CN103664878A - Hetero-aromatic ring and derivative type tyrosine kinase inhibitor thereof - Google Patents
Hetero-aromatic ring and derivative type tyrosine kinase inhibitor thereof Download PDFInfo
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- CN103664878A CN103664878A CN201210337340.4A CN201210337340A CN103664878A CN 103664878 A CN103664878 A CN 103664878A CN 201210337340 A CN201210337340 A CN 201210337340A CN 103664878 A CN103664878 A CN 103664878A
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention belongs to the technical field of medicaments, and in particular relates to a hetero-aromatic ring shown by a general formula (I) as well as a derivative type tyrosine kinase inhibitor, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X, Z, W, R1, R2, R3, L1, L2, a, b, c, d, e, p, q, A and B are as defined in the specification. The invention also relates to preparation methods of these compounds, a pharmaceutical preparation containing these compounds, and important functions of these compounds in preparation of medicaments for treating B cell related leukemia (such as B cell chronic lymphocytic carcinoma and non-hodgkin lymphoma) and autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus and the like).
Description
1, technical field
The invention belongs to medical technical field, be specifically related to hetero-aromatic ring and derivatives class tyrosine kinase inhibitor thereof, its pharmacy acceptable salt or its steric isomer, the preparation method of these compounds, the pharmaceutical preparation that contains these compounds, and these compounds are for example, in the relevant leukemia (B cell chronic lymphocytic cancer, non-Hodgkin lymphoma) of preparation treatment B cell, and play an important role in autoimmune disorder (such as rheumatoid arthritis, systemic lupus erythematous etc.).
2, background technology
Protein kinase forms one of maximum family of people's fermentoid, and to protein, regulates many different signal conductive processes (T Hunter, Cell 1987 50:823-829) 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 Med 2004 55:477).The inhibitor of the protein kinase therefore, playing a role in B cell activation should be for the cell-mediated disease pathology therapeutical agent as useful in autoantibody generates of 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) is 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 Immunity 19953:283 of survival; Ellmeier etc., J.Exp.Med.2000 192:1611).People's Btk sudden change causes the chain gamma-globulin of illness X to lack mass formed by blood stasis (XLA) Immunol.Rev.2005 203:200 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.Proved the dose-dependently effect (Z.Pan etc., Chem.Med Chem.2007 2:58) of selectivity Btk inhibitor in mouse arthritis model.
Btk is also by may relate to the cell expressing of lysis except B cell.Such as Btk, by mastocyte mast cell-expressed and Btk defective type derived from bone marrow, shown the threshing (J.Biol.Chem.2005280:40261 such as Iwaki) of impaired antigen induction.This shows that Btk can be used for the treatment of the reaction of pathologic mastocyte 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 Med 2003197:1603 such as () Horwood.Therefore, the alpha mediated inflammation of TNF can be regulated by small molecules Btk inhibitor.In addition, therefore the Btk having reported plays a role (IsIam and Smith Immunol.Rev.2000178:49) in apoptosis, and Btk inhibitor will be effective J.Exp.Med.2005 201:1837 such as () Feldhahn for some B cell lymphoma for the treatment of 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 the PCI-32765 studying in the clinical II phase is also many target spots inhibitor, to Btk restraining effect, is non-reversibility, is used for the treatment of lymphoma, leukemia and autoimmune disease.
Not yet selective Btk inhibitor listing at present, the fastest medicine of research is that AVL-292(structure is not yet announced), in the clinical I phase, to study, irreversible selectivity suppresses Btk, is used for the treatment of leukemia and autoimmune disease.
It is target that the medicine that exploitation has good antitumor action and a treating autoimmune diseases effect is simultaneously take in the present invention, has found the Btk inhibitor of highly selective.
3, summary of the invention
It is target that the medicine that exploitation has good antitumor action and a treating autoimmune diseases effect is simultaneously take in the present invention, has found hetero-aromatic ring and the derivatives class tyrosine kinase inhibitor thereof of highly selective.
