CN108727382A - Heterocyclic compound as BTK inhibitor and its application - Google Patents

Heterocyclic compound as BTK inhibitor and its application Download PDF

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CN108727382A
CN108727382A CN201710258020.2A CN201710258020A CN108727382A CN 108727382 A CN108727382 A CN 108727382A CN 201710258020 A CN201710258020 A CN 201710258020A CN 108727382 A CN108727382 A CN 108727382A
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alkyl
amino
group
compound
phenyl
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CN108727382B (en
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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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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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Abstract

The present invention relates to as BTK 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 BTK inhibitory activity and the compound to prepare the application in treating or preventing BTK relevant diseases or inhibiting the drug of BTK：

Description

Heterocyclic compound as BTK inhibitor and its application
Technical field
The present invention relates to medicinal chemistry arts；Specifically, the present invention relates to BTK inhibitory activity compound and its Using.
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 (BTK) is mainly expressed in B cell, and leaching is distributed in Bar system, hematopoiesis and hematological system.In recent years in relation to B cell especially for B cell non-Hodgkin's lymph cancer and rheumatoid It is arthritic the study found that BTK often will appear unconventionality expression.BTK is the pass in B cell antigen receptor (BCR) signal path Key kinases can adjust maturation, the differentiation of normal B cells, also closely related with a variety of B cell lymphoid tissue disorders.
BTK is the member of non-receptor protein tyrosine kinase Tec families.Tec families are only secondary in the non-receptor kinase of the mankind In the 2nd large family of Src families, Major Members include BTK, BMX (etk), ITK, TEC and TXK (RLK).BTK was in 1993 It is determined as the defects of people X- linked agammaglobulinemias (X-linked agammaglobulinemia, XLA) egg In vain.This albumen has expression (in addition to the thick liquid cell finally broken up) in B cell stages, in pre-B lymphocyte mistake It crosses as during later stage B cell, Btk is cell differentiation and increment institute indispensable gene, and thin in B cell lymphoma, acute lymphoblastic There is expression in born of the same parents' leukaemia (ALL) and plasmacytoma.In addition, also there is a small amount of expression in bone marrow cell and erythroid progenitor cells.
Include 5 main domains in BTK structures, is PH structural domains (Pleckstrin homology), TH structures respectively Domain (Tec homology), SH3 structural domains (Src homology 3), SH2 structural domains (Src homology 2) and SH1 structures Domain (Src homology1).Wherein PH structural domains include transcription factor BAP-135/TFII-I and activity down-regulation factor PIN1, The binding site of IBTK, while also being responsible for mediating the effect of BTK and the 2nd messenger phosphatidylinositol triphosphoric acid (PIP3).TH structures Domain is adjacent with PH structural domains, is made of 80 amino acid residues, including BTK motifs (Zn co-factors binding site), PKC- β are combined Site and the conserved region of rich proline motif.SH1 structural domains include activation ring, ATP-binding site, catalyst converter and allosteric suppression Film-making section.The activation (phosphorylation) of BTK initially occurs in the activation ring in SH1 structural domains, and further activation is happened at packet In SH2 and SH3 structural domains containing main autophosphorylation site.These SH structural domains also include that BTK is carried out required for nucleocytoplasmic shuttle Nuclear localization signal (NLS) and the downstreams nuclear export sequence (NES) BTK have multiple receptors, including growth factor, B cell antigen, become Change the factor and nonspecific immunity receptor etc..Therefore, the activation energy of BTK causes various kinds of cell process, such as cell Proliferation, survival, divides Change, angiogenesis, cell factor synthesis and antigen submission etc..
BTK activation processs are complicated, and the important step during this is that BTK moves to cell membrane.Some on cell membrane The stimulation that receptor receives respective ligand is activated, the signal transduction kinases that simultaneously phosphorylation intracellular is raised by cognition of activation The PI3K of PI3K, phosphorylation then convert the PIP2 on film to the 2nd courier PIP3.PIP3 is attached to the PH structural domains of BTK, BTK can then be raised to cell membrane, and Tyr-551 residues are then carried out in Tyr-223 residues by Syk and Lyn tyrosine phosphorylations Autophosphorylation can be tied to have the BTK of physiological activity activation by its SH2 structural domain and adaptin BLNK/SLP65 It closes, the compound of generation is with post activation phospholipase C γ 2 (PLC- γ 2), and then initiation cascade reaction eventually leads to and holds into the cell Continuous flow of calcium ions, and indirect activation downstream signaling pathway, such as MEK/ERK, p38MAPK, NK/SAPK access.BTK functions obtain The type mutation of obtaining also has been confirmed in colorectal cancer, acute lymphoblastic leukemia (ALL), chronic myelocytic leukemia (CML). Therefore, the occurrence and development that the abnormal activation of BTK dependent forms access is proved to kinds of tumors are closely related.
BTK micromolecular inhibitors have good prospect for treatment hematologic malignancies and Autoimmune Disorders disease.According to Shandong is current most noticeable BTK targeted inhibitions agent for Buddhist nun (ibrutinib), to a variety of B in preclinical and clinical research Cell tumour and autoimmune disease have significant therapeutic effect, listing have been approved by the FDA in the United States, for treating jacket cell Lymthoma (MCL) and CLL.Other multiple compounds also have been enter into clinical investigation phase or face such as CC-292 and ONO-4059 Bed later stage conceptual phase.
There is still a need for exploitation activity height, the BTK inhibitor of high specificity for this field.
Invention content
Disease is mediated the purpose of the present invention is to provide active high, high specificity BTK inhibitor and its preparing treatment BTK Application in the drug of disease.
In a first aspect, the present invention provides compound or its salt shown in Formulas I is preparing BTK inhibitor or preparing treatment or pre- Purposes in the drug for the disease that anti-BTK is mediated：
In formula,
R is hydrogen, C1-C3Low alkyl group, C1-C3Lower alkoxy, halogen (for example, F, Cl, Br), amino, substituted ammonia Base；
B is selected from the group：(C3-C8) naphthenic base, (C3-C8) heterocycle, (C6-C10) aryl or the (C5- optionally replaced C10) aromatic heterocyclic；
R2It is each independently selected from following group：
Work as Z1For-C (O)-when, Z2ForAlternatively, working as Z1ForWhen, Z2For-C (O)-；
R3It is selected from the group：Hydrogen, the C optionally replaced1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, the C optionally replaced3-C8 Naphthenic base, the C optionally replaced1-C10Alkoxy, the aryl optionally replaced, the benzyl optionally replaced, the heterocycle optionally replaced, The aromatic heterocyclic ,-O- (CH) optionally replacedn-O-C1-C3Alkyl；
N be 1-3 integer, preferably 1.
In a particular embodiment, B 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 ', R1It is not present, R ' is selected from C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；
R1It is each independently selected from hydrogen, halogen, C1-C3Alkoxy, C1-C3Alkyl, C1-C4Alkylamidoalkyl, substituted piperazine Base, substituted high piperazine base, substituted morpholinyl, substituted thio-morpholinyl, 4-N- methyl piperazines base, 4-N- Acetylpiperazines Base, 4-N, N- lupetidines base, substituted piperidyl ,-NRaRb, wherein RaAnd RbAlkyl can be independently selected from and contain azanyl；
M is 0-7, preferably any integer of 1-7；
B、R2、Z1And Z2As defined above.
In a particular embodiment, the compound is as shown in Formula Il -1 or II-2：
In formula, B, R1、R2、R3As defined above；
M is 0-5, preferably the integer of 1-5.
In a particular embodiment, shown in the following formula III -1 of the compound or III-2：
In formula,
R2It is selected from
R3Selected from H；C1-C6Alkyl, preferably methyl or isopropyl；The C of phenyl substitution1-C6Alkyl；The phenoxy group optionally replaced Phenyl；Or the benzyl optionally replaced；
R4、R5、R6、R7And R8It is independently selected from the following group：
In a particular embodiment, in formula,
R2It is selected from
R3Selected from H or C1-C6Alkyl (preferably methyl or propyl or isopropyl)；
R4For H, C1-C3Alkoxy (preferably methoxyl group)；
R5For H, C1-C3Alkyl (preferably methyl) or C1-C3Alkoxy (preferably methoxyl group)；
R6For H or
R7And R8For H.
In second aspect, the present invention provides particular compound selected from the group below or prepared by its pharmaceutically acceptable salt BTK inhibitor or preparation treat or prevent the purposes in the drug for the disease that BTK is mediated：
In a particular embodiment, the disease that the BTK is mediated is cancer or autoimmune disease.
In a particular embodiment, the cancer includes hematologic malignancies or solid tumor, such as：Acute lymphoblastic Leukaemia (ALL), chronic myelocytic leukemia (CML), lymphoma mantle cell (MCL), colorectal cancer；The autoimmune disease packet Include rheumatoid arthritis, anti-organ transplant rejection, psoriasis or lupus erythematosus.
In the third aspect, the present invention provides the disease method that BTK is mediated that treats or prevents, including by the present invention first or the Compound described in two aspects or the pharmaceutical composition comprising the compound give the object of this needs.
In fourth aspect, the present invention provides compound or its salt shown in Formulas I：
In formula,
R、B、R2、Z1And Z2As defined above,
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)n-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle Alkyl oxy, amide groups, the carbamoyl optionally replaced, n be 1-3 integer, preferably 1；
And/or
R2It 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 or NRcRd, and Rc、RdIt is independently selected from H, C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；
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)n-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle Alkyl oxy, amide groups, the carbamoyl optionally replaced, n be 1-3 integer, preferably 1；
Or
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；
R2It 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)n-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle Alkyl oxy, amide groups, the carbamoyl optionally replaced, n be 1-3 integer, preferably 1；
R2It is selected from the group：
In a particular embodiment, the compound is as shown in Formulas I -1：
In formula, A R '；
R1It is not present；
R ' is C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；
B、R2、Z1And Z2As defined above.
In a particular embodiment, R ' is C1-C3Alkyl, C1-C3Halogenated 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 BTK, the IC of the BTK inhibitory activity of some of compounds with high selectivity50Value reaches nM grades Not.The present invention is completed on this basis.
The present inventor has synthesized a series of candidate compounds with BTK inhibitory activity.Pass through the candidate compound to obtaining Object carries out Optimal Structure Designing, it was found that the novel pyrimido-pyrimidine heterocyclic compounds with potential BTK inhibitory activity of a batch. Molecular level activity rating is carried out to obtained compound, multiple compounds are to BTK inhibitory activity IC50Value reaches nM ranks.
