CN108721298A - As the pyrimido heterocyclic compound of bruton's tyrosine kinase inhibitor and its application - Google Patents

As the pyrimido heterocyclic compound of bruton's tyrosine kinase inhibitor and its application Download PDF

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CN108721298A
CN108721298A CN201710258052.2A CN201710258052A CN108721298A CN 108721298 A CN108721298 A CN 108721298A CN 201710258052 A CN201710258052 A CN 201710258052A CN 108721298 A CN108721298 A CN 108721298A
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alkyl
phenyl
optionally replaced
amino
optionally
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李洪林
丁健
徐玉芳
谢华
赵振江
陈海洋
刁妍妍
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East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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Abstract

The present invention relates to as bruton's tyrosine kinase inhibitor heterocyclic compound and its application.Specifically, the present invention relates to compounds, pharmaceutical composition containing compound of formula I wherein shown in the Formulas I for having bruton's tyrosine kinase inhibitory activity and the compound to prepare the application in treating or preventing bruton's tyrosine kinase relevant disease or inhibiting the drug of bruton's tyrosine kinase：

Description

As the pyrimido heterocyclic compound of bruton's tyrosine kinase inhibitor and its application
Technical field
The present invention relates to medicinal chemistry arts；Specifically, the present invention relates to inhibit to live with bruton's tyrosine kinase The compound of property and its application.
Background technology
Immunocyte can be generally divided into T cell and two class of B cell, and the Major Function of wherein B cell is that secretion is various anti- Body help human body resists the intrusion of various alien enemies.Bruton tyrosine kinase (bruton's tyrosine kinase) is mainly in B cell Expression, is distributed in lymphatic system, hematopoiesis and hematological system.It is drenched in recent years especially for B cell non-Hodgkin's in relation to B cell Bar cancer and rheumatoid arthritis the study found that bruton's tyrosine kinase often will appear unconventionality expression.Bruton's tyrosine Kinases is the Key kinases in B cell antigen receptor (BCR) signal path, can adjust maturation, the differentiation of normal B cells, It is closely related with a variety of B cell lymphoid tissue disorders.
Bruton's tyrosine kinase is the member of non-receptor protein tyrosine kinase Tec families.Tec families be the mankind it is non-by Be only second to the 2nd large family of Src families in body kinases, Major Members include bruton's tyrosine kinase, BMX (etk), ITK, TEC and TXK (RLK).Bruton's tyrosine kinase was determined in 1993 as people's X- linked agammaglobulinemias (X- Linked agammaglobulinemia, XLA) the defects of albumen.This albumen has table in B cell stages Up to (in addition to the thick liquid cell finally broken up), during pre-B lymphocyte transition is later stage B cell, bruton's tyrosine kinase For cell differentiation and increment institute indispensable gene, and in B cell lymphoma, acute lymphoblastic leukemia (ALL) and plasmacytoma In have expression.In addition, also there is a small amount of expression in bone marrow cell and erythroid progenitor cells.
Include 5 main domains in bruton's tyrosine kinase structure, is PH structural domains (Pleckstrin respectively Homology), TH structural domains (Tec homology), SH3 structural domains (Src homology 3), SH2 structural domains (Src Homology 2) and SH1 structural domains (Src homology1).Wherein PH structural domains include transcription factor BAP-135/TFII-I And the binding site of activity down-regulation factor PIN1, I bruton's tyrosine kinase, while also being responsible for that bruton's tyrosine is mediated to swash The effect of enzyme and the 2nd messenger phosphatidylinositol triphosphoric acid (PIP3).TH structural domains are adjacent with PH structural domains, residual by 80 amino acid Base is constituted, including bruton's tyrosine kinase motif (Zn co-factors binding site), PKC- β binding sites and rich proline base The conserved region of sequence.SH1 structural domains include that activation ring, ATP-binding site, catalyst converter and allosteric inhibit segment.Bu Ludun junket ammonia The activation (phosphorylation) of acid kinase initially occurs in the activation ring in SH1 structural domains, and further activation is happened at comprising master In SH2 the and SH3 structural domains for wanting autophosphorylation site.These SH structural domains also include that bruton's tyrosine kinase progress caryoplasm is worn There are multiple receptors in the required nuclear localization signal of shuttle (NLS) and nuclear export sequence (NES) bruton's tyrosine kinase downstream, including Growth factor, B cell antigen, chemotactic factor (CF) and nonspecific immunity receptor etc..Therefore, the activation energy of bruton's tyrosine kinase draws Send out various kinds of cell process, such as cell Proliferation, survival, differentiation, angiogenesis, cell factor synthesis and antigen submission.
Bruton's tyrosine kinase activation process is complicated, and the important step during this is that bruton's tyrosine kinase moves Move on to cell membrane.The stimulation that some receptors on cell membrane receive respective ligand is activated, and simultaneously phosphorus is raised in activation by knowing from experience It is acidified the signal transduction kinases PI3K of intracellular, the PI3K of phosphorylation then converts the PIP2 on film to the 2nd courier PIP3.PIP3 The PH structural domains of bruton's tyrosine kinase are attached to, bruton's tyrosine kinase can then be raised to cell membrane, Tyr-551 Residue then carries out autophosphorylation to have physiological activity work by Syk and Lyn tyrosine phosphorylations in Tyr-223 residues The bruton's tyrosine kinase of change can be combined by its SH2 structural domain with adaptin BLNK/SLP65, the compound of generation with Post activation phospholipase C γ 2 (PLC- γ 2), and then cause cascade reaction and eventually lead to flow of calcium ions lasting into the cell, and Indirect activation downstream signaling pathway, such as MEK/ERK, p38MAPK, NK/SAPK access.Bruton's tyrosine kinase function acquisition type Mutation has also been confirmed in colorectal cancer, acute lymphoblastic leukemia (ALL), chronic myelocytic leukemia (CML).Cause This, the occurrence and development that the abnormal activation of bruton's tyrosine kinase dependent form access is proved to kinds of tumors are closely related.
Bruton's tyrosine kinase micromolecular inhibitor has treatment hematologic malignancies and Autoimmune Disorders disease There is good prospect.It is current most noticeable bruton's tyrosine kinase targeted inhibition agent to replace Buddhist nun (ibrutinib) according to Shandong, There is significant therapeutic effect to a variety of B cell tumours and autoimmune disease in preclinical and clinical research, by the U.S. FDA approval listings, for treating lymphoma mantle cell (MCL) and CLL.Other multiple compounds, such as CC-292 and ONO-4059, Also clinical investigation phase or clinical late conceptual phase are had been enter into.
There is still a need for exploitation activity height, the bruton's tyrosine kinase inhibitor of high specificity for this field.
Invention content
The purpose of the present invention is to provide active high, high specificity bruton's tyrosine kinase inhibitor and its preparing Treat the application in the disease mediated drug of bruton's tyrosine kinase.
In a first aspect, the present invention, which provides compound or its salt shown in Formulas I, is preparing bruton's tyrosine kinase inhibitor Or the purposes in the drug of the disease of preparation treatment or prevention bruton's tyrosine kinase mediation：
In formula,
R is hydrogen, C1-C3Low alkyl group, C1-C3Lower alkoxy, halogen (for example, F, Cl, Br), amino, substituted ammonia Base；
X is N or CR5R6；
Y is C or O；
When X is N,For double bond, and Y is C；
When X is CR5R6When,For singly-bound, and Y is O；Or when X is CR5R6When,For double bond, and Y is C；
B is selected from the group：(C3-C8) naphthenic base, (C3-C8) heterocycle, (C6-C10) aryl or the (C5- optionally replaced C10) aromatic heterocyclic；
R1It is selected from：H, the C optionally replaced1-C6Alkyl, NR7R8, the optionally C that replaces6-C10Aryl；
R3It is selected from：Hydrogen, the C optionally replaced1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, the C optionally replaced3-C8Cycloalkanes Base, the C optionally replaced1-C10Alkoxy, the aryl optionally replaced, the benzyl optionally replaced, the heterocycle optionally replaced, optionally Substituted aromatic heterocyclic ,-O- (CH)z-O-C1-C3Alkyl；Z be 1-3 integer, preferably 1；
R4It is selected from：Hydrogen, the C optionally replaced1-C6Alkyl, nitro, amino, halogen, the C optionally replaced1-C6Alkoxy, optionally Substituted acyloxy, the acylamino- optionally replaced, the acyl group optionally replaced；
M stands alone as 0-7, preferably 1-7, the integer of more preferable 1-3；
R5And R6Respectively stand alone as H or C1-C6Alkyl (preferably C1-C3Alkyl)；
R7And R8Respectively stand alone as H or C1-C6Alkyl.
In a preferred embodiment, B is selected from various substituted phenyl ring, nitrogenous five-membered ring, nitrogenous hexatomic ring or C3-C8Ring Alkyl.
In a particular embodiment, B is selected from：
R4It is selected from：
In a particular embodiment, the compound is as shown in following formula I -1：
In formula,
A is phenyl ring, five yuan or hexa-member heterocycle, C3-C8Naphthenic base or R '；
When A is R ', n 0, and R ' is selected from C1-C6Alkyl, C1-C6Halogenated alkyl or C6-C10Aryl formoxyl；
R2It is selected from：Hydrogen, halogen, the C optionally replaced1-C6Alkoxy, the acyloxy optionally replaced, amino, optionally takes hydroxyl The acylamino- in generation, the C optionally replaced1-C6Alkyl, sulfonic group, amino-sulfonyl, carbamoyl, carboxyl, optionally replaces CN Alkoxyl formyl, the N- alkylpiperazinyls optionally replaced, the morpholinyl that optionally replaces, optionally replaces the phenyl optionally replaced Piperidyl, the pyrrole radicals optionally replaced, the pyrrolidinyl ,-NR optionally replacedaRb, the optional pyridyl group that replaces；RaAnd RbRespectively It is independently selected from alkyl and alkenyl；
N stands alone as 0-7, preferably 1-7, the integer of more preferable 1-3；
X、Y、B、R1、R3、R4It is as defined above with m.
In a particular embodiment, the compound is as shown in Formula Il -1：
In formula,
B、R2、R3、R4, m and n it is as defined above；
Alternatively, the compound is as shown in Formula Il -2：
In formula,
B、R2、R4、R5、R6, m and n it is as defined above；
Alternatively, the compound is as shown in Formula Il -3：
In formula,
B、R1、R2、R3、R4, m and n it is as defined above.
In a particular embodiment,
In Formula II -1,
R2It is selected from：Hydrogen, halogen, the C optionally replaced1-C6Alkoxy, the pyrrolidinyl ,-NR optionally replacedaRb, carbamyl Base, the acylamino- optionally replaced ,-(CH2)oThe N- alkylpiperazinyls that optionally replace, optionally replace the morpholinyl that optionally replaces Piperidyl, the integer that o is 0-2, RaAnd RbIt is each independently selected from C1-C3Alkyl；Wherein R2It is not located at 2 of its residing phenyl ring；
R3It is selected from：Hydrogen, the C optionally replaced1-C6Alkyl, the C optionally replaced6-C10Aryl, the C optionally replaced3-C8Cycloalkanes Base；
B is selected from phenyl ring or nitrogenous five-membered ring；
R4It is selected from：The acylamino- optionally replaced, the acyl group optionally replaced；
M and n are as defined above；
In Formula II -2,
R5、R6It is independently selected from H, substituted or unsubstituted C1-C6(preferably C1-C3) alkyl；
B is phenyl ring；
R2It is selected from：The C optionally replaced1-C6Alkyl (preferably C1-C3Alkyl), the N- alkylpiperazinyls that optionally replace, optionally take The C in generation1-C6Alkoxy (preferably C1-C3Alkoxy)；
R4It is selected from：The acylamino- optionally replaced；
M and n are as defined above.
In second aspect, the present invention provides compound selected from the group below or its pharmaceutically acceptable salt and is preparing Bu Ludun Tyrosine kinase inhibitor or preparation treat or prevent the purposes in the drug for the disease that bruton's tyrosine kinase mediates：
In a particular embodiment, the disease that the bruton's tyrosine kinase mediates is cancer or is lost with autoimmunity Adjust disease.
In a particular embodiment, the cancer is selected from the group：Acute lymphoblastic leukemia (ALL), chronic grain are thin Born of the same parents' leukaemia (CML), lymphoma mantle cell (MCL), colorectal cancer；The Autoimmune Disorders disease include rheumatoid arthritis, Anti- organ transplant rejection, psoriasis, lupus erythematosus.
In the third aspect, the present invention provides the disease method that bruton's tyrosine kinase mediates that treats or prevents, including will Compound described in first or second aspect of the present invention or the pharmaceutical composition comprising the compound give pair of this needs As.
In fourth aspect, the present invention provides compound or its pharmaceutically acceptable salt shown in Formulas I：
In formula,
X、Y、B、R1、R3、R4It is as defined above with m；
Wherein,
R is hydrogen, C1-C3Low alkyl group, C1-C3Lower alkoxy, halogen (for example, F, Cl, Br), amino or NRcRd, and Rc、RdIt is independently selected from H, C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；
And/or
R3It is selected from the group：Hydrogen, (C3-C6) naphthenic base, (C1-C8) heterocycle, (C1-C8) alkoxy ,-O- (CH)n-O-C1-C3 Alkyl, benzyl, (C6-C10) aryl or (C5-C10) aromatic heterocyclic, wherein the aryl and aromatic heterocyclic are optionally with one Replace to five or less groups：Halogen, nitro, cyano, hydroxyl, amino, (C1-C8) alkyl, (C1-C8) alkoxy, (C3-C6) ring Alkyl, (C6-C10) aryloxy group, (C5-C10) heterocycle ,-O- (CH)z-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle Alkyl oxy, amide groups, the carbamoyl optionally replaced；Z be 1-3 integer, preferably 1；
And/or
R4It is selected from the group：
In a preferred embodiment,
R is hydrogen, C1-C3Low alkyl group, C1-C3Lower alkoxy, halogen (for example, F, Cl, Br), amino；
R3It is selected from the group：Hydrogen, (C3-C6) naphthenic base, (C1-C8) heterocycle, (C1-C8) alkoxy ,-O- (CH)n-O-C1-C3 Alkyl, benzyl, (C6-C10) aryl or (C5-C10) aromatic heterocyclic, wherein the aryl and aromatic heterocyclic are optionally with one Replace to five or less groups：Halogen, nitro, cyano, hydroxyl, amino, (C1-C8) alkyl, (C1-C8) alkoxy, (C3-C6) ring Alkyl, (C6-C10) aryloxy group, (C5-C10) heterocycle ,-O- (CH)z-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle Alkyl oxy, amide groups, the carbamoyl optionally replaced；Z be 1-3 integer, preferably 1；
Or
R is hydrogen, C1-C3Low alkyl group, C1-C3Lower alkoxy, halogen (for example, F, Cl, Br), amino；
R4It is selected from the group：
Or
R3It is selected from the group：Hydrogen, (C3-C6) naphthenic base, (C1-C8) heterocycle, (C1-C8) alkoxy ,-O- (CH)n-O-C1-C3 Alkyl, benzyl, (C6-C10) aryl or (C5-C10) aromatic heterocyclic, wherein the aryl and aromatic heterocyclic are optionally with one Replace to five or less groups：Halogen, nitro, cyano, hydroxyl, amino, (C1-C8) alkyl, (C1-C8) alkoxy, (C3-C6) ring Alkyl, (C6-C10) aryloxy group, (C5-C10) heterocycle ,-O- (CH)z-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle Alkyl oxy, amide groups, the carbamoyl optionally replaced；Z be 1-3 integer, preferably 1；
R4It is selected from the group：
In a particular embodiment, the compound is as shown in following formula I -1：
In formula,
A is that R ', n 0, and R ' are selected from C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；
X、Y、B、R1、R3、R4It is as defined above with m.
In a particular embodiment, R ' is C1-C6Alkyl (preferably C1-C3Alkyl), C1-C6Halogenated alkyl (preferably C1-C3 Halogenated alkyl).
In a particular embodiment, R3It is selected from the group：
In a particular embodiment, R3For：
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.
Specific implementation mode
After extensive and in-depth study, it was unexpectedly found that the compound that a collection of structure is completely new, these spread out inventor Biology can high activity, inhibit bruton's tyrosine kinase with high selectivity, the bruton's tyrosine of some of compounds swashs The IC of enzyme inhibition activity50Value reaches nM ranks.The present invention is completed on this basis.
The present inventor has synthesized a series of candidate compounds with bruton's tyrosine kinase inhibitory activity.By to obtaining The candidate compound arrived carries out Optimal Structure Designing, it was found that a batch is novel to have potential bruton's tyrosine kinase inhibitory activity Pyrimido-pyrimidine heterocyclic compounds.Molecular level activity rating is carried out to obtained compound, multiple compounds are to cloth Shandong tyrosine-kinase enzyme inhibition activity IC50Value reaches nM ranks.
Term defines
Group of the present invention has the meaning that this field routinely understands.For clarity, present document relates to some Group definition is as follows：
Herein, " alkyl " refers to the branched-chain or straight-chain alkyl for the saturation that carbon chain lengths are 1-10 carbon atom, preferred alkane Base includes long 2-8,1-6,1-4,3-8, the alkyl of 1-3 carbon atom not etc..The example of alkyl includes but not limited to： Methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, heptyl etc..Alkyl can be replaced by one or more substituent groups, example Such as replaced by halogen or halogenated alkyl.For example, alkyl can be by alkyl or alkyl that 1-4 fluorine atom replaces The alkyl replaced by fluoro-alkyl.Alkyl as described herein can also be substituted with aryl, to be formed, such as benzyl.
Similarly, it is 3-10 that herein " naphthenic base ", which refers to carbon chain lengths, the substitution of preferably 3-8 carbon atom or not Substituted saturated cyclic alkyls, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl etc..
Herein, " alkoxy " refers to by alkyl-substituted oxygroup.Preferred alkoxy is the alcoxyl of long 1-6 carbon atom Base, the alkoxy of more preferably long 1-4 carbon atom, the alkoxy of more preferably long 1-3 carbon atom.The example packet of alkoxy It includes but is not limited to：Methoxyl group, ethyoxyl, propoxyl group etc..Alkoxy can be replaced by one or more substituent groups, such as by halogen Or halogenated alkyl substitution.For example, it can be by fluoro that alkoxy, which can be by alkyl or alkyl that 1-4 fluorine atom replaces, Alkyl-substituted alkyl.
Herein, " alkenyl " usually indicates the univalence hydrocarbyl at least one double bond, and it is former to usually contain 2-8 carbon Son preferably comprises 2-6 carbon atom, can be linear chain or branched chain.The example of alkenyl includes but not limited to vinyl, propylene Base, isopropenyl, cyclobutenyl, isobutenyl, hexenyl etc..
Herein, " alkynyl " usually indicates the univalence hydrocarbyl at least one three key, usually contains 2-8 carbon atom, 2-6 carbon atom is preferably comprised, more generally contains 2-4 carbon atom, can be linear chain or branched chain.The example of alkenyl includes second Alkynyl, propinyl, isopropynyl, butynyl, butynyl, hexin base etc..
Herein, " halogen " refers to fluorine, chlorine, bromine or iodine.
Herein, " aryl " refers to the monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms, including phenyl, naphthalene Base, phenanthryl, anthryl, indenyl, Fluorene bases, tetrahydro naphthyl, indanyl etc..Aryl optionally by 1-5 (for example, 1,2, 3,4 or 5) substituent group substitution selected from the following：Halogen, C1-4 aldehyde radicals, C1-6 alkyl, cyano, nitro, amino, hydroxyl, hydroxyl first Alkoxy (such as trifluoromethoxy), carboxyl, the C1-4 alkane that base, the alkyl (such as trifluoromethyl) of halogen substitution, halogen replace Oxygroup, ethoxycarbonyl, N (CH3) and C1-4 acyl groups etc., heterocycle or heteroaryl etc..
" heterocycle " used herein includes but not limited to heteroatomic 5 yuan or 6 circle heterocyclic rings for being selected from O, S or N containing 1-3 Group, including but not limited to furyl, thienyl, pyrrole radicals, pyrrolidinyl, pyrazolyl, imidazole radicals, triazolyl, oxazolyls, pyrrole It mutters base, pyridyl group, pyrimidine radicals, pyrazinyl, piperidyl, morpholinyl etc..
" aromatic heterocyclic " used herein refers to and having 6,10 or 14 electronics in ring body containing 5-14 annular atom It fastens shared.And institute's ontaining annular atoms are carbon atom and optional 1-3 hetero atom from oxygen, nitrogen, sulphur.Useful aromatic heterocyclic Including piperazinyl, morpholinyl, piperidyl, pyrrolidinyl, thienyl, furyl, pyranose, pyrrole radicals, imidazole radicals, pyrazolyl, Pyridyl group, including but not limited to 2- pyridyl groups, 3- pyridyl groups and 4- pyridyl groups, pyrazinyl, pyrimidine radicals etc..
Aromatic heterocyclic is optionally replaced by 1-5 (for example, 1,2,3,4 or 5) substituent groups selected from the following：Halogen, C1-4 aldehyde radicals, C1-6 linear or branched alkyl groups, cyano, nitro, amino, hydroxyl, methylol, halogen substitution alkyl (such as three Methyl fluoride), halogen substitution alkoxy (such as trifluoromethoxy), carboxyl, C1-4 alkoxies, ethoxycarbonyl, N (CH3) and C1-4 acyl groups.
Herein, " acyloxy " refers to the group that structural formula is "-O-C (O)-R ", wherein R can be selected from alkyl, alkenyl (example Such as, C1-6 or C1-3 alkenyls) and alkynyl.The R is optionally substituted.
Herein, " acylamino- " refers to the group that structural formula is "-R '-NH-C (O)-R ", wherein and R ' can be selected from hydrogen or alkyl, R can be selected from alkyl, alkenyl (for example, C1-6 or C1-3 alkenyls), alkynyl, by NRcRdSubstituted alkyl, by NRcRdSubstitution Alkenyl and NRcRdSubstituted alkynyl, the alkyl being optionally substituted by halogen, the alkenyl replaced by cyano, wherein RcAnd RdIt can be selected from Alkyl and alkenyl.
Herein, acyl group refers to that organic or inorganic oxyacid removes remaining atomic group after one or more hydroxyls, is led to Formula such as R-C (O)-shown, wherein R can be selected from alkyl, alkenyl (for example, C1-6 or C1-3 alkenyls), alkynyl, by NRcRdIt takes The alkyl in generation, by NRcRdSubstituted alkenyl and NRcRdSubstituted alkynyl, the alkyl being optionally substituted by halogen, the chain replaced by cyano Alkenyl, wherein RcAnd RdIt can be selected from alkyl and alkenyl.
" aryl formoxyl " used herein refers to aryl, such as (C6-C10) aryl and formoxyl formation, and is passed through The group that formoxyl is connected with the agent structure of compound.
Herein, " optionally replace " and refer to substituent group that it is modified optionally by 1-5 (for example, 1,2,3,4 or 5 It is a) substituent group substitution selected from the following：Halogen, C1-4 aldehyde radicals, C1-6 linear or branched alkyl groups, cyano, nitro, amino, hydroxyl, Alkoxy (such as trifluoromethoxy), carboxyl, the C1- that methylol, the alkyl (such as trifluoromethyl) of halogen substitution, halogen replace 4 alkoxies, ethoxycarbonyl, N (CH3) and C1-4 acyl groups.
The compound of the present invention and its application
For the purpose of the present invention, the present invention provides compound or its salt shown in following formula I and swashs preparing bruton's tyrosine Enzyme inhibitor or preparation treat or prevent the purposes in the drug for the disease that bruton's tyrosine kinase mediates：
In formula,
R is hydrogen, C1-C3Low alkyl group, C1-C3Lower alkoxy, halogen (for example, F, Cl, Br), amino, substituted ammonia Base；
X is N or CR5R6；
Y is C or O；
When X is N,For double bond, and Y is C；
When X is CR5R6When,For singly-bound, and Y is O；Or when X is CR5R6When,For double bond, and Y is C；
B is selected from the group：(C3-C8) naphthenic base, (C3-C8) heterocycle, (C6-C10) aryl or the (C5- optionally replaced C10) aromatic heterocyclic；R1It is selected from：H, the C optionally replaced1-C6Alkyl, NR7R8, the optionally C that replaces6-C10Aryl；R3It is selected from：Hydrogen, The C optionally replaced1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, the C optionally replaced3-C8Naphthenic base, the C optionally replaced1-C10 Alkoxy, the aryl optionally replaced, the benzyl optionally replaced, the heterocycle optionally replaced, the aromatic heterocyclic ,-O- optionally replaced (CH)z-O-C1-C3Alkyl；Z be 1-3 integer, preferably 1；R4It is selected from：Hydrogen, the C optionally replaced1-C6Alkyl, nitro, amino, halogen Element, the C optionally replaced1-C6Alkoxy, the acyloxy optionally replaced, the acylamino- optionally replaced, the acyl group optionally replaced；M is only It stands as 0-7, preferably 1-7, the integer of more preferable 1-3；R5And R6Respectively stand alone as H or C1-C6Alkyl (preferably C1-C3Alkyl)；R7 And R8Respectively stand alone as H or C1-C6Alkyl.