Concrete technical scheme is as follows, and the compound shown in following general formula (I), its pharmacy acceptable salt or its steric isomer are provided:
Wherein, X, Z and W independently represent respectively C-Ra or N,
And when X is C-Ra, when Z is different with W, be N,
Ra represents hydrogen atom, halogen atom ,-CN ,-CF
3, C
1-4alkyl, C
1-4alkoxyl group, amino or-OH;
Ring A and ring B independently represent respectively phenyl, and 3-7 unit cycloalkyl contains N, O, the heteroatomic 3-7 of S unit Heterocyclylalkyl, 4-7 unit's heteroaryl or 6-10 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 by one or two methyl or through trifluoromethyl, replace 1, the sub-propadiene base of 3-, 1,1-or vinylene, ethynylene, or be not substituted or by one to four methyl or 1,3-butadiene-Isosorbide-5-Nitrae-subunit of replacing through trifluoromethyl;
D represents covalent linkage or C
1-6alkylidene group;
E represents hydrogen atom, C
1-4alkoxyl group, amino, 3-7 unit cycloalkyl, 6-10 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;
R
2expression-L
4-R
5,
L
4represent covalent linkage ,-NH-,-N (C
1-3alkyl)-,-O-,-C (O)-,-C (O) NH-,-O-C
1-3alkylidene group-,-S-C
1-3alkylidene group-or-S (O)
m-,
R
5represent hydrogen atom, halogen atom ,-CN ,-CF
3, C
2-4thiazolinyl, C
2-4alkynyl, C
1-4alkyl, amino ,-NH (C
1-3alkyl) ,-N (C
1-3alkyl)
2,-OH ,-O (C
1-3alkyl), 3-7 unit cycloalkyl, phenyl or 5-6 unit heteroaryl;
Described C
1-4moieties, cycloalkyl, heteroaryl can be further by one to four Q
1replace,
Q
1represent 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) replaces;
Described heteroaryl contains 1-4 heteroatoms, is independently selected from respectively N, O or S;
M represents 0,1 or 2;
P and q independently represent respectively 0,1,2,3 or 4.
Be preferably:
Wherein, X, Z and W independently represent respectively C-Ra or N,
And when X is C-Ra, when Z is different with W, be N,
Ra represents hydrogen atom, halogen atom ,-CF
3, methyl, methoxyl group, amino or-OH;
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;
R
2expression-L
4-R
5,
L
4represent covalent linkage ,-NH-,-N (C
1-3alkyl)-,-O-,-C (O)-,-C (O) NH-,-O-C
1-3alkylidene group-,-S-C
1-3alkylidene group-or-S (O)
m-,
R
5represent hydrogen atom, halogen atom ,-CF
3, C
1-4alkyl, amino ,-NH (C
1-3alkyl) ,-N (C
1-3alkyl)
2,-OH ,-O (C
1-3alkyl) ,-C (O) (C
1-3alkyl) or 4-7 unit cycloalkyl;
Described C
1-4moieties, cycloalkyl, heteroaryl, spirane structure ring structure, caged scaffold can be further by one to four Q
1replace,
Q
1represent 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) replaces;
Described heteroaryl, spirane structure ring structure, caged scaffold contain 1-4 heteroatoms, are independently selected from respectively N, O or S;
M represents 0,1 or 2;
P and q independently represent respectively 0,1,2,3 or 4.
Be preferably:
Wherein, X, Z and W independently represent respectively CH or N,
And when X is CH, when Z is different with W, be N;
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
2expression-NH-independently respectively ,-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, and morpholinyl,
or two-(methyl) amino;
R
1represent hydrogen atom, halogen atom, the methyl, the methoxyl group that are not substituted or are replaced by one to four 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;
R
2represent hydrogen atom, fluorine atom, chlorine atom ,-CF
3, methyl, ethyl, sec.-propyl, amino, methylamino; ethylamino, two-(methyl) amino ,-OH, methoxyl group, oxyethyl group, formyl radical; ethanoyl, formamyl, methyl sulfenyl, ethyl sulfenyl, methyl sulphonyl, amino-sulfonyl; tetramethylene base, tetramethylene oxygen base, pentamethylene base, cyclohexyl, azetidinyl, pyrrolidyl; pyrrolidone-base, imidazolidine base, tetrahydrochysene oxazolyl, piperidyl, piperazinyl, morpholinyl; pyrazolyl, imidazolyl, triazol radical, pyridyl or pyrimidyl
Described methylamino, ethylamino, two-(methyl) amino, methyl sulfenyl, ethyl sulfenyl, methyl sulphonyl, amino-sulfonyl are further to be replaced by one or two identical or different methoxyl group, pyrrolidyl, imidazolidine base, piperidyl, morpholinyl, piperazinyl
Described tetramethylene base, pentamethylene base, cyclohexyl, phenyl, pyrryl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl group, pyridyl, pyrimidyl, azetidinyl, pyrrolidyl, imidazolidine base, tetrahydrochysene oxazolyl, piperidyl, morpholinyl, piperazinyl can be further by one or two identical or different Q
1replace,
Q
1represent halogen atom, methyl, amino, methylamino, dimethylamino, hydroxyl, methoxyl group, methoxycarbonyl, formamyl, methylamino formyl radical or two-(methyl) formamyl;
M represents 0,1 or 2;
P and q independently represent respectively 0,1 or 2.