Term defines
Group of the present invention has the meaning that this field routinely understands.Some group definitions being referred to herein are such as Under：
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, C1-4Aldehyde radical, C1-6Alkyl, cyano, nitro, amino, hydroxyl, hydroxyl first Alkoxy (such as trifluoromethoxy), carboxyl, the C that base, the alkyl (such as trifluoromethyl) of halogen substitution, halogen replace1-4Alcoxyl Base, ethoxycarbonyl, N (CH3) and C1-4Acyl group 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, C1-4Aldehyde radical, C1-6Linear or branched alkyl group, cyano, nitro, amino, hydroxyl, methylol, halogen substitution alkyl (such as trifluoro Methyl), halogen substitution alkoxy (such as trifluoromethoxy), carboxyl, C1-4Alkoxy, ethoxycarbonyl, N (CH3) and C1-4 Acyl group.
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.
" aryl formoxyl " used herein refers to aryl, such as (C6-C10) aryl is formed with formoxyl, and passes through first The group that acyl group 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, C1-4Aldehyde radical, C1-6Linear or branched alkyl group, cyano, nitro, amino, hydroxyl, hydroxyl Alkoxy (such as trifluoromethoxy), carboxyl, the C that methyl, the alkyl (such as trifluoromethyl) of halogen substitution, halogen replace1-4Alkane Oxygroup, ethoxycarbonyl, N (CH3) and C1-4Acyl group.
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, inhibits so as to prepare BTK Agent prepares the drug for treating or preventing the disease that BTK is mediated：
In formula,
R is hydrogen, C1-C3Low alkyl group, C1-C3Lower alkoxy, halogen (for example, F, Cl, Br), amino, substituted ammonia Base；
B is selected from the group：(C3-C8) naphthenic base, (C3-C8) heterocycle, (C6-C10) aryl or the (C5- optionally replaced C10) aromatic heterocyclic；
R2It is each independently selected from following group：
Work as Z1For-C (O)-when, Z2ForAlternatively, working as Z1ForWhen, Z2For-C (O)-；
R3It is selected from the group：Hydrogen, the C optionally replaced1-C10Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, the C optionally replaced3-C8 Naphthenic base, the C optionally replaced1-C10Alkoxy, the aryl optionally replaced, the benzyl optionally replaced, the heterocycle optionally replaced, The aromatic heterocyclic ,-O- (CH) optionally replacedn-O-C1-C3Alkyl；
N be 1-3 integer, preferably 1.
In a particular embodiment, B can be 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 ', R1It is not present, R ' is selected from C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；
R1It is each independently selected from hydrogen, halogen, C1-C3Alkoxy, C1-C3Alkyl, C1-C4Alkylamidoalkyl, substituted piperazine Base, substituted high piperazine base, substituted morpholinyl, substituted thio-morpholinyl, 4-N- methyl piperazines base, 4-N- Acetylpiperazines Base, 4-N, N- lupetidines base, substituted piperidyl ,-NRaRb, wherein RaAnd RbAlkyl can be independently selected from and contain azanyl；
M is 0-7, preferably any integer of 1-7；
B、R2、Z1And Z2As defined above.
Still further, the compound of the present invention can be as shown in Formula Il -1 or II-2：
In formula, B, R1、R2、R3As defined above；
M is 0-5, preferably the integer of 1-5.
Further, the compound of the present invention can be shown in following formula III -1 or III-2：
In formula,
R2It is selected from
R3Selected from H；C1-C6Alkyl, preferably methyl or isopropyl；The C of phenyl substitution1-C6Alkyl；The phenoxy group optionally replaced Phenyl；Or the benzyl optionally replaced；
R4、R5、R6、R7And R8It is independently selected from the following group：
Alternatively,
R2It is selected from
R3Selected from H or C1-C6Alkyl (preferably methyl or propyl or isopropyl)；
R4For H, C1-C3Alkoxy (preferably methoxyl group)；
R5For H, C1-C3Alkyl (preferably methyl) or C1-C3Alkoxy (preferably methoxyl group)；
R6For H or
R7And R8For H.
In a particular embodiment, the present invention provides compound selected from the group below or its pharmaceutically acceptable salt is being made Standby BTK inhibitor or preparation treat or prevent the purposes in the drug for the disease that BTK is mediated：
Upper table is shown in the structure and its BTK 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 BTK inhibitory activity, the present invention provides a kind of for inhibiting BTK's Pharmaceutical composition, the composition contain the compound of the present invention or its pharmaceutically acceptable salt and medicine of therapeutically effective amount Acceptable carrier or excipient on.
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 BTK.Herein, institute The disease for stating BTK mediations is cancer or autoimmune disease；Wherein, the cancer includes hematologic malignancies or solid tumor, example Such as：Acute lymphoblastic leukemia (ALL), chronic myelocytic leukemia (CML), lymphoma mantle cell (MCL), colorectal cancer；Institute It includes rheumatoid arthritis, anti-organ transplant rejection, psoriasis or lupus erythematosus to state autoimmune disease.
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 the diseases for treating or preventing BTK mediations Method, this method include giving the object of this needs with the compound of the present invention or pharmaceutical composition.Medication include but Various medications well known in the art are not limited to, can be determined according to the actual conditions of patient.These methods include but not It is 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,
R、B、R2、Z1And Z2As defined above,
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)n-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle Alkyl oxy, amide groups, the carbamoyl optionally replaced, n be 1-3 integer, preferably 1；
And/or
R2It is selected from the group：
In a preferred embodiment, above-mentioned R, R2And R3It 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 or NRcRd, and Rc、RdIt is independently selected from H, C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；
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)n-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle Alkyl oxy, amide groups, the carbamoyl optionally replaced, n be 1-3 integer, preferably 1；
Or
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；
R2It 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)n-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle Alkyl oxy, amide groups, the carbamoyl optionally replaced, n be 1-3 integer, preferably 1；
R2It is selected from the group：
In a particular embodiment, the completely new compound of structure of the invention is as shown in Formulas I -1：
In formula, A R '；R1It is not present；R ' is C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；B, R2、Z1And Z2As defined above.
Further, R ' can be C1-C3Alkyl, C1-C3Halogenated alkyl.
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 BTK；
2. the compound of the present invention is to the high selectivity of BTK；With
3. the compound of the present invention is exploitation energy high activity, inhibits the drug of BTK to lay a good foundation with high selectivity, have 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.BTK inhibitory activity detection methods
The expression of 1.1BTK recombinant proteins
1) structure of PfastBac1-BTK carriers
BTK target fragments (M1-S695) are subjected to PCR amplification, by PCR product and carrier PfastBac 1 with BamHI and XhoI carries out double digestion, and digestion products are ligated and transformed into DH5 α competent cells, selects monoclonal and by sequence verification, most The correct recombinant plasmid pFastBac1-BTK of sequence is obtained eventually.
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) BTK protein expressions 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 1.2BTK 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 1.3BTK inhibitor
The horizontal screening experiment of BTK inhibitor molecules selects ThermoFisher companiesAssay Kit (PV3190).Experimental method is：Compound to be detected is subjected to concentration gradient dilution, 2.5 μ L are added in 384 orifice plates Test Compounds, every group of three parallel controls add 5 μ L BTK Kinase/Peptide Substrate Mixture, 2.5 μ L ATP Solution vibrate 30s mixings, are incubated at room temperature 1h；5 μ L Development Solution are added, are vibrated 30s mixings are incubated at room temperature 1h；Then 5 μ L Stop Reagent are added, vibrate 30s mixings, are believed using microplate reader detection fluorescence Number, excitation wavelength 400nm, launch wavelength is respectively 445nm and 520nm.Measure inhibition of the compound under 7 concentration gradients Rate calculates the IC of each compound by 8.0 matched curves of Origin50Value.
The synthesis technology of pyrimido [4,5-d] pyrimidine -2,4 (1H, 3H)-cyclohexadione compounds of the present invention is as follows：
Reagent and condition：(a)DIPEA,CH3CN,reflux；(b)ArNH2,CH3CN,reflux；(c)NaOH,THF, reflux；(d)R3NH2,HATU,DIPEA,DMF；(e)NaH,CDI,THF,reflux；(f)trifluoroacetic acide, CH2Cl2,0℃ to r.t；(g)acyl chloride,Et3N,CH2Cl2,0℃ to r.t
In above-mentioned preparation flow, R3、R4、R5With reference to the definition of corresponding group above.Those skilled in the art can basis Practical prepare needs, and the various initial compounds that this field routinely obtains is used to prepare corresponding compound for raw material.
Embodiment 1
The specific synthetic method of above-mentioned steps a-g is as follows：
The synthesis of 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- chlorine pyrimidine -5- Ethyl formates
Bis- chloro- 5- nitro-pyrimidines (2.210g, 10mmol) of 2,4-, DIPEA (1.290g, 10mmol) are weighed in 50mL single port The dissolving of 15mL acetonitriles is added in flask.(3- aminophenyls) t-butyl carbamate (2.080g, 10mmol) is separately taken to be dissolved in 10mL second Nitrile is added drop-wise in above-mentioned reaction solution, drips reflux 2h.TLC tracks to raw material conversion, is cooled to room temperature, and filters, and acetonitrile is washed It washs, filter cake drying obtains 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- chlorine pyrimidine -5- Ethyl formate 3.371g, Yield 86%.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)+.
The conjunction of 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- (phenyl amino) pyrimidine -5- Ethyl formates At
Weigh 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- chlorine pyrimidine -5- Ethyl formates (1.960g, 5mmol), the dissolving of 40mL acetonitriles, temperature rising reflux 3h is added in 100mL single-necked flasks in aniline (0.558g, 6mmol).TLC is tracked Raw material converts, and is cooled to room temperature, and filters, washing, and filter cake drying obtains 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) ammonia Base) -2- (phenyl amino) pyrimidine -5- Ethyl formate 1.930g, yield 86%.1H NMR(400MHz,CDCl3)δ10.46(s, 1H), 8.76 (s, 1H), 7.57 (d, J=8.0Hz, 2H), 7.36 (t, J=7.6Hz, 3H), 7.23 (d, J=8.0Hz, 1H), 7.16 (t, J=7.2Hz, 1H), 7.04 (d, J=7.6Hz, 1H), 6.36 (s, 1H), 4.37 (q, J=7.2Hz, 2H), 1.54 (s, 9H), 1.41 (t, J=7.2Hz, 3H) .LC-MS:m/z:450.4(M+H)+.
