1 (2)-yl) phenylcarbamate (0.551 g; 1.2 mmol); reacted 2 hours under 80 °C, the silicagel column (dichloromethane of dichloro Yue alkane one is crossed in concentration：Methanol=100:1) g of yellow solid 0.23 is obtained, liquid phase purifying is further prepared（Methanol：Water=60%) obtain the g of white solid 0.14, yield is 23.2%.

(2) 1- (3- aminophenyls) -3- cyclopropyl -7- (5- Yue epoxide pyridine -2- bases amino) -3,4- dihydros Pyrimido [4,5-0 pyrimidines -2 (1/) -

In thousand dry reaction bulbs, add 3- (3- cyclopropyl -7- (5- methoxypyridine -2- bases amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2 /)-yl) phenyl amino Yue tert-butyl acrylates (0.14 g, 0.278 mmol), the mL of dichloro Yue alkane 4 and the mL of trifluoracetic acid 3 are stirred 1 hour under ice-water bath, it is spin-dried for, is directly used in next step reaction.

(3) N- (3- (3- cyclopropyl -7- (5- Yue epoxide pyridine -2- bases amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2)-yl) benzene

Crude product obtained in the previous step is dissolved with 5 mL tetrahydrofurans, pH is adjusted extremely with DIEA

9-10, acryloyl chloride (30 mg are added dropwise under water water-bath, 0.334 mmol), react 10 minutes after completion of dropping, stop after reaction, methanol is added to be quenched, it is spin-dried for reaction solution and obtains yellow crude, methanol washing, filtering, filtration cakes torrefaction obtains the mg of light yellow solid 45, and two step yields are 35.3%.

Molecular formula： C₂₄H₂₃N₇0₃Molecular weight：457.2 mass spectrum（M+H ): 458.2 'H-NMR^-DMSO, 400 MHz, 6ppm): δ 10.30 (IH, s), 9.39 (IH, s),

8.20 (IH, s), 7.85 (IH, d), 7.75 (IH, d), 7.60 (IH, s), 7.46 (IH, t), 7.22 (IH, d), 6.98 (IH, d), 6.77 (IH, dd), 6.41 (IH, dd), 6.23 (IH, dd), 5.74 (IH, dd), 4.46 (2H, s), 3.70 (3H, s), 2.72-2.63 (IH, m), 0.81-0.72 (2H, m), 0.72-0.65 (2H, m)

Embodiment 17；The preparation of V- (3- (3- cyclopropyl-7- (oxazole-2- bases amino)-2- oxo-3,4- dihydro-pyrimidins and i4,5-ffl pyrimidines-1 (2-yl) phenyl) acrylamide (compound 17)

(1) 3- (3- cyclopropyl -7- (oxazole -2- bases amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2/yl) phenylcarbamic acid

168 mg (2 mmol) 2- An Ji oxazoles are dissolved in 20 mL tetrahydrofurans, 80 mg (2mmol) 60 are added^o/ 々 NaH, 50 °C of stirring 1.5h, add 459 mg (1 mmol) sm, 80 °C of reaction 5h, rotation thousand, column chromatography（DCM:MeOH=20:1), prepare liquid phase and purify to obtain the mg of white solid 55, yield 11.9%

(2) 1- (3- aminophenyls) -3- cyclopropyl -7- (oxazole -2- bases amino) simultaneously [preparation of 4,5- pyrimidines -2 (1/7) -one of -3,4- dihydro-pyrimidins

By 55 mg (0.12 mmol) 3- (3- cyclopropyl -7- (oxazole -2- bases amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2/)-yl) phenyl amino Yue tert-butyl acrylates are dissolved in 3 mL DCM, add 2 mL trifluoroacetic acids, react at room temperature 4 h, TLC monitoring reactions terminate, and are spin-dried for solvent, are directly used in the next step.

(3) AK3- (3- cyclopropyl -7- (oxazole -2- bases amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- /] pyrimidine -1 (2/)-yl) phenyl) acrylamide preparation

Upper step reaction product is dissolved in 5 mL THF, 65 mg (0.5 mmol) DIEA is added, 11 mg (0.12 mmol) acryloyl chloride is added under water-bath, 0.5 h of reaction is finished.Solvent is spin-dried for, liquid phase is prepared and purifies to obtain the mg of white solid 7, the step yield 14% of the above two.