Be preferably:
Wherein, X, Z and W independently represent respectively CH or N,
And when X is CH, when Z is different with W, be N;
Ring A and ring B independently represent respectively phenyl, pyridyl or piperidyl;
L
1and L
2respectively independently expression-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, and morpholinyl,
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 ,-NHC (O) O-C
3h
7,-O (CH
3) ,-O (C (CH
3)
3) ,-S (O)
2-C
3h
7, phenyl, pyrryl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl group or pyridyl,
Described phenyl, pyrryl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl group, pyridyl can be further by one or two identical or different Q
1replace,
Q
1represent formamyl, methylamino formyl radical or two-(methyl) formamyl;
R
2represent hydrogen atom, fluorine atom ,-CF
3, methyl, amino, methylamino;-OH, methoxyl group, ethanoyl, formamyl; be not substituted or by the ethylamino of methoxy substitution the ethyl sulfenyl that is not substituted or is replaced by methoxyl group, piperidyl, morpholinyl, two-(methyl) amino; methyl sulfenyl, methyl sulphonyl, amino-sulfonyl; tetramethylene base, cyclohexyl, azetidinyl; piperidyl, piperazinyl or morpholinyl
Described tetramethylene base, cyclohexyl, azetidinyl, piperidyl, piperazinyl, morpholinyl can be further by one or two identical or different methyl, amino, hydroxyl or methoxy substitution;
M represents 0,1 or 2;
P and q independently represent respectively 0 or 1.
More preferably:
Wherein, X, Z and W independently represent respectively CH or N,
And when X is CH, when Z is different with W, be N;
Ring A and ring B independently represent respectively phenyl;
L
1and L
2difference is expression-NH-independently;
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 O or-O-CH
2cH
2-, R
4expression-O (CH
3) or pyridyl,
Described pyridyl can be further by one or two identical or different Q
1replace Q
1represent formamyl, methylamino formyl radical or two-(methyl) formamyl;
R
2represent hydrogen atom, fluorine atom ,-CF
3, methyl, amino; methylamino ,-OH, methoxyl group; be not substituted or by the ethylamino of methoxy substitution the ethyl sulfenyl that is not substituted or is replaced by methoxyl group, morpholinyl, two-(methyl) amino; methyl sulfenyl, methyl sulphonyl, amino-sulfonyl; tetramethylene base; piperidyl, piperazinyl or morpholinyl
Described tetramethylene base, piperidyl, piperazinyl, morpholinyl can be further by one or two identical or different methyl, amino, hydroxyl or methoxy substitution;
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
1-6alkylidene group " refer to that the alkyl of the straight or branched that contains 1-6 carbon atom removes a structure after hydrogen atom, comprising " 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.Preferred 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.
" 3-7 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 " 3-6 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.
" 3-7 unit Heterocyclylalkyl " of the present invention refers to and contains the first cyclic group of one or more heteroatomic 3-7, and described " heteroatoms " refers to nitrogen-atoms, Sauerstoffatom, sulphur atom etc.The first heterocyclic radical of preferred 3-6, more preferably 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, isoxzzole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine etc.
" 6-10 unit two ring structures " refer to and contain the bicyclic groups (can not contain or contain and more than one heteroatoms) that 6-10 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] Dioxins base, six hydrogen-2H-pentamethylene is [b] [1 also, 4] Dioxins base,
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 two the formed 6-8 of adjacent atom unit cyclic groups, 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] Dioxins base, six hydrogen-2H-pentamethylene is [b] [Isosorbide-5-Nitrae] Dioxins base etc. also.
" 6-8 unit caged scaffold " of the present invention refers to by two or more ring texturees and shares each other two the formed 6-8 of non-conterminous atom unit cyclic groups, and its specific embodiment includes but are not limited to:
deng.
Particularly preferred compound comprises:
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 etc.
Reaction scheme:
Reactions steps:
The preparation of step 1 intermediate 1
5-bromouracil (1 equivalent) is mixed with raw material 1 (at least 5 equivalent), solvent-free, or add a small amount of polar solvent (water, ethanol, propyl carbinol etc.) heating (100-150 degree) stirring reaction a few hours to 5-bromouracil to disappear.Cooling, separate out solid, filter, obtain intermediate 1.When raw material 1 is mercaptan, need when reaction, add equivalent alkali (as sodium hydroxide).
The preparation of step 2 intermediate 2
Intermediate 1 (1 equivalent) is mixed with quantity of solvent phosphorus oxychloride (at least 10 equivalent), add approximately two equivalent DMAs, heating (90-110 degree) stirring reaction a few hours to intermediate 1 disappears.Cooling, pour in frozen water, separate out solid, filter, dry, obtain intermediate 2.Or concentration response system, column chromatography, obtains intermediate 2.
The preparation of step 3 intermediate 3
Method 1: intermediate 2 (1 equivalent) is mixed with raw material 2 (1.1-1.3 equivalent), add appropriate solvent (as tetrahydrofuran (THF), propyl carbinol etc.), heating (80-120 degree) stirring reaction a few hours to intermediate 2 disappears.Cooling, concentration response system, column chromatography, obtains intermediate 3.