The synthesis of 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- (phenyl amino) pyrimidine -5- formic acid
Weigh 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- (phenyl amino) pyrimidine -5- Ethyl formates (1.796g, 4mmol) is added the dissolving of 30mL tetrahydrofurans, 1M NaOH solution 10mL is added dropwise, are warming up in 100mL single-necked flasks 50 DEG C, stir 3h.TLC tracks to raw material conversion, is cooled to room temperature, and dilute hydrochloric acid is added and adjusts pH to acidity, filters, washes, filter Cake is dried, and 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- (phenyl amino) pyrimidine -5- formic acid 1.499g are obtained, Yield 89%.1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.82(s,1H),9.36(s,1H),8.70(s,1H), 7.69 (d, J=8.0Hz, 2H), 7.63 (s, 1H), 7.43 (s, 1H), 7.26-7.21 (m, 4H), 6.98 (t, J=6.8Hz, 1H),1.47(s,9H).HRMS(ESI):Calculated value C22H24N5O4(M+H)+422.1828 experiment value 422.1823.
The conjunction of 3- (5- (methylcarbamoyl -2- (phenyl amino) pyrimidine -4- amino) phenyl) t-butyl carbamate At
Weigh 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- (phenyl amino) pyrimidine -5- formic acid The dissolving of 10mL anhydrous DMFs is added in 50mL flasks in (1.263g, 3mmol), DIPEA (0.774g, 6mmol).Separately take HATU (1.368g, 3.6mmol) is added portionwise in above-mentioned reaction solution, 1h is stirred at room temperature.Addition methylamine hydrochloride (0.396g, 6mmol), it is stirred overnight at room temperature.TLC tracks raw material conversion, and ice water is added, and filters, and washing obtains 3- (5- (methylcarbamoyls Base -2- (phenyl amino) pyrimidine -4- amino) phenyl) t-butyl carbamate 0.612g, yield 47%.1H NMR(400MHz, DMSO-d6) δ 11.33 (s, 1H), 9.59 (s, 1H), 9.31 (s, 1H), 8.64 (s, 1H), 8.50 (d, J=4.8Hz, 1H), 7.68 (d, J=7.8Hz, 2H), 7.62 (s, 1H), 7.49 (br, 1H), 7.23 (t, J=7.8Hz, 2H), 7.19 (d, J= 8.0Hz, 1H), 7.15 (d, J=8.0Hz, 1H), 6.96 (t, J=7.2Hz, 1H), 2.79 (d, J=4.4Hz, 3H), 1.47 (s, 9H).LC-MS:m/z:435.2(M+H)+.
(3- (3- methyl -2,4- dioxos -7- (phenyl amino) -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidines -1 (2H) - Base) phenyl) t-butyl carbamate
Weigh 3- (5- (methylcarbamoyl -2- (phenyl amino) pyrimidine -4- amino) phenyl) t-butyl carbamate (0.434g,1mmol)、K2CO3The dissolving of 5mL anhydrous tetrahydro furans, temperature rising reflux is added in 25mL flasks in (0.276g, 2mmol) Overnight.TLC tracks raw material conversion, is cooled to room temperature, and ice water is added, and EA is extracted, and collected organic layer, rotary evaporation removes solvent, Crude product detaches (EA/PE=2 through silica gel column chromatography:1, v/v) 193mg, yield 42%, are obtained.1H NMR(400MHz,DMSO-d6) δ 9.62 (s, 1H), 8.92 (s, 1H), 7.66 (s, 1H), 7.52 (d, J=8.0Hz, 1H), 7.45 (t, J=8.0Hz, 1H), 7.36-7.32 (m, 2H), 7.02 (d, J=8.0Hz, 3H), 6.90 (d, J=7.6Hz, 1H), 3.29 (s, 3H), 1.45 (s, 9H).HRMS(ESI):Calculated value C24H25N6O4(M+H)+461.1937 experiment value 461.1939.
1- (3- aminophenyls) -3- methyl -7- (phenyl amino) pyrimido [4,5-d] pyrimidine -2,4 (1H, 3H)-diketone Synthesis
Weigh (3- (3- methyl -2,4- dioxos -7- (phenyl amino) -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidines -1 (2H)-yl) phenyl) t-butyl carbamate (0.193g, 0.42mmol) is in 50mL flasks, and addition 5mL dichloromethane dissolves, slowly It is slow that 1mL trifluoroacetic acids are added dropwise, it is stirred overnight at room temperature.TLC tracks raw material conversion, and saturation NaHCO is added3Solution neutralizes, dichloromethane Alkane extracts, collected organic layer, and rotary evaporation removes solvent, obtains 1- (3- aminophenyls) -3- methyl -7- (phenyl amino) pyrimido [4,5-d] pyrimidine -2,4 (1H, 3H)-diketone 0.136g, yield 90%, product is not purified to be directly used in the next step.
N- (3- (3- methyl -2,4- dioxos -7- (phenyl amino) -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidines -1 (2H) - Base) phenyl) acrylamide synthesis (serial number 1)
Weigh 1- (3- aminophenyls) -3- methyl -7- (phenyl amino) pyrimido [4,5-d] pyrimidines -2,4 (1H, 3H)-two The dissolving of 3mL dichloromethane, ice bath is added in ketone (0.136g, 0.38mmol), DIPEA (0.097g, 0.76mmol) and 25mL flasks Lower stirring 15 minutes.Separately acryloyl chloride (0.041g, 0.46mmol) is taken to be dissolved in 1mL dichloromethane, is added drop-wise in above-mentioned reaction solution, It is stirred overnight at room temperature.TLC tracks raw material conversion, is spin-dried for, and crude product detaches (EA/PE=1.5 through silica gel column chromatography:1, v/v) N-, is obtained (3- (3- methyl -2,4- dioxos -7- (phenyl amino) -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)-yl) phenyl) third Acrylamide 83mg, yield 53%.1H NMR(400MHz,DMSO-d6) δ 10.38 (s, 1H), 8.93 (s, 1H), 7.82 (d, J= 3.2Hz, 1H), 7.80 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.33-7.29 (m, 2H), 7.15 (d, J=7.8Hz, 1H), 7.02-6.96 (m, 2H), 6.89 (t, J=6.0Hz, 1H), 6.44 (dd, J=17.2Hz, J=10.4Hz, 1H), 6.26 (dd, J =17.2Hz, J=1.6Hz, 1H), 5.76 (dd, J=10.4Hz, J=2.0Hz, 1H), 3.30 (s, 3H) .HRMS (ESI):Meter Calculation value C22H19N6O3(M+H)+415.1519 experiment value 415.1512.
Following compound synthesizes to obtain according to the method for above-mentioned steps a-g：
((7- ((2- methoxyphenyls) amino) -3- methyl -2,4- dioxo -3,4- dihydro-pyrimidins are simultaneously [4,5-d] by 3- by N- Pyrimidine -1 (2H)) phenyl) acrylamide (serial number 2)
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.89(s,1H),8.68(s,1H),7.80(s,1H), 7.76 (d, J=8.0Hz, 1H), 7.50 (t, J=8.0Hz, 1H), 7.41 (d, J=8.0Hz, 1H), 7.12 (d, J=7.6Hz, 1H), 6.95 (d, J=7.6Hz, 2H), 6.44 (dd, J=16.8Hz, J=10.0Hz, 1H), 6.25 (dd, J=17.2Hz, J= 2.0Hz, 1H), 5.76 (dd, J=10.4Hz, J=2.0Hz, 1H), 3.78 (s, 3H), 3.29 (s, 3H) .HRMS (ESI) are calculated Value C23H21N6O4[M+H]+445.1624 experiment value 445.1631.
((7- ((4- methoxyphenyls) amino) -3- methyl -2,4- dioxo -3,4- dihydro-pyrimidins are simultaneously [4,5-d] by 3- by N- Pyrimidine -1 (2H)) phenyl) acrylamide (serial number 3)
1H NMR(400MHz,DMSO-d6) δ 10.37 (s, 1H), 10.23 (s, 1H), 8.88 (s, 1H), 7.82 (d, J= 8.0Hz, 1H), 7.79 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.22 (d, J=7.6Hz, 2H), 7.12 (d, J=8.0Hz, 1H), 6.56 (d, J=7.6Hz, 2H), 6.44 (dd, J=16.8Hz, J=10.0Hz, 1H), 6.24 (dd, J=16.8Hz, J= 1.6Hz, 1H), 5.76 (dd, J=10.0Hz, J=1.6Hz, 1H), 3.65 (s, 3H), 3.29 (s, 3H) .HRMS (ESI) are calculated Value C23H21N6O4[M+H]+445.1624 experiment value 445.1627.
N- (3- (7- ((2- methoxyl group -4- morphlinophenyls) amino) -3- methyl -2,4- dioxo -3,4- dihydro-pyrimidins And [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 4)
1H NMR (400MHz, DMSO-d6) δ 10.36 (s, 1H), 8.80 (s, 1H), 8.44 (s, 1H), 8.03 (s, 1H) 7.85 (d, J=8.0Hz, 1H), 7.69 (t, J=2.0Hz, 1H), 7.52 (t, J=8.4Hz, 1H), 7.31 (d, J=8.8Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 6.57 (d, J=2.0Hz, 1H), 6.45 (dd, J=16.8Hz, J=10.0Hz, 1H), 6.26 (dd, J=17.2Hz, J=2.0Hz, 1H), 5.77 (dd, J=10.4Hz, J=2.0Hz, 1H), 3.77 (s, 3H), 3.58-3.54 (m, 4H), 3.06-2.99 (m, 4H), 2.05 (s, 3H) .HRMS (ESI) calculated values C27H28N7O5[M+H]+ 528.1995 experiment value 528.1993.
N- (3- (7- ((2- methoxyl group -4- thiomorpholines are for phenyl) amino) -3- methyl -2,4- dioxo -3,4- dihydros Pyrimido [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 5)
H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.84(s,1H),8.60(s,1H),8.85(s,1H), 7.70 (s, 1H), 7.48 (t, J=8.0Hz, 1H), 7.17 (d, J=8.4Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 6.44 (dd, J=17.2Hz, J=10.0Hz, 1H), 6.27 (dd, J=16.8Hz, J=2.0Hz, 1H), 5.97 (s, 1H), 5.77 (dd, J=10.0Hz, J=1.6Hz, 1H), 3.75 (s, 3H), 3.42-3.39 (m, 4H), 3.28 (s, 3H), 2.66-2.63 (m, 4H) .HRMS (ESI) calculated values C27H28N7O4S[M+H]+546.1923 experiment value 546.1924.
