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CN103864792A - Heterocyclic nitrogen compound acting as tyrosine kinase inhibitor - Google Patents

Heterocyclic nitrogen compound acting as tyrosine kinase inhibitor Download PDF

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Publication number
CN103864792A
CN103864792A CN201310680756.0A CN201310680756A CN103864792A CN 103864792 A CN103864792 A CN 103864792A CN 201310680756 A CN201310680756 A CN 201310680756A CN 103864792 A CN103864792 A CN 103864792A
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hydrogen atom
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CN103864792B (en
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张倩
张艳
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SHANDONG HENRY MEDICAL SCIENCE AND TECHNOLOGY Co Ltd
KBP Biosciences Co Ltd
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SHANDONG HENRY MEDICAL SCIENCE AND TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/36—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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Abstract

The invention belongs to the technical field of medicine, particularly relates to a heterocyclic nitrogen compound which acts as a tyrosine kinase inhibitor and is represented by a general formula (I) as well as a deuterated material, pharmaceutically acceptable salt or stereisomer thereof. In the general formula (I), X, W, R1, R2, R3, L1, L2, a, b, c, d, e, p, q, a ring A and a ring B are defined in specification. The invention further relates to a preparation method of the compounds, a pharmaceutic preparation containing the compounds, and important actions of the compounds in treatment of leukemia (such as B cell chronic lymphocytic carcinoma and non-hodgkin lymphoma) related to B cell, and autoimmune diseases (such as rheumatoid arthritis and systemic lupus erythematosus).

Description

As the nitrogenous of tyrosine kinase inhibitor lopps compound
1, technical field
The invention belongs to medical technical field, be specifically related to as the nitrogenous of tyrosine kinase inhibitor lopps compound, its deuterated thing, its pharmacy acceptable salt or its steric isomer, the preparation method of described compound, the pharmaceutical preparation that contains described compound, and described compound is for example, in the relevant leukemia (B cell chronic lymphocytic cancer, non-Hodgkin lymphoma) of preparation treatment B cell, and such as, play an important role in autoimmune disorder (rheumatoid arthritis, systemic lupus erythematous etc.).
2, background technology
One of maximum family of protein kinase composition people fermentoid, and to protein, regulate many different signal conductive processes (T.Hunter, Cell198750:823-829) by adding phosphate group.Especially, Tyrosylprotein kinase phosphorylated protein is at the phenol moieties of tyrosine residues.Family tyrosine kinase comprises the member who controls Growth of Cells, migration and differentiation.Abnormal kinase activity has related to many human diseasess, comprises cancer, autoimmune disease and inflammatory diseases.Because protein kinase belongs to the crucial conditioning agent of cell signaling, they provide the target that regulates cell function by small molecules kinase inhibitor, and therefore become good medicinal design target.Except the treatment of kinase mediated lysis, the selectivity of kinase activity and effectively inhibitor also can be used for studying cell signaling process and identify that other has the cell target for the treatment of meaning.
There is good evidence in the keying action about B cell in the pathogenesis of autoimmunization and/or inflammatory diseases.The inflammatory diseases that the therapeutical agent based on protein that consumes B cell causes for autoantibody as Rituxan as rheumatoid arthritis be effectively (Rastetter etc., Annu Rev Med200455:477).The inhibitor of the protein kinase therefore, playing a role in B cell activation should be the disease pathology therapeutical agent as useful in autoantibody generate cell-mediated for B.
A series of B cell responses are controlled in signal conduction by B-cell receptor (BCR), comprise that propagation and differentiation are to ripe antibody-producting cell.BCR is that the crucial point of adjustment of B cytoactive and abnormal signal conduction can cause the B cell proliferation of imbalance and the formation of pathogenicity bo autoantibody, and it causes various autoimmune disease and/or inflammatory diseases.Bu Ludun (Bruton ' s) tyrosine protein kinase (Btk) be at the film near-end of BCR and the relevant kinases of non-BCR in downstream immediately.The shortage of Btk has shown the conduction of blocking-up BCR signal, and therefore the inhibition of Btk can be effective methods for the treatment of of the cell-mediated lysis of blocking-up B.
Btk is the member of Tyrosylprotein kinase Tec family, and shows it is that early stage B cell forms and mature B cell activates and crucial conditioning agent (Khan etc., the Immunity19953:283 of survival; Ellmeier etc., J.Exp.Med.2000192:1611).People's Btk sudden change causes the chain gamma-globulin of illness X to lack mass formed by blood stasis (XLA) Immunol.Rev.2005203:200 such as () Lindvall.These patients are immunocompromised hosts, and show impaired B cell maturation, the immunoglobulin (Ig) of reduction and periphery b cell level, the immunne response that does not rely on T cell of minimizing and at the post-stimulatory calciokinesis weakening of BCR.
The evidence of the effect about Btk in autoimmune disease and inflammatory diseases is provided by Btk-deficient mice model.In the clinical front mouse model of systemic lupus erythematous (SLE), Btk deficient mice shows the remarkable improvement of progression of disease.In addition, Btk-deficient mice has resistance (Jansson and Holmdahl Clin.Exp.Immunol.199394:459) to collagen-induced sacroiliitis.Prove selectivity Btk inhibitor dose-dependently effect (Z.Pan etc., Chem.Med Chem.20072:58) in mouse arthritis model.
Btk is also by the cell expressing that may relate to lysis except B cell.Such as Btk is shown the threshing (J.Biol.Chem.2005280:40261 such as Iwaki) of impaired antigen induction by mastocyte mast cell-expressed and Btk defective type derived from bone marrow.This shows that Btk can be used for the treatment of pathologic mastocyte and react as transformation reactions and asthma.In addition the TNF α that the monocyte from XLA patient that, wherein lacks Btk activity reduces after being presented at and stimulating generates J Exp Med2003197:1603 such as () Horwood.Therefore, the alpha mediated inflammation of TNF can be regulated by small molecules Btk inhibitor.In addition, the Btk having reported plays a role (IsIam and Smith Immunol.Rev.2000178:49) in apoptosis, and therefore Btk inhibitor will be effective J.Exp.Med.2005201:1837 such as () Feldhahn for treatment some B cell lymphoma and leukemia.
The Dasatinib of listing in 2006 is many target spots inhibitor, and Btk is had to stronger restraining effect, is used for the treatment of chronic lymphocytic leukemia; In addition be also many target spot inhibitor by the PCI-32765 of FDA approval listing in November, 2013, is non-reversibility to Btk restraining effect, is used for the treatment of lymphoma, leukemia and autoimmune disease.
Figure BDA0000436297380000021
Not yet selective Btk inhibitor listing at present, the fastest medicine of research is that CC-292(structure is as follows), enter in by the end of October, 2013 the clinical II phase study, it,, as irreversible selectivity inhibition Btk, is used for the treatment of rheumatoid arthritis.
Figure BDA0000436297380000022
The object of this invention is to provide good highly selective Btk inhibitor, it can be used in and prevents and/or treats leukemia, inflammatory and/or the autoimmune disorder that B cell is relevant.
3, summary of the invention
The present invention taking exploitation there is good antitumor action and treating autoimmune diseases effect simultaneously medicine as target, found highly selective as the nitrogenous of tyrosine kinase inhibitor lopps compound.
Concrete technical scheme is as follows, and the compound shown in following general formula (I), its deuterated thing, its pharmacy acceptable salt or its steric isomer are provided:
Wherein, X and W independently represent respectively C-Ra, C=O or N-Rb,
And when X is different with W, be C=O,
Ra represents hydrogen atom, halogen atom ,-CN ,-CF 3, by 1-2 identical or different Q 1replace or unsubstituted C 1-4alkyl, C 1-4alkoxy C 0-4alkyl, amino, C 3-6cycloalkyl C 0-4alkyl, phenyl C 0-4alkyl, naphthyl C 0-4alkyl, the heteroaryl C of 5-10 unit 0-4alkyl or-OH,
Rb represents not exist, and hydrogen atom, by 1-2 identical or different Q 1replace or unsubstituted C 1-4alkyl, C 1-4alkoxy C 0-4alkylidene group, C 3-6cycloalkyl C 0-4alkyl, phenyl C 0-4alkyl, naphthyl C 0-4alkyl or the heteroaryl C of 5-10 unit 0-4alkyl,
Q 1represent C 1-4alkoxyl group, C 1-3carbalkoxy, formamyl, C 1-3alkyl-carbamoyl, 3-8 unit cycloalkyl or contain N or the heteroatomic 3-8 of O unit heterocyclic radical;
R 2represent hydrogen atom, halogen atom ,-CF 3, C 1-4alkyl, C 1-4alkoxyl group, amino or-OH;
Ring A and ring B independently represent respectively phenyl, and 3-8 unit cycloalkyl contains N, O, the heteroatomic 3-8 of S unit Heterocyclylalkyl, 4-7 unit's heteroaryl or 6-12 unit two ring structures;
L 1and L 2independently represent respectively covalent linkage ,-NH-,-N (C 1-3alkyl)-,-O-,-S (O) m-,-N (C 1-3alkyl) C (O)-,-C (O) N (C 1-3alkyl)-,-N (C 1-3alkyl) S (O) 2-or-S (O) 2n (C 1-3alkyl)-;
A represents covalent linkage, is not substituted or by C 1-4the imino-that alkyl replaces;
Represent-CO-of b or-SO 2-;
C represent not to be substituted or replace by one or two methyl or through trifluoromethyl 1, the sub-propadiene base of 3-, 1,1-or vinylene, ethynylene, or the 1,3-butadiene-Isosorbide-5-Nitrae-subunit that is not substituted or replaces by one to four methyl or through trifluoromethyl;
D represents covalent linkage or C 1-6alkylidene group;
E represents hydrogen atom, C 1-4alkoxyl group, amino, 3-8 unit cycloalkyl, 6-12 unit two ring structures, C 1-4alkylamino or two-(C 1-4alkyl) amino, wherein moieties can be identical or different;
R 1and R 3independently represent respectively hydrogen atom, halogen atom, cyano group, nitro, C 2-4thiazolinyl, C 2-4alkynyl or-L 3-R 4,
L 3represent covalent linkage ,-NH-,-N (C 1-3alkyl)-,-O-,-O-C 1-3alkylidene group-,-S-C 1-3alkylidene group-,-S (O) m-,-C (O)-,-NHC (O)-,-N (C 1-3alkyl) C (O)-,-C (O) NH-,-C (O) N (C 1-3alkyl)-,-NHS (O) 2-,-N (C 1-3alkyl) S (O) 2-,-S (O) 2nH-,-S (O) 2n (C 1-3alkyl)-,-OC (O)-or-C (O) O-,
R 4represent hydrogen atom, C 1-4alkyl ,-N (C 1-3alkyl) 2,-NHC (O) O-(C 1-4alkyl) ,-OH ,-O (C 1-4alkyl) ,-S (O) 2(C 1-3alkyl), 3-8 unit cycloalkyl, phenyl or 5-6 unit heteroaryl;
Above-mentioned C 1-3alkyl and C 1-4moieties in alkyl, cycloalkyl, heteroaryl can be further by 1-4 identical or different Q 2replace,
Q 2represent halogen atom, C 1-3alkyl, amino, C 1-3alkylamino, two-(C 1-3alkyl) amino, hydroxyl, C 1-3alkoxyl group, C 1-3carbalkoxy, formamyl, C 1-3alkyl-carbamoyl, two-(C 1-3alkyl) formamyl or 3-6 unit cycloalkyl, wherein Q 1can be identical or different;
On described cycloalkyl, two ring structures, carbon atom can be by 1-4 identical or different N, NH, N (C 1-3alkyl), O, S (O) m, C (O) replace;
Described heteroaryl can contain 1-4 heteroatoms, and described heteroatoms is independently selected from respectively N, O or S;
Figure BDA0000436297380000041
represent singly-bound or two key;
M represents 0,1 or 2;
P and q independently represent respectively 0,1,2,3 or 4.
Compound shown in general formula (I), its deuterated thing, its pharmacy acceptable salt or its steric isomer, be preferably:
Wherein, X and W independently represent respectively C-Ra, C=O or N-Rb, and X is C=O when different with W,
Ra represents hydrogen atom, halogen atom ,-CF 3, methyl, ethyl, methoxyl group, methoxy ethyl, amino, cyclopropyl, phenyl, benzyl, naphthyl, pyrryl, furyl or pyridyl,
Rb represents not exist, and hydrogen atom, by 1-2 identical or different Q 1replace or unsubstituted C 1-3alkyl, C 1-3alkoxy C 0-3alkylidene group or C 3-6cycloalkyl C 0-3alkylidene group, phenyl, benzyl, naphthyl, pyrryl, furyl or pyridyl,
Q 1represent C 1-3alkoxyl group, C 1-3carbalkoxy or contain N or the heteroatomic 5-7 of O unit heterocyclic radical;
R 2represent hydrogen atom or amino;
Ring A and ring B independently represent respectively phenyl, and 5-6 unit cycloalkyl contains N, O, the heteroatomic 5-6 of S unit Heterocyclylalkyl, 5-6 unit's heteroaryl or 8-10 unit two ring structures;
L 1and L 2independently represent respectively covalent linkage ,-NH-,-N (CH 3)-,-O-,-S (O) m-,-N (CH 3) C (O)-,-C (O) N (CH 3)-,-N (CH 3) S (O) 2-or-S (O) 2n (CH 3)-;
A represents covalent linkage, is not substituted or by CH 3the imino-replacing;
Represent-CO-of b or-SO 2-;
C represents not to be substituted or by one or two methyl substituted vinylene or ethynylene;
D represents covalent linkage or methylene radical;
E represents hydrogen atom, methoxyl group, amino, piperidyl, morpholinyl, 6-9 unit spirane structure, 6-8 unit ring structure, 6-8 unit caged scaffold, methylamino or two-(methyl) amino;
R 1and R 3independently represent respectively hydrogen atom, halogen atom, nitro or-L 3-R 4,
L 3represent covalent linkage ,-NH-,-N (C 1-3alkyl)-,-O-,-O-C 1-3alkylidene group-,-S-C 1-3alkylidene group-,-S (O) m-,-C (O)-,-NHC (O)-,-C (O) NH-,-NHS (O) 2-,-S (O) 2nH-,-OC (O)-or-C (O) O-,
R 4represent hydrogen atom, C 1-4alkyl ,-N (C 1-3alkyl) 2,-NHC (O) O-(C 1-4alkyl) ,-OH ,-O (C 1-4alkyl) ,-S (O) 2(C 1-3alkyl), 5-6 unit cycloalkyl, phenyl or 5-6 unit heteroaryl;
Above-mentioned C 1-3moieties, cycloalkyl, heteroaryl, spirane structure ring structure, caged scaffold in alkyl can be further by 1-4 identical or different Q 2replace,
Q 2represent halogen atom, C 1-3alkyl, amino, C 1-3alkylamino, two-(C 1-3alkyl) amino, hydroxyl, C 1-3alkoxyl group, C 1-3carbalkoxy, formamyl, C 1-3alkyl-carbamoyl, two-(C 1-3alkyl) formamyl or 5-6 unit cycloalkyl, wherein Q 1can be identical or different;
On described cycloalkyl, two ring structures, carbon atom can be by 1-4 identical or different N, NH, N (C 1-3alkyl), O, S (O) m, C (O) replace;
Described heteroaryl, spirane structure ring structure, caged scaffold can contain 1-4 heteroatoms, and described heteroatoms is independently selected from respectively N, O or S;
Figure BDA0000436297380000051
represent singly-bound or two key;
M represents 0,1 or 2;
P and q independently represent respectively 0,1,2,3 or 4.