Method 2: adopt Buchwald – Hartwig coupling.Intermediate 2 (1 equivalent) is mixed with raw material 2 (1-1.3 equivalent), add appropriate solvent (being generally toluene, dioxane etc.), the palladium catalyst of catalytic amount (is generally Pd
2(dba)
3, Pd (OAc)
2), the part of catalytic amount (being generally Xantphos, BINAP), alkali (Cs
2cO
3, NaOtBu) (1.1-1.5 equivalent), fully replaces rare gas element (as nitrogen, argon gas), and heating (70-120 degree) stirring reaction a few hours to intermediate 2 disappears.Cooling, concentration response system, column chromatography, obtains intermediate 3.
The preparation of step 4 intermediate 4
Method 1: intermediate 3 (1 equivalent) is mixed with raw material 3 (1-1.3 equivalent), add appropriate solvent (as the trimethyl carbinol, tertiary amyl alcohol etc.), add alkali (as DIEA, or the acid of catalytic amount (as acetic acid, trifluoroacetic acid etc.) 1-1.5 equivalent),, heating (80-120 degree), or under microwave, heating (80-120 degree) stirring reaction a few hours to intermediate 3 disappears.Cooling, concentration response system, column chromatography, obtains intermediate 4.
Method 2: adopt Buchwald-Hartwig coupling.Operation, with the method 2 of step 3, only need change raw material 2 into raw material 3.
The preparation of step 5 intermediate 5
Intermediate 4 (1 equivalent) is dissolved in to methylene dichloride, adds quantity of solvent trifluoroacetic acid, or pass into hydrogen chloride gas, room temperature or cooling lower stirring reaction to intermediate 4 disappears.Concentrated, obtain intermediate 5, be directly used in the next step.
The preparation of step 6 formula (I) compound
Intermediate 5 (1 equivalent) is dissolved in to suitable solvent (as THF, methylene dichloride, acetone, DMF, or be mixed solvent), the alkali (as DIEA) that adds 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 5 and disappear.Cancellation reaction, concentrated, column chromatography or mesolow are prepared liquid phase purifying and are obtained formula I compound.
X in reaction scheme, Z, W, R
1, R
2, R
3, L
1, L
2, a, b, c, d, e, p, q, A and B as mentioned before.
Clinically, formula I compound of the present invention, its steric isomer can be used with the form of dissociating or the form of its pharmacy acceptable salt.The aobvious alkalescence of formula I compound of the present invention, 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 I compound compound of the present invention 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 I compound compound of the present invention, 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 I compound compound of the present invention, 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 I compound compound of the present invention, its pharmacy acceptable salt 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 play an important role in autoimmune disorder (such as rheumatoid arthritis, systemic lupus erythematous etc.).
Formula I compound compound of the present invention, 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, people's method for example, the method comprises: at least one chemical entities providing in this article with the Mammals effective dosage of 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 the patient's of the acute inflammatory response for the treatment of the inhibition with autoimmunization and/or inflammatory diseases or response Btk activity and/or B cell proliferation method.
Autoimmunization and/or inflammatory diseases that use can affect according to compound of the present invention and composition 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 pernicious pathology of B cell, the pernicious B cell lymphoma that includes but not limited to of B cell, 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.
Shown 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 that 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).
To express the leukemia of the bcr-abl fusion gene that the transposition by chromosome dyad 9 and 22 causes relevant to some for Btk activity.Thisly extremely conventionally in chronic myelocytic derived leukocythemia, observe.Btk is in essence by bcr-abl tyrosine phosphorylation, this cause in bcr-abl cell, prevent apoptotic downstream survival signaling (N.Feldhahn etc., J.Exp.Med.2005,201 (11), 1837-1852).
The compounds of this invention is compared with immediate prior art, has the following advantages:
(1) formula I compound of the present invention or its pharmacy acceptable salt there is good BTK kinase inhibitory activity and side effect little;
(2) formula I compound of the present invention or its pharmacy acceptable salt demonstrate good biologically stable, and it is more lasting to act on, and bioavailability is high;
(3) the compounds of this invention preparation technology is simple, and medicine purity is high, steady quality, is easy to carry out large-scale commercial production.
By pharmacological evaluation, further set forth the compounds of this invention beneficial effect 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 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,pH?7.5，0.0015%Brij-35，10mM?MgCl2，2mM?DTT）；
2. stop buffer (100mM HEPES, pH 7.5,0.015%Brij-35,0.2%Coating Reagent#3,50mM EDTA);
3. 50 times of compound solutions (adopt solution that 100%DMSO sets 50 times of maximum concentrations using compound dissolution test preparation 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. to containing in 384 orifice plates of 5 μ L compound solutions, add 10 μ L 2.5 * enzyme solution;
5. hatch at ambient temperature 10min;
6. in every hole, add 10 μ L2.5 * peptide solution
4. reaction terminating
Hatch after appropriate time for 28 ℃, 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 GraphPad 5.0 softwares to carry out curve fitting, fit equation is Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X) * HillSlope)), draws IC
50value.