In a preferred embodiment, B is selected from various substituted phenyl ring, nitrogenous five-membered ring, nitrogenous hexatomic ring or C3-C8Ring Alkyl.
Further, B can be selected from：
R4It is selected from：
Further, the compound of the present invention can be as shown in following formula I -1：
In formula,
A is phenyl ring, five yuan or hexa-member heterocycle, C3-C8Naphthenic base or R '；
When A is R ', n 0, and R ' is selected from C1-C6Alkyl, C1-C6Halogenated alkyl or C6-C10Aryl formoxyl；
R2It is selected from：Hydrogen, halogen, the C optionally replaced1-C6Alkoxy, the acyloxy optionally replaced, amino, optionally takes hydroxyl The acylamino- in generation, the C optionally replaced1-C6Alkyl, sulfonic group, amino-sulfonyl, carbamoyl, carboxyl, optionally replaces CN Alkoxyl formyl, the N- alkylpiperazinyls optionally replaced, the morpholinyl that optionally replaces, optionally replaces the phenyl optionally replaced Piperidyl, the pyrrole radicals optionally replaced, the pyrrolidinyl ,-NR optionally replacedaRb, the optional pyridyl group that replaces；RaAnd RbRespectively It is independently selected from alkyl and alkenyl；
N stands alone as 0-7, preferably 1-7, the integer of more preferable 1-3；
X、Y、B、R1、R3、R4It is as defined above with m.
Still further, the compound of the present invention is as shown in Formula Il -1：
In formula,
B、R2、R3、R4, m and n it is as defined above；
Alternatively, the compound is as shown in Formula Il -2：
In formula,
B、R2、R4、R5、R6, m and n it is as defined above；
Alternatively, the compound is as shown in Formula Il -3：
In formula,
B、R1、R2、R3、R4, m and n it is as defined above.
Still further,
In Formula II -1,
R2It is selected from：Hydrogen, halogen, the C optionally replaced1-C6Alkoxy, the pyrrolidinyl ,-NR optionally replacedaRb, carbamyl Base, the acylamino- optionally replaced ,-(CH2)oThe N- alkylpiperazinyls that optionally replace, optionally replace the morpholinyl that optionally replaces Piperidyl, the integer that o is 0-2, RaAnd RbIt is each independently selected from C1-C3Alkyl；Wherein R2It is not located at 2 of its residing phenyl ring；
R3It is selected from：Hydrogen, the C optionally replaced1-C6Alkyl, the C optionally replaced6-C10Aryl, the C optionally replaced3-C8Cycloalkanes Base；
B is selected from phenyl ring or nitrogenous five-membered ring；
R4It is selected from：The acylamino- optionally replaced, the acyl group optionally replaced；
M and n are as defined above；
In Formula II -2,
R5、R6It is independently selected from H, substituted or unsubstituted C1-C6(preferably C1-C3) alkyl；
B is phenyl ring；
R2It is selected from：The C optionally replaced1-C6Alkyl (preferably C1-C3Alkyl), the N- alkylpiperazinyls that optionally replace, optionally take The C in generation1-C6Alkoxy (preferably C1-C3Alkoxy)；
R4It is selected from：The acylamino- optionally replaced；
M and n are as defined above.
In a particular embodiment, the present invention provides compound selected from the group below or its pharmaceutically acceptable salt is being made Standby bruton's tyrosine kinase inhibitor is prepared in the drug for treating or preventing the disease that bruton's tyrosine kinase mediates Purposes：
Upper table is shown in the structure and its bruton's tyrosine kinase inhibitory activity of the compounds of this invention, wherein：
Activity is appointed as the IC of the compound of " A "50≤10nM；
Activity is appointed as the IC of the compound of " B "50It is 10<IC50≤100nM；
Activity is appointed as the IC of the compound of " C "50It is 100<IC50≤1000nM；
Activity is appointed as the IC of the compound of " D "50For 1000nM<IC50。
On the basis of the compounds of this invention can have bruton's tyrosine kinase inhibitory activity, the present invention provides a kind of Pharmaceutical composition for inhibiting bruton's tyrosine kinase, the composition contain therapeutically effective amount the compound of the present invention or Its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient.
The example of the pharmaceutically acceptable salt of the compounds of this invention includes but not limited to inorganic and acylate, such as salt Hydrochlorate, hydrobromate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and grass Hydrochlorate；And it is formed with alkali such as sodium hydroxyl, three (hydroxymethyl) aminomethanes (TRIS, amine butantriol) and N-METHYL-ALPHA-L-GLUCOSAMINE Inorganic and organic alkali salt.
Although each Man's Demands are different, those skilled in the art can determine that each in pharmaceutical composition of the present invention is lived The optimal dose of property ingredient.Under normal circumstances, the compound of the present invention or its pharmaceutically acceptable salt, it is daily to mammal Oral medication, dose is according to about 0.0025 to 50 mg kg of body weight.It is preferred that about 0.01 to 10 milli of per kilogram oral medication Gram.For example, unit oral doses may include about 0.01 to 50 milligrams, preferably about 0.1 to 10 milligrams of the compounds of this invention. Unit dose can be given one or many, be daily one or more pieces, and every contains about 0.1 to 50 milligrams, and eligibly about 0.25 To 10 milligrams of the compounds of this invention or its solvate.
The pharmaceutical composition of the present invention can be formulated into the dosage form of suitable various administration routes, including but not limited to quilt It is configured to for parenteral, subcutaneously, vein, muscle is intraperitoneal, transdermal, and oral cavity is intrathecal, encephalic, nasal cavity or topical route administration Form, for treating tumour and other diseases.Dosage is to effectively improve or eliminate the dose of one or more illnesss.For The treatment of specified disease, effective quantity are the doses for being enough to improve or in some manner mitigate symptom related with disease.It is such Dose can be used as single dose application, or can be administered according to effective therapeutic scheme.Dosage also permits healing disease, still It is administered typically to the symptom for improving disease.Repetitively administered is generally required to realize that required symptom improves.The dosage of medicine will According to the age of patient, health and weight, the type of concurrent treatment, the frequency for the treatment of and required treatment benefit determine.
The pharmaceutical preparation of the present invention can give any mammal, as long as they can obtain the treatment of the compounds of this invention Effect.The most importantly mankind in these mammals.
The compound of the present invention or its pharmaceutical composition can be used for treating the various diseases mediated by bruton's tyrosine kinase Disease.Herein, the disease that the bruton's tyrosine kinase mediates is cancer or autoimmune disease；Wherein, the cancer Including hematologic malignancies or solid tumor, such as：Acute lymphoblastic leukemia (ALL), chronic myelocytic leukemia (CML), Lymphoma mantle cell (MCL), colorectal cancer；The autoimmune disease includes rheumatoid arthritis, anti-organ transplant rejection, anti-ox Psoriasis or lupus erythematosus.
The pharmaceutical preparation of the present invention can manufacture in a known manner.For example, by traditional mixing, granulation, ingot processed, dissolving, Or freezing dry process manufacture.When manufacturing oral preparation, in combination with solid adjuvant material and reactive compound, selective ground and mixed Object.After if necessary or appropriate amount of addition agent being added when necessary, granulate mixture is processed, obtains tablet or pastille core.
Suitable auxiliary material especially filler, such as carbohydrate such as lactose or sucrose, mannitol or sorbierite；Cellulose preparation or Calcium phosphate, such as tricalcium phosphate or calcium monohydrogen phosphate；And binder, such as gelatinized corn starch, including cornstarch, wheaten starch, Rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, or Polyvinylpyrrolidone.If desired, can increase disintegrant, than starch as mentioned above and carboxymethyl starch, crosslinking is poly- Vinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate.Adjuvant especially flowing regulator and lubricant, example Such as, silica, talcum, stearates, such as magnesium calcium stearate, stearic acid or polyethylene glycol.If desired, Ke Yi Give pastille cores The suitable coating of gastric juice can be resisted by providing.For this purpose, concentration saccharide solution can be applied.This solution can contain Arabic tree Glue, talcum, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide paint solution and suitable organic solvent or solvent mixing Object.In order to prepare the coating of resistant to gastric juice, cellulose solution appropriate, such as cellulose acetate phthalic acid or hydroxypropyl can be used Ylmethyl cellulose phthalic acid.Dyestuff or pigment can be added to the coating of tablet or pastille core.For example, for identification or In order to characterize the combination of active constituent dosage.
Based on above compound and pharmaceutical composition, the present invention further provides treat or prevent bruton's tyrosine kinase The method of the disease of mediation, this method include giving the object of this needs with the compound of the present invention or pharmaceutical composition.It gives Prescription method includes but not limited to various medications well known in the art, can be determined according to the actual conditions of patient.These Method is including but not limited to parenteral, subcutaneous, vein, muscle, intraperitoneal, transdermal, oral cavity, intrathecal, encephalic, nasal cavity or topical route Administration.
In a particular embodiment, the present invention provides compound or its salts shown in the completely new Formulas I of structure：
In formula,
X、Y、B、R1、R3、R4It is as defined above with m；
Wherein,
R is hydrogen, C1-C3Low alkyl group, C1-C3Lower alkoxy, halogen (for example, F, Cl, Br), amino or NRcRd, and Rc、RdIt is independently selected from H, C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；
And/or
R3It is selected from the group：Hydrogen, (C3-C6) naphthenic base, (C1-C8) heterocycle, (C1-C8) alkoxy ,-O- (CH)n-O-C1-C3 Alkyl, benzyl, (C6-C10) aryl or (C5-C10) aromatic heterocyclic, wherein the aryl and aromatic heterocyclic are optionally with one Replace to five or less groups：Halogen, nitro, cyano, hydroxyl, amino, (C1-C8) alkyl, (C1-C8) alkoxy, (C3-C6) ring Alkyl, (C6-C10) aryloxy group, (C5-C10) heterocycle ,-O- (CH)z-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle Alkyl oxy, amide groups, the carbamoyl optionally replaced；Z be 1-3 integer, preferably 1；
And/or
R4It is selected from the group：
In a preferred embodiment, above-mentioned R, R3And R4It can be in any combination.For example, it may be following combination：
R is hydrogen, C1-C3Low alkyl group, C1-C3Lower alkoxy, halogen (for example, F, Cl, Br), amino；
R3It is selected from the group：Hydrogen, (C3-C6) naphthenic base, (C1-C8) heterocycle, (C1-C8) alkoxy ,-O- (CH)n-O-C1-C3 Alkyl, benzyl, (C6-C10) aryl or (C5-C10) aromatic heterocyclic, wherein the aryl and aromatic heterocyclic are optionally with one Replace to five or less groups：Halogen, nitro, cyano, hydroxyl, amino, (C1-C8) alkyl, (C1-C8) alkoxy, (C3-C6) ring Alkyl, (C6-C10) aryloxy group, (C5-C10) heterocycle ,-O- (CH)z-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle Alkyl oxy, amide groups, the carbamoyl optionally replaced；Z be 1-3 integer, preferably 1；
Or
R is hydrogen, C1-C3Low alkyl group, C1-C3Lower alkoxy, halogen (for example, F, Cl, Br), amino；
R4It is selected from the group：
Or
R3It is selected from the group：Hydrogen, (C3-C6) naphthenic base, (C1-C8) heterocycle, (C1-C8) alkoxy ,-O- (CH)n-O-C1-C3 Alkyl, benzyl, (C6-C10) aryl or (C5-C10) aromatic heterocyclic, wherein the aryl and aromatic heterocyclic are optionally with one Replace to five or less groups：Halogen, nitro, cyano, hydroxyl, amino, (C1-C8) alkyl, (C1-C8) alkoxy, (C3-C6) ring Alkyl, (C6-C10) aryloxy group, (C5-C10) heterocycle ,-O- (CH)z-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle Alkyl oxy, amide groups, the carbamoyl optionally replaced；Z be 1-3 integer, preferably 1；
R4It is selected from the group：
In a particular embodiment, the completely new compound of structure of the invention is as shown in following formula I -1：
In formula,
A is that R ', n 0, and R ' are selected from C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；
X、Y、B、R1、R3、R4It is defined as above with m.
Further, R ' can be C1-C6Alkyl (preferably C1-C3Alkyl), C1-C6Halogenated alkyl (preferably C1-C3Alkyl halide Base).
In a preferred embodiment, R3It can be selected from the group：
More preferably
In a particular embodiment, the substituent group in general formula of the present invention is any specific chemical combination disclosed by the invention respectively Corresponding group in object.
Advantages of the present invention：
1. the compound of the present invention has excellent inhibitory activity to bruton's tyrosine kinase；
2. the compound of the present invention is to the high selectivity of bruton's tyrosine kinase；With
3. the compound of the present invention is exploitation energy high activity, inhibits the drug of bruton's tyrosine kinase to establish with high selectivity Determine basis, has great industrialization and commercialization foreground and market value, remarkable in economical benefits.
Technical scheme of the present invention is further described below in conjunction with specific implementation case, but following case study on implementation is not constituted Limitation of the present invention, the various method of administration that all principles and technological means according to the present invention use, belongs to the present invention Range.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, or is built according to manufacturer The condition of view.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Materials and methods
1. bruton's tyrosine kinase inhibitory activity detection method
The expression of 1.1 bruton's tyrosine kinase recombinant proteins
1) structure of PfastBac1- bruton's tyrosine kinases carrier
Bruton's tyrosine kinase target fragment (M1-S695) is subjected to PCR amplification, by PCR product and carrier PfastBac 1 carries out double digestion with BamHI and XhoI, and digestion products are ligated and transformed into DH5 α competent cells, select Dan Ke It is grand and pass through sequence verification, it is final to obtain the correct recombinant plasmid pFastBac1- bruton's tyrosine kinases of sequence.
2) acquisition of baculoviral
The plasmid swivel base built to DH10Bac competent cells is subjected to blue hickie screening, picking swivel base is successfully single Clone extracts rod granule after shaking bacterium, and identifies rod granule by bacterium solution PCR.It will identify correct rod granule transfection Sf9 cells, obtain respectively Obtain the P3 Strain of P1, P2 and more high titre.
3) bruton's tyrosine kinase protein expression and identification
Sf9 cells are cultivated to logarithmic phase (about 2 × 106A cell/mL), the P3 Strain addition with high titre is contained In the Sf9 cell culture mediums of logarithmic phase growth, after 27 DEG C are cultivated 3 days, 500 × g centrifuges 5min, abandons supernatant, bacterium is received, in -80 DEG C It preserves.Then Western blot (Western Blot) is used to detect protein expression situation.
The purifying of 1.2 bruton's tyrosine kinase recombinant proteins
At room temperature, the bacterial sediment of P3 Strain expression is collected by centrifugation with 1790rpm rotating speeds.Dissolve thalline cracking used Liquid is 250mM NaCl, 0.25%NP-40,50mM CHES (pH 9.0).It is crushed thalline with high-pressure cell crusher, then 4 DEG C, 45min is centrifuged under 12000rpm, collects supernatant.Supernatant is added in Ni-NTA chromatographic columns, is washed using imidazole concentration gradient method De- destination protein, and collect protein liquid after elution.Destination protein eluent will be contained to concentrate, and it is minimum to imidazole concentration to change liquid. At 4 DEG C, the dialysis of TEV enzymes and digestion 16h is added, goes over Ni-NTA chromatographic columns again, collects and flows through liquid without His-Tag, Buffer solution used in digestion is 200mM NaCl, 20mM CHES (pH 9.0), 1mM TCEP.Finally use HiTrap Superdex75 Molecular sieve isolates and purifies albumen, and equilibration buffer is 100mM NaCl, 10mM Tris-HCl pH 8.5,1mM used in molecular sieve TCEP。
The screening at molecular level of 1.3 bruton's tyrosine kinase inhibitor
The horizontal screening experiment of bruton's tyrosine kinase inhibitor molecules selects the Z '-of ThermoFisher companiesAssay Kit(PV3190).Experimental method is：Compound to be detected is subjected to concentration gradient dilution, in 384 holes 2.5 μ L Test Compounds are added in plate, every group of three parallel controls add 5 μ L bruton's tyrosine kinases Kinase/ Peptide Substrate Mixture, 2.5 μ L ATP Solution vibrate 30s mixings, are incubated at room temperature 1h；Add 5 μ L Development Solution vibrate 30s mixings, are incubated at room temperature 1h；Then 5 μ L Stop Reagent are added, vibrate 30s Mixing detects fluorescence signal using microplate reader, and excitation wavelength 400nm, launch wavelength is respectively 445nm and 520nm.Measurementization Inhibiting rate of the object under 7 concentration gradients is closed, the IC of each compound is calculated by 8.0 matched curves of Origin50Value.
The synthesis of 7 (8H)-pteridine ketone compounds of the present invention is as follows：
Reagent and condition：(a) amine, DIPEA, 1,4- dioxane, r.t.；(b) ArNH2, DIPEA, 1,4- dioxane, r.t.；(c)Pd/C,H2,EtOH；(d) R2COCOOEt, HOAc, EtOH, reflux.
In above-mentioned preparation flow, R1、R2、R3、R4、R5With reference to the definition of corresponding group above.Those skilled in the art The various initial compounds that this field routinely obtains can be used as raw material according to needs are actually prepared, prepare the chemical combination of the present invention Object.
Embodiment 1
The specific synthetic method of above-mentioned steps a-d is as follows：
The synthesis of (4- (the chloro- 5- nitro-pyrimidines -4- amino of 2-) phenyl) t-butyl carbamate
It weighs 2,4-, bis- chloro- 5- nitro-pyrimidines (190mg, 0.98mmol) to be placed in 25mL round-bottomed flasks, 6mL 1 is added, 4- dioxane, is stirred at room temperature, separately takes (4- aminophenyls) t-butyl carbamate (200mg, 0.96mmol), N, N- bis- different Propylethylamine (137mg, 1.06mmol) is dissolved in 4mL Isosorbide-5-Nitraes-dioxane, and is added drop-wise in above-mentioned reaction solution, after being added dropwise to complete, Continue to be stirred at room temperature 1 hour, TLC tracks to raw material and converts completely.Rotary evaporation removes solvent, and crude product is through silica gel column chromatography (petrol ether/ethyl acetate=10:1, v/v) it detaches, obtains (4- (the chloro- 5- nitro-pyrimidines -4- amino of 2-) phenyl) carbamic acid Tert-butyl ester orange solids 301mg, yield 82%.
1H NMR(400MHz,DMSO-d6):δ 10.38 (s, 1H), 9.47 (s, 1H), 9.12 (s, 1H), 7.49 (d, J= 8.4Hz, 2H), 7.39 (d, J=8.4Hz, 2H), 1.49 (s, 9H).
The synthesis of (4- (2- (4- Methoxyphenylaminos) -5- nitro-pyrimidine -4- amino) phenyl) t-butyl carbamate
Weigh (4- (the chloro- 5- nitro-pyrimidines -4- amino of 2-) phenyl) t-butyl carbamate (50mg, 0.14mmol), right Aminoanisole (17mg, 0.14mmol), n,N-diisopropylethylamine (18mg, 0.18mmol) are placed in 10mL round-bottomed flasks, 5mL Isosorbide-5-Nitraes-dioxane is added, stirs 4 hours at room temperature, TLC tracks to raw material and converts completely.Rotary evaporation removes solvent, Crude product is through silica gel column chromatography (petrol ether/ethyl acetate=4:1, v/v) it purifies, obtains (4- (2- (4- Methoxyphenylaminos)- 5- nitro-pyrimidine -4- amino) phenyl) t-butyl carbamate yellow solid 51mg, yield 82%.
1H NMR(400MHz,DMSO-d6):δ10.30(s,1H),10.26(s,1H),9.45(s,1H),9.04(s, 1H), 7.49 (d, J=8.8Hz, 2H), 7.45 (d, J=8.8Hz, 2H), 7.40 (d, J=8.6Hz, 2H), 6.75 (d, J= 8.6Hz,2H),3.73(s,3H),1.50(s,9H)。
The synthesis of (4- (5- amino -2- (4- Methoxyphenylaminos) pyrimidine -4- amino) phenyl) t-butyl carbamate
Weigh (4- (2- (4- Methoxyphenylaminos) -5- nitro-pyrimidine -4- amino) phenyl) t-butyl carbamate (45mg, 0.10mmol) is placed in 50mL round-bottomed flasks, and 20mL ethyl alcohol, 5mg palladium carbons (10%Pd) is added, is passed through hydrogen, room temperature Under be stirred overnight.After reaction, it filters, filtrate is spin-dried for, crude product is through silica gel column chromatography (methylene chloride/methanol=5:1, v/ V) it purifies, obtains (4- (5- amino -2- (4- Methoxyphenylaminos) pyrimidine -4- amino) phenyl) light powder of t-butyl carbamate Color solid 30mg, yield 83%.
1H NMR(400MHz,DMSO-d6):δ 9.23 (s, 1H), 8.42 (s, 1H), 8.10 (s, 1H), 7.62 (d, J= 9.2Hz, 2H), 7.56 (s, 1H), 7.53 (d, J=9.2Hz, 2H), 7.40 (d, J=8.8Hz, 2H), 6.77 (d, J=8.8Hz, 2H),3.70(s,3H),1.48(s,9H)。
The conjunction of (4- (2- (4- Methoxyphenylaminos) -7- oxos -8 (7H)-pteridyl) phenyl) t-butyl carbamate At
Weigh (4- (5- amino -2- (4- Methoxyphenylaminos) pyrimidine -4- amino) phenyl) t-butyl carbamate (30mg, 0.07mmol) is placed in 10mL round-bottomed flasks, and 0.29mL glacial acetic acid, 5mL absolute ethyl alcohols is added, glyoxalic acid is then added Ethyl ester (50% toluene solution) (16mg, 0.08mmol) is heated to return stirring and stays overnight.After reaction, there is solid precipitation, take out Filter, filter cake ethyl alcohol, ammonium hydroxide, deionized water are washed, dry.Obtain (4- (2- (4- Methoxyphenylaminos) -7- oxos -8 (7H)-pteridyl) phenyl) t-butyl carbamate yellow solid 18mg, yield 76%.
1H NMR(400MHz,DMSO-d6):δ10.08(s,1H),9.64(s,1H),8.84(s,1H),8.03(s,1H), 7.65 (d, J=8.4Hz, 2H), 7.30-7.28 (m, 4H), 6.61 (br, 2H), 3.67 (s, 3H), 1.52 (s, 9H).
The synthesis (serial number 1) of 8- (4- aminophenyls) -2- (4- methoxyphenyls) -7 (8H)-pteridinone
Weigh (4- (2- (4- Methoxyphenylaminos) -7- oxos -8 (7H)-pteridyl) phenyl) t-butyl carbamate (18mg, 0.04mmol) is placed in 5mL round-bottomed flasks, and 2mL dichloromethane is added, is stirred at 0 DEG C, 0.5mL trifluoroacetic acids are added. It then proceedes to stir at 0 DEG C 1 hour, stir 1 hour at room temperature.After reaction, saturated sodium bicarbonate solution is added to neutralize To solution meta-alkalescence, (3 × 50mL) is extracted with dichloromethane, organic phase deionized water, saturated nacl aqueous solution wash, anhydrous Sodium sulphate is dried, and solvent is spin-dried for.It is solid to obtain 8- (4- aminophenyls) -2- (4- methoxyphenyls) -7 (8H)-pteridinone yellow Body 14mg, yield 99%.mp>300℃.
