CN106660993A - Certain protein kinase inhibitors - Google Patents
Certain protein kinase inhibitors Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention relates to certain protein kinase inhibitors. Provided are certain EGFR mutant selective inhibitors, pharmaceutical compositions thereof, and methods of use therefor.
Description
Technical field
The present invention relates to the new aminopyrimidine ring derivatives of a class and its pharmaceutically acceptable salt, such compound is optional
Epidermal growth factor (EGFR) kinase activity of selecting property mutation inhibiting, and as Drug therapy mammal, the especially mankind
Proliferative disease, such as cancer.The invention further relates to using the compound in treating cancer shares, and containing
State the pharmaceutical preparation of compound.
Background technology
Protein tyrosine kinase catalytic phosphatase group is transferred to the tyrosine residue of a protein substrate from ATP or GTP
On.Protein tyrosine kinase can be divided into receptor (such as EGFR, HER-2, VEGFR, FGFR) or non-receptor (such as Src, Jak,
Abl).The effect of receptor tyrosine kinase is to activate the secondary signal factor by phosphorylation, by signal from extracellular conduction
It is extremely intracellular.Various kinds of cell process is all including propagation, carbohydrate utilization, protein synthesis, blood by these signal enablings
Pipe generation, cell growth and cell survival.
The inappropriate or out of control activation of tyrosine kinase activity, the overexpression of such as kinases or mutation, have been found to by
Cause uncontrollable cell growth.Existing numerous evidences prove that EGFR take part in human tumor and develop, in all entities
More than more than 60% expression at least one EGFR or its part in tumor.The overexpression of EGFR is common in breast carcinoma, pulmonary carcinoma, head and neck cancer
And bladder cancer.
The first generation is reversible, the competitive EGFR kinase inhibitors of ATP, such as gefitinib and Erlotinib, is effective clinic
Treatment carry the nonsmall-cell lung cancer of EGFR kinase regions Activating mutations clinical treatment means (Nature, 2009,462,
1070-107).Although first generation EGFR inhibitor shows challenging clinical efficacy, elapse over time, Ji Husuo
Some patients generate drug resistance to these inhibitor, the drug resistance of for example keep goal person's mutation T 790M, gefitinib and Erlotinib
There are T790M mutation in about half in mutation.(Proc.Natl.Acad.Sci.U.S.A.2008,105,2070-2075) additionally,
T790M is mutated also congenital presence, and T790M mutation may have independent carcinogenesis.
The medicine researched and developed at present, including second filial generation covalency inhibitor such as Afatinib, HKI-272, Canertinib and Da Ke
For Buddhist nun, but dose-dependent toxicity such as diarrhoea and erythra are shown, due to inhibiting open country simultaneously to T790M medicament-resistant mutations effectively
The EGFR of raw type.
Therefore, the EGFR Kinase Selectivities inhibitor of mutation still in the urgent need to.Although the EGFR Selective depressions of mutation
Agent suppresses in the literature it has been reported that such as WO 2013014448 and WO 2012061299 to new E GFR Catastrophic selection
The demand of agent is still very urgent, and in treatment abnormal hyperplasia, it is in curative effect, stability, selectivity, safety, pharmacodynamicss for it
On the one hand feature and Pharmacokinetic Characteristics at least have advantage.The present invention relates to a class new E GFR Catastrophic selection suppresses
Agent.
The content of the invention
The present invention relates to a class novel aminopyrimidine ring derivatives and its pharmaceutical compositions, and as the application of medicine.
In one aspect, the present invention provides the compound shown at least one formula (I)：
And/or its at least one pharmaceutically acceptable salt,
Wherein：
Q is selected from aryl and heteroaryl；
X is selected from N and C；
Y is selected from N and C；
R1It is selected from：Hydrogen, C1-10Alkyl, C3-10Cycloalkyl, C3-10Cycloalkyl-C1-4Alkyl, heterocyclic radical and heterocyclic radical-C1-4Alkane
Base, wherein each alkyl, cycloalkyl and heterocyclic radical are unsubstituted or by least one, such as 1,2,3 or 4, are independently selected from
R6aSubstituent group replace；
R1’Selected from hydrogen and halogen；
R2And R3It is respectively selected from：Hydrogen, halogen, hydroxyl, CN, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, C3-10Cycloalkyl,
C3-10Cycloalkyl-C1-4Alkyl, heterocyclic radical, heterocyclic radical-C1-4Alkyl, aryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4
Alkyl, wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl and heterocyclic radical are unsubstituted or by least one, such as 1,2,3 or 4
It is individual, it is independently selected from R6aSubstituent group replace, wherein each aryl and heteroaryl are unsubstituted or by least one, such as 1,2,
3 or 4, it is independently selected from R6bSubstituent group replace；Or R2And R3One is cooperatively constituted together with the carbon atom being connected with them
Containing 0,1,2 or 3 heteroatomic 5-6 yuan of rings for being independently selected from oxygen, sulfur and nitrogen, the ring can be unsubstituted or by 1 or 2
Selected from R6aSubstituent group replace；
Each R4Independently selected from：Hydrogen, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, C3-10Cycloalkyl ,-OR8、-NR7S(O)rR8、-NO2,-halogen ,-S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC
(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8With-CR7(N-OR8)；Wherein each C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynes
Base and C3-10Cycloalkyl is unsubstituted or by least one, such as 1,2,3 or 4, is independently selected from R6aSubstituent group replace；
Each R5Independently selected from：Hydrogen, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, C3-10Cycloalkyl, C3-10Cycloalkyl-
C1-4Alkyl, heterocyclic radical, heterocyclic radical-C1-4Alkyl, aryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl ,-OR8、-
NR7S(O)rR8、-NO2, halogen ,-S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-O
(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)
R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8With-CR7(N-OR8), wherein each C1-10Alkyl, C2-10Thiazolinyl,
C2-10Alkynyl, C3-10Cycloalkyl and heterocyclic radical are unsubstituted or by least one, such as 1,2,3 or 4, are independently selected from R6a's
Substituent group replaces；Each aryl and heteroaryl are unsubstituted or by least one, such as 1,2,3 or 4, are independently selected from R6b's
Substituent group replaces；
Each R6aIndependently selected from：C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, C3-10Cycloalkyl ,-OR8、-NR7S(O)rR8、-NO2, halogen ,-S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-
(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-
(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O
(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)
(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC
(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8With-CR7(N-OR8)；
Each R6bIndependently selected from：R6a, aryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl；
Each R7With each R8Independently selected from：Hydrogen, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, cycloalkyl, cycloalkyl-
C1-4Alkyl, heterocyclic radical, heterocyclic radical C1-4Alkyl, aryl, heteroaryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl；
Wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl and heterocyclic radical are unsubstituted or by least one, such as 1,2,3 or 4, solely
It is vertical to be selected from R6aSubstituent group replace, wherein each aryl and heteroaryl are unsubstituted or by least one, such as 1,2,3 or 4
It is individual, it is independently selected from R6bSubstituent group replace；Or R7And R8Collectively form together with the single or multiple atoms being connected with them together
One containing 0,1 or 2 extra heteroatomic 4-12 circle heterocycles for being independently selected from oxygen, sulfur and nitrogen, the ring can not taken
Generation or by 1 or 2 be selected from R6bSubstituent group replace；
Each R9With each R10Independently selected from：Hydrogen, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, cycloalkyl, cycloalkyl-
C1-4Alkyl, heterocyclic radical, heterocyclic radical-C1-4Alkyl, aryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl；Or R9With
R10Collectively form together with the single or multiple carbon atoms being connected with them together and be independently selected from oxygen, sulfur and nitrogen containing 0,1 or 2
Heteroatomic 3-7 yuan of rings, the ring can be unsubstituted or by 1 or 2 selected from R6aSubstituent group replace；
M is independently selected from 0,1,2 and 3；
N is independently selected from 0,1,2 and 3；
Each r is independently selected from 1 and 2；
Each t is independently selected from 1,2 and 3.
On the other hand, the present invention provide pharmaceutical composition, it include at least one formula (I) compound and/or its at least one
Individual pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.
On the other hand, the present invention is provided to the method for adjusting mutation EGFR, the method include to system in need or
Individuality gives at least one formula (I) compound and/or at least one pharmaceutically acceptable salt or pharmacy group of therapeutically effective amount
Compound, so as to adjust mutation EGFR.
On the other hand, present invention also offers the side for the treatment of, improvement or prevention to the disease of the EGFR responses of mutation inhibiting
Method, pharmaceutically may be used including at least one formula (I) compound and/or at least one for giving system in need or individual effective dose
The salt or pharmaceutical compositions of acceptance, or be used in combination with another medicine, treat above-mentioned disease.
On the other hand, the invention provides at least one formula (I) compound and/or at least one pharmaceutically acceptable
Salt, for the purposes of the medicine manufacture of the EGFR mediation diseases for the treatment of mutation.The compound can individually or with another curative
Thing is used in combination the EGFR mediation diseases for the treatment of mutation, wherein the disease is autoimmune disease, transplanting disease, infectivity
Disease or cell generation disorders.
Additionally, the invention provides treatment cell proliferative disorders method, the method include give system in need
Or at least one formula (I) compound and/or at least one pharmaceutically acceptable salt or pharmaceutical compositions of individual effective dose, or
It is used in combination with another medicine, treats above-mentioned disease.
Or, the invention provides at least one formula (I) compound and/or at least one pharmaceutically acceptable salt, use
In the purposes of the medicine of manufacture treatment cell proliferative disorders.In a particular embodiment, the compound can individually or with it is another
Medicine is used in combination treatment cell proliferative disorders, wherein the disease includes but is not limited to lymphoma, osteosarcoma, melanocyte
Tumor or mammary gland, kidney, prostate, colorectum, thyroid, ovary, pancreas, neuron, lung, uterus or gastroenteric tumor.
In the said method using compound of the present invention, at least one formula (I) compound and/or at least one medicine
Acceptable salt can be used for the system being made up of cell or tissue, or mammal, such as human or animal experimenter on.
Specific embodiment
Terminology used herein is defined as follows：
" alkyl " refers to the side chain with specific carbon number and straight chain saturated aliphatic hydrocarbons group.It is outer except as otherwise indicating,
" alkyl " refers to C1-C6Alkyl.For example, " C1-C6" C in alkyl "1-C6" refer to the straight of 1,2,3,4,5 or 6 carbon atoms
Line or the group of branch arrangement.For example, " C1-C8Alkyl " include but is not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl,
The tert-butyl group, isobutyl group, amyl group, hexyl, heptyl, octyl group, nonyl and decyl etc..
" cycloalkyl " refers to the representative examples of saturated aliphatic cyclic hydrocarbon group with specific carbon number.The outer, " cycloalkanes except as otherwise indicating
Base " refers to C3-C10Cycloalkyl.For example, " cycloalkyl " includes but is not limited to cyclopropyl, methyl-cyclopropyl, 2,2- dimethyl-ring
Butyl, 2- ethyI-cyclopentyls and cyclohexyl.
" thiazolinyl " is referred to containing 2-10 carbon atom and the non-aromatic straight chain of at least one carbon-carbon double bond, branch or ring-type
Alkyl.In certain embodiments, there is 1 carbon-carbon double bond, up to 4 nonaromatic carbon-carbon double bonds there may be.Therefore,
“C2-6Thiazolinyl " refers to the thiazolinyl containing 2-6 carbon atom.Alkenyl group include but is not limited to vinyl, acrylic, cyclobutenyl,
2- methyl butenes base and cyclohexenyl group.Straight chain, branch or annulus in thiazolinyl may contain double bond, and if indicating replacement alkene
Basis representation its may be substituted.
" alkynyl " is referred to containing 2-10 carbon atom and the straight chain of at least one triple carbon-carbon bonds, branch or cyclic hydrocarbon group.
In some embodiments, there may be 3 triple carbon-carbon bonds.Therefore, " C2-6Alkynyl " refers to the alkynyl containing 2-6 carbon atom.Alkynyl group
Including but not limited to acetenyl, propinyl, butynyl, 3- methylbutynyls etc..Straight chain, branch or annulus in alkynyl can
Three keys can be contained, substituted alkynyl represents that it may be substituted if indicating.
" aryl " includes：5 yuan and 6 yuan of aromatic carbocyclics, such as phenyl；Bicyclic, such as naphthalene of at least one aromatic carbocyclic
Three rings of base, indane and 1,2,3,4- tetrahydroquinolines and at least one aromatic carbocyclic, such as fluorenes.If aryl substituent is bicyclo-
Or three ring and wherein at least to have a ring be non-aromatic ring, then be considered as coupling by aromatic ring.
For example, aryl includes 5 yuan and 6 yuan of aromatic carbocyclics, and these aromatic carbocyclics are selected from N, O and S with containing one or more
Heteroatomic 5-7 circle heterocycles condense, condition be connection site be aromatic carbocyclic.It is being formed by the benzene analog derivative for replacing and
There is the biradical of free valency electron on annular atom, be named as the phenylene free radical for replacing.It is multi-ring derived from monovalence
The biradical that its name of hydrocarbon free radical is ended up with "-yl ", it is gone again on containing free valency carbon atom electronically
Obtained from falling a hydrogen atom, its it is entitled in hydrocarbon radical name plus "-sub- (- idene) ", for example, there is two companies
The naphthyl for connecing site is thus referred to as naphthylene.But the definition of aryl does not include heteroaryl, does not overlap yet, individually define such as
Under.Therefore, if the aromatic ring fusion of one or more aromatic carbocyclics and heterocycle, the ring system for being formed is considered as heteroaryl,
Rather than defined herein aryl.
" halogen " refers to fluorine, chlorine, bromine and iodine.
" heteroaryl " is referred to
5 yuan to 8 yuan of aromatic monocyclic, the ring contains selected from N, O and S, and number is 1 to 4, in certain embodiments for
The hetero atom of 1 to 3, remaining is carbon atom；
8 yuan to 12 membered bicyclics, the ring contains selected from N, O and S, and number is 1 to 4, is in certain embodiments 1 to 3
Individual hetero atom, remaining is carbon atom, and wherein at least one hetero atom is occurred in aromatic ring；With
11 yuan to 14 membered tricyclics.The ring contains selected from N, O and S, and number is 1 to 4, is in certain embodiments 1 to 3
Individual hetero atom, remaining is carbon atom, and wherein at least one hetero atom is occurred in aromatic ring.
When the sum of S in heteroaryl and O is more than 1, these hetero atoms are not adjacent to each other.In certain embodiments, heteroaryl
The sum of S and O is not more than 2 in base.In certain embodiments, the sum of S and O is not more than 1 in heteroaryl.
The example of heteroaryl includes but is not limited to (numbering of connection site is preferential, it is intended that for 1) 2- pyridine radicals, 3- pyridines
Base, 4- pyridine radicals, 2,3- pyrazinyls, 3,4- pyrazinyls, 2,4- pyrimidine radicals, 3,5- pyrimidine radicals, 1- pyrazolyls, 2,3- pyrazolyls,
2,4- imidazolinyl, isoxazolyl, oxazolyls, thiazolyl, thiadiazole base, tetrazole radical, thienyl, benzothienyl, furyl,
Benzofuranyl, benzimidazoline base, indolinyl, pyridizin base, triazolyl, quinolyl, pyrazolyl and 5,6,7,8- tetra-
Hydrogen isoquinoline base.
Further, heteroaryl includes but is not limited to pyrrole radicals, isothiazolyl, triazine radical, pyrazinyl, pyridazinyl, indole
Base, BTA base, quinolizidine morpholine base and isoquinolyl.Such as following definition to heterocyclic radical, " heteroaryl " includes nitrogenous heteroaryl
The N oxidized derivatives of base.
With " base " ending, its derivative biradical is exactly to contain free valency for the name of monovalence heteroaryl free radical
Obtained from removing a hydrogen atom on carbon atom electronically again, the name of the biradical ties up to the name of monovalent radical
Claim to add " sub- (- idene) ", for example：The pyridine radicals for having two connection site are referred to as pyridylidene.The definition of heteroaryl is not wrapped
Containing aryl as defined above, also do not overlap.
If heteroaryl substituent for and bicyclo- or and three rings, and the ring of wherein at least one is nonaromatic or without miscellaneous original
Son, then it has been generally acknowledged that being respectively by aromatic rings or containing the connection of heteroatomic ring.
" heterocycle " (and thus develop such as " heterocycle " or " heterocyclic radical ") refers to single cyclic aliphatic hydrocarbon, generally there is 3
To 12 annular atoms, at least containing 2 carbon atoms, additionally containing the 1-3 hetero atom independently selected from oxygen, sulfur and nitrogen, also refer to
Containing at least one above-mentioned heteroatomic combination.Or, heterocycle defined above is probably polycyclic system (such as bicyclo-), wherein
Two or more rings by condensing or bridging connection, wherein at least one ring contain one or more be independently selected from oxygen,
The hetero atom of sulfur, nitrogen." heterocycle " also refer to 5 yuan and 6 yuan of aromatic carbocyclics condense containing one or more selected from nitrogen, oxygen and sulfur
Heteroatomic 5 yuan to 7 circle heterocycles, condition is connection site on heterocycle.Heterocycle can be saturation or containing one or more pairs
Key (i.e. part is unsaturated).Heterocycle can be replaced by oxo (oxo).Carbon atom or hetero atom on heterocycle can be connection position
Point, on condition that forming a stable structure.When substituted base on heterocycle, the substituent group can be with any miscellaneous original on heterocycle
Son or carbon atom connection, on condition that forming a stable chemical constitution.Heterocycle described herein defines not overlap with heteroaryl.
Suitable heterocycle includes, for example (connection site priority ordering is 1) 1- pyrrolidinyls, 2- pyrrolidinyls, 2,4- miaows
Oxazolidinyl, 2,3- pyrazolidine ketone groups, piperidino, 2- piperidyls, 3- piperidyls, 4- piperidyls and 2,5- piperazinyls.Also include
2- morpholinyls and morpholinyl (oxygen atom Position Number is preferably 1).Heterocycle containing substituent group is also included by one or more oxygen
The ring system that generation replaces, such as piperidyl-N- oxides, morpholinyl-N- oxides, 1- oxo -1- thio-morpholinyls and 1,1- dioxy
Generation -1- thio-morpholinyls.Bis-heterocyclic compounds include, for example：
" aralkyl " used herein refers to the alkyl that aryl replaces.The aralkyl of example includes benzyl, phenethyl and naphthalene
Methyl etc..In some implementations, aralkyl is containing 7-20 or 7-11 carbon atom.As use " aryl C1-4During alkyl ", wherein
“C1-4" refer to the carbon number of moieties rather than aryl moiety.Similarly, as use " aryl C1-10During alkyl ", wherein
“C1-10" refer to the carbon number of moieties rather than aryl moiety.
" cycloheteroalkylalkyl " used herein refers to the alkyl that heterocyclic radical replaces.As use " heterocyclic radical C1-6During alkyl ", its
In " C1-6" refer to the carbon number of moieties rather than heterocyclyl moieties.
" cycloalkyl-alkyl " used herein refers to the alkyl of cycloalkyl substituted.As use " C3-10During cycloalkyl-alkyl ",
Wherein " C3-10" refer to the carbon number of cycloalkyl moiety rather than moieties.As use " C3-7During cycloalkyl-alkyl ", wherein
“C3-7" refer to the carbon number of cycloalkyl moiety rather than moieties.As use " C3-8During cycloalkyl-alkyl ", wherein " C3-8”
Refer to the carbon number of cycloalkyl moiety rather than moieties.When use " cycloalkyl C1-10During alkyl ", wherein " C1-10" refer to
The carbon number of moieties rather than cycloalkyl moiety.
" heteroaryl alkyl " used herein refers to the alkyl that heteroaryl replaces.As use " heteroaryl C1-4During alkyl ", its
In " C1-4" refer to the carbon number of cycloalkyl moiety rather than heteroaryl moieties.Similarly, as use " heteroaryl C1-10Alkyl "
When, wherein " C1-10" refer to the carbon number of moieties rather than heteroaryl moieties.
To avoid ambiguity, for example：When alkyl, cycloalkyl, cycloheteroalkylalkyl, aryl and/or its heteroaryl replacement is mentioned,
Its meaning refers to that each these group individually replaces, or refers to that these group mixing replace.That is,：If R1It is aralkyl, virtue
Base section can be unsubstituted or by least one, and such as 1,2,3 or 4 is independently chosen from R6bSubstituent group replace, alkane
Base section is alternatively unsubstituted or by least one, and such as 1,2,3 or 4 is independently chosen from R6aSubstituent group.
" pharmaceutically acceptable salt " is referred to and pharmaceutically acceptable nontoxic alkali or acid, including inorganic or organic base and
Salt made by inorganic or organic acid.The salt of inorganic base can be selected from, for example：Aluminum, ammonium, calcium, copper, ferrum, ferrous iron, lithium, magnesium, manganese, two
Valency manganese, potassium, sodium, zinc salt.Further, the salt of pharmaceutically acceptable inorganic base may be selected from ammonium, calcium, magnesium, potassium and sodium salt.In solid
One or more crystal structures are there may be in salt, it is also possible to there is the form of hydrate.Pharmaceutically acceptable organic nothing
The salt of malicious alkali may be selected from, for example：Primary amine, secondary amine and tertiary ammonium salt, replace replacement amine, cyclammonium and the alkalescence of amine including naturally occurring from
Sub-exchange resin such as arginine, glycine betaine, caffeine, choline, N, N- dibenzyl-ethylenediamins, diethylamine, 2-diethylaminoethanol,
DMAE, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, group ammonia
Acid, Hai Baming amine, 2-aminopropane., lysine, methylglucamine, morpholine, piperazine, piperidines, many polyimide resins, procaine, purine, cocoa
Alkali, triethylamine, trimethylamine and tripropyl amine (TPA), trometamol.