Experimental result: as follows:
In Vitro Anti bruton's tyrosine kinase (BTK) activity of table 1 the compounds of this invention
Wherein, +++ represent IC
50(nM) <50nM; ++ represent IC
50(nM) <500nM.
Experiment conclusion:
From table, the inhibition that 1 pair of BTK kinases of the compounds of this invention has had is active.
4, embodiment
The embodiment of form, is described in further detail foregoing of the present invention by the following examples.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.
the preparation of embodiment 14-(4-(6-(3-acrylamido anilino) pyrazine-2-base is amino) phenoxy group)-N-picoline-2-methane amide (compound 1)
(1) preparation of 3-(6-chloropyrazine-2-base is amino) the phenylcarbamic acid tert-butyl ester
Take 2,6-dichloropyrazine (3.0g, 20mmol); 3-aminophenyl t-butyl carbamate (4.165g, 20mmol), three (dibenzalacetone) two palladium (0.183g; 0.2mmol), 1,1 '-dinaphthalene-2; 2 '-bis-diphenyl phosphines (0.436g, 0.7mmol), potassium tert.-butoxide (4.49g; 40mmol), add 50mL toluene to make solvent, the reaction of nitrogen protection lucifuge is 4 hours at 90 ℃; after stopped reaction, cooling, directly measure 1/2 reaction solution and directly cast single step reaction.
(2) preparation of 3-(6-(4-(2-(methyl-carbamoyl) pyridin-4-yl oxygen base) anilino) pyrazine-2-base is amino) the phenylcarbamic acid tert-butyl ester
Measure the reaction solution of previous step 1/2; in reaction solution, add 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (2.43g; 10mmol); three (dibenzalacetone) two palladiums (91.5mg, 0.1mmol), 1; 1 '-dinaphthalene-2; 2 '-bis-diphenyl phosphines (140mg, 0.225mmol), potassium tert.-butoxide (2.24g; 20mmol); at 90 ℃, the reaction of nitrogen protection lucifuge is 6 hours, is cooled to room temperature after stopped reaction, and concentrating under reduced pressure is mixed sample; cross silicagel column; eluent ethyl acetate, obtains yellow solid 1.87g, and yield is 35.4%.
(3) preparation of 4-(4-(6-(3-amino-benzene amido) pyrazine-2-base is amino) phenoxy group)-N-picoline-2-methane amide
Take 3-(6-(4-(2-(methyl-carbamoyl) pyridin-4-yl oxygen base) anilino) pyrazine-2-base is amino) the phenylcarbamic acid tert-butyl ester (1.055g; 2.0mmol); add 5mL methylene dichloride; 5mL trifluoracetic acid; under ice-water bath, stir one hour; LC-MS shows that reaction finishes, and is spin-dried for to obtain thickness oily matter, directly casts single step reaction.
(4) preparation of 4-(4-(6-(3-acrylamido anilino) pyrazine-2-base is amino) phenoxy group)-N-picoline-2-methane amide
In dry reactor, 4-(4-(6-(3-amino-benzene amido) pyrazine-2-base is amino) the phenoxy group)-N-picoline-2-methane amide that adds step to obtain, tetrahydrofuran (THF) 20mL, at-10 ℃, add DIEA(2.1mL, 12mmol), reaction solution is alkalescence, keep this temperature to drip acrylate chloride (199mg, 2.2mmol), dropwise rear reaction 2 hours, after stopped reaction, directly mix sample, cross silicagel column, by little polarity, sweep away most of impurity, by ethyl acetate, sweep away product and small portion impurity, obtain brown color crude product, cross anti-phase preparative column purifying and obtain white product 115mg, two step yields are 11.9%.
Molecular formula: C
26h
23n
7o
3molecular weight: 481.19 mass spectrums (m/e): 481.8 (M).
1H-NMR(d
6-DMSO,400MHz)δ
ppm：10.50(1H,s),9.36(1H,s),9.22(1H,s),8.77(1H,d),8.48(1H,d),7.83(1H,s),7.74(2H,d),7.58(2H,d),7.39(1H,d),7.35(1H,d),7.24-7.14(2H,m),7.12(1H,dd),7.05(2H,d),6.34(1H,dd),6.14(1H,d),5.56(1H,d),2.77(3H,d).
the preparation of embodiment 24-(4-(6-(3-acrylamido anilino) pyridine-2-base is amino) phenoxy group)-N-picoline-2-methane amide (compound 2)
(1) preparation of 3-(6-bromopyridine-2-base is amino) the phenylcarbamic acid tert-butyl ester
Take 2,6-dibromo pyridine (3.0g, 12.7mmol), 3-aminophenyl t-butyl carbamate (3.17g, 15.2mmol), palladium (57mg, 0.25mmol), 1,1 '-dinaphthalene-2,2 '-bis-diphenyl phosphine (0.16g, 0.26mmol), salt of wormwood (6.0g, 43.4mmol), add 20mL toluene to make solvent, 116 ° of C microwave reactions 0.5 hour, after stopped reaction, concentrated, silica gel column chromatography (sherwood oil-sherwood oil: ethyl acetate=5:1) obtain yellow solid 1.9g, yield 41.1%.