1H NMR(400MHz,DMSO-d6):δ 10.04 (br, 1H), 8.81 (s, 1H), 8.00 (s, 1H), 7.40 (d, J= 7.6Hz, 2H), 6.98 (d, J=8.4Hz, 2H), 6.73 (d, J=8.4Hz, 2H), 6.67 (br, 2H), 5.44 (s, 2H), 3.70 (s,3H)。13C NMR(100MHz,DMSO-d6):δ159.19,158.53,157.17,154.95,151.76,149.66, 146.68,133.17,129.22,122.66,121.04,120.70,114.37,113.87,55.55.HPLC purity: 97.6%, Retention time=12.59min.HRMS (ESI):exact mass calcd for C19H17N6O2[M+H ]+,361.1413,found 361.1414。
Following compound synthesizes to obtain according to the method for above-mentioned steps：
8- (3- aminophenyls) -2- (4- methoxyphenyls) -7 (8H)-pteridinone (serial number 2)
Yellow solid, yield 86%, mp 270.5-270.9 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.06 (br, 1H), 8.83 (s, 1H), 8.01 (s, 1H), 7.41 (d, J= 8.0Hz, 2H), 7.22 (t, J=8.0Hz, 1H), 6.75 (d, J=7.6Hz, 1H), 6.67 (br, 2H), 6.53 (s, 1H), 6.48 (d, J=7.6Hz, 1H), 5.35 (s, 2H), 3.69 (s, 3H) .HPLC purity:94.4%, Retention time= 12.90min.HRMS(ESI):exact mass calcd for C19H17N6O2[M+H]+,361.1413,found 361.1413.
2- (3- aminophenyls) -8- (4- methoxyphenyls) -7 (8H)-pteridinone (serial number 3)
Yellow solid, yield 85%, mp 244.5-245.4 DEG C
1H NMR(400MHz,DMSO-d6):δ 9.91 (s, 1H), 8.85 (s, 1H), 8.04 (s, 1H), 7.35 (d, J= 8.8Hz, 2H), 7.16 (d, J=8.8Hz, 2H), 6.68-6.65 (m, 3H), 6.16 (d, J=7.2Hz, 1H), 4.63 (s, 2H), 3.86(s,3H).HPLC purity:98.9%, Retention time=12.57min.HRMS (ESI):exact mass calcd for C19H17N6O2[M+H]+,361.1413,found 361.1411.
2- (4- aminophenyls) -8- (4- methoxyphenyls) -7 (8H)-pteridinone (serial number 4)
Yellow solid, yield 88%, mp 281.5-282.3 DEG C
1H NMR(400MHz,DMSO-d6):δ 9.87 (s, 1H), 8.77 (s, 1H), 7.97 (s, 1H), 7.32 (d, J= 8.8Hz, 2H), 7.13 (d, J=8.8Hz, 2H), 7.08 (br, 2H), 6.24 (br, 2H), 4.84 (s, 2H), 3.88 (s, 3H) .HPLC purity:95.2%, Retention time=11.91min.HRMS (ESI):exact mass calcd for C19H17N6O2[M+H]+,361.1413,found 361.1417.
N- (3- (2- ((4- methoxyphenyls) amino) -7- oxos -8 (7H) pteridyl) phenyl) acrylamide (serial number 6)
Yellow solid, yield 74%, mp 260.9-261.5 DEG C
1H NMR(400MHz,DMSO-d6):δ10.42(s,1H),10.10(br,1H),8.85(s,1H),8.05(s, 1H), 7.84 (d, J=8.0Hz, 1H), 7.78 (s, 1H), 7.56 (t, J=8.0Hz, 1H), 7.31 (br, 2H), 7.13 (d, J= 8.0Hz, 1H), 6.58 (br, 2H), 6.45 (dd, J=16.8,10.4Hz, 1H), 6.26 (dd, J=16.8,1.6Hz, 1H), 5.77 (dd, J=10.4,1.6Hz, 1H), 3.65 (s, 3H) .HPLC purity:97.0%, Retention time= 13.11min.HRMS(ESI):exact mass calcd for C22H19N6O3[M+H]+,415.1519,found 415.1516.
N- (4- (2- ((4- methoxyphenyls) amino) -7- oxos -8 (7H) pteridyl) phenyl) propionamide (serial number 7)
Yellow solid, yield 78%, mp 258.5-259.1 DEG C
1H NMR(400MHz,DMSO-d6):δ10.15(s,1H),10.08(br,1H),8.85(s,1H),8.04(s, 1H), 7.80 (d, J=8.4Hz, 2H), 7.35-7.33 (m, 4H), 6.61 (br, 2H), 3.67 (s, 3H), 2.41 (q, J= 7.6Hz, 2H), 1.14 (t, J=7.6Hz, 3H) .HPLC purity:99.3%, Retention time= 13.05min.HRMS(ESI):exact mass calcd for C22H21N6O3[M+H]+,417.1675,found 417.1674.
N- (3- (2- ((4- methoxyphenyls) amino) -7- oxos -8 (7H) pteridyl) phenyl) propionamide (serial number 8)
Yellow solid, yield 80%, mp 298.9-299.4 DEG C
1H NMR(400MHz,DMSO-d6):δ10.13(s,1H),10.09(s,1H),8.85(s,1H),8.04(s, 1H), 7.74 (d, J=8.0Hz, 1H), 7.71 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.31 (br, 2H), 7.07 (d, J= 8.0Hz, 1H), 6.59 (br, 2H), 3.67 (s, 3H), 2.33 (q, J=7.6Hz, 2H), 1.07 (t, J=7.6Hz, 3H) .HPLC purity:98.1%, Retention time=13.13min.HRMS (ESI):exact mass calcd for C22H21N6O3[M+H]+,417.1675,found 417.1678.
N- (3- ((8- (4- methoxyphenyls) -7- oxos -8 (7H) pteridine -2- bases) phenyl) acrylamides (serial number 9)
Yellow solid, yield 73%, mp 243.3-244.0 DEG C
1H NMR(400MHz,DMSO-d6):δ10.17(s,1H),10.01(s,1H),8.89(s,1H),8.07(s,1H), 7.63 (br, 1H), 7.33 (d, J=8.8Hz, 2H), 7.27 (d, J=8.0Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 7.11 (d, J=8.8Hz, 2H), 6.89 (br, 1H), 6.46 (dd, J=17.0,10.2Hz, 1H), 6.25 (dd, J=17.0,1.8Hz, 1H), 5.74 (dd, J=10.2,1.8Hz, 1H), 3.85 (s, 3H) .HPLC purity:99.0%, Retention time= 12.91min.HRMS(ESI):exact mass calcd for C22H19N6O3[M+H]+,415.1519,found 415.1519.
N- (4- ((8- (4- methoxyphenyls) -7- oxos -8 (7H) pteridine -2- bases) phenyl) acrylamides (serial number 10)
Yellow solid, yield 77%, mp 275.3-276.4 DEG C
1H NMR(400MHz,DMSO-d6):δ10.19(br,1H),10.03(s,1H),8.87(s,1H),8.05(s, 1H), 7.36-7.34 (m, 6H), 7.16 (d, J=8.4Hz, 2H), 6.41 (dd, J=17.0,10.2Hz, 1H), 6.23 (dd, J =17.0,1.6Hz, 1H), 5.72 (dd, J=10.2,1.6Hz, 1H), 3.92 (s, 1H) .HPLC purity:96.9%, Retention time=12.75min.HRMS (ESI):exact mass calcd for C22H19N6O3[M+H]+, 415.1519,found 415.1524。
4- (2- ((4- methoxyphenyls) amino) -7- oxos -8 (7H) pteridyl) phenyl acrylate (serial number 11)
Yellow solid, yield 69%, mp 257.2-258.0 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.15 (s, 1H), 8.87 (s, 1H), 8.06 (s, 1H), 7.51 (d, J= 8.8Hz, 2H), 7.45 (d, J=8.8Hz, 2H), 7.31 (br, 2H), 6.69 (br, 2H), 6.60 (dd, J=17.2,1.6Hz, 1H), 6.51 (dd, J=17.2,9.9Hz, 1H), 6.22 (dd, J=9.9,1.6Hz, 1H), 3.67 (s, 3H) .HPLC purity:97.8%, Retention time=15.64min.HRMS (ESI):exact mass calcd for C22H18N5O4[M+H]+,416.1359,found 416.1359.
(E) -4- (dimethylamino)-N- (4- (2- ((4- methoxyphenyls) amino) -7- oxos -8 (7H) pteridyl) benzene Base) -2- crotonamides (serial number 12)
Yellow solid, yield 55%, mp 273.5-274.3 DEG C
1H NMR(400MHz,DMSO-d6):δ10.45(s,1H),10.10(br,1H),8.85(s,1H),8.05(s, 1H), 7.87 (d, J=8.8Hz, 2H), 7.37 (d, J=8.8Hz, 2H), 7.30 (br, 2H), 6.82 (td, J=15.4, 6.0Hz, 1H), 6.60 (br, 2H), 6.40 (d, J=15.4Hz, 1H), 3.63 (s, 3H), 3.27 (d, J=5.2Hz, 2H), 2.33(s,6H).HPLC purity:97.7%, Retention time=10.47min.HRMS (ESI):exact mass calcd for C25H26N7O3[M+H]+,472.2097,found 472.2095.
(E) -4- (dimethylamino)-N- (3- (2- ((4- methoxyphenyls) amino) -7- oxos -8 (7H) pteridyl) benzene Base) -2- crotonamides (serial number 13)
Yellow solid, yield 47%, mp 185.1-185.9 DEG C
1H NMR(400MHz,DMSO-d6):δ10.33(s,1H),10.08(br,1H),8.86(s,1H),8.05(s, 1H), 7.83 (d, J=8.0Hz, 1H), 7.78 (s, 1H), 7.55 (t, J=8.0Hz, 1H), 7.32 (br, 2H), 7.11 (d, J= 8.0Hz, 1H), 6.74 (td, J=15.2,5.6Hz, 1H), 6.59 (br, 2H) 6.30 (d, J=15.2Hz, 1H), 3.66 (s, 3H), 3.06 (d, J=5.6Hz, 2H), 2.17 (s, 6H) .HPLC purity:98.3%, Retention time= 10.74min.HRMS(ESI):exact mass calcd for C25H24N7O3[M+H]+,472.2097,found 472.2094.
(E)-4- (dimethylamino)-N- (4-(7- oxos-2- (phenylamino)-8 (7H) pteridyl) phenyl)-2- crotonamides (serial number 14)
Yellow solid, yield 53%, mp 225.3-226.1 DEG C
1H NMR(400MHz,DMSO-d6):δ10.37(s,1H),10.19(br,1H),8.90(s,1H),8.08(s, 1H), 7.87 (d, J=8.4Hz, 2H), 7.42 (d, J=7.6Hz, 2H), 7.38 (d, J=8.4Hz, 2H), 7.03 (br, 1H), 6.88 (t, J=7.6Hz, 1H), 6.82 (td, J=15.4,5.6Hz, 1H), 6.37 (d, J=15.4Hz, 1H), 3.14 (d, J= 5.6Hz,2H),2.24(s,6H).HPLC purity:98.2%, Retention time=10.55min.HRMS (ESI): exact mass calcd for C24H24N7O2[M+H]+,442.1991,found 442.1989.
(E)-4- (dimethylamino)-N- (3-(7- oxos-2- (phenylamino)-8 (7H) pteridyl) phenyl)-2- crotonamides (serial number 15)
Yellow solid, yield 46%, mp 183.8-184.3 DEG C
1H NMR(400MHz,DMSO-d6):δ10.32(s,1H),10.17(s,1H),8.90(s,1H),8.08(s, 1H), 7.81-7.79 (m, 2H), 7.55 (t, J=8.0Hz, 1H), 7.41 (d, J=7.2Hz, 2H), 7.12 (d, J=8.0Hz, 1H), 7.01 (br, 2H), 6.87 (t, J=7.2Hz, 1H), 6.73 (td, J=15.2,5.6Hz, 1H), 6.28 (d, J= 15.2Hz, 1H), 3.05 (d, J=5.6Hz, 2H), 2.16 (s, 6H) .HPLC purity:98.2%, Retention time= 10.85min.HRMS(ESI):exact mass calcd for C24H24N7O2[M+H]+,442.1991,found 442.1996.
N- (4- (7- oxo -2- phenylaminos) -8 (7H) pteridyls) phenyl) acrylamide (serial number 16)
Yellow solid, yield 79%, mp>300℃.
1H NMR(400MHz,DMSO-d6):δ10.44(s,1H),10.19(br,1H),8.90(s,1H),8.09(s, 1H), 7.88 (d, J=8.4Hz, 2H), 7.41-7.38 (m, 4H), 7.03 (br, 2H), 6.88 (t, J=7.2Hz, 1H), 6.53 (dd, J=16.8,10.4Hz, 1H), 6.35 (dd, J=16.8,1.6Hz, 1H), 5.84 (dd, J=10.4,1.6Hz, 1H) .HPLC purity:96.1%, Retention time=12.68min.HRMS (ESI):exact mass calcd for C21H17N6O2[M+H]+,385.1413,found 385.1405.
N- (3- (7- oxo -2- phenylaminos) -8 (7H) pteridyls) phenyl) acrylamide (serial number 17)
Yellow solid, yield 74%, mp 270.1-270.9 DEG C
1H NMR(400MHz,DMSO-d6):δ10.42(s,1H),10.19(s,1H),8.91(s,1H),8.09(s, 1H), 7.84-7.81 (m, 2H), 7.57 (t, J=8.0Hz, 1H), 7.41 (br, 2H), 7.15 (d, J=7.6Hz, 1H), 7.02 (br, 2H), 6.87 (t, J=7.6Hz, 1H), 6.45 (dd, J=16.8,10.4Hz, 1H), 6.26 (dd, J=16.8,1.6Hz, 1H), 5.77 (dd, J=10.4,1.6Hz, 1H) .HPLC purity:96.8%, Retention time= 13.27min.HRMS(ESI):exact mass calcd for C21H17N6O2[M+H]+,385.1413,found 385.1413.
N- (4- (2- ((4- chlorphenyls) amino) -7- oxos -8 (7H) pteridyl) phenyl) acrylamide (serial number 18)
Yellow solid, yield 81%, mp>300℃.
1H NMR(400MHz,DMSO-d6):δ10.46(s,1H),10.34(s,1H),8.92(s,1H),8.11(s, 1H), 7.88 (d, J=8.8Hz, 2H), 7.41-7.36 (m, 4H), 7.06 (br, 2H), 6.53 (dd, J=16.8,10.4Hz, 1H), 6.36 (dd, J=16.8,1.6Hz, 1H), 5.84 (dd, J=10.4,1.6Hz, 1H) .HPLC purity:94.3%, Retention time=14.43min.HRMS (ESI):exact mass calcd for C21H16N6O2Cl[M+H]+, 419.1023,found 419.1031.
N- (3- (2- ((4- chlorphenyls) amino) -7- oxos -8 (7H) pteridyl) phenyl) acrylamide (serial number 19)
Yellow solid, yield 78%, mp 259.1-259.8 DEG C
1H NMR(400MHz,DMSO-d6):δ10.44(s,1H),10.34(br,1H),8.93(s,1H),8.11(s, 1H), 7.84 (s, 1H), 7.81 (d, J=8.4Hz, 1H), 7.59 (t, J=8.0Hz, 1H), 7.43 (d, J=7.2Hz, 2H), 7.15 (d, J=7.6Hz, 1H), 6.46 (dd, J=16.8,10.4Hz, 1H), 6.26 (dd, J=16.8,1.8Hz, 1H), 5.77 (dd, J=10.12,1.8Hz, 1H) .HPLC purity:97.4%, Retention time=13.83min.HRMS (ESI): exact mass calcd for C21H16N6O2Cl[M+H]+,419.1023,found 419.1027.
N- (4- (2- ((4- morpholinyl phenyls) amino) -7- oxos -8 (7H) pteridyl) phenyl) acrylamide (serial number 20)
Red solid, yield 63%, mp>300℃.
1H NMR(400MHz,DMSO-d6):δ10.44(s,1H),10.00(s,1H),8.82(s,1H),8.02(s, 1H), 7.88 (d, J=8.0Hz, 1H), 7.36 (d, J=8.4Hz, 1H), 7.22 (br, 2H), 6.59 (br, 2H), 6.52 (dd, J =17.2,10.2Hz, 1H), 6.33 (d, J=17.2Hz, 1H), 5.85 (d, J=10.2Hz, 1H), 3.67 (br, 4H), 2.92 (br,4H).HPLC purity:97.3%, Retention time=12.21min.HRMS (ESI):exact mass calcd for C25H24N7O3[M+H]+,470.1941,found 470.1932.
N- (3- (2- ((4- morpholinyl phenyls) amino) -7- oxos -8 (7H) pteridyl) phenyl) acrylamide (serial number 21)
Red solid, yield 87%, mp>300℃.
1H NMR(400MHz,DMSO-d6):δ10.43(s,1H),10.06(s,1H),8.84(s,1H),8.03(s,1H), 7.92 (br, 1H), 7.72 (s, 1H), 7.56 (t, J=7.6Hz, 1H), 7.27 (br, 2H), 7.12 (d, J=7.2Hz, 1H), 6.58 (br, 2H), 6.45 (dd, J=16.8,10.4Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.78 (d, J=10.4Hz, 1H),3.71(br,4H),2.94(br,4H).HPLC purity:98.7%, Retention time=11.71min.HRMS (ESI):exact mass calcd for C25H24N7O3[M+H]+,470.1941,found 470.1939.
N- (4- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) -7- oxos -8 (7H) pteridyl) phenyl) propylene Amide (serial number 22)
Red solid, yield 72%, mp 299.1-299.8 DEG C
1H NMR(400MHz,DMSO-d6):δ10.51(s,1H),10.06(s,1H),8.83(s,1H),8.03(s,1H), 7.89 (d, J=8.4Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 7.17 (d, J=6.4Hz, 1H), 6.56-6.49 (m, 3H), 6.34 (d, J=16.8Hz, 1H), 5.85 (d, J=10.8Hz, 1H), 2.94 (br, 4H), 2.37 (br, 4H), 2.20 (s, 3H) .HPLC purity:97.0%, Retention time=10.02min.HRMS (ESI):exact mass calcd for C26H27N8O2[M+H]+,483.2257,found 483.2259.
N- (3- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) -7- oxos -8 (7H) pteridyl) phenyl) propylene Amide (serial number 23)
Red solid, yield 81%, mp 268.3-269.1 DEG C
1H NMR(400MHz,DMSO-d6):δ10.45(s,1H),10.06(s,1H),8.84(s,1H),8.04(s,1H), 7.93 (br, 1H), 7.73 (s, 1H), 7.56 (t, J=8.0Hz, 1H), 7.25 (br, 2H), 7.12 (d, J=8.0Hz, 1H), 6.57 (br, 2H), 6.46 (dd, J=16.8,10.4Hz, 1H), 6.27 (dd, J=16.8,1.8Hz, 1H), 5.78 (dd, J= 10.4,1.8Hz,1H),2.98(br,4H),2.42(br,4H),2.22(s,3H).HPLC purity:96.5%, Retention time=9.99min.HRMS (ESI):exact mass calcd for C26H27N8O2[M+H]+, 483.2257,found 483.2259.
N- (3- (7- oxos -2- ((4- (piperidin-1-yl) phenyl) amino) -7- oxos -8 (7H) pteridyl) phenyl) propylene Amide (serial number 24)
Red solid, yield 75%, mp 279.3-280.2 DEG C
1H NMR(400MHz,DMSO-d6):δ10.44(s,1H),10.03(s,1H),8.83(s,1H),8.02(s,1H), 7.94 (br, 1H), 7.73 (s, 1H), 7.55 (t, J=8.0Hz, 1H), 7.24 (br, 2H), 7.11 (d, J=8.0Hz, 1H), 6.57 (br, 2H), 6.46 (dd, J=17.0,10.2Hz, 1H), 6.26 (dd, J=17.0,1.8Hz, 1H), 5.77 (dd, J= 10.2,1.8Hz,1H),2.95(br,4H),1.57(br,4H),1.49(br,2H).HPLC purity:95.3%, Retention time=15.12min.HRMS (ESI):exact mass calcd for C26H26N7O2[M+H]+, 468.2148,found 468.2146.
N- (3- (7- oxos -2- ((4- (pyrrolidin-1-yl) phenyl) amino) -7- oxos -8 (7H) pteridyl) phenyl) third Acrylamide (serial number 25)
Red solid, yield 77%, mp 279.5-280.1 DEG C
1H NMR(400MHz,DMSO-d6):δ10.40(s,1H),9.92(s,1H),8.79(s,1H),7.99(s,1H), 7.90 (br, 1H), 7.74 (br, 1H), 7.54 (t, J=8.0Hz, 1H), 7.20 (br, 2H), 7.10 (d, J=8.0Hz, 1H), 6.46 (dd, J=17.0,10.2Hz, 1H), 6.26 (dd, J=17.0,1.8Hz, 1H), 6.20 (br, 2H), 5.77 (dd, J= 10.2,1.8Hz,1H),3.10(br,4H),1.91(br,4H).HPLC purity:99.3%, Retention time= 15.12min.HRMS(ESI):exact mass calcd for C25H24N7O2[M+H]+,454.1991,found 454.1995.
N- (3- (2- ((4- (diethylamino) phenyl) amino) -7- oxos -8 (7H) pteridyl) phenyl) acrylamide (serial number 26)
Red solid, yield 72%, mp 273.5-274.5 DEG C
1H NMR(400MHz,DMSO-d6):δ10.42(s,1H),9.92(s,1H),8.80(s,1H),8.00(s,1H), 7.92 (br, 1H), 7.73 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.19 (br, 2H), 7.09 (d, J=8.0Hz, 1H), 6.46 (dd, J=17.0,10.2Hz, 1H), 6.32 (br, 2H), 6.27 (dd, J=17.0,1.8Hz, 1H), 5.76 (dd, J= 10.2,1.8Hz, 1H), 3.20 (br, 4H), 1.00 (t, J=6.8Hz, 6H) .HPLC purity:96.2%, Retention Time=14.69min.HRMS (ESI):exact mass calcd for C25H26N7O2[M+H]+,456.2148,found 456.2143.
N- (3- (2- ((4- acetylamino phenyls) amino) -7- oxos -8 (7H) pteridyl) phenyl) acrylamide (serial number 27)
Yellow solid, yield 78%, mp 295.3-295.8 DEG C
1H NMR(400MHz,DMSO-d6):δ10.43(s,1H),10.16(br,1H),9.78(s,1H),8.87(s, 1H), 8.06 (s, 1H), 7.82 (d, J=8.0Hz, 1H), 7.79 (s, 1H), 7.56 (t, J=8.0Hz, 1H), 7.32 (br, 2H), 7.23 (br, 2H), 7.15 (d, J=8.0Hz, 1H), 6.46 (dd, J=17.0,10.2Hz, 1H), 6.25 (dd, J= 17.0,1.8Hz, 1H), 5.76 (dd, J=10.2,1.8Hz, 1H), 1.98 (s, 3H) .HPLC purity:95.4%, Retention time=10.68min.HRMS (ESI):exact mass calcd for C23H20N7O3[M+H]+, 442.1628,found 442.1624.
4- ((8- (3- acrylamidos phenyl) -7- oxo -7,8- dihydropteridine -2- bases) amino) benzamide (serial number 28)
Yellow solid, yield 76%, mp 299.3-299.8 DEG C
1H NMR(400MHz,DMSO-d6):δ10.43(s,1H),10.40(s,1H),8.95(s,1H),8.13(s,1H), 7.86 (s, 1H), 7.79 (d, J=8.0Hz, 1H), 7.71 (br, 1H), 7.61 (t, J=8.0Hz, 1H), 7.55 (d, J= 7.6Hz, 2H), 7.47 (br, 2H), 7.18 (d, J=7.6Hz, 2H), 6.44 (dd, J=17.0,10.2Hz, 1H), 6.25 (dd, J=17.0,1.8Hz, 1H), 5.76 (dd, J=10.2,1.8Hz, 1H) .HPLC purity:95.6%, Retention time =10.00min.HRMS (ESI):exact mass calcd for C22H18N7O3[M+H]+,428.1471,found 428.1476.