N- (3- (7- ((4- (4- acetyl group -3-) -2- methoxyphenyls) amino) -3- methyl -2,4- dioxos -3,4- two Hydrogen pyrimido [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 6)
1H NMR (400MHz, DMSO-d6) δ 10.34 (s, 1H), 8.83 (s, 1H), 8.59 (s, 1H), 7.86 (s, 1H) 7.69 (s, 1H), 7.48 (t, J=8.4Hz, 1H), 7.17 (d, J=8.8Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 6.55 (s, 1H), 6.44 (dd, J=17.2Hz, J=10.4Hz, 1H), 6.26 (dd, J=17.2Hz, J=1.6Hz, 1H), 5.99 (s, 1H), 5.76 (dd, J=10.0Hz, J=1.2Hz, 1H), 3.76 (s, 3H), 3.58-3.54 (m, 4H), 3.28 (s, 3H), 3.05-2.99 (m, 4H), 2.05 (s, 3H) .HRMS (ESI) calculated values C29H31N8O5[M+H]+571.2417, experiment value 571.2417。
N- (3- (7- ((4- (4- (dimethylamino) piperidines) -2- methoxyphenyls) amino) -3- methyl -2,4- dioxos - 3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 7)
1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.83(s,1H),8.54(s,1H),7.88-7.86(m, 1H), 7.70 (s, 1H), 7.47 (t, J=8.0Hz, 1H), 7.16 (d, J=8.4Hz, 1H), 7.08 (d, J=8.0Hz, 1H), 6.50-6.43 (m, 2H), 6.26 (dd, J=16.8Hz, J=1.6Hz, 1H), 5.98 (s, 1H), 5.76 (dd, J=10.0Hz, J =1.2Hz, 1H), 3.75 (s, 3H), 3.59-3.58 (m, 2H), 3.28 (s, 3H), 2.60-2.55 (m, 2H), 2.22 (s, 6H), 1.82-1.79 (m, 2H), 1.47-1.40 (m, 2H) .HRMS (ESI) calculated values C30H35N8O4[M+H]+571.2781, experiment value 571.2780。
N- (3- (7- ((4- (4- (dimethylamino) piperidines) -2- methoxyphenyls) amino) -3- ethyl -2,4- dioxos - 3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 8)
1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),10.56(s,1H),8.84(s,1H),8.62(s,1H), 7.92-7.90 (m, 1H), 7.71 (s, 1H), 7.48 (t, J=8.0Hz, 1H), 7.17 (d, J=6.8Hz, 1H), 7.10 (d, J= 7.2Hz, 1H), 6.55-6.49 (m, 2H), 6.28 (dd, J=16.8Hz, J=1.6Hz, 1H), 6.00 (s, 1H), 5.78 (dd, J =11.2Hz, J=1.2Hz, 1H), 3.94 (q, J=6.4Hz, 2H), 3.76 (s, 3H), 3.72-3.68 (m, 2H), 2.73 (s, 6H), 2.60 (t, J=8.0Hz, 1H), 2.63-2.58 (m, 2H), 2.09 (d, J=11.2Hz, 2H), 1.72-1.68 (m, 2H), 1.18 (t, J=6.4Hz, 3H) .HRMS (ESI) (m/z):(M+H)+calcd forC31H37N8O4585.2938,found, 585.2928.
N- (3- (7- ((4- (4- (dimethylamino) piperidines) -2- methoxyphenyls) amino) -3- propyl -2,4- dioxos - 3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 9)
1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),8.84(s,1H),8.63(s,1H),7.92(s,1H), 7.69 (s, 1H), 7.49 (t, J=8.0Hz, 1H), 7.19 (d, J=6.8Hz, 1H), 7.10 (d, J=7.8Hz, 1H), 6.54- 6.48 (m, 2H), 6.28 (dd, J=16.8Hz, J=1.2Hz, 1H), 6.00 (s, 1H), 5.78 (dd, J=10.4Hz, J= 1.6Hz, 1H), 3.86 (t, J=6.8Hz, 2H), 3.76 (s, 3H), 3.72-3.69 (m, 2H), 3.26-3.21 (m, 1H), 2.72 (s, 6H), 2.62-2.57 (m, 2H), 2.07 (d, J=11.2Hz, 2H), 1.70-1.67 (m, 2H), 1.65-1.60 (m, 2H), 0.90 (t, J=7.2Hz, 3H) .HRMS (ESI) (m/z):(M+H)+calcd for C32H39N8O4 599.3094,found, 599.3099.
N- (3- (7- ((4- (4- (dimethylamino) piperidines) -2- methoxyphenyls) amino) -3- isopropyl -2,4- dioxies Generation -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 10)
H NMR(400MHz,DMSO-d6)δ10.55(s,1H),8.83(s,1H),8.60(s,1H),7.91(s,1H), 7.69 (s, 1H), 7.48 (t, J=8.0Hz, 1H), 7.19 (d, J=5.6Hz, 1H), 7.10 (d, J=7.6Hz, 1H), 6.55- 6.48 (m, 2H), 6.28 (dd, J=17.2Hz, J=1.6Hz, 1H), 6.00 (s, 1H), 5.78 (dd, J=10.0Hz, J= 1.6Hz,1H),5.17-5.10(m,1H),3.76(s,3H),3.72-3.68(m,2H),3.26-3.20(m,1H),2.72(s, 6H), 2.63-2.59 (m, 2H), 2.07 (d, J=10.8Hz, 2H), 1.70-1.67 (m, 2H), 1.44 (d, J=6.8Hz, 6H) .HRMS(ESI)(m/z):(M+H)+calcd forC32H39N8O4599.3094,found,599.3079.
N- (3- (3- benzyls -7- ((4- (4- (dimethylamino) piperidines) -2- methoxyphenyls) amino) -2,4- dioxos - 3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 11)
1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),8.87(s,1H),8.69(s,1H),7.91(s,1H), 7.69 (s, 1H), 7.48 (t, J=8.0Hz, 1H), 7.38 (d, J=7.2Hz, 2H), 7.33 (t, J=7.2Hz, 2H), 7.26 (t, J=7.2Hz, 1H), 7.19 (d, J=8.0Hz, 1H), 7.11 (d, J=6.8Hz, 1H), 6.54-6.47 (m, 2H), 6.27 (dd, J=16.8Hz, J=1.6Hz, 1H), 6.01-5.99 (m, 1H), 5.77 (dd, J=10.0Hz, J=1.6Hz, 1H), 5.10(s,2H),3.76(s,3H),3.72-3.69(m,2H),3.27-3.21(m,1H),2.73(s,6H),2.62-2.57(m, 2H), 2.08 (d, J=11.2Hz, 2H), 1.71-1.68 (m, 2H) .HRMS (ESI) (m/z):(M+H)+calcd forC36H39N8O4647.3094,found,647.3088.
N- (3- (7- ((4- (4- (dimethylamino) piperidines) -2- methoxyphenyls) amino) -2,4- dioxo -3- benzene second Base -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 12)
1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.85(s,1H),8.67(s,1H),7.91(s,1H), 7.72 (s, 1H), 7.49 (t, J=8.0Hz, 1H), 7.32 (t, J=7.6Hz, 2H), 7.26-7.23 (m, 3H), 7.19 (d, J= 12.8Hz, 1H), 7.07 (d, J=6.8Hz, 1H), 6.56-6.49 (m, 2H), 6.28 (dd, J=17.2Hz, J=1.6Hz, 1H), 6.01-5.99 (m, 1H), 5.78 (dd, J=10.4Hz, J=1.6Hz, 1H), 4.10-4.08 (m, 2H), 3.77 (s, 3H), 3.72-3.69 (m, 2H), 3.24-3.19 (m, 1H), 2.90 (t, J=7.6Hz, 2H), 2.71 (s, 6H), 2.62-2.57 (m, 2H), 2.07 (d, J=11.2Hz, 2H), 1.70-1.68 (m, 2H) .HRMS (ESI) (m/z):(M+H)+calcd forC37H41N8O4661.3251,found,661.3251.
N- (3- (7- ((4- (4- (dimethylamino) piperidines) -2- methoxyphenyls) amino) -2,4- dioxos -3- (3- benzene Propyl) -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 13)
1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.81(s,1H),8.60(s,1H),7.92(s,1H), 7.78 (s, 1H), 7.48 (t, J=8.0Hz, 1H), 7.28-7.19 (m, 5H), 7.14 (t, J=7.2Hz, 1H), 7.07 (d, J= 7.2Hz, 1H), 6.61-6.52 (m, 2H), 6.29 (dd, J=17.2Hz, J=1.6Hz, 1H), 6.02 (s, 1H), 5.78 (dd, J =10.0Hz, J=1.6Hz, 1H), 3.94 (t, J=7.2Hz, 2H), 3.76 (s, 3H), 3.22-3.17 (m, 1H), 2.69 (s, 6H), 2.68-2.63 (m, 4H), 2.08 (d, J=10.4Hz, 2H), 1.94 (t, J=6.8Hz, 2H) .HRMS (ESI) (m/z): (M+H)+calcd forC38H43N8O4675.3407,found,675.3403.
N- (3- (3- isopropyls -7- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) -2,4- dioxos - 3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 14)
1H NMR(400MHz,DMSO-d6) δ 10.64 (s, 1H), 8.83 (s, 1H), 8.63 (s, 1H), 7.85 (d, J= 7.2Hz, 1H), 7.73 (s, 1H), 7.47 (t, J=8.0Hz, 1H), 7.20 (d, J=8.4Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 6.56-6.51 (m, 2H), 6.27 (dd, J=17.2Hz, J=1.6Hz, 1H), 6.03-6.01 (m, 1H), 5.77 (dd, J =10.4Hz, J=1.2Hz, 1H), 5.17-5.10 (m, 1H), 3.76 (s, 3H), 3.29 (t, J=4.0Hz, 4H), 3.20 (t, J =4.0Hz, 4H), 2.75 (s, 3H), 1.44 (d, J=6.4Hz, 6H) .HRMS (ESI) (m/z):(M+H)+calcd forC30H35N8O4571.2781,found,571.2775.
N- (3- (3- isopropyls -7- ((3- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) -2,4- dioxos - 3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 15)
1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),10.18(s,1H),8.88(s,1H),7.89(s,1H), 7.72 (s, 1H), 7.50 (t, J=8.0Hz, 1H), 7.13 (d, J=8.0Hz, 1H), 6.91 (s, 1H), 6.49 (dd, J= 16.8Hz, J=10.0Hz, 1H), 6.43-6.41 (m, 1H), 6.27 (dd, J=16.8Hz, J=1.6Hz, 1H), 5.77 (dd, J =10.0Hz, J=1.6Hz, 1H), 5.18-5.11 (m, 1H), 3.56 (s, 3H), 3.04-3.01 (m, 8H), 2.63 (s, 3H), 1.44 (d, J=6.8Hz, 6H) .HRMS (ESI) (m/z):(M+H)+calcd forC30H35N8O4571.2781,found, 571.2773.