(2) preparation of 3-(6-(4-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) anilino) pyridine-2-base is amino) the phenylcarbamic acid tert-butyl ester
Take 3-(6-bromopyridine-2-base is amino) the phenylcarbamic acid tert-butyl ester (1.9g; 5.22mmol); 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (1.27g; 5.22mmol); three (dibenzalacetone) two palladiums (48mg, 0.052mmol), 1; 1 '-dinaphthalene-2; 2 '-bis-diphenyl phosphines (113mg, 0.181mmol), potassium tert.-butoxide (1.16g; 10.3mmol); under 90 ° of C, the reaction of nitrogen protection lucifuge is 6 hours, stopped reaction, concentrating under reduced pressure; silica gel column chromatography (sherwood oil → sherwood oil: ethyl acetate=3:1) obtain off-white color solid 2.1g, yield is 76.4%.
(3) preparation of 4-(4-(6-(3-amino-benzene amido) pyridine-2-base is amino) phenoxy group)-N-picoline-2-methane amide
Take 3-(6-(4-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) anilino) pyridine-2-base is amino) the phenylcarbamic acid tert-butyl ester (1.0g; 1.9mmol); add 5mL methylene dichloride; 5mL trifluoracetic acid; under ice-water bath, stir 1 hour; LC-MS shows that reaction finishes, and is spin-dried for to obtain thick product, directly casts single step reaction.
(4) preparation of 4-(4-(6-(3-acrylamido anilino) pyridine-2-base is amino) phenoxy group)-N-picoline-2-methane amide
In dry reactor, 4-(4-(6-(3-amino-benzene amido) pyridine-2-base is amino) the phenoxy group)-N-picoline-2-methane amide that adds previous step, tetrahydrofuran (THF) 10mL, under-10 ° of C, add DIEA (0.49g, 3.8mmol), reaction solution is alkalescence, keep this temperature to drip acrylate chloride (190mg, 2.1mmol), dropwise rear reaction 2 hours, after stopped reaction, concentrated, silica gel column chromatography gradient elution (sherwood oil～sherwood oil: ethyl acetate=1:5) obtain red-brown solid 0.50g, two step yields are 54.7%.
Molecular formula: C
27h
24n
6o
3molecular weight: 480.19 mass spectrums (m/e): 480.8 (M).
1H-NMR(CDCl
3,400MHz)δ
ppm：8.38(1H,d),8.13-8.04(3H,m),7.65(1H,d),7.34-7.28(3H,m),7.25-7.14(2H,m),7.00(2H,dd),6.94(2H,d),6.88(1H,br?s),6.81(1H,br?s),6.40(1H,d),6.30-6.18(3H,m),5.66(1H,d),3.02(3H,d).
the preparation of embodiment 34-(4-(4-(3-acrylamido anilino)-5-(dimethylin) pyrimidine-2--amino) phenoxy group)-N-picoline-2-methane amide (compound 3)
(1) preparation of 4-(4-(4-bromopyridine-2-base is amino) phenoxy group)-N-picoline-2-methane amide
Take palladium (14mg; 0.062mmol) and Xantphos (0.244g; 0.422mmol) join 10mL 1; in 4-dioxane; under ice bath, add successively 2; 4-dibromo pyridine (0.50g, 2.11mmol), 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (0.513g; 2.11mmol) and potassium tert.-butoxide (0.356g; 3.17mmol), nitrogen protection, is warming up to 100 ° of C reactions 6 hours; cooling; concentrated, silica gel column chromatography gradient elution (sherwood oil～sherwood oil: ethyl acetate=1:1) obtain off-white color solid 0.42g, yield 49.8%.
(2) preparation of 3-(2-(4-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) anilino) pyridin-4-yl is amino) the phenylcarbamic acid tert-butyl ester
Take 4-(4-(4-bromopyridine-2-base is amino) phenoxy group)-N-picoline-2-methane amide (0.42g, 1.05mmol) with 3-aminophenyl t-butyl carbamate (0.219g, 1.05mmol) be mixed in 20mL ethanol, the HCl aqueous solution 10.5mL that adds 0.1M, be warming up to 90 ° of C reactions 72 hours, cooling, concentrated, silica gel column chromatography (methylene dichloride-methylene dichloride: methyl alcohol=20:1) obtain yellow solid 0.21g, yield 38%.