N- (4- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) -7- oxos -8 (7H)-pteridyl) Phenyl) acrylamide (serial number 29)
Red solid, yield 71%, mp 265.4-266.2 DEG C
1H NMR(400MHz,DMSO-d6):δ10.43(s,1H),8.80(s,1H),8.42(s,1H),8.03(s,1H), 7.85 (d, J=8.6Hz, 2H), 7.34 (d, J=8.6Hz, 2H), 7.25 (d, J=8.8Hz, 1H), 6.54-6.48 (m, 2H), 6.33 (dd, J=17.0,1.6Hz, 1H), 6.02 (br, 1H), 5.84 (dd, J=10.2,1.6Hz, 1H), 3.76 (s, 3H), 3.02(br,4H),2.43(br,4H),2.23(s,3H).HPLC purity:97.1%, Retention time= 11.44min.HRMS(ESI):exact mass calcd for C27H29N8O3[M+H]+,513.2363,found 513.2362.
N- (3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) -7- oxos -8 (7H)-pteridyl) Phenyl) acrylamide (serial number 30)
Red solid, yield 77%, mp 184.7-185.1 DEG C
1H NMR(400MHz,DMSO-d6):δ10.41(s,1H),8.80(s,1H),8.44(br,1H),8.02(s,1H), 7.86 (br, 1H), 7.71 (s, 1H), 7.52 (t, J=8.0Hz, 1H), 7.30 (d, J=7.6Hz, 1H), 7.09 (d, J= 8.0Hz, 1H), 6.53 (s, 1H), 6.46 (dd, J=17.0,10.2Hz, 1H), 6.26 (dd, J=17.0,1.8Hz, 1H), 6.02 (br, 1H), 5.78 (dd, J=10.2,1.8Hz, 1H), 3.76 (s, 3H), 3.04 (br, 4H), 2.44 (br, 4H), 2.23 (s,3H).HPLC purity:96.2%, Retention time=10.68min.HRMS (ESI):exact mass calcd for C27H29N8O3[M+H]+,513.2363,found 513.2361.
N- (4- (- 8 (7H)-pteridyl of 2- ((4- anisyls) amino) -6- methyl -7- oxos) phenyl) acrylamide (serial number 31)
Yellow solid, yield 78%, mp>300℃.
1H NMR(400MHz,DMSO-d6):δ 10.44 (s, 1H), 9.90 (br, 1H), 8.77 (s, 1H), 7.87 (d, J= 8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.29 (br, 2H), 6.59 (br, 2H), 6.52 (dd, J=17.0,10.0Hz, 1H), 6.33 (dd, J=17.0,1.9Hz, 1H), 5.82 (dd, J=10.0,1.9Hz, 1H), 3.61 (s, 3H), 2.42 (s, 3H).HPLC purity:95.9%, Retention time=13.60min.HRMS (ESI):exact mass calcd for C23H21N6O3[M+H]+,429.1675,found 429.1671.
N- (3- (- 8 (7H)-pteridyl of 2- ((4- anisyls) amino) -6- methyl -7- oxos) phenyl) acrylamide (serial number 32)
Yellow solid, yield 66%, mp 285.3-286.0 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.42 (s, 1H), 9.93 (br, 1H), 8.78 (s, 1H), 7.83 (d, J= 8.0Hz, 1H), 7.77 (s, 1H), 7.56 (t, J=8.0Hz, 1H), 7.31 (br, 2H), 7.11 (d, J=8.0Hz, 1H), 6.58 (br, 2H), 6.45 (dd, J=17.0,10.2Hz, 1H), 6.26 (d, J=17.0Hz, 1H), 5.77 (d, J=10.2Hz, 1H), 3.65(s,3H),2.42(s,3H).HPLC purity:98.6%, Retention time=13.51min.HRMS (ESI): exact mass calcd for C23H21N6O3[M+H]+,429.1675,found 429.1675.
(S) -8- (1- acryloyl group -3- pyrrolidinyls) -2- ((2- methoxyl groups) -4- (4- methyl-1s-piperazinyl) phenyl) Amino) -7 (8H) pteridinones (serial number 33)
Orange red solid, yield 40%.
1H NMR(400MHz,DMSO-d6):δ8.96(s,1H),8.73(s,0.5H),8.72(s,0.5H),7.86(s, 0.5H), 7.84 (s, 0.5H), 7.32 (m, 1H), 6.57 (s, 1H), 6.43-6.42 (m, 1H), 6.16 (ddd, J=16.8, 10.0,2.4Hz, 1H), 5.72 (dd, J=10.0,2.4Hz, 1H), 5.65 (dd, J=10.0,2.4Hz, 1H), 4.08 (t, J= 10.2Hz,0.5H),3.88-3.82(m,0.5H),3.76(s,3H),3.67-3.62(m,1H),3.58-3.55(m,1H), 3.21-3.17(m,4H),2.81-2.71(m,1H),2.68-2.61(m,4H),2.38(s,1.4H),2.34(s,1.6H), 2.04-1.96(m,2H).HRMS(ESI)(m/z):[M+H]+calcd forC25H31N8O3,491.2519；found, 491.2520.HPLC purity:95.7%, retention time=9.43min.
(R) -8- (1- acryloyl group -3- pyrrolidinyls) -2- ((2- methoxyl groups) -4- (4- methyl-1s-piperazinyl) phenyl) Amino) -7 (8H) pteridinones (serial number 34)
Orange red solid, yield 40%.
1H NMR(400MHz,DMSO-d6):δ8.94(s,1H),8.72-8.71(m,1H),7.86-7.84(m,1H), 7.33 (t, J=8.4Hz, 1H), 6.56 (s, 1H), 6.42-6.40 (m, 1H), 6.16 (ddd, J=16.8,10.4,2.4Hz, 1H), 5.70 (dd, J=10.4,2.4Hz, 1H), 5.65 (dd, J=10.4,2.4Hz, 1H), 4.10 (t, J=10.2Hz, 0.5H),3.88-3.83(m,0.6H),3.76(s,3H),3.67-3.62(m,1H),3.58-3.55(m,1H),3.15-3.10 (m,4H),2.82-2.64(m,1H),2.45(br,4H),2.23(s,3H),2.06-1.96(m,1H).HRMS(ESI)(m/z): [M+H]+calcd for C25H31N8O3,491.2519；found,491.2473.
(S) -8- (1- acryloyl group -3- piperidyls) -2- ((2- methoxyl groups) -4- (4- methyl-1s-piperazinyl) phenyl) ammonia Base) -7 (8H) pteridinones (serial number 35)
Orange red solid, yield 38%.
1H NMR(400MHz,DMSO-d6):δ9.14(br,1H),8.71(s,1H),7.83(s,1H),7.22-7.21(m, 1H),6.80-6.62(m,2H),6.48-6.47(m,1H),6.15-6.08(m,1H),5.71-5.60(m,1H),4.82-4.76 (m,0.6H),4.34-4.24(m,1H),3.95-3.92(m,1H),3.74(s,3H),3.14(br,4H),2.46(br,4H), 1.64(br,2H),1.34-1.30(m,1H).HRMS(ESI)(m/z):[M+H]+calcd for C26H33N8O3,505.2676； found,505.2676.
N- (3- (2- ((3- methoxyl groups-4- (methyl-1-piperazinyl) phenyl) amino)-7- oxos-8 (7H)-pteridyl) benzene Base) acrylamide (serial number 36)
Red solid, yield 55%.
1H NMR(400MHz,DMSO-d6):δ10.41(s,1H),10.00(br,1H),8.86(s,1H),8.04(s, 1H), 7.87 (d, J=8.0Hz, 1H), 7.73 (s, 1H), 7.54 (t, J=8.0Hz, 1H), 7.11 (d, J=8.0Hz, 1H), 7.04-6.95 (m, 2H), 6.48-6.42 (m, 2H), 6.27 (dd, J=17.2,2.0Hz, 1H), 5.77 (dd, J=10.0, 2.0Hz,1H),3.55(s,3H),2.83(br,4H),2.43(br,4H),2.22(s,3H).HRMS(ESI)(m/z):[M+H]+ calcd for C27H29N8O3,513.2363；found,513.2362.
N- (3- (2- ((3- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxos) -8 (7H) pteridyls) Phenyl) acrylamide (serial number 37)
Yellow solid, yield 63%.
1H NMR(400MHz,DMSO-d6):δ10.41(s,1H),10.04(s,1H),8.86(s,1H),8.04(s,1H), 7.87 (d, J=8.0Hz, 1H), 7.76 (s, 1H), 7.55 (t, J=8.0Hz, 1H), 7.22 (s, 1H), 7.13-7.10 (m, 2H), 6.70-6.69 (m, 1H), 6.45 (dd, J=17.0,10.2Hz, 1H), 6.26 (dd, J=17.0,2.0Hz, 1H), 5.76 (dd, J=10.2,2.0Hz, 1H), 2.70 (br, 4H), 2.44 (br, 4H), 2.23 (s, 3H), 1.97 (s, 3H) .HRMS (ESI) (m/z):[M+H]+calcd for C27H29N8O2,497.2413；found,497.2428.
N- (3- (2- ((2- methoxyl group -5- methyl -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxos -8 (7H) - Pteridyl) phenyl) acrylamide (serial number 38)
Red solid, yield 50%.
1H NMR(400MHz,DMSO-d6):δ10.38(s,1H),8.82(s,1H),8.37(s,1H),8.04(s,1H), 7.82 (d, J=8.0Hz, 1H), 7.74 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.29 (s, 1H), 7.10 (d, J= 8.8Hz, 1H), 6.62 (s, 1H), 6.45 (dd, J=16.8,2.0Hz, 1H), 6.25 (dd, J=16.8,2.0Hz, 1H), 5.77-5.76(m,1H),3.78(s,1H),2.76(br,4H),2.46(br,4H),2.24(s,3H),1.85(s,3H).HRMS (ESI)(m/z):[M+H]+calcd for C28H31N8O3,527.2519；found,527.2518.
N- (3- (2- ((4- (4- acetyl group -1- piperazinyls) -2- methoxyphenyls) amino) -7- oxos -8 (7H)-pteridine Base) phenyl) acrylamide (serial number 39)
Red solid, yield 50%.
1H NMR(400MHz,DMSO-d6):δ10.36(s,1H),8.80(s,1H),8.44(s,1H),8.03(s,1H), 7.86 (d, J=8.0Hz, 1H), 7.69 (t, J=2.0Hz, 1H), 7.52 (t, J=8.0Hz, 1H), 7.32 (d, J=8.8Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 6.57 (d, J=2.4Hz, 1H), 6.45 (dd, J=17.0,2.0Hz, 1H), 6.27 (dd, J=17.0,10.0Hz, 1H), 6.09 (br, 1H), 5.77 (dd, J=10.0,2.0Hz, 1H), 3.77 (s, 1H), 3.58- 3.54(m,4H),3.06-3.00(m,4H),2.05(s,3H).HRMS(ESI)(m/z):[M+H]+calcd for C28H29N8O4,541.2312；found,541.2312.
N- (3- (2- ((4- (2- (4- methyl-1s-piperazinyl) ethyl) phenyl) amino) -7- oxos -8 (7H)-pteridyl) Phenyl) acrylamide (serial number 40)
Yellow solid, yield 50%.
1H NMR(400MHz,DMSO-d6):δ10.41(s,1H),10.13(s,1H),8.88(s,1H),8.07(s,1H), 7.88 (d, J=8.0Hz, 1H), 7.77 (s, 1H), 7.57 (t, J=8.0Hz, 1H), 7.31-7.30 (m, 2H), 7.14 (d, J= 8.0Hz, 1H), 6.86 (br, 2H), 6.45 (dd, J=16.8,10.0Hz, 1H), 6.26 (dd, J=16.8,2.0Hz, 1H), 5.77 (dd, J=10.0,2.0Hz, 1H), 2.56 (t, J=7.6Hz, 2H), 2.39-2.31 (m, 9H), 2.15 (s, 3H) .HRMS (ESI)(m/z):[M+H]+calcd for C28H31N8O2,511.2570；found,511.2571.
N- (3- (2- ((2- (methoxyethoxy) -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxos -8 (7H) - Pteridyl) phenyl) acrylamide (serial number 41)
Orange red solid, yield 61%.
1H NMR(400MHz,CDCl3):δ8.78(s,1H),8.65-8.62(m,1H),8.24(s,1H),8.07(s, 1H), 7.85 (s, 1H), 7.41 (br, 3H), 6.93 (d, J=5.6Hz, 1H), 6.44 (s, 1H), 6.33 (d, J=17.0Hz, 1H), 6.10 (dd, J=17.0,10.4Hz, 1H), 5.78 (d, J=10.4Hz, 1H), 4.10 (br, 2H), 3.69 (br, 2H), 3.43(s,3H),3.08(br,4H),2.54(br,4H),2.34(s,3H).HRMS(ESI)(m/z):[M+H]+calcd for C29H33N8O4,557.2625；found,557.2621.
N- (3- (2- ((4- (4- (2- ethoxys) -1- piperazinyls) -2- methoxyphenyls) amino) -7- oxos -8 (7H) - Pteridyl) phenyl) acrylamide (serial number 43)
Orange solids, yield 53%.
1H NMR(400MHz,DMSO-d6):δ10.39(s,1H),8.79(s,1H),8.43(s,1H),8.02(s,1H), 7.85 (d, J=7.6Hz, 1H), 7.71 (s, 1H), 7.52 (t, J=8.0Hz, 1H), 7.30 (d, J=7.6Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 6.52 (s, 1H), 6.45 (dd, J=16.8,10.0Hz, 1H), 6.27 (dd, J=16.8,2.0Hz, 1H), 6.02 (br, 1H), 5.78 (dd, J=10.0,2.0Hz, 1H), 4.43 (t, J=5.2Hz, 1H), 3.76 (s, 3H), 3.56-3.52 (m, 2H), 3.04 (br, 4H), 2.53 (t, J=4.8Hz, 4H), 2.44 (t, J=6.0Hz, 1H) .HRMS (ESI) (m/z):[M+H]+calcdfor C29H33N8O3,543.2468；found,543.2466.
N- (3- (2- ((4- (2- (4- methyl-1s-piperazinyl) ethyl) phenyl) amino) -7- oxos -8 (7H)-pteridyl) Phenyl) acrylamide (serial number 44)
Red solid, yield 50%.
1H NMR(400MHz,DMSO-d6):δ10.41(s,1H),8.80(s,1H),8.43(s,1H),8.03(s,1H), 7.88-7.87 (m, 1H), 7.70 (s, 1H), 7.52 (t, J=8.0Hz, 1H), 7.29 (d, J=8.0Hz, 1H), 7.09 (d, J= 8.0Hz, 1H), 6.52 (s, 1H), 6.46 (dd, J=17.2,10.0Hz, 1H), 6.27 (dd, J=17.2,2.0Hz, 1H), 6.04 (br, 1H), 5.78 (dd, J=10.0,2.0Hz, 1H), 3.76 (s, 3H), 3.60-3.58 (m, 2H), 2.58 (t, J= 10.8Hz, 2H), 2.20-2.18 (m, 7H), 1.82-1.79 (d, J=12Hz, 2H), 1.48-1.40 (m, 2H) .HRMS (ESI) (m/z):[M+H]+calcd for C29H33N8O3,541.2676；found,541.2674.
N- (3- (6- isopropyls -2- ((4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxos -8 (7H)-pteridyl) Phenyl) acrylamide (serial number 45)
Red solid 163mg, yield 75%.
1H NMR(400MHz,DMSO-d6):δ 10.42 (s, 1H), 9.85 (br, 1H), 8.79 (s, 1H), 7.91 (d, J= 6.4Hz, 1H), 7.71 (s, 1H), 7.55 (t, J=8.0Hz, 1H), 7.25 (s, 2H), 7.11 (d, J=8.0Hz, 1H), 6.59- 6.58 (m, 2H), 6.45 (dd, J=17.0,10.2Hz, 1H), 6.26 (dd, J=17.0,2.0Hz, 1H), 5.78 (dd, J= 10.2,2.0Hz, 1H), 3.45-3.38 (m, 1H), 2.97 (br, 4H), 2.42 (br, 4H), 2.21 (s, 3H), 1.25 (d, J= 6.8Hz,6H).HRMS(ESI)(m/z):[M+H]+calcd for C29H33N8O2,525.2726；found,525.2728.
N- (3- (2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxo -6- phenyl -8 (7H) - Pteridyl) phenyl) acrylamide (serial number 46)
Red solid, yield 75%.
1H NMR(400MHz,DMSO-d6):δ10.41(s,1H),8.87(s,1H),8.41(s,1H),8.21-8.19(m, 2H), 7.89-7.88 (m, 1H), 7.75 (t, J=2.0Hz, 1H), 7.54 (t, J=8.0Hz, 1H), 7.50-7.48 (m, 3H), 7.35 (d, J=8.8Hz, 1H), 7.17-7.14 (m, 1H), 6.54 (d, J=2.0Hz, 1H), 6.46 (dd, J=17.0, 10.2Hz, 1H), 6.27 (dd, J=17.0,2.0Hz, 1H), 6.05 (br, 1H), 5.78 (dd, J=10.2,2.0Hz, 1H), 3.78(s,3H),3.05(br,4H),2.45(br,4H),2.23(s,3H).HRMS(ESI)(m/z):[M+H]+calcd for C33H33N8O3,589.2676；found,589.2676.
8- (1- acryloyl group -4- piperidyls) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7 (8H)-pteridinone (serial number 47)
Orange solids, yield 53%.
1H NMR(400MHz,DMSO-d6):δ8.83(s,1H),8.71(s,1H),7.83(s,1H),7.53(br,1H), 6.85 (dd, J=17.2,10.4Hz, 1H), 6.61 (d, J=2.4Hz, 1H), 6.47 (d, J=8.0Hz, 1H), 6.13 (dd, J =17.2,2.4Hz, 1H), 5.70 (dd, J=10.4,2.4Hz, 1H), 5.29 (br, 1H), 4.60 (d, J=10.4Hz, 1H), 4.20 (d, J=12.8Hz, 1H), 3.80 (s, 3H), 3.13 (t, J=4.8Hz, 4H), 2.59-2.53 (m, 3H), 2.45 (t, J =4.8Hz, 4H), 2.22 (s, 3H), 1.67 (d, J=10.0Hz, 2H), 1.23 (s, 1H)
(R) -8- ((1- acryloyl group -3- piperidyls) methyl) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) benzene Base) amino) -7 (8H)-pteridinones (serial number 48)
Orange solids, yield 61%.
1H NMR(400MHz,DMSO-d6):δ8.92(s,1H),8.74(s,1H),7.91-7.89(m,1H),7.50- 7.44 (m, 1H), 6.75 (dd, J=16.8,10.4Hz, 1H), 6.64 (s, 1H), 6.56-6.51 (m, 1H), 6.02 (d, J= 16.8Hz,1H),5.64-5.54(m,1H),4.13-4.10(m,1H),3.94-3.83(m,3H),3.76(s,3H),3.16 (br, 4H), 3.03-2.98 (m, 1H), 2.84-2.74 (m, 1H), 2.47 (t, J=4.8Hz, 4H), 1.92-1.91 (m, 1H), 1.64-1.57(m,2H),1.30-1.23(m,3H).
(S) -8- ((1- acryloyl group -3- piperidyls) methyl) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) benzene Base) amino) -7 (8H)-pteridinones (serial number 49)
Orange solids, yield 54%.
1H NMR(400MHz,DMSO-d6):δ8.92(s,1H),8.74(s,1H),7.91-7.89(m,1H),7.49- 7.43 (m, 1H), 6.75 (dd, J=16.4,10.4Hz, 1H), 6.64 (s, 1H), 6.56-6.51 (m, 1H), 6.02 (d, J= 16.4Hz,1H),5.64-5.54(m,1H),4.13-4.08(m,1H),3.94-3.86(m,3H),3.76(s,3H),3.16 (br, 4H), 3.03-2.97 (m, 1H), 2.84-2.74 (m, 1H), 2.47 (t, J=4.8Hz, 4H), 1.92 (br, 1H), 1.64- 1.57(m,2H),1.30-1.20(m,3H).
N- (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) amino) -7- oxygen - 8 (7H)-pteridyls of generation) phenyl) acrylamide (serial number 50)
Red solid, yield 61%.
1H NMR(400MHz,DMSO-d6):δ10.37(s,1H),8.76(s,1H),8.41(br,1H),7.99(s,1H), 7.84-7.83 (m, 1H), 7.69 (t, J=2.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.26-7.19 (m, 1H), 7.09 (d, J=8.0Hz, 1H), 6.45 (dd, J=16.8,10.4Hz, 1H), 6.29-6.24 (m, 2H), 5.77 (dd, J=10.4, 2.0Hz,1H),3.74(s,3H),2.84(s,3H),2.35-2.33(m,2H),2.19(s,6H).
((2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) amino) -6- is different by 3- by N- - 8 (7H)-pteridyl of propyl -7- oxos) phenyl) acrylamide (serial number 51)
Orange solids, yield 62%.
1H NMR(400MHz,DMSO-d6):δ 10.37 (s, 1H), 8.72 (s, 1H), 8.21 (s, 1H), 7.84 (d, J= 8.0Hz, 1H), 7.69 (s, 1H), 7.51 (t, J=8.0Hz, 1H), 7.26 (d, J=7.6Hz, 1H), 7.09 (d, J=8.4Hz, 1H), 6.45 (dd, J=16.8,10.4Hz, 1H), 6.29-6.24 (m, 2H), 5.87 (br, 1H), 5.76 (dd, J=10.4, 2.0Hz, 1H), 3.75 (s, 3H), 3.43-3.38 (m, 1H), 2.84 (s, 3H), 2.34 (t, J=6.8Hz, 2H), 2.19 (s, 6H), 1.24 (d, J=6.8Hz, 6H)
N- (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) amino) -7- oxygen - 8 (7H)-pteridyl of generation -6- phenyl) phenyl) acrylamide (serial number 52)
Red solid, yield 64%.
1H NMR(400MHz,DMSO-d6):δ10.39(s,1H),8.83(s,1H),8.38(br,1H),8.21-8.18 (m, 2H), 7.87 (d, J=7.2Hz, 1H), 7.75 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.49-7.47 (m, 3H), 7.28 (br, 1H), 7.15 (d, J=8.4Hz, 1H), 6.46 (dd, J=16.8,10.0Hz, 1H), 6.29-6.25 (m, 2H), 5.83 (br, 1H), 5.76 (dd, J=10.0,2.0Hz, 1H), 3.76 (s, 3H), 3.35 (br, 2H), 2.85 (s, 3H), 2.35 (t, J=5.6Hz, 2H), 2.20 (s, 6H)
(R) -8- ((1- acryloyl group -3- piperidyls) methyl) -6- isopropyls -2- ((2- methoxyl groups -4- (4- methyl-1s - Piperazinyl) phenyl) amino) -7 (8H)-pteridinones (serial number 53)
Yellow solid, yield 55%.
1H NMR(400MHz,DMSO-d6):δ 8.70 (br, 2H), 7.57-7.52 (m, 1H), 6.76 (dd, J=16.4, 10.4Hz,1H),6.64(s,1H),6.57-6.51(m,1H),6.05-5.98(m,1H),5.64-5.53(m,1H),4.15- 3.96 (m, 3H), 3.90-3.87 (m, 1H), 3.78 (s, 3H), 3.16 (br, 4H), 3.04-2.75 (m, 2H), 2.47 (t, J= 3.6Hz, 4H), 2.24 (s, 3H), 1.94 (br, 1H), 1.66-1.61 (m, 2H), 1.20 (d, J=6.8Hz, 6H)
(R) -8- (1- acryloyl group -3- piperidyls) -2- ((2- methoxyl groups) -4- (4- methyl-1s-piperazinyl) phenyl) ammonia Base) -7 (8H) pteridinones (serial number 54)
Orange solids, yield 46%.
1H NMR(400MHz,DMSO-d6):δ9.17(s,1H),8.71(s,1H),7.83(s,1H),7.20(br,1H), 6.81(br,1H),6.68-6.62(m,2H),6.47(br,1H),6.14-6.08(m,1H),5.72-5.61(m,1H),4.78- 4.72(m,1H),4.35-4.24(m,1H),3.95-3.82(m,1H),3.73(s,3H),3.14(br,4H),2.46(br, 4H),2.23(s,3H),1.62(br,2H),1.34-1.26(m,1H).
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino)-5- ((6- isopropyl-8- methyl) oxo-7-7-, 8- dihydro -2- pteridyls) amino) -4- methoxyphenyls) acrylamide (serial number 55)
Yellow solid, yield 43%.