Compound shown in general formula (I), its deuterated thing, its pharmacy acceptable salt or its steric isomer, be preferably:
Wherein, X represents CH or N-Rb, and W represents C-Ra, C=O or N-Rb,
Ra represents hydrogen atom, halogen atom, and methyl, ethyl, methoxyl group, cyclopropyl, phenyl, benzyl, naphthyl, pyrryl, furyl or pyridyl,
Rb represents not exist, and hydrogen atom, by 1-2 identical or different Q 1replace or unsubstituted methyl, ethyl, cyclopropane base, pentamethylene base or THP trtrahydropyranyl,
Q 1represent C 1-3alkoxyl group or contain N or the heteroatomic 5-6 of O unit heterocyclic radical;
R 2represent hydrogen atom or amino;
Ring A and ring B independently represent respectively phenyl, contain the heteroatomic 5-6 unit's cycloalkyl of N or 5-6 unit heteroaryl;
L 1and L 2respectively expression-NH-independently ,-O-or-S (O) m-;
A represents covalent linkage or imino-;
Represent-CO-of b;
C represents vinylene;
D represents covalent linkage or methylene radical;
E represents hydrogen atom, piperidyl, morpholinyl or two-(methyl) amino;
R 1represent hydrogen atom, halogen atom, the methyl, the methoxyl group that are not substituted or are replaced by 1-4 identical or different halogen atom, methylamino or two-(methyl) amino;
R 3represent hydrogen atom, halogen atom or-L 3-R 4,
L 3represent covalent linkage ,-NH-,-N (C 1-3alkyl)-,-O-,-O-C 1-3alkylidene group-,-S-C 1-3alkylidene group ,-S (O) m-,-C (O)-,-NHC (O)-,-C (O) NH-,-OC (O)-or-C (O) O-,
R 4represent hydrogen atom, methyl, ethyl ,-N (C 1-3alkyl) 2,-NHC (O) O-C 3h 7,-O (CH 3) ,-O (CH 2cH 3) ,-O (C (CH 3) 3) ,-S (O) 2-C 3h 7, pentamethylene base, cyclohexyl, pyrrolidyl, tetrahydrofuran base, piperidyl, morpholinyl, piperazinyl, phenyl, pyrryl, imidazolyl, thiazolyl ， oxazolyl, thiadiazolyl group, pyridyl or pyrimidyl;
Described pentamethylene base, cyclohexyl, phenyl, pyrryl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl group, pyridyl, pyrimidyl can be further by 1-2 identical or different Q 2replace,
Q 2represent halogen atom, methyl, amino, methylamino, dimethylamino, hydroxyl, methoxyl group, methoxycarbonyl, formamyl, methylamino formyl radical or two-(methyl) formamyl;
Figure BDA0000436297380000061
represent singly-bound or two key;
M represents 0,1 or 2;
P and q independently represent respectively 0,1 or 2.
Compound shown in general formula (I), its deuterated thing, its pharmacy acceptable salt or its steric isomer, more preferably:
Wherein, X represents CH or N-Rb, and W represents C-Ra, C=O or N-Rb,
Ra represents hydrogen atom, halogen atom, and methyl, ethyl, methoxyl group or cyclopropyl,
Rb represents not exist, hydrogen atom, and cyclopropane base, THP trtrahydropyranyl, by 1 Q 1replace or unsubstituted methyl or ethyl,
Q 1represent methoxyl group or pyrrolidyl;
R 2represent hydrogen atom;
Ring A and ring B independently represent respectively phenyl, pyridyl or piperidyl;
L 1represent covalent linkage;
L 2expression-NH-or-O-;
A represents covalent linkage or imino-;
Represent-CO-of b;
C represents vinylene;
D represents covalent linkage or methylene radical;
E represents hydrogen atom, piperidyl or two-(methyl) amino;
R 1represent hydrogen atom, fluorine atom, chlorine atom, trifluoromethyl, methoxyl group or trifluoromethoxy;
R 3represent hydrogen atom, fluorine atom, chlorine atom or-L 3-R 4,
L 3represent covalent linkage ,-NH-,-N (CH 3)-,-O-,-O-CH 2cH 2-or-S (O) m-,
R 4represent hydrogen atom, methyl, ethyl, dimethylamino ,-NHC (O) O-C 3h 7,-O (CH 3) ,-O (C (CH 3) 3) ,-S (O) 2-C 3h 7, morpholinyl, phenyl, pyrryl, imidazolyl, thiazolyl ， oxazolyl, thiadiazolyl group or pyridyl,
Described phenyl, pyrryl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl group, pyridyl can be further by 1-2 identical or different Q 2replace,
Q 2represent formamyl, methylamino formyl radical or two-(methyl) formamyl;
represent singly-bound or two key;
M represents 0,1 or 2;
P and q independently represent respectively 0 or 1.
Compound shown in general formula (I), its deuterated thing, its pharmacy acceptable salt or its steric isomer, more preferably:
Wherein, X represents CH or N-Rb, and W represents C-Ra, C=O or N-Rb,
Ra represents hydrogen atom or cyclopropyl,
Rb represents not exist, hydrogen atom, methyl, cyclopropane base, THP trtrahydropyranyl, CH 3oCH 2cH 2-or
Figure BDA0000436297380000072
R 2represent hydrogen atom;
Ring A represents phenyl;
Ring B represents phenyl or pyridyl;
L 1represent covalent linkage;
L 2expression-NH;
A represents imino-;
Represent-CO-of b;
C represents vinylene;
D represents covalent linkage;
E represents hydrogen atom;
R 1represent hydrogen atom;
R 3expression-L 3-R 4, L 3represent covalent linkage ,-O-or-O-CH 2cH 2-, R 4expression-O (CH 3), dimethylamino, morpholinyl or pyridyl,
Described pyridyl can be further by 1-2 identical or different Q 2replace Q 2represent formamyl, methylamino formyl radical or two-(methyl) formamyl;
Figure BDA0000436297380000081
represent singly-bound or two key;
P represents 0;
Q represents 1.
Detailed Description Of The Invention
" C of the present invention 1-6alkyl " refer to the alkyl of the straight or branched that contains 1-6 carbon atom, comprising " C 1-4alkyl ", " C 1-3alkyl " etc., the example includes but not limited to for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, 2-methyl-propyl, 1-methyl-propyl, 1,1-dimethyl ethyl etc.Term " C 1-4alkyl ", " C 1-3alkyl " refer to the specific examples that contains 1 to 4,1 to 3 carbon atom in above-mentioned example.
" C of the present invention 0-6alkylidene group " refer to covalent linkage (C 0alkylidene group) or contain 1-6 carbon atom (C 1-6alkylidene group) the alkyl of straight or branched remove a structure after hydrogen atom, comprising " C 0-4alkylidene group ", " C 0-3alkylidene group ", " C 1-4alkylidene group ", " C 1-3alkylidene group " etc., the example includes but not limited to for example methylene radical (CH 2-), ethylidene (CH 2cH 2-), propylidene (CH 2cH 2cH 2-), butylidene (CH 2cH 2cH 2cH 2-) etc.Term " C 1-4alkylidene group ", " C 1-3alkylidene group " refer to the specific examples that contains 1 to 4,1 to 3 carbon atom in above-mentioned example.
" C of the present invention 2-4thiazolinyl " refer to the straight or branched thiazolinyl that the carbonatoms that contains two keys is 2-4; The example includes but not limited to for example vinyl, 1-propenyl, 2-propenyl, 1-methyl ethylene, 1-butylene base, crotyl, 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl.
" C of the present invention 2-4alkynyl " refer to the alkynyl of the straight or branched that the carbonatoms that contains three key is 2-4; The example includes but not limited to such as ethynyl, 2-propynyl, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl etc.
" C of the present invention 1-4alkoxyl group ", " C 1-4alkylamino ", " two (C 1-4alkyl) amino ", " C 1-4alkoxy carbonyl ", " C 1-4alkyl sulfenyl ", " C 1-4alkyl sulphonyl ", " C 1-4alkyl sulphinyl ", " C 1-4alkyl amino sulfonyl ", " C 1-4alkylamino sulfinyl ", refer to respectively " C 1-4alkyl-O-" group, " C 1-4alkyl-NH-" group, " (C 1-4alkyl) 2n-" group, " C 1-4alkyl-O-C (O)-" group, " C 1-4alkyl-S-" group, " C 1-4alkyl-SO 2-" group, " C 1-4alkyl-SO-" group, " C 1-4alkyl-SO 2-NH-", " C 1-4alkyl-SO-NH-" group, wherein " C 1-4alkyl " as defined above.
" C of the present invention 1-6alkoxyl group " refer to term " C 1-6alkyl " group that is connected with other structures by Sauerstoffatom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.Preferably C 1-4alkoxyl group, more preferably C 1-3alkoxyl group.Term " C 1-4alkoxyl group ", " C 1-3alkoxyl group " refer to term " C 1-4alkyl ", " C 1-3alkyl " group that is connected with other structures by Sauerstoffatom.
" C of the present invention 1-6alkylamidoalkyl " refer to " C 1-6alkyl " group that is connected with other structures by amide group.
" halogen " of the present invention refers to fluorine atom, chlorine atom, bromine atoms or iodine atom etc.
" C of the present invention 1-4alkoxy C 0-4alkylidene group, C 3-6cycloalkyl C 0-4alkylidene group, phenyl C 0-4alkylidene group, naphthyl C 0-4alkylidene group, the heteroaryl C of 5-10 unit 0-4alkylidene group " refer to C 1-4alkoxyl group, C 3-6cycloalkyl, phenyl, naphthyl, 5-10 unit heteroaryl pass through C 0-4the group that alkylidene group is connected with other structures, wherein " C 0-4alkylidene group " as defined above.
" 3-8 unit cycloalkyl " of the present invention refers to that annular atoms is all carbon atom, remove a cyclic alkyl group that hydrogen atom is derivative, comprising for example " 3-8 unit cycloalkyl ", " 3-6 unit cycloalkyl ", " 4-6 unit cycloalkyl ", " 5-7 unit cycloalkyl ", " 5-6 unit cycloalkyl ", the example includes but not limited to: cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, suberane base, cyclooctane base etc.
" 3-8 unit Heterocyclylalkyl " of the present invention refers to and contains the first cyclic group of one or more heteroatomic 3-8, and described " heteroatoms " refers to nitrogen-atoms, Sauerstoffatom, sulphur atom etc.Preferably 3-7 unit Heterocyclylalkyl, 3-6 unit heterocyclic radical, more preferably 5-7 unit heterocyclic radical, 5-6 unit heterocyclic radical.Specific examples includes but are not limited to 2,5-dihydro-thiophene base, 4,5-pyrazoline base, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-4H-1,3-oxazinyl, ethylenimine base, azetidinyl, Thietane base, tetrahydrofuran base, Pyrrolidine base, imidazolidyl, pyrazolidyl, tetrahydrofuran base, Isosorbide-5-Nitrae-dioxane base, 1,3-dioxane base, 1,3-dithian base, morpholinyl, piperazinyl etc.
" 4-7 unit heteroaryl " refers to and contains the aromaticity group that 4-7 annular atoms (wherein at least containing a heteroatoms) forms, comprise " 5-7 unit heteroaryl " " 5-6 unit heteroaryl ", its specific examples includes but not limited to for example furans, pyrroles, thiophene, imidazoles, oxazole, isoxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine etc.
" 6-12 unit two ring structures " refer to and contain the bicyclic groups (can not contain or contain and more than one heteroatoms) that 6-12 annular atoms forms, comprise " 7-10 unit two ring structures ", " 8-10 unit two ring structures ", " 6-9 unit spirane structure ", " 6-8 unit ring structure ", " 6-8 unit caged scaffold " etc.Its specific examples includes but not limited to two rings [3.1.0] hexyl, two ring [4.1.0] heptane bases, two ring [2.2.0] hexyls, two ring [3.2.0] heptane bases, two ring [4.2.0] octyls, octahydro pentalene base, octahydro-1H-indenyl, naphthane base, ten tetrahydrochysene phenanthryl, dicyclo [3.1.0] oneself-2-thiazolinyl, dicyclo [4.1.0] heptan-3-thiazolinyl, dicyclo [3.2.0] heptan-3-thiazolinyl, dicyclo [4.2.0] is pungent-3-thiazolinyl, 1, 2, 3, 3a-tetrahydrochysene pentalene base, 2, 3, 3a, 4, 7, 7a-six hydrogen-1H-indenyl, 1, 2, 3, 4, 4a, 5, 6, 8a-octalin base, 1, 2, 4a, 5, 6, 8a-hexahydro-naphthyl, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10-decahydro phenanthryl, tetramethylene Pyrrolidine base, pentamethylene Pyrrolidine base, azetidine imidazolidyl, 3-oxabicyclo is [3.1.0] hexyl also, hexahydro furyl [3, 4-b] [1, 4] dioxin bases, also [b] [1 of six hydrogen-2H-pentamethylene, 4] dioxin bases,
Figure BDA0000436297380000091
Figure BDA0000436297380000092
Figure BDA0000436297380000101
Figure BDA0000436297380000102
and two ring structures of aromaticity, include but not limited to benzofuryl, benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl-, indazolyl, benzotriazole base, quinolyl, isoquinolyl, acridyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridinyl, 1, 3-dihydro benzo furyl, benzo [d] [1.3] dioxa cyclopentenyl, isoindoline base, chromanyl, 1, 2, 3, 4-Pyrrolidine also [3, 4-c] pyrryl, 5, 6-glyoxalidine [1.2-a] pyrazine-7 (8H)-Ji, 5, 6-dihydro-1, 7-naphthyridines-7 (8H)-Ji, 5H-pyrroles [3.4-b] pyridine-6 (7H)-Ji, 7, 8-dihydropyridine [4.3-d] pyrimidine-6 (5H)-Ji, 2, 3, 6, 7-tetrahydrochysene-1H-pyrazoles [4.3-c] pyridine-5 (4H)-Ji, 6, 7-thiazoline [5.4-c] pyridine-5 (4H)-Ji etc.
Term " 7-10 unit two ring structures ", " 8-10 unit two ring structures " refer to the specific examples that contains 7 to 10,8 to 10 carbon atoms in above-mentioned example.