N- (3- (3- isopropyls-7- ((3- methyl-4- (4- methylpiperazine-1-yls) phenyl) amino) dioxo-3-2,4-, 4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 16)
1H NMR (400MHz, DMSO-d6) δ 10.54 (s, 1H), 10.22 (s, 1H), 8.88 (s, 1H), 7.90 (d, J=
7.2Hz, 1H), 7.74 (s, 1H), 7.51 (t, J=8.0Hz, 1H), 7.18 (s, 1H), 7.13 (d, J=8.0Hz, 1H), 7.08 (d, J=6.4Hz, 1H), 6.69 (d, J=7.6Hz, 1H), 6.50 (dd, J=17.2Hz, J=10.4Hz, 1H), 6.26 (dd, J=17.2Hz, J=1.6Hz, 1H), 5.76 (dd, J=10.4Hz, J=1.6Hz, 1H), 5.18-5.11 (m, 1H), 3.12 (t, J=4.0Hz, 4H), 2.92 (t, J=4.0Hz, 4H), 2.70 (s, 3H), 1.97 (s, 3H), 1.44 (d, J= 7.2Hz,6H).HRMS(ESI)(m/z):(M+H)+calcd forC30H35N8O3555.2832,found,555.2831.
N- (3- (7- ((4- (4- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) amino) -3- isopropyls Base -2,4- dioxo -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 17)
1H NMR(400MHz,CDCl3)δ8.94(s,1H),8.45(s,1H),7.95(s,1H),7.83(s,1H),7.68 (d, J=8.0Hz, 1H), 7.46 (t, J=8.0Hz, 1H), 7.35 (d, J=8.8Hz, 1H), 7.04 (d, J=7.6Hz, 1H), 6.38 (dd, J=16.8Hz, J=1.6Hz, 1H), 6.27-6.17 (m, 2H), 5.83 (dd, J=9.6Hz, J=1.6Hz, 1H), 5.69 (d, J=10.4Hz, 1H), 5.36-5.29 (m, 1H), 3.81 (s, 3H), 3.39 (t, J=7.6Hz, 2H), 2.88 (s, 3H), 2.45 (t, J=7.6Hz, 2H), 2.32 (s, 6H), 1.55 (d, J=6.8Hz, 6H) .HRMS (ESI) (m/z):(M+H)+ calcd forC30H37N8O4573.2938,found,573.2932.
N- (3- (7- ((4- (2- (dimethylamino) ethyoxyl) -2- methoxyphenyls) amino) -3- isopropyl -2,4- dioxies Generation -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 18)
H NMR (400MHz, DMSO-d6) δ 10.39 (s, 1H), 8.84 (s, 1H), 8.64 (s, 1H), 7.80 (d, J= 7.2Hz, 1H), 7.71 (s, 1H), 7.48 (t, J=8.0Hz, 1H), 7.22 (d, J=8.0Hz, 1H), 7.10 (d, J=6.0Hz, 1H), 6.52-6.42 (m, 2H), 6.29 (dd, J=17.2Hz, J=10.4Hz, 1H), 5.99-5.78 (m, 1H), 5.75 (dd, J =10.4Hz, J=1.6Hz, 1H), 5.15-5.11 (m, 1H), 3.95 (t, J=4.0Hz, 4H), 3.75 (s, 3H), 2.61 (t, J =4.0Hz, 4H), 2.22 (s, 6H), 1.44 (d, J=6.8Hz, 6H) .HRMS (ESI) (m/z):(M+H)+calcd forC29H34N7O5560.2621,found,560.2627.
N- (3- (3- isopropyls -7- ((2- methylaminos -4- (4- (- 1 base of 4- methyl piperazines) piperidin-1-yl) phenyl) ammonia Base) -2,4- dioxo -3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 19)
1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.82(s,1H),8.57(s,1H),7.91(s,1H), 7.70 (s, 1H), 7.47 (t, J=8.0Hz, 1H), 7.18 (d, J=6.8Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 6.56- 6.49 (m, 2H), 6.27 (dd, J=16.8Hz, J=1.6Hz, 1H), 5.99-5.97 (m, 1H), 5.77 (dd, J=10.0Hz, J =1.6Hz, 1H), 5.17-5.10 (m, 1H), 3.76 (s, 3H), 3.64-3.61 (m, 2H), 2.96-2.75 (m, 6H), 2.60- 2.56 (m, 6H), 1.87-1.85 (m, 1H), 1.54-1.50 (m, 2H), 1.44 (d, J=6.8Hz, 6H) .HRMS (ESI) (m/ z):(M+H)+calcd forC35H44N9O4654.3516,found,654.3519.
N- (3- (7- ((4- (4- acetylpiperazines base) -2- methoxyphenyls) amino) -3- ethyl -2,4- dioxos -3,4- Dihydro-pyrimidin simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 20)
1H NMR (400MHz, DMSO-d6) δ 1038 (s, 1H), 885 (s, 1H), 864 (s, 1H), 788 (d, J=40Hz, 1H), 7.69 (s, 1H), 7.49 (t, J=8.0Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 7.12 (d, J=7.6Hz, 1H), 6.55 (s, 1H), 6.46 (dd, J=17.2Hz, J=10.0Hz, 1H), 6.27 (dd, J=16.8Hz, J=1.6Hz, 1H), 6.00-5.97 (m, 1H), 5.78 (dd, J=10.0Hz, J=2.0Hz, 1H), 3.94 (q, J=6.4Hz, 2H), 3.77 (s, 3H), 3.58-3.54 (m, 4H), 3.05-2.98 (m, 4H), 2.06 (s, 3H), 1.19 (t, J=6.8Hz, 3H) .HRMS (ESI) Calculated value C30H33N8O5[M+H]+585.2574 experiment value 585.2572.
N- (3- (7- ((4- (4- acetylpiperazines base)-2- methoxyphenyls) amino) dioxo-3-3- isopropyl-2,4-, 4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)) phenyl) acrylamide (serial number 21)
H NMR(400MHz,DMSO-d6) δ 10.37 (s, 1H), 8.83 (s, 1H), 8.61 (s, 1H), 7.86 (d, J= 8.0Hz, 1H), 7.67 (s, 1H), 7.48 (t, J=8.0Hz, 1H), 7.17 (d, J=7.6Hz, 1H), 7.10 (d, J=7.6Hz, 1H), 6.55 (s, 1H), 6.45 (dd, J=16.8Hz, J=10.0Hz, 1H), 6.27 (dd, J=16.8Hz, J=1.6Hz, 1H), 6.00-5.97 (m, 1H), 5.78 (dd, J=10.0Hz, J=2.0Hz, 1H), 5.15-5.11 (m, 1H), 3.76 (s, 3H), 3.57-3.54 (m, 4H), 3.05-2.97 (m, 4H), 2.05 (s, 3H), 1.44 (d, J=6.4Hz, 6H) .HRMS (ESI) Calculated value C31H35N8O5[M+H]+599.2730 experiment value 599.2731.
N- (3- (7- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -3- benzyl -2,4- dioxos - 3,4- dihydro-pyrimidins simultaneously [4,5-d] pyrimidine -1 (2H)-yl) phenyl) acrylamide (serial number 22)
1H NMR(400MHz,DMSO-d6) δ 10.36 (s, 1H), 8.87 (s, 1H), 8.69 (s, 1H), 7.87 (d, J= 5.6Hz, 1H), 7.68 (s, 1H), 7.48 (t, J=8.0Hz, 1H), 7.38 (d, J=6.8Hz, 2H), 7.33 (t, J=7.2Hz, 2H), 7.26 (t, J=7.2Hz, 1H), 7.17 (d, J=8.0Hz, 1H), 7.12 (d, J=7.8Hz, 1H), 6.55 (s, 1H), 6.44 (dd, J=16.8Hz, J=10.0Hz, 1H), 6.26 (dd, J=17.2Hz, J=2.0Hz, 1H), 5.98 (s, 1H), 5.77 (dd, J=10.0Hz, J=1.6Hz, 1H), 5.09 (s, 2H), 3.76 (s, 3H), 3.58-3.55 (m, 4H), 3.05- 2.97 (m, 4H), 2.05 (s, 3H) .HRMS (ESI) calculated values C35H35N8O5[M+H]+647.2730 experiment value 647.2735.
The specific synthetic method of compound 23 is as follows：
Reagent and condition：(a)-(e) is as previously described；(f) N, N, N'- trimethyl ethylenediamine, K2CO3,DMSO；(n)Zn, NH4Cl,CH3OH；(o) acyl chlorides, Et3N,CH2Cl2, 0 DEG C-room temperature.
7- ((4- ((2- (dimethylamino) ethyl) (methyl) amino -2- methoxyl group -5- nitrobenzophenones) amino) -3- first The synthesis of base -1- phenyl pyrimidines simultaneously [4,5-d] pyrimidine -2,4 (1H, 3H)-diketone
Weighing 7- ((the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) amino), simultaneously [4,5-d] is phonetic for -3- methyl-1s-phenyl pyrimidine Pyridine -2,4 (1H, 3H)-diketone (438mg, 1mmol), K2CO3(207mg, 1.5mmol), N, N, N'- trimethyl ethylenediamines (153mg, 1.5mmol) is added 4mL DMSO dissolvings, is warming up to 90 DEG C, stirs 4h in 10mL single-necked flasks.TLC tracks to original Material conversion, is cooled to room temperature, and ice water is added, and ethyl acetate extraction is collected organic phase, is spin-dried for, crude product is detached through silica gel column chromatography (DCM/CH3OH=20:1, v/v) 7- ((4- ((2- (dimethylamino) ethyl) (methyl) amino -2- methoxyl group -5- nitros, are obtained Phenyl) amino) -3- methyl-1s-phenyl pyrimidine simultaneously [4,5-d] pyrimidine -2,4 (1H, 3H)-diketone 358mg, yield 69%.1H NMR(400MHz,CDCl3)δ8.97(s,1H),7.88(s,1H),7.63(s,1H),7.46-7.43(m,3H),7.19-7.16 (m, 2H), 6.52 (s, 1H), 3.83 (s, 3H), 3.39 (s, 3H), 3.08 (t, J=6.4Hz, 2H), 2.71 (s, 3H), 2.41 (t, J=6.8Hz, 2H), 2.17 (s, 6H) .LC-MS:m/z:521.3(M+H)+.
7- ((5- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) amino) -3- first The synthesis of base -1- phenyl pyrimidines simultaneously [4,5-d] pyrimidine -2,4 (1H, 3H)-diketone
Weigh 7- ((4- ((2- (dimethylamino) ethyl) (methyl) amino -2- methoxyl group -5- nitrobenzophenones) amino) - 3- methyl-1s-phenyl pyrimidine simultaneously [4,5-d] pyrimidine -2,4 (1H, 3H)-diketone (312mg, 0.6mmol) in 50mL single-necked flasks, The dissolving of 8mL methanol is added, instills 1mL saturated ammonium chloride solutions, zinc powder (390mg, 6mmol) is added and is stirred overnight at room temperature.TLC with Track to raw material converts, and filters out zinc powder, and filtrate is spin-dried for, and crude product detaches (DCM/CH through silica gel column chromatography3OH=15:1, v/v) it, obtains 7- ((5- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) amino) -3- methyl-1s-benzene Yl pyrimidines simultaneously [4,5-d] pyrimidine -2,4 (1H, 3H)-diketone 180mg, yield 61%.