1H NMR(400MHz,DMSO-d6):δ10.08(s,1H),8.96(s,1H),8.73(s,1H),8.64(s,1H), 7.02 (s, 1H), 6.42 (dd, J=16.4,10.0Hz, 1H), 6.24 (d, J=16.4Hz, 1H), 5.75 (d, J=10.4Hz, 1H),3.85(s,3H),3.59(s,3H),3.43-3.36(m,1H),2.89(br,2H),2.71(s,3H),2.35(br,2H), 2.23 (s, 6H), 1.20 (d, J=6.8Hz, 6H)
(S) -8- (1- acryloyl group -3- pyrrolidinyls) -6- isopropyls -2- ((3- methyl -4- (4- methyl-1s-piperazinyl) Phenyl) amino) -7 (8H)-pteridinones (serial number 56)
Yellow solid, yield 81%.
1H NMR(400MHz,DMSO-d6):δ9.90(s,1H),8.77(s,0.6H),8.76(s,0.4H),7.49-7.41 (m, 2H), 6.93 (t, J=7.2Hz, 1H), 6.73-6.47 (m, 1H), 6.23-6.15 (m, 1H), 6.03-5.94 (m, 1H), 5.76-5.65 (m, 1H), 4.22 (t, J=8.8Hz, 0.6H), 4.02-3.86 (m, 1.7H), 3.83-3.65 (m, 1.7H), 3.47-3.40(m,1H),2.92-2.85(m,1H),2.78(br,4H),2.46(br,4H),2.23(s,3H),2.20(s, 3H), 2.14-2.07 (m, 1H), 1.20 (d, J=6.4Hz, 6H) .HRMS (ESI) (m/z):[M+H]+calcd for C28H37N8O2[M+H]+517.3039；found,517.3038.
(S) -8- (1- acryloyl group -3- pyrrolidinyls) -2- ((3- methyl -4- (4- methyl-1s-piperazinyl) phenyl) ammonia Base) -6- phenyl -7 (8H)-pteridinone (serial number 57)
Orange solids, yield 77%.
1H NMR(400MHz,DMSO-d6):δ10.09(s,1H),8.88(s,1H),8.13(br,2H),7.52-7.49 (m,5H),6.98-6.96(m,1H),6.74-6.48(m,1H),6.23-6.15(m,1H),6.13-6.02(m,1H),5.73- 5.65(m,1H),4.28-4.24(m,0.5H),4.12-3.90(m,1.7H),3.85-3.67(m,1.8H),3.52-3.44(m, 1H),2.94-2.89(m,1H),2.82(br,4H),2.28(s,3H),2.22(s,3H).HRMS(ESI)(m/z):[M+H]+ calcd for C31H35N8O2[M+H]+551.2883；found,551.2880.
(S) -8- (1- acryloyl group -3- pyrrolidinyls) -6- isopropyls -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazine Base) phenyl) amino) -7 (8H)-pteridinones (serial number 58)
Orange solids, yield 54%.
1H NMR(400MHz,DMSO-d6):δ8.71(s,1H),8.69(s,0.5H),8.68(s,0.5H),7.39(t,J =7.6Hz, 1H), 6.57 (s, 1H), 6.41 (d, J=8.8Hz, 1H), 6.17 (dd, J=16.4Hz, 10.8Hz, 1H), 5.86- 5.80 (m, 1H), 5.72-5.63 (m, 1H), 4.12 (t, J=8.8Hz, 0.6H), 3.91-3.86 (m, 0.6H), 3.77 (s, 3H),3.69-3.64(m,1H),3.59(br,1H),3.40-3.38(m,0.8H),3.12(br,4H),2.81-2.70(m, 1H), 2.45 (br, 4H), 2.23 (s, 3H), 2.09-1.98 (m, 1H), 1.18 (d, J=6.4Hz, 6H) .HRMS (ESI) (m/ z):[M+H]+calcd for 533.2989；found,533.2994.
(S) -8- (1- acryloyl group -3- pyrrolidinyls) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) ammonia Base) -6- phenyl -7 (8H)-pteridinone (serial number 59)
Red solid, yield 63%.
1H NMR(400MHz,DMSO-d6):δ8.90(s,1H),8.79(s,1H),8.10(br,2H),7.46(br,3H), 7.41-3.39 (m, 1H), 6.58-6.42 (m, 3H), 6.17 (dd, J=16.4Hz, 10.4Hz, 1H), 5.98-5.82 (m, 1H), 5.72-5.64 (m, 1H), 4.16 (t, J=8.8Hz, 0.6H), 3.95-3.90 (m, 0.6H), 3.78 (s, 3H), 3.71 (t, J= 9.6Hz,0.8H),3.60(br,1H),3.40-3.34(m,1H),3.13(br,4H),2.83-2.71(m,1H),2.45(br, 4H),2.23(s,3H),2.12-2.02(m,1H).HRMS(ESI)(m/z):[M+H]+calcd for C31H35N8O3[M+H]+ 567.2832；found,567.2831.
(S, E) -8- (1- (4- (dimethylamino) -2- crotonyls) -3- pyrrolidinyls) -2- ((3- methyl -4- (4- first Base -1- piperazinyls) phenyl) amino) -6- phenyl -7 (8H)-pteridinone (serial number 61)
Orange solids, yield 82%.
1H NMR(400MHz,DMSO-d6):δ10.10(s,1H),8.88(s,1H),8.12(s,2H),7.49(br,5H), 6.97 (d, J=8.4Hz, 1H), 6.72-6.61 (m, 1H), 6.54-6.31 (m, 1H), 6.10-6.00 (m, 1H), 4.28-4.24 (m,0.6H),4.05-4.00(m,0.7H),3.93-3.86(m,1.5H),3.81-3.76(m,1.5H),3.73-3.67(m, 1H), 3.55 (br, 4H), 3.18 (d, J=6.8Hz, 2H), 3.08 (d, J=5.2Hz, 1H), 2.83 (br, 4H), 2.57 (s, 3H),2.32(s,1.5H),2.30(s,1.5H),2.57(s,3H),2.22(s,3H),2.17(s,3H).HRMS(ESI)(m/ z):[M+H]+calcd for C34H42N9O2[M+H]+608.3461；found,608.3466.
(E) -8- (1- (4- (dimethylamino) -2- crotonyls) -4- piperidyls) -2- ((2- methoxyl groups -4- (4- first Base -1- piperazinyls) phenyl) amino) -7 (8H)-pteridinones (serial number 62)
Red solid, yield 71%, mp 157.3-157.6 DEG C
1H NMR(400MHz,DMSO-d6):δ8.86(s,1H),8.72(s,1H),7.83(s,1H),7.54(br,1H), 6.64-6.62 (m, 3H), 6.47 (d, J=7.6Hz, 1H), 5.27 (br, 1H), 4.61-4.58 (m, 1H), 4.21-4.18 (m, 1H), 3.79 (s, 3H), 3.14 (br, 4H), 3.05-3.04 (br, 2H), 2.57 (br, 4H), 2.46 (t, J=4.0Hz, 4H), 2.23(s,3H),2.16(s,6H),1.67(br,2H).HRMS(ESI)(m/z):[M+H]+calcd for C29H40N9O3, 562.3254；found,562.3259.
N- (3- (6- isopropyls -2- ((3- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxos -8 (7H) pteridyl) phenyl) acrylamide (serial number 64)
Yellow solid, yield 69%.mp 249.0-249.5 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.42 (s, 1H), 9.83 (br, 1H), 8.82 (s, 1H), 7.87 (d, J= 8.0Hz, 1H), 7.73 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.12 (d, J=8.0Hz, 1H), 7.04 (br, 1H), 6.96 (br, 1H), 6.49-6.42 (m, 2H), 6.26 (dd, J=16.8Hz, 2.0Hz, 1H), 5.77 (dd, J=10.0Hz, 2.0Hz, 1H), 3.55 (s, 3H), 3.44-3.39 (m, 1H), 2.82 (br, 4H), 2.42 (br, 4H), 2.21 (s, 3H), 1.25 (d, J= 6.8Hz,6H).HRMS(ESI)(m/z):[M+H]+calcd for C30H35N8O3,555.2832；found,555.2838.
N- (3- (2- ((3- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxos -6- (trifluoromethyl) - 8 (7H)-pteridyls) phenyl) acrylamide (serial number 65)
Brown solid, yield 59%, mp>300℃.
1H NMR(400MHz,DMSO-d6):δ 10.44 (s, 1H), 10.40 (s, 1H), 9.00 (s, 1H), 7.88 (d, J= 7.2Hz, 1H), 7.81 (s, 1H), 7.56 (t, J=8.0Hz, 1H), 7.14 (d, J=8.0Hz, 1H), 7.01 (d, J=7.2Hz, 1H), 6.95 (s, 1H), 6.49-6.42 (m, 2H), 6.27 (d, J=16.4Hz, 1H), 5.77 (d, J=10.4Hz, 1H), 3.53 (s,3H),2.83(br,4H),2.41(br,4H),2.21(s,3H).HRMS(ESI)(m/z):[M+H]+calcd for C28H28N8O3F3,581.2236；found,581.2241.
(S) -8- (1- acryloyl group -3- pyrrolidinyls) -2- ((3- methyl -4- (4- methyl 1- piperazinyls) phenyl) ammonia Base) -7 (8H) pteridinones (serial number 66)
Yellow solid, yield 45%, mp 215.5-215.7 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.08 (s, 1H), 8.81 (d, J=3.2Hz, 1H), 7.89 (d, J= 6.8Hz, 1H), 7.47-7,42 (m, 2H), 6.93 (t, J=6.8Hz, 1H), 6.72-6.46 (m, 1H), 6.22-6.6.14 (m, 1H), 5.98-5.88 (m, 1H), 5.75-5.64 (m, 1H), 4.20 (t, J=8.8,1H), 4.00-3.64 (m, 4H), 3.47- 3.40(m,1H),2.78(br,4H),2.45(s,3H),2.23(s,3H),2.20(br,4H).HRMS(ESI)(m/z):[M+H ]+calcd for C25H31N8O2,475.2570；found,475.2550.
(S) -8- (- 3 pyrrolidinyl of 1- acryloyl groups) -2- ((3- methoxyl groups -4 (4- methyl-1s-piperazinyl) phenyl) ammonia Base) -6- phenyl -7 (8H) pteridinone (serial number 67)
Orange solids, yield 40%, mp 208.3-208.8 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.10 (s, 1H), 8.88 (d, J=3.2,1H), 8.13-8.12 (m, 2H), 7.48 (d, J=2.4Hz, 1H), 7.47 (s, 1H), 7.34-7.27 (m, 2H), 6.81 (t, J=8.4Hz, 1H), 6.74-6.48 (m, 1H), 6.23-6.15 (m, 1H), 6.12-6.04 (m, 1H), 5.76-5.65 (m, 1H), 4.25 (t, J=9.2,1H), 4.13-3.76(m,3H),3.76(s,3H),3.74-3.67(m,1H),3.51-3.44(m,1H),2.91(br,4H),2.44 (br,4H),2.21(s,3H).HRMS(ESI)(m/z):[M+H]+calcd for C31H35N8O3,567.2832；found, 567.2835.
(S, E) -8- (1- (4- (dimethylamino) -2- crotonyls) 3- pyrrolidinyls) -2- ((3- methyl -4- (4- first Base -1- piperazinyls) phenyl) amino) -6- isopropyls -7 (8H) pteridinone (serial number 68)
Red solid, yield 62%, mp 159.9-160.7 DEG C
1H NMR(400MHz,DMSO-d6):δ 9.94 (s, 1H), 8.77 (d, J=3.6Hz, 1H), 7.49-7.40 (m, 2H), 6.94 (d, J=8.4,1H), 6.72-6.61 (m, 1H), 6.53 (d, J=15.2Hz, 0.5H), 6.34 (d, J= 15.2Hz, 0.5H), 6.04-5.91 (m, 1H), 4.22 (t, J=8.4Hz, 1H), 4.00-3.64 (m, 4H), 3.40-3.35 (m, 2H), 3.22 (t, J=6.4Hz, 1H), 3.10 (d, J=6.0Hz, 1H), 2.82 (br, 4H), 2.61 (br, 4H), 2.34 (d, 11.2Hz, 3H), 2.28 (s, 3H), 2.20 (br, 4H), 2.19 (s, 3H), 1.20 (d, J=6.8Hz, 6H) .HRMS (ESI) (m/ z):[M+H]+calcd for C31H44N9O2,574.3618；found,574.3584.
N- (3- (6- isopropyls -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxos -8 (7H) pteridyl) phenyl) acrylamide (serial number 69)
Orange solids, yield 65%, mp 242.9-243.9 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.42 (s, 1H), 8.75 (s, 1H), 8.26 (s, 1H), 7.87 (d, J= 7.2Hz, 1H), 7.71 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.34 (d, J=8.8Hz, 1H), 7.10 (d, J=8.8Hz, 1H), 6.53 (d, J=2.0Hz, 1H), 6.46 (dd, J=16.8Hz, 10.0Hz, 1H), 6.27 (dd, J=16.8Hz, 2.0Hz, 1H), 6.12-6.00 (m, 1H), 5.78 (dd, J=10.0Hz, 2.0Hz), 3.76 (s, 3H), 3.44-3.41 (m, 1H), 3.04 (br, 4H), 2.43 (t, J=4.8Hz, 4H), 2.22 (s, 3H), 1.25 (d, J=6.8Hz, 6H) .HRMS (ESI) (m/z):[M+ H]+calcd for C30H35N8O3,555.2832；found,555.2821.
N- (3- (2- ((2- methoxyl group -5- methyl -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxo -6- benzene (7H) pteridine of base -8 ketone group) phenyl) acrylamide (serial number 70)
Yellow solid, yield 62%, mp 292.9-293.4 DEG C
1H NMR(400MHz,DMSO-d6):δ10.41(s,1H),8.90(s,1H),8.36(br,1H),8.21-8.18 (m, 2H), 7.84 (d, J=8.0Hz, 1H), 7.80 (s, 1H), 7.55 (t, J=8.0Hz, 1H), 7.50-7.48 (m, 3H), 7.33 (s, 1H), 7.16 (d, J=7.6Hz, 1H), 6.63 (s, 1H), 6.45 (dd, J=16.8Hz, 10.0Hz, 1H), 6.26 (dd, J=16.8Hz, 1.6Hz), 5.77 (dd, J=10.0Hz, 1.6Hz, 1H), 3.79 (s, 3H), 2.77 (br, 4H), 2.48 (br,4H),2.25(s,3H),1.85(br,3H).HRMS(ESI)(m/z):[M+H]+calcd for C34H35N8O3, 603.2832；found,603.2834.
N- (3- (6- isopropyls -2- ((2- methoxyl group -5- methyl -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxygen - 8 (7H) pteridyls of generation) phenyl) acrylamide (serial number 71)
Orange solids, yield 60%, mp 227.5-228.5 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.40 (s, 1H), 8.79 (s, 1H), 8.22 (s, 1H), 7.82 (d, J= 8.0Hz, 1H), 7.73 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.31 (s, 1H), 7.11 (d, J=7.6Hz, 1H), 6.62 (s, 1H), 6.44 (dd, J=16.8Hz, 10.0Hz, 1H) .6.25 (dd, J=16.8Hz, 0.8Hz, 1H), 5.75 (d, J= 10.0Hz,1H),3.78(s,3H),3.43-3.39(m,1H),2.77(br,4H),2.26(s,3H),1.85(br,3H),1.24 (d, J=6.8Hz, 6H) .HRMS (ESI) (m/z):[M+H]+calcd for C31H37N8O3,569.2989；found, 569.2989.
(S) -8- (1- acryloyl group -3- pyrrolidinyls) -2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) - 3- aminomethyl phenyls) amino) -6- phenyl -7 (8H) pteridinone (serial number 72)
Red solid, yield 40%, mp 256.1-256.4 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.08 (s, 1H), 8.88 (d, J=3.2Hz, 1H), 8.13-8.12 (m, 2H), 7.52-7.45 (m, 5H), 7.02 (dd, J=8.4Hz, 5.6Hz, 1H), 6.74-6.49 (m, 1H), 6.23-6.15 (m, 1H),6.12-6.02(m,1H),5.75-5.65(m,1H),4.28-4.23(m,1H),4.15-4.12(m,1H),3.94-3.68 (m, 3H), 3.52-3.44 (m, 1H), 2.90 (t, J=6.8Hz, 2H), 2.61 (s, 3H), 2.35 (t, J=6.8Hz, 2H), 2.22(s,3H),2.13(br,6H).HRMS(ESI)(m/z):[M+H]+calcd for C31H37N8O2,553.3039； found,553.3031.
(S) -8- (1- acryloyl group -3- pyrrolidinyls) -2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) - 3- methoxyphenyls) amino) -6- phenyl -7 (8H) pteridinone (serial number 73)
Dark red solid, yield 49%, mp 260.0-260.2 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.09 (s, 1H), 8.88 (d, J=2.8Hz, 1H), 8.131 (br, 2H), 7.49-7.48 (m, 3H), 7.34-7.25 (m, 2H), 6.81 (t, J=7.2Hz, 1H), 6.76-6.49 (m, 1H), 6.23-6.05 (m, 2H), 5.75-5.65 (m, 1H), 4.25 (t, J=8.4Hz, 1H) .4.06-3.82 (m, 3H), 3.77 (s, 3H), 3.74- 3.67 (m, 1H), 3.05 (t, J=7.2Hz, 2H), 2.94-2.79 (m, 1H), 2.68 (s, 3H), 2.36 (t, J=7.2Hz, 2H),2.13(s,6H).HRMS(ESI)(m/z):[M+H]+calcd for C31H37N8O3,569.2989；found, 569.2988.
N- (3- (2- ((3- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxo -6- phenyl -8 (7H) Pteridyl) phenyl) acrylamide (serial number 74)
Red solid, yield 81%, mp 264.7-265.5 DEG C
1H NMR(400MHz,DMSO-d6):δ10.43(s,1H),10.01(s,1H),8.93(s,1H),8.22-8.19 (m, 2H), 7.90 (d, J=7.6Hz, 1H), 7.79 (s, 1H), 7.56 (t, J=8.0Hz, 1H), 7.49 (t, J=3.2Hz, 1H), 7.17 (d, J=8.4Hz, 1H), 7.07 (br, 1H), 6.97 (br, 1H), 6.46 (dd, J=16.8Hz, 10.0Hz, 1H), 6.27 (dd, J=16.8Hz, 1.6Hz, 1H), 5.77 (dd, J=10.0Hz, J=1.6Hz, 1H), 3.56 (s, 3H), 2.83 (br,4H),2.41(br,4H),2.21(s,3H).HRMS(ESI)(m/z):[M+H]+calcd for C33H33N8O3, 589.2676；found,589.2642.
N- (3- (6- cyclohexyl -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxos -8 (7H) pteridyl) phenyl) acrylamide (serial number 75)
Yellow solid, yield 82%, mp 268.9-269.4 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.40 (s, 1H), 8.73 (s, 1H), 8.24 (s, 1H), 7.85 (d, J= 8.0Hz, 1H), 7.69 (t, J=1.6Hz, 1H), 7.52 (t, J=8.0Hz, 1H), 7.33 (d, J=9.2Hz, 1H), 7.10- 7.08 (m, 1H), 6.53 (d, J=2.4Hz, 1H), 6.45 (dd, J=16.8Hz, 10.0Hz, 1H), 6.26 (dd, J= 16.8Hz, 2.0Hz, 1H), 6.06 (br, 1H), 5.77 (dd, J=10.0Hz, 2.0Hz, 1H), 3.76 (s, 3H), 3.03 (br, 4H), 2.43 (t, J=4.8Hz, 4H), 2.22 (s, 3H), 3.41 (d, J=12.0Hz, 2H), 1.82 (d, J=12.0Hz, 2H), 1.72 (d, J=12.0Hz, 2H), 1.53-1.23 (m, 6H).HRMS(ESI)(m/z):[M+H]+calcd for C33H39N8O3, 595.3145；found,595.3141.
(S) -8- ((1- acryloyl group -3- piperidyls) methyl) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) benzene Base) amino) -6- phenyl -7 (8H) pteridinone (serial number 76)
Red solid, yield 49%, mp 208.3-209.3 DEG C
1H NMR(400MHz,DMSO-d6):δ8.88(s,1H),8.81(s,1H),8.18-8.16(m,2H),7.59- 7.52 (m, 1H), 7.47 (t, J=3.2Hz, 3H), 6.75 (dd, J=16.4Hz, 10.0,1H), 6.64 (s, 1H), 6.55 (dd, J=17.2Hz, 8.8Hz, 1H), 6.03 (d, J=16.4Hz, 1H), 5.58 (dd, J=32.8Hz, 10.0Hz, 1H), 4.19- 4.06 (m, 3H), 3.89-3.83 (m, 1H), 3.79 (s, 3H), 3.17 (br, 4H), 3.05-2.55 (m, 2H), 2.48 (t, J= 4.8Hz,4H),2.24(s,3H),2.00(br,1H),1.66(br,2H),1.26-1.23(m,2H)。HRMS(ESI)(m/z): [M+H]+calcd for C33H39N8O3,595.3145；found,595.3157.
(R) -8- (1- acryloyl group -3- piperidyls) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) ammonia Base) -6- phenyl -7 (8H) pteridinone (serial number 77)
Red solid, yield 38%, mp 134.9-135.1 DEG C
1H NMR(400MHz,DMSO-d6):δ9.17(s,1H),8.79(s,1H),8.11-8.09(m,2H),7.77- 7.46 (m, 3H), 7.24 (br, 1H), 6.84-6.63 (m, 2H), 6.49 (s, 1H), 6.06-6.19 (m, 1H), 5.67 (dd, J= 37,2Hz,9.6Hz,1H),5.00-4.27(m,3H),3.75(s,3H),3.14(s,4H),2.49(s,4H),2.24(s,3H), 1.69(br,2H),1.35(br,1H),1.23(s,1H)。HRMS(ESI)(m/z):[M+H]+calcd for C32H37N8O3, 581.2989；found,581.2972.
(R) -8- (1- acryloyl group -3- piperidyls) -6- cyclohexyl -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) Phenyl) amino) -7 (8H) pteridinones (serial number 78)
Yellow solid, yield 53%, mp 94.2-94.7 DEG C
1H NMR(400MHz,DMSO-d6):δ8.96(s,1H),8.65(s,1H),7.23(br,1H),6.83-6.61(m, 2H), 6.47 (s, 1H), 6.15-6.08 (m, 1H), 5.66 (dd, J=36Hz, 9.6Hz, 1H), 4.84 (br, 1H), 4.29 (br, 1H),3.95(br,1H),3.72(s,3H),3.13(br,4H),2.46(br,4H),2.23(s,3H),1.81-1.63(m, 7H),1.44-1.23(m,9H).HRMS(ESI)(m/z):[M+H]+calcd for C32H43N8O3,587.3458； found587.3458.
N- (3- (- 8 (7H) butterflies of 2- ((3- methyl -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxygroup -6- phenyl Piperidinyl) phenyl) acrylamide (serial number 79)
Yellow solid, yield 68%, mp 265.0-265.2 DEG C
1H NMR(400MHz,DMSO-d6):δ10.43(s,1H),10.04(s,1H),8.92(s,1H),8.22-8.19 (m, 2H), 7.89 (d, J=8.0Hz, 1H), 7.81 (s, 1H), 7.57 (t, J=8.0Hz, 1H), 7.50-7.49 (m, 3H), 7.25 (s, 1H), 7.19 (s, 1H), 7.17 (s, 1H), 6.71 (br, 1H), 6.46 (dd, J=16.8Hz, 10.4Hz, 1H), 6.26 (dd, J=16.8Hz, 1.6Hz, 1H), 5.77 (dd, J=10.4Hz, 1.6Hz, 1H), 2.7 (br, 4H), 2.44 (br, 4H),2.23(s,3H),1.98(s,3H).HRMS(ESI)(m/z):[M+H]+calcd for C33H33N8O2,573.2726； found,573.2729.
N- (3- (2- ((2- methoxyl groups -4- (4- (4- methyl-1s-piperazinyl) piperidyl) phenyl) amino) -7- oxos -6- Phenyl -8 (7H) pteridyl) phenyl) acrylamide (serial number 80)
Red solid, yield 40%, mp>300℃.