" 6-9 unit volution base " of the present invention refers to that a class has at least two rings to share the 6-9 unit condensed ring structure that an atom forms.Its specific embodiment includes but are not limited to: spiroheptane 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] ninth of the ten Heavenly Stems-6-thiazolinyl, spiral shell [4.4] ninth of the ten Heavenly Stems-6-thiazolinyl, spiral shell [4.4] ninth of the ten Heavenly Stems-2,7-dialkylene, 2-oxa-spiroheptane base, 6-oxaspiro [2.5] octyl, 4-oxa--7-amido spiral shell [2.5] octyl, 2-amido spiroheptane base, 2-oxa--6-amido spiroheptane base, 2-amido spiral shell [3.4] octyl, 6-oxa--2-amido spiral shell [3.4] octyl, 2-oxa--6-amido spiral shell [3.4] octyl, 2-oxaspiro [3.4] octyl, 5-oxaspiro [3.5] nonyl, 7-amido spiral shell [3.5] nonyl, 2-amido spiral shell [4.4] nonyl, 2-oxa--7-amido spiral shell [4.4] nonyl, 2-oxaspiro [4.4] nonyl, 1,7-dioxo spiro [4.4] nonyl, Isosorbide-5-Nitrae, 7-trioxa spiral shell [4.4] nonyl, 6-amido spiral shell [3.4] is pungent-7-thiazolinyl, 2-oxa--6-amido spiral shell [3.4] is pungent-7-thiazolinyl, 7-amido spiral shell [3.5] ninth of the ten Heavenly Stems-5-thiazolinyl, 2-amido spiral shell [4.4] ninth of the ten Heavenly Stems-7-thiazolinyl etc.
" 6-8 unit ring structure " of the present invention refers to by two or more ring texturees and shares each other the 6-8 unit cyclic group that two adjacent atoms form, and its specific embodiment includes but are not limited to: two ring [3.1.0] hexyls, two ring [4.1.0] heptane bases, two ring [2.2.0] hexyls, two ring [3.2.0] heptane bases, two ring [4.2.0] octyls, dicyclo [3.1.0] oneself-2-thiazolinyl, dicyclo [4.1.0] heptan-3-thiazolinyl, dicyclo [3.2.0] heptan-3-thiazolinyl, dicyclo [4.2.0] is pungent-3-thiazolinyl, benzofuryl, benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl-, indazolyl, benzotriazole base, quinolyl, isoquinolyl, acridyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, thieno-[2,3-b] thienyl, thieno-[3,2-b] thienyl, benzo [b] thienyl, benzo [b] thiazolyl, tetramethylene Pyrrolidine base, pentamethylene Pyrrolidine base, azetidine imidazolidyl, 3-oxabicyclo is [3.1.0] hexyl also, hexahydro furyl [3,4-b] [Isosorbide-5-Nitrae] dioxin base, six hydrogen-2H-pentamethylene is [b] [Isosorbide-5-Nitrae] dioxin base etc. also.
" 6-8 unit caged scaffold " of the present invention refers to by two or more ring texturees and shares each other the 6-8 unit cyclic group that two non-conterminous atoms form, and its specific embodiment includes but are not limited to:
Figure BDA0000436297380000112
Figure BDA0000436297380000113
deng.
Particularly preferred compound comprises:
Figure BDA0000436297380000114
Figure BDA0000436297380000121
Above-claimed cpd of the present invention can adopt method and/or other technology known to persons of ordinary skill in the art of in following flow process, describing to synthesize, but is not limited only to following methods.
For simplicity, the present invention uses well-known abbreviation to represent number of chemical compound, includes but not limited to
DMF:N, dinethylformamide; THF: tetrahydrofuran (THF); DIEA:N, N-diisopropylethylamine; DMA: dimethylamine; M-CPBA: metachloroperbenzoic acid; LAH: Lithium Aluminium Hydride etc.
Reaction scheme 1:
Figure BDA0000436297380000122
Reactions steps:
Step 1: the preparation of intermediate 1
In dry reaction flask, add raw material 1(1 equivalent), add polar solvent (as DMF, DMA) to dissolve, add raw material 2(1 equivalent), alkali (as salt of wormwood) (2 equivalent), reacting by heating a few hours, is cooled to room temperature, reaction solution is poured in frozen water, filter, filter cake washs with frozen water, and vacuum-drying obtains intermediate 1.
Step 2: the preparation of intermediate 2
In dry reaction flask, add intermediate 1 (1 equivalent), add tetrahydrofuran (THF) to dissolve, at-78 DEG C, add Lithium Aluminium Hydride (3-5 equivalent) in batches, after dropwising, treat that temperature rises to room temperature, add saturated aqueous ammonium chloride solution, under room temperature, stir half an hour, filter, filtrate adds water, extraction, concentrated organic phase, column chromatography, obtains intermediate 2.
Step 3: the preparation of intermediate 3
In dry reaction flask, add intermediate 2(1 equivalent), methylene dichloride dissolves, and adds Manganse Dioxide (20-40 equivalent), and under room temperature, stirring reaction spends the night, and filters, and uses organic solvent washing filter cake, is spin-dried for organic phase, obtains intermediate 3, is directly used in next step reaction.
Step 4: the preparation of intermediate 4
In dry reaction bottle, intermediate 3(1 equivalent) with polar solvent (as methyl alcohol) dissolving, add raw material 3(1.5-3 equivalent), acetic acid (minimum 1.5 equivalents), stirring reaction a few hours under room temperature, add sodium borohydride (2-5 equivalent), stoichiometric number hour, cancellation, organic solvent extraction, concentrated organic phase, column chromatography, obtains intermediate 4.Also can tetrahydrofuran (THF) will be dissolved in after imines aftertreatment, with tetrahydrochysene lithium aluminium reducing.
Step 5: the preparation of intermediate 5
In dry reactor, add intermediate 4(1 equivalent), add appropriate solvent (as tetrahydrofuran (THF), methylene dichloride) to dissolve, add alkali (as DIEA) (3 equivalent), under ice-water bath, add raw material 4(0.5-1.5 equivalent), dropwise rear continuation reaction, then cancellation, with organic solvent extraction, column chromatography, obtains intermediate 5.
Step 6: the preparation of intermediate 6
In dry reaction flask, add intermediate 5(1 equivalent), add appropriate solvent (as methylene dichloride) to dissolve, under ice-water bath, add metachloroperbenzoic acid (1.5-3 equivalent), rise to room temperature and continue reaction, cancellation, with organic solvent extraction, concentrated that intermediate 6 is directly used in next step reaction.
Step 7: the preparation of intermediate 7
In dry reaction flask, add intermediate 6(1 equivalent), add appropriate solvent (as tertiary amyl alcohol) to dissolve, add raw material 5(1-1.5 equivalent), concentrated hydrochloric acid or trifluoracetic acid (0.5-1.5 equivalent), back flow reaction, be cooled to cancellation after room temperature, with organic solvent extraction, concentrated, column chromatography, obtains intermediate 7.
Step 8: the preparation of intermediate 8
Add appropriate solvent (as methylene dichloride) to dissolve in intermediate 7 (1 equivalent), add quantity of solvent trifluoroacetic acid, or pass into hydrogen chloride gas, room temperature or cooling lower stirring reaction to intermediate 7 disappear.Concentrated, obtain intermediate 8, be directly used in the next step.
Step 9: the preparation of formula I compound
Intermediate 8 (1 equivalent) is dissolved in to suitable solvent (as tetrahydrofuran (THF), methylene dichloride, acetone, DMF, or be mixed solvent), add the alkali (as DIEA) of 2-3 equivalent, cooling under (20 degree to-10 degree), slowly splash into raw material 4 (0.9-1.1 equivalent) stirring reaction to intermediate 8 and disappear.Cancellation reaction, concentrated, column chromatography or mesolow are prepared liquid phase purifying and are obtained formula I compound.
Reaction scheme 2:
Figure BDA0000436297380000141
Step 1: the preparation of intermediate 1
In dry reaction flask, add raw material 1(1 equivalent), add appropriate solvent (as methylene dichloride) to dissolve, add raw material 2(1.5 equivalent), Salicylaldoxime (2 equivalent), pyridine (2 equivalent), at room temperature reaction is spent the night, and filters, and after filtrate is concentrated, silica gel column chromatography obtains intermediate 1.
Step 2: the preparation of formula I compound
Intermediate 1 (1 equivalent) is dissolved in to suitable solvent (as tertiary amyl alcohol), adds raw material 3(1-1.5 equivalent), finally add several concentrated hydrochloric acids, reflux to intermediate 2 disappears.Cooling, concentrated, preparation liquid phase purifying obtains formula I compound.
X, W in reaction scheme, R 1, R 2, R 3, L 1, L 2, a, b, c, d, e, p, q, ring A and ring B as mentioned before.
Clinically, formula of the present invention (I) compound, its deuterated thing, its steric isomer can use with the form of dissociating or the form of its pharmacy acceptable salt.The aobvious alkalescence of formula of the present invention (I) compound, can form acid salt with mineral acid or organic acid.Example hydrochloric acid salt, hydrofluoride, hydrochloride, hydrobromate, hydriodate, vitriol, trifluoroacetate, benzene sulfonate, mesylate, fluoroform sulphonate, esilate, carbonate, nitrate, phosphoric acid salt, phosphite, maleate, tartrate, Citrate trianion, acetate, benzoate, esilate, fumarate, oxalate, gluconate, hydroxyl acetate, isethionic acid, lactic acid salt, Lactobionate, Lactobionate, malate, mesylate, succinate, tosilate, glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.
Formula of the present invention (I) compound compound or its pharmacy acceptable salt, owing to there being unsymmetrical carbon, can exist with a kind of optically active isomer form, and therefore, the present invention also comprises these optically active isomers and composition thereof.
Formula of the present invention (I) compound compound, its deuterated thing, its pharmacy acceptable salt or its steric isomer can form pharmaceutical composition with one or more pharmaceutical carriers.Described pharmaceutical composition can be made clinically the conventional formulation using, can be oral or the mode such as administered parenterally be applied to the patient who needs this treatment.As tablet, particle, capsule, powder, injection, inhalation, sublingual administration preparation, syrup, gel, ointment, suppository, lotion, nasal cavity drop, sprays, preparation capable of permeating skin etc.These preparations can pass through ordinary method, add pharmaceutical carrier and are prepared from as vehicle, tamanori, moistening agent, disintegrating agent, thickening material etc.
Formula of the present invention (I) compound compound, its deuterated thing, its pharmacy acceptable salt or its steric isomer have good BTK kinase inhibitory activity, are the medicines better with good antitumor action and treating autoimmune diseases effect.Formula of the present invention (I) compound compound, its its pharmacy acceptable salt of deuterated thing or its steric isomer are treated the relevant leukemia (for example B cell chronic lymphocytic cancer, non-Hodgkin lymphoma) of B cell in preparation simultaneously, and such as, play an important role in autoimmune disorder (rheumatoid arthritis, systemic lupus erythematous etc.).
Formula of the present invention (I) compound compound, its deuterated thing, its pharmacy acceptable salt or its steric isomer are a kind of kinase inhibitor, particularly Btk inhibitor.These inhibitor can be used for the treatment of the disease of one or more response kinase inhibition in Mammals, comprise that response Btk suppresses and/or the disease of the inhibition of B cell proliferation.Do not wish to be bound by any specific theory, believe that the interaction of the compounds of this invention and Btk causes the inhibition of Btk activity, and therefore obtain these compound pharmaceutical application.Therefore, the present invention includes and be used for the treatment of the inhibition with response Btk activity and/or the Mammals that suppresses the disease of B cell proliferation, for example people's method, the method comprises: at least one chemical entities providing in this article of Mammals effective dosage with such disease.Can for example pass through to measure experimentally the haemoconcentration of compound, or in theory by calculating bioavailability, determine effective concentration.Except Btk, also may include but not limited to by affected other kinases other Tyrosylprotein kinase and serine/threonine kinase.
Kinases plays significant effect in control elementary cell process aspect the signal conducting path of propagation, differentiation and dead (apoptosis).Abnormal kinase activity has implied that, in various diseases, described disease comprises kinds cancer, autoimmunization and/or inflammatory diseases and acute inflammatory response.The versatility effect of kinases in key cells signal conducting path provides the remarkable chance of the novel drugs of identification target kinases and signal conducting path.
An embodiment comprises that treatment has the patient's of the acute inflammatory response of the inhibition of autoimmunization and/or inflammatory diseases or response Btk activity and/or B cell proliferation method.
Use autoimmunization and/or the inflammatory diseases that can affect according to compound of the present invention and composition to include but not limited to: psoriatic, transformation reactions, regional enteritis, irritable bowel syndrome, sjogren disease, the hyperacute rejection of tissue grafts rejection and transplant organ, asthma, systemic lupus erythematous (with relevant glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-relevant with other vasculitis), autoimmunization hemolytic and thrombocytopenic symptom, Gourde(G) Paasche syndrome (with relevant glomerulonephritis and pulmonary apoplexy), atherosclerosis, rheumatoid arthritis, chronic idiopathic thrombocytopenic purpura (ITP), Addison disease, Parkinson's disease, alzheimer's disease, diabetes, septic shock and myasthenia gravis.
What comprise herein is methods for the treatment of, wherein by least one chemical entities providing herein and antiphlogiston combination medicine-feeding.Antiphlogiston includes but not limited to: NSAID, non-specific and COX-2 specificity cyclooxygenase enzyme inhibitors, gold compound, cortical steroid, methotrexate, Tumor Necrosis Factor Receptors (TNF) receptor antagonist, immunosuppressor and methotrexate.
The example of NSAID includes but not limited to, Ibuprofen BP/EP, flurbiprofen, Naproxen Base and naproxen sodium, diclofenac, the combination of diclofenac sodium and Misoprostol, sulindac, benzene daybreak propionic acid, diflunisal, piroxicam, indomethacin, R-ETODOLAC, fenoprofen calcium, Ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium and Oxychloroquine.The example of NSAID also comprises that COX-2 specific inhibitor is as celecoxib, valdecoxib, Lu meter Kao former times and/or L-791456.
In some embodiments, antiphlogiston is salicylate or salt.Salicylate or salt include but not limited to acetylsalicylic acid or Asprin, sodium salicylate and choline salicylate and magnesium salicylate.
Antiphlogiston can also be cortical steroid.For example, cortical steroid can be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone phosphate disodium, or prednisone.
In other embodiments, antiphlogiston is that gold compound is as Sodium Aurothiomalate or auranofin.
The present invention also comprises that wherein antiphlogiston is metabolic poison if dihydrofolate reductase inhibitor is if methotrexate or dihydroorotate salt dehydrogenase inhibitor are as the embodiment of leflunomide.
It is anti-monoclonal antibody (as according to storehouse pearl monoclonal antibody or training gram pearl monoclonal antibody) that other embodiment of the present invention relates to wherein at least one anti-inflammatory compound, TNF antagonist is as the combination of etanercept (entanercept) or infliximab, and described infliximab is a kind of anti-TNF alpha monoclonal antibody.