When this patent indication compound is alkali, needs prepare its salt with least one pharmaceutically acceptable non-toxic acid,
These acid are selected from inorganic and organic acid.For example, selected from acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethane sulfonic acid,
Fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methane sulphur
Acid, glactaric acid, nitric acid, flutter acid, pantothenic acid, phosphoric acid, succinic acid, sulphuric acid, tartaric acid and p-methyl benzenesulfonic acid.In certain embodiments, may be used
These acid are selected, for example：Citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulphuric acid, fumaric acid and tartaric acid.
" protection group " (Pg) refer to a class for other functional group reactionses on compound and intercept or protect particular functional
The substituent group of group.For example, " amino protecting group " refers to be connected on amino and intercepts or protect amido functional group on compound to take
Dai Ji.Suitable amido protecting group include acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and
9-fluorenylmethyloxycarbonyl (Fmoc).Equally, " hydroxyl protecting group " refers to that a class hydroxyl substituent can effectively stop or protect hydroxyl work(
Energy.Appropriate protection group includes but is not limited to acetyl group and silylation." carboxyl-protecting group " refers to that a class carboxyl substituent can have
Effect stops or protects the function of carboxyl.Conventional carboxyl-protecting group includes but is not limited to-CH2CH2SO2Ph, cyanoethyl, 2- (front three silicon
Base) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfenyl) ethyl, 2-
(diphenylphosphine)-ethyl and nitro-ethyl etc..For the general description and operation instruction of protection group, T.W.Greene is seen,
Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991。
" giving " or " administration " of at least one compound and/or its at least one pharmaceutically acceptable salt is referred to need
The individual compound or its pharmaceutically acceptable salt provided in the present invention to be treated.
" effective dose " refers to that target compound or its pharmaceutically acceptable salt can cause tissue, system, animal or people
Class occur can biology for observing of studied personnel, veterinary, clinician or other clinical staffs or medical response dosage.
" compositionss " include：The product of the special component comprising specified quantitative, and any directly or indirectly these specified quantitatives
Special component the product for combining.Pharmaceutical compositions are included：Comprising effective ingredient and the inert fraction as carrier
Product, and any two or plural composition are directly or indirectly, product made by by combination, compound or aggregation,
Or the product produced by one or more ingredient breakdown, or by one or more compositions occur other types reaction or
Interact the product for producing.
" pharmaceutically acceptable " refer to it is compatible with other components in preparation, and to user without unacceptable murder by poisoning.
1. the present invention provides the compound shown at least one formula (I)：
And/or its at least one pharmaceutically acceptable salt,
Wherein：
Q is selected from aryl and heteroaryl；
X is selected from N and C；
Y is selected from N and C；
R1It is selected from：Hydrogen, C1-10Alkyl, C3-10Cycloalkyl, C3-10Cycloalkyl-C1-4Alkyl, heterocyclic radical and heterocyclic radical-C1-4Alkane
Base, wherein each alkyl, cycloalkyl and heterocyclic radical are unsubstituted or by least one, such as 1,2,3 or 4, are independently selected from
R6aSubstituent group replace；
R1’Selected from hydrogen and halogen；
R2And R3It is respectively selected from：Hydrogen, halogen, hydroxyl, CN, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, C3-10Cycloalkyl,
C3-10Cycloalkyl-C1-4Alkyl, heterocyclic radical, heterocyclic radical-C1-4Alkyl, aryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4
Alkyl, wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl and heterocyclic radical are unsubstituted or by least one, such as 1,2,3 or 4
It is individual, it is independently selected from R6aSubstituent group replace, wherein each aryl and heteroaryl are unsubstituted or by least one, such as 1,2,
3 or 4, it is independently selected from R6bSubstituent group replace；Or R2And R3One is cooperatively constituted together with the carbon atom being connected with them
Containing 0,1,2 or 3 heteroatomic 5-6 yuan of rings for being independently selected from oxygen, sulfur and nitrogen, the ring can be unsubstituted or by 1 or 2
Selected from R6aSubstituent group replace；
Each R4Independently selected from：Hydrogen, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, C3-10Cycloalkyl ,-OR8、-NR7S(O)rR8、-NO2,-halogen ,-S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC
(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8With-CR7(N-OR8)；Wherein each C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynes
Base and C3-10Cycloalkyl is unsubstituted or by least one, such as 1,2,3 or 4, is independently selected from R6aSubstituent group replace；
Each R5Independently selected from：Hydrogen, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, C3-10Cycloalkyl, C3-10Cycloalkyl-
C1-4Alkyl, heterocyclic radical, heterocyclic radical-C1-4Alkyl, aryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl ,-OR8、-
NR7S(O)rR8、-NO2, halogen ,-S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-O
(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)
R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8With-CR7(N-OR8), wherein each C1-10Alkyl, C2-10Thiazolinyl,
C2-10Alkynyl, C3-10Cycloalkyl and heterocyclic radical are unsubstituted or by least one, such as 1,2,3 or 4, are independently selected from R6a's
Substituent group replaces；Each aryl and heteroaryl are unsubstituted or by least one, such as 1,2,3 or 4, are independently selected from R6b's
Substituent group replaces；
Each R6aIndependently selected from：C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, C3-10Cycloalkyl ,-OR8、-NR7S(O)rR8、-NO2, halogen ,-S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-
(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-
(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O
(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)
(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC
(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8With-CR7(N-OR8)；
Each R6bIndependently selected from：R6a, aryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl；
Each R7With each R8Independently selected from：Hydrogen, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, cycloalkyl, cycloalkyl-
C1-4Alkyl, heterocyclic radical, heterocyclic radical C1-4Alkyl, aryl, heteroaryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl；
Wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl and heterocyclic radical are unsubstituted or by least one, such as 1,2,3 or 4, solely
It is vertical to be selected from R6aSubstituent group replace, wherein each aryl and heteroaryl are unsubstituted or by least one, such as 1,2,3 or 4
It is individual, it is independently selected from R6bSubstituent group replace；Or R7And R8Collectively form together with the single or multiple atoms being connected with them together
One containing 0,1 or 2 extra heteroatomic 4-12 circle heterocycles for being independently selected from oxygen, sulfur and N, the ring can be unsubstituted
Or by 1 or 2 be selected from R6bSubstituent group replace；
Each R9With each R10Independently selected from：Hydrogen, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, cycloalkyl, cycloalkyl-
C1-4Alkyl, heterocyclic radical, heterocyclic radical-C1-4Alkyl, aryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl；Or R9With
R10Collectively form together with the single or multiple carbon atoms being connected with them together and be independently selected from oxygen, sulfur and nitrogen containing 0,1 or 2
Heteroatomic 3-7 yuan of rings, the ring can be selected from R by 1-26aSubstituent group replace；
M is independently selected from 0,1,2 and 3；
N is independently selected from 0,1,2 and 3；
Each r is independently selected from 1 and 2；
Each t is independently selected from 1,2 and 3.
2. at least one compound in 1, and/or its at least one pharmaceutically acceptable salt, wherein X is selected from N and C,
Y is selected from C.
3. the compounds of any one of 1-2 at least one, and/or its at least one pharmaceutically acceptable salt, wherein X choosings
From in N, Y is selected from C.
4. at least one compound of any one of 1-2, and/or its at least one pharmaceutically acceptable salt, wherein X
All it is C with Y, also,
N=2, a R5It is (3R) -3- (dimethylamino) pyrroles -1- bases, (3S) -3- (dimethylamino) pyrroles -1- bases, 3-
(dimethylamino) azetidin -1- bases, [2- (dimethylamino) ethyl]-(methyl) amino, [2- (methylamino) ethyl] (methyl)
Amino, 5- methyl -2,5- diaza spiros [3.4] certain herbaceous plants with big flowers -2- bases, (3aR, 6aR) -5- six-hydrogen of methyl-pyrroles [3,4-b] pyrroles -1
(2H)-base, 1- methyl isophthalic acids, 2,3,6- tetrahydropyridine -4- bases, 4- methylpiperazine-1-yls, 4- [2- (dimethylamino) -2- oxygen second
Base] piperazine -1- bases, methyl [2- (4- methylpiperazine-1-yls) ethyl] amino, methyl [2- (morpholine -4- bases) ethyl] amino, 1-
Amino -1,2,3,6- tetrahydropyridine -4- bases or 4- [(2S) -2- aminopropionyls] piperazine -1- bases, another R5For methoxyl group or
Methyl,
R1、R1’And R2For hydrogen, and R3For hydrogen, fluorine, chlorine, methyl or cyano group when,
Q be not 4,5,6,7- nafoxidines [1,5-a] pyridin-3-yl, pyrazoles [1,5-a] pyridin-3-yl or 1H- indole-
3- bases..
5. at least one compound of any one of 1-4, and/or its at least one pharmaceutically acceptable salt, wherein leading to
Formula is
6. at least one compound of any one of 1-5, and/or its at least one pharmaceutically acceptable salt, wherein R1’
Selected from hydrogen.
7. at least one compound of any one of 1-5, and/or its at least one pharmaceutically acceptable salt, wherein R1’
Selected from fluorine.
8. at least one compound of any one of 1-7, and/or its at least one pharmaceutically acceptable salt, wherein R1
Selected from hydrogen.
9. at least one compound of any one of 1-8, and/or its at least one pharmaceutically acceptable salt, wherein R2
Selected from hydrogen.
10. at least one compound of any one of 1-9, and/or its at least one pharmaceutically acceptable salt, wherein
R3Selected from hydrogen, halogen and C1-10Alkyl.
11. 10 at least one compound, and/or its at least one pharmaceutically acceptable salt, wherein R3Selected from hydrogen.
At least one compound of any one of 12. 1-11, and/or its at least one pharmaceutically acceptable salt, wherein
Q is selected from heteroaryl.
13. 12 at least one compound, and/or its at least one pharmaceutically acceptable salt, wherein Q is selected from
At least one compound of any one of 14. 1-13, and/or its at least one pharmaceutically acceptable salt, wherein
R4Selected from hydrogen, C1-10Alkyl, halogen and cyano group, wherein C1-10Alkyl is unsubstituted or by least one, such as 1,2,3 or 4
It is individual, it is independently selected from R6aSubstituent group replace.
15. 14 at least one compound, and/or its at least one pharmaceutically acceptable salt, wherein R4Selected from hydrogen,
Methyl, halogen and cyano group, wherein methyl are unsubstituted or are independently selected from R by least one6aSubstituent group replace, preferably
R6aFor fluorine.
At least one compound of any one of 16. 1-15, and/or its at least one pharmaceutically acceptable salt, wherein
R5It is independently selected from OR8, heterocyclic radical, NR7R8, wherein heterocyclic radical is unsubstituted or by least one, such as 1,2,3 or 4, solely
It is vertical to be selected from R6aSubstituent group replace.
17. 16 at least one compound, and/or its at least one pharmaceutically acceptable salt, wherein R5It is independently selected from
Methoxyl group, ethyoxyl, isopropoxy, piperazine -1- bases, 4- methylpiperazine-1-yls, methyl (2- (methylamino) ethyl) amino, (2-
(dimethylamino) ethyl) (methyl) amino, (2- (ethyl) (methyl) amino) ethyl) (methyl) amino and (methyl (2- (N- first
Yl acetamide base) ethyl) amino).
18. at least one compounds are selected from：
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (6- methoxyl group -2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (ethyl (methyl) amino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl isophthalic acid H-
Indol-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (6- methoxyl group -2- (methyl (2- (N- methylacetamidos) ethyl) amino) -5- ((4- (1- methyl isophthalic acid H- Yin
Diindyl -3- bases) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (6- ethyoxyl -2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- ethyoxyl -5- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (6- isopropoxy -2- (methyl (2- (N- methylacetamidos) ethyl) amino) -5- ((4- (1- methyl isophthalic acid H-
Indol-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- isopropoxy -5- ((4- (1- Methyl-1H-indoles -
3- yls) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (piperazine -1- bases)
Pyridin-3-yl) acrylamide,
N- (6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (4- methyl piperidines -
1- yls) pyridin-3-yl) acrylamide,
N- (6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (piperidin-1-yl)
Pyridin-3-yl) acrylamide,
N- (6- ethyoxyl -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (4- methyl piperidines -
1- yls) pyridin-3-yl) acrylamide,
N- (6- isopropoxy -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (piperidines -1-
Base) pyridin-3-yl) acrylamide,
N- (6- isopropoxy -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (4- methyl piperazines
Pyridine -1- bases) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-)
Pyrimidine -2-base) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 6-)
Pyrimidine -2-base) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-)
Pyrimidine -2-base) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 4-)
Pyrimidine -2-base) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((the fluoro- 4- of 5- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) second
Base) (methyl) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((5- methyl -4- (1- methyl isophthalic acid H-
Indol-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (3- ((2- (dimethylamino) ethyl) (methyl) amino) -5- methoxyl group -6- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridine -2- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) phenyl) -2- fluoropropene amide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl indolizine -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl indolizine -3- bases)
Pyrimidine -2-base) amino) phenyl) acrylamide,
N- (5- ((4- (1- cyano group indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (1- cyano group indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -4- methoxyphenyls) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizine -3- bases) pyrimidine -2-base) amino) -
6- methoxypyridine -3- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizine -3- bases) pyrimidine -2-base) amino) -
4- methoxyphenyls) acrylamide,
N- (5- ((4- (1- chlorine indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (1- chlorine indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -4- methoxyphenyls) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- methyl indolizine -1- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- methyl indolizine -1- bases)
Pyrimidine -2-base) amino) phenyl) acrylamide,
N- (5- ((4- (3- cyano group indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (3- cyano group indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -4- methoxyphenyls) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizine -1- bases) pyrimidine -2-base) amino) -
6- methoxypyridine -3- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizine -1- bases) pyrimidine -2-base) amino) -
4- methoxyphenyls) acrylamide,
N- (5- ((4- (3- chlorine indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (3- chlorine indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -4- methoxyphenyls) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- Methyl-1H-indole -1-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- Methyl-1H-indole -1-
Base) pyrimidine -2-base) amino) phenyl) acrylamide,
N- (6- methoxyl group -5- ((4- (3- Methyl-1H-indole -1- bases) pyrimidine -2-base) amino) -2- (4- methyl piperazines -
1- yls) pyridin-3-yl) acrylamide,
N- (4- methoxyl group -5- ((4- (3- Methyl-1H-indole -1- bases) pyrimidine -2-base) amino) -2- (4- methyl piperazines -
1- yls) phenyl) acrylamide,
N- (5- ((4- (3- cyano-1 H-indol -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl)
(methyl) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (3- cyano-1 H-indol -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl)
(methyl) amino) -4- methoxyphenyls) acrylamide,
N- (5- ((4- (1- chlorine imidazoles [1,5-a] and pyridin-3-yl) pyrimidine -2-base) amino) -2- ((2- (dimethylamino)
Ethyl) (methyl) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (1- chlorine imidazoles [1,5-a] and pyridin-3-yl) pyrimidine -2-base) amino) -2- ((2- (dimethylamino)
Ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- (trifluoromethyl) imidazoles
[1,5-a] and pyridin-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- (trifluoromethyl) imidazoles
[1,5-a] and pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methylimidazole .s [1,5-a]
And pyridin-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- (Methylimidazole. [1,5-
A] and pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methylimidazole .s [1,5-a]
And pyridin-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide,
N- (5- ((4- (1,2- pyrrolin [3,2,1-hi] indole -5- bases) pyrimidine -2-base) amino) -2- ((2- (diformazans
Amino) ethyl) (methyl) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (1,2- pyrrolin [3,2,1-hi] indole -5- bases) pyrimidine -2-base) amino) -2- ((2- (diformazans
Amino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- methyl isophthalic acid H- indazole -1-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- methyl isophthalic acid H- indazole -1-
Base) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl isophthalic acid H- indazole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl isophthalic acid H- indazole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- Methylimidazole .s [1,5-a]
And pyridine -1- bases) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- Methylimidazole .s [1,5-a]
And pyridine -1- bases) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide,
With its pharmaceutically acceptable salt.
On the other hand, the invention provides a kind of medicine group for including any one compound at least one 1-18
Close and its pharmaceutically acceptable salt, wherein the route of administration of compositionss include oral, parenteral, intraperitoneal, intravenous injection,
Intra-arterial injection, transdermal, Sublingual, intramuscular, rectum, oral cavity, intranasal, liposome, via suction, vagina, ophthalmic, are administered by local
(such as by conduit or support), subcutaneous, fatty interior, intraarticular or intrathecal.
On the other hand, the invention provides comprising a compound at least one above-mentioned 1-18 and its pharmaceutically may be used
The medicine box of the salt of acceptance；And including the description of following one or more information：Compositionss are applied to which kind of disease, compositionss
Storage information, dosage information and how using the explanation of compositionss.In a special change, medicine box includes multiple dose form
Compound.
On the other hand, the invention provides comprising a compound at least one above-mentioned 1-18 and its pharmaceutically may be used
The product of the salt of acceptance；And packaging material.In a kind of change, packaging material include a container.In a special change
In, tell that container includes label, it indicates one or more herein below：Compound is applied to which kind of disease, storage information, agent
Amount information and/or how using the explanation of compositionss.In another kind of change, product includes the compound of multiple dose form.
On the other hand, the invention provides a kind of Therapeutic Method, comprising giving at least one 1-18 to certain individuality
Any one compound and its pharmaceutically acceptable salt.
On the other hand, the invention provides a kind of any one compound and its pharmacy by least one 1-18
The method that upper acceptable salt acts on the EGFR so as to mutation inhibiting with the EGFR of mutation.
On the other hand, the invention provides a kind of method of the EGFR of mutation inhibiting, including making at least one 1-18
Any one compound and its pharmaceutically acceptable salt occur in certain in vivo, to suppress the activity of EGFR of vivo mutations
Method.
On the other hand, the invention provides a kind of method for treating morbid state, the activity of EGFR of mutation causes this
The pathology and/or symptom of disease, the method comprising make any one compound at least one 1-18 of therapeutically effective amount and
Its pharmaceutically acceptable salt occurs in certain individuality in vivo, improves its morbid state.
In the change of above-mentioned each method, morbid state is selected from：Carcinous proliferative disease (for example brain, lung, squamous cell,
Bladder, stomach, pancreas, mammary gland, head, neck, kidney, ovary, prostate, colon, epidermis, esophagus, testis, gynecological or thyroid carcinoma)；It is non-
Carcinous proliferative disease (such as benign cutaneous hypertrophy (such as psoriasises), restenosiss and benign prostatauxe (BPH))；Pancreas
It is scorching；Kidney disease；Pain；Blastocyte is prevented to be implanted into；Treatment and blood vessel generation or angiogenesis-associated diseases (such as tumor vessel
Generate, acute and chronic infectious disease such as rheumatoid arthritiss, atherosclerosiss, inflammatory bowel, dermatosiss such as silver is considered to be worth doing
Disease, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, senile degeneration of macula, blood
Tuberculation, glioma, melanoma, Kaposi's sarcoma and ovarian cancer, breast carcinoma, pulmonary carcinoma, cancer of pancreas, carcinoma of prostate, knot
Intestinal cancer and epidermoid carcinoma)；Asthma；Neutrophil chemotaxis (for example, the reperfusion injury of myocardial infarction and apoplexy and struvite
Arthritis)；Septic shock；The disease that T cell is connected to, wherein immunosuppressant are very valuable (such as prevention of organ transplant rejection, shifting
Graft versus host disease, systemic lupus erythematosus (sle), multiple sclerosiss and rheumatoid arthritis)；Atherosclerosiss；Suppress to growth
The horn cell of factor cocktails reaction；Chronic obstructive pulmonary disease (COPD) and other diseases.
On the other hand, the invention provides a kind of method for treating morbid state, the EGFR genetic mutation of mutation is caused
The pathology and/or symptom of the disease, such as melanoma, pulmonary carcinoma, colon cancer and other types tumor.
On the other hand, the present invention relates to any one compound at least one 1-18 and its pharmaceutically acceptable
Purposes of the salt as medicine.On the other hand, the present invention relates to any one compound and its pharmacy at least one 1-18
Purposes of the upper acceptable salt as the EGFR drug manufacture of mutation inhibiting.
On the other hand, the present invention relates to any one compound at least one 1-18 and its pharmaceutically acceptable
The production of pathology and/or the medicine of the morbid state of symptom that salt is caused as the activity of EGFR for the treatment of mutation.
Administration and pharmaceutical compositions
Usually, compound of the present invention will be with therapeutically effective amount via any known in the art common and acceptable
Mode, individually or share administration with one or more medicines.Therapeutically effective amount can be with widely varied, depending on experimenter
Disease severity, age and relative health, the drug effect of compound used therefor and other general technical ability known in the art.
For example, for the treatment of neoplastic disease and disease of immune system, required dosage will be according to mode of administration, concrete disease to be treated
Disease and desirable effect and it is different.