1H NMR(400MHz,CDCl3) δ 8.94 (s, 1H), 8.11 (s, 1H), 7.60 (t, J=7.6Hz, 2H), 7.52 (t, J=7.2Hz, 1H), 7.33 (d, J=7.6Hz, 2H), 6.89 (s, 1H), 6.51 (s, 1H), 3.70 (s, 3H), 3.40 (s, 3H), 2.81 (t, J=6.4Hz, 2H), 2.52 (s, 3H), 2.29 (t, J=6.8Hz, 2H), 2.19 (s, 6H) .LC-MS:m/z:491.3 (M+H)+.
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((6- methyl -5,7- dioxos - 8- phenyl -5,6,7,8- tetrahydropyrimidines simultaneously [4,5-d] pyrimidine -2-base) amino) phenyl) and acrylamide synthesis (serial number 23)
Weigh 7- ((5- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) amino) - 3- methyl-1s-phenyl pyrimidine simultaneously [4,5-d] pyrimidine -2,4 (1H, 3H)-diketone (147mg, 0.3mmol), DIPEA (77mg, 0.6mmol) in 25mL flasks, the dissolving of 3mL dichloromethane is added, is stirred 15 minutes under ice bath.It is another take acryloyl chloride (33mg, It 0.36mmol) is dissolved in 1mL dichloromethane, is added drop-wise in above-mentioned reaction solution, is stirred overnight at room temperature.TLC tracks raw material conversion, rotation Dry, crude product detaches (DCM/CH through silica gel column chromatography3OH=15:1, v/v) N- (2- ((2- (dimethylamino) ethyl) (first, is obtained Base) amino) -4- methoxyl groups -5- ((6- methyl -5,7- dioxo -8- phenyl -5,6,7,8- tetrahydropyrimidines simultaneously [4,5-d] pyrimidines - 2- yls) amino) phenyl) acrylamide 80mg, yield 49%.
1H NMR(400MHz,CDCl3)δ9.36(s,1H),9.08(s,1H),7.88(s,1H),7.50-7.46(m,5H), 6.58 (dd, J=17.2Hz, J=10.0Hz, 1H), 6.48 (dd, J=17.2Hz, J=1.6Hz, 1H), 5.83 (dd, J= 10.0Hz, J=2.0Hz, 1H), 3.83 (s, 3H), 3.48 (s, 3H), 3.23 (t, J=6.0Hz, 2H), 3.06 (t, J= 6.4Hz,2H),2.77(s,6H),2.68(s,3H).HRMS(ESI):Calculated value C28H33N8O4(M+H)+545.2625, experiment value 545.2630。
The synthesis of the 5,8- dihydropteridine -6,7- cyclohexadione compounds of the present invention is as follows：
Reagent and condition：(a)(Boc)2O,Et3N,CH3OH, room temperature, for 24 hours；(b) bis- chloro- 5- nitro-pyrimidines of 2,4-, Na2CO3,DMF,-70℃,1h；(c) arylamine, DIPEA, THF, room temperature, overnight；(d)H2, Pd/C, MeOH, room temperature, 10h；(e) Diethy-aceto oxalate, triethylamine, EtOH, reflux, 30h；(f) alkyl halide, Cs2CO3, DMF, room temperature, overnight；(g) trifluoroacetic acid, CH2Cl2, room temperature, 5h；(h) acryloyl chloride, Et3N,CH2Cl2, 0 DEG C is arrived room temperature, overnight.
Embodiment 2
The synthesis of (3- aminophenyls) t-butyl carbamate
Weigh 1,3- phenylenediamines (10.800g, 100mmol), triethylamine (10.100g, 100mmol) is burnt in 250mL single port Bottle is added the dissolving of 100mL methanol, is stirred 15 minutes under condition of ice bath.Separately Boc- acid anhydrides (21.800g, 100mmol) is taken to be dissolved in 40mL methanol is added drop-wise in above-mentioned reaction solution, after being added dropwise to complete, is stirred at room temperature 24 hours.TLC tracks raw material conversion, and rotation is steamed Hair removes solvent, and crude product is through silica gel column chromatography (petrol ether/ethyl acetate=4:1, v/v) it detaches, obtains (3- aminophenyls) ammonia Base t-butyl formate white solid 13.312g, yield 64%.1H NMR(400MHz,CDCl3) δ 7.03 (t, J=8.0Hz, 1H), 6.96 (s, 1H), 6.55 (dd, J=8.0Hz, J=1.2Hz, 1H), 6.43 (s, 1H), 6.36 (dd, J=8.0Hz, J= 1.6Hz,1H),3.54(s,2H),1.51(s,9H).LC-MS:m/z:209.1(M+H)+.
The synthesis of (3- (the chloro- 5- nitro-pyrimidines -4- amino of 2-) phenyl) t-butyl carbamate
Weigh 2,4-, bis- chloro- 5- nitro-pyrimidines (1.940g, 10mmol), n,N-diisopropylethylamine (2.580g, 20mmol) in 100mL round-bottomed flasks, 30mL DMF dissolvings are added, are stirred 10 minutes under condition of ice bath.Separately take (3- aminobenzenes Base) t-butyl carbamate (2.080g, 10.0mmol) is dissolved in 20mL DMF, and it is slowly dropped in above-mentioned reaction solution, drips Afterwards, it is stirred at room temperature 2 hours.TLC tracking raw materials convert completely, and ice water is added into reaction solution, solid is precipitated, filters, washes, does It is dry.Crude product CH2Cl2Recrystallization, obtains (3- (the chloro- 5- nitro-pyrimidines -4- amino of 2-) phenyl) t-butyl carbamate orange solids 2.950g yield 81%.
1H NMR(400MHz,CDCl3) δ 10.19 (s, 1H), 9.20 (s, 1H), 7.84 (s, 1H), 7.36 (d, J= 5.2Hz,2H),7.21-7.18(m,1H),6.63(s,1H),1.56(s,9H).LC-MS:m/z:366.1(M+H)+.
(3- ((2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -5- nitro-pyrimidine -4- bases) amino) benzene Base) t-butyl carbamate synthesis
Weigh (3- (the chloro- 5- nitro-pyrimidines -4- amino of 2-) phenyl) t-butyl carbamate (2.920g, 8mmol), N, N- The dissolving of 30mL tetrahydrofurans is added in 100mL three-necked flasks in diisopropylethylamine (2.064g, 16mmol).Separately take 2- methoxies Base -4- (4- methyl piperazines base) aniline (1.768g, 8mmol) is dissolved in 15mL tetrahydrofurans, is slowly dropped under argon gas protective condition In above-mentioned reaction solution, after dripping, temperature rising reflux is overnight.TLC tracks raw material conversion, and rotary evaporation removes partial solvent, is precipitated Solid filters, tetrahydrofuran washing, dry.Crude product CH2Cl2Recrystallization, obtains (3- ((2- ((2- methoxyl groups -4- (4- methyl piperazines Piperazine base) phenyl) amino) -5- nitro-pyrimidine -4- bases) amino) phenyl) t-butyl carbamate red brown solid 3.340g, yield 76%.
1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.42(s,1H),9.19(s,1H),9.03(s,1H), 7.54 (s, 1H), 7.39 (d, J=8.4Hz, 1H), 7.22 (t, J=8.8Hz, 2H), 7.09 (t, J=8.0Hz, 1H), 6.61 (d, J=1.6Hz, 1H), 6.34 (d, J=8.8Hz, 1H), 3.76 (s, 3H), 3.15 (t, J=4.4Hz, 4H), 2.47 (t, J= 4.4Hz,4H),2.24(s,3H),1.47(s,9H).LC-MS:m/z:551.4(M+H)+.
(3- ((5- amino -2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) t-butyl carbamate synthesis
Weigh (3- ((2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -5- nitro-pyrimidine -4- bases) ammonia Base) phenyl) t-butyl carbamate (3.300g, 6mmol), palladium-carbon catalyst (0.318g, 0.3mmol, 10%Pd) is in 250mL In heavy wall pressure bottle, the dissolving of 80mL methanol is added, is passed through hydrogen, reacts at room temperature 6 hours.TLC tracks raw material conversion, filters, filter Liquid is spin-dried for, crude product ethyl alcohol recrystallization, obtains (3- ((5- amino -2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) Pyrimidine-4-yl) amino) phenyl) t-butyl carbamate white solid 2.775g, yield 89%.
1H NMR(400MHz,DMSO-d6) δ 9.32 (s, 1H), 8.17 (s, 1H), 7.99 (d, J=8.8Hz, 1H), 7.96 (s, 1H), 7.59 (s, 1H), 7.32 (d, J=8.0Hz, 1H), 7.16 (t, J=8.0Hz, 1H), 7.06 (d, J=8.0Hz, 1H), 6.98 (s, 1H), 6.60 (d, J=2.4Hz, 1H), 6.38 (dd, J=8.8Hz, J=2.4Hz, 1H), 4.39 (s, 2H), 3.82 (s, 3H), 3.07 (t, J=4.4Hz, 4H), 2.48 (t, J=4.4Hz, 4H), 2.25 (s, 3H), 1.48 (s, 9H) .LC- MS:m/z:521.3(M+H)+.
(3- (2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6,7- dioxo -6,7- dihydropteridines -8 (5H)) phenyl) t-butyl carbamate synthesis
Weigh (3- ((5- amino -2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) t-butyl carbamate (2.600g, 5mmol), triethylamine (1.010g, 10mmol) in 100mL flasks, be added 40mL ethyl alcohol dissolves.Diethy-aceto oxalate (2.190g, 15mmol), temperature rising reflux 48 hours are added into reaction solution.TLC tracking is former Material conversion, filters, and ethyl alcohol washs filter cake, dry.Obtain (3- (2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) - 6,7- dioxo -6,7- dihydropteridines -8 (5H)) phenyl) t-butyl carbamate yellow solid 2.155g, yield 75%.