Molecular formula： C₂₁H₁₉N₇0₃Molecular weight：417.2 mass spectrums (M+H): 418.2

^-NMRCDMSO-^, 400 MHz, 6ppm):δ 10.22 (IH, s), 10.19 (IH, s), 8.18 (IH, s), 7.63 (1H, d), 7.58 (IH, s), 7.53 (IH, s), 7.35 (IH, t), 6.96-6.91 (2H, m), 6.42 (IH, dd), 6.24 (IH, d), 5.75 (IH, d), 4.45 (2H, s), 2.69-2.61 (IH, m), 0.79-0.71 (2H, m), 0.69-0.63 (2H, m)

The iV-i3- of embodiment 18 (3- cyclopropyl -7- 6- Yue epoxide pyridin-3-yls amino) -2- oxos

- 3,4- dihydro-pyrimidins are simultaneously【The Η of 4,5-^1 pyrimidines-Κ 2)-yl) phenyl) -4- (dimethylamino) but-2-enamides

(1) 1- (3- aminophenyls) -3- cyclopropyl -7- (6- Yue epoxide pyridin-3-yls amino) -3,4- dihydro-pyrimidins simultaneously [(1/) -one of 4,5- ^ pyrimidines -2

In dry reaction bulb, 3- (3- cyclopropyl -7- (6- Yue epoxide pyridin-3-yls amino) -2- oxos -3,4- dihydro-pyrimidin simultaneously [(2 /)-bases of 4,5- ^ pyrimidines -1 are added）Phenylcarbamate (0.504 g, 1.0 mmol), the mL of dichloromethane 15 and the mL of trifluoracetic acid 10, stir 1 small under water water-bath When, it is spin-dried for, is directly used in next step reaction.

(2) system of 4- bromines but-2-ene acyl chlorides

In thousand dry reaction bulbs, 4- bromocrotonic acids are added（0.165 g, 1.0 mmol), few drops of DMF are added dropwise in the mL of dichloromethane 10, and oxalyl chloride (0.191 g, 1.5 mmol) is added at room temperature, are stirred 1 hour at room temperature, concentration is spin-dried for, and are directly used in next step reaction.

(3) bromo- (3- (3- cyclopropyl -7- (6- methoxypyridine -3- bases the amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [preparations of (2)--2- acrylamides of 4,5- pyrimidines -1 of 4-

1-(3- the aminophenyls)-3- cyclopropyl-7- (6- Yue epoxide pyridin-3-yls amino)-3 that the first step is obtained, 4- dihydro-pyrimidins simultaneously [4,5- /] pyrimidine-2 (1/ /) -one crude product 10 mL tetrahydrofurans and 5 mL NMP dissolvings, add 3 mL DIEA, the mL of tetrahydrofuran solution 5 of second step reaction gained 4- bromine but-2-ene acyl chlorides is added dropwise under ice-water bath, reacted 30 minutes after completion of dropping, be directly used in next step reaction.

(4) Λ Κ 3- (3- cyclopropyl -7- (6- Yue epoxide pyridin-3-yls amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidine -1 (2 Η)-yls) -4- (dimethylamino) but-2-enamides preparation

Weigh hydrochloride (0.816 g of two Yue amine, 10.0 mmol) it is added in the reaction system of step, react 48 hours at room temperature, decompression steams most of solvent, 100 mL ethyl acetate are added, saturated common salt water washing three times, organic phase is dried, concentration, crosses the silicagel column (dichloromethane of dichloro Yue alkane one：Methanol=15:1) mg of light yellow solid 115, overall yield 22.3% are obtained.