Usually, satisfied result is can reach when daily dosage is 0.001 to 100mg/kg body weight, specifically, from about
0.03 to 2.5mg/kg body weight.The daily dose of relatively large mammal, the such as mankind, from about 0.5mg to about 2000mg, or can have more
For body, from 0.5mg to 1000mg, with the administration of convenient form, for example, with divided dose at most four times a day or with slow release shape
Formula.The unit dosage form of suitable oral administration includes about 1 to 50mg active component.
Compound of the present invention can be administered in pharmaceutical compositions form, be administered by any conventional route；Such as Jing
Intestinal, for example orally, for example in the form of tablets or capsules, parenteral, such as with Injectable solution or suspension formation；Or local is given
Medicine, such as with lotion, gel, ointment or ointment, or with nose or suppository form.
It is pharmaceutically acceptable with least one containing the compound with free alkali or pharmaceutically acceptable salt form of the present invention
Carrier or diluent pharmaceutical compositions, can in a usual manner pass through mixing, granulation, coating, dissolving or lyophilization flow process
To manufacture.For example, pharmaceutical compositions include a compound of the present invention and at least one pharmaceutical acceptable carrier or dilution
Agent is combined, can in a usual manner by being mixed with pharmaceutical acceptable carrier or diluent.For oral unit dose
Form is included, for example, the active substance from about 0.1mg to about 500mg.
In one embodiment, pharmaceutical compositions are the solution of active component, comprising suspensoid or dispersion, such as isotonic water
Solution.In the case of the freeze-dried composition for only including active component or mixing with the carrier of such as Mannitol, dispersion or suspension
Liquid can be using front being supplemented.Pharmaceutical compositions can be sterilized and/or contain adjuvant, such as preservative, stabilizer, wetting agent
Or emulsifying agent, dissolution accelerator, the salt of regulation osmotic pressure and/or buffer agent.Suitable preservative includes but are not limited to antioxygen
Agent such as ascorbic acid, such as microbicide, sorbic acid or benzoic acid.Solution or suspension can also include viscosifier, including
But it is not limited only to sodium carboxymethyl cellulose, carboxymethyl cellulose, glucosan, polyvinylpyrrolidone, gelatin, or solubilizing agent, example
Such as Tween 80 (Polyethylene oxide (20) sorbitan monooleate).
Suspension may include the vegetable oil as oil components, synthesis or semisynthetic oil in oil, be usually used in injection
Purpose.Embodiment include containing as acid constituents with 8 to 22 carbon atoms, or in some embodiments, from 12 to 22
The liquid aliphatic acid esters of the long-chain fatty acid of individual carbon atom.Suitable liquid aliphatic acid esters include but is not limited to lauric acid, 13
Alkanoic acid, myristic acid, pentadecanoic acid, Palmic acid, heptadecanoic acid, stearic acid, arachidic acid, behenic acids or corresponding unsaturated acids,
Such as Oleic acid, elaidic acid, erucic acid, brassidic acid and linoleic acid, if it is desired, can contain antioxidant, such as Vitamin E,
3- carotene or 3,5- di-t-butyl hydroxy-methylbenzenes.The alkoxide component of these fatty acid esters can have six carbon atom, and
Can be unit price or multivalence, such as the alcohol of single -, two-or three valency.Suitable alkoxide component include but is not limited to methanol, ethanol, third
Alcohol, butanol or amylalcohol or its isomer, ethylene glycol and glycerol.
Other suitable fatty acid esters include but is not limited to ethyl oleate, isopropyl myristate, isopropyl palmitate,M2375 (polyoxyethylene glycerol),M1944CS is (by the unsaturated poly- second of alcoholysis almond oil
Diolation glyceride and containing glyceride and macrogol ester), LABRASOLTM(the saturation Polyethylene Glycol prepared by alcoholysis TCM
Change glyceride and comprising glyceride and macrogol ester；Can obtain from French GaKefosse companies), and/or812 (the saturated fat acid glycerol three esters of a length of C8 to C12 of chain of German H ü ls AG companies), and vegetable oil
Such as Oleum Gossypii semen, almond oil, olive oil, Oleum Ricini, Oleum sesami, Oleum Glycines or Oleum Arachidis hypogaeae semen.
Pharmaceutical composition for oral administration can be by, for example, by by active component and one or more solid
Carrier mixes, if it is desired, the mixture obtained by granulating, and by add other excipient process the mixture or
Grain, with form tablet or label.
Suitable carrier includes but is not limited to filler, for example sugar, such as Lactose, sucrose, Mannitol or Sorbitol, fiber
Plain preparation and/or calcium phosphate, such as tricalcium phosphate or calcium hydrogen phosphate, and also binding agent, such as starch, such as Semen Maydiss, Semen Tritici aestivi,
Rice or potato starch, methylcellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidine
Ketone, and/or, if desired, disintegrating agent, such as above-mentioned starch, carboxymethyl starch, crospolyvinylpyrrolidone, alginic acid or
Its salt, such as sodium alginate.Other excipient includes flowing regulator and lubricant, such as silicic acid, Pulvis Talci, stearic acid or its
Salt, such as magnesium stearate or calcium stearate, and/or Polyethylene Glycol, or derivatives thereof.
Can provide suitably for tablet cores, the coating of optional enteric, by using particularly, the sugar juice of concentration, its
May include Radix Acaciae senegalis, Talcum, polyvinylpyrrolidone, Polyethylene Glycol and/or titanium dioxide, or honor is suitable organic molten
Agent or the coating solution of solvent mixture, or, for enteric coating, suitable cellulosicss, such as acetylcellulose neighbour's benzene two
The preparation of formic acid esters or hydroxypropylmethyl cellulose phthalate solution.Dyestuff or pigment can add tablet or tablet bag
In clothing, such as recognition purpose or the active component of instruction various dose.
Pharmaceutical composition for oral administration can also include hard capsule, including gelatin or containing gelatin and plasticizer,
Such as glycerol or the soft seal capsule of Sorbitol.Hard capsule can the granule containing active component form, for example with filler such as
Corn starch, binding agent and/or fluidizer such as Pulvis Talci or magnesium stearate, and optional stabilizer mixing.It is living in soft capsule
Property composition can dissolve or be suspended in suitable liquid excipient such as fatty oil, paraffin oil or liquid macrogol or ethylene glycol
Or in the fatty acid ester of Propylene Glycol, stabilizer and detergent thereto, the fatty acid ester type of such as polyoxyethylene sorbitol,
Can add.
Suitable for the pharmaceutical composition of rectally, such as suppository, it includes the combination of active component and suppository base.Close
Suitable suppository base is, for example, naturally occurring or synthetic triglyceride, paraffin hydrocarbon, Polyethylene Glycol or higher alkanols.
Being suitable to the pharmaceutical composition of parenteral can include the active component of water-soluble form, such as water soluble salt or bag
Aqueous injectable suspensions containing the material for increasing viscosity, such as sodium carboxymethyl cellulose, the aqueous solution of Sorbitol and/or Portugal are poly-
Sugar, if it is desired, and stabilizer.By active component, optionally with excipient, or in a cryodesiccated form,
And can be before parenterai administration by adding solution made by suitable solvent.The solution for using, for example, for gastrointestinal
External administration, it is also possible to as infusion solution.The preparation of ejection preparation generally aseptically, is filled into, for example, ampoule or little
In bottle, and the container of sealing.
Compound of the present invention can as unique active component, or with other immunomodulatory treatments it is useful or
The useful medicine of antitumor activity disease is administered together.For example, compound of the present invention with to the effective medicine of above-mentioned various diseases
Learn compositionss to be used together, it is, for example possible to use compound of the present invention and cyclophosphamide, 5-fluorouracil, fludarabine,
Gemcitabine, cisplatin, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituximab list
Anti-, doxorubicin, gefitinib or imatinib；Or also with cyclosporin, rapamycin, ascosin or their immunity
Inhibitory analogues, such as cyclosporin A, CYCLOSPORIN G, FK-506, sirolimuss and everolimuses, glucocorticoid, such as：Sprinkle
Buddhist nun pine, cyclophosphamide, azathioprine, methotrexate, gold salt, sulfasalazine, antimalarial, brequinar, leflunomide, imidazoles stand
Guest, Mycophenolic Acid, Mycophenolic Acid, phenols acids and 15- deoxyspergualins, such as immunosuppressant monoclonal antibody, monoclonal anti
Body leukocyte receptors, such as MHC, CD2, CD3, CD4, CD7, CD25, CD28, I CD40, CD45, CD58, CD80, CD86,
CD152, CD137, CD154, ICOS, LFA-1, VLA-4 or their part, or other immunomodulatory compounds, for example
CTLA41g。
Present invention also offers drug regimen, such as a kind of medicine box, it a) be compound disclosed in this invention that it is included, can
Think free form or pharmaceutically acceptable salt form, and b) at least one co-drug.The medicine box can be used comprising it and said
Bright book.
Embodiment
Compound or its at least one pharmaceutically acceptable salt synthetic method have various, and what is included in this example is tool
Representational method.It should be noted, however, that the compound of at least one Formulas I or it is at least one pharmaceutically acceptable
Salt is likely to be obtained by the synthesis of other synthetic routes.
In certain compound of formula (I), the connection between atom and other atoms may cause the presence of special stereoisomerism
Body (such as chiral centre).Synthesizing the compound or its at least one pharmaceutically acceptable salt of at least one formula (I) may produce not
The mixture of same isomer (enantiomer, diastereomer).It is unless stated otherwise certain specific spatial configuration, institute
The compound enumerated includes its different stereoisomer that may be present.
The compound of at least one formula (I) can also make the acid-addition salts of pharmaceutical acceptable, for example, by by the present invention
The form of the free alkali of compound and pharmaceutically acceptable inorganic or organic acid reaction.Or by the chemical combination of at least one formula (I)
Thing in the form of free acid with pharmaceutically acceptable inorganic or organic alkali reaction, be made into pharmaceutically acceptable base addition salts.
It is suitable for the inorganic and organic bronsted lowry acids and bases bronsted lowry of pharmaceutically acceptable salt of preparation formula (I) compound in the definitional part of this specification
It is described.Additionally, the form of formula (I) compound salt can also be prepared by using the salt of initiation material or intermediate.
The free acid or free alkali of formula (I) compound can be prepared into by its corresponding base addition salts or acid-addition salts
Arrive.The acid addition salt form thereof of formula (I) compound can change into corresponding free alkali, for example by with suitable alkali (such as hydroxide
Ammonium salt solution, sodium hydroxide etc.) process.The addition salt forms of formula (I) compound can be converted into corresponding free acid, for example, pass through
Processed with suitable acid (such as hydrochloric acid).
The N- oxides of the compound of at least one formula (I) or its at least one pharmaceutically acceptable salt can pass through this area
Known method is obtained.For example, N- oxides can be by the condition by the non-oxidised form of formula (I) compound at close 0 DEG C
Lower and oxidant (such as trifluoro peracetic acid, peroxy maleic acid, benzoyl hydroperoxide, peracetic acid and metachloroperbenzoic acid) exists
Reaction in inert organic solvents (such as dichloromethane halogenated hydrocarbon) is obtained.Alternatively, the N- oxides of formula (I) compound also can lead to
The N- oxides for crossing initiation material are prepared.
The compound of formula I of non-oxidised form can by by its N- oxide and reducing agent (such as sulfur, sulfur dioxide, triphenyl
Phosphine, lithium borohydride, sodium borohydride, Phosphorous chloride. and phosphorus tribromide etc.) it is organic molten in corresponding inertia under conditions of 0～80 DEG C
Reaction in agent (such as acetonitrile, ethanol and hydration dioxane) is obtained.
The protection derivant of compound of formula I can be prepared by method well known in the art.With regard to protection group
Group addition and removal detailed technology description referring to：T.W.Greene,Protecting Groups in Organic
Synthesis,3rd edition,John Wiley&Sons,Inc.1999。
Mark and general knowledge used in these reactions, chart is consistent with existing scientific literature with example, for example,
Journal of the American Chemical Society or journal of biological chemistry.Unless otherwise stated, the single-letter of standard or triliteral abbreviation is often referred to L
Type amino acid residue.Unless otherwise stated, all initiation materials for using can buy commercially available from market supply, when using not
It is further purified.For example, following abbreviation can be used in example and entire disclosure：G (gram), mg (milligram), L (liter), mL (millis
Rise), μ L (microlitre), psi (pound per square inch), M (mole), mM (mM), i.v. (intravenous injection), Hz (hertz), MHz
(megahertz), mol (mole), mmol (mM), RT (ambient temperature), min (minute), h (hour), mp (fusing point), TLC are (thin
Layer chromatography), Rr (retention time), RP (anti-phase), MeOH (methanol), i-PrOH (isopropanol), TEA (triethylamine), TFA (three
Fluoroethanoic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), DME
(1,2- dimethyl ether), DCM (dichloromethane), DCE (dichloroethanes), DMF (DMF), DMPU (N, N- diformazans
Base acrylic urea), CDI (1,1- carbonyl dimidazoles), IBCF (isobutyl chlorocarbonate), HOAc (acetic acid), HOSu (N- hydroxysuccinimidyls
Acid imide), HOBT (1- hydroxy benzo triazoles), Et2(1- (3- dimethylaminopropyls) 3- ethyls carbon is sub- for O (ether), EDCI
Amine hydrochlorate), BOC (tertbutyloxycarbonyl), FMOC (9- fluorenylmethyloxycarbonyls), DCC (dicyclohexylcarbodiimide), CBZ (Bian oxygen
Carbonyl), Ac (acetyl group), atm (atmospheric pressure), TMSE (2- (trimethylsilyl) ethyl), TMS (trimethylsilyl), TIPS (three isopropyls
Base silane), TBS (tert-butyl group dimethyl silyl), DMAP (dimethyl aminopyridine), Me (methyl), OMe (methoxyl group), Et (second
Base), tBu (tert-butyl group), HPLC (high performance liquid chromatography), BOP (double (2- oxo -3- oxazolidinyl) secondary phosphoryl chloride phosphorus oxychloride), TBAF
(tetrabutyl ammonium fluoride), mCPBA (metachloroperbenzoic acid).
Ether or Et2O each means ether；Saline then refers to saturation NaCl aqueous solution.Unless otherwise stated, all of temperature is equal
Refer to a DEG C temperature (degree Celsius), all of reaction is reacted in inert atmosphere at room temperature.
1H H NMR spectroscopies are recorded using the nuclear magnetic resonance spectrometers of Bruker Avance 400.Chemical shift is to be represented with ppm.
Coupling constant (Hz) in units of hertz.Apparent multiformity is described with Fractionation regimen, and is set to s (unimodal), d (bimodal), t
(triplet), q (quartet), m (multiplet) and br (general peak)
Low Resolution Mass Spectra (MS) and compound purity data from Waters ZQ LC-MS chromatographs one pole lever system,
The system is equipped with electron spray ion detector (ESI), ultraviolet detector (220 and 254nm) and evaporative light scattering detector
(ELSD).Thin layer chromatography uses the silica gel plate (60F-254) of 0.25mmE.Merck companies, and 5% phosphomolybdic acid ethanol is molten
Liquid, 1,2,3-indantrione monohydrate or p- Oxybenzenes based sols are simultaneously observed under uviol lamp.Rapid column chromatography use silica gel (230-400 mesh,
Merck companies).
Synthetic route
At least one formula (I) compound and/or its at least one pharmaceutically acceptable salt can be synthesized by distinct methods, and one
A little illustrative methods provide following and embodiment.Other synthetic methods can be by those skilled in the art according to the letter of present disclosure
Breath is easily proposed by.
It may be necessary to protecting to reactive group in all reactions as described below, in case these active groups participate in it
Its undesirable reaction：These groups for example hydroxyl, amino, imido grpup, containing sulfydryl or carboxyl, in final product contain these bases
Group.Conventional blocking group refers to T.W.Greene and P.G.M.Wuts in " Protective Groups in
Organic Chemistry"John Wiley and Sons,1991。
The synthetic route of all compounds of the present invention is illustrated by following route and embodiment.Initiation material source used
In commercial goods or can according to existing process or herein example method prepare.
Intermediate listed by figure below is obtained according to document, or according to existing similar synthetic method synthesis.
The compound of formula I of the present invention can be prepared by route shown in Fig. 1.Formula III intermediate passes through with formula IV amino aromatic hydrocarbons
Other amination conditions that Buchwald aminating reactions or document are provided are coupled and obtain intermediate VII or VI, the nitre of intermediate VII
The reduction in single solvent or mixed solvent such as alcohol-water of base iron powder/ammonium chloride obtains amine VIII, and intermediate VIII can also
Obtained by the protection group on the amino for removing intermediate VI.Intermediate VI can be by intermediate III and amino-aromatic hydrocarbons V idols
Connection is obtained.Amine VIII and acid IX or acyl chlorides X is condensed to yield compound I.Compound I can also be obtained by following two-step reaction,
Amine VIII first and acyl chlorides XI reacts, and then in aqueous solution of the alkali such as sodium hydroxide, elimination reaction occurs.
Another alternative synthetic route of key intermediate amine VIII is as shown in Figure 2.The XIV of amine XIII and halo
Or XV is coupled under the conditions of similarity shown in Fig. 1, or from the nitro compound VII or intermediate VI known to document in Fig. 1 institutes
Amine VIII is converted under conditions of showing.
As shown in figure 3, in some cases, compound of formula I under conditions of shown in Fig. 1 or Fig. 2, by intermediate III
It is coupled with intermediate VIa and obtains.
The preparation method of VIaa is as shown in Figure 4.With business provide dichloro pyrimidine as initiation material, successively through the area of chlorine
Field selectivity substitution reaction, bromination, amination, deprotection, acetylation and reduction reaction obtain intermediate VIaa.
Used as the explanation of the preparation of intermediate X IV, the synthetic method of XIVa is as shown in Figure 5.Commercially available dichloro pyrimidine
Successively subsequently there is halogenating reaction with amine, sodium alkyl alcohol reaction and intermediate X IVa is obtained.
It is able to carry out or avoid occurring side reaction to ensure reaction in some cases, the enforcement of reaction is suitable shown in above-mentioned route
Sequence can have been adjusted.Following examples are used to fully understand the present invention, it is impossible to be taken as any restriction.
Embodiment 1
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- (4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2 --amino) pyridin-3-yl) acrylamide (1)
The chloro- 2- methoxyl groups -3- nitropyridines (1a) of 6-
In dry tetrahydrofuran (30mL) solution of 2,6- dichloro-3-nitropyridines (5.79g, 30.0mmol), at 0 DEG C
Under be initially charged methanol (1.15mL, 28.5mmol), divide afterwards 4 batches add sodium hydride (60%, 1.20g, 30.0mmol).Stir at 0 DEG C
After mixing 1h, 1h is stirred at room temperature.Mixed liquor adds water (50mL) dilution, ethyl acetate extraction (2 × 30mL).Extract Jing salt is washed
It is dried with anhydrous magnesium sulfate afterwards.Solvent evaporated, residue normal hexane is recrystallized to give the chloro- 2- methoxyl groups -3- nitropyridines of 6-
(1a) for faint yellow solid (4.04g, 71%).