1H NMR(400MHz,DMSO-d6):δ10.44(s,1H),8.86(s,1H),8.41(s,1H),8.20-8.19(m, 2H), 7.90 (br, 1H), 7.75 (s, 1H), 7.54 (t, J=8.0Hz, 1H), 7.50-7.48 (m, 3H), 7.33 (d, J= 6.4Hz, 1H), 7.15 (d, J=8.0Hz, 1H), 6,52 (br, 1H), 6.47 (dd, J=16.8Hz, 10.0Hz, 1H), 6.27 (dd, J=16.8Hz, 1.6Hz, 1H), 6.04 (br, 1H), 5.78 (dd, J=10.0Hz, 1.6Hz), 3.77 (s, 3H), 3.61 (d, J=8.4Hz, 2H), 2.60-2.54 (m, 5H), 2.39-2.30 (m, 5H), 1,81 (d, J=11.6Hz, 2H), 1.51- 1.43(m,2H).HRMS(ESI)(m/z):[M+H]+calcd for C38H42N9O3,672.3411；found,672.3407.
8- (1- acryloyl group -3- pyrrolidinyls) -2- ((3- methyl -4- (4- methyl-1s-piperazinyl) phenyl) amino) -6- Phenyl -7 (8H) pteridinone (serial number 81)
Orange solids, yield 65%.
1H NMR(400MHz,DMSO-d6):δ 10.08 (s, 1H), 8.87 (d, J=2.8Hz, 1H), 8.13-8.11 (m, 2H), 7.51-7.46 (m, 5H), 6.97-6.93 (m, 1H), 6.70 (dd, J=16.8Hz, 10.4,1H), 6.51 (dd, J= 16.8Hz, 10.4Hz, 1H), 6.23-6.15 (m, 1H), 6.11-6.01 (m, 1H), 5.75-5.65 (m, 1H), 4.25 (t, J= 8.8Hz,1H),4.06-3.68(m,3H),3.52-3.45(m,1H),2.95-2.86(m,1H),2.79(br,4H),2.46 (br,4H),2.23(s,3H),2.21(s,3H),2.17-2.12(m,1H).HRMS(ESI)(m/z):[M+H]+calcd for C31H35N8O2,551.2883；found,551.2883.
(S) -8- (1- acryloyl group -3- pyrrolidinyls) -6- cyclohexyl -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazine Base) phenyl) amino) -7 (8H) pteridinones (serial number 82)
Orange solids, yield 49%, mp 117.9-118.2 DEG C
1H NMR(400MHz,DMSO-d6):δ 8.71 (s, 1H), 8.66 (d, J=3.6Hz, 1H), 7.39 (t, J= 8.0Hz, 1H), 6.63-6.59 (m, 0.5H), 6.57 (s, 1H), 6.49-6.45 (m, 0.5H), 6.41 (d, J=9.2Hz, 1H), 6.20-6.13 (m, 1H), 5.82 (br, 1H), 5.73-5.63 (m, 1H), 4.11 (t, J=9.2Hz, 0.5H), 3.87 (dd, J= 12.0Hz,8.8Hz,0.5H),3.69-3.58(m,2H),3.18-3.04(m,5H),2.80-2.65(m,1H),2.45(br, 4H), 2.23 (s, 3H), 2.09 (br, 0.5H), 1.99 (br, 0.5H), 1.81 (t, J=11.2Hz, 4H), 1.70 (d, J= 11.2Hz,1H),1.45-1.16(m,6H).HRMS(ESI)(m/z):[M+H]+calcd for C31H41N8O3,573.3302； found,573.3304.
8- (3- aminophenyls) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -6- phenyl -7 (8H) pteridinone (serial number 83)
Orange solids, yield 84%, mp 235.5-235.7 DEG C
1H NMR(400MHz,DMSO-d6):δ8.84(s,1H),8.39(br,1H),8.19-8.17(m,2H),7.49- 7.47 (m, 4H), 7.21 (t, J=8.0Hz, 1H), 6.72 (d, J=7.2Hz, 1H), 6.571-6.56 (m, 2H), 6.52 (d, J =8.0Hz, 1H), 6.19 (br, 1H), 5.34 (s, 2H), 3.79 (s, 3H), 3.08 (br, 4H), 2.45 (t, J=4.4Hz, 4H),2.23(s,3H).HRMS(ESI)(m/z):[M+H]+calcd for C30H31N8O2,535.2570；found, 535.2569.
N- (3- (6- (4- fluorophenyls) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxos - 8 (7H) pteridyls) phenyl) acrylamide (serial number 84)
Orange solids, yield 73%, mp 262.3-262.7 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.43 (s, 1H), 8.87 (s, 1H), 8.44 (s, 1H), 8.29 (dd, J= 8.4Hz, 6.0Hz, 1H), 7.89 (br, 1H), 7.77 (s, 1H), 7.55 (t, J=8.0Hz, 1H), 7.36-7.31 (m, 3H), 7.15 (d, J=8.4Hz, 1H), 6.54 (s, 1H), 6.47 (dd, J=16.8Hz, 10.0Hz, 1H), 6.28 (dd, J= 16.8Hz, 1.6Hz, 1H), 6.04 (br, 1H), 5.78 (dd, J=10.0Hz, 1.6Hz, 1H), 3.78 (s, 3H), 3.05 (br, 4H), 2.44 (t, J=4.4Hz, 4H), 2.23 (s, 3H) .HRMS (ESI) (m/z):[M+H]+calcd for C33H32N8O3F, 607.2581；found,607.2589.
N- (3- (6- (2- fluorophenyls) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- oxos - 8 (7H) pteridyls) phenyl) acrylamide (serial number 85)
Orange solids, yield 67%.
1H NMR(400MHz,DMSO-d6):δ10.42(s,1H),8.85(s,1H),8.50(s,1H),7.86(s,1H), 7.76 (s, 1H), 7.64-7.68 (t, J=8.0Hz, 1H), 7.52-7.56 (t, J=8.0Hz, 2H), 7.31-7.35 (t, J= 8.0Hz, 3H), 7.14 (d, J=8.0Hz, 1H), 6.54 (s, 1H), 6.46 (dd, J=16.0Hz, 8.0Hz, 1H), 6.27 (d, J =16.0Hz, 1H), 6.03 (br, 1H), 5.78 (d, J=8.0Hz, 1H), 3.77 (s, 3H), 3.05 (br, 4H), 2.43 (s, 4H),2.22(s,3H).HRMS(ESI)(m/z):[M+H]+calcd for C33H32N8O3F,607.2503；found, 607.2534.
N- (3- (2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -6- (4- methoxyphenyls) -7- Oxo -8 (7H) pteridyl) phenyl) acrylamide (serial number 88)
Orange solids, yield 65%, mp 296.5-297.3 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.43 (s, 1H), 8.84 (s, 1H), 8.34 (s, 1H), 8.26 (d, J= 8.8Hz, 1H), 7.89 (d, J=7.2Hz, 1H), 7.74 (s, 1H), 7.55 (t, J=8.0Hz, 1H), 7.36 (d, J=8.4Hz, 1H), 7.15 (d, J=8.4Hz, 1H), 7.05 (d, J=9.2Hz, 1H), 6.54 (s, 1H), 6.47 (dd, J=16.8Hz, 10.0Hz, 1H), 6.27 (dd, J=16.8Hz, 1.6Hz, 1H), 6.06 (br, 1H), 5.78 (d, J=10.0Hz, 1.6Hz, 1H),3.84(s,3H),3.78(s,3H),3.05(br,4H),2.44(br,4H),2.23(s,3H).HRMS(ESI)(m/z): [M+H]+calcd for C34H35N8O4,619.2781；found,619.2780.
N- (3- (6- (3,5- difluorophenyls) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- Oxo -8 (7H) pteridyl) phenyl) acrylamide (serial number 89)
Red solid, yield 64%, mp 291.2-291.4 DEG C
1H NMR(400MHz,DMSO-d6):δ 10.43 (s, 1H), 8.92 (s, 1H), 8.57 (s, 1H), 7.96 (d, J= 7.2Hz, 1H), 7.87 (br, 1H), 7.77 (s, 1H), 7.54 (t, J=8.0Hz, 1H), 7.43-7.39 (m, 1H), 7.33 (s, 1H), 7.14 (d, J=7.2Hz, 1H), 6.54 (s, 1H), 6.47 (dd, J=16.8Hz, 10.0,1H), 6.27 (dd, J= 16.8Hz, 1.6Hz, 1H), 6.00 (br, 1H), 5.78 (dd, J=10.0Hz, 1.6Hz, 1H), 3.77 (s, 3H), 3.05 (br, 4H),2.43(br,4H),2.22(s,3H).HRMS(ESI)(m/z):[M+H]+calcd for C33H31N8O3F2,625.2487； found,625.2482.
N- (3- (6- (3,4- difluorophenyls) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -7- Oxo -8 (7H) pteridyl) phenyl) acrylamide (serial number 90)
Orange solids, yield 67%, Mp>300℃.
1H NMR(400MHz,DMSO-d6):δ10.43(s,1H),8.89(s,1H),8.50(br,1H),8.28-8.23 (m,1H),8.15(br,1H),7.87(s,1H),7.77(s,1H),7.61-7.52(m,2H),7.34(s,1H),7.14(d,J =8.4Hz, 1H), 6.54 (s, 1H), 6.47 (dd, J=16.8Hz, 10.0Hz, 1H), 6.27 (dd, J=16.8Hz, 1.6Hz, 1H), 6.02 (br, 1H), 5.78 (dd, J=10.0Hz, 1.6Hz, 1H), 3.77 (s, 3H), 3.05 (br, 4H), 2.43 (t, J= 4.4Hz,4H),2.22(s,3H).HRMS(ESI)(m/z):[M+H]+calcd for C33H31N8O3F2,625.2487；found, 625.2478.
N- (3- (2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -6- (3- methoxyphenyls) -7- Oxo -8 (7H) pteridyl) phenyl) acrylamide (serial number 91)
Brown solid, yield 52%, Mp>300℃.
1H NMR(400MHz,DMSO-d6):δ10.42(s,1H),8.88(s,1H),8.45(s,1H),7.89(s,1H), 7.82-7.81 (m, 2H), 7.76 (s, 1H), 7.55 (t, J=8.0Hz, 1H), 7.41 (t, J=8.0Hz, 1H), 7.36-7.34 (br, 1H), 7.16 (d, J=7.6Hz, 1H), 7.08 (d, J=8.4Hz, 1H), 6.54 (s, 1H), 6.47 (dd, J=16.8Hz, 10.4Hz, 1H), 6.28 (d, J=17.2Hz, 1H), 6.04 (br, 1H), 5.80 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.05(br,4H),2.44(br,4H),2.23(s,3H).HRMS(ESI)(m/z):[M+H]+calcd for C34H35N8O4, 619.2781；found,619.2780.
N- (3- (2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -4- methyl -6- phenyl -7- oxygen - 8 (7H) pteridyls of generation) phenyl) acrylamide (serial number 92)
Brown solid, yield 85%.
1H NMR(400MHz,DMSO-d6):δ10.40(s,1H),8.25-8.28(m,2H),8.20(s,1H),7.90(d, J=8.0Hz, 1H), 7.72 (s, 1H), 7.54 (t, J=8.0Hz, 1H), 7.48-7.50 (m, 3H), 7.38 (d, J=8.0Hz, 1H), 7.12 (d, J=8.0Hz, 1H), 6.53 (d, J=4.0Hz, 1H), 6.46 (dd, J=16.0Hz, 8.0Hz, 1H), 6.27 (dd, J=16.0Hz, 4.0Hz, 1H), 6.03 (br, 1H), 5.77 (m, 1H), 3.82 (s, 3H), 3.03 (s, 4H), 2.72 (s, 3H),2.44(br,4H),2.23(s,3H).HRMS(ESI)(m/z):[M+H]+calcd for C34H35N8O4,603.2754； found,603.2750.
N- (3- (6- (4- fluorophenyls) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -4- methyl - 7- oxos -8 (7H) pteridyl) phenyl) acrylamide (serial number 93)
Brown solid, yield 73%.
1H NMR(400MHz,DMSO-d6):δ10.48(s,1H),8.33-8.37(m,2H),8.22(s,1H),7.91(d, J=8.0Hz, 1H), 7.74 (s, 1H), 7.54 (t, J=8.0Hz, 1H), 7.30-7.38 (m, 3H), 7.12 (d, J=8.0Hz, 1H), 6.53 (s, 1H), 6.48 (dd, J=16.0Hz, 8.0Hz, 1H), 6.27 (d, J=16.0Hz, 1H), 6.01 (br, 1H), 5.78 (d, J=8.0Hz, 1H), 3.77 (s, 3H), 3.06 (s, 4H), 2.70 (s, 3H), 2.53 (s, 4H), 2.29 (s, 3H) .HRMS(ESI)(m/z):[M+H]+calcd for C34H35N8O4,621.2738；found,603.2726.
The following institute of synthesis of 1,4- dihydro -2H- pyrimidos [4,5-d] [1,3] oxazines -2- ketone compounds of the present invention Show：
Reagent and condition：(a) (3- aminophenyls) t-butyl carbamate, DIPEA, CH3CN, reflux, 6h；(b) LiAlH4,THF,0℃,4h；(c)MnO2,CH2Cl2, room temperature, overnight；(d) Grignard Reagent, THF, 0 DEG C, 5h；(e)CDI,K2CO3, THF flows back, overnight；(f) arylamine, trifluoroacetic acid, trifluoroethanol, reflux, for 24 hours；(g) trifluoroacetic acid, CH2Cl2, room temperature, 5h； (h) acryloyl chloride, Et3N,CH2Cl2, 0 DEG C is arrived room temperature, overnight.
Embodiment 2
The specific synthetic method of above-mentioned steps a-h is as follows：
The synthesis of 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- chlorine pyrimidine -5- Ethyl formates
Weigh bis- chloro- 5- pyrimidinecarboxylic acids ethyl esters (22.100g, 100mmol) of 2,4-, DIPEA (12.900g, 100mmol) in The dissolving of 100mL acetonitriles is added in 500mL single-necked flasks.Separately take (3- aminophenyls) t-butyl carbamate (20.800g, 100mL acetonitriles 100mmol) are dissolved in, are added drop-wise in above-mentioned reaction solution, reflux 6h is dripped.TLC tracks to raw material conversion, cooling It to room temperature, filters, acetonitrile washing, it is phonetic to obtain 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- chlorine for filter cake drying Pyridine -5- Ethyl formates 33.710g.
1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),9.50(s,1H),8.80(s,1H),7.70(s,1H), 7.35 (d, J=8.0Hz, 1H), 7.29 (t, J=8.0Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 4.38 (q, J=7.2Hz, 2H), 1.49 (s, 9H), 1.36 (t, J=7.2Hz, 3H) .LC-MS:m/z:393.1(M+H)+.
(3-((2- chloro- 5- (methylol) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate
Weigh 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- chlorine pyrimidine -5- Ethyl formates (31.360g, 80mmol) in 5000mL two mouth flasks, the dissolving of 100mL anhydrous tetrahydro furans, ice bath stirring 10 minutes is added.Separately take lithium aluminium hydride (12.160g, 320mmol) is dissolved in 150mL anhydrous tetrahydro furans, is slowly dropped in above-mentioned reaction solution, is dripped ice bath and is stirred It mixes 4 hours.TLC tracks raw material conversion, and reaction solution is instilled to 250mL saturations NH in batches4In Cl aqueous solutions, ethyl acetate extraction, Collected organic layer, anhydrous Na2SO4Dry, rotary evaporation removes solvent.Crude product is through silica gel column chromatography separating purification (petroleum ether/second Acetoacetic ester=2:1,v/v).Obtain (3- ((2- chloro- 5- (methylol) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate 3.638g。
1H NMR(400MHz,CDCl3) δ 8.38 (s, 1H), 7.87 (s, 1H), 7.70 (s, 1H), 7.34 (d, J=8.4Hz, 1H), 7.25 (t, J=8.0Hz, 1H), 7.05 (d, J=8.0Hz, 1H), 6.66 (s, 1H), 4.65 (s, 2H), 1.52 (s, 9H) .LC-MS:m/z:351.1(M+H)+.
(3-((the chloro- 5- formylpyrimidins-4- bases of 2-) amino) phenyl) t-butyl carbamate
Weigh (3- ((2- chloro- 5- (methylol) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate (3.500g, 10mmol) in 100mL single-necked flasks, the dissolving of 40mL dichloromethane is added.Be added portionwise manganese dioxide (58%, 15.000g, 100mmol), it is stirred overnight at room temperature.TLC tracks raw material conversion, pads suction filtered through kieselguhr, and filtrate is spin-dried for, and crude product is through silica gel column chromatography Isolate and purify (petrol ether/ethyl acetate=4:1,v/v).Obtain (3- ((the chloro- 5- formylpyrimidins -4- bases of 2-) amino) phenyl) ammonia Base t-butyl formate 2.850g.
1H NMR(400MHz,CDCl3) δ 10.60 (s, 1H), 9.89 (s, 1H), 8.56 (s, 1H), 7.82 (t, J= 2.0Hz, 1H), 7.39 (d, J=8.8Hz, 1H), 7.31 (t, J=8.0Hz, 1H), 7.20 (d, J=8.0Hz, 1H), 6.58 (s, 1H),1.53(s,9H).LC-MS:m/z:349.1(M+H)+.
(3- ((the chloro- 5- of 2- (1- ethoxys) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate
Weigh (3- ((the chloro- 5- formylpyrimidins -4- bases of 2-) amino) phenyl) t-butyl carbamate (1.044g, 3mmol) in 50mL two mouth flasks, the dissolving of 20mL anhydrous tetrahydro furans, argon gas protection, ice bath stirring 10 minutes is added.Separately take first Base magnesium bromide (1M in THF, 9mL), is slowly added into above-mentioned reaction solution, drips ice bath stirring 5 hours.TLC tracking is former Reaction solution is poured into 30mL and is saturated NH by material conversion4In Cl aqueous solutions, ethyl acetate extraction, collected organic layer, anhydrous Na2SO4It is dry Dry, rotary evaporation removes solvent.Crude product is through silica gel column chromatography separating purification (petrol ether/ethyl acetate=2:1,v/v).Obtain (3- ((the chloro- 5- of 2- (1- ethoxys) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate 0.831g.
1H NMR(400MHz,CDCl3) δ 8.83 (s, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.29 (d, J=8.4Hz, 1H), 7.23 (t, J=8.0Hz, 1H), 7.05 (d, J=8.0Hz, 1H), 6.67 (s, 1H), 4.87 (q, J=6.4Hz, 1H), 1.55 (d, J=6.4Hz, 3H), 1.52 (s, 9H) .LC-MS:m/z:365.1(M+H)+.
(3- (chloro- 4- methyl -2- oxos -2H- pyrimidos [4,5-d] [1,3] oxazines -1 (the 4H)-yls of 7-) phenyl) amino first Tert-butyl acrylate
Weigh (3- ((the chloro- 5- of 2- (1- ethoxys) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate (0.815g, 2.2mmol), potassium carbonate (0.455g, 3.3mmol), 1,1'- carbonyl dimidazoles (1.069g, 6.6mmol) are burnt in 25mL single port Bottle is added 10mL anhydrous tetrahydro furans, is refluxed overnight.TLC tracks raw material conversion, and ice water, dichloromethane extraction is added, and collection has Machine layer, anhydrous Na2SO4Dry, rotary evaporation removes solvent.Crude product is through silica gel column chromatography separating purification (petrol ether/ethyl acetate =2:1,v/v).It obtains (3- (chloro- 4- methyl -2- oxos -2H- pyrimidos [4,5-d] [1,3] oxazines -1 (the 4H)-yls of 7-) phenyl) T-butyl carbamate 0.754g.
1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.54(s,1H),7.61(s,1H),7.41-7.36(m, 2H), 6.98 (d, J=6.8Hz, 1H), 5.86 (q, J=6.4Hz, 1H), 1.74 (d, J=6.4Hz, 3H), 1.47 (s, 9H) .LC-MS:m/z:391.1(M+H)+.
(3- (7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-4- methyl-2- oxo-2H- pyrimidines And [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) t-butyl carbamate
Weigh (3- (chloro- 4- methyl -2- oxos -2H- pyrimidos [4,5-d] [1,3] oxazines -1 (the 4H)-yls of 7-) phenyl) ammonia Base t-butyl formate (0.737g, 1.89mmol), 2- methoxyl groups -4- (4- methylpiperazine-1-yls) aniline (0.502g, 2.27mmol) in 50mL two mouth flasks, the dissolving of 15mL trifluoroethanols is added, trifluoroacetic acid (210 μ L, 2.84mmol), argon is added dropwise Gas shielded, temperature rising reflux 24 hours.TLC tracks raw material conversion, is cooled to room temperature, and saturation NaHCO is added3Aqueous solution is neutralized to alkali Property.Dichloromethane extracts, collected organic layer, anhydrous Na2SO4Dry, rotary evaporation removes solvent.Crude product is through silica gel column chromatography point From purifying (methylene chloride/methanol=30:1,v/v).Obtain (3- (7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) ammonia Base) -4- methyl -2- oxo -2H- pyrimidos [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) t-butyl carbamate 0.294g%.
1H NMR(400MHz,CDCl3) δ 8.46 (s, 1H), 8.18 (d, J=8.8Hz, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 7.24-7.20 (m, 3H), 6.69 (s, 1H), 6.54 (d, J=2.4Hz, 1H), 6.50 (dd, J=8.8Hz, J=2.4Hz, 1H), 4.52 (q, J=6.8Hz, 1H), 3.85 (s, 3H), 3.17 (t, J=4.4Hz, 4H), 2.60 (t, J=4.8Hz, 4H), 2.36 (s, 3H), 1.51 (s, 9H), 1.49 (d, J=6.0Hz, 3H) .LC-MS:m/z:576.3(M+H)+.
((7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-4- methyl-2- oxos-2H- are phonetic by 3- by N- Pyridine simultaneously [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) acrylamide (serial number 94)
Weigh (3- (7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-4- methyl-2- oxos-2H- Pyrimido [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) t-butyl carbamate (0.277g, 0.48mmol) is mono- in 25mL Mouth flask is added the dissolving of 6mL dichloromethane, 1mL trifluoroacetic acids is added dropwise, are stirred at room temperature 5 hours.TLC tracks raw material conversion, is added It is saturated NaHCO3Aqueous solution is neutralized to alkalinity.Dichloromethane extracts, collected organic layer, anhydrous Na2SO4Dry, rotary evaporation removes Solvent, crude product react in next step without isolating and purifying to be directly used in.
Previous step is taken off into Boc products (0.187g, 0.39mmol) and is dissolved in 5mL dichloromethane, be added triethylamine (0.060g, 0.6mmol), ice bath stirring 10 minutes.Acryloyl chloride (42 μ L, 0.51mmol) separately is taken, 1mL dichloromethane is dissolved in, is added to It states in reaction solution, is stirred overnight at room temperature.TLC tracks raw material conversion, and saturation NaHCO is added3Aqueous solution is neutralized to alkalinity.Dichloromethane Alkane extracts, collected organic layer, anhydrous Na2SO4Dry, rotary evaporation removes solvent, and crude product is through silica gel column chromatography separating purification (two Chloromethanes/methanol=20:1,v/v).Obtain N- (3- (7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-4- Methyl -2- oxo -2H- pyrimidos [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) acrylamide 0.091g.
1H NMR(400MHz,DMSO-d6) δ 10.46 (s, 1H), 8.23 (s, 1H), 7.85 (d, J=8.0Hz, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.47 (t, J=8.0Hz, 1H), 7.27 (d, J=8.4Hz, 1H), 7.10 (d, J=8.0Hz, 1H), 6.56 (d, J=1.2Hz, 1H), 6.48 (dd, J=16.8Hz, J=9.6Hz, 1H), 6.27 (dd, J=17.2Hz, J= 1.6Hz, 1H), 6.11-6.09 (m, 1H), 5.77 (dd, J=16.8Hz, J=1.6Hz, 1H), 5.73 (q, J=6.4Hz, 1H), 3.76 (s, 3H), 3.22-3.20 (m, 4H), 3.02-2.99 (m, 4H), 2.61 (s, 3H), 1.70 (d, J=6.4Hz, 3H) .HRMS(ESI)(m/z):(M+H)+calcd for C28H32N7O4 530.2516,found,530.2512.