Molecular formula： C₂₇¾。N₈0₃Molecular weight：514.2 mass spectrum（M+H ): 515.3 ^-NMR^-DMSO, 400 MHz, 5ppm):δ 10.51 (IH, s), 9.32 (IH, s), 8.16 (IH, s), 8.01 (IH, s), 7.71 (IH, d), 7.67-7.58 (2H, m), 7.43 (IH, t), 6.97 (IH, d), 6.74 (IH, dt), 6.44 (IH, d), 6.39-6.28 (IH, m), 4.43 (2H, s), 3.85-3.76 (2H, m), 3.71 (3H, s), 2.73-2.62 (7H, m), 0.80-0.72 (2H, m), 0.72-0.63 (2H, m) 7V-i3-i3- cyclopropyl -7- 6- methoxypyridine -3- bases the amino of embodiment 19) -2- oxo -3,4- dihydro-pyrimidins are simultaneously【4,5- pyrimidine -2H bases) phenyl) -4- morpholine but-2-ene barefoot amine (compounds

(1) 1- (3- aminophenyls) -3- cyclopropyl -7- (6- methoxypyridine -3- bases amino) -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -2 (1/) -

In dry reaction bulb, add 3- (3- cyclopropyl -7- (6- methoxypyridine -3- bases amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2)-yl) phenyl amino Yue tert-butyl acrylates (0.504 g, 1.0 mmol), the mL of dichloromethane 15 and the mL of trifluoracetic acid 10 are stirred 1 hour under water water-bath, rotation thousand, is directly used in next step reaction.

(2) system of 4- bromines but-2-ene acyl chlorides

In dry reaction bulb, 4- bromocrotonic acids are added（0.165 g, 1.0 mmol), few drops of DMF are added dropwise in the mL of dichloromethane 10, and oxalyl chloride (0.191 g, 1.5 mmol) is added at room temperature, are stirred 1 hour at room temperature, concentration is spin-dried for, and are directly used in next step reaction.

(3) the bromo- N- of 4- (3- (3- cyclopropyl -7- (6- methoxypyridine -3- bases amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5 pyrimidines -1 (2/)-yl) phenyl) but-2-enamides preparation

1- (3- the aminophenyls) -3- cyclopropyl -7- (6- Yue epoxide pyridin-3-yls amino) -3 that the first step is obtained, 4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -2 (1/) -one crude product is dissolved with 10 mL tetrahydrofurans and 5 mL NMP, pH to 9-10 is adjusted with DIEA；Reacted 30 minutes after the mL of tetrahydrofuran solution 5 of second step reaction gained 4- bromine but-2-ene acyl chlorides, completion of dropping are added dropwise under water water-bath, be directly used in next step reaction.

(4) N- (3- (3- cyclopropyl -7- (6- Yue epoxide pyridin-3-yls amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2H)-yl) benzene -4- morpholine but-2-enamides preparation

Weigh morpholine (0.261 g, 3.0 mmol) it is added in the reaction system of step, react 24 hours at room temperature, decompression steams most of solvent, 100 mL ethyl acetate are added, saturated common salt water washing three times, organic phase is dried, concentration, crosses the silicagel column (dichloromethane of dichloromethane one：Methanol=25:1) mg of light yellow solid 270, overall yield 48.5% are obtained.

Molecular formula： C₂₉H₃₂N₈0₄Molecular weight：556.3 mass spectrum（M+H): 557.3

¹H-NMR ( ₆-DMSO, 400 MHz, 5ppm):(the 1H of δ 10.18, s), 9.31 (1H, s), 8.16 (1H, s), 8.01 (1H, s), 7.68-7.58 (3H, m), 7.40 (1H, t), 6.93 (1H, d), 6.75-6.63 (1H, m), 6.40-6.29 (1H, m), 6.26 (1H, d), 4.43 (2H, s), 3.71 (3H, s), 3.57 (4H, t), 3.10 (2H, d), 2.71-2.63 (1H, m), 2.40-2.33 (4H, m), 0.80-0.72 (2H, m), 0.72-0.64 (2H, m)

ν-the 3- of embodiment 20 7-cyclopropyl-7- (6- methoxypyridine-3- bases amino)-2- oxos-3,4- dihydro-pyrimidins and i4,5- pyrimidines-K2H)-yl) phenyl 4- (pyrrolidin-1-yl) but-2-enamides (compound 20) preparation

(1) 1-(3- aminophenyls)-3- cyclopropyl-7- (6- methoxypyridines-- base amino)-3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine-2 (1/ /) -one

In dry reaction bulb, add 3- (3- cyclopropyl -7- (6- Yue epoxide pyridin-3-yls amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-^] pyrimidine -1 (2/)-yl) phenylcarbamate (0.504 g, 1.0 mmol), the mL of dichloro Yue alkane 15 and the mL of trifluoracetic acid 10 are stirred 1 hour under water water-bath, it is spin-dried for, is directly used in next step reaction.