Other embodiment of the present invention relate to wherein at least one active drug be immunosuppressant compounds as being selected from methotrexate, leflunomide, cyclosporin A, tacrolimus, the combination of the immunosuppressant compounds in azathioprine and mycophenolate mofetile.
B cell and the B cell precursor of expressing Btk have implied in the pathology of B Xi Bao Evil, B Xi Bao Evil includes but not limited to B cell lymphoma, lymphoma (comprising Huo Qijin and non-Hodgkin lymphoma), hair cell lymphoma, multiple myeloma, chronic and acute myelocyte derived leukocythemia and chronic and acute Lymphocytic leukemia.
Show that Btk is is the inhibitor of the dead inducement signal conduction mixture of Fas/APO-1 in lymphoidocyte (CD-95) (DISC) at B-.The destiny of leukemia/lymphoma cell may be the reverse proapoptosis effect of the caspase being activated by DISC and comprise Btk and/or the upstream anti-apoptotic regulation mechanism of its substrate between balance (Vassilev etc., J.Biol.Chem.1998,274,1646-1656).
Also find that Btk inhibitor can be used as chemical sensitizer, therefore can be for combining with other chemotherapeutic drug, described chemotherapeutic drug is the medicine of cell death inducing particularly, as antineoplastic agent, immunosuppressor etc.The example of other chemotherapeutic drug that can be used in combination with chemical sensitization inhibitor includes but are not limited to topoisomerase I inhibitor (camptothecine or Hycamtin), Topoisomerase II inhibitors (as daunomycin and Etoposide), alkylating agent is (as endoxan, melphalan and BCNU), (for example antibody is as anti-CD20 antibodies for the medicament (as PTX and vinealeucoblastine(VLB)) of tubulin guiding and biotechnological formulation, IDEC8, immunotoxin and cytokine).
The leukemia of the bcr-abl fusion gene that Btk activity has been caused by the transposition of chromosome dyad 9 and 22 to some expression is relevant.Thisly extremely conventionally in chronic myelocytic derived leukocythemia, observe.Btk is in essence by bcr-abl tyrosine phosphorylation, and this initiation prevents apoptotic downstream survival signaling (N.Feldhahn etc., J.Exp.Med.2005,201 (11), 1837-1852) in bcr-abl cell.
The compounds of this invention, compared with immediate prior art, has the following advantages:
(1) formula of the present invention (I) compound, its deuterated thing, its pharmacy acceptable salt have good BTK kinase inhibitory activity;
(2) formula of the present invention (I) compound, its deuterated thing, its pharmacy acceptable salt demonstrate good biologically stable, and toxic side effect is little, and security window is large;
(3) the compounds of this invention preparation technology is simple, and steady quality is easy to carry out large-scale commercial production.
Further set forth the compounds of this invention beneficial effect by pharmacological evaluation below, but this should 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
in Vitro Anti bruton's tyrosine kinase (BTK) determination of activity 1 of I the compounds of this invention
Trial-product:
The compounds of this invention: self-control, its chemical name and structural formula and preparation method are shown in the Preparation Example of each compound.
Experimental technique:
The implication of representative of abridging in following experiment is as follows:
ATP: Triphosaden; BTK: bruton's tyrosine kinase; Mg: milligram; ML: milliliter; μ g: microgram;
μ l: microlitre; MM: every liter of mmole; EDTA: ethylenediamine tetraacetic acid (EDTA); DMSO: dimethyl sulfoxide (DMSO);
SD: standard deviation.
1. test materials
BTK: purchased from Carna, Cat.No.08-080; ATP: purchased from Sigma, Cat.No.A7699-1G, CAS No.987-65-5; DMSO: purchased from Sigma, Cat.No.D2650, Lot.No.474382; EDTA: purchased from Sigma, Cat.No.E5134, CAS No.60-00-4; 96 orifice plates: purchased from Corning, Cat.No.3365, Lot.No.22008026; 384 orifice plates: purchased from Corning, Cat.No.3573, Lot.No.12608008.
2. test is prepared with reagent
①1x?Kinase?base?buffer（50mM?HEPES,pH7.5，0.0015%Brij-35，10mM?MgCl2，2mM?DTT）；
2. stop buffer (100mM HEPES, pH7.5,0.015%Brij-35,0.2%Coating Reagent#3,50mM EDTA);
3. 50 times of compound solutions (adopting 100%DMSO using the solution of 50 times of compound dissolution test preparation setting maximum concentrations as storing solution).
3. enzyme reaction
1. the compound solution of 50 times is carried out to a series of 3 times of dilutions with 100%DMSO, totally 10 concentration gradients, then with 1x kinase buffer using 10 times of the solution dilutions of each concentration as test compound concentration, 5 μ L/ holes.
2. prepare 2.5 × enzyme solution: enzyme is added to 1 × kinase base buffer;
3. prepare 2.5x peptide solution: FAM-labeled peptide and ATP are added in 1 × kinase base buffer;
4. add 10 μ L2.5 × enzyme solution to containing in 384 orifice plates of 5 μ L compound solutions;
5. hatch at ambient temperature 30min;
6. in every hole, add 10 μ L2.5 × peptide solution
4. reaction terminating
Hatch after appropriate time for 28 DEG C, in every hole, add 25 μ L stop buffers to carry out termination reaction.
5. data read
After stop buffer termination reaction, Caliper reading of data.
6. fitting of a curve draws IC 50
Calculate inhibiting rate (%)=(maximum turnover ratio-compound turnover ratio)/(maximum turnover ratio-minimum transition rate) × 100
Adopt GraphPad5.0 software to carry out curve fitting, fit equation is Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X) * HillSlope)), draws IC 50value.
Experimental result:
In Vitro Anti bruton's tyrosine kinase (BTK) activity of table 1 the compounds of this invention
Experiment conclusion:
From table, the compounds of this invention 1 has stronger inhibition activity to BTK kinases.
in Vitro Anti bruton's tyrosine kinase (BTK) determination of activity 2 of II the compounds of this invention
Trial-product:
Contrast medicine: KHP-1315, Shandong Henry Pharmaceutical Technology Co., Ltd.'s self-control;
The compounds of this invention: self-control, its chemical name and structural formula and preparation method are shown in the Preparation Example of each compound.
Experimental technique:
1. test materials
HTRFR KinEASE tM– 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; MgCl 2: purchased from Sigma, CAS No.7786-30-3, Lot.No.101M8701V; 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, Lot.No.E1112 Φ 6Y.
2. test is prepared with reagent
①1×Kinase?buffer（5mM?MgCl 2,1mM?DTT,50nM?SEB）；
2. that DTT stoste is diluted to 100mM with sterilized water for injection is for subsequent use as storing solution for DTT;
3. ATP is for subsequent use with the storing solution of sterilized water for injection preparation 5mM;
4. 10mM compound solution: the compound storing solution that adopts 100%DMSO that compound dissolution is mixed with to 10mM is for subsequent use.
3. the enzyme reaction stage
1. by 20 times of 100%DMSO dilutions for the compound solution of 10mM, after 2 times of redilution, carry out a series of 3 times of dilutions, totally 10 concentration gradients, then with 1x kinase buffer using 100 times of the solution dilutions of each concentration as test compound concentration, 4 μ L/ holes.
2. prepare 5 × Enzyme solution: enzyme is added to 1 × kinase buffer, 2 μ L/ holes.
3. under 25 DEG C of conditions, hatch 30min.
4. prepare 5 × TK Substrate-biotin: TK Substrate-biotin is added in 1 × kinase buffer to 2 μ L/ holes;
5. prepare 5 × ATP: ATP is added in 1 × kinase base buffer to 2 μ L/ holes;
6. under 25 DEG C of conditions, hatch 40min;
4. the detection reaction stage
1. prepare 4 × Streptavidin-XL665: Streptavidin-XL665 is added
Figure BDA0000436297380000191
in Detection buffer, 5 μ L/ holes.
2. every hole adds 5 μ L TK Antibody-Cryptate again.
3. under 25 DEG C of conditions, hatch 60min.
5. data read
After the detection reaction stage completes, detect respectively the fluorescent value of sample at 615nm and 665nm place by microplate reader.
6. fitting of a curve draws IC 50
Adopt GraphPad5.0 software to carry out curve fitting, fit equation is Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X) * HillSlope)), draws IC 50value.
Experimental result:
In Vitro Anti bruton's tyrosine kinase (BTK) activity of table 2 the compounds of this invention
Experiment conclusion:
From table 2, the compounds of this invention has stronger inhibition activity to BTK kinases.
4, embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following examples.All technology realizing based on foregoing of the present invention all belong to scope of the present invention.
((8-(3-acrylamido phenyl)-6-methyl-7-oxo-5,6,7,8-tetrahydropyrimidine is [4,5-d] pyrimidine-2-base also for 4-for embodiment 14- amino) phenoxy group) preparation of-N-picoline-2-methane amide (compound 1)
Figure BDA0000436297380000211
(1) 5-(methylamino) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone
Figure BDA0000436297380000212
5-bromouracil (10g, 52.4mmol) is joined in 27% methylamine alcohol solution of 50mL, finish back flow reaction 16h.System is cooling, and suction filtration obtains faint yellow solid 4.7g, yield 63.5%.
The preparation of the chloro-N-methylpyrimidine-5-of (2) 2,4-bis-amine
By 5-(methylamino) pyrimidine-2,4 (1H, 3H)-diketone (4.7g, 33.3mmol) is added to 50mL POCl 3in, the DMA of dropping 2mL, finishes 110 DEG C of reaction 24h.Cooling, concentrating under reduced pressure system, adds 20mL toluene to be again spin-dried for system, obtains oily matter and pours in frozen water, uses Na 2cO 3be neutralized to neutrality, ethyl acetate extraction, dry, concentrated organic phase obtains product 1.5g, yield 25.3%.
(3) preparation of 3-(the chloro-5-of 2-(methylamino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000214
Chloro-2,4-bis-N-methylpyrimidine-5-amine (1.5g, 8.43mmol) is added in the propyl carbinol of 10mL, then adds 3-aminophenyl t-butyl carbamate (1.756g, 8.43mmol), then add Et 3n (1.7g, 16.8mmol) finishes, 110 DEG C of reaction 16h.Cooling, concentrated, column chromatography (PE:EA=10:1-1:2) obtains product 800mg, yield 27.2%.
(4) preparation of 3-(5-(methylamino)-2-(4-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) anilino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000221
By 3-(the chloro-5-of 2-(methylamino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester (800mg, 2.29mmol) be dissolved in 4mL ethanol, add again 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (556mg, 2.29mmol), finish 100 DEG C of reaction 3h of microwave.Cooling, concentrated, column chromatography (DCM:MeOH=100:1-4:1) obtains product 350mg, yield 27.5%.
(5) preparation of 3-(7-methyl-2-(4-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) anilino)-8-oxo-7H-purine-9 (8H)-yl) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000222
By 3-(5-(methylamino)-2-(4-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) anilino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester (350mg; 0.629mmol) be dissolved in 4mL THF; add again DIEA(325mg; 2.52mmol); under ice bath, add again triphosgene (63mg; 0.212mmol), finish 0 DEG C of reaction 3h.In system, add the NaHCO that 10mL is saturated 3the aqueous solution, DCM extraction, concentrated, column chromatography (DCM:MeOH=100:1-4:1) obtains product 250mg, yield 68.2%.
(6) preparation of 4-(4-(9-(3-aminophenyl)-7-methyl-8-oxo-8,9-dihydro-7H-purine-2-base amino) phenoxy group)-N-picoline-2-methane amide
Figure BDA0000436297380000223
By 3-(7-methyl-2-(4-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) anilino)-8-oxo-7H-purine-9 (8H)-yl) the phenylcarbamic acid tert-butyl ester (250mg; 0.429mmol) be dissolved in the DCM of 7mL; logical HCl gas reaction 1h under ice bath; concentrate system, obtains product crude product 250mg.
(7) preparation of 4-(4-(9-(3-acrylamido)-7-methyl-8-oxo-8,9-dihydro-7H-purine-2-base amino) phenoxy group)-N-picoline-2-methane amide
Figure BDA0000436297380000231
By 4-(4-(9-(3-aminophenyl)-7-methyl-8-oxo-8,9-dihydro-7H-purine-2-base amino) phenoxy group)-N-picoline-2-methane amide crude product 250mg is dissolved in 3mL THF, add again 0.3mL DMF hydrotropy, at-15 DEG C, drip the THF solution 0.5mL containing 39mg (0.431mmol) acrylate chloride, finish at this temperature and react 2h.Drip 5 methyl alcohol cancellation, concentrate system, preparation liquid phase purifying (methyl alcohol: water=60% goes out main peak) obtains product 60mg, two step yields 26.1%.
Molecular formula: C 28h 24n 8o 4molecular weight: 536.19 mass spectrums (m/e): 536.5
1H-NMR(d 6-DMSO,400MHz,δppm)：10.38(1H,s),9.58(1H,s),8.75(1H,q),8.55(1H,s),8.47(1H,d),8.28(1H,s),8.04-7.98(1H,m),7.85(2H,d),7.70(1H,d),7.51(1H,t),7.37-7.31(2H,m),7.10(1H,dd),7.05(2H,d),6.42(1H,dd),6.22(1H,dd),5.71(1H,dd),3.40(3H,s),2.77(3H,d).
embodiment 24-(4-(7-(3-acrylamido phenyl)-7H-pyrrolo-[2,3-d] pyrimidine-2--amino) phenoxy group)-N-methyl the preparation of pyridine-2-carboxamide (compound 2)
Figure BDA0000436297380000232
(1) preparation of the chloro-7-of 2-(3-nitrophenyl)-7H-pyrrolo-[2,3-d] pyrimidine
Figure BDA0000436297380000233
Chloro-2-7H-pyrrolo-[2,3-d] pyrimidine (1.54g, 10.0mmol) and 3-nitrophenyl boric acid (2.51g, 15.0mmol) are dissolved in dry methylene dichloride (60mL).Add wherein Salicylaldoxime (3.64g, 20.0mmol) and pyridine (1.58g, 20.0mmol), reaction is at room temperature reacted 24 hours, filter, repeatedly use washed with dichloromethane solid, silica gel column chromatography (sherwood oil: ethyl acetate=5:1) after filtrate is concentrated, obtain white solid 1.42g, yield 51.7%.
(2) preparation of 3-(the chloro-7H-pyrrolo-of 2-[2,3-d] pyrimidin-7-yl) aniline
Figure BDA0000436297380000234
By chloro-2-7-(3-nitrophenyl)-7H-pyrrolo-[2,3-d] pyrimidine (1.42g, 5.17mmol) is dissolved in the mixing solutions of tetrahydrofuran (THF) and methyl alcohol (40mL, v/v=1:1), add wherein ammonium chloride (2.76g, 51.6mmol) and zinc powder (3.38g, 51.7mmol), reaction is at room temperature stirred 18 hours, suction filtration, filtrate is concentrated, obtains white solid 1.26g, is directly used in next step.