1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.14(s,1H),7.59(s,1H),7.57(s,1H), 7.55 (d, J=8.0Hz, 1H), 7.43 (t, J=8.0Hz, 1H), 7.26 (d, J=8.8Hz, 1H), 6.95 (d, J=7.6Hz, 1H), 6.53 (d, J=2.4Hz, 1H), 6.06 (d, J=8.0Hz, 1H), 3.77 (s, 3H), 3.03 (t, J=4.4Hz, 4H), 2.44 (t, J=4.4Hz, 4H), 2.22 (s, 3H), 1.45 (s, 9H) .HRMS (ESI):Calculated value C29H35N8O5(M+H)+ 575.2730 experiment value 575.2725.
N- (3- (2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6,7- dioxo -6,7- dihydro butterflies Pyridine -8- (5H)) phenyl) acrylamide synthesis (serial number 24)
Weigh (3- (2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6,7- dioxo -6,7- dihydro butterflies Pyridine -8 (5H)) phenyl) for t-butyl carbamate (0.861g, 1.5mmol) in 50mL round-bottomed flasks, addition 10mL dichloromethane is molten Solution, is slowly dropped into 2mL trifluoroacetic acids, is stirred overnight at room temperature.TLC tracks raw material conversion, and saturation NaHCO is added3Solution is neutralized to Alkalinity, dichloromethane extraction, collected organic layer, rotary evaporation remove solvent, obtain 8- (3- aminophenyls) -2- ((2- methoxyl groups - 4- (4- methyl piperazines base) phenyl) amino) -5,8- dihydropteridine -6,7- diketone 491mg, yield 69%, product is not purified straight It connects and is used for the next step.
Weigh 8- (3- aminophenyls) -2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -5,8- dihydro butterflies Pyridine -6,7- diketone (0.474g, 1mmol), Et3It is molten that 10mL dichloromethane is added in 25mL flasks in N (0.152g, 1.5mmol) It solves, is stirred 10 minutes under condition of ice bath.Separately acryloyl chloride (105 μ L, 1.3mmol) is taken to be dissolved in 2mL dichloromethane, is slowly added to It states in reaction solution, drips and be stirred overnight at room temperature.TLC tracks raw material conversion, and ice water is added, and dichloromethane extraction is collected organic Layer, rotary evaporation remove dissolving, and crude product is through silica gel column chromatography separating purification (DCM/CH3OH=15:1,v/v).Obtain N- (3- (2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6,7- dioxo -6,7- dihydropteridines -8- (5H)) phenyl) third Acrylamide 124mg, yield 23%.
1H NMR(400MHz,DMSO-d6) δ 10.69 (s, 1H), 8.22 (s, 1H), 7.51 (d, J=8.0Hz, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.52 (t, J=8.0Hz, 1H), 7.28 (d, J=8.8Hz, 1H), 7.08 (d, J=8.0Hz, 1H), 6.59-6.52 (m, 2H), 6.26 (dd, J=16.8Hz, J=1.2Hz, 1H), 6.07 (d, J=8.4Hz, 1H), 5.77 (dd, J=10.0Hz, J=1.2Hz, 1H), 3.78 (s, 3H), 3.31 (t, J=4.4Hz, 4H), 3.20 (t, J=4.4Hz, 4H),2.74(s,3H).HRMS(ESI):Calculated value C31H39N8O5(M+H)+529.2312 experiment value 529.2312.
(3- (5- ethyls -2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6,7- dioxos -6,7- two Hydrogen pteridine -8 (5H)) phenyl) t-butyl carbamate synthesis
Weigh (3- (2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6,7- dioxo -6,7- dihydro butterflies Pyridine -8 (5H)) phenyl) t-butyl carbamate (0.861g, 1.5mmol), Cs2CO3(0.587g, 1.8mmol) in 25mL flasks, 10mLDMF dissolvings are added, iodoethane (180 μ L, 2.25mmol) is added dropwise, drips and is stirred overnight at room temperature.TLC tracks raw material and turns Change, water is added, dichloromethane extraction, collected organic layer, rotary evaporation removing solvent, crude product is through silica gel column chromatography separating purification (DCM/CH3OH=20:1,v/v).(3- (5- ethyls -2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6, 7- dioxos -6,7- dihydropteridine -8 (5H)) phenyl) t-butyl carbamate 414mg, yield 46%.
1H NMR(400MHz,CDCl3) δ 8.59 (s, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.54 (d, J=8.0Hz, 1H), 7.50 (t, J=8.0Hz, 1H), 7.44 (s, 1H), 6.99 (d, J=7.2Hz, 1H), 6.72 (s, 1H), 6.45 (d, J= 2.4Hz, 1H), 6.17 (d, J=6.8Hz, 1H), 4.55 (q, J=7.2Hz, 2H), 3.83 (s, 3H), 3.14 (t, J=4.4Hz, 4H), 2.62 (t, J=4.4Hz, 4H), 2.38 (s, 3H), 1.51 (t, J=6.8Hz, 3H), 1.48 (s, 9H) .HRMS (ESI): Calculated value C31H39N8O5(M+H)+603.3043 experiment value 603.3043.
N- (3- (5- ethyls -2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6,7- dioxos -6,7- Dihydropteridine -8- (5H)) phenyl) acrylamide synthesis (serial number 26)
Weigh (3- (5- ethyls-2- ((2- methoxyl groups-4- (4- methyl piperazines base) phenyl) amino) dioxo-6-6,7-, 7- dihydropteridines -8 (5H)) phenyl) in 50mL round-bottomed flasks, 10mL is added in t-butyl carbamate (0.400g, 0.66mmol) Dichloromethane dissolves, and is slowly dropped into 2mL trifluoroacetic acids, is stirred overnight at room temperature.TLC tracks raw material conversion, and saturation NaHCO is added3 Solution is neutralized to alkalinity, and dichloromethane extracts, collected organic layer, rotary evaporation removing solvent, crude product recrystallize with dichloromethane, Obtain 8- (3- aminophenyls) -5- ethyls -2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -5,8- dihydropteridines - 6,7- diketone 185mg, yield 55%, product is directly used in the next step.
8- (3- aminophenyls) -5- ethyls -2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -5 is weighed, 8- dihydropteridines -6,7- diketone (0.180g, 0.36mmol), Et310mL is added in 25mL flasks in N (0.055g, 0.54mmol) Dichloromethane dissolves, and is stirred 10 minutes under condition of ice bath.Separately acryloyl chloride (38 μ L, 0.47mmol) is taken to be dissolved in 1mL dichloromethane, It is slowly added in above-mentioned reaction solution, drips and be stirred overnight at room temperature.TLC tracks raw material conversion, and ice water, dichloromethane extraction is added It takes, collected organic layer, rotary evaporation removes dissolving, and crude product is through silica gel column chromatography separating purification (DCM/CH3OH=15:1,v/v). Obtain N- (3- (5- ethyls -2- ((2- methoxyl groups -4- (4- methyl piperazines base) phenyl) amino) -6,7- dioxo -6,7- dihydro butterflies Pyridine -8- (5H)) phenyl) acrylamide 98mg, yield 49%.
1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.57(s,1H),7.92(s,1H),7.89(s,1H), 7.70 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.32 (d, J=8.8Hz, 1H), 7.10 (d, J=7.6Hz, 1H), 6.53 (d, J=2.4Hz, 1H), 6.45 (dd, J=17.2Hz, J=10.4Hz, 1H), 6.26 (dd, J=16.8Hz, J=1.6Hz, 1H), 6.06-6.04 (m, 1H), 5.77 (dd, J=10.0Hz, J=1.6Hz, 1H), 4.42 (q, J=7.2Hz, 2H), 3.77 (s, 3H), 3.02 (t, J=4.4Hz, 4H), 2.45 (t, J=4.4Hz, 4H), 2.23 (s, 3H), 1.40 (t, J=7.2Hz, 3H).HRMS(ESI):Calculated value C29H33N8O4(M+H)+557.2625 experiment value 557.2615.
Following compound synthesizes to obtain according to the method for above-mentioned steps：
N- (3- (2-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino) dioxo-6-5- methyl-6,7-, 7- dihydropteridines -8- (5H)-yl) phenyl) acrylamide (serial number 25)
1H NMR(400MHz,DMSO-d6) δ 10.46 (s, 1H), 8.48 (s, 1H), 7.92 (d, J=8.0Hz, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 7.07 (d, J=8.0Hz, 1H), 6.53 (d, J=1.6Hz, 1H), 6.46 (dd, J=16.8Hz, J=10.0Hz, 1H), 6.26 (dd, J=17.2Hz, J= 1.6Hz, 1H), 6.02 (d, J=8.4Hz, 1H), 5.77 (dd, J=10.0Hz, J=1.2Hz, 1H), 3.77 (s, 3H), 3.55- 3.53(m,4H),3.06-3.02(m,4H),2.57(s,3H),2.32(s,3H).HRMS(ESI):Calculated value C28H31N8O4(M+ H)+543.2468 experiment value 543.2470.
N- (3- (2-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino) propyl-6-6,7- dioxo-5-, 7- dihydropteridines -8- (5H)-yl) phenyl) acrylamide (serial number 27)
1H NMR(400MHz,DMSO-d6) δ 10.70 (s, 1H), 8.58 (s, 1H), 7.97 (s, 1H), 7.91 (d, J= 8.0Hz, 1H), 7.77 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.35 (d, J=8.8Hz, 1H), 7.11 (d, J=8.0Hz, 1H), 6.59-6.52 (m, 2H), 6.26 (dd, J=16.8Hz, J=1.2Hz, 1H), 6.11-6.09 (m, 1H), 5.77 (dd, J =10.0Hz, J=1.6Hz, 1H), 4.32 (t, J=6.8Hz, 2H), 3.78 (s, 3H), 3.31-3.29 (m, 4H), 3.16- 3.14 (m, 4H), 2.72 (s, 3H), 1.85-1.77 (m, 2H), 1.01 (t, J=7.2Hz, 3H) .HRMS (ESI):Calculated value C30H35N8O4(M+H)+571.2781 experiment value 571.2780.
N- (3- (5- isopropyls-2-((2- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-6,7- dioxos- 6,7- dihydropteridines -8- (5H)-yl) phenyl) acrylamide (serial number 28)
1H NMR(400MHz,DMSO-d6) δ 10.63 (s, 1H), 8.57 (s, 1H), 7.96 (s, 1H), 7.90 (d, J= 8.4Hz, 1H), 7.75 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.36 (d, J=8.8Hz, 1H), 7.11 (d, J=7.6Hz, 1H), 6.60 (d, J=2.0Hz, 1H), 6.54 (dd, J=16.8Hz, J=10.0Hz, 1H), 6.27 (dd, J=16.8Hz, J= 1.6Hz, 1H), 6.12-6.10 (m, 1H), 5.77 (dd, J=10.0Hz, J=1.6Hz, 1H), 5.38-5.30 (m, 1H), 3.79 (s, 3H), 3.31-3.29 (m, 4H), 3.26-3.24 (m, 4H), 2.79 (s, 3H), 1.40 (d, J=6.4Hz, 6H) .HRMS (ESI):Calculated value C30H35N8O4(M+H)+571.2781 experiment value 571.2780.