(2) system of 4- bromines but-2-ene acyl chlorides

In dry reaction bulb, 4- bromocrotonic acids are added（0.165 g, 1.0 mmol), few drops of DMF are added dropwise in the mL of dichloromethane 10, and oxalyl chloride (0.191 g, 1.5 mmol) is added at room temperature, are stirred 1 hour at room temperature, concentration is spin-dried for, and are directly used in next step reaction.

(3) the bromo- Λ Κ 3- of 4- (3- cyclopropyl -7- (6- methoxypyridine -3- bases amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-J] pyrimidine -1 (2 /)-yl) phenyl) but-2-enamides preparation

1-(3- the aminophenyls)-3- cyclopropyl-7- (6- methoxypyridine-3- bases amino)-3 that the first step is obtained, 4- dihydro-pyrimidins simultaneously [4,5- pyrimidines-2 (1/) -one crude product is dissolved with 10 mL tetrahydrofurans and 5 mL NMP, pH to 9-10 is adjusted with DIEA；Second step reaction gained is added dropwise under water water-bath Reacted 30 minutes after the mL of tetrahydrofuran solution 5 of 4- bromine but-2-ene acyl chlorides, completion of dropping, be directly used in next step reaction.

(4) N- (3- (3- ring Yu Ji-7- (6- methoxypyridine-3- bases amino)-2- oxos-3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines-1 (2H)-yl) benzene-4- (pyrrolidines-1-yl) but-2-enamides preparation

Weigh pyrrolidines (0.213 g, 3.0 mmol) it is added in the reaction system of step, react 24 hours at room temperature, decompression steams most of solvent, 100 mL ethyl acetate are added, saturated common salt water washing three times, organic phase is dried, concentration, crosses the silicagel column (dichloromethane of dichloromethane one：Methanol=10:1) mg of yellow solid 220, overall yield 40.7% are obtained.

Molecular formula： C₂₉H₃₂N₈0₃Molecular weight：540.3 mass spectrum（M+H ): 541.3 ^-NMR^-DMSO+DsO, 400 MHz, 5ppm): δδ. 15 (】Η, s), 7.99 (1 Η, s), 7.68-7.60 (3H, m), 7.40 (1H, t), 6.93 (1H, d), 6.74 (1H, dt), 6.38-6.23 (2H, m), 4.42 (2H, s), 3.70 (3H, s), 3.38-3.30 (2H, m), 2.69-2.62 (1H, m), 2.62-2.55 (4H, m), 1.76-1.68 (4H, m), 0.79-0.72 (2H, m), 0.69-0.63 (2H, m)

(- 2- oxo -3,4- dihydro-pyrimidins are simultaneously by 3- (3- cyclopropyl -7-f6- Yue epoxide pyridin-3-yls amino) by the N- of embodiment 21【4,5-f l pyrimidine radicals) phenyl) -4- (piperazine -1- bases) but-2-enamides

(1) preparation of l-(3- aminophenyls) -3- cyclopropyl -7- (6- methoxypyridine -3- bases amino) -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -2 (1/ /) -one

In dry reaction bulb, 3- (3- cyclopropyl -7- (6- methoxypyridine -3- bases amino) -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5-ii] pyrimidine -1 (2/ /)-bases are added）Phenylcarbamate (0.504 g, 1.0 mmol), the mL of dichloro Yue alkane 15 and the mL of trifluoracetic acid 10, are stirred 1 hour under water water-bath, rotation thousand, are directly used in next step reaction.

(2) system of 4- bromines but-2-ene acyl chlorides

In dry reaction bulb, 4- bromocrotonic acids are added（0.165 g, 1.0 mmol), few drops of DMF are added dropwise in the mL of dichloromethane 10, and oxalyl chloride (0.191 g, 1.5 mmol) is added at room temperature, are stirred 1 hour at room temperature, concentration is spin-dried for, and are directly used in next step reaction.