N
1
- (6- methoxyl group -5- nitropyridine -2- bases)-N
1
,N
2
,N
2
- Trimethylethane -1,2- diamidogen (1b)
By the chloro- 2- methoxyl groups -3- nitropyridines (1a) (3.77g, 20.0mmol) of 6- and N1,N1,N2- Trimethylethane -1,
Ethanol (45mL) solution of 2- diamidogen (2.24g, 22.0mmol) is heated to reflux 3h, is evaporated off under reduced pressure solvent, residue silica gel
Column chromatography purification, eluant is methylene chloride/methanol/ammonia (92:6:2), N is obtained1- (6- methoxyl group -5- nitropyridine -2-
Base)-N1,N2,N2- Trimethylethane -1, and 2- diamidogen (1b) (2.40g, 47%).MS-ESI(m/z):255[M+1]+。
N
1
- (the bromo- 6- methoxyl groups -5- nitropyridines -2- bases of 3-)-N
1
,N
2
,N
2
- Trimethylethane -1,2- diamidogen (1c)
In N1- (6- methoxyl group -5- nitropyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (1b)
Acetonitrile (30mL) suspension of (1.33g, 5.24mmol) add at 0 DEG C N- bromo-succinimides (1.40g,
7.82mmol), 1h is stirred at 0 DEG C.Evaporated under reduced pressure solvent, residue over silica gel column chromatography purification, eluant is dichloromethane/first
Alcohol/ammonia (92:6:2) yellow solid N, is obtained1- (the bromo- 6- methoxyl groups -5- nitropyridines -2- bases of 3-)-N1,N2,N2- trimethyl
Ethane -1,2- diamidogen (1c) (1.47g, 84%).MS-ESI(m/z):333and 335[1:1,M+1]+。
N
2
- (2- (dimethylamino) ethyl)-N
3
- (diphenylmethylene) -6- methoxyl group-N
2
- methyl-5-nitro pyridine -2,3-
Diamidogen (1d)
By N1- (the bromo- 6- methoxyl groups -5- nitropyridines -2- bases of 3-)-N1,N2,N2- Trimethylethane -1,2- diamidogen (1c)
(666mg,2.00mmol)、Pd2(dba)3(55mg, 0.060mmol), (+/-)-BINAP (75mg, 0.120mmol), hexichol first
Toluene (8mL) mixed liquor of ketimide (471mg, 2.60mmol) and sodium tert-butoxide (250mg, 2.60mmol) is under nitrogen protection
110 DEG C of reaction 2h are heated to, room temperature is subsequently cooled to.Pad kieselguhr solids removed by filtration, ethyl acetate washing.Filtrate decompression is steamed
Distillation goes solvent, residue by silicagel column chromatography purification (eluant is the ethyl acetate/normal hexane of 20-40%) to obtain N2-(2-
(dimethylamino) ethyl)-N3- (diphenylmethylene) -6- methoxyl group-N2- methyl-5-nitro pyridine -2,3- diamidogen (1d) is yellow
Solid (227mg, 26%).MS-ESI(m/z):434[M+1]+。
N
2
- (2- (dimethylamino) ethyl) -6- methoxyl group-N
2
- methyl-5-nitro pyridine -2,3- diamidogen (1e)
Under room temperature, in N2- (2- (dimethylamino) ethyl)-N3- (diphenylmethylene) -6- methoxyl group-N2- methyl-5-nitro
Methanol (5mL) solution of pyridine -2,3- diamidogen (1d) (194mg, 0.45mmol) adds concentrated hydrochloric acid (1mL).Under mixture room temperature
After stirring 1h, diluted with saturated sodium bicarbonate solution, ethyl acetate extraction (3 ×).Extract Jing water and salt washing after, anhydrous sulfur
Sour magnesium is dried.Evaporated under reduced pressure solvent, residue by silicagel column chromatography purification (eluant is the ethanol/methylene of 3-10%)
To N2- (2- (dimethylamino) ethyl) -6- methoxyl group-N2- methyl-5-nitro pyridine -2,3- diamidogen (1e) is yellow solid
(12.4mg, 10%).MS-ESI(m/z):270[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- nitropyridine -3- bases) acrylamide
(1f)
At 0 DEG C, to N2- (2- (dimethylamino) ethyl) -6- methoxyl group-N2- methyl-5-nitro pyridine -2,3- diamidogen
(1e) tetrahydrofuran-water (10 of (12.4mg, 0.046mmol):Mixture 1,1mL) add 3- chlorpromazine chlorides (14mg,
0.11mmol), 0.5h is stirred at 0 DEG C, sodium hydroxide (20mg, 0.50mmol) is added, mixed liquor is heated to 60 DEG C of reaction 3h, cold
But to room temperature, dilute, ethyl acetate extraction (2 ×), evaporated under reduced pressure extract solvent.Residue by silicagel column chromatography purification
(eluant is 5% ethanol/methylene) obtains N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5-
Nitropyridine -3- bases) and acrylamide (1f) (6.7mg, 45%).MS-ESI(m/z):324.2[M+1]+。
N- (5- amino -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- pyridinyl methoxy -3- bases) acrylamide
(1g)
By N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- nitropyridine -3- bases) acryloyl
The ethanol of amine (1f) (6.7mg, 0.021mmol), iron powder (7.0mg, 0.12mmol) and ammonium chloride (1.1mg, 0.021mmol)-
Water (3:1,2mL) mixture is heated to reflux 6h, evaporated under reduced pressure solvent, residue over silica gel column chromatography purification, and eluant is dichloro
Methane/methanol/ammonia (92:6:2) N- (5- amino -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxies, are obtained
Pyridin-3-yl) and acrylamide (1g) (3.6mg, 59%).MS-ESI(m/z):294[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- (4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (1)
By N- (5- amino -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- pyridinyl methoxy -3- bases) acrylamide
(1g) (3.6mg, 0.012mmol), 3- (2- chloropyrimide -4- bases) -1- Methyl-1H-indoles (1h) (6.0mg, 0.025mmol)
(being prepared according to document WO2013/14448) and the 2- amylalcohols (0.5mL) of hydration p-methyl benzenesulfonic acid (4.7mg, 0.025mmol)
Mixture be heated to 105 DEG C reaction 2h, evaporated under reduced pressure solvent, residue over silica gel column chromatography purification, eluant be dichloromethane/
Methanol (95:5) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- (4- (1- methyl isophthalic acid H-, are obtained
Indol-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (1) (5.0mg, 82%).MS-ESI(m/z):500[M+
1]+。
Embodiment 2
N- (6- methoxyl group -2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (2)
Tert-butyl group 2- ((6- methoxyl group -5- nitropyridine -2- bases) (methyl) amino) ethyl (methyl) carbamate
(2b)
By 1a (4.00g, 21.3mmol) and tertbutyl methyl (2- (methylamino) ethyl) carbamate (2a, 4.38g,
22.3mmol) (prepared according to document, J.Med.Chem., 1992,35, ethanol (47mL) solution 565) is heated to reflux 3h, subtracts
Pressure solvent evaporated, residue over silica gel column chromatography purification, eluant is 15-30% ethyl acetate/normal hexane, obtains tert-butyl group 2-
((6- methoxyl group -5- nitropyridine -2- bases) (methyl) amino) (63%) 4.65g, is ethyl (methyl) carbamate (2b)
Yellow solid.MS-ESI(m/z):341[M+1]+。
Tert-butyl group 2- ((the bromo- 6- methoxyl groups -5- nitropyridines -2- bases of 3-) (methyl) amino) ethyl (methyl) carbamic acid
Ester (2c)
At 0 DEG C, to tert-butyl group 2- ((6- methoxyl group -5- nitropyridine -2- bases) (methyl) amino) ethyl (methyl) ammonia
In the acetonitrile suspension of carbamate (2b) (4.32g, 12.7mmol) add N- bromo-succinimides (3.40g,
19.1mmol), 1h is stirred at 0 DEG C of mixture, evaporated under reduced pressure solvent, residue over silica gel column chromatography purification, eluant is 20-
30% ethyl acetate/normal hexane, obtains tert-butyl group 2- ((the bromo- 6- methoxyl groups -5- nitropyridines -2- bases of 3-) (methyl) amino) second
Base (methyl) carbamate (2c), be yellow solid (5.00g, 93%).MS-ESI(m/z):419and 421[1:1,M+1
And M+3]+。
Tert-butyl group 2- ((3- (diphenyl methylene) -6- methoxyl group -5- nitropyridine -2- bases) (methyl) amino) ethyl (first
Base) carbamate (2d)
By 2- ((the bromo- 6- methoxyl groups -5- nitropyridines -2- bases of 3-) (methyl) amino) ethyl (methyl) carbamate
(2c)(2.095g,5.00mmol)、Pd2(dba)3(137mg,0.150mmol)、(+/-)-BINAP(187mg,0.300mmol)、
The mixing of benzophenone imine (1.177g, 6.50mmol) and sodium tert-butoxide (624mg, 6.50mmol) in toluene (20mL)
Thing, heats under a nitrogen 110 DEG C of reaction 3h, is cooled to room temperature, and pad kieselguhr filters solid, and ethyl acetate washing, evaporated under reduced pressure is molten
Agent, residue over silica gel column chromatography purification, eluant is 20-40% ethyl acetate/normal hexane, obtains tert-butyl group 2- ((3- (two
Benzylidene) -6- methoxyl group -5- nitropyridine -2- bases) (methyl) amino) ethyl (methyl) carbamate (2d) is yellowish
Color solid (600mg, 23%).MS-ESI(m/z):520[M+1]+。
Tert-butyl group 2- ((3- amino -6- methoxyl group -5- nitropyridine -2- bases) (methyl) amino) ethyl (methyl) amino first
Acid esters (2e)
Under room temperature, to tert-butyl group 2- ((3- (diphenyl methylene) -6- methoxyl group -5- nitropyridine -2- bases) (methyl) ammonia
Base) ethyl (methyl) carbamate (2d) (580mg, 1.12mmol) ethanol (20mL) solution add hydrochloric acid (1N,
0.5mL), 50 DEG C of reaction 7h are heated to.Mixture is diluted with saturated sodium bicarbonate solution, ethyl acetate extraction (3 ×), extract
Jing after water and salt washing, magnesium sulfate is dried, evaporated under reduced pressure solvent, residue over silica gel column chromatography purification, and eluant is 20-40%
Ethyl acetate/normal hexane, obtains tert-butyl group 2- ((3- amino -6- methoxyl group -5- nitropyridine -2- bases) (methyl) amino) ethyl
(methyl) carbamate (2e), be orange solids (280mg, 68%).MS-ESI(m/z):356[M+1]+。
Tert-butyl group 2- ((3- acrylamido -6- methoxyl group -5- nitropyridine -2- bases) (methyl) amino) ethyl (methyl)
Carbamate (2f)
At 0 DEG C, to tert-butyl group 2- ((3- amino -6- methoxyl group -5- nitropyridine -2- bases) (methyl) amino) ethyl (first
Base) carbamate (2e) (280mg, 0.789mmol) tetrahydrofuran-water (10:3- chlorine propionyl 1,5.5mL) is added in solution
Chlorine (120mg, 0.946mmol), 0 DEG C of stirring 0.5h, adds sodium hydroxide NaOH (126mg, 3.76mmol), and mixture is heated to
Room temperature is cooled to after 65 DEG C of reaction 1h.Mixture dilute with water, ethyl acetate extraction (2 ×).Evaporated under reduced pressure solvent, residue is used
Silica gel column chromatography purification, eluant is 30-50% ethyl acetate/normal hexane, obtains tert-butyl group 2- ((3- acrylamido -6- first
Epoxide -5- nitropyridine -2- bases) (methyl) amino) ethyl (methyl) carbamate (2f) (185mg, 57%).MS-ESI
(m/z):410.3[M+1]+。
Tert-butyl group 2- ((3- acrylamido -5- amino -6- methoxypyridine -2- bases) (methyl) amino) ethyl (methyl)
Carbamate (2g)
By tert-butyl group 2- ((3- acrylamido -6- methoxyl group -5- nitropyridine -2- bases) (methyl) amino) ethyl (first
Base) carbamate (2f) (185mg, 0.452mmol), iron powder (152mg, 2.71mmol), ammonium chloride (24.2mg,
Alcohol-water (3 0.452mmol):1,15mL) it is heated to reflux 1h.Pad kieselguhr solids removed by filtration, ethyl acetate washing.Filter
Liquid diluted ethyl acetate, water and salt are washed, and evaporated under reduced pressure solvent obtains tert-butyl group 2- ((3- acrylamido -5- ammonia of crude product
Base -6- methoxypyridine -2- bases) (methyl) amino) (87%) 149mg, is brown oil to ethyl (methyl) carbamate (2g)
Shape.MS-ESI(m/z):380[M+1]+。
N- (6- methoxyl group -2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (2)
By tert-butyl group 2- ((3- acrylamido -5- amino -6- methoxypyridine -2- bases) (methyl) amino) ethyl (first
Base) carbamate (2g) (94.0mg, 0.248mmol), 3- (2- chloropyrimide -4- bases) -1- Methyl-1H-indoles (1h,
72.5mg, 0.298mmol) and one hydration p-methyl benzenesulfonic acid (56.6mg, 0.298mmol) 2- amylalcohols (1.5mL) mixture add
Heat to 105 DEG C are reacted 2h.Evaporated under reduced pressure solvent, residue over silica gel column chromatography purification, eluant is methylene chloride/methanol/ammonia
(92:7:1), obtain N- (6- methoxyl group -2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1- Methyl-1H-indoles -
3- yls) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (2) (100.0mg, 83%).MS-ESI(m/z):487.4[M+
1]+。
Embodiment 3
N- (2- ((2- (ethyl (methyl) amino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl isophthalic acid H-
Indol-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (3)
At room temperature, in N- (6- methoxyl group -2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1- methyl isophthalic acid H-
Indol-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (2) (15.4mg, 0.0317mmol) the chloroethenes of 1,2- bis-
Acetaldehyde (content 40%, 9.0mg, 0.082mmol in water) and sodium triacetoxy borohydride are added in alkane (1mL) solution
(8.7mg, 0.041mmol), stirs after 1h under mixture room temperature, adds saturated sodium bicarbonate aqueous solution (5mL) dilution, dichloromethane
Alkane extracts (2 × 5mL), and extract is dried with sodium sulfate, evaporated under reduced pressure solvent, residue by silicagel column chromatography purification, eluant
For methylene chloride/methanol/ammonia (95:4:1) N- (2- ((2- (ethyl (methyl) amino) ethyl) (methyl) amino) -6- first, is obtained
Epoxide -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (3) is that brown is consolidated
Body (12.5mg, 77%).MS-ESI(m/z):515[M+1]+。
Embodiment 4
N- (6- methoxyl group -2- (methyl (2- (N- methyl vinyl amidos) ethyl) amino) -5- (4- (1- methyl isophthalic acid H- Yin
Diindyl -3- bases) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (4)
To N- (6- methoxyl group -2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (2) (28.3mg, 0.058mmol) dichloromethane (1mL) solution
DIPEA (15.2 μ L, 0.087mmol) is added, 0 DEG C is cooled to, Deca acetic anhydride (dichloromethane of 0.20mL contains 5.9mg) is molten
Liquid.Mixture is stirred at room temperature 1h, adds saturated sodium bicarbonate aqueous solution (5mL) dilution, dichloromethane extraction (2 × 5mL), extraction
Liquid is dried with sodium sulfate, evaporated under reduced pressure solvent, residue by silicagel column chromatography purification, and eluant is 2-3% methanol/dichloromethane
Alkane, obtain N- (6- methoxyl group -2- (methyl (2- (N- methyl vinyl amidos) ethyl) amino) -5- (4- (1- Methyl-1H-indoles -
3- yls) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (4), be yellow solid (15.1mg, 49%).MS-ESI(m/
z):528.4[M+1]+。
Embodiment 5
((4- (1- Methyl-1H-indole -3- bases) is phonetic for 6- ethyoxyl -2- (methyl (2- (methylamino) ethyl) amino) -5- for N-
Pyridine -2- bases) amino) pyridin-3-yl) acrylamide (5)
6- chloro-2-ethoxies -3- nitropyridines (5a)
Methanol is substituted for ethanol by the preparation of 6- chloro-2-ethoxies -3- nitropyridines (5a) according to the synthetic method of 1a.
MS-ESI(m/z):203[M+1]+。
((4- (1- Methyl-1H-indole -3- bases) is phonetic for 6- ethyoxyl -2- (methyl (2- (methylamino) ethyl) amino) -5- for N-
Pyridine -2- bases) amino) pyridin-3-yl) acrylamide (5)
Title compound N- (6- ethyoxyl -2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1- methyl isophthalic acid H- Yin
Diindyl -3- bases) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (5) preparation (36.1mg) is according to the synthesis side of embodiment 2
Method, by the chloro- 2- methoxyl groups -3- nitropyridines (1a) of 6- 6- chloro-2-ethoxies -3- nitropyridines (5a) is substituted for.MS-ESI(m/
z):501[M+1]+。
Embodiment 6
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- ethyoxyl -5- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (6)
At room temperature, to N- (6- ethyoxyl -2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1- methyl isophthalic acid H-
Indol-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (5) (10.1mg, 0.020mmol) the chloroethenes of 1,2- bis-
In alkane (0.6mL) solution add acetaldehyde (content 37%, 17mg in water) and sodium triacetoxy borohydride (6.4mg,
0.030mmol), stir under mixture room temperature after 1h, add saturated sodium bicarbonate aqueous solution (2mL) dilution, dichloromethane extraction
(2 × 2mL), extract is dried with sodium sulfate, evaporated under reduced pressure solvent, and residue by silicagel column chromatography purification, eluant is 5-
10% methylene chloride/methanol, obtains N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- ethyoxyl -5- ((4- (1-
Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (6), be gray solid (8.5mg,
82%).MS-ESI(m/z):515[M+1]+。
Embodiment 7
N- (6- isopropoxy -2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (7)
The chloro- 2- isopropoxies -3- nitropyridines (7a) of 6-
Methanol is substituted for isopropyl by the preparation of the chloro- 2- isopropoxies -3- nitropyridines (7a) of 6- according to the synthetic method of 1a
Alcohol.MS-ESI(m/z):217[M+1]+。
N- (6- isopropoxy -2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (7)
The preparation of title compound 7 (36.1mg) according to the synthetic method of embodiment 2, by the chloro- 2- methoxyl groups -3- nitros of 6-
Pyridine (1a) is substituted for the chloro- 2- isopropoxies -3- nitropyridines (7a) of 6-.MS-ESI(m/z):515[M+1]+。
Embodiment 8
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- isopropoxy -5- (4- (1- Methyl-1H-indoles -
3- yls) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (8)
Title compound 8 (6.3mg, preparation 75%) according to the synthetic method of embodiment 6, by N- (6- ethyoxyl -2-
(methyl (2- (methylamino) ethyl) amino) -5- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) pyridine -3-
Base) acrylamide (5) be substituted for N- (6- isopropoxy -2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1- methyl -
1H- indol-3-yls) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (7).MS-ESI(m/z):529[M+1]+。
Embodiment 9
N- (6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (piperazine -1- bases)
Pyridin-3-yl) acrylamide (9)
The preparation of title compound 9 (25mg) according to the synthetic method of embodiment 2, by the tert-butyl group (2- (methylamino) ethyl)
Carbamate (2a) is substituted for t-butylpiperazine -1- carbamates.MS-ESI(m/z):485[M+1]+。
Embodiment 10
N- (6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (4- methyl piperazines -
1- yls) pyridin-3-yl) acrylamide (10)
The preparation of title compound 10 (5.2mg) according to the synthetic method of embodiment 6, by N- (6- ethyoxyl -2- (methyl
(2- (methylamino) ethyl) amino) -5- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) pyridin-3-yl) propylene
Amide (5) be substituted for N- (6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (piperazine -
1- yls) pyridin-3-yl) acrylamide (9).MS-ESI(m/z):499[M+1]+。
Embodiment 11
N- (6- ethyoxyl -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (piperazine -1- bases)
Pyridin-3-yl) acrylamide (11)
The preparation of title compound 11 (55mg) according to the synthetic method of embodiment 2, respectively by methyl (2- (methylamino) second
Base) carbamate (2a) is substituted for t-butylpiperazine -1- carboxylates, the chloro- 2- methoxyl groups -3- nitropyridines (1a) of 6- replaced
Into 6- chloro-2-ethoxies -3- nitropyridines (5a).MS-ESI(m/z):499[M+1]+。
Embodiment 12