Following compound synthesizes to obtain according to the method for above-mentioned steps a-g：
((7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-4- ethyl-2-oxos-2H- are phonetic by 3- by N- Pyridine simultaneously [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) acrylamide (serial number 95)
1H NMR(400MHz,DMSO-d6) δ 10.46 (s, 1H), 8.22 (s, 1H), 7.85 (d, J=8.4Hz, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.47 (t, J=8.0Hz, 1H), 7.26 (d, J=8.4Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 6.55 (d, J=2.0Hz, 1H), 6.48 (dd, J=16.8Hz, J=6.8Hz, 1H), 6.27 (dd, J=16.8Hz, J= 1.6Hz, 1H), 6.10-6.09 (m, 1H), 5.77 (dd, J=10.0Hz, J=1.6Hz, 1H), 5.55 (t, J=6.8Hz, 1H), 3.76 (s, 3H), 3.19 (t, J=4.4Hz, 4H), 2.92 (t, J=4.4Hz, 4H), 2.56 (s, 3H), 2.09-1.95 (m, 2H), 1.03 (t, J=7.2Hz, 3H) .HRMS (ESI) (m/z):(M+H)+calcd for C29H34N7O4 544.2672, found,544.2654.
((7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-4- propyl-2- oxos-2H- are phonetic by 3- by N- Pyridine simultaneously [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) acrylamide (serial number 96)
1H NMR(400MHz,DMSO-d6) δ 10.45 (s, 1H), 8.22 (s, 1H), 7.85 (d, J=8.0Hz, 1H), 7.80 (s, 1H), 7.66 (s, 1H), 7.47 (t, J=8.0Hz, 1H), 7.25 (d, J=8.4Hz, 1H), 7.08 (d, J=8.0Hz, 1H), 6.54 (d, J=2.0Hz, 1H), 6.48 (dd, J=16.8Hz, J=10.0Hz, 1H), 6.26 (dd, J=16.8Hz, J= 1.6Hz, 1H), 6.10-6.09 (m, 1H), 5.77 (dd, J=9.6Hz, J=1.6Hz, 1H), 5.60 (t, J=7.2Hz, 1H), 3.76 (s, 3H), 3.14 (t, J=4.4Hz, 4H), 2.79 (t, J=4.4Hz, 4H), 2.47 (s, 3H), 2.00-1.92 (m, 2H), 1.56-1.44 (m, 2H), 0.99 (t, J=7.2Hz, 3H) .HRMS (ESI) (m/z):(M+H)+calcd for C30H36N7O4 558.2829,found,558.2836.
N- (3- (7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-4- isopropyl-2- oxos-2H- Pyrimido [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) acrylamide (serial number 97)
1H NMR(400MHz,DMSO-d6) δ 10.52 (s, 1H), 8.22 (s, 1H), 7.87 (d, J=8.0Hz, 1H), 7.85 (s, 1H), 7.64 (s, 1H), 7.47 (t, J=8.0Hz, 1H), 7.26 (d, J=7.6Hz, 1H), 7.05 (d, J=7.6Hz, 1H), 6.57 (d, J=1.6Hz, 1H), 6.50 (dd, J=16.8Hz, J=10.0Hz, 1H), 6.26 (dd, J=16.8Hz, J= 1.6Hz, 1H), 6.14-6.10 (m, 1H), 5.77 (dd, J=10.0Hz, J=1.6Hz, 1H), 5.40 (d, J=4.8Hz, 1H), 3.77 (s, 3H), 3.18 (t, J=4.4Hz, 4H), 2.74 (s, 3H), 2.27-2.22 (m, 1H), 1.04 (d, J=6.8Hz, 3H), 0.99 (d, J=6.8Hz, 3H) .HRMS (ESI) (m/z):(M+H)+calcd for C30H36N7O4 558.2829, found,558.2831.
N- (3- (7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-2- oxo-2H- pyrimidos [4, 5-d] [1,3] oxazines -1 (4H)-yl) phenyl) acrylamide (serial number 98)
1H NMR(400MHz,CDCl3+CD3OD) δ 8.09 (s, 1H), 7.89 (s, 1H), 7.75 (d, J=8.4Hz, 1H), 7.47 (t, J=8.0Hz, 1H), 7.42-7.39 (m, 1H), 7.07 (d, J=7.6Hz, 1H), 6.42-6.38 (m, 2H), 6.15 (d, J=7.2Hz, 1H), 5.71 (dd, J=9.2Hz, J=2.8Hz, 1H), 5.36 (s, 2H), 3.80 (s, 3H), 3.37 (t, J =4.8Hz, 4H), 3.24 (t, J=4.8Hz, 4H), 2.82 (s, 3H) .HRMS (ESI) (m/z):(M+H)+calcd forC27H30N7O4 516.2359,found,516.2364.
The specific synthetic method of compound 006-008 is as follows：
Reagent and condition：(a) Grignard Reagent, THF, 0 DEG C, 6h；(b)CDI,K2CO3, THF, reflux, overnight；(c) aryl Amine, trifluoroacetic acid, trifluoroethanol, reflux, for 24 hours；(d) trifluoroacetic acid, CH2Cl2, room temperature, 5h；(e) acryloyl chloride, Et3N, CH2Cl2, 0 DEG C is arrived room temperature, overnight.
(3- ((the chloro- 5- of 2- (2- hydroxyl propyl- 2- yls) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate
Weigh 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- chlorine pyrimidine -5- Ethyl formates (2.352g, 6mmol) in 50mL two mouth flasks, the dissolving of 20mL anhydrous tetrahydro furans, argon gas protection, ice bath stirring 10 minutes is added.Separately take first Base magnesium bromide (1M in THF, 24mL), is slowly added into above-mentioned reaction solution, drips ice bath stirring 6 hours.TLC tracking is former Reaction solution is poured into 50mL and is saturated NH by material conversion4In Cl aqueous solutions, ethyl acetate extraction, collected organic layer, anhydrous Na2SO4It is dry Dry, rotary evaporation removes solvent.Crude product is through silica gel column chromatography separating purification (petrol ether/ethyl acetate=2.5:1,v/v).? (3- ((the chloro- 5- of 2- (2- hydroxyl propyl- 2- yls) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate 1.586g.
1H NMR(400MHz,DMSO-d6) δ 10.01 (s, 1H), 9.41 (s, 1H), 8.12 (s, 1H), 7.62 (t, J= 2.0Hz, 1H), 7.40 (dd, J=8.0Hz, J=1.2Hz, 1H), 7.25 (t, J=8.4Hz, 1H), 7.13 (d, J=8.8Hz, 1H),6.43(s,1H),1.56(s,6H),1.48(s,9H).LC-MS:m/z:379.1(M+H)+.
(3- (chloro- 4,4- dimethyl -2- oxos -2H- pyrimidos [4,5-d] [1,3] oxazines -1 (the 4H)-yls of 7-) phenyl) ammonia Base t-butyl formate
Weigh (3- ((the chloro- 5- of 2- (2- hydroxyl propyl- 2- yls) pyrimidine-4-yl) amino) phenyl) t-butyl carbamate (1.512g, 4mmol), potassium carbonate (0.828g, 6mmol), 1,1'- carbonyl dimidazoles (1.296g, 8mmol) are burnt in 25mL single port Bottle is added 10mL anhydrous tetrahydro furans, is refluxed overnight.TLC tracks raw material conversion, and ice water, dichloromethane extraction is added, and collection has Machine layer, anhydrous Na2SO4Dry, rotary evaporation removes solvent.Crude product is through silica gel column chromatography separating purification (petrol ether/ethyl acetate =2.5:1,v/v).Obtain (3- (chloro- 4,4- dimethyl -2- oxos -2H- pyrimidos [4,5-d] [1,3] oxazines -1 (the 4H)-yls of 7-) Phenyl) t-butyl carbamate 1.049g.
1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.64(s,1H),7.57(s,1H),7.41-7.36(m, 2H),7.01-6.99(m,1H),1.79(s,6H),1.47(s,9H).LC-MS:m/z:405.1(M+H)+.
(3- (7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-4,4- dimethyl-2- oxos-2H- Pyrimido [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) t-butyl carbamate
Weigh (3- (chloro- 4,4- dimethyl -2- oxos -2H- pyrimidos [4,5-d] [1,3] oxazines -1 (the 4H)-yls of 7-) benzene Base) t-butyl carbamate (1.010g, 2.5mmol), 2- methoxyl groups -4- (4- methylpiperazine-1-yls) aniline (0.663g, 3mmol) in 50mL two mouth flasks, the dissolving of 15mL trifluoroethanols is added, trifluoroacetic acid (280 μ L, 3.77mmol) is added dropwise, argon gas is protected Shield, temperature rising reflux 24 hours.TLC tracks raw material conversion, is cooled to room temperature, and saturation NaHCO is added3Aqueous solution is neutralized to alkalinity. Dichloromethane extracts, collected organic layer, anhydrous Na2SO4Dry, rotary evaporation removes solvent.Crude product detaches pure through silica gel column chromatography Change (methylene chloride/methanol=25:1,v/v).Obtain (3- (7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)- 4,4- dimethyl -2- oxo -2H- pyrimidos [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) t-butyl carbamate 0.516g。
1H NMR(400MHz,CDCl3) δ 8.07 (s, 1H), 7.51 (d, J=8.4Hz, 2H), 7.47-7.43 (m, 2H), 7.01 (d, J=7.2Hz, 1H), 6.45 (s, 1H), 6.44 (d, J=2.4Hz, 1H), 6.18-6.16 (m, 1H), 3.82 (s, 3H), 3.16 (t, J=4.4Hz, 4H), 2.67 (t, J=4.4Hz, 4H), 2.42 (s, 3H), 1.80 (s, 6H), 1.49 (s, 9H) .LC-MS:m/z:590.4(M+H)+.
N- (3- (7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-4,4- dimethyl-2- oxos- 2H- pyrimidos [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) acrylamide (serial number 99)
Weigh (3- (7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-4,4- dimethyl-2- oxos- 2H- pyrimidos [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) t-butyl carbamate (0.500g, 0.85mmol) is in 25mL Single-necked flask is added the dissolving of 6mL dichloromethane, 1mL trifluoroacetic acids is added dropwise, are stirred at room temperature 5 hours.TLC tracks raw material conversion, adds Enter to be saturated NaHCO3Aqueous solution is neutralized to alkalinity.Dichloromethane extracts, collected organic layer, anhydrous Na2SO4Dry, rotary evaporation removes Solvent, crude product is gone to be reacted in next step without isolating and purifying to be directly used in.
Previous step is taken off into Boc products (0.335g, 0.68mmol) and is dissolved in 5mL dichloromethane, be added triethylamine (0.102g, 1.02mmol), ice bath stirring 10 minutes.Acryloyl chloride (72 μ L, 0.88mmol) separately is taken, 1mL dichloromethane is dissolved in, is added to It states in reaction solution, is stirred overnight at room temperature.TLC tracks raw material conversion, and saturation NaHCO is added3Aqueous solution is neutralized to alkalinity.Dichloromethane Alkane extracts, collected organic layer, anhydrous Na2SO4Dry, rotary evaporation removes solvent, and crude product is through silica gel column chromatography separating purification (two Chloromethanes/methanol=20:1,v/v).N- (3- (7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-4, 4- dimethyl -2- oxo -2H- pyrimidos [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) acrylamide 0.165g.
1H NMR(400MHz,CDCl3) δ 8.08 (s, 1H), 7.79 (d, J=8.0Hz, 1H), 7.74 (s, 1H), 7.47 (t, J=8.0Hz, 1H), 7.38-7.36 (m, 1H), 7.05 (d, J=7.6Hz, 1H), 6.41 (d, J=2.0Hz, 1H), 6.36- 6.33 (m, 2H), 6.13 (s, 1H), 5.70 (dd, J=9.2Hz, J=2.4Hz, 1H), 3.80 (s, 3H), 3.17 (t, J= 4.4Hz, 4H), 2.80 (t, J=4.4Hz, 4H), 2.50 (s, 3H), 1.80 (s, 6H) .HRMS (ESI) (m/z):(M+H)+ calcd forC29H34N7O4 544.2672,found,544.2698.
007 and 008 compound synthesizes to obtain according to the method for above-mentioned steps a-e below：
N- (3- (7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-4,4- diethyl-2- oxos- 2H- pyrimidos [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) acrylamide (serial number 100)
1H NMR(400MHz,CDCl3) δ 9.42 (s, 1H), 7.96 (s, 1H), 7.89 (s, 1H), 7.81 (d, J=5.6Hz, 1H), 7.53 (s, 1H), 7.42 (t, J=8.0Hz, 1H), 7.33-7.31 (m, 1H), 6.99 (d, J=7.6Hz, 1H), 6.55- 6.49 (m, 1H), 6.36-6.32 (m, 2H), 6.12 (d, J=7.6Hz, 1H), 5.65 (d, J=10.4Hz, 1H), 3.78 (s, 3H), 3.41 (t, J=4.4Hz, 4H), 3.21 (t, J=4.4Hz, 4H), 2.80 (s, 3H), 2.11-1.96 (m, 4H), 1.00 (t, J=7.2Hz, 6H) .HRMS (ESI) (m/z):(M+H)+calcd forC31H38N7O4 572.2985,found, 572.2981.
N- (3- (7-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-4,4- diisopropyl base-2- oxygen Generation -2H- pyrimidos [4,5-d] [1,3] oxazines -1 (4H)-yl) phenyl) acrylamide (serial number 101)
1H NMR(400MHz,CDCl3) δ 8.06 (s, 1H), 7.96 (s, 1H), 7.77 (d, J=4.8Hz, 1H), 7.49 (s, 1H), 7.41 (t, J=8.0Hz, 1H), 6.97 (d, J=8.0Hz, 1H), 6.40 (d, J=2.0Hz, 1H), 6.36 (dd, J= 16.8Hz, J=1.2Hz, 1H), 6.18-6.12 (m, 2H), 5.68 (dd, J=10.4Hz, J=1.2Hz, 1H), 3.79 (s, 3H), 3.09 (t, J=4.4Hz, 4H), 2.58 (t, J=4.8Hz, 4H), 2.36 (s, 3H), 2.07-2.00 (m, 2H), 1.96- 1.89 (m, 2H), 1.54-1.38 (m, 4H), 0.97 (t, J=7.2Hz, 6H) .HRMS (ESI) (m/z):(M+H)+calcd forC33H42N7O4 600.3298,found,600.3297.
The specific synthetic method of compound 132-133 is as follows：
Reagent and condition：(a)R1NH2, DIPEA, 1,4- dioxane, r.t.；(b)R2H2, DIPEA, 1,4- dioxies six Ring, r.t.；(c)Pd/C,H2,EtOH；(d) YCOCOOEt, HOAc, EtOH, reflux.
In above-mentioned preparation flow, the definition of R, R1, R2, Y with reference to corresponding group above.Those skilled in the art can root Factually prepared by border to need, and uses the various initial compounds that this field routinely obtains for raw material, prepares the compound of the present invention.
Embodiment 3
The specific synthetic method of above-mentioned steps a-d is as follows：
The synthesis of (4- (the chloro- 6- methyl-5-nitros pyrimidine -4- amino of 2-) phenyl) t-butyl carbamate
Weigh bis- chloro- 6- methyl-5-nitros pyrimidine 2.07g (10mmol) of 2,4-, potassium carbonate 2.07g (15mmol) is placed in In 250mL round-bottomed flasks, 100mL dichloromethane is added, room temperature mechanical agitation weighs (3- aminophenyls) t-butyl carbamate 2.08g (10mmol) is dissolved in 50ml dichloromethane, is slowly added drop-wise in reaction, after the completion of being added dropwise to, is continued in condition of ice bath Lower stir about 1 hour, TLC tracks to raw material and converts completely, directly pumps pressure rotary evaporation and removes solvent, with ethyl alcohol recrystallization, It after filter cake is drained plus the mashing of 1000ml water, then filters with 500ml water washings one time, obtains compared with pure compound (4- (the chloro- 6- of 2- Methyl-5-nitro pyrimidine -4- amino) phenyl) t-butyl carbamate orange solids 3.41g, yield about 90%.
1H NMR(400MHz,DMSO-d6):δ9.91(s,1H),9.43(s,1H),7.64(s,1H),7.27-7.31(m, 1H),7.23-7.24(m,2H),2.55(s,3H),1.48(s,9H)。
(3- ((2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6- methyl-5-nitros pyrimidine-4-yl) Amino) phenyl) t-butyl carbamate synthesis
Weigh 2- methoxyl groups -4- (4- methyl-1s-piperazine) aniline 2.21g (10mmol), N, N- diisopropylethylamine 2.58g (20mmol), (3- (the chloro- 5- nitro-pyrimidines -4- amino of 2-) phenyl) t-butyl carbamate 3.79g (10mmol) are placed in 250ml It in round-bottomed flask, is dissolved with 100ml tetrahydrofurans, argon gas protection, heated overnight at reflux, TLC tracks to raw material and converts completely.Rotation Turn evaporation and remove about 70ml solvents, filter out solid, filter cake is washed with 50ml tetrahydrofurans, and filtrate rotary evaporation removes most of Solvent is subsequently poured into water, there is red brown solid precipitation, filters, filter cake is washed with deionized water, dry, and methylene chloride/methanol is pure Change, (3- ((2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6- methyl-5-nitros pyrimidine-4-yl) is obtained Amino) phenyl) t-butyl carbamate red brown solid 91g, yield about 71%.
1H NMR(400MHz,DMSO-d6):δ10.27(s,1H),9.42(s,1H),8.86(s,1H),7.52(s,1H), 7.39 (d, J=8.0Hz, 1H), 7.19 (s, 2H), 7.09 (s, 1H), 6.60 (s, 1H), 6.32 (s, 1H), 3.76 (s, 3H), 3.42(s,3H),3.15(s,4H),2.61(s,4H),2.27(s,3H),1.47(s,9H)。
(3- ((5- amino -2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6 methylpyrimidine -4- bases) ammonia Base) phenyl) t-butyl carbamate synthesis
Weigh (3- ((2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6- methyl-5-nitro pyrimidines -4- Base) amino) phenyl) t-butyl carbamate (5.64g, 10mmol), palladium-carbon catalyst (0.56g, 0.5mmol, 10%Pd) in In 500mL round-bottomed flask bottles, 100mL methanol and the dissolving of 200ml dichloromethane is added, is passed through hydrogen, reacts at room temperature 12 hours. TLC tracks raw material conversion, filters, and filtrate is spin-dried for, and crude product ethyl alcohol recrystallization obtains (3- ((5- amino -2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6 methylpyrimidine -4- bases) amino) phenyl) t-butyl carbamate white solid 4.86g, yield 91%.
1H NMR(400MHz,DMSO-d6) δ 10.27 (s, 1H), 9.42 (s, 1H), 8.87 (d, J=8.0Hz, 1H), 7.53 (s, 1H), 7.39 (d, J=8.0Hz, 1H), 7.32 (d, J=8.0Hz, 1H), 7.16 (t, J=8.0Hz, 1H), 7.06 (d, J= 8.0Hz, 1H), 6.60 (d, J=2.4Hz, 1H), 6.38 (dd, J=8.8Hz, J=2.4Hz, 1H), 4.39 (s, 2H), 3.76 (s, 3H), 3.42 (s, 3H), 3.07 (t, J=4.4Hz, 4H), 2.48 (t, J=4.4Hz, 4H), 2.25 (s, 3H), 1.48 (s, 9H).
(3- (2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -4- methyl -7- oxo -6- phenyl -8 (7H)-pteridyl) phenyl) t-butyl carbamate synthesis
Weigh (3- ((5- amino -2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6 methylpyrimidine -4- Base) amino) phenyl) t-butyl carbamate 2.67g (5mmol) is placed in 250mL round-bottomed flasks, be added 10mL glacial acetic acid, Then ethyl benzoylformate 890mg (5mmol) is added in 150mL absolute ethyl alcohols, be heated to return stirring about 8h, and TLC is tracked to Raw material converts completely.After reaction, rotary evaporation removes solvent, adds a small amount of ethyl alcohol dissolving, filters, filter cake ethyl alcohol, Ammonium hydroxide, deionized water washing, it is dry.If there is impurity, with ethyl alcohol heating washing one time, (3- (2- ((2- methoxyl group -4- (4- are obtained Methyl-1-piperazinyl) phenyl) amino)-8 (7H)-pteridyl of-4- methyl-7- oxo-6- phenyl) phenyl) the tertiary fourth of carbamic acid Ester Orange red solid 2.2g, yield 70%.
1H NMR(400MHz,DMSO-d6):δ9.64(s,1H),8.24-8.26(m,2H),8.21(s,1H),7.59(s, 1H), 7.56 (d, J=8.0Hz, 1H), 7.47-7.50 (m, 3H), 7.44 (d, J=8.0Hz, 1H), 7.38 (d, J=8.0Hz, 1H), 7.00 (d, J=8.0Hz, 1H), 6.54 (s, 1H), 6.07 (br, 1H), 3.79 (s, 3H), 3.07 (br, 4H), 2.71 (s, 3H),2.46(br,4H),2.24(s,3H),1.45(s,9H).
8- (3- aminophenyls) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -4- methyl -6- benzene The synthesis of base -7 (8h)-pteridinone
Weigh (3- (2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -4- methyl -7- oxo -6- benzene Base -8 (7H)-pteridyl) phenyl) t-butyl carbamate 6.48g (10mmol) is placed in 250mL round-bottomed flasks, 100mL is added Dichloromethane stirs at 0 DEG C, and 25mL trifluoroacetic acids are added dropwise.It then proceedes to stir 0.5h under ice bath, stirs 2h, TLC at room temperature Raw material is tracked to convert completely.After reaction, direct rotary evaporation removes solvent, is dissolved in water, saturated sodium bicarbonate solution It is neutralized to solution meta-alkalescence, there are a large amount of solids to be precipitated, is filtered, filter cake is washed with deionized, and dries, obtains 8- (3- aminobenzenes Base) -7 (8h)-pteridinones of -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -4- methyl -6- phenyl are red Solid 4.99g, yield 91%.
1H NMR(400MHz,DMSO-d6):δ9.64(s,1H),8.24-8.26(m,2H),8.21(s,1H),7.59(s, 1H), 7.56 (d, J=8.0Hz, 1H), 7.47-7.50 (m, 3H), 7.44 (d, J=8.0Hz, 1H), 7.38 (d, J=8.0Hz, 1H), 7.00 (d, J=8.0Hz, 1H), 6.54 (s, 1H), 5.32 (s, 2H), 3.79 (s, 3H), 3.07 (br, 4H), 2.71 (s, 3H),2.46(br,4H),2.24(s,3H),1.45(s,9H).
N- (3- (2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -4- methyl -7- oxo -6- benzene Base -8 (7H)-pteridyl) phenyl) acrylamide synthesis (serial number 102)
Weigh 8- (3- aminophenyls) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -4- methyl - 6- phenyl -7 (8h)-pteridinone 1.4g (2.55mmol) is placed in 100mL round-bottomed flasks, and 3mL N-Methyl pyrrolidones are added, It is stirred under ice bath, separately takes acryloyl chloride 275mg (3.06mmol) to be dissolved in 20mL acetonitriles, and be added drop-wise in above-mentioned reaction solution, be added dropwise 0.5h is stirred under ice bath after the completion, stirs 3h at room temperature, TLC tracks to raw material and converts completely.Reaction solution rotary evaporation is removed Then solvent is added drop-wise in sodium bicarbonate aqueous solution, there is red solid precipitation, is filtered, and filter cake is washed with deionized, dry, Methylene chloride/methanol purifies, and obtains N- (3- (2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -4- first - 8 (7H)-pteridyl of base -7- oxo -6- phenyl) phenyl) acrylamide Orange red solid 1.0g, yield 67%.
1H NMR(400MHz,DMSO-d6):δ10.40(s,1H),8.25-8.27(m,2H),8.20(s,1H),7.90 (d, J=8.0Hz, H), 7.72 (s, 1H), 7.54 (t, J=8.0Hz, 1H), 7.48-7.50 (m, 3H), 7.38 (d, J= 8.0Hz, 1H), 7.12 (d, J=8.0Hz, 1H), 6.53 (d, J=4.0Hz, 1H), 6.46 (q, J=8.0,1H), 6.27 (dd, J =8.0,4.0Hz, 1H), 6.03 (br, 1H), 5.78 (dd, J=8.0,4.0Hz, 1H), 3.78 (s, 3H), 3.03 (br, 4H), 2.72 (s, 3H), 2.44 (t, J=4.0Hz, 4H), 2.23 (s, 3H)
N- (3- (6- (4- fluoro-phenyls) -2- ((2- methoxyl groups -4- (4- methyl-1s-piperazinyl) phenyl) amino) -4- first - 8 (7H)-pteridyl of base -7- oxos) phenyl) acrylamide synthesis (serial number 103)
Red brown solid, yield 61%.