(3) the bromo- N- of 4- (3- (3- cyclopropyl -7- (6- methoxypyridine -3- bases amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-t] pyrimidine -1 (2/-yl) phenyl) but-2-enamides preparation

1- (3- the aminophenyls) -3- cyclopropyl -7- (6- Yue epoxide pyridin-3-yls amino) -3 that the first step is obtained, 4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -2 (1/ /) -one crude product 10 mL tetrahydrofurans and 5 mL NMP dissolvings, pH to 9-10 is adjusted with DIEA, the mL of tetrahydrofuran solution 5 of second step reaction gained 4- bromine but-2-ene acyl chlorides is added dropwise under ice-water bath, reacted 30 minutes after completion of dropping, be directly used in next step reaction.

(4) 4- (4- (3- (3- cyclopropyl -7- (6- methoxypyridine -3- bases amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2 base) phenylamino) -4- oxo but-2-enes base) piperazine -1- Yue tert-butyl acrylates preparation

Weigh piperazine -1- t-butyl formates（0.558 g, 3.0 mmol) it is added to the reactant of step In system, react 24 hours at room temperature, decompression steams most of solvent, add 100 mL ethyl acetate, saturated common salt water washing three times, organic phase is dried, silicagel column (the dichloro Yue alkane of dichloro Yue alkane one is crossed in concentration：Yue alcohol=25：1) mg of light yellow solid 490 is obtained, three steps add up to yield 74.7%.

(5) N- (3- (3- cyclopropyl-7- (6- first radon yl pyridines-3- bases amino)-2- oxos-3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine-1 (2/ /)-yl)-4- (piperazine-1-yl) but-2-enamides preparation

In thousand dry reaction bulbs, add 4- (4- (3- (3- cyclopropyl -7- (6- Yue epoxide pyridin-3-yls amino) -2- oxos -3, 4- dihydro-pyrimidins simultaneously [4, 5-d] pyrimidine-1 (2 /)-yl) phenylamino)-4- oxo but-2-enes base) piperazine-1-t-butyl formate (0.49 g, 0.747 mmol), the mL of the dichloromethane 10 and mL of trifluoracetic acid 15, stir 1 hour at room temperature, pH is adjusted to alkalescent with sodium hydrate aqueous solution, concentration is spin-dried for, obtained crude product is washed with methanol, filtering, filtration cakes torrefaction, obtain the g of off-white powder 0.21, yield 50.5%.

Molecular formula： C₂₉H₃₃N₉0₃Molecular weight：555.3 mass spectrum（M+H ): 556.3 ]H-NMR(6 -DMSO, 400 MHz, 6ppm):δ 10.17 (1 Η, s), 9.30 (1 Η, s), 8. 16 (1H, s), 8.01 (1H, s), 7.68-7.58 (3H, m), 7.39 (1H, t), 6.93 (1H_}D), 6.70 (1 H, dt), 6.34 (1H, d), 6.24 (1 H, d), 4.43 (2H, s), 3.71 (3H, s), 3.05 (2H, d), 2.72-2.63 (5H, m), 2.32-2.24 (4H, m), 0.80-0.71 (2H, m), 0.71-0.64 (2H, m)

Embodiment 22 7V-i3-i3- cyclopropyl -7- (l- methyl-li-pyrazole-3-yl amino) -2- oxos -3,4- dihydro-pyrimidins and 4,5-^ pyrimidines-U2H)-yl) phenyl) and propylene barefoot amine (compound 22) preparation

(1) 3- (3- cyclopropyl -7- (mesyl) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5-i] pyrimidines - 1 (2//>Base) the tertiary fourth of phenyl amino Yue acid

In dry reaction bulb, add 3- (3- cyclopropyl -7- (first dredges base) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2)-yl) phenylcarbamate (9.0 g, 21.05 mmol), with each 50 mL of dichloromethane lOOmL and methanol, metachloroperbenzoic acid (10.89 g are added under ice-water bath, 63.15 mmol), room temperature reaction 2.5 hours, stop reaction, be then concentrated under reduced pressure column chromatography（PE:EA=1:2) 9.05 g white solids are obtained, yield is 93.6%.