N- (3- (2- ((3- methyl-4- (4- methylpiperazine-1-yls) phenyl) amino) dioxo-6-5- isopropyl-6,7-, 7- dihydropteridines -8- (5H)-yl) phenyl) acrylamide (serial number 29)
1H NMR(400MHz,DMSO-d6) δ 10.54 (s, 1H), 9.61 (s, 1H), 8.61 (s, 1H), 7.91 (d, J= 8.0Hz, 1H), 7.76 (s, 1H), 7.55 (t, J=8.0Hz, 1H), 7.20 (s, 1H), 7.13 (d, J=8.0Hz, 1H), 6.69 (d, J=8.8Hz, 1H), 6.50 (dd, J=17.2Hz, J=10.4Hz, 1H), 6.26 (dd, J=17.2Hz, J=2.0Hz, 1H), 5.76 (dd, J=10.0Hz, J=1.6Hz, 1H), 5.37-5.31 (m, 1H), 2.94-2.91 (m, 4H), 2.85-2.82 (m, 4H), 2.58 (s, 3H), 1.99 (s, 3H), 1.40 (d, J=6.0Hz, 6H) .HRMS (ESI):Calculated value C30H35N8O3(M+ H)+555.2832 experiment value 555.2833.
N- (3- (2-((3- methoxyl groups-4- (4- methylpiperazine-1-yls) phenyl) amino)-5- isopropyl-6,7- dioxos- 6,7- dihydropteridines -8- (5H)-yl) phenyl) acrylamide (serial number 30)
1H NMR(400MHz,DMSO-d6) δ 10.59 (s, 1H), 9.57 (s, 1H), 8.62 (s, 1H), 7.90 (d, J= 8.4Hz, 1H), 7.75 (s, 1H), 7.54 (t, J=8.0Hz, 1H), 7.12 (d, J=7.6Hz, 1H), 7.04-6.99 (m, 2H), 6.55-6.49 (m, 2H), 6.27 (dd, J=17.2Hz, J=2.0Hz, 1H), 5.77 (dd, J=10.0Hz, J=1.6Hz, 1H), 5.37-5.31 (m, 1H), 3.57 (s, 3H), 3.19-3.07 (m, 8H), 2.74 (s, 3H), 1.40 (d, J=6.0Hz, 6H).HRMS(ESI):Calculated value C30H35N8O4(M+H)+571.2781 experiment value 571.2782.
((2- ((4-((2- (dimethylamino) ethyl) (methyl) amino)-2- methoxyphenyls) amino)-5- is different by 3- by N- Propyl -6,7- dioxo -6,7- dihydropteridines -8- (5H)-yl) phenyl) acrylamide (serial number 31)
1H NMR(400MHz,CDCl3) δ 8.69 (s, 1H), 8.57 (s, 1H), 7.75 (s, 1H), 7.71 (d, J=8.0Hz, 1H), 7.61 (s, 1H), 7.44 (t, J=8.0Hz, 1H), 6.98 (d, J=8.0Hz, 1H), 6.35 (dd, J=16.4Hz, J= 0.8Hz, 1H), 6.26-6.19 (m, 2H), 5.92-5.90 (m, 1H), 5.64 (dd, J=10.0Hz, J=1.2Hz, 1H), 5.49-5.43 (m, 1H), 3.80 (s, 3H), 3.40 (t, J=7.6Hz, 2H), 2.87 (s, 3H), 2.50 (t, J=7.6Hz, 2H), 2.35 (s, 6H), 1.48 (d, J=6.0Hz, 6H) .HRMS (ESI):Calculated value C30H37N8O4(M+H)+573.2938, it is real Test value 573.2939.
N- (3- (2- ((4- (2- (dimethylamino) ethyoxyl) -2- methoxyphenyls) amino) -5- isopropyls -6,7- two Oxo -6,7- dihydropteridines -8- (5H)-yl) phenyl) acrylamide (serial number 32)
1H NMR(400MHz,DMSO-d6) δ 10.64 (s, 1H), 8.57 (s, 1H), 8.01 (s, 1H), 7.87 (d, J= 8.4Hz, 1H), 7.78 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.39 (d, J=7.2Hz, 1H), 7.11 (d, J=8.0Hz, 1H), 6.60 (d, J=2.4Hz, 1H), 6.54 (dd, J=17.2Hz, J=10.4Hz, 1H), 6.26 (dd, J=17.2Hz, J= 2.0Hz, 1H), 6.16-6.14 (m, 1H), 5.76 (dd, J=10.0Hz, J=1.6Hz, 1H), 5.37-5.31 (m, 1H), 4.21 (t, J=4.8Hz, 2H), 3.78 (s, 3H), 3.26 (t, J=4.8Hz, 2H), 2.69 (s, 6H), 1.40 (d, J=6.0Hz, 6H).HRMS(ESI):Calculated value C29H34N7O5(M+H)+560.2621 experiment value 560.2625.
N- (3- (5- isopropyls -2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) ammonia Base) -8 (5H)-yl of -6,7- dioxo -6,7- dihydropteridines) phenyl) acrylamide (serial number 33)
1H NMR(400MHz,DMSO-d6) δ 10.58 (s, 1H), 8.56 (s, 1H), 7.94 (d, J=8.0Hz, 1H), 7.91 (s, 1H), 7.72 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.32 (d, J=8.8Hz, 1H), 7.11 (d, J=8.4Hz, 1H), 6.55-6.48 (m, 2H), 6.27 (dd, J=17.2Hz, J=2.0Hz, 1H), 6.08-6.06 (m, 1H), 5.78 (dd, J =10.0Hz, J=1.6Hz, 1H), 5.36-5.30 (m, 1H), 3.77 (s, 3H), 3.62-3.60 (m, 2H), 3.00-2.92 (m, 4H), 2.69-2.67 (m, 2H), 2.56 (t, J=11.6Hz, 3H), 2.42-2.39 (m, 2H), 1.82-1.81 (m, 2H), 1.54-1.49 (m, 1H), 1.39 (d, J=6.4Hz, 6H) .HRMS (ESI):Calculated value C35H44N9O4(M+H)+654.3516, it is real Test value 654.3512.
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 (15)

1. compound or its salt shown in Formulas I is in preparing BTK inhibitor or preparing the drug for treating or preventing the disease that BTK is mediated Purposes：
In formula,
R is hydrogen, C1-C3Low alkyl group, C1-C3Lower alkoxy, halogen (for example, F, Cl, Br), amino, substituted amino；
B is selected from the group：(the C optionally replaced3-C8) naphthenic base, (C3-C8) heterocycle, (C6-C10) aryl or (C5-C10) heteroaromatic Base；
R2It is each independently selected from following group：
Work as Z1For-C (O)-when, Z2ForAlternatively, working as Z1ForWhen, Z2For-C (O)-；
R3It is selected from the group：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)n-O-C1-C3Alkyl；
N be 1-3 integer, preferably 1.
2. compound as described in claim 1, which is characterized in that B 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 ', R1It is not present, R ' is selected from C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；
R1It is each independently selected from hydrogen, halogen, C1-C3Alkoxy, C1-C3Alkyl, C1-C4Alkylamidoalkyl, takes substituted piperazinyl The high piperazine base in generation, substituted morpholinyl, substituted thio-morpholinyl, 4-N- methyl piperazines base, 4-N- acetylpiperazinyls, 4- N, N- lupetidine base, substituted piperidyl ,-NRaRb, wherein RaAnd RbAlkyl can be independently selected from and contain azanyl；
M is 0-7, preferably any integer of 1-7；
B、R2、Z1And Z2As claims 1 or 2 limits.
4. purposes as claimed in claim 3, which is characterized in that the compound is as shown in Formula Il -1 or II-2：
In formula, B, R1、R2、R3As defined in claim 3；
M is 0-5, preferably the integer of 1-5.
5. purposes as claimed in claim 4, which is characterized in that shown in the following formula III -1 of the compound or III-2：
In formula,
R2It is selected from
R3Selected from H；C1-C6Alkyl, preferably methyl or isopropyl；The C of phenyl substitution1-C6Alkyl；The phenoxy group benzene optionally replaced Base；Or the benzyl optionally replaced；
R4、R5、R6、R7And R8It is independently selected from the following group：
6. purposes as claimed in claim 5, which is characterized in that in formula,
R2It is selected from
R3Selected from H or C1-C6Alkyl (preferably methyl or propyl or isopropyl)；
R4For H, C1-C3Alkoxy (preferably methoxyl group)；
R5For H, C1-C3Alkyl (preferably methyl) or C1-C3Alkoxy (preferably methoxyl group)；
R6For H or
R7And R8For H.
7. compound selected from the group below or its pharmaceutically acceptable salt are preparing BTK inhibitor or are preparing treatment or prevention BTK Purposes in the drug of the disease of mediation：
8. the purposes as described in any one of claim 1-7, which is characterized in that the disease that the BTK is mediated is for cancer or certainly Body immunological diseases.
9. purposes as claimed in claim 8, which is characterized in that the cancer includes hematologic malignancies or solid tumor, such as： Acute lymphoblastic leukemia (ALL), chronic myelocytic leukemia (CML), lymphoma mantle cell (MCL), colorectal cancer；It is described from Body immunological diseases include rheumatoid arthritis, anti-organ transplant rejection, psoriasis or lupus erythematosus.
Include by the compound or packet described in any one of claim 1-7 10. treating or preventing the disease method that BTK is mediated Pharmaceutical composition containing the compound gives the object of this needs.
11. compound or its salt shown in Formulas I：
In formula,
R、B、R2、Z1And Z2As 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)n-O-C1-C3Alkyl, C3-C6Cycloalkyl oxy, C3-C6Heterocycle alkane Base oxygroup, amide groups, the carbamoyl optionally replaced, n be 1-3 integer, preferably 1；
And/or
R2It is selected from the group：
12. compound or its salt as claimed in claim 11, which is characterized in that the compound is as shown in Formulas I -1：
In formula, A R '；
R1It is not present；
R ' is C1-C6Alkyl, C1-C6Halogenated alkyl or (C6-C10) aryl formoxyl；
B、R2、Z1And Z2As claim 11 defines.
13. compound as claimed in claim 12, which is characterized in that R ' is C1-C3Alkyl, C1-C3Halogenated alkyl.
14. the compound as described in any one of claim 11-12, which is characterized in that R3It is selected from the group：
15. compound as claimed in claim 14, which is characterized in that R3For：
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