(3) preparation of 4-(4-(4-(3-amino-benzene amido) pyridine-2-base is amino) phenoxy group)-N-picoline-2-methane amide
Take 3-(2-(4-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) anilino) pyridin-4-yl is amino) the phenylcarbamic acid tert-butyl ester (0.21g; 0.399mmol); add 5mL methylene dichloride; under ice-water bath, add 5mL trifluoracetic acid; rise to stirring at room 1 hour; concentrated, directly cast single step reaction.
(4) preparation of 4-(4-(4-(3-acrylamido anilino) pyridine-2-base is amino) phenoxy group)-N-picoline-2-methane amide
To crude product obtained in the previous step, add 5mL methylene dichloride, under-10 ° of C, add DIEA (78mg, 0.6mmol), keep this temperature to drip acrylate chloride (36mg, 0.4mmol), dropwise rear reaction 0.5 hour, after stopped reaction, concentrated, preparative chromatography purifying (methyl alcohol: water=60%) obtain off-white color solid 40mg, two step yields are 20.9%.
Molecular formula: C
27h
24n
6o
3molecular weight: 480.19 mass spectrums (m/e): 480.6 (M).
1H-NMR(d
6-DMSO,400MHz)δ
ppm：10.25(1H,s),9.55-9.08(2H,br?s),8.77(1H,q),8.50(1H,d),7.81(1H,d),7.73(1H,s),7.66-7.55(2H,m),7.39(1H,d),7.31(2H,d),7.20-7.10(3H,m),6.97-6.89(1H,m),6.52-6.39(3H,m),6.24(1H,dd),5.74(1H,dd),2.77(3H,d).
With reference to above-mentioned preparation method, can also prepare following compound:
Claims (10)
1. lead to compound, its pharmacy acceptable salt or its steric isomer shown in formula I:
Wherein, X, Z and W independently represent respectively C-Ra or N,
And when X is C-Ra, when Z is different with W, be N,
Ra represents hydrogen atom, halogen atom ,-CN ,-CF
3, C
1-4alkyl, C
1-4alkoxyl group, amino or-OH;
Ring A and ring B independently represent respectively phenyl, and 3-7 unit cycloalkyl contains N, O, the heteroatomic 3-7 of S unit Heterocyclylalkyl, 4-7 unit's heteroaryl or 6-10 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 by one or two methyl or through trifluoromethyl, replace 1, the sub-propadiene base of 3-, 1,1-or vinylene, ethynylene, or be not substituted or by one to four methyl or 1,3-butadiene-Isosorbide-5-Nitrae-subunit of replacing through trifluoromethyl;
D represents covalent linkage or C
1-6alkylidene group;
E represents hydrogen atom, C
1-4alkoxyl group, amino, 3-7 unit cycloalkyl, 6-10 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;
R
2expression-L
4-R
5,
L
4represent covalent linkage ,-NH-,-N (C
1-3alkyl)-,-O-,-C (O)-,-C (O) NH-,-O-C
1-3alkylidene group-,-S-C
1-3alkylidene group-or-S (O)
m-,
R
5represent hydrogen atom, halogen atom ,-CN ,-CF
3, C
2-4thiazolinyl, C
2-4alkynyl, C
1-4alkyl, amino ,-NH (C
1-3alkyl) ,-N (C
1-3alkyl)
2,-OH ,-O (C
1-3alkyl), 3-7 unit cycloalkyl, phenyl or 5-6 unit heteroaryl;
Described C
1-4moieties, cycloalkyl, heteroaryl can be further by one to four Q
1replace,
Q
1represent 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) replaces;
Described heteroaryl contains 1-4 heteroatoms, is independently selected from respectively N, O or S;
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 pharmacy acceptable salt or its steric isomer:
Wherein, X, Z and W independently represent respectively C-Ra or N,
And when X is C-Ra, when Z is different with W, be N,
Ra represents hydrogen atom, halogen atom ,-CF
3, methyl, methoxyl group, amino or-OH;
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;
R
2expression-L
4-R
5,
L
4represent covalent linkage ,-NH-,-N (C
1-3alkyl)-,-O-,-C (O)-,-C (O) NH-,-O-C
1-3alkylidene group-,-S-C
1-3alkylidene group-or-S (O)
m-,
R
5represent hydrogen atom, halogen atom ,-CF
3, C
1-4alkyl, amino ,-NH (C
1-3alkyl) ,-N (C
1-3alkyl)
2,-OH ,-O (C
1-3alkyl) ,-C (O) (C
1-3alkyl) or 4-7 unit cycloalkyl;
Described C
1-4moieties, cycloalkyl, heteroaryl, spirane structure ring structure, caged scaffold can be further by one to four Q
1replace,
Q
1represent 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) replaces;
Described heteroaryl, spirane structure ring structure, caged scaffold contain 1-4 heteroatoms, are independently selected from respectively N, O or S;
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 pharmacy acceptable salt or its steric isomer:
Wherein, X, Z and W independently represent respectively CH or N,
And when X is CH, when Z is different with W, be N;
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
2expression-NH-independently respectively ,-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, and morpholinyl,
or two-(methyl) amino;
R
1represent hydrogen atom, halogen atom, the methyl, the methoxyl group that are not substituted or are replaced by one to four 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;