(2) preparation of 3- (3- cyclopropyl -7- (1- Yue base pyrazole-3-yls amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2/)-yl) benzene

In dry reaction bulb, 3- (3- cyclopropyl -7- (Yue bases sulfonyl) -2- oxos -3,4- dihydro-pyrimidin simultaneously [(2/ /)-yl of 4,5- pyrimidine -1) phenyl amino Yue tert-butyl acrylates are added（0.46 g, l.Ommol) amine of and 1_ Yue bases pyrazoles _ 3（117mg, 1.20 mmol), dissolved with 40 mL tert-pentyl alcohols, then add trifluoracetic acid（0.114g, l.Ommol), back flow reaction 12 hours in 100 °C of oil baths stops reaction, is cooled to after room temperature, be concentrated under reduced pressure column chromatography（PE:EA=1:2) 190 mg faint yellow solids are obtained, yield is 39.9%.

(3) 1- (the stupid base of 3- amino) -3- cyclopropyl -7- (1- methylpyrazole -3- bases amino) -3,4- dihydro-pyrimidins simultaneously [4,5-^] pyrimidine -2 (preparation of 1//-one

In dry reaction bulb, add 3- (3- cyclopropyl -7- (1- Yue base pyrazole-3-yls amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5- ^ pyrimidines -1 (2)-yl) phenyl amino Yue tert-butyl acrylates (0.19g, 0.399 mmol), dissolved with 15.0 mL dichloromethane, trifluoroacetic acid 7.0mL, completion of dropping are added dropwise under conditions of water-bath, room temperature continues to stir 1.5h, stop reaction, then It is concentrated under reduced pressure, gained grease is directly used in next step reaction.

(4) (3- (3- cyclopropyl -7- (1- methyl isophthalic acids/- pyrazole-3-yl amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines -1 (2H)-yl) is standby by/^-

Crude product obtained in the previous step is added in dry reaction bulb, tetrahydrofuran is added " 5 mL, are used

DIEA is adjusted and is added dropwise to acryloyl chloride under pH to 9-10,0 °C（72 mg, 0.798 mmol), continue after completion of dropping to react 15 min, stop after reaction, add methanol and be quenched, so after Minus pressure concentration column chromatographies（DCM:MeOH=50:1) faint yellow solid is obtained, is then dissolved with a small amount of dichloromethane and Yue alcohol, a large amount of ether is added and separates out solids, suction filtration obtains 60 mg white solids, and yield is 34.9 %.

Molecular formula： C₂₂H₂₂N₈0₂Molecular weight：430.2 mass spectrum（M+H ): 431.2 ^-NMRC^-DMSO, 400 MHz, 5ppm):δ 10.23 (IH, s), 9.47 (IH, s), 8.12 (IH, s), 7.70 (IH, d), 7.55 (IH, t), 7.40 (IH, t), 7.09 (IH, s), 6.95 (1H, d), 6.41 (IH, dd), 6.23 (IH, dd), 5.74 (IH, dd), 5.55-5.45 (IH, m), 4.41 (2H, s), 3.58 (3H, s), 2.70-2.62 (IH, m), 0.80-0.71 (2H, m), 0.70-0.63 (2H, m)

23 V-i3- of embodiment-cyclopropyl -7-il- methyl-I-pyrazoles -4- bases amino) -2- oxo -3,4- dihydro-pyrimidins are simultaneously【4,5-f/1 pyrimidine-l (2Jy)-yl) 4 dimethylamino of phenyl）But-2-enamides

(1) (3- cyclopropyl -7- (l- Yue base pyrazoles -4- bases amino) -2- oxo -3,4- dihydros are phonetic by 3- Pyridine simultaneously [4,5- pyrimidines -1 (2/ /)-yl) benzene preparation

In dry reaction bulb; add 3- (3- cyclopropyl -7- (first Moraine acyl groups) -2- oxos -3; 4- dihydro-pyrimidins simultaneously [4; 5-d] pyrimidine -1 (2 /)-yl) phenylcarbamate (3.15 g, 6.86 mmol) and the amine of 1- Yue bases pyrazoles -4（799 mg, 8.23 mmol), dissolved with 100 mL tert-pentyl alcohols, add trifluoracetic acid（0.782 g, 6.86 mmol), back flow reaction 5 hours in 100 °C of oil baths stops reaction, is cooled to room temperature, be concentrated under reduced pressure column chromatography（PE:EA=1:2) 3.20g faint yellow solids are obtained, yield is 97.9%.