(3) preparation of N-(3-(the chloro-7H-pyrrolo-of 2-[2,3-d] pyrimidin-7-yl) phenyl) acrylamide
Figure BDA0000436297380000241
By 3-(the chloro-7H-pyrrolo-of 2-[2,3-d] pyrimidin-7-yl) aniline (1.26g, 5.15mmol) and N, N-diisopropylethylamine (1.34g, 10.4mmol) be dissolved in tetrahydrofuran (THF) (30mL), slowly drip wherein acrylate chloride (461mg, 5.10mmol) at-20 DEG C, stir 2 hours, add anhydrous methanol cancellation, concentrated, silica gel column chromatography (sherwood oil: ethyl acetate=2:1), obtain white solid 807mg, yield 52.4%.
(4) preparation of 4-(4-(7-(3-acrylamido phenyl)-7H-pyrrolo-[2,3-d] pyrimidine-2--amino) phenoxy group)-N-picoline-2-methane amide
Figure BDA0000436297380000242
By N-(3-(the chloro-7H-pyrrolo-[2 of 2-, 3-d] pyrimidin-7-yl) phenyl) acrylamide (448mg, 1.50mmol) and 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (401mg, 1.65mmol), then add 40mL tertiary amyl alcohol to be dissolved, finally add 1 concentrated hydrochloric acid, in the oil bath of 100 DEG C, return stirring spends the night.Cooling, concentrated, high pressure is prepared liquid phase purifying, obtains white solid 96mg, yield 12.7%.
Molecular formula: C 28h 23n 7o 3molecular weight: 505.19 mass spectrums (m/e): 506.2
1H-NMR(d 6-DMSO,400MHz,δppm)：10.41(1H,s),9.73(1H,s),8.90-8.70(2H,m),8.48(1H,s),8.31(1H,s),7.95(2H,d),7.65-7.43(4H,m),7.39(1H,m),7.18-6.97(3H,m),6.71(1H,m),6.47-6.30(1H,m),6.25-6.10(1H,m),5.65-5.54(1H,m),2.78(3H,m).
embodiment 3N-(3-(2-(4-(2-methoxy ethoxy) anilino)-7-methyl-8-oxo-7H-purine-9 (8H)-yl) phenyl) third the preparation of alkene acid amides (compound 3)
Figure BDA0000436297380000251
(1) preparation of 4-(2-methoxy ethoxy) aniline
Figure BDA0000436297380000252
1-(2-methoxy ethoxy)-4-oil of mirbane (1.97g, 10mmol) is joined in the methanol solution of 50mL, add 10% Pd/C197mg, finish logical H 2room temperature reaction 16h.Suction filtration is removed solid, concentrated incarnadine oily matter 1.6g, the yield 95.7% of obtaining of filtrate.
(2) preparation of 3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylamino-) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000253
By 4-(2-methoxy ethoxy) aniline (668mg, 4.0mmol) be dissolved in the ethanol of 6mL, add again 3-(the chloro-5-of 2-(methylamino-) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester (1.4g, 4.0mmol), finish 100 DEG C of reaction 3h of microwave.Cooling, system is spin-dried for, column chromatography (DCM:MeOH=100:1-4:1) obtains product 900mg, yield 46.8%.
(3) preparation of 3-(2-(4-(2-methoxy ethoxy) anilino)-7-methyl-8-oxo-7H-purine-9 (8H)-yl) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000254
By 3-(2-(4-(2-methoxy ethoxy) anilino)-5-(methylamino-) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester (450mg, 0.94mmol) be dissolved in the THF of 4mL, add again DIEA(485mg, 3.75mmol), under ice bath, add again triphosgene (93mg, 0.31mmol), finish 0 DEG C of reaction 3h.Add to system the NaHCO that 10mL is saturated 3the aqueous solution, DCM extraction, is spin-dried for organic phase, and column chromatography (DCM:MeOH=100:1-4:1) obtains product 350mg, yield 73.4%.
(4) preparation of 9-(3-aminophenyl)-2-(4-(2-methoxy ethoxy) anilino)-7-methyl-7H-purine-8 (9H)-one
Figure BDA0000436297380000261
By 3-(2-(4-(2-methoxy ethoxy) anilino)-7-methyl-8-oxo-7H-purine-9 (8H)-yl) the phenylcarbamic acid tert-butyl ester (350mg, 0.69mmol) be dissolved in the DCM of 7mL, logical HCl gas reaction 1h under ice bath, system is spin-dried for, obtains product crude product 350mg.
(5) preparation of N-(3-(2-(4-(2-methoxy ethoxy) anilino)-7-methyl-8-oxo-7H-purine-9 (8H)-yl) phenyl) acrylamide
Figure BDA0000436297380000262
The product crude product 350mg that upper step is obtained is dissolved in the THF of 3mL, then adds the DMF hydrotropy of 0.3mL, drips the THF solution 0.5mL containing acrylate chloride (62mg, 0.69mmol) at-15 DEG C, finishes at this temperature and reacts 2h.Drip 5 methyl alcohol cancellation reactions, system is spin-dried for, preparation liquid phase purifying (methyl alcohol: water=50% goes out main peak) obtains product 74mg, two step yields 23.3%.
Molecular formula: C 24h 24n 6o 4molecular weight: 460.19 mass spectrums (m/e): 461.3
1H-NMR(d 6-DMSO,400MHz,δppm)：10.39(1H,s),9.19(1H,s),8.21(1H,s),8.00(1H,s),7.71(1H,d),7.58(2H,d),7.50(1H,t),7.33(1H,t),6.77(2H,d),6.47(1H,dd),6.28(1H,dd),5.79(1H,dd),3.98(2H,t),3.61(2H,t),3.38(3H,s),3.28(3H,s).
embodiment 4N-(3-(7-(2-methoxy ethyl)-2-(6-methoxypyridine-3-base amino)-8-oxo-7H-purine-9 (8H)-yl) phenyl) preparation of acrylamide (compound 6)
Figure BDA0000436297380000263
(1) 5-(2-methoxyethyl amine) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone
Figure BDA0000436297380000271
By 5-bromouracil (4.0g, 20.9mmol) and 2-methoxyethyl amine (6.0g, 79.9mmol), EtOH (30mL) mixes, be heated to 100 DEG C of reaction 16h, be cooled to room temperature, filter, filter cake washes twice with ethanol, obtains solid 3.5g, yield: 90.4%.
The preparation of the chloro-N-of (2) 2,4-bis-(2-methoxy ethyl) pyrimidine-5-amine
By 5-(2-methoxyethyl amine) pyrimidine-2,4 (1H, 3H)-diketone (3.5g, 18.9mmol), add phosphorus oxychloride 50mL, at 110 DEG C of reaction 14h, cooling, pour into (100mL) in frozen water, be extracted with ethyl acetate twice, washing, dry concentrated, column chromatography (PE:EA=10:1-3:1), obtains product 600mg, yield: 14.3%.
(3) preparation of 3-(the chloro-5-of 2-(2-methoxyethyl amine) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
By 2, the chloro-N-of 4-bis-(2-methoxy ethyl) pyrimidine-5-amine (600mg, 2.70mmol), 3-aminophenyl t-butyl carbamate (564mg, 2.71mmol) is dissolved in dioxane (15mL), adds successively 4, two diphenylphosphine-9 of 5-, 9-dimethyl oxa-anthracene (155mg, 0.268mmol), Cs 2cO 3(1.06g, 3.25mmol), Pd (OAc) 2(60mg, 0.267mmol), under nitrogen protection, heats 80 DEG C of reaction 16h, is chilled to room temperature, and concentrated, column chromatography (PE:EA=10:1--1:1) obtains product 500mg, yield: 47%.
(4) preparation of 3-(the chloro-7-of 2-(2-methoxy ethyl)-8-oxo-7H-purine-9 (8H)-yl) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000274
Get 3-(the chloro-5-of 2-(2-methoxyethyl amine) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester (200mg, 0.508mmol) be dissolved in the THF of 4mL, add again DIEA(263mg, 2.04mmol), under ice bath, drip again triphosgene (76mg, THF solution 1mL 0.256mmol), finishes 0 DEG C of reaction 2h.Add saturated NaHCO 3aqueous solution 10mL, with DCM extraction, is spin-dried for organic phase and obtains product crude product 220mg.
(5) preparation of 3-(7-(2-methoxy ethyl)-2-(6-methoxypyridine-3-base amino)-8-oxo-7H-purine-9 (8H)-yl) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000281
Upper step product crude product 220mg is dissolved in the DMA of 2mL, then adds 6-methoxypyridine-3-amine (65mg, 0.524mmol), drip 4 Glacial acetic acid, finish 100 DEG C of reactions 3 days.In system, add water, ethyl acetate extraction, is spin-dried for, and column chromatography (DCM:MeOH=100:1-4:1) obtains product 120mg, two step yield 46.5%.
(6) preparation of 9-(3-aminophenyl)-7-(2-methoxy ethyl)-2-(6-methoxypyridine-3-base amino)-7H-purine-8 (9H)-one hydrochloride
Figure BDA0000436297380000282
By 3-(7-(2-methoxy ethyl)-2-(6-methoxypyridine-3-base amino)-8-oxo-7H-purine-9 (8H)-yl) the phenylcarbamic acid tert-butyl ester (120mg, 0.236mmol) be dissolved in the DCM of 7mL, logical HCl gas reaction 1h under ice bath, system is spin-dried for, obtains product crude product 110mg.
(7) preparation of N-(3-(7-(2-methoxy ethyl)-2-(6-methoxypyridine-3-base amino)-8-oxo-7H-purine-9 (8H)-yl) phenyl) acrylamide
Figure BDA0000436297380000283
Upper step product crude product 110mg is dissolved in the THF of 2mL, add again the DMF hydrotropy of 0.1mL, add DIEA to system be alkalescence (pH=9), drip the THF solution 0.3mL containing 22mg (0.243mmol) acrylate chloride at-15 DEG C, finish at this temperature and react 1h.Drip 5 methyl alcohol, system is spin-dried for, preparation liquid phase purifying (methyl alcohol: water=40%) obtains product 20mg, two step yields 18.4%.
Molecular formula: C 23h 23n 7o 4molecular weight: 461.18 mass spectrums (M+H): 462.2
1H-NMR(d 6-DMSO,400MHz)：δ10.39(1H,s),9.31(1H,s),8.41(1H,d),8.24(1H,s),8.04-7.96(2H,m),7.71(1H,d),7.50(1H,t),7.33(1H,d),6.68(1H,d),6.45(1H,dd),6.27(1H,dd),5.78(1H,dd),4.04(2H,t),3.76(3H,s),3.65(2H,t),3.28(3H,s).
embodiment 5N-(3-(2-(6-methoxypyridine-3-base amino)-8-oxo-7-(tetrahydrochysene-2H-pyrans-4-yl)-7H-purine -9-(8H)-yl) phenyl) preparation of acrylamide (compound 7)
Figure BDA0000436297380000291
The preparation of (1) 2,4-dichloro pyrimidine-5-amine
Figure BDA0000436297380000292
By chloro-2,4-bis-5-nitro-pyrimidine (3.86g, 20mmol), iron powder (5.6g, 100mmol) is added in Glacial acetic acid (50mL), stirring at room temperature 6h.Add ethyl acetate dilution, suction filtration, filtrate is washed with saturated aqueous sodium carbonate, and saturated common salt washing is dry, is spin-dried for, and obtains thick product 3.3g.
The preparation of the chloro-N-of (2) 2,4-bis-(tetrahydrochysene-2H-pyrans-4-yl) pyrimidine-5-amine
Figure BDA0000436297380000293
Upper step is obtained 2, the thick product of 4-dichloro pyrimidine-5-amine 3.3g is dissolved in the methylene dichloride of 50mL, add again dihydro-2H-pyrans-4 (3H)-one (2.38g, 23.8mmol),-10 DEG C drip titanium tetrachloride (2.22mL, methylene dichloride 10mL 20.1mmol), stirring at room temperature 12h.Add sodium cyanoborohydride (3.45g, 54.9mmol) to react again 10h.System adds water, and acetoacetic ester extraction three times for second is dry, is spin-dried for, and column chromatography (PE:EA=5:1--1:2) obtains product 900mg, two step yields 18.2%:.
(3) preparation of 3-(the chloro-5-of 2-(tetrahydrochysene-2H-pyrans-4-base amino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000294
By 2, the chloro-N-of 4-bis-(tetrahydrochysene-2H-pyrans-4-yl) pyrimidine-5-amine (900mg, 3.63mmol) with 3-aminophenyl t-butyl carbamate (757mg, 3.63mmol) be dissolved in the propyl carbinol of 20mL, add the rear 110 DEG C of reaction 16h of triethylamine (800mg, 7.91mmol).System is spin-dried for, and column chromatography (PE:EA=10:1--1:3) obtains product 600mg, yield: 39.4%.
(4) preparation of 3-(2-(6-methoxypyridine-3-base amino)-5-(tetrahydrochysene-2H-pyrans-4-base amino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000301
By 3-(the chloro-5-of 2-(tetrahydrochysene-2H-pyrans-4-base amino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester (600mg, 1.43mmol) with 5-amino-2-methoxypyridine (177mg, 1.43mmol) be dissolved in 25mL tertiary amyl alcohol, 120 DEG C of microwave reaction 4h.System is spin-dried for, and preparation liquid phase purifying (methyl alcohol: water=40%), obtains product 240mg, yield: 33.1%.
(5) 3-(preparation of 5-(chloroformyl (tetrahydrochysene-2H-pyrans-4-base amino)-2-(6-methoxypyridine-3-base amino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000302
By 3-(2-(6-methoxypyridine-3-base amino)-5-(tetrahydrochysene-2H-pyrans-4-base amino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester (240mg, 0.473mmol) be dissolved in 5mL tetrahydrofuran (THF), add again N, N-diisopropylethylamine (244mg, 1.89mmol), finish the 1mL tetrahydrofuran solution that drips triphosgene (70mg, 0.236mmol) at 0 DEG C, room temperature reaction 3h.System is spin-dried for and is directly used in next step reaction.
(6) preparation of 3-(2-(6-methoxypyridine-3-base amino)-8-oxo-7-(tetrahydrochysene-2H-pyrans-4-yl)-7H-purine-9-(8H)-yl) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000303
Upper step product is dissolved in the toluene of 5mL, adds DIPEA (129mg, 1mmol), 100 DEG C of reaction 16h.System is spin-dried for, and column chromatography (PE:EA=5:1--1:3) obtains product 80mg, two step yields: 31.7%.