R
2represent hydrogen atom, fluorine atom, chlorine atom ,-CF
3, methyl, ethyl, sec.-propyl, amino, methylamino; ethylamino, two-(methyl) amino ,-OH, methoxyl group, oxyethyl group, formyl radical; ethanoyl, formamyl, methyl sulfenyl, ethyl sulfenyl, methyl sulphonyl, amino-sulfonyl; tetramethylene base, tetramethylene oxygen base, pentamethylene base, cyclohexyl, azetidinyl, pyrrolidyl; pyrrolidone-base, imidazolidine base, tetrahydrochysene oxazolyl, piperidyl, piperazinyl, morpholinyl; pyrazolyl, imidazolyl, triazol radical, pyridyl or pyrimidyl
Described methylamino, ethylamino, two-(methyl) amino, methyl sulfenyl, ethyl sulfenyl, methyl sulphonyl, amino-sulfonyl are further to be replaced by one or two identical or different methoxyl group, pyrrolidyl, imidazolidine base, piperidyl, morpholinyl, piperazinyl
Described tetramethylene base, pentamethylene base, cyclohexyl, phenyl, pyrryl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl group, pyridyl, pyrimidyl, azetidinyl, pyrrolidyl, imidazolidine base, tetrahydrochysene oxazolyl, piperidyl, morpholinyl, piperazinyl can be further by one or two identical or different Q
1replace,
Q
1represent halogen atom, methyl, amino, methylamino, dimethylamino, hydroxyl, methoxyl group, methoxycarbonyl, formamyl, methylamino formyl radical or two-(methyl) formamyl;
M represents 0,1 or 2;
P and q independently represent respectively 0,1 or 2.
4. compound as claimed in claim 3, its pharmacy acceptable salt or its steric isomer:
Wherein, X, Z and W independently represent respectively CH or N,
And when X is CH, when Z is different with W, be N;
Ring A and ring B independently represent respectively phenyl, pyridyl or piperidyl;
L
1and L
2respectively independently expression-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, and morpholinyl,
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 ,-NHC (O) O-C
3h
7,-O (CH
3) ,-O (C (CH
3)
3) ,-S (O)
2-C
3h
7, phenyl, pyrryl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl group or pyridyl,
Described phenyl, pyrryl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl group, pyridyl can be further by one or two identical or different Q
1replace,
Q
1represent formamyl, methylamino formyl radical or two-(methyl) formamyl;
R
2represent hydrogen atom, fluorine atom ,-CF
3, methyl, amino, methylamino;-OH, methoxyl group, ethanoyl, formamyl; be not substituted or by the ethylamino of methoxy substitution the ethyl sulfenyl that is not substituted or is replaced by methoxyl group, piperidyl, morpholinyl, two-(methyl) amino; methyl sulfenyl, methyl sulphonyl, amino-sulfonyl; tetramethylene base, cyclohexyl, azetidinyl; piperidyl, piperazinyl or morpholinyl
Described tetramethylene base, cyclohexyl, azetidinyl, piperidyl, piperazinyl, morpholinyl can be further by one or two identical or different methyl, amino, hydroxyl or methoxy substitution;
M represents 0,1 or 2;
P and q independently represent respectively 0 or 1.
5. compound as claimed in claim 4, its pharmacy acceptable salt or its steric isomer:
Wherein, X, Z and W independently represent respectively CH or N,
And when X is CH, when Z is different with W, be N;
Ring A and ring B independently represent respectively phenyl;
L
1and L
2difference is expression-NH-independently;
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 O or-O-CH
2cH
2-, R
4expression-O (CH
3) or pyridyl,
Described pyridyl can be further by one or two identical or different Q
1replace Q
1represent formamyl, methylamino formyl radical or two-(methyl) formamyl;
R
2represent hydrogen atom, fluorine atom ,-CF
3, methyl, amino; methylamino ,-OH, methoxyl group; be not substituted or by the ethylamino of methoxy substitution the ethyl sulfenyl that is not substituted or is replaced by methoxyl group, morpholinyl, two-(methyl) amino; methyl sulfenyl, methyl sulphonyl, amino-sulfonyl; tetramethylene base; piperidyl, piperazinyl or morpholinyl
Described tetramethylene base, piperidyl, piperazinyl, morpholinyl can be further by one or two identical or different methyl, amino, hydroxyl or methoxy substitution;
P represents 0;
Q represents 1.
6. compound as claimed in claim 5, its pharmacy acceptable salt or its steric isomer, wherein compound is selected from:
7. the preparation method who contains compound, 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)
Wherein X, Z, 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 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 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 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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