N- (6- ethyoxyl -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (4- methyl piperazines -
1- yls) pyridin-3-yl) acrylamide (12)
The preparation of title compound 12 (7.2mg) according to the synthetic method of embodiment 6, by N- (6- ethyoxyl -2- (methyl
(2- (methylamino) ethyl) amino) -5- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) pyridin-3-yl) propylene
Amide (5) be substituted for N- (6- ethyoxyl -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (piperazine -
1- yls) pyridin-3-yl) acrylamide (11).MS-ESI(m/z):513[M+1]+。
Embodiment 13
N- (6- isopropoxy -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (piperazine -1-
Base) pyridin-3-yl) acrylamide (13)
Title compound 13 (75mg) prepares the synthetic method according to embodiment 2, respectively by tertbutyl methyl (2- (first ammonia
Base) ethyl) carbamate (2a) is substituted for t-butylpiperazine -1- carbamates, by the chloro- 2- methoxyl groups -3- nitro pyrroles of 6-
Pyridine (1a) is substituted for the chloro- 2- isopropoxies -3- nitropyridines (7a) of 6-.MS-ESI(m/z):513[M+1]+。
Embodiment 14
N- (6- isopropoxy -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (4- methyl piperazines
Piperazine -1- bases) pyridin-3-yl) acrylamide (14)
The preparation of title compound 14 (7.4mg) according to the synthetic method of embodiment 6, by N- (6- ethyoxyl -2- (methyl
(2- (methylamino) ethyl) amino) -5- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) pyridin-3-yl) propylene
Amide (5) is substituted for N- (6- isopropoxy -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (piperazines
Piperazine -1- bases) pyridin-3-yl) acrylamide (13).MS-ESI(m/z):527[M+1]+。
Embodiment 15
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-)
Pyrimidine -2-base) amino) -6- pyridinyl methoxy -3- bases) acrylamide (15)
N
1
- (the chloro- 3- nitropyridines -2- bases of 6-)-N
1
,N
2
,N
2
- Trimethylethane -1,2- diamidogen (15a)
At 0 DEG C, to the chloro- 3- nitropyridines (19.3g, 100.0mmol) of 2,6- and triethylamine (20.2g, 200.0mmol)
Dry methylene chloride (200mL) solution in be slowly added dropwise N1,N1,N2- Trimethylethane -1,2- diamidogen (10.2g,
Dry methylene chloride (20ml) solution 100.0mmol), more than 0.5h, 0 DEG C of stirring 1.5h of reactant mixture.Mixture water
(200mL) dilute, dichloromethane extraction (100mL × 3).Merge organic layer, saline (200mL) is washed, sodium sulfate is dried, cross and filter
Solid, filtrate is gone to be concentrated to give N1- (the chloro- 3- nitropyridines -2- bases of 6-)-N1,N2,N2- Trimethylethane -1,2- diamidogen
(15a), be yellow oily (23.8g, 91%).MS-ESI(m/z):259[M+1]+。
N
1
- (6- methoxyl group -3- nitropyridine -2- bases)-N
1
,N
2
,N
2
- Trimethylethane -1,2- diamidogen (15b)
At 0-5 DEG C, to N1- (the chloro- 3- nitropyridines -2- bases of 6-)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15a)
Feldalat NM (10.8g, 183.8mmol) is added in methanol (200mL) solution of (23.8g, 91.9mmol), mixture is heated to reflux
2h, is cooled to room temperature, is evaporated methanol, is diluted with water (200mL), dichloromethane extraction (200mL × 2).Merge organic layer, water
(200mL × 2) and saline (200mL) are washed, and sodium sulfate is dried.Filter out solid, filtrate reduced in volume, crude product Jing silica gel column chromatographies
Purification, eluant is ethyl acetate/petroleum ether (1:1), N is obtained1- (6- methoxyl group -3- nitropyridine -2- bases)-N1,N2,N2-
Trimethylethane -1,2- diamidogen (15b), be yellow oily (18.0g, 77%).MS-ESI(m/z):255[M+1]+。
N
1
- (5- iodo -6- methoxyl group -3- nitropyridine -2- bases)-N
1
,N
2
,N
2
- Trimethylethane -1,2- diamidogen (15c)
At 0-5 DEG C, to N1- (6- methoxyl group -3- nitropyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen
(15b) in glacial acetic acid (120mL) solution of (11.0g, 43.1mmol) points 3 batches add N-iodosuccinimides (11.6g,
51.8mmol), 4.5h is stirred under mixture room temperature.Evaporated under reduced pressure solvent, is diluted with water (300mL), ethyl acetate extraction
(200mL × 3), merge organic layer, and water (200mL × 2) and saline (200mL) are washed, and sodium sulfate is dried.Filter out solid, filtrate
Concentrating under reduced pressure, crude product Jing silica gel column chromatography purification, eluant is ethyl acetate/petroleum ether (1:1), N is obtained1- (5- iodo -6-
Methoxyl group -3- nitropyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15c), be yellow oily (14.0g,
88%).MS-ESI(m/z):381[M+1]+。
N
1
- (5- ((diphenylmethylene) amino) -6- methoxyl group -3- nitropyridine -2- bases)-N
1
,N
2
,N
2
- trimethyl second
Alkane -1,2- diamidogen (15d)
Under inert nitrogen, by N1- (5- iodo -6- methoxyl group -3- nitropyridine -2- bases)-N1,N2,N2- trimethyl second
Alkane -1,2- diamidogen (15c) (10.0g, 26.2mmol), three (dibenzalacetone) two palladium (0) (1.2g, 1.3mmol), (+/-) -
2,2'- double (diphenyl phosphine) -1,1'- dinaphthalenes (1.6g, 2.6mmol), benzophenone imine (7.1g, 39.4mmol) and sodium tert-butoxide
Toluene (150mL) mixture of (3.8g, 39.4mmol) is heated to 110 DEG C of reaction 16h.Room temperature is cooled to, pad kieselguhr is filtered
Solid is removed, ethyl acetate is washed, evaporated under reduced pressure solvent, and residue by silicagel column chromatography purification, eluant is ethyl acetate, is obtained
To N1- (5- ((diphenylmethylene) amino) -6- methoxyl group -3- nitropyridine -2- bases)-N1,N2,N2- Trimethylethane -1,
2- diamidogen (15d), be Red oil (2.2g, 19%).MS-ESI(m/z):434[M+1]+。
N
2
- (2- (dimethylamino) ethyl) -6- methoxyl group-N
2
- Methyl-3-nitropyridine -2,5- diamidogen (15e)
Under room temperature, to N1- (5- ((diphenylmethylene) amino) -6- methoxyl group -3- nitropyridine -2- bases)-N1,N2,
N2Tetrahydrofuran (150mL) solution of-Trimethylethane -1,2- diamidogen (15d) (2.2g, 5.1mmol) adds 0.5N hydrochloric acid
(24mL), 1.5h is stirred at room temperature.Evaporated under reduced pressure tetrahydrofuran, it is 9-10 that potassium carbonate adjusts pH value.The mixture dichloromethane of generation
Alkane extracts (30mL × 4), merges organic layer, and saline (200mL) is washed, and sodium sulfate is dried.Filter out solid, filtrate reduced in volume,
Residue by silicagel column chromatography purification, eluant is methylene chloride/methanol (20:1～10:1), N is obtained2- (2- (dimethylamino)
Ethyl) -6- methoxyl group-N2- Methyl-3-nitropyridine -2,5- diamidogen (15e), be Red oil (0.7g, 51%).MS-ESI
(m/z):270[M+1]+。
The fluoro- 1- Methyl-1H-indoles (15f) of 7-
At 0-5 DEG C, add in DMF (10mL) solution of the fluoro- 1H- indole (1.0g, 7.4mmol) of 7-
Enter sodium hydride (60% is distributed in mineral oil, 0.44g, 11.1mmol), stir 20 minutes under the suspension room temperature for obtaining, room temperature
Lower addition iodomethane (0.7mL, 11.1mmol), is stirred at room temperature 1h.Reaction water (40mL) is quenched, and mixture is extracted with ethyl acetate
Take (30mL × 3), merge organic layer, water (30mL × 3) and saline (30mL) are washed, and sodium sulfate is dried.Solid is filtered out, filtrate subtracts
Pressure concentration, residue by silicagel column chromatography purification, eluant is ethyl acetate/petroleum ether (1:20), obtain the fluoro- 1- methyl of 7--
1H- indole (15f), be weak yellow liquid (1.0g, 91%).MS-ESI(m/z):150[M+1]+。
3- (2- chloropyrimide -4- bases) the fluoro- 1- Methyl-1H-indoles (15g) of -7-
By the fluoro- 1- Methyl-1H-indoles (15f) (0.60g, 4.0mmol) of 7-, 2,4- dichloro pyrimidines (0.60g,
4.0mmol), 60 DEG C of stirrings of 1，2-ethandiol dimethyl ether (12mL) solution of anhydrous ferric chloride (III) (0.65g, 4.0mmol)
7h.Reaction add water (40mL) be quenched, the mixture for obtaining is extracted with ethyl acetate (30mL × 3), merge organic layer, water (30mL
× 3) wash with saline (30mL), sodium sulfate is dried.Filter out solid, filtrate reduced in volume, residue by silicagel column chromatography purification,
Eluant is ethyl acetate/petroleum ether (1:5～1:2) 3- (2- chloropyrimide -4- bases) the fluoro- 1- Methyl-1H-indoles of -7-, are obtained
(15g), be brown solid (0.50g, 48%).MS-ESI(m/z):262[M+1]+。
N
2
- (2- (dimethylamino) ethyl)-N
5
- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-base) -6- first
Epoxide-N
2
- Methyl-3-nitropyridine -2,5- diamidogen (15h)
By the fluoro- 1- Methyl-1H-indoles (15g) (30.0mg, 0.11mmol) of 3- (2- chloropyrimide -4- bases) -7-, N2-(2-
(dimethylamino) ethyl) -6- methoxyl group-N2- Methyl-3-nitropyridine -2,5- diamidogen (15e) (31.0mg, 0.11mmol), carbon
Sour caesium (112.0mg, 0.33mmol), three (dibenzalacetone) two palladium (0) (21.0mg, 0.022mmol), (+/-) -2,2'-
Dioxane (3mL) mixture of double (diphenyl phosphine) -1,1'- dinaphthalenes (29.0mg, 0.044mmol) stirs 7h, cooling at 100 DEG C
To room temperature.Reaction add water (40mL) be quenched, the mixture for obtaining is extracted with ethyl acetate (30mL × 3), merge organic layer, water
(30mL × 3) and saline (30mL) are washed, and sodium sulfate is dried.Filter out solid, filtrate reduced in volume, residue by silicagel column chromatography
Purification, eluant is methylene chloride/methanol/ammonia (100:5:0.5), N is obtained2- (2- (dimethylamino) ethyl)-N5-(4-(7-
Fluoro- 1- Methyl-1H-indoles -3- bases) pyrimidine -2-base) -6- methoxyl group-N2- Methyl-3-nitropyridine -2,5- diamidogen (15h),
For yellow solid (34.0mg, 60%).MS-ESI(m/z):495[M+1]+。
N
2
- (2- (dimethylamino) ethyl)-N
5
- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-base) -6- first
Epoxide-N
2
- picoline -2,3,5- triamines (15i)
By N2- (2- (dimethylamino) ethyl)-N5- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-base) -6-
Methoxyl group-N2- Methyl-3-nitropyridine -2,5- diamidogen (15h) (34.0mg, 0.07mmol), iron powder (41.0mg,
0.73mmol), the ethanol (12mL) of ammonium chloride (13.0mg, 0.24mmol) and the mixture of water (3mL) are stirred at 80 DEG C
1.5h.Filter solid, washing with alcohol (5mL × 3), filtrate reduced in volume.Residue by silicagel column chromatography purification, eluant is two
Chloromethanes/methanol/ammonia (100:5:0.5～100:10:0.5), N is obtained2- (2- (dimethylamino) ethyl)-N5- ((7- is fluoro- for 4-
1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl group-N2- methyl-N2- picoline -2,3,5- triamines (15i) are
Yellow oily (28.0mg, 88%).MS-ESI(m/z):465[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-)
Pyrimidine -2-base) amino) -6- pyridinyl methoxy -3- bases) acrylamide (15)
At 0 DEG C, to N2- (2- (dimethylamino) ethyl)-N5- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-
Base) -6- methoxyl group-N2- methyl-N2The anhydrous dichloromethane of-picoline -2,3,5- triamines (15i) (28.0mg, 0.06mmol)
Acryloyl chloride (5.5mg, 0.06mmol), 0 DEG C of stirring 1h are added in alkane (1mL) solution.Reaction saturated sodium bicarbonate aqueous solution
(20mL) it is quenched, the mixture for obtaining extracts (20mL × 3) with dichloromethane.Merge organic layer, water (20mL × 3) and saline
(20mL) wash, sodium sulfate is dried.Filter out solid, filtrate reduced in volume, residue by silicagel column chromatography purification, eluant is two
Chloromethanes/methanol/ammonia (100:5:0.5～100:10:0.5) N- (2- ((2- (dimethylamino) ethyl) (methyl) ammonia, is obtained
Base) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-base) amino) -6- pyridinyl methoxy -3- bases) acrylamide
(15), be yellow solid (20.0mg, 65%).MS-ESI(m/z):519[M+1]+。
Embodiment 16
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 6-)
Pyrimidine -2-base) amino) -6- methoxypyridine -3- bases) acrylamide (16)
The preparation of title compound 16 (20.0mg) is substituted for the fluoro- 1H- indole of 7- according to the synthetic method of embodiment 15
The fluoro- 1H- indole of 6-.MS-ESI(m/z):519[M+1]+。
Embodiment 17
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-)
Pyrimidine -2-base) amino) -6- methoxypyridine -3- bases) acrylamide (17)
The preparation of title compound 17 (25.0mg) is substituted for the fluoro- 1H- indole of 7- according to the synthetic method of embodiment 15
The fluoro- 1H- indole of 5-.MS-ESI(m/z):519[M+1]+。
Embodiment 18
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 4-)
Pyrimidine -2-base) amino) -6- methoxypyridine -3- bases) acrylamide (18)
The preparation of title compound 18 (23.0mg) is substituted for the fluoro- 1H- indole of 7- according to the synthetic method of embodiment 15
The fluoro- 1H- indole of 4-.MS-ESI(m/z):519[M+1]+。
Embodiment 19
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((the fluoro- 4- of 5- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) -6- methoxypyridine -3- bases) acrylamide (19)
3- (the chloro- 5-FU -4- bases of 2-) -1- Methyl-1H-indoles (19a)
By 1- Methyl-1H-indoles (0.50g, 3.8mmol), the chloro- 5-FUs (0.64g, 3.8mmol) of 2,4- bis-, anhydrous
60 DEG C of stirring 7h of 1,2- glycol dimethyl ethers (7.0mL) solution of iron chloride (III) (0.62g, 3.8mmol).Reaction adds water
(40mL) it is quenched, the mixture for obtaining is extracted with ethyl acetate (30mL × 3), merges organic layer, water (30mL × 3) and saline
(30mL) wash, sodium sulfate is dried.Filter out solid, filtrate reduced in volume, residue by silicagel column chromatography purification, eluant is second
Acetoacetic ester/petroleum ether (1:5～1:2) 3- (the chloro- 5-FU -4- bases of 2-) -1- Methyl-1H-indoles (19a), are obtained, is brown
Solid (0.54g, 54%).MS-ESI(m/z):262[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((the fluoro- 4- of 5- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) -6- methoxypyridine -3- bases) acrylamide (19)
The preparation of title compound 19 (23.0mg) according to the synthetic method of embodiment 15, by 3- (2- chloropyrimide -4- bases) -
The fluoro- 1- Methyl-1H-indoles (15g) of 7- are substituted for 3- (the chloro- 5-FU -4- bases of 2-) -1- Methyl-1H-indoles (19a).MS-
ESI(m/z):519[M+1]+。
Embodiment 20
N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) second
Base) (methyl) amino) -6- methoxypyridine -3- bases) acrylamide (20)
3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indoles (20a)
By 1- Methyl-1H-indoles (0.50g, 3.8mmol), 2,4,5- trichloropyrimidines (0.64g, 3.8mmol), anhydrous chlorine
Change 60 DEG C of stirring 7h of 1,2- glycol dimethyl ethers (7.0mL) solution of ferrum (III) (0.62g, 3.8mmol).Reaction adds water
(40mL) it is quenched, the mixture for obtaining is extracted with ethyl acetate (30mL × 3), merges organic layer, water (30mL × 3) and saline
(30mL) wash, sodium sulfate is dried.Filter out solid, filtrate reduced in volume, residue by silicagel column chromatography purification, eluant is second
Acetoacetic ester/petroleum ether (1:5～1:2) 3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indoles (20a), are obtained, is brown
Solid (0.56g, 53%).MS-ESI(m/z):278[M+1]+。
N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) second
Base) (methyl) amino) -6- methoxypyridine -3- bases) acrylamide (20)
The preparation of title compound 20 (20.0mg) according to the synthetic method of embodiment 15, by 3- (2- chloropyrimide -4- bases) -
The fluoro- 1- Methyl-1H-indoles (15g) of 7- are substituted for 3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indoles (20a).MS-
ESI(m/z):535[M+1]+。
Embodiment 21
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((5- methyl -4- (1- methyl isophthalic acid H- Indol-3-yl)It is phoneticPyridine -2- bases) amino) pyridin-3-yl) acrylamide (21)
3- (the chloro- 5- methylpyrimidines -4- bases of 2-) -1- Methyl-1H-indoles (21a)
By 1- Methyl-1H-indoles (0.50g, 3.8mmol), the chloro- 5- methylpyrimidines (0.64g, 3.8mmol) of 2,4- bis-, nothing
60 DEG C of stirring 7h of 1,2- glycol dimethyl ethers (7.0mL) solution of water iron chloride (III) (0.62g, 3.8mmol).Reaction adds water
(40mL) it is quenched, the mixture for obtaining is extracted with ethyl acetate (30mL × 3), merges organic layer, water (30mL × 3) and saline
(30mL) wash, sodium sulfate is dried.Filter out solid, filtrate reduced in volume, residue by silicagel column chromatography purification, eluant is second
Acetoacetic ester/petroleum ether (1:5～1:2) 3- (the chloro- 5- methylpyrimidines -4- bases of 2-) -1- Methyl-1H-indoles (21a), are obtained, is palm fibre
Color solid (0.50g, 47%).MS-ESI(m/z):258[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((5- methyl -4- (1- methyl isophthalic acid H-
Indol-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (21)
The preparation of title compound 21 (26.0mg) according to the synthetic method of embodiment 15, by 3- (2- chloropyrimide -4- bases) -
The fluoro- 1- Methyl-1H-indoles (15g) of 7- are substituted for 21a.MS-ESI(m/z):515[M+1]+。
Embodiment 22
N- (3- ((2- (dimethylamino) ethyl) (methyl) amino) -5- methoxyl group -6- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridine -2- bases) acrylamide (22)
The bromo- 3- methoxyl groups -2- nitropyridines (22a) of 5-
The synthetic method that the preparation of the bromo- 3- methoxyl groups -2- nitropyridines (22a) of 5- is described according to US2006/84665.
The tert-butyl group (2- ((5- methoxyl group -6- nitropyridine -3- bases) (methyl) amino) ethyl) (methyl) carbamate
(22b)
Under nitrogen, by the bromo- 3- methoxyl groups -2- nitropyridines (22a) (2.8g, 12.02mmol) of 5-, tertbutyl methyl (2-
(methylamino) ethyl) carbamate (2.67g, 13.22mmol), palladium (0.27g, 1.20mmol), Xantphos
Toluene (56mL) mixture of (0.69g, 1.20mmol) and cesium carbonate (11.7g, 35.91mmol) stirs 2.5h at 100 DEG C.It is mixed
Compound is cooled to room temperature, add water (200mL) be quenched, ethyl acetate extraction (3 × 50mL).Extract is washed with salt, and sodium sulfate is done
It is dry, concentration, silica gel column chromatography purification, eluant is 50% ethyl acetate/normal hexane, obtains the tert-butyl group (2- ((5- methoxyl group -6-
Nitropyridine -3- bases) (methyl) amino) ethyl) (methyl) carbamate (22b), be yellow solid (3.0g, 73%).MS-
ESI(m/z):341[M+1]+。
The tert-butyl group (2- ((the bromo- 5- methoxyl groups -6- nitropyridines -2- bases of 2-) (methyl) amino) ethyl (methyl) amino first
Acid esters (22c)
At 0 DEG C, to the tert-butyl group (2- ((5- methoxyl group -6- nitropyridine -3- bases) (methyl) amino) ethyl) (methyl)
Glacial acetic acid (30mL) mixture of carbamate (22b) (1.70g, 5.00mmol) adds the ice of bromine (0.88g, 5.50mmol)
Acetic acid (5mL) solution.0.5h is stirred at 0 DEG C of mixture, is stirred at room temperature, add water (150mL) dilution, ethyl acetate extraction (3 ×).