(7) preparation of 9-(3-aminophenyl)-2-(6-methoxypyridine-3-base amino)-7-(tetrahydrochysene-2H-pyrans-4-yl)-7H-purine-8-(9H)-one
Figure BDA0000436297380000304
By 3-(2-(6-methoxypyridine-3-base amino)-8-oxo-7-(tetrahydrochysene-2H-pyrans-4-yl)-7H-purine-9-(8H)-yl) the phenylcarbamic acid tert-butyl ester (80mg, 0.15mmol) be dissolved in the DCM of 4mL, logical HCl gas reaction 1h under ice bath, system is spin-dried for, anhydrous diethyl ether washed twice, obtains product 65mg crude product.
(8) preparation of N-(3-(2-(6-methoxypyridine-3-base amino)-8-oxo-7-(tetrahydrochysene-2H-pyrans-4-yl)-7H-purine-9-(8H)-yl) phenyl) acrylamide
Figure BDA0000436297380000311
Upper step product 65mg crude product is dissolved in the THF of 2mL, add again the DMF hydrotropy of 0.1mL, add DIEA to system be alkalescence (pH=9), drip the THF solution 0.3mL containing 12mg (0.133mmol) acrylate chloride at-15 DEG C, finish at this temperature and react 1h.Drip 5 methyl alcohol cancellation reactions, system is spin-dried for, high pressure is prepared liquid phase separation purification and is obtained product 3mg, two step yields 4.1%.
Molecular formula: C 25h 25n 7o 4molecular weight: 487.2 mass spectrums (M+H): 488.2
1H-NMR(CDCl 3,400MHz)：δ8.24(1H,s),8.17(1H,s),8.11(1H,s),7.93(1H,dd),7.74(1H,d),7.56-7.51(1H,m),7.48-7.41(2H,m),7.07(1H,s),6.68(1H,d),6.44(1H,d),6.28(1H,dd),5.79(1H,d),4.71-4.58(1H,m),4.17(2H,dd),3.90(3H,s),3.58(2H,t),2.40-2.20(2H,m),1.94-1.86(2H,m).
embodiment 6N-(3-(8-cyclopropyl-2-(4-morpholine anilino)-9H-purine-9-yl) phenyl) acrylamide (compound 10) preparation
Figure BDA0000436297380000312
(1) preparation of 3-(2-(4-morpholine anilino)-5-nitro-pyrimidine-4-base amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000313
By 3-(the chloro-5-nitro-pyrimidine-4-of 2-base amino) the phenylcarbamic acid tert-butyl ester (3.65g, 10mmol) with 4-morpholine aniline (1.78g, 10mmol), DMSO (30mL) mixes, then adds DIEA (3.87g, 30mmol) room temperature reaction 2h, system is poured in frozen water, filtered, filter cake washes with water twice, dry, obtain solid crude product 5.25g.
(2) preparation of 3-(5-amino-2-(4-morpholine anilino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000321
Upper step product crude product 5.25g is added in 100mL THF and 100mL MeOH, then adds zinc powder (6.66g, 102mmol), ammonium chloride (5.46g, 102mmol) room temperature reaction 16h, system suction filtration, filtrate is spin-dried for, obtains product crude product 6g.
(3) preparation of 3-(8-cyclopropyl-2-(4-morpholine anilino)-9H-purine-9-yl) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000322
By 3-(5-amino-2-(4-morpholine anilino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester (500mg, 1.05mmol) be dissolved in the MeOH of 10mL, add again cyclopropyl formaldehyde (70mg, 1mmol), drip Glacial acetic acid (180mg, 3mmol), finish room temperature reaction 2 days.In system, add water, DCM extraction three times, is spin-dried for, and column chromatography (PE:EA=5:1-1:1) obtains product 160mg, yield 30.3%.
(4) preparation of 9-(3-aminophenyl)-8-cyclopropyl-N-(4-morpholinyl phenyl)-9H-purine-2-amine
Figure BDA0000436297380000323
By 3-(8-cyclopropyl-2-(4-morpholine anilino)-9H-purine-9-yl) the phenylcarbamic acid tert-butyl ester (160mg, 0.303mmol) be dissolved in the DCM of 7mL, under ice bath, logical HCl gas reaction 1h, is spin-dried for system, obtains product crude product 160mg.
(5) preparation of N-(3-(8-cyclopropyl-2-(4-morpholine anilino)-9H-purine-9-yl) phenyl) acrylamide
Figure BDA0000436297380000324
Upper step product crude product 160mg is dissolved in the THF of 2mL, add again the DMF hydrotropy of 0.1mL, add DIEA to system be alkalescence (pH=9), drip acrylate chloride (27mg at-15 DEG C, THF solution 0.3mL 0.298mmol), finishes at this temperature and reacts 1h.Drip 5 methyl alcohol cancellation, system is spin-dried for, preparation liquid phase purifying (methyl alcohol: water=60%) obtains product 22mg, two step yields 15.1%.
Molecular formula: C 27h 27n 7o 2molecular weight: 481.2 mass spectrums (M+H): 482.2
1H-NMR(d 6-DMSO,400MHz)：δ10.48(1H,s),9.29(1H,s),8.65(1H,d),8.05(1H,s),7.77(1H,d),7.63-7.54(3H,m),7.34(1H,d),6.77(2H,d),6.47(1H,dd),6.29(1H,d),5.81(1H,d),3.70(4H,t),2.95(4H,t),1.95-1.86(1H,m),1.15-1.09(2H,m),1.08-1.01(2H,m).
embodiment 7N-(3-(7-(cyclopropyl methyl)-2-(4-morpholine anilino)-8-oxo-7H-purine-9 (8H)-yl) phenyl) propylene the preparation of acid amides (compound 11)
Figure BDA0000436297380000331
(1) preparation of 3-(5-(cyclopropyl-methylamine base)-2-(4-morpholine anilino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000332
3-(5-amino-2-(4-morpholine anilino) pyrimidine-4-yl amino) phenylcarbamic acid tert-butyl ester crude product 1g is dissolved in to methyl alcohol (10mL), add Glacial acetic acid (180mg, 3mmol), add ring the third formaldehyde (100mg, 1.43mmol), add immediately again sodium cyanoborohydride (130mg, 2.07mmol), room temperature reaction 2h, add saturated sodium bicarbonate aqueous solution 20mL cancellation, DCM extraction three times, is spin-dried for organic phase, and column chromatography (PE:EA=5:1--1:2) obtains product 200mg.
(2) (4-((3-((tertbutyloxycarbonyl) amino) phenyl) amino)-2-((4-morpholine-4-base phenyl) amino) pyrimidine-5-yl) cyclopropyl methyl) preparation of urethanum
Figure BDA0000436297380000333
Get 3-(5-(cyclopropyl-methylamine base)-2-(4-morpholine anilino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester (200mg, 0.376mmol) be dissolved in the THF of 3mL, add again Vinyl chloroformate (43mg, 0.4mmol), finish 60 DEG C of reaction 2h.System is cooling, adds 1mL methyl alcohol, and system is spin-dried for, and is directly used in next step reaction.
(3) preparation of 3-(7-(cyclopropyl methyl)-2-(4-morpholine anilino)-8-oxo-7H-purine-9 (8H)-yl) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000341
Upper step product crude product is dissolved in the ethanol of 2mL, then adds salt of wormwood (104mg, 0.753mmol), finish 50 DEG C of reaction 3h.In system, add water, with dilute hydrochloric acid adjusting, pH is extremely neutral, ethyl acetate extracting twice, and organic phase is spin-dried for, and column chromatography (PE:EA=5:1--1:1) obtains product 120mg, two step yield 57.2%.
(4) preparation of 9-(3-aminophenyl)-7-(cyclopropyl methyl)-2-(4-morpholine anilino)-7H-purine-8 (9H)-one
Figure BDA0000436297380000342
By 3-(7-(cyclopropyl methyl)-2-(4-morpholine anilino)-8-oxo-7H-purine-9 (8H)-yl) the phenylcarbamic acid tert-butyl ester (120mg, 0.215mmol) be dissolved in the DCM of 7mL, logical HCl gas reaction 1h under ice bath, system is spin-dried for, obtains product crude product 120mg.
(5) preparation of N-(3-(7-(cyclopropyl methyl)-2-(4-morpholine anilino)-8-oxo-7H-purine-9 (8H)-yl) phenyl) acrylamide
Figure BDA0000436297380000343
Upper step product crude product 120mg is dissolved in the THF of 2mL, add again the DMF hydrotropy of 0.1mL, add DIEA to system be alkalescence (pH=9), drip the THF solution 0.3mL of 19mg (0.21mmol) acrylate chloride at-15 DEG C, finish, at this temperature, react 1h.Drip 5 methyl alcohol cancellation, system is spin-dried for, preparation liquid phase purifying (methyl alcohol: water=60%) obtains product 20mg, two step yields 18.2%.
Molecular formula: C 28h 29n 7o 3molecular weight: 511.2 mass spectrums (M+H): 512.3
1H-NMR(d 6-DMSO,400MHz)：δ10.41(1H,s),9.17(1H,s),8.31(1H,s),7.99(1H,s),7.72(1H,d),7.55(2H,d),7.50(1H,t),7.35(1H,d),6.78(2H,d),6.47(1H,dd),6.28(1H,d),5.79(1H,d),3.75(2H,d),3.73-3.67(4H,m),2.96(4H,t),0.88-0.80(1H,m),0.57-0.50(2H,m),0.45-0.38(2H,m).
embodiment 8N-(3-(7-(cyclopropyl methyl)-2-(6-methoxypyridine-3-base amino)-8-oxo-7H-purine-9 (8H)-yl) benzene base) preparation of acrylamide (compound 12)
Figure BDA0000436297380000351
(1) preparation of 3-(2-(6-methoxypyridine-3-base amino)-5-nitro-pyrimidine-4-base amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000352
By 3-(the chloro-5-nitro-pyrimidine-4-of 2-base amino) the phenylcarbamic acid tert-butyl ester (3.65g, 10mmol) with 6-methoxypyridine-3-amine (1.25g, 10mmol), DMSO (20mL) mixes, then adds DIEA (2.58g, 20mmol) room temperature reaction 2h, system is poured in frozen water, filtered, filter cake washes with water twice, dry, obtain crude product 5.05g solid.
(2) preparation of 3-(5-amino-2-(6-methoxypyridine-3-base amino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000353
Upper step product crude product 5.05g is added in 100mL THF, 100mL MeOH, then adds zinc powder (6.5g, 100mmol), ammonium chloride (5.35g, 100mmol) room temperature reaction 16h, suction filtration, is spin-dried for filtrate, obtains product crude product 5.8g.
(3) preparation of 3-(5-(cyclopropyl-methylamine)-2-(6-methoxypyridine-3-base amino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000354
3-(5-amino-2-(6-methoxypyridine-3-base amino) pyrimidine-4-yl amino) phenylcarbamic acid tert-butyl ester 1.7g crude product is dissolved in to methyl alcohol (30mL), add Glacial acetic acid (306mg, 5.1mmol), add again cyclopropyl formaldehyde (150mg, 2.14mmol), add immediately again sodium cyanoborohydride (221mg, 3.52mmol), room temperature reaction 3h, add saturated sodium bicarbonate aqueous solution 40mL cancellation, DCM extraction three times, is spin-dried for organic phase, and column chromatography (PE:EA=5:1--1:2) obtains product 500mg.
(4) preparation of (4-((3-((tertbutyloxycarbonyl) amino) phenyl) amino)-2-((6-methoxypyridine-3-yl) amino) pyrimidine-5-yl) (cyclopropyl methyl) urethanum
Figure BDA0000436297380000361
Get 3-(5-(cyclopropyl-methylamine)-2-(6-methoxypyridine-3-base amino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester (477mg, 1mmol) be dissolved in the THF of 3mL, add again Vinyl chloroformate (120mg, 1.1mmol), finish 60 DEG C of reaction 2h.System is cooling, adds 1mL methyl alcohol, is spin-dried for, and is directly used in next step reaction.
(5) preparation of 3-(7-(cyclopropyl methyl)-2-(6-methoxypyridine-3-base amino)-8-oxo-7H-purine-9 (8H)-yl) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000362
Upper step product crude product is dissolved in the ethanol of 10mL, adds salt of wormwood (276mg, 2.0mmol), 50 DEG C of reaction 2h, then be warming up to 60 DEG C of reaction 2h.Reaction finishes to add water in rear system, and with dilute hydrochloric acid adjusting, pH is extremely neutral, ethyl acetate extracting twice, and organic phase is spin-dried for, and column chromatography (PE:EA=5:1--1:1) obtains product 350mg, two step yield 69.5%.
(6) preparation of 9-(3-aminophenyl)-7-(cyclopropyl methyl)-2-(6-methoxypyridine-3-base amino)-7H-purine-8 (9H)-one
Figure BDA0000436297380000363
By 3-(7-(cyclopropyl methyl)-2-(6-methoxypyridine-3-base amino)-8-oxo-7H-purine-9 (8H)-yl) the phenylcarbamic acid tert-butyl ester (350mg, 0.695mmol) be dissolved in the DCM of 7mL, logical HCl gas reaction 1h under ice bath, system is spin-dried for, with ether by twice of solids wash, suction filtration, obtains product crude product 330mg.
(7) preparation of N-(3-(7-(cyclopropyl methyl)-2-(6-methoxypyridine-3-base amino)-8-oxo-7H-purine-9 (8H)-yl) phenyl) acrylamide
Figure BDA0000436297380000371
Upper step product crude product 330mg is dissolved in the THF of 4mL, then adds the DMF hydrotropy of 0.2mL, add DIEA to system be alkalescence (pH=9), drip the THF solution 0.5mL of 55mg (0.61mmol) acrylate chloride at-15 DEG C, finish at this temperature and react 1h.Drip 5 methyl alcohol, system is spin-dried for, preparation liquid phase purifying (methyl alcohol: water=60%) obtains product 72mg, two step yields 22.6%.
Molecular formula: C 24h 23n 7o 3molecular weight: 457.2 mass spectrums (M+H): 457.9
1H-NMR(CDCl 3,400MHz)：δ8.25(1H,d),8.06(1H,br?s),8.04(1H,s),7.95(1H,dd),7.64(1H,d),7.55-7.44(3H,m),6.84(1H,s),6.70(1H,d),6.46(1H,dd),6.28(1H,dd),5.81(1H,dd),3.91(3H,s),3.79(2H,d),0.94-0.83(1H,m),0.70-0.62(2H,m),0.49-0.42(2H,m).
embodiment 9N-(3-(7-(cyclopropyl methyl)-2-(6-(dimethylamino) pyridin-3-yl amino)-8-oxo-7H-purine-9 (8H)- base) phenyl) preparation of acrylamide (compound 13)
Figure BDA0000436297380000372
(1) preparation of 3-(2-(6-(dimethylamino) pyridin-3-yl amino)-5-nitro-pyrimidine-4-base amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000373
By 3-(the chloro-5-nitro-pyrimidine-4-of 2-base amino) the phenylcarbamic acid tert-butyl ester (1.23g, 3.36mmol) and N 2, N 2-lutidine-2,5-diamines (462mg, 3.37mmol), DMSO (20mL) mixes, add DIEA (869mg, 6.73mmol) room temperature reaction 2h, system is poured in frozen water again, filter, filter cake washes twice with water, obtains solid crude product 1.6g.