(2) 1- (the stupid base of 3- amino) -3- cyclopropyl -7- (1- methyl-pyrazol-4-yls amino) -3,4- dihydro-pyrimidins simultaneously [(preparation of 1 ketone of 4,5- pyrimidines -2

In dry reaction bulb, 3- (3- cyclopropyl -7- (1- methyl-pyrazol-4-yls amino) -2- oxos -3,4- dihydro-pyrimidin simultaneously [4,5- pyrimidines -1 (2)-base are added）Phenylcarbamate (0.953 g, 2.0 mmol), dissolved with 30.0 mL dichloromethane, the mL of trifluoroacetic acid 12.0 is added dropwise under water-bath, completion of dropping, room temperature continues to stir lh, stops reaction, then it is concentrated under reduced pressure, gained grease is directly used in four-step reaction.

(3) preparation of 4- bromines but-2-ene acyl chlorides

、ci

4- bromocrotonic acids are added in thousand dry reaction bulbs（330 mg, 2.0 mmol), dissolved with dichloromethane 30mL, oxalyl chloride is added dropwise under ice bath（381 mg, 3.0 mmol), l h are reacted at room temperature after completion of dropping, stops after reaction, is concentrated under reduced pressure, gained grease is directly used in next step reaction.

(4) 4- it is bromo--(3- (3- cyclopropyl -7- (1- methyl-pyrazol-4-yls amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2/ /)-yl) phenyl) but-2-enamides preparation

In dry reaction bulb, add 1- (3- aminophenyls) -3- cyclopropyl -7- (1- Yue base pyrazoles -4- bases amino) -3,4- dihydro-pyrimidins simultaneously [4,5-tf] pyrimidine -2 (1/) -one crude product 30 mL tetrahydrofurans and 8 mL NMP dissolvings, then system pH is adjusted to alkalescence with DIEA, the tetrahydrofuran solution of 4- bromine but-2-ene acyl chlorides is added dropwise under condition of ice bath, continue ice bath after dripping and stir 1 h, stop reaction, gained system is directly used in next step reaction.

(5) vV- (3- (3- cyclopropyl -7- (1- methyl isophthalic acid 7- pyrazoles -4- bases amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5-] pyrimidine -1 (2 /)-yl) phenyl) -4- (two Yue amino) but-2-enamides preparation

Take 10 mL dimethylamine agueous solutions, extracted one time with 20 mL dichloromethane, and dry organic phase, then the half of four-step reaction system is taken, the mL of dichloro Yue alkane solution 2 of two Yue amine is added thereto, then the Chenization Potassium of catalytic amount is added, 48 h are reacted under conditions of lucifuge water-bath, be concentrated under reduced pressure column chromatography（DCM:MeOH=5:1) light yellow solid is obtained, then it is dissolved with a small amount of Yue alcohol, a large amount of ether is added and separates out solid, suction filtration obtains the mg of faint yellow solid 65.

Molecular formula： C₂₅H₂₉N₉0₂Molecular weight：487.2 mass spectrum（M+H ): 488.2

^-NMR^-DMSO, 400 MHz, 5ppm):δ 10.93 (IH, s), 9.35 (IH, s), 8.11 (IH, s), 7.89 (IH, m), 7.67 (IH, s), 7.49 (1H, t), 7.15-6.90 (2H, m), 6.80 (IH, dt), 6.72-6.50 (2H, m), 4.41 (2H, s), 3.93-3.76 (2H, m), 3.46 (3H s), 2.80-2.62 (7H, m), 0.85-0.64 (4H, m)

The 7V- of embodiment 24 (3- (3- cyclopropyl -7- (l- methyl-li-pyrazoles -4- bases amino) -2- oxos

- 3,4- dihydro-pyrimidins【4,5- pyrimidine-lO^ bases) phenyl) -4- (pyrrolidin-1-yls）But-2-enamides compound 24) preparation

(1) 3- (3- cyclopropyl -7- (l- methyl-pyrazol-4-yls amino) -2- oxos -3,4- dihydro-pyrimidin simultaneously [preparations of 4,5- pyrimidine -1 (2/yl) benzene

In dry reaction bulb, 3- (3- cyclopropyl -7- (Yue sulfonyls) -2- oxo -3,4- dihydros are added^πClose pyridine simultaneously [4,5-d] pyrimidine -1 (2)-yl) phenylcarbamate（3.15g, 6.86 mmol) and the amine of 1- methylpyrazoles -4（799 mg, 8.23 mmol), dissolved with 100 mL tert-pentyl alcohols, add trifluoracetic acid（0.782 g, 6.86 mmol), back flow reaction 5 hours in 100 °C of oil baths stops reaction, is cooled to room temperature, be concentrated under reduced pressure column chromatography（PE:EA=1:2) 3.20g faint yellow solids are obtained, yield is 97.9%.