Extract saturated sodium bicarbonate aqueous solution and salt are washed, and sodium sulfate is dried.Evaporated under reduced pressure solvent, residue over silica gel column chromatography
Purification, eluant be 20-40% ethyl acetate/normal hexane, obtain the tert-butyl group (2- ((the bromo- 5- methoxyl groups -6- nitropyridines of 2- -
2- yls) (methyl) amino) ethyl (methyl) carbamate (22c), be yellow solid (1.53g, 73%).MS-ESI(m/z):
419.2and 421.2[1:1, M+1 and M+3]+。
The tert-butyl group (2- ((2- ((diphenyl methylene) amino) -5- methoxyl group -6- nitropyridine -3- bases) (methyl) amino)
Ethyl (methyl) carbamate (22d)
By the tert-butyl group (2- ((the bromo- 5- methoxyl groups -6- nitropyridines -2- bases of 2-) (methyl) amino) ethyl (methyl) amino
Formic acid esters (22c) (419mg, 1.00mmol), Pd2(dba)3(27.5mg,0.030mmol)、(+/-)-BINAP(37.4mg,
0.060mmol), benzophenone imine (199mg, 1.10mmol) and sodium tert-butoxide (192mg, 2.00mmol) are at toluene (5mL)
In mixture, under a nitrogen heat 80 DEG C reaction 4h.It is cooled to room temperature, evaporated under reduced pressure solvent.One after the other add tetrahydrofuran
(14mL) with 0.5N hydrochloric acid (14mL), mixture is stirred at room temperature 1.5h, sodium bicarbonate (50mL) dilution, ethyl acetate extraction (2
×).Jing after salt washing, magnesium sulfate is dried extract, evaporated under reduced pressure solvent, residue over silica gel column chromatography purification, and eluant is
20-50% ethyl acetate/normal hexane, obtains the tert-butyl group (2- ((2- ((diphenyl methylene) amino) -5- methoxyl group -6- nitro pyrroles
Pyridine -3- bases) (methyl) amino) ethyl (methyl) carbamate (22d), be yellow solid (76mg, 21%).MS-ESI(m/
z):356.2[M+1]+。
The tert-butyl group (2- ((2- acrylamido -5- methoxyl group -6- nitropyridine -3- bases) (methyl) amino) ethyl (first
Base) carbamate (22e)
At 0 DEG C, to the tert-butyl group (2- ((2- ((diphenyl methylene) amino) -5- methoxyl group -6- nitropyridine -3- bases) (first
Base) amino) ethyl (methyl) carbamate (22d) (75mg, 0.211mmol) acetonitrile (3mL) mixture in add 3- chlorine
Propionyl chloride (53.6mg, 0.422mmol), DMAP (51.5mg, 0.422mmol) and DIPEA (81.7mg, 0.633mmol).Mixing
0 DEG C of stirring 2.5h of thing, adds sodium hydroxide (10N, 0.8mL).Mixture is stirred at room temperature 1.5h, dilute, ethyl acetate extraction
Take (2 ×).Evaporated under reduced pressure solvent, residue over silica gel column chromatography purification, eluant is 5% ethanol/methylene, obtains tertiary fourth
Base (2- ((2- acrylamido -5- methoxyl group -6- nitropyridine -3- bases) (methyl) amino) ethyl (methyl) carbamate
(22e) (28.5mg, 33%).MS-ESI(m/z):410.2[M+1]+。
The tert-butyl group (2- ((2- acrylamido -6- amino -5- pyridinyl methoxy -3- bases) (methyl) amino) ethyl (methyl)
Carbamate (22f)
By the tert-butyl group (2- ((2- acrylamido -5- methoxyl group -6- nitropyridine -3- bases) (methyl) amino) ethyl (first
Base) carbamate (22e) (28.5mg, 0.070mmol), iron powder (19.5mg, 0.348mmol) and ammonium chloride (3.7mg,
Alcohol-water (3 0.070mmol):1,15mL) mixture is heated to reflux 2h.Evaporated under reduced pressure solvent, residue over silica gel column chromatography
Purification, eluant is 92:6:2 methylene chloride-methanols-ammonia, obtain the tert-butyl group (2- ((2- acrylamido -6- amino -5- methoxies
Pyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22f) (9.0mg, 34%).MS-ESI(m/z):380.2
[M+1]+。
The tert-butyl group (2- ((2- acrylamido -5- methoxyl group -6- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-
Base) amino) pyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22g)
By the tert-butyl group (2- ((2- acrylamido -6- amino -5- pyridinyl methoxy -3- bases) (methyl) amino) ethyl (first
Base) carbamate (22f) (8.6mg, 0.023mmol), 3- (2- chloropyrimide -4- bases) -1- Methyl-1H-indoles (1h,
6.6mg,0.027mmol)、Pd2(dba)3(3.4mg, 0.0036mmol), BINAP (2.2mg, 0.0036mmol) and cesium carbonate
Dioxane (0.5mL) mixture of (11mg, 0.034mmol) is heated to 100 DEG C of reaction 2.5h.Dilute, dichloromethane
Extraction.Evaporated under reduced pressure solvent, residue over silica gel column chromatography purification, eluant is 95:5 methylene chloride-methanol, obtains tertiary fourth
Base (2- ((2- acrylamido -5- methoxyl group -6- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) pyridine -
3- yls) (methyl) amino) ethyl (methyl) carbamate (22g) (3.3mg, 25%).MS-ESI(m/z):586.3[M+1
]+。
N- (3- ((2- (dimethylamino) ethyl) (methyl) amino) -5- methoxyl group -6- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridine -2- bases) acrylamide (22)
Under room temperature, to the tert-butyl group (2- ((2- acrylamido -5- methoxyl group -6- ((4- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22g) dichloromethane (3.3mg)
Alkane (0.5mL) solution adds trifluoroacetic acid (0.5mL).Mixture is stirred at room temperature 40 minutes.Solvent evaporated, adds NaBH (OAc)3
(3.5mg), 1,2- dichloroethanes (0.3mL) and formaldehyde (37% water, 15mg).Mixture is stirred at room temperature 1h, and sodium bicarbonate dilutes,
Dichloromethane is extracted.Crude product Jing silica gel column chromatography purification, eluant is 95:4:1 methylene chloride-methanol-ammonia, obtains N-
(3- ((2- (dimethylamino) ethyl) (methyl) amino) -5- methoxyl group -6- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-
Base) amino) pyridine -2- bases) acrylamide (22) (2.5mg, 89%).MS-ESP:501.4[M+1]+。
Embodiment 23
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide (23)
N
2
- (2- (dimethylamino) ethyl) -6- methoxyl group-N
2
- methyl-N
5
- (4- (1- Methyl-1H-indole -3- bases) is phonetic
Pyridine -2- bases) -3- nitropyridines -2,5- diamidogen (23a)
The preparation of title compound 23a according to the synthetic method of embodiment 2, by N1- (5- iodo -6- methoxyl group -3- nitros
Pyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (2g) is substituted for N2- (2- (dimethylamino) ethyl) -6- methoxies
Base-N2- Methyl-3-nitropyridine -2,5- diamidogen (15e).MS-ESI(m/z):477[M+1]+。
N
2
- (2- (dimethylamino) ethyl) -6- methoxyl group-N
2
- methyl-N
5
- (4- (1- Methyl-1H-indole -3- bases) is phonetic
Pyridine -2- bases) pyridine -2,3,5- triamines (23b)
The preparation of title compound 23b according to the synthetic method of 15i, by N1- (5- iodo -6- methoxyl group -3- nitro pyrroles
Pyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15h) is substituted for N2- (2- (dimethylamino) ethyl) -6- methoxies
Base-N2- methyl-N5- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -3- nitropyridines -2,5- diamidogen (23a).MS-
ESI(m/z):447[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide (23)
By N2- (2- (dimethylamino) ethyl) -6- methoxyl group-N2- methyl-N5- (4- (1- Methyl-1H-indole -3- bases) is phonetic
Pyridine -2- bases) pyridine -2,3,5- triamines (23b) (20mg, 0.045mmol), HOBT (18mg, 0.135mmol), EDCI (26mg,
0.135), DMF (2ml) mixture of triethylamine (14mg, 0.135mmol) stirs 3h at 35 DEG C.Reaction is cooled to room temperature, plus
Water (5mL) is quenched.Mixture adjusts pH 9～10, ethyl acetate (8mL × 3) with sodium carbonate.Merge organic layer, saline (20mL)
Wash, sodium sulfate is dried.Solids removed by filtration, the concentration of filtrate low pressure, residue by silicagel column chromatography purification, eluant is dichloromethane
Alkane/methanol (10:1), obtain N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl -
1H- indol-3-yls) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide (23).MS-ESI(m/z):518[M+1
]+。
Embodiment 24
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) phenyl) -2- fluoropropene amide (24)
N
1
- (2- (dimethylamino) ethyl) -5- methoxyl group-N
1
- methyl -2- Nitrobenzol -1,4- diamidogen (24a)
By the fluoro- 2- methoxyl groups -5- nitroanilines (3.0g, 16.0mmol) of 4- (according to document WO2013/14448 prepare),
N1,N1,N2The DMA mixture of-Trimethylethane -1,2- diamidogen (2.0g, 19.7mmol) and DIPEA (2.7g, 20.8mmol) exists
80 DEG C of stirring 5h, are cooled to room temperature.DMA is evaporated, add water (50mL) dilution, dichloromethane extraction (50mL × 3).Merge organic
Layer, water (100mL) and saline (100mL) are washed, and sodium sulfate is dried, solids removed by filtration, the concentration of filtrate low pressure, residue over silica gel
Column chromatography purification, eluant is methylene chloride/methanol (20:1～10:1), N is obtained1- (2- (dimethylamino) ethyl) -5- methoxies
Base-N1- methyl -2- Nitrobenzol -1,4- diamidogen (24a).MS-ESI(m/z):269[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) phenyl) -2- fluoropropene amide (24)
The preparation of title compound 24 according to the synthetic method of embodiment 23, by N2- (2- (methoxyl group) ethyl) -6- methoxies
Base-N2- Methyl-3-nitropyridine -2,5- diamidogen (15e) is substituted for N1- (2- (dimethylamino) ethyl) -5- methoxyl group-N1- first
Base -2- Nitrobenzol -1,4- diamidogen (24a).MS-ESI(m/z):517[M+1]+。
Embodiment 25
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl indolizine -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (25)
1- (2- ethyoxyl -2- oxygen ethyls) -2- ethylpyridines -1-ization bromine (25a)
To in ethanol (200mL) mixture of 2- ethylpyridines (10g, 0.09mol) add 2- bromoacetates (23g,
0.14mmol), 16h is heated to reflux, is subsequently cooled to room temperature, low pressure concentration, the crude product 1- (2- ethyoxyl -2- oxygen second for obtaining
Base) -2- ethylpyridines -1-ization bromine (25a) without be further purified for next step reaction.MS-ESI(m/z):194[M]+。
Ethyl 1- methyl indolizine -3- carboxylates (25b)
To 1- (2- ethyoxyl -2- oxygen ethyls) -2- ethylpyridines -1-ization bromine (25a) (10g, 0.036mol) and potassium carbonate
Middle addition (the E)-ethyl 2- cyano group -3- ethoxy acrylates of the ethanol solution (100mL) of (15g, 0.10mol) (25g,
0.14mol).Mixture is heated to reflux 15h, is subsequently cooled to room temperature, concentrating under reduced pressure, the extraction of residue ethyl acetate (50mL ×
3).The organic layer of merging is washed with salt, and sodium sulfate is dried, and is filtered, concentrating under reduced pressure.Residue silica gel column chromatography purification, eluant
For n-hexane/ethyl acetate (50:1～20:1) ethyl 1- methyl indolizine -3- carboxylates (25b), is obtained.MS-ESI(m/z):
275[M+1]+。
N- methoxyl group-N, 1- dimethyl indolizine -3- amide (25c)
At 0 DEG C, to ethyl 1- methyl indolizine -3- carboxylates (25b) (3.0g, 0.014mol) and N, O- dimethylhydroxylamine hydrochloric acid
Isopropylmagnesium chloride (2M in Et are added in tetrahydrofuran (50mL) solution of salt (3.6g, 0.037mol)2O,35mL,
0.07mol).Add water after mixture stirring 1h and be quenched, ethyl acetate extraction (50mL × 3).Merge organic layer, salt washing, sulphuric acid
Sodium is dried, and filters, concentrating under reduced pressure, residue silica gel column chromatography purification, and eluant is n-hexane/ethyl acetate (20:1～10:
1) N- methoxyl group-N, 1- dimethyl indolizine -3- amide (25c), are obtained.MS-ESI(m/z):219[M+1]+。
1- (1- methyl indolizine -3- bases) ethyl ketone (25d)
At 0 DEG C, to N- methoxyl group-N, the tetrahydrofuran of 1- dimethyl indolizine -3- amide (25c) (2.6g, 0.012mol)
Methyl-magnesium-bromide (3M ether, 8.0mL, 0.024mol) is added in solution (50mL).Add water after mixture stirring 1h and be quenched, acetic acid
Ethyl ester extracts (50mL × 3).Merge organic layer, salt washing, sodium sulfate is dried, filters, and concentrating under reduced pressure obtains crude product 1- (1- first
Base indolizine -3- bases) ethyl ketone (25d), reacts without being further purified for next step.MS-ESI(m/z):174[M+1]+。
(E) -1- (1- methyl indolizine -3- bases) -3- (pyrrolidin-1-yl) propyl- 2- alkene -1- ketone (25e)
At 25 DEG C, to the DMF-DMA (25mL) of 1- (1- methyl indolizine -3- bases) ethyl ketone (25d) (2.0g, 0.012mol)
Pyrrolidine (10mL, 0.12mol) is added in solution.After 90 DEG C of stirring 1h of mixture, ethyl acetate extraction (50mL × 3).It is organic
Layer is washed with salt, and sodium sulfate is dried, and is filtered, concentrating under reduced pressure.Residue silica gel column chromatography purification, eluant is normal hexane/acetic acid
Ethyl ester (10:1～2:1) (E) -1- (1- methyl indolizine -3- bases) -3- (pyrrolidin-1-yl) propyl- 2- alkene -1- ketone (25e), is obtained.
MS-ESI(m/z):255[M+1]+。
4- (1- methyl indolizine -3- bases) pyrimidine -2- amine (25f)
At 25 DEG C, to (E) -1- (1- methyl indolizine -3- bases) -3- (pyrrolidin-1-yl) propyl- 2- alkene -1- ketone (25e)
In isopropanol (10mL) solution of (1.0g, 0.0039mol) and potassium carbonate (2.7g, 0.012mol) add guanidine hydrochloride (1.1g,
0.19mol).After 130 DEG C of stirring 16h of mixture, room temperature, ethyl acetate extraction (50mL × 3) are cooled to.Organic layer saline
Wash, sodium sulfate is dried, filter, concentrating under reduced pressure.Residue silica gel column chromatography purification, eluant is methylene chloride/methanol (30:1),
Obtain 4- (1- methyl indolizine -3- bases) pyrimidine -2- amine (25f).MS-ESI(m/z):225[M+1]+。
N
2
- (2- (dimethylamino) ethyl) -6- methoxyl group-N
2
- methyl-N
5
- (4- (1- methyl indolizine -3- bases) pyrimidine -2-
Base) -3- nitropyridines -2,5- diamidogen (25g)
At 25 DEG C, to 4- (1- methyl indolizine -3- bases) pyrimidine -2- amine (25f) (150mg, 0.67mmol), N1- (5- iodine
Generation -6- methoxyl group -3- nitropyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15c) (382mg, 0.33mmol
Xantphos is added with toluene (5mL) and 1,4- dioxane (2.5mL) solution of cesium carbonate (0.87g, 2.67mmol)
The palladium (75mg, 0.33mmol) of (193mg, 0.33mmol).Stir after 3h at 110 DEG C of mixture, be cooled to room temperature, acetic acid
Ethyl ester extracts (50mL x 3).Organic layer is washed with salt, and sodium sulfate is dried, and is filtered, concentrating under reduced pressure.Residue silica gel column chromatography is pure
Change, eluant is methylene chloride/methanol (40:1～20:1), N is obtained2- (2- (dimethylamino) ethyl) -6- methoxyl group-N2- first
Base-N5- (4- (1- methyl indolizine -3- bases) pyrimidine -2-base) -3- nitropyridines -2,5- diamidogen (25g).MS-ESI(m/z):477
[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl indolizine -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (25)
The preparation of title compound 25 according to the synthetic method of embodiment 15, by N1- (5- iodo -6- methoxyl group -3- nitros
Pyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15c) is substituted for N2- (2- (dimethylamino) ethyl) -6- methoxies
Base-N2- methyl-N5- (4- (1- methyl indolizine -3- bases) pyrimidine -2-base) -3- nitropyridines -2,5- diamidogen (25g).MS-ESI
(m/z):501[M+1]+。
Embodiment 26
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl indolizine -3- bases)
Pyrimidine -2-base) amino) phenyl) acrylamide (26)
N
1
- (4- iodo -5- methoxyl group -2- nitrobenzophenones)-N
1
,N
2
,N
2
- Trimethylethane -1,2- diamidogen (26a)
At 0 DEG C, to N1- (2- (dimethylamino) ethyl) -5- methoxyl group-N1- methyl -2- Nitrobenzol -1,4- diamidogen (24a)
Sodium nitrite (1.28g, 17.9mmol) is added in the 1N sulfuric acid solutions (50mL) of (3.2g, 11.9mmol).0 DEG C of stirring of mixture
15 minutes, it is subsequently adding potassium iodide (4.0g, 23.8mmol).90 DEG C of stirring 1h of mixture, are cooled to room temperature, and with sodium carbonate pH is adjusted
9～10.The mixture for obtaining is extracted with ethyl acetate (20mL × 3), merges organic layer, and saline (20mL) is washed, and sodium sulfate is dried,
Filter, concentrating under reduced pressure.Residue silica gel column chromatography purification, eluant is methylene chloride/methanol (20:1), N is obtained1- (4- iodine
Generation -5- methoxyl group -2- nitrobenzophenones)-N1,N2,N2- Trimethylethane -1,2- diamidogen (26a).MS-ESI(m/z):380[M+1
]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl indolizine -3- bases)
Pyrimidine -2-base) amino) phenyl) acrylamide (26)
The preparation of title compound 26 according to the synthetic method of embodiment 25, by N1- (5- iodo -6- methoxyl group -3- nitros
Pyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15c) is substituted for N1- (4- iodo -5- methoxyl group -2- Nitrobenzol
Base)-N1,N2,N2- Trimethylethane -1,2- diamidogen (26a).MS-ESI(m/z):500[M+1]+。
Embodiment 27
N- (5- ((4- (1- cyano group indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -6- methoxypyridine -3- bases) acrylamide (27)
1- (2- ethyoxyl -2- oxygen ethyls) pyridine -1-ization bromine (27a)
To in ethanol (200mL) mixture of pyridine (10g, 0.09mol) add 2- bromoacetates (23g,
0.14mmol), 16h is heated to reflux, is subsequently cooled to room temperature, low pressure concentration, the crude product 1- (2- ethyoxyl -2- oxygen ethyls) for obtaining
Pyridine -1-ization bromine (27a) without be further purified for next step reaction.MS-ESI(m/z):167[M]+。
Ethyl 1- cyano group indolizine -3- carboxylates (27b)
To 1- (2- ethyoxyl -2- oxygen ethyls) pyridines -1-ization bromine (27a) (10g, 0.04mol) and triethylamine (29mL,
(E) -3- methacrylonitriles (10g, 0.12mol) are added in ethanol solution (250mL) 0.2mol).Mixture is heated to reflux
15h, is subsequently cooled to room temperature, concentrating under reduced pressure, residue ethyl acetate extraction (50mL × 3).The organic layer of merging is washed with salt,
Sodium sulfate is dried, and filters, concentrating under reduced pressure.Residue silica gel column chromatography purification, eluant is n-hexane/ethyl acetate (50:1～
20:1) ethyl 1- cyano group indolizine -3- carboxylates (27b), is obtained.MS-ESI(m/z):215[M+1]+。
N- (5- ((4- (1- cyano group indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -6- methoxypyridine -3- bases) acrylamide (27)
The preparation of title compound 27 according to the synthetic method of embodiment 25, by ethyl 1- methyl indolizine -3- carboxylates
(25b) it is substituted for ethyl 1- cyano group indolizine -3- carboxylates (27b).MS-ESI(m/z):501[M+1]+。
Embodiment 28
N- (5- ((4- (1- cyano group indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -4- methoxyphenyls) acrylamide (28)
The preparation of title compound 28 according to the synthetic method of embodiment 27, by N1- (5- iodo -6- methoxyl group -3- nitros
Pyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15c) is substituted for N1- (4- iodo -5- methoxyl group -2- Nitrobenzol
Base)-N1,N2,N2- Trimethylethane -1,2- diamidogen (26a).MS-ESI(m/z):511[M+1]+。
Embodiment 29
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizine -3- bases) pyrimidine -2-base) amino) -
6- methoxypyridine -3- bases) acrylamide (29)
2- ethylpyridines are substituted for 2- methyl pyrroles by the preparation of title compound 29 according to the synthetic method of embodiment 25
Pyridine.MS-ESI(m/z):487[M+1]+。
Embodiment 30
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizine -3- bases) pyrimidine -2-base) amino) -
4- methoxyphenyls) acrylamide (30)
The preparation of title compound 30 according to the synthetic method of embodiment 29, by N1- (5- iodo -6- methoxyl group -3- nitros
Pyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15c) is substituted for N1- (4- iodo -5- methoxyl group -2- Nitrobenzol
Base)-N1,N2,N2- Trimethylethane -1,2- diamidogen (26a).MS-ESI(m/z):486[M+1]+。
Embodiment 31
N- (5- ((4- (1- chlorine indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -6- methoxypyridine -3- bases) acrylamide (31)
Ethyl indolizine -3- carboxylates (31a)
The preparation of title compound ethyl indolizine -3- carboxylates (31a) according to the synthetic method of compound 25b, by 2- second
Yl pyridines are substituted for 2- picolines.MS-ESI(m/z):190[M+1]+。
Ethyl 1- chlorine indolizine -3- carboxylates (31b)
At 0 DEG C, N- chlorine is added in DMF (5mL) solution of ethyl indolizine -3- carboxylates (31a) (0.4g, 2.2mmol)
For succimide (0.3g, 2.2mmol), 1h is stirred at 25 DEG C of mixture, ethyl acetate extraction (50mL × 3). merging has
Machine layer is washed with salt, and sodium sulfate is dried, concentrating under reduced pressure.Residue silica gel column chromatography purification, eluant is n-hexane/ethyl acetate
(50:1) ethyl 1- chlorine indolizine -3- carboxylates (31b), is obtained.MS-ESI(m/z):224[M+1]+。
N- (5- ((4- (1- chlorine indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia Base) -6- methoxypyridine -3- bases) acrylamide(31)
The preparation of title compound 31 according to the synthetic method of embodiment 25, by ethyl 1- methyl indolizine -3- carboxylates
(25b) it is substituted for ethyl 1- chlorine indolizine -3- carboxylates (31b).MS-ESI(m/z):521[M+1]+。
Embodiment 32
N- (5- ((4- (1- chlorine indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -4- methoxyphenyls) acrylamide (32)
The preparation of title compound 32 according to the synthetic method of embodiment 31, by N1- (5- iodo -6- methoxyl group -3- nitros
Pyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15c) is substituted for N1- (4- iodo -5- methoxyl group -2- Nitrobenzol
Base)-N1,N2,N2- Trimethylethane -1,2- diamidogen (26a).MS-ESI(m/z):520[M+1]+。
Embodiment 33
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- methyl indolizine -1- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (33)
3- methyl indolizine -1- formonitrile HCNs (33a)
By 2- bromine propionic aldehyde (7.26g, 53.4mmol) and the tetrahydrofuran (70mL) of 2- pyridylacetonitriles (6.3g, 53.4mmol)
70 DEG C of mixture heating 24h.Mixture concentrating under reduced pressure, residue ethyl acetate and hydrochloric acid (20mL, 2M) dilute, and organic layer is used
Saturated sodium bicarbonate solution and salt are washed, and sodium sulfate is dried, concentrating under reduced pressure.Residue residue silica gel column chromatography purification, eluting
Agent is petrol ether/ethyl acetate (10:1～5:1) 3- methyl indolizine -1- formonitrile HCNs (33a), is obtained.MS-ESI(m/z):157[M+
1]+。
1- (3- methyl indolizine -1- bases) ethane -1- imines (33b)
Under ice-water bath, add in the tetrahydrofuran solution of 3- methyl indolizine -1- formonitrile HCNs (33a) (1.6g, 10.3mmol)
3M methyl-magnesium-bromides (18mL), are stirred at room temperature 15h.Mixture is quenched with saturated ammonium chloride solution, dichloromethane extraction.Organic layer
Jing salt is washed, and sodium sulfate is dried, and is concentrated under reduced pressure to give 1- (3- methyl indolizine -1- bases) ethane -1- imines (33b).MS-ESI(m/
z):173[M+1]+。
1- (3- methyl indolizine -1- bases) ethane -1- ketone (33c)
Under room temperature, to the tetrahydrofuran of 1- (3- methyl indolizine -1- bases) ethane -1- imines (33b) (1.0g, 5.8mmol)
Solution adds 6N sulphuric acid (60mL), is heated to 55 DEG C of reaction 24h, is cooled to room temperature.Reactant mixture water and dichloromethane are dilute
Release, isolate organic layer, washed with saturated sodium bicarbonate solution and salt, sodium sulfate is dried, concentrating under reduced pressure.Residue residue silicon
It is gel column chromatography eluting, obtain 1- (3- methyl indolizine -1- bases) ethane -1- ketone (33c).MS-ESI(m/z):174[M+1]+。
1- (3- methyl indolizine -1- bases) -3- (pyrrolidin-1-yl) propyl- 2- alkene -1- ketone (33d)
At 25 DEG C, to the DMF solution of 1- (3- methyl indolizine -1- bases) ethane -1- ketone (33c) (110mg, 0.7mmol)
Middle addition DMF-DMA (170mg, 1.4mmol) and pyrrolidine (50mg, 0.7mmol).After 90 DEG C of stirring 1.5h of mixture.Cooling
To room temperature, ethyl acetate extraction.Organic layer is washed with salt, and sodium sulfate is dried, and is concentrated under reduced pressure to give crude product 1- (3- methyl Yin
Piperazine -1- bases) -3- (pyrrolidin-1-yl) propyl- 2- alkene -1- ketone (33d).MS-ESI(m/z):255[M+1]+。
4- (3- methyl indolizine -1- bases) pyrimidine -2- amine (33e)
To 1- (3- methyl indolizine -1- bases) -3- (pyrrolidin-1-yl) propyl- 2- alkene -1- ketone (33d) (300mg, 1.2mmol)
Aqueous isopropanol in add guanidine hydrochloride (337mg, 3.5mmol) and potassium carbonate (662mg, 4.8mmol).Mixture is in tube sealing
20h is stirred in 120 DEG C.It is cooled to room temperature, ethyl acetate extraction.Organic layer is washed with salt, and sodium sulfate is dried, and is filtered, and is reduced pressure dense
Contracting obtains 4- (3- methyl indolizine -1- bases) pyrimidine -2- amine (33e).MS-ESI(m/z):225[M+1]+。
N
2
- (2- (dimethylamino) ethyl) -6- methoxyl group-N
2
- methyl-N
5
- (4- (3- methyl indolizine -3- bases) pyrimidine -2-
Base) -3- nitropyridines -2,5- diamidogen (33f)
Under nitrogen protection, by 4- (3- methyl indolizine -1- bases) pyrimidine -2- amine (33e) (30.0mg, 0.13mmol), 25c
(76.0mg, 0.20mmol), palladium (15.0mg, 0.07mmol), Xantphos (38.0mg, 0.07mmol) and cesium carbonate
The toluene (1mL) of (170mg, 0.52mmol) and the mixture of dioxane (0.5mL) are heated to 110 DEG C of reaction 3h.It is cooled to
Room temperature, dilute, ethyl acetate extraction.Organic layer is washed with salt, and sodium sulfate is dried, concentrating under reduced pressure.Residue silica gel column layer
Analysis purification, eluant is 9% ethanol/methylene, obtains N2- (2- (dimethylamino) ethyl) -6- methoxyl group-N2- methyl-
N5- (4- (3- methyl indolizine -3- bases) pyrimidine -2-base) -3- nitropyridines -2,5- diamidogen (33f).MS-ESI(m/z):477[M+
1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- methyl indolizine -1- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (33)
The preparation of title compound 33 according to the synthetic method of embodiment 15, by N1- (5- iodo -6- methoxyl group -3- nitros
Pyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15c) is substituted for N2- (2- (dimethylamino) ethyl) -6- methoxies
Base-N2- methyl-N5- (4- (3- methyl indolizine -3- bases) pyrimidine -2-base) -3- nitropyridines -2,5- diamidogen (33f).MS-ESI
(m/z):501[M+1]+.