(2) preparation of 3-(5-amino-2-(6-(dimethylamino) pyridin-3-yl amino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000381
Upper step product crude product 1.6g is added in 50mL THF and 50mL MeOH, then adds zinc powder (2.19g, 33.5mmol), ammonium chloride (1.8g, 33.6mmol) room temperature reaction 16h, suction filtration, filtrate is spin-dried for, and obtains product crude product 1.6g.
(3) preparation of 3-(5-(cyclopropyl-methylamine base)-2-(6-(dimethylamino) pyridin-3-yl amino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000382
Upper step product crude product 1.6g is dissolved in to methyl alcohol (20mL), adds Glacial acetic acid (274mg, 4.57mmol), add again cyclopropyl formaldehyde (152mg, 2.17mmol), more immediately add sodium cyanoborohydride (198mg, 3.15mmol), room temperature reaction 2h, add saturated sodium bicarbonate aqueous solution 40mL cancellation, DCM extraction three times, is spin-dried for organic phase, column chromatography (PE:EA=2:1--1:3) obtains product 600mg, three step yields: 36.3%.
(4) preparation of (4-((3-((tertbutyloxycarbonyl) amino) phenyl) amino)-2-((6-(dimethylamino) pyridin-3-yl) amino) pyrimidine-5-yl) (cyclopropyl methyl) urethanum
Figure BDA0000436297380000383
Get 3-(5-(cyclopropyl-methylamine base)-2-(6-(dimethylamino) pyridin-3-yl amino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester (600mg, 1.22mmol) be dissolved in the THF of 20mL, add again Vinyl chloroformate (125mg, 1.15mmol), finish 30 DEG C of reaction 2h.System adds 1mL methyl alcohol, and system is spin-dried for, and is directly used in next step reaction.
(5) preparation of 3-(7-(cyclopropyl methyl)-2-(6-(dimethylamino) pyridin-3-yl amino)-8-oxo-7H-purine-9 (8H)-yl) the phenylcarbamic acid tert-butyl ester
Upper step product crude product is dissolved in the ethanol of 10mL, adds salt of wormwood (337mg, 2.44mmol), finish, 60 DEG C of reaction 2h.Reaction finishes to add water in rear system, and with dilute hydrochloric acid adjusting, pH is extremely neutral, ethyl acetate extracting twice, and organic phase is spin-dried for, and column chromatography (PE:EA=3:1--1:2) obtains product 300mg, two step yield 50.5%.
(6) preparation of 9-(3-aminophenyl)-7-(cyclopropyl methyl)-2-(6-(dimethylamino) pyridin-3-yl amino)-7H-purine-8 (9H)-copper powder
Figure BDA0000436297380000391
By 3-(7-(cyclopropyl methyl)-2-(6-(dimethylamino) pyridin-3-yl amino)-8-oxo-7H-purine-9 (8H)-yl) the phenylcarbamic acid tert-butyl ester (300mg, 0.581mmol) be dissolved in the DCM of 7mL, logical HCl gas reaction 1h under ice bath, system is spin-dried for, with ether, by solids wash twice, suction filtration obtains product crude product 260mg.
(7) preparation of N-(3-(7-(cyclopropyl methyl)-2-(6-(dimethylamino) pyridin-3-yl amino)-8-oxo-7H-purine-9 (8H)-yl) phenyl) acrylamide
Figure BDA0000436297380000392
Upper step product crude product 260mg is dissolved in the THF of 4mL, add again the DMF hydrotropy of 0.2mL, add DIEA to system be alkalescence (pH=9), drip the THF solution 0.3mL of 45mg (0.497mmol) acrylate chloride at-15 DEG C, finish at this temperature and react 1h.Drip 5 methyl alcohol, system is spin-dried for, preparation liquid phase purifying (methyl alcohol: water=60%) obtains product 55mg, two step yields 20.1%.
Molecular formula: C 25h 26n 8o 2molecular weight: 470.22 mass spectrums (M+H): 470.9
1H-NMR(CDCl 3,400MHz)：δ8.23(1H,d),8.01(1H,s),7.97(1H,s),7.77(1H,dd),7.75-7.68(1H,m),7.56-7.44(3H,m),6.67(1H,s),6.51(1H,d),6.47(1H,d),6.27(1H,dd),5.80(1H,d),3.78(2H,d),3.06(6H,s),1.25-1.18(1H,m),0.68-0.61(2H,m),0.48-0.42(2H,m).
embodiment 104-(4-(9-(3-acrylamido phenyl)-8-cyclopropyl-9H-purine-2-base amino) phenoxy group)-N-picoline the preparation of-2-methane amide (compound 14)
Figure BDA0000436297380000401
(1) preparation of 3-(2-(4-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) anilino)-5-nitro-pyrimidine-4-base amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000402
By 3-(the chloro-5-nitro-pyrimidine-4-of 2-base amino) the phenylcarbamic acid tert-butyl ester (2.74g, 7.49mmol) be dissolved in the DMSO of 25mL, under room temperature, drip 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (1.82g, 7.49mmol) with DIEA (1.45g, DMSO solution 10mL 11.2mmol), 10min drips off, and finishes, and at this temperature, reacts 2h.System is poured in frozen water, separated out yellow solid, suction filtration obtains 4.30g crude product.
(2) preparation of 3-(5-amino-2-(4-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) anilino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000403
Upper step product crude product 4.30g is added in 50mL THF and 50mL MeOH, then adds zinc powder (4.87g, 74.9mmol), ammonium chloride (4.01g, 75.0mmol) room temperature reaction 16h, suction filtration, is spin-dried for filtrate, obtains crude product 4.10g.
(3) preparation of 3-(8-cyclopropyl-2-(4-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) anilino)-9H-purine-9-yl) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000411
Upper step product crude product 1.60g is dissolved in the MeOH of 20mL, then adds cyclopropyl formaldehyde (300mg, 4.29mmol), drip Glacial acetic acid (534mg, 8.90mmol), finish room temperature reaction 2 days.In system, add water, DCM extraction three times, is spin-dried for, and column chromatography (PE:EA=5:1-1:1) obtains product 340mg.
(4) preparation of 4-(4-(9-(3-aminophenyl)-8-cyclopropyl-9H-purine-2-base amino) phenoxy group)-N-picoline-2-methane amide
Figure BDA0000436297380000412
Upper step product (340mg, 0.574mmol) is dissolved in the DCM of 7mL, under ice bath, logical HCl gas reaction 1h, is spin-dried for system, obtains product crude product 340mg.
(5) preparation of 4-(4-(9-(3-acrylamido phenyl)-8-cyclopropyl-9H-purine-2-base amino) phenoxy group)-N-picoline-2-methane amide
Figure BDA0000436297380000413
Upper step product crude product 340mg is dissolved in the THF of 3mL, add again the DMF hydrotropy of 0.1mL, add DIEA to system be alkalescence (pH=9), drip acrylate chloride (50.0mg at-15 DEG C, THF solution 0.3mL 0.552mmol), finishes at this temperature and reacts 1h.Drip 5 methyl alcohol cancellation, system is spin-dried for, preparation liquid phase purifying (methyl alcohol: water=60%) obtains product 70mg, two step yields 22.3%.
Molecular formula: C 30h 26n 8o 3molecular weight: 546.2 mass spectrums (M+H): 547.2
1H-NMR(CDCl 3,400MHz)：δ8.71(1H,s),8.37(1H,d),8.24(1H,s),8.19(1H,s),8.07(1H,q),7.66(1H,d),7.62-7.54(3H,m),7.50(1H,t),7.39(1H,s),7.31(1H,d),7.03-6.92(3H,m),6.41(1H,d),6.16(1H,dd),5.68(1H,d),3.04(3H,d),2.08-1.97(1H,m),1.18-1.10(2H,m),1.04-0.95(2H,m).
embodiment 11N-(3-(8-cyclopropyl-2-(6-methoxypyridine-3-base amino)-9H-purine-9-yl) phenyl) acrylamide (is changed compound 15) preparation
Figure BDA0000436297380000421
(1) preparation of 3-(8-cyclopropyl-2-(6-methoxypyridine-3-base amino)-9H-purine-9-yl) the phenylcarbamic acid tert-butyl ester
3-(5-amino-2-(6-methoxypyridine-3-base amino) pyrimidine-4-yl amino) phenylcarbamic acid tert-butyl ester crude product 2.40g is dissolved in the MeOH of 40mL, add again cyclopropyl formaldehyde (320mg, 4.57mmol), drip Glacial acetic acid (720mg, 12.0mmol), finish room temperature reaction 2 days.In system, add water, DCM extraction three times, is spin-dried for, and column chromatography (PE:EA=5:1-1:1) obtains product 440mg.
(2) preparation of 9-(3-aminophenyl)-8-cyclopropyl-N-(6-methoxypyridine-3-yl)-9H-purine-2-amine
Figure BDA0000436297380000423
By 3-(8-cyclopropyl-2-(6-methoxypyridine-3-base amino)-9H-purine-9-yl) the phenylcarbamic acid tert-butyl ester (440mg, 0.929mmol) be dissolved in the DCM of 8mL, logical HCl gas reaction 1h under ice bath, system is spin-dried for, after ether washing, obtains product crude product 400mg.
(3) preparation of N-(3-(8-cyclopropyl-2-(6-methoxypyridine-3-base amino)-9H-purine-9-yl) phenyl) acrylamide
Upper step product crude product 400mg is dissolved in the THF of 4mL, add again the DMF hydrotropy of 0.1mL, add DIEA to system be alkalescence (pH=9), drip acrylate chloride (80.0mg at-15 DEG C, THF solution 0.3mL 0.884mmol), finishes at this temperature and reacts 1h.Drip methyl alcohol cancellation, system is spin-dried for, preparation liquid phase purifying (methyl alcohol: water=60%) obtains product 90mg, two step yields 22.7%.
Molecular formula: C 23h 21n 7o 2molecular weight: 427.2 mass spectrums (M+H): 428.2
1H-NMR(DMSO-d 6,400MHz)：δ10.46(1H,s),9.45(1H,s),8.68(1H,s),8.41(1H,d),8.06-8.00(2H,m),7.77(1H,d),7.59(1H,t),7.34(1H,d),6.66(1H,d),6.45(1H,dd),6.28(1H,d),5.80(1H,d),3.76(3H,s),1.93-1.85(1H,m),1.16-1.10(2H,m),1.07-1.00(2H,m).
embodiment 12N-(3-(8-cyclopropyl-2-(6-(dimethylamino) pyridin-3-yl amino)-9H-purine-9-yl) phenyl) acrylamide the preparation of (compound 16)
Figure BDA0000436297380000431
(1) preparation of 3-(2-(6-(dimethylamino) pyridin-3-yl amino)-5-nitro-pyrimidine-4-base amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000432
By 3-(the chloro-5-nitro-pyrimidine-4-of 2-base amino) the phenylcarbamic acid tert-butyl ester (1.23g, 3.36mmol) and N 2, N 2-lutidine-2,5-diamines (462mg, 3.37mmol), DMSO (20mL) mixes, add DIEA (869mg, 6.73mmol) room temperature reaction 2h, system is poured in frozen water again, filter, filter cake washes twice with water, obtains solid crude product 1.6g.
(2) preparation of 3-(5-amino-2-(6-(dimethylamino) pyridin-3-yl amino) pyrimidine-4-yl amino) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000433
Upper step product crude product 1.6g is added in 50mL THF and 50mL MeOH, then adds zinc powder (2.19g, 33.5mmol),
Ammonium chloride (1.8g, 33.6mmol) room temperature reaction 16h, suction filtration, filtrate is spin-dried for, and obtains product crude product 1.6g.
(3) preparation of 3-(8-cyclopropyl-2-(6-(dimethylamino) pyridin-3-yl amino)-9H-purine-9-yl) the phenylcarbamic acid tert-butyl ester
Figure BDA0000436297380000434
Upper step product crude product 437mg is dissolved in the MeOH of 10mL, then adds cyclopropyl formaldehyde (77mg, 1.10mmol), drip Glacial acetic acid (180mg, 3.00mmol), finish room temperature reaction 2 days.In system, add water, DCM extraction three times, is spin-dried for, and column chromatography (PE:EA=5:1-1:1) obtains product 300mg.
(4) N 5-(9-(3-aminophenyl)-8-cyclopropyl-9H-purine-2-yl)-N 2, N 2-lutidine-2, the preparation of 5-amine
By 3-(8-cyclopropyl-2-(6-(dimethylamino) pyridin-3-yl amino)-9H-purine-9-yl) the phenylcarbamic acid tert-butyl ester (300mg, 0.616mmol) be dissolved in the DCM of 7mL, logical HCl gas reaction 1h under ice bath, system is spin-dried for, obtains product crude product 300mg.
(5) preparation of N-(3-(8-cyclopropyl-2-(6-(dimethylamino) pyridin-3-yl amino)-9H-purine-9-yl) phenyl) acrylamide
Figure BDA0000436297380000442
Upper step product crude product 300mg is dissolved in the THF of 3mL, add again the DMF hydrotropy of 0.1mL, add DIEA to system be alkalescence (pH=9), drip acrylate chloride (54.0mg at-15 DEG C, THF solution 0.3mL 0.597mmol), finishes at this temperature and reacts 1h.Drip methyl alcohol cancellation, system is spin-dried for, preparation liquid phase purifying (methyl alcohol: water=65%) obtains product 88mg, two step yields 32.4%.
Molecular formula: C 24h 24n 8o molecular weight: 440.5 mass spectrums (M+H): 441.2
1H-NMR(DMSO-d 6,400MHz)：δ10.46(1H,s),9.17(1H,s),8.62(1H,s),8.28(1H,d),8.02(1H,s),7.86(1H,dd),7.76(1H,d),7.58(1H,t),7.33(1H,d),6.50(1H,d),6.46(1H,dd),6.29(1H,dd),5.80(1H,dd),2.92(6H,s),1.92-1.82(1H,m),1.15-1.08(2H,m),1.07-0.98(2H,m).