(2) 1- (3- aminophenyls) -3- cyclopropyl -7- (1- methyl-pyrazol-4-yls amino) -3,4- dihydro-pyrimidins simultaneously [4,5-tJ pyrimidines -2 (1 /) -

In dry reaction bulb, add 3- (3- cyclopropyl -7- (1- methyl-pyrazol-4-yls amino) -2- oxos -3,4- dihydro-pyrimidins simultaneously [4,5- ^ pyrimidines -1 (2)-yl) phenyl amino Yue tert-butyl acrylates (0.953 g, 2.0 mmol), dissolved with 30.0 mL dichloro Yue alkane,;The mL of trifluoroacetic acid 12.0, completion of dropping are added dropwise under water-bath, room temperature continues to stir lh, stops reaction, be then concentrated under reduced pressure, gained grease is directly used in four-step reaction.

(3) preparation of 4- bromines but-2-ene acyl chlorides

4- bromocrotonic acids are added in dry reaction bulb（330 mg, 2.0 mmol), dissolved with dichloromethane 30mL,;Oxalyl chloride is added dropwise under water-bath（381 mg, 3.0 mmol), l h are reacted at room temperature after completion of dropping, stops after reaction, is concentrated under reduced pressure, gained grease is directly used in next step reaction.

(4) preparation of 4- Huan-(3- (3- cyclopropyl -7- (1- methyl-pyrazol-4-yls amino) -2- oxo -3,4- dihydro-pyrimidins simultaneously [4,5- pyrimidines-- yl) phenyl) but-2-enamides

In dry reaction bulb, 1- (3- aminophenyls) -3- cyclopropyl -7- (1- methyl-pyrazol-4-yls amino) -3,4- dihydro-pyrimidins simultaneously [4,5- are added] pyrimidine -2 (1/ /) -one crude product 30 mL tetrahydrofurans and 8mLNMP dissolvings, then system pH is adjusted to alkalescence with DIEA, the tetrahydrofuran solution of 4- bromine but-2-ene acyl chlorides is added dropwise under condition of ice bath, continue ice bath after dripping and stir 1 h, stop reaction, gained system is directly used in next step reaction.

(5) N- (3- (3- cyclopropyl -7- (the 7- pyrazoles -4- bases amino of 1- Yue bases -1) -2- oxos -3,4- dihydro-pyrimidins [4,5-] pyrimidine -1 (2/)-yl) -4- (pyrrolidin-1-yl) but-2-enamides preparation

The half of four-step reaction system is taken, pyrrolidines is added thereto（213 mg, 3.0 mmol), the KI of catalytic amount is added, 48 h are reacted under conditions of lucifuge water-bath, be concentrated under reduced pressure column chromatography (DCM:MeOH=5:1) light yellow solid is obtained, then it is dissolved with a small amount of Yue alcohol, a large amount of ether is added and separates out solid, suction filtration obtains the mg of faint yellow solid 165, then further preparing liquid phase with high pressure purifies（Acetonitrile/water=35%) obtain 11 mg white solids.

Molecular formula： C₂₇H₃₁N₉0₂Molecular weight：513.3 mass spectrum（M+H): 514.3 400 MHz, 5ppm):δ 10.43 (1 Η, s), 9.35 (1H, s), 8.12 (1H, s), 7.87-7.45 (3H, m), 7.09-6.95 (2H, m), 6.75 (1H, dt), 6.66-6.50 (1H, m), 6.38 (1H, d), 4.42 (2H, s), 3.85-3.65 (2H, m), 3.47 (3H S), 3.15-2.87 (4H, m), 2.71-2.62 (1H, m), 1.92-1.80 (4H, m), 0.80-0.64 (4H, m)

Using similar to above-mentioned preparation method, following compound is also prepared for：

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