Embodiment 34
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- methyl indolizine -1- bases)
Pyrimidine -2-base) amino) phenyl) acrylamide (34)
The preparation of title compound 34 according to the synthetic method of embodiment 33, by N1- (5- iodo -6- methoxyl group -3- nitros
Pyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15c) is substituted for N1- (4- iodo -5- methoxyl group -2- Nitrobenzol
Base)-N1,N2,N2- Trimethylethane -1,2- diamidogen (26a).MS-ESI(m/z):500[M+1]+。
Embodiment 35
N- (5- ((4- (3- cyano group indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -6- methoxypyridine -3- bases) acrylamide (35)
1- acetyl indolizine -3- formonitrile HCNs (35a)
By 1- (cyanogen methyl) pyridine -1-ization bromine (10g, 50.3mmol), 4- methoxyl group butyl- 3- alkene -2- ketone (5.1g,
50.3mmol) with 80 DEG C of heating 7h of ethanol (100mL) mixture of triethylamine (10g, 100.6mmol).Reactant mixture reduces pressure
Concentration, residue from dichloromethane and water dilute, and separate organic layer, and salt washing, sodium sulfate is dried, concentration.Residue is in isopropyl
0.5h is stirred in alcohol, is filtered, be dried to obtain yellow solid 1- acetyl indolizine -3- formonitrile HCNs (35a).MS-ESI(m/z):185[M+1
]+。
1- (3- (pyrrolidin-1-yl) acryloyl group) indolizine -3- formonitrile HCNs (35b)
DMF- is added in the DMF solution of 1- (3- methyl indolizine -1- bases) ethane -1- ketone (33c) (110mg, 0.7mmol)
DMA (170mg, 1.4mmol) and pyrrolidine (50mg, 0.7mmol).After 90 DEG C of stirring 1.5h of mixture.After being cooled to room temperature, second
Acetoacetic ester is extracted.Organic layer is washed with salt, and sodium sulfate is dried, and is concentrated under reduced pressure to give crude product 1- (3- methyl indolizine -1- bases) -3-
(pyrrolidin-1-yl) propyl- 2- alkene -1- ketone (33d).To the DMF of 1- acetyl indolizine -3- formonitrile HCNs (35a) (400mg, 2.17mmol)
DMF-DMA (516mg, 4.34mmol) and pyrrolidine (308mg, 4.34mmol) are added in solution.90 DEG C of stirring 1.5h of mixture
Afterwards.After being cooled to room temperature, ethyl acetate extraction.Organic layer is washed with salt, and sodium sulfate is dried, and is concentrated under reduced pressure to give crude product 1- (3-
(pyrrolidin-1-yl) acryloyl group) indolizine -3- formonitrile HCNs (35b).MS-ESI(m/z):266[M+1]+。
1- (the close pyridine -4- bases of 2- amino) indolizine -3- formonitrile HCNs (35c)
To the n-butyl alcohol of 1- (3- (pyrrolidin-1-yl) acryloyl group) indolizine -3- formonitrile HCNs (35b) (637mg, 2.4mmol)
Guanidine hydrochloride (690mg, 7.2mmol) and potassium carbonate (1.3g, 9.6mmol) are added in solution.After 115 DEG C of stirring 20h of mixture.It is cold
But to room temperature, dilute, ethyl acetate extraction.Organic layer is washed with salt, and sodium sulfate is dried, and is concentrated under reduced pressure to give crude product 1-
(the close pyridine -4- bases of 2- amino) indolizine -3- formonitrile HCNs (35c).MS-ESI(m/z):236[M+1]+。
N- (5- ((4- (3- cyano group indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -6- methoxypyridine -3- bases) acrylamide (35)
The preparation of title compound 35 according to the synthetic method of embodiment 33, by 4- (3- methyl indolizine -1- bases) pyrimidine -2-
Amine (33e) is substituted for 1- (the close pyridine -4- bases of 2- amino) indolizine -3- formonitrile HCNs (35c).MS-ESI(m/z):512[M+1]+。
Embodiment 36
N- (5- ((4- (3- cyano group indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -4- methoxyphenyls) acrylamide (36)
The preparation of title compound 36 according to the synthetic method of embodiment 35, by N1- (5- iodo -6- methoxyl group -3- nitros
Pyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15c) is substituted for N1- (4- iodo -5- methoxyl group -2- Nitrobenzol
Base)-N1,N2,N2- Trimethylethane -1,2- diamidogen (26a).MS-ESI(m/z):511[M+1]+。
Embodiment 37
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizine -1- bases) pyrimidine -2-base) amino) -
6- methoxypyridine -3- bases) acrylamide (37)
1- (2- ethyoxyl -2- oxygen ethyls) pyridine -1-ization bromine (37a)
To in ethanol (200mL) mixture of pyridine (10g, 0.09mol) add 2- bromoacetates (23g,
0.14mmol), 16h is heated to reflux, is subsequently cooled to room temperature, crude product 1- (2- ethyoxyl -2- oxygen ethyls) pyridine -1-ization for obtaining
Bromine (27a) without be further purified for next step reaction.MS-ESI(m/z):167[M]+.Under a nitrogen, by pyridine
70 DEG C of heating 1h of ethanol (20mL) solution of (2.00g, 25.30mmol) and 2- bromoacetates (6.3g, 38.00mmol).Subtract
Pressure concentration, residue pad kieselguhr is filtered, and petroleum ether obtains 6.9 grams of 1- (2- ethyoxyl -2- oxygen ethyls) pyridine -1-ization
Bromine (37a).MS-ESI(m/z):167[M+1]+。
Ethyl 1- acetyl indolizine -3- carboxylates (37b)
1- (2- ethyoxyl -2- oxygen ethyls) pyridines -1-ization bromine (27a) (10g, 0.04mol) and triethylamine (29mL,
(E) -3- methacrylonitriles (10g, 0.12mol) are added in ethanol solution (250mL) 0.2mol).Mixture is heated to reflux
15h, concentrating under reduced pressure, residue (50mL × 3).The organic layer of merging is washed with salt, and sodium sulfate is dried, and is filtered, concentrating under reduced pressure.It is residual
Excess silica gel column chromatography purification, eluant is n-hexane/ethyl acetate (50:1～20:1) ethyl 1- cyano group indolizine -3-, are obtained
Carboxylate.At 20 DEG C, to 1- (2- ethyoxyl -2- oxygen ethyls) pyridines -1-ization bromine (37a) (5.50g, 15.10mmol) and 4- first
The ethanol solution (65mL) of the ketone (2.3g, 22.3mmol) of epoxide butyl- 3- alkene -2 adds triethylamine (4.50g, 44.60mmol).It is mixed
80 DEG C of compound is heated overnight, and is subsequently cooled to room temperature, dilute, ethyl acetate extraction (3 × 50mL).Organic layer decompression is dense
Contracting.Residue silica gel column chromatography purification obtains ethyl 1- acetyl indolizine -3- carboxylates (37b) (2.65g).MS-ESI(m/z):
232[M+1]+。
1- (indolizine -1- bases) ethane -1- ketone (37c)
At 20 DEG C, to the methanol solution (30mL) of ethyl 1- acetyl indolizine -3- carboxylates (37b) (2.60g, 11.3mmol)
Add 10% sodium hydroxide (2.0g, 50.6m mol).65 DEG C of heating 1h of mixture, concentrating under reduced pressure removes solvent, adds poly phosphorus
Sour (10.0g) and methanol (40ml), 65 DEG C of mixture is heated 40 minutes.It is cooled to room temperature, dilute, dichloromethane extraction (3
× 50mL) extract sodium bicarbonate and salt washing, sodium sulfate be dried, be concentrated to give 1- (indolizine -1- bases) ethane -1- ketone (37c)
(1.23g)。MS-ESI(m/z):160[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizine -1- bases) pyrimidine -2-base) amino) -
6- methoxypyridine -3- bases) acrylamide (37)
The preparation of title compound 37 replaces 1- acetyl indolizine -3- formonitrile HCNs (35a) according to the synthetic method of embodiment 35
Into 1- (indolizine -1- bases) ethane -1- ketone (37c).MS-ESI(m/z):487[M+1]+。
Embodiment 38
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizine -1- bases) pyrimidine -2-base) amino) -
4- methoxyphenyls) acrylamide (38)
The preparation of title compound 38 according to the synthetic method of embodiment 37, by N1- (5- iodo -6- methoxyl group -3- nitros
Pyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15c) is substituted for N1- (4- iodo -5- methoxyl group -2- Nitrobenzol
Base)-N1,N2,N2- Trimethylethane -1,2- diamidogen (26a).MS-ESI(m/z):486[M+1]+。
Embodiment 39
N- (5- ((4- (3- chlorine indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -6- methoxypyridine -3- bases) acrylamide (39)
1- (3- chlorine indolizine -1- bases) ethane -1- ketone (39a)
The acetonitrile (6mL) of 1- (indolizine -1- bases) ethane -1- ketone (37c), Cu-lyt. (962mg, 5.7mmol) is mixed
Thing is stirred at room temperature 4h, and add water (10mL) dilution, dichloromethane extraction (3 × 10mL).Extract sodium sulfate is dried, concentrating under reduced pressure.
Residue silica gel column chromatography purification, eluant is petrol ether/ethyl acetate (8:1～6:1) 1- (3- chlorine indolizine -1- bases), is obtained
Ethane -1- ketone (39a).MS-ESI(m/z):194[M+1]+。
N- (5- ((4- (3- chlorine indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -6- methoxypyridine -3- bases) acrylamide (39)
The preparation of title compound 39 replaces 1- acetyl indolizine -3- formonitrile HCNs (35a) according to the synthetic method of embodiment 35
Into 1- (3- chlorine indolizine -1- bases) ethane -1- ketone (39a).MS-ESI(m/z):521[M+1]+。
Embodiment 40
N- (5- ((4- (3- chlorine indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -4- methoxyphenyls) acrylamide (40)
The preparation of title compound 40 according to the synthetic method of embodiment 39, by N1- (5- iodo -6- methoxyl group -3- nitros
Pyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15c) is substituted for N1- (4- iodo -5- methoxyl group -2- Nitrobenzol
Base)-N1,N2,N2- Trimethylethane -1,2- diamidogen (26a).MS-ESI(m/z):520[M+1]+。
Embodiment 41
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- Methyl-1H-indole -1-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (41)
1- (2- chloropyrimide -4- bases) -3- Methyl-1H-indoles (41a)
Under room temperature, to 2,4- dichloro pyrimidines (2.89g, 20.0mmol) and 3- Methyl-1H-indoles (1.31g, 10.0mmol)
DMA (50mL) solution add HOBT (306mg, 2.0mmol) and potassium carbonate (1.93g, 14.0mmol), 70 DEG C of mixture to stir
24h, add water (50mL) dilution, ethyl acetate extraction (2 × 30mL). and extract salt is washed, and sodium sulfate is dried, concentrating under reduced pressure.It is residual
Excess silica gel column chromatography purification, eluant is petrol ether/ethyl acetate (10:1～5:1), obtain 1- (2- chloropyrimide -4- bases) -
3- Methyl-1H-indoles (41a), be yellow solid (1g, 40%).
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- Methyl-1H-indole -1-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (41)
As the preparation of title compound 41 (17.3mg) same to 1, by 3- (2- chloropyrimide -4- bases) -1- Methyl-1H-indoles
(1h) 1- (2- chloropyrimide -4- bases) -3- Methyl-1H-indoles (41a) are substituted for.MS-ESI(m/z):501[M+1]+。
Embodiment 42
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- Methyl-1H-indole -1-
Base) pyrimidine -2-base) amino) phenyl) acrylamide (42)
N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (3- Methyl-1H-indole -1- bases) pyrimidine -2- amine (42a)
By 1- (2- chloropyrimide -4- bases) -3- Methyl-1H-indoles (41a) (278mg, 1.14mmol), the fluoro- 2- methoxies of 4-
Base -5- nitroanilines (213mg, 1.14mmol) (being prepared according to document WO2013/14448) and a hydration p-methyl benzenesulfonic acid
2- amylalcohols (4mL) mixture of (260mg, 1.37mmol) heats 105 DEG C of reaction 2h, filters, and (4- is fluoro- to be concentrated under reduced pressure to give N-
2- methoxyl group -5- nitrobenzophenones) and -4- (3- Methyl-1H-indole -1- bases) pyrimidine -2- amine (42a) (320mg, 72%).MS-ESI
(m/z):394[M+1]+。
N
1
- (2- (dimethylamino) ethyl) -5- methoxyl group-N
1
- methyl-N
4
- (4- (3- Methyl-1H-indole -1- bases) is phonetic
Pyridine -2- bases) -2- Nitrobenzol -1,4- diamidogen (42b)
By N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (3- Methyl-1H-indole -1- bases) pyrimidine -2- amine (42a)
(160mg,0.407mmol)、N1,N1,N2- Trimethylethane -1,2- diamidogen (0.064mL, 0.489mmol) and DIPEA
The DMA mixture of (0.088mL, 0.529mmol) heats 3h at 85 DEG C.Concentrating under reduced pressure, residue by silicagel column chromatography purification, washes
De- agent is methylene chloride/methanol/ammonia (92:6:2), N is obtained1- (2- (dimethylamino) ethyl) -5- methoxyl group-N1- methyl-N4-
(4- (3- Methyl-1H-indole -1- bases) pyrimidine -2-base) -2- Nitrobenzol -1,4- diamidogen (42b) (139mg, 73%).