With reference to above-mentioned preparation method, can also prepare following compound:
Figure BDA0000436297380000443
Figure BDA0000436297380000451
Figure BDA0000436297380000471
Figure BDA0000436297380000481

Claims (10)

1. the compound shown in general formula (I), its deuterated thing, its pharmacy acceptable salt or its steric isomer:
Figure FDA0000436297370000011
Wherein, X and W independently represent respectively C-Ra, C=O or N-Rb,
And when X is different with W, be C=O,
Ra represents hydrogen atom, halogen atom ,-CN ,-CF 3, by 1-2 identical or different Q 1replace or unsubstituted C 1-4alkyl, C 1-4alkoxy C 0-4alkyl, amino, C 3-6cycloalkyl C 0-4alkyl, phenyl C 0-4alkyl, naphthyl C 0-4alkyl, the heteroaryl C of 5-10 unit 0-4alkyl or-OH,
Rb represents not exist, and hydrogen atom, by 1-2 identical or different Q 1replace or unsubstituted C 1-4alkyl, C 1-4alkoxy C 0-4alkylidene group, C 3-6cycloalkyl C 0-4alkyl, phenyl C 0-4alkyl, naphthyl C 0-4alkyl or the heteroaryl C of 5-10 unit 0-4alkyl,
Q 1represent C 1-4alkoxyl group, C 1-3carbalkoxy, formamyl, C 1-3alkyl-carbamoyl, 3-8 unit cycloalkyl or contain N or the heteroatomic 3-8 of O unit heterocyclic radical;
R 2represent hydrogen atom, halogen atom ,-CF 3, C 1-4alkyl, C 1-4alkoxyl group, amino or-OH;
Ring A and ring B independently represent respectively phenyl, and 3-8 unit cycloalkyl contains N, O, the heteroatomic 3-8 of S unit Heterocyclylalkyl, 4-7 unit's heteroaryl or 6-12 unit two ring structures;
L 1and L 2independently represent respectively covalent linkage ,-NH-,-N (C 1-3alkyl)-,-O-,-S (O) m-,-N (C 1-3alkyl) C (O)-,-C (O) N (C 1-3alkyl)-,-N (C 1-3alkyl) S (O) 2-or-S (O) 2n (C 1-3alkyl)-;
A represents covalent linkage, is not substituted or by C 1-4the imino-that alkyl replaces;
Represent-CO-of b or-SO 2-;
C represent not to be substituted or replace by one or two methyl or through trifluoromethyl 1, the sub-propadiene base of 3-, 1,1-or vinylene, ethynylene, or the 1,3-butadiene-Isosorbide-5-Nitrae-subunit that is not substituted or replaces by one to four methyl or through trifluoromethyl;
D represents covalent linkage or C 1-6alkylidene group;
E represents hydrogen atom, C 1-4alkoxyl group, amino, 3-7 unit cycloalkyl, 6-12 unit two ring structures, C 1-4alkylamino or two-(C 1-4alkyl) amino, wherein moieties can be identical or different;
R 1and R 3independently represent respectively hydrogen atom, halogen atom, cyano group, nitro, C 2-4thiazolinyl, C 2-4alkynyl or-L 3-R 4,
L 3represent covalent linkage ,-NH-,-N (C 1-3alkyl)-,-O-,-O-C 1-3alkylidene group-,-S-C 1-3alkylidene group-,-S (O) m-,-C (O)-,-NHC (O)-,-N (C 1-3alkyl) C (O)-,-C (O) NH-,-C (O) N (C 1-3alkyl)-,-NHS (O) 2-,-N (C 1-3alkyl) S (O) 2-,-S (O) 2nH-,-S (O) 2n (C 1-3alkyl)-,-OC (O)-or-C (O) O-,
R 4represent hydrogen atom, C 1-4alkyl ,-N (C 1-3alkyl) 2,-NHC (O) O-(C 1-4alkyl) ,-OH ,-O (C 1-4alkyl) ,-S (O) 2(C 1-3alkyl), 3-7 unit cycloalkyl, phenyl or 5-6 unit heteroaryl;
Above-mentioned C 1-3alkyl and C 1-4moieties in alkyl, cycloalkyl, heteroaryl can be further by 1-4 identical or different Q 2replace,
Q 2represent halogen atom, C 1-3alkyl, amino, C 1-3alkylamino, two-(C 1-3alkyl) amino, hydroxyl, C 1-3alkoxyl group, C 1-3carbalkoxy, formamyl, C 1-3alkyl-carbamoyl, two-(C 1-3alkyl) formamyl or 3-6 unit cycloalkyl, wherein Q 1can be identical or different;
On described cycloalkyl, two ring structures, carbon atom can be by 1-4 identical or different N, NH, N (C 1-3alkyl), O, S (O) m, C (O) replace;
Described heteroaryl can contain 1-4 heteroatoms, and described heteroatoms is independently selected from respectively N, O or S;
Figure FDA0000436297370000021
represent singly-bound or two key;
M represents 0,1 or 2;
P and q independently represent respectively 0,1,2,3 or 4.
2. compound as claimed in claim 1, its deuterated thing, its pharmacy acceptable salt or its steric isomer:
Wherein, X and W independently represent respectively C-Ra, C=O or N-Rb,
And when X is different with W, be C=O,
Ra represents hydrogen atom, halogen atom ,-CF 3, methyl, ethyl, methoxyl group, methoxy ethyl, amino, cyclopropyl, phenyl, benzyl, naphthyl, pyrryl, furyl or pyridyl,
Rb represents not exist, and hydrogen atom, by 1-2 identical or different Q 1replace or unsubstituted C 1-3alkyl, C 1-3alkoxy C 0-3alkylidene group or C 3-6cycloalkyl C 0-3alkylidene group, phenyl, benzyl, naphthyl, pyrryl, furyl or pyridyl,
Q 1represent C 1-3alkoxyl group, C 1-3carbalkoxy or contain N or the heteroatomic 5-7 of O unit heterocyclic radical;
R 2represent hydrogen atom or amino;
Ring A and ring B independently represent respectively phenyl, and 5-6 unit cycloalkyl contains N, O, the heteroatomic 5-6 of S unit Heterocyclylalkyl, 5-6 unit's heteroaryl or 8-10 unit two ring structures;
L 1and L 2independently represent respectively covalent linkage ,-NH-,-N (CH 3)-,-O-,-S (O) m-,-N (CH 3) C (O)-,-C (O) N (CH 3)-,-N (CH 3) S (O) 2-or-S (O) 2n (CH 3)-;
A represents covalent linkage, is not substituted or by CH 3the imino-replacing;
Represent-CO-of b or-SO 2-;
C represents not to be substituted or by one or two methyl substituted vinylene or ethynylene;
D represents covalent linkage or methylene radical;
E represents hydrogen atom, methoxyl group, amino, piperidyl, morpholinyl, 6-9 unit spirane structure, 6-8 unit ring structure, 6-8 unit caged scaffold, methylamino or two-(methyl) amino;
R 1and R 3independently represent respectively hydrogen atom, halogen atom, nitro or-L 3-R 4,
L 3represent covalent linkage ,-NH-,-N (C 1-3alkyl)-,-O-,-O-C 1-3alkylidene group-,-S-C 1-3alkylidene group-,-S (O) m-,-C (O)-,-NHC (O)-,-C (O) NH-,-NHS (O) 2-,-S (O) 2nH-,-OC (O)-or-C (O) O-,
R 4represent hydrogen atom, C 1-4alkyl ,-N (C 1-3alkyl) 2,-NHC (O) O-(C 1-4alkyl) ,-OH ,-O (C 1-4alkyl) ,-S (O) 2(C 1-3alkyl), 5-6 unit cycloalkyl, phenyl or 5-6 unit heteroaryl;
Above-mentioned C 1-3moieties, cycloalkyl, heteroaryl, spirane structure ring structure, caged scaffold in alkyl can be further by 1-4 identical or different Q 2replace,
Q 2represent halogen atom, C 1-3alkyl, amino, C 1-3alkylamino, two-(C 1-3alkyl) amino, hydroxyl, C 1-3alkoxyl group, C 1-3carbalkoxy, formamyl, C 1-3alkyl-carbamoyl, two-(C 1-3alkyl) formamyl or 5-6 unit cycloalkyl, wherein Q 1can be identical or different;
On described cycloalkyl, two ring structures, carbon atom can be by 1-4 identical or different N, NH, N (C 1-3alkyl), O, S (O) m, C (O) replace;
Described heteroaryl, spirane structure ring structure, caged scaffold can contain 1-4 heteroatoms, and described heteroatoms is independently selected from respectively N, O or S;
Figure FDA0000436297370000031
represent singly-bound or two key;
M represents 0,1 or 2;
P and q independently represent respectively 0,1,2,3 or 4.
3. compound as claimed in claim 2, its deuterated thing, its pharmacy acceptable salt or its steric isomer:
Wherein, X represents CH or N-Rb, and W represents C-Ra,, C=O or N-Rb,
Ra represents hydrogen atom, halogen atom, and methyl, ethyl, methoxyl group, cyclopropyl, phenyl, benzyl, naphthyl, pyrryl, furyl or pyridyl,
Rb represents not exist, and hydrogen atom, by 1-2 identical or different Q 1replace or unsubstituted methyl, ethyl, cyclopropane base, pentamethylene base or THP trtrahydropyranyl,
Q 1represent C 1-3alkoxyl group or contain N or the heteroatomic 5-6 of O unit heterocyclic radical;
R 2represent hydrogen atom or amino;
Ring A and ring B independently represent respectively phenyl, contain the heteroatomic 5-6 unit's cycloalkyl of N or 5-6 unit heteroaryl;
L 1and L 2independently represent respectively covalent linkage ,-NH-,-O-or-S (O) m-;
A represents covalent linkage or imino-;
Represent-CO-of b;
C represents vinylene;
D represents covalent linkage or methylene radical;
E represents hydrogen atom, piperidyl, morpholinyl or two-(methyl) amino;
R 1represent hydrogen atom, halogen atom, the methyl, the methoxyl group that are not substituted or are replaced by 1-4 identical or different halogen atom, methylamino or two-(methyl) amino;
R 3represent hydrogen atom, halogen atom or-L 3-R 4,
L 3represent covalent linkage ,-NH-,-N (C 1-3alkyl)-,-O-,-O-C 1-3alkylidene group-,-S-C 1-3alkylidene group ,-S (O) m-,-C (O)-,-NHC (O)-,-C (O) NH-,-OC (O)-or-C (O) O-,
R 4represent hydrogen atom, methyl, ethyl ,-N (C 1-3alkyl) 2,-NHC (O) O-C 3h 7,-O (CH 3) ,-O (CH 2cH 3) ,-O (C (CH 3) 3) ,-S (O) 2-C 3h 7, pentamethylene base, cyclohexyl, pyrrolidyl, tetrahydrofuran base, piperidyl, morpholinyl, piperazinyl, phenyl, pyrryl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl group, pyridyl or pyrimidyl;
Described pentamethylene base, cyclohexyl, phenyl, pyrryl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl group, pyridyl, pyrimidyl can be further by 1-2 identical or different Q 2replace,
Q 2represent halogen atom, methyl, amino, methylamino, dimethylamino, hydroxyl, methoxyl group, methoxycarbonyl, formamyl, methylamino formyl radical or two-(methyl) formamyl;
Figure FDA0000436297370000041
represent singly-bound or two key;
M represents 0,1 or 2;
P and q independently represent respectively 0,1 or 2.
4. compound as claimed in claim 3, its deuterated thing, its pharmacy acceptable salt or its steric isomer:
Wherein, X represents CH or N-Rb,
W represents C-Ra, C=O or N-Rb,
Ra represents hydrogen atom, halogen atom, and methyl, ethyl, methoxyl group or cyclopropyl,
Rb represents not exist, hydrogen atom, and cyclopropane base, THP trtrahydropyranyl, by 1 Q 1replace or unsubstituted methyl or ethyl,
Q 1represent methoxyl group or pyrrolidyl;
R 2represent hydrogen atom;
Ring A and ring B independently represent respectively phenyl, pyridyl or piperidyl;
L 1represent covalent linkage;
L 2expression-NH-or-O-;
A represents covalent linkage or imino-;
Represent-CO-of b;
C represents vinylene;
D represents covalent linkage or methylene radical;
E represents hydrogen atom, piperidyl or two-(methyl) amino;
R 1represent hydrogen atom, fluorine atom, chlorine atom, trifluoromethyl, methoxyl group or trifluoromethoxy;
R 3represent hydrogen atom, fluorine atom, chlorine atom or-L 3-R 4,
L 3represent covalent linkage ,-NH-,-N (C 3h 7)-,-O-,-O-CH 2cH 2-or-S (O) m-,
R 4represent hydrogen atom, methyl, ethyl, dimethylamino ,-NHC (O) O-C 3h 7,-O (CH 3) ,-O (C (CH 3) 3) ,-S (O) 2-C 3h 7, morpholinyl, phenyl, pyrryl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl group or pyridyl,
Described phenyl, pyrryl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl group, pyridyl can be further by 1-2 identical or different Q 2replace,
Q 2represent formamyl, methylamino formyl radical or two-(methyl) formamyl;
Figure FDA0000436297370000051
represent singly-bound or two key;
M represents 0,1 or 2;
P and q independently represent respectively 0 or 1.
5. compound as claimed in claim 4, its deuterated thing, its pharmacy acceptable salt or its steric isomer:
Wherein, X represents CH or N-Rb,
W represents C-R x, C=O or N-Rb,
Ra represents hydrogen atom or cyclopropyl,
Rb represents not exist, hydrogen atom, methyl, cyclopropane base, THP trtrahydropyranyl, CH 3oCH 2cH 2-or
R 2represent hydrogen atom;
Ring A represents phenyl;
Ring B represents phenyl or pyridyl;
L 1represent covalent linkage;
L 2expression-NH;
A represents imino-;
Represent-CO-of b;
C represents vinylene;
D represents covalent linkage;
E represents hydrogen atom;
R 1represent hydrogen atom;
R 3expression-L 3-R 4, L 3represent covalent linkage ,-O-or-O-CH 2cH 2-, R 4expression-O (CH 3), dimethylamino, morpholinyl or pyridyl,
Described pyridyl can be further by 1-2 identical or different Q 2replace Q 2represent formamyl, methylamino formyl radical or two-(methyl) formamyl;
Figure FDA0000436297370000061
represent singly-bound or two key;
P represents 0;
Q represents 1.
6. be selected from following compound, its deuterated thing, its pharmacy acceptable salt or its steric isomer:
Figure FDA0000436297370000062
7. contain the preparation method of compound, its deuterated thing, its pharmacy acceptable salt or its steric isomer described in claim 1-6 any one, it is characterized in that, compound shown in formula III is reacted to the preparation method who prepares compound shown in formula II with compound shown in formula (IV)
Figure FDA0000436297370000071
Wherein X, W, ring A, ring B, L 1, L 2, R 1, R 2, R 3, p and q define as claim 1.
8. pharmaceutical composition, contains compound, its deuterated thing, its pharmacy acceptable salt or its steric isomer described in claim 1-6 any one, also comprises the second therapeutical agent that is selected from antineoplastic agent, immunosuppressor and/or antiphlogiston.
9. the pharmaceutical preparation that contains compound, its deuterated thing, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers described in claim 1-6 any one is pharmaceutically acceptable arbitrary formulation.
10. the compound as described in claim 1-6 any one, its deuterated thing, its pharmacy acceptable salt or its steric isomer are for the preparation of preventing and/or treating leukemia, inflammatory and/or the autoimmune disorder that B cell is relevant.
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