1H NMR(400MHz,DMSO-d6):δ10.48(s,1H),8.33-8.37(m,2H),8.22(s,1H),7.91 (d, J=8.0Hz, H), 7.74 (s, 1H), 7.54 (t, J=8.0Hz, 1H), 7.30-7.38 (m, 3H), 7.12 (d, J= 8.0Hz, 1H), 6.53 (s, 1H), 6.48 (q, J=8.0,1H), 6.27 (dd, J=8.0,2.0Hz, 1H), 6.01 (br, 1H), 5.78 (d, J=8.0Hz, 1H), 3.77 (s, 3H), 3.06 (br, 4H), 2.70 (s, 3H), 2.53 (br, 4H), 2.29 (s, 3H)
The specific synthetic method of compound 134-137 is as follows：
Reagent and condition：(a)R1NH2, DIPEA, acetonitrile, reflux, 6h.；(b) lithium aluminium hydride reduction, THF, 0 DEG C, 4h.；(c) two Manganese oxide, dichloromethane, 6h；(d) Grignard Reagent, THF, 0 DEG C, 4h；(e) manganese dioxide manganese dioxide, dichloromethane, 6h；(f) YCH2COOEt,K2CO3,DMF,8h；(g) m-CPBA, dichloromethane, 12h；(h)R2NH2,TFA,2-Butanol,110℃。
In above-mentioned preparation flow, R1、R2、R5, Y with reference to corresponding group above definition.Those skilled in the art can root Factually prepared by border to need, and uses the various initial compounds that this field routinely obtains for raw material, prepares the compound of the present invention.
Embodiment 4
The specific synthetic method of above-mentioned steps a-d is as follows：
The synthesis of 4- (3- t-butoxycarbonyl aminos aniline) -2- methylthiopyrimidine -5- ethyl carbonates
Weigh the chloro- 2- methylthiopyrimidines -5- ethyl carbonates 2.33g (10mmol) of 4-, (3- aminophenyls) carbamic acid uncle Butyl ester 2.08g (10mmol), DIPEA 2.58g (20mmol) are placed in 250ml flasks, and the dissolving of 80ml acetonitriles is added, then adds Heat reflux, after reacting about 4 hours, TLC tracks to raw material and converts completely, stops reaction and is cooled to room temperature, directly filters, cold second Nitrile lotion filter cake three times, dry to get phonetic to pure 4- (3- t-butoxycarbonyl aminos aniline) -2- methyl mercaptos by filter cake infrared baking oven Pyridine -5- ethyl carbonate white solid 3.84g, yield 95%.
1H NMR(400MHz,CDCl3) δ 10.37 (s, 1H), 8.76 (s, 1H), 7.90 (s, 1H), 7.34 (d, J= 8.0Hz, 1H), 7.24 (t, J=8.0Hz, 1H), 7.02 (d, J=8.0Hz, 1H), 6.53 (s, 1H), 4.38 (q, J=8.0Hz, J=16.0Hz, 2H), 2.55 (s, 3H), 1.52 (s, 9H), 1.40 (t, J=8.0Hz, 3H)
(the synthesis of tertiary butyl -3- (5- (methylol) -2- (methyl mercapto) pyrimidine -4- substituted-aminos) benzamide carbonic ether
4- (3- t-butoxycarbonyl aminos aniline) -2- methylthiopyrimidine -5- ethyl carbonates 2.02g (5mmol) are weighed to be placed in In 250ml flasks, the dissolving of 50ml anhydrous tetrahydro furans is added, under condition of ice bath, 20mlLiAlH is slowly added dropwise4(1M in THF), continuation is added dropwise to react 0.5 hour under condition of ice bath, TLC tracks to raw material and converts completely, then adds into reaction Entering saturated ammonium chloride and stops reaction, rotary evaporation removes tetrahydrofuran, is then extracted with ethyl acetate, saturated common salt water washing, Anhydrous sodium sulfate is dried, and rotary evaporation removes solvent, and crude product is through silica gel column chromatography (petrol ether/ethyl acetate=3:1, v/v) divide From obtaining (tertiary butyl -3- (5- (methylol) -2- (methyl mercapto) pyrimidine -4- substituted-aminos) benzamide carbonic ether white solid 760mg, yield 42%.
1H NMR(400MHz,CDCl3) δ 8.02 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.36 (dd, J=4.0, 8.0Hz, 1H), 7.22 (t, J=8.0Hz, 1H), 6.95 (dd, J=4.0,8.0Hz, 1H), 6.52 (s, 1H), 4.61 (s, 2H), 2.52(s,3H),1.52(s,9H).
3- ((5- formoxyls -2- (methyl mercapto) pyrimidines -4- substitution) amino) phenyl) t-butyl carbamate synthesis
Weigh (tertiary butyl -3- (5- (methylol) -2- (methyl mercapto) pyrimidine -4- substituted-aminos) benzamide carbonic ether 362mg (1mmol) is added the dissolving of 50ml dichloromethane, activated manganese dioxide 870mg is then added in 100ml flasks About 4 hours of (10mmol) stirring at normal temperature, TLC track to raw material and convert completely, suction filtered through kieselguhr, and filtrate rotary evaporation removes molten Agent, crude product is through silica gel column chromatography (petrol ether/ethyl acetate=10:1, v/v) it detaches, obtains 3- ((5- formoxyls -2- (first sulphur Base) pyrimidine -4- substitutions) amino) phenyl) t-butyl carbamate faint yellow solid 306mg, yield 85%.
1H NMR(400MHz,CDCl3)δ10.61(s,1H),9.77(s,1H),8.43(s,1H),7.98(s,1H),7.36 (dd, J=4.0,8.0Hz, 1H), 7.25-7.29 (m, 1H), 7.03 (dd, J=4.0,8.0Hz, 1H), 6.51 (s, 1H), 2.59 (s,3H),1.53(s,9H).
3- (simultaneously [2,3-d] pyrimidine -8 (7 hydrogen)-replaces 2- (methyl mercapto) -7- oxo pyridines) phenyl) t-butyl carbamate Synthesis
By 3- ((5- formoxyls -2- (methyl mercapto) pyrimidines -4- substitutions) amino) phenyl) t-butyl carbamate 360mg (1mmol) and (EtO)2P(O)CH2CO2Et is added the anhydrous THF dissolvings of 50ml, then adds under condition of ice bath in 100ml flasks Enter 48mgNaH (2mmol), addition finishes about 4 hours of stirring at normal temperature, and TLC tracks to raw material and converts completely, and water quenching is slowly added dropwise It goes out, filtrate rotary evaporation removes solvent, and crude product is through silica gel column chromatography (petrol ether/ethyl acetate=20:1, v/v) it detaches, obtains 3- (simultaneously [2,3-d] pyrimidine -8 (7 hydrogen)-replaces 2- (methyl mercapto) -7- oxo pyridines) phenyl) t-butyl carbamate yellow solid 270mg, yield 71%.
1H NMR(500MHz,CDCl3) δ 9.10 (s, 1H), 8.09 (dt, J=7.5,2.0Hz, 1H), 7.72 (t, J= 2.0Hz, 1H), 7.56 (d, J=11.0Hz, 1H), 7.41 (t, J=7.4Hz, 1H), 7.34 (dt, J=7.5,2.0Hz, 1H), 6.65 (s, 1H), 6.44 (d, J=10.8Hz, 1H), 2.54 (s, 3H), 1.50 (s, 9H)
3- (simultaneously [2,3-d] pyrimidine -8 (7 hydrogen)-replaces 2- (methylsulfonyl) -7- oxo pyridines) phenyl) t-butyl carbamate Synthesis
By 3- (simultaneously [2,3-d] pyrimidine -8 (7 hydrogen)-replaces 2- (methylsulfonyl) -7- oxo pyridines) phenyl) the tertiary fourth of carbamic acid Ester 922mg (2.4mmol) is added 60ml dichloromethane and dissolves, be added portionwise under condition of ice bath in 30min in 100ml flasks M-CPBA 1.24g (7.2mmol), addition, which finishes, is slowly increased to be stirred at room temperature about 8 hours, and TLC tracks to raw material and turns completely Change, 30ml is added and is saturated Na2S2O3Continue to stir half an hour, dichloromethane extraction is dried over anhydrous sodium sulfate, rotary evaporation removes Solvent is removed, crude product is through silica gel column chromatography (petrol ether/ethyl acetate=10:1, v/v) it detaches, obtains 3- (2- (methylsulfonyl) -7- oxygen Replace for pyrido [2,3-d] pyrimidine -8 (7 hydrogen) -) phenyl) t-butyl carbamate white solid 808mg, yield 81%.
1H NMR (500MHz, CDCl3) δ 9.17 (s, 1H), 8.30 (t, J=2.0Hz, 1H), 7.61-7.55 (m, 2H), 7.39 (t, J=7.5Hz, 1H), 7.16 (dt, J=7.5,2.0Hz, 1H), 6.63 (s, 1H), 6.44 (d, J=10.8Hz, 1H), 3.25(s,3H),1.50(s,9H).
((simultaneously [2,3-d] is phonetic for -7- oxo pyridines by 2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) by 3- Pyridine -8 (7 hydrogen)-replace) phenyl) and t-butyl carbamate synthesis
By 3- (simultaneously [2,3-d] pyrimidine -8 (7 hydrogen)-replaces 2- (methyl mercapto) -7- oxo pyridines) phenyl) the tertiary fourth of carbamic acid Ester 808mg (1.94mmol), 2- methoxyl groups -4- (4- methyl piperazines -1- substitutions) aniline 430mg (1.94mmol) are burnt in 100ml In bottle, the dissolving of 50ml sec-butyl alcohols is added, then adds TFA 145 microlitres (1.94mmol), 110 DEG C of heating stirrings are about 12 small When, TLC tracks to raw material and converts completely, and rotary evaporation removes solvent, and crude product is through silica gel column chromatography (methylene chloride/methanol=30: 1, v/v) detach, obtain (3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) -7- oxo pyridines simultaneously [2, 3-d] pyrimidine -8 (7 hydrogen)-substitution) phenyl) t-butyl carbamate yellow solid 756mg, yield 70%.
1H NMR(500MHz,CDCl3) δ 8.71 (s, 1H), 8.53 (t, J=1.9Hz, 1H), 7.56 (d, J=10.8Hz, 1H), 7.46-7.35 (m, 2H), 7.24 (dt, J=7.3,2.1Hz, 1H), 6.91 (d, J=7.5Hz, 1H), 6.60 (s, 1H), 6.44 (d, J=10.8Hz, 1H), 6.40-6.31 (m, 2H), 5.10 (s, 1H), 3.94 (s, 3H), 3.20 (t, J=5.2Hz, 4H), 2.98 (t, J=5.1Hz, 4H), 2.60 (s, 3H), 1.50 (s, 9H)
8- (3- aminophenyls) -2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrido [2,3- D] pyrimidine -7 (8 hydrogen) -one synthesis
By ((- 7- oxo pyridines are simultaneously [2,3-d] by 2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) by 3- Pyrimidine -8 (7 hydrogen)-replaces) phenyl) t-butyl carbamate 756mg (1.36mmol) is in 50ml flasks, addition 16ml dichloros Methane dissolves, and then adds 4mlTFA, 4h is stirred at room temperature, and TLC tracks to raw material and converts completely, and rotary evaporation removes solvent, Crude product is through silica gel column chromatography (methylene chloride/methanol=30:1, v/v) it detaches, obtains 8- (3- aminophenyls) -2- ((2- methoxies Base -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrido [2,3-d] pyrimidine -7 (8 hydrogen) -one yellow solid 571mg, yield 92%.
1H NMR(400MHz,DMSO-d6) δ 8.71 (s, 1H), 8.08 (s, 1H), 7.87 (d, J=9.6,1H), 7.45 (d, ), J=8.8,1H 7.18 (t, J=8.0Hz, 1H), 6.71 (d, J=8.4Hz, 1H), 6.55 (d, J=2.4Hz, 2H), 6.36- 6.41 (m, 3H), 6.15 (br, 1H), 5.25 (br, 2H), 3.79 (s, 3H), 3.06 (t, J=4.8Hz, 4H), 2.45 (t, J= 4.8Hz,4H),2.23(s,3H).
((- 7- oxo pyridines are simultaneously [2,3-d] by 2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) by 3- by N- Pyrimidine -8 (7 hydrogen)-replace) phenyl) and acrylamide synthesis (serial number 104)
By 8- (3- aminophenyls) -2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrido [2, 3-d] (8 hydrogen) the -one 571mg of pyrimidine -7 (1.25mmol) is in 50ml flasks, addition 20ml anhydrous methylene chlorides dissolving, at 0 DEG C Acryloyl chloride 225mg (2.5mmol) is slowly added dropwise into system for condition, is added dropwise and continues to stir 4h, it is complete that TLC tracks to raw material Full conversion, rotary evaporation remove solvent, and crude product is through silica gel column chromatography (methylene chloride/methanol=30:1, v/v) it detaches, obtains N- (3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) -7- oxo pyridines simultaneously [2,3-d] pyrimidines -8 (7 Hydrogen)-substitution) phenyl) acrylamide yellow solid 316mg, yield 62%.
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.74(s,1H),8.15(s,1H),7.86-7.92(m, 2H), 7.60 (s, 1H), 7.51 (t, J=8.0Hz, 1H), 7.29 (d, J=8.8Hz, 1H), 7.01 (d, J=8.0Hz, 1H), 6.52 (d, J=1.6Hz, 1H), 6.40-6.47 (m, 2H), 6.28 (dd, J=1.6,17.2Hz, 1H), 6.02 (br, 1H), 5.78(m,1H),3.77(s,3H),3.03(m,4H),2.44(m,4H),2.03(s,3H).
((- 5- methyl -7- oxo pyridines are simultaneously by 2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) by 3- by N- [2,3-d] pyrimidine -8 (7 hydrogen)-replace) phenyl) and acrylamide synthesis (serial number 105)
1H NMR(400MHz,DMSO-d6) δ 10.33 (s, 1H), 8.80 (s, 1H), 8.09 (s, 1H), 7.89 (d, J= 6.8Hz, 1H), 7.56 (s, 1H), 7.50 (t, J=8.0Hz, 1H), 7.28 (d, J=8.8Hz, 1H), 6.98 (d, J=7.6Hz, 1H), 6.51 (s, 1H), 6.47 (dd, J=1.6,17.2Hz, 1H), 6.32 (s, 1H), 6.27 (d, J=6.8Hz, 1H), 6.01 (br,1H),5.78(m,1H),3.78(s,3H),3.03(m,4H),2.43-2.46(m,7H),2.03(s,3H).
((- 7- oxo -5- phenylpyridines are simultaneously by 2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) by 3- by N- [2,3-d] pyrimidine -8 (7 hydrogen)-replace) phenyl) and acrylamide synthesis (serial number 106)
1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.42(s,1H),8.27(s,1H),7.90(s,1H), 7.52-7.67 (m, 8H), 7.29 (d, J=8.8Hz, 1H), 7.07 (d, J=7.6Hz, 1H), 6.57 (s, 1H), 6.51 (dd, J =10.0,16.8Hz, 1H), 6.39 (s, 1H), 6.29 (dd, J=2.0,10.0Hz, 1H), 6.10 (br, 1H), 5.79 (dd, J =2.0,16.8Hz 1H), 3.78 (s, 3H), 2.96 (m, 4H), 2.43 (s, 3H)
N- (3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) -5- methyl -7- oxo -6- phenyl Pyrido [2,3-d] pyrimidine -8 (7 hydrogen)-replace) phenyl) and acrylamide synthesis (serial number 107)
1H NMR(400MHz,DMSO-d6) δ 10.34 (s, 1H), 8.89 (s, 1H), 8.11 (s, 1H), 7.87 (d, J= 8.0Hz, 1H), 7.64 (s, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (t, J=7.2Hz, 1H), 7.34-7.38 (m, 1H), 7.29-7.31 (m, 3H), 7.04 (d, J=8.0Hz, 1H), 6.53 (d, J=1.6Hz, 1H), 6.47 (dd, dd, J=17.2, 10.0Hz, 1H), 6.27 (dd, J=1.6,16.8Hz, 1H), 6.03 (br, 1H), 5.78 (dd, J=1.6,10.0Hz 1H), 3.79(s,3H),3.03(m,4H),2.44-2.45(m,4H),2.30(s,3H),2.23(s,3H).
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To be made various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (14)

1. compound or its salt shown in Formulas I is preparing bruton's tyrosine kinase inhibitor or is preparing treatment or prevention Bu Ludun junket Purposes in the drug for the disease that histidine kinase mediates：
In formula,
R is hydrogen, C1-C3Low alkyl group, C1-C3Lower alkoxy, halogen (for example, F, Cl, Br), amino, substituted amino；
X is N or CR5R6；
Y is C or O；
When X is N,For double bond, and Y is C；
When X is CR5R6When,For singly-bound, and Y is O；Or when X is CR5R6When,For double bond, and Y is C；
B is selected from the group：(C3-C8) naphthenic base, (C3-C8) heterocycle, (C6-C10) aryl or (C5-C10) virtue optionally replaced Heterocycle；
R1It is selected from：H, the C optionally replaced1-C6Alkyl, NR7R8, the optionally C that replaces6-C10Aryl；
R3It is selected from：Hydrogen, the C optionally replaced1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, the C optionally replaced3-C8Naphthenic base is appointed Choose the C in generation1-C10Alkoxy, the benzyl optionally replaced, the heterocycle that optionally replaces, optionally replaces the aryl optionally replaced Aromatic heterocyclic ,-O- (CH)z-O-C1-C3Alkyl；Z be 1-3 integer, preferably 1；
R4It is selected from：Hydrogen, the C optionally replaced1-C6Alkyl, nitro, amino, halogen, the C optionally replaced1-C6Alkoxy, optionally substitution Acyloxy, the acylamino- optionally replaced, the acyl group that optionally replaces；
M stands alone as 0-7, preferably 1-7, the integer of more preferable 1-3；
R5And R6Respectively stand alone as H or C1-C6Alkyl (preferably C1-C3Alkyl)；
R7And R8Respectively stand alone as H or C1-C6Alkyl.
2. compound as described in claim 1, which is characterized in that B is selected from：
R4It is selected from：
3. purposes as claimed in claim 1 or 2, which is characterized in that the compound is as shown in following formula I -1：
In formula,
A is phenyl ring, five yuan or hexa-member heterocycle, C3-C8Naphthenic base or R '；
When A is R ', n 0, and R ' is selected from C1-C6Alkyl, C1-C6Halogenated alkyl or C6-C10Aryl formoxyl；
R2It is selected from：Hydrogen, halogen, the C optionally replaced1-C6Alkoxy, the acyloxy that optionally replaces, amino, optionally replaces hydroxyl Acylamino-, the C optionally replaced1-C6Alkyl, CN, sulfonic group, amino-sulfonyl, carbamoyl, carboxyl, the alcoxyl optionally replaced Formoxyl, the phenyl optionally replaced, the N- alkylpiperazinyls optionally replaced, the morpholinyl optionally replaced, the piperidines optionally replaced Base, the pyrrole radicals optionally replaced, the pyrrolidinyl ,-NR optionally replacedaRb, the optional pyridyl group that replaces；RaAnd RbIt is respectively independent Selected from alkyl and alkenyl；
N stands alone as 0-7, preferably 1-7, the integer of more preferable 1-3；
X、Y、B、R1、R3、R4As defined in claim 1 with m.
4. purposes as claimed in claim 3, which is characterized in that the compound is as shown in Formula Il -1：
In formula,
B、R2、R3、R4, m and n as defined in claim 3；
Alternatively, the compound is as shown in Formula Il -2：
In formula,
B、R2、R4、R5、R6, m and n as defined in claim 3；
Alternatively, the compound is as shown in Formula Il -3：
In formula,
B、R1、R2、R3、R4, m and n as defined in claim 3.
5. purposes as claimed in claim 4, which is characterized in that
In Formula II -1,
R2It is selected from：Hydrogen, halogen, the C optionally replaced1-C6Alkoxy, the pyrrolidinyl ,-NR optionally replacedaRb, carbamoyl, Acylamino-, the-(CH optionally replaced2)oThe N- alkylpiperazinyls that optionally replace, the morpholinyl optionally replaced, the piperazine optionally replaced Piperidinyl, the integer that o is 0-2, RaAnd RbIt is each independently selected from C1-C3Alkyl；Wherein R2It is not located at 2 of its residing phenyl ring；
R3It is selected from：Hydrogen, the C optionally replaced1-C6Alkyl, the C optionally replaced6-C10Aryl, the C optionally replaced3-C8Naphthenic base；
B is selected from phenyl ring or nitrogenous five-membered ring；
R4It is selected from：The acylamino- optionally replaced, the acyl group optionally replaced；
M and n are as defined in claim 4；
In Formula II -2,
R5、R6It is independently selected from H, substituted or unsubstituted C1-C6(preferably C1-C3) alkyl；
B is phenyl ring；
R2It is selected from：The C optionally replaced1-C6Alkyl (preferably C1-C3Alkyl), the N- alkylpiperazinyls that optionally replace, optionally replace C1-C6Alkoxy (preferably C1-C3Alkoxy)；
R4It is selected from：The acylamino- optionally replaced；
M and n are as defined in claim 4.
6. compound selected from the group below or its pharmaceutically acceptable salt are preparing bruton's tyrosine kinase inhibitor or preparation Treat or prevent the purposes in the drug for the disease that bruton's tyrosine kinase mediates：
7. the purposes as described in any one of claim 1-6, which is characterized in that the disease that the bruton's tyrosine kinase mediates Disease be cancer or with Autoimmune Disorders disease.
8. purposes as claimed in claim 7, which is characterized in that the cancer is selected from the group：Acute lymphoblastic leukemia (ALL), chronic myelocytic leukemia (CML), lymphoma mantle cell (MCL), colorectal cancer；The Autoimmune Disorders disease includes Rheumatoid arthritis, anti-organ transplant rejection, psoriasis, lupus erythematosus.
9. treating or preventing the disease method that bruton's tyrosine kinase mediates, including will be described in any one of claim 1-6 Compound or pharmaceutical composition comprising the compound give the object of this needs.
10. compound shown in Formulas I or its pharmaceutically acceptable salt：
In formula,
X、Y、B、R1、R3、R4With m as claims 1 or 2 defines；
Wherein,
R is hydrogen, C1-C3Low alkyl group, C1-C3Lower alkoxy, halogen (for example, F, Cl, Br), amino or NRcRd, and Rc、Rd It is independently selected from H, C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；
And/or
R3It is selected from the group：Hydrogen, (C3-C6) naphthenic base, (C1-C8) heterocycle, (C1-C8) alkoxy ,-O- (CH)n-O-C1-C3Alkyl, Benzyl, (C6-C10) aryl or (C5-C10) aromatic heterocyclic, wherein the aryl and aromatic heterocyclic are optionally with one to five A following group substitution：Halogen, nitro, cyano, hydroxyl, amino, (C1-C8) alkyl, (C1-C8) alkoxy, (C3-C6) cycloalkanes Base, (C6-C10) aryloxy group, (C5-C10) heterocycle ,-O- (CH)z-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle alkane Base oxygroup, amide groups, the carbamoyl optionally replaced；Z be 1-3 integer, preferably 1；
And/or
R4It is selected from the group：
11. compound or its salt as claimed in claim 10, which is characterized in that the compound is as shown in following formula I -1：
In formula,
A is that R ', n 0, and R ' are selected from C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；
X、Y、B、R1、R3、R4It is limited with m such as claims 10.
12. compound as claimed in claim 11, which is characterized in that R ' is C1-C6Alkyl (preferably C1-C3Alkyl), C1-C6Halogen Substituted alkyl (preferably C1-C3Halogenated alkyl).
13. the compound as described in any one of claim 10-12, which is characterized in that R3It is selected from the group：
14. compound as claimed in claim 13, which is characterized in that R3For：
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