MS-ESI(m/z):476[M+1]+。
N
1
- (2- (dimethylamino) ethyl) -5- methoxyl group-N
1
- methyl-N
4
- (4- (3- Methyl-1H-indole -1- bases) is phonetic
Pyridine -2- bases) -2- Nitrobenzol -1,4- diamidogen (42c)
By N1- (2- (dimethylamino) ethyl) -5- methoxyl group-N1- methyl-N4- (4- (3- Methyl-1H-indole -1- bases) is phonetic
Pyridine -2- bases) -2- Nitrobenzol -1,4- diamidogen (42b) (139mg, 0.293mmol), iron powder (98mg, 1.76mmol) and ammonium chloride
The alcohol-water (3 of (22.0mg, 0.293mmol):1,15mL) mixture is heated to reflux 1h.Pad kieselguhr is filtered, and ethyl acetate is washed
Wash, cleaning mixture adds diluted ethyl acetate, water and salt to wash.Evaporated under reduced pressure solvent, residue by silicagel column chromatography purification, eluant
For methylene chloride/methanol/ammonia (92:6:2), N is obtained1- (2- (dimethylamino) ethyl) -5- methoxyl group-N1- methyl-N4-(4-
(3- Methyl-1H-indole -1- bases) pyrimidine -2-base) and -2- Nitrobenzol -1,4- diamidogen (42c) (120mg, 92%).MS-ESI(m/
z):446[M+1]+。
The chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- methyl isophthalic acid H- Yin
Diindyl -1- bases) pyrimidine -2-base) amino) phenyl) propionic acid amide. (42d)
At 0 DEG C, to N1- (2- (dimethylamino) ethyl) -5- methoxyl group-N1- methyl-N4- (4- (3- Methyl-1H-indoles-
1- yls) pyrimidine -2-base) -2- Nitrobenzol -1,4- diamidogen (42c) (120mg, 0.27mmol) tetrahydrofuran-water (10:1,3mL)
Mixture adds 3- chlorpromazine chlorides (0.031mL, 0.32mmol), 0 DEG C of stirring 2h to add ammonia (0.5mL), dilute, second
Acetoacetic ester is extracted.Solvent evaporated, residue by silicagel column chromatography purification, eluant is 2-5% ethanol/methylene, obtains 3-
(((4- (3- Methyl-1H-indole -1- bases) is phonetic for 2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- for chloro- N-
Pyridine -2- bases) amino) phenyl) propionic acid amide. (42d) (100mg, 69%).MS-ESI(m/z):536[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- Methyl-1H-indole -1-
Base) pyrimidine -2-base) amino) phenyl) acrylamide (42)
Under room temperature, to the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3-
Methyl-1H-indole -1- bases) pyrimidine -2-base) amino) phenyl) propionic acid amide. (42d) (100mg, 0.187mmol) tetrahydrofuran -
Water (10:1,2mL) solution adds sodium hydroxide (60mg, 1.5mmol), stirs 2h, dilute, ethyl acetate extraction.Decompression
Solvent evaporated, residue by silicagel column chromatography purification, eluant is 1-2% ethanol/methylene, obtains N- (2- ((2- (diformazans
Amino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- Methyl-1H-indole -1- bases) pyrimidine -2-base) amino) benzene
Base) and acrylamide (42) (60mg, 65%).MS-ESI(m/z):500[M+1]+。
Embodiment 43
N- (6- methoxyl group -5- ((4- (3- Methyl-1H-indole -1- bases) pyrimidine -2-base) amino) -2- (4- methyl piperazines -
1- yls) pyridin-3-yl) acrylamide (43)
N- (4- methoxyl group -5- ((4- (3- Methyl-1H-indole -1- bases) pyrimidine -2-base) amino) -2- (piperazine -1- bases)
Phenyl) acrylamide (43a)
The preparation of title compound 43a (10mg) according to the synthetic method of embodiment 41, by N1,N1,N2- Trimethylethane-
1,2- diamidogen is substituted for t-butylpiperazine -1- carboxylates.MS-ESI(m/z):485[M+1]+。
N- (6- methoxyl group -5- ((4- (3- Methyl-1H-indole -1- bases) pyrimidine -2-base) amino) -2- (4- methyl piperazines -
1- yls) pyridin-3-yl) acrylamide (43)
The preparation of title compound 43 (4.9mg) according to the synthetic method of embodiment 6, by N- (6- ethyoxyl -2- (methyl
(2- (methylamino) ethyl) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) pyridin-3-yl) third
Acrylamide (5) is substituted for N- (4- methoxyl group -5- ((4- (3- Methyl-1H-indole -1- bases) pyrimidine -2-base) amino) -2- (piperazines
Piperazine -1- bases) phenyl) acrylamide (43a).MS-ESI(m/z):499[M+1]+。
Embodiment 44
N- (4- methoxyl group -5- ((4- (3- Methyl-1H-indole -1- bases) pyrimidine -2-base) amino) -2- (4- methyl piperazines -
1- yls) phenyl) acrylamide (44)
The preparation of title compound 44 according to the synthetic method of embodiment 42, by N1,N1,N2- Trimethylethane -1,2- two
Amine is substituted for 1- methyl piperazines.MS-ESI(m/z):498[M+1]+。
Embodiment 45
N- (5- ((4- (3- cyano-1 H-indol -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl)
(methyl) amino) -6- methoxypyridine -3- bases) acrylamide (45)
1- (2- chloropyrimide -4- bases) -1H- indole -3-formonitriles (45b)
Title compound 1- (2- chloropyrimide -4- bases) -1H- indole -3-formonitriles (45b) preparation (220mg) is according to 41a's
Synthetic method, 3- Methyl-1H-indoles are substituted for into 1H- indole -3-formonitriles (45a), and (preparation method of this reagent is according to text
Offer：JOC 1958,23,1178).MS-ESI(m/z):255[M+1]+。
N- (5- ((4- (3- cyano-1 H-indol -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl)
(methyl) amino) -6- methoxypyridine -3- bases) acrylamide (45)
The preparation of title compound 45 (7.0mg) according to the synthetic method of embodiment 15, by 3- (2- chloropyrimide -4- bases) -
The fluoro- 1- Methyl-1H-indoles (15g) of 7- are substituted for 1- (2- chloropyrimide -4- bases) -1H- indole -3-formonitriles (45b).MS-ESI(m/
z):512[M+1]+。
Embodiment 46
N- (5- ((4- (3- cyano-1 H-indol -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl)
(methyl) amino) -4- methoxyphenyls) acrylamide (46)
The preparation of title compound 46 (5mg) according to the synthetic method of embodiment 45, by N2- (2- (dimethylamino) second
Base) -6- methoxyl group-N2- Methyl-3-nitropyridine -2,5- diamidogen (15e) is substituted for N1- (2- (dimethylamino) ethyl) -5- first
Epoxide-N1- methyl -2- nitropyridines -1,4- diamidogen (24a).MS-ESI(m/z):511[M+1]+。
Embodiment 47
N- (5- ((4- (1- chlorine imidazoles [1,5-a] and pyridin-3-yl) pyrimidine -2-base) amino) -2- ((2- (dimethylamino)
Ethyl) (methyl) amino) -6- methoxypyridine -3- bases) acrylamide (47)
2- (first sulfydryl)-N- (pyridine -2- bases) pyrimidine -4- amide (47a)
By pyridine -2- base methylamines (900mg, 8.3mmol), 2- (first sulfydryl) pyrimidine -4- carboxylic acids (1g, 5.9mmol) (according to
Document WO2006/117368 prepare), HOBT (2.4g, 17.7mmol), EDCI (3.4g, 17.7mmol), triethylamine (1.78g,
DMF (10ml) mixture 17.7mmol) is stirred at room temperature 2h.Reaction be cooled to room temperature, add water (10mL) be quenched, sodium carbonate adjust pH
9～10, ethyl acetate extraction (15mL × 3).Merge organic layer, salt washing (20mL), sodium sulfate is dried, solids removed by filtration,
Filtrate concentrates, residue by silicagel column chromatography purification, and eluant is petrol ether/ethyl acetate (2:1～1:1) 2- (first mercaptos, are obtained
Base)-N- (pyridine -2- bases) pyrimidine -4- amide (47a).MS-ESI(m/z):247[M+1]+。
3- (2- (first sulfydryl) pyrimidine-4-yl) imidazoles [1,5-a] and pyridine (47b)
By the acetonitrile solution of 2- (first sulfydryl)-N- (pyridine -2- bases) pyrimidine -4- amide (47a) (370mg, 1.5mmol)
(2mL) phosphorus oxychloride (2.5mL), 85 DEG C of stirring 20h of mixture are added.Room temperature is cooled to, is quenched with water (10mL).Use hydroxide
Sodium adjusts pH 8-9, dichloromethane extraction (8mL × 3).Merge organic layer, salt washing (20mL), sodium sulfate is dried, and concentrating under reduced pressure is obtained
To crude product 3- (2- (first sulfydryl) pyrimidine-4-yl) imidazoles [1,5-a] and pyridine (47b).MS-ESI(m/z):243[M+1]+。
The chloro- 3- of 1- (2- (first sulfydryl) pyrimidine-4-yl) imidazoles [1,5-a] and pyridine (47c)
Under room temperature, to 3- (2- (first sulfydryl) pyrimidine-4-yl) imidazoles [1,5-a] and pyridine (200mg, 0.83mmol)
DMF (2mL) solution adds N- chlorosuccinimides (144mg, 1.08mmol), and 2h is stirred at room temperature, and adds water and is quenched (5mL).
The mixture for arriving extracts (5mL × 2) with dichloromethane, merges organic layer, and salt washing (10mL), sodium sulfate is dried, concentrating under reduced pressure
Obtain the chloro- 3- of crude product 1- (2- (first sulfydryl) pyrimidine-4-yl) imidazoles [1,5-a] and pyridine (47c).MS-ESI(m/z):277[M+
1]+。
4- (1- chlorine imidazoles [1,5-a] and pyridin-3-yl) pyrimidine -2- alcohol (47d)
To the chloro- 3- of 1- (2- (first sulfydryl) pyrimidine-4-yl) imidazoles [1,5-a] and pyridine (47c) (150mg, 0.54mmol)
NMP (5mL) solution in add 10% sodium hydroxide (2mL), 100 DEG C of stirring 24h.Reaction is cooled to room temperature, is adjusted with 2N hydrochloric acid
pH 5-6.The mixture for obtaining extracts (10mL × 3) with dichloromethane, merges organic layer, and salt washing (20mL), sodium sulfate is done
It is dry, it is concentrated to give crude product 4- (1- chlorine imidazoles [1,5-a] and pyridin-3-yl) pyrimidine -2- alcohol (47d).MS-ESI(m/z):247[M
+1]+。
A- chloro- 3- (2- chloropyrimide -4- bases) imidazoles [1,5-a] and pyridine (47e)
By the acetonitrile of 4- (1- chlorine imidazoles [1,5-a] and pyridin-3-yl) pyrimidine -2- alcohol (47d) (140mg, 0.57mmol)
Solution (1mL) adds phosphorus oxychloride (1mL), 80 DEG C of stirring 1.5h of mixture to be cooled to room temperature, be quenched with water (5mL).Use hydrogen-oxygen
Change sodium and adjust pH 8-9, dichloromethane extraction (8mL × 3).Merge organic layer, salt washing (20mL), sodium sulfate is dried, concentrating under reduced pressure
Obtain the chloro- 3- of crude product 1- (2- chloropyrimide -4- bases) imidazoles [1,5-a] and pyridine (47e).MS-ESI(m/z):265[M+1]+。
N
1
- (4- (1- chlorine imidazoles [1,5-a] and pyridin-3-yl) pyrimidine -2-base)-N
4
- (2- (dimethylamino) ethyl) -2-
Methoxyl group-N
4
- methyl-5-nitro benzene -1,4- diamidogen (47f)
By the chloro- 3- of 1- (2- chloropyrimide -4- bases) imidazoles [1,5-a] and pyridine (47e) (54mg, 0.20mmol), N2-(2-
(dimethylamino) ethyl) -6- methoxyl group-N2- Methyl-3-nitropyridine -2,5- diamidogen (15e) (61mg, 0.22mmol) and first
90 DEG C of stirring 3h of isopropanol (2.5mL) mixture of sulfonic acid (27mg, 0.24mmol), cooling reaction adds water (10mL) to room temperature
It is quenched, sodium carbonate adjusts pH 8～9, ethyl acetate extraction (30mL × 3).Merge organic layer, water (30mL) and salt washing (30mL),
Sodium sulfate is dried, solids removed by filtration, filtrate concentration, and residue by silicagel column chromatography purification, eluant is methylene chloride/methanol
(10:1), N is obtained1- (4- (1- chlorine imidazoles [1,5-a] and pyridin-3-yl) pyrimidine -2-base)-N4- (2- (dimethylamino) ethyl)-
2- methoxyl group-N4- methyl-5-nitro benzene -1,4- diamidogen (47f).MS-ESI(m/z):498[M+1]+。
N- (5- ((4- (1- chlorine imidazoles [1,5-a] and pyridin-3-yl) pyrimidine -2-base) amino) -2- ((2- (dimethylamino)
Ethyl) (methyl) amino) -6- methoxypyridine -3- bases) acrylamide (47)
The preparation of title compound (47) according to the synthetic method of embodiment 15, by N2- (2- (dimethylamino) ethyl)-N5-
(4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-base) -6- methoxyl group-N2- Methyl-3-nitropyridine -2,5- diamidogen
(15h) it is substituted for N1- (4- (1- chlorine imidazoles [1,5-a] and pyridin-3-yl) pyrimidine -2-base)-N4- (2- (dimethylamino) ethyl)-
2- methoxyl group-N4- methyl-5-nitro benzene -1,4- diamidogen (47f).MS-ESI(m/z):468[M+1]+。
Embodiment 48
N- (5- ((4- (1- chlorine imidazoles [1,5-a] and pyridin-3-yl) pyrimidine -2-base) amino) -2- ((2- (dimethylamino)
Ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (48)
The preparation of title compound 48 according to the synthetic method of embodiment 47, by N2- (2- (dimethylamino) ethyl) -6- first
Epoxide-N2- Methyl-3-nitropyridine -2,5- diamidogen (15e) is substituted for N1- (2- (dimethylamino) ethyl) -5- methoxyl group-N1-
Methyl -2- nitropyridines -1,4- diamidogen (24a).MS-ESI(m/z):521[M+1]+。
Embodiment 49
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- (trifluoromethyl) imidazoles
[1,5-a] and pyridin-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (49)
1- iodo -3- (2- (first sulfydryl) pyrimidine-4-yl) imidazoles [1,5-a] and pyridine (49a)
Under room temperature, to 3- (2- (first sulfydryl) pyrimidine-4-yl) imidazoles [1,5-a] and pyridine (47b) (300mg,
DMF (5mL) solution 1.24mmol) adds N-iodosuccinimide (362mg, 1.61mmol), stirs under mixture room temperature
2h.Reaction water (5mL) is quenched, the mixed liquor (8mL × 2) that dichloromethane is obtained by extraction.Merge organic layer, saline (10mL)
Wash, sodium sulfate is dried, and is concentrated under reduced pressure to give 1- iodo -3- (2- (first sulfydryl) pyrimidine-4-yl) imidazoles [1,5-a] and pyridine
(49a)。MS-ESI(m/z):369[M+1]+。
3- (2- (first sulfydryl) pyrimidine-4-yl) -1- (trifluoromethyl) imidazoles [1,5-a] and pyridine (49b)
By 1- iodo -3- (2- (first sulfydryl) pyrimidine-4-yl) imidazoles [1,5-a] and pyridine (49a) (200mg,
0.54mmol), (trifluoromethyl) trimethyl silane (153mg, 1.08mmol), orthophenanthroline (194mg, 1.08mmol), front three
Ylboronic acid ester (112mg, 1.08mmol), potassium fluoride (63mg, 1.08mmol) and Hydro-Giene (Water Science). (I) (154mg, 0.81mmol)
60 DEG C of dimethyl sulfoxide (5mL) mixture is stirred overnight.Cooling reaction to room temperature, add water (10mL) be quenched, ethyl acetate extraction
(10mL×3).Merge organic layer, washed with water (20mL) and saline (20mL), sodium sulfate is dried, solids removed by filtration, filtrate
Concentration, residue by silicagel column chromatography purification, eluant is ethyl acetate/petroleum ether (1:2) (2- (first sulfydryl) is phonetic, to obtain 3-
Pyridine -4- bases) -1- (trifluoromethyl) imidazoles [1,5-a] and pyridine (49b).MS-ESI(m/z):311[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- (trifluoromethyl) imidazoles
[1,5-a] and pyridin-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (49)
The preparation of title compound 49 according to the synthetic method of embodiment 47, by the chloro- 3- of 1- (2- (first sulfydryl) pyrimidine -4-
Base) imidazoles [1,5-a] and pyridine (47c) is substituted for 3- (2- (first sulfydryl) pyrimidine-4-yl) -1- (trifluoromethyl) imidazoles [1,5-
A] and pyridine (49b).MS-ESI(m/z):556[M+1]+。
Embodiment 50
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- (trifluoromethyl) imidazoles
[1,5-a] and pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (50)
The preparation of title compound 50 according to the synthetic method of embodiment 47, by N2- (2- (dimethylamino) ethyl) -6- first
Epoxide-N2- Methyl-3-nitropyridine -2,5- diamidogen (15e) is substituted for N1- (2- (dimethylamino) ethyl) -5- methoxyl group-N1-
Methyl -2- nitropyridines -1,4- diamidogen (24a).MS-ESI(m/z):555[M+1]+。
Embodiment 51
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methylimidazole .s [1,5-a]
And pyridin-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (51)
1- methyl -3- (2- (first sulfydryl) pyrimidine-4-yl) imidazoles [1,5-a] and pyridine (51a)
Pyridine -2- base methylamines are substituted for 1- (pyridine -2- by the preparation of title compound 51a according to the synthetic method of 47b
Base) ethane -1- amine.MS-ESI(m/z):257[M+1]+。
3- (2- chloropyrimide -4- bases) -1- Methylimidazole .s [1,5-a] and pyridine (51b)
The preparation of title compound 51b according to the synthetic method of 47e, by the chloro- 3- of 1- (2- (first sulfydryl) pyrimidine-4-yl) miaow
Azoles [1,5-a] and pyridine (47c) is substituted for 1- methyl -3- (2- (first sulfydryl) pyrimidine-4-yl) imidazoles [1,5-a] and pyridine
(51a)。MS-ESI(m/z):245[M+1]+。
N
2
- (2- (dimethylamino) ethyl) -6- methoxyl group-N
2
- methyl-N
5
- (4- (1- Methylimidazole .s [1,5-a] and pyridine-
3- yls) pyrimidine -2-base) pyridine -2,3,5- triamines (51c)
The preparation of title compound (51c) according to the synthetic method of 15i, by 3- (2- chloropyrimide -4- bases) the fluoro- 1- first of -7-
Base -1H- indole (15g) is substituted for 3- (2- chloropyrimide -4- bases) -1- Methylimidazole .s [1,5-a] and pyridine (51b).MS-ESI(m/
z):448[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methylimidazole .s [1,5-a]
And pyridin-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (51)
The preparation of title compound 51 according to the synthetic method of embodiment 15, by N2- (2- (dimethylamino) ethyl)-N5-
(4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-base) -6- methoxyl group-N2- methyl-N2- picoline -2,3,5- three
Amine (15i) is substituted for N2- (2- (dimethylamino) ethyl) -6- methoxyl group-N2- methyl-N5- (4- (1- Methylimidazole .s [1,5-a] and
Pyridin-3-yl) pyrimidine -2-base) pyridine -2,3,5- triamines (51c).MS-ESI(m/z):502[M+1]+。
Embodiment 52
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- (Methylimidazole. [1,5-
A] and pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (52)
The preparation of title compound 52 according to the synthetic method of embodiment 51, by N2- (2- (dimethylamino) ethyl) -6- first
Epoxide-N2- Methyl-3-nitropyridine -2,5- diamidogen (15e) is substituted for N1- (2- (dimethylamino) ethyl) -5- methoxyl group-N1-
Methyl -2- nitropyridines -1,4- diamidogen (24a).MS-ESI(m/z):501[M+1]+.
Embodiment 53
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methylimidazole .s [1,5-a]
And pyridin-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide (53)
The preparation of title compound (53) according to the synthetic method of embodiment 23, by N2- (2- (dimethylamino) ethyl) -6-
Methoxyl group-N2- methyl-N5- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) pyridine -2,3,5- triamines (23b) is substituted for
N2- (2- (dimethylamino) ethyl) -6- methoxyl group-N2- methyl-N5- (4- (1- Methylimidazole .s [1,5-a] and pyridine-
3- yls) pyrimidine -2-base) pyridine -2,3,5- triamines (51c).MS-ESI(m/z):520[M+1]+。
Embodiment 54
N- (5- ((4- (1,2- pyrrolin [3,2,1-hi] indole -5- bases) pyrimidine -2-base) amino) -2- ((2- (diformazans
Amino) ethyl) (methyl) amino) -6- methoxypyridine -3- bases) acrylamide (54)
2- (2- nitrobenzophenones) ethanol (54a)
By 1- methyl -2- Nitrobenzol (48g, 0.35mol), formaldehyde (10.4g, 0.35mol), 20% sodium hydroxide
(3.6ml) with 50 DEG C of heating 2h of mixture of dimethyl sulfoxide, then mixture is cooled to room temperature, dilute (200mL), acetic acid second
Ester extracts (300mL × 3).Merge organic layer, water (200mL × 2) and saline (200mL) are washed, and sodium sulfate is dried, be filtered to remove solid
Body, filtrate concentration, residue by silicagel column chromatography purification, eluant is ethyl acetate/petroleum ether (1:1) 2- (2- nitros, are obtained
Phenyl) ethanol (54a), be brown oil (14.4g, 25%).
Fert-butyidimethylsilyl (2- nitrophenethyloxies) silane (54b)
Add in dry methylene chloride (15ml) solution of 2- (2- nitrobenzophenones) ethanol (54a) (1.7g, 0.01mol)
Imidazoles (0.88g, 0.013mol) and tert-butyl chloro-silicane (2.1g, 0.014mol), are stirred at room temperature 2h.Then filter mixed
Compound, dichloromethane (30mL) dilution, 1N hydrochloric acid (30mL), water and sodium bicarbonate aqueous solution are washed, and merge organic layer, and sodium sulfate is done
Dry, solids removed by filtration, filtrate is concentrated to give fert-butyidimethylsilyl (2- nitrophenethyloxies) silane (54b), is brown oil
(2.8g, 97%).
7- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -1H- indole (54c)
- 70 DEG C, under nitrogen, to the dry of fert-butyidimethylsilyl (2- nitrophenethyloxies) silane (54b) (4.5g, 16mmol)
Dry tetrahydrofuran (50ml) solution Deca vinyl magnesium bromide (56ml, 56mmol).Mixture is to slowly warm up to room temperature, will mix
Thing pours aqueous ammonium chloride solution, ethyl acetate extraction (50mL) into.Merge organic layer, sodium sulfate is dried, solids removed by filtration, filtrate
Concentration, residue by silicagel column chromatography purification, eluant is ethyl acetate/petroleum ether (1:100) 7- (the 2- ((tert-butyl groups, are obtained
Dimethyl silicon substrate) epoxide) ethyl) -1H- indole (54c), be yellow oily (2.6g, 59%).MS-ESI(m/z):276[M+1
]+。
2- (3- (2- chloropyrimide -4- bases) -1H- indole -7- bases) ethanol (54d)
The preparation of title compound 54d (0.33g, 30%, brown solid) according to the synthetic method of 15g, by the fluoro- 1- first of 7-
Base -1H- indole (15f) is substituted for 7- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -1H- indole (54c).MS-ESI
(m/z):274[M+1]+。
7- (2- chloroethyls) -3- (2- chloropyrimide -4- bases) -1H- indole (54e)
At 0 DEG C, by 2- (3- (2- chloropyrimide -4- bases) -1H- indole -7- bases) ethanol (54d) (50mg, 0.18mmol)
It is dried CAN (5ml) suspension Deca sulphinyl chlorine (0.44mg, 0.36mmol).The mixture for obtaining is stirred overnight at room temperature, cooling
To room temperature, sodium bicarbonate aqueous solution (20ml) extraction, ethyl acetate extraction (20mL).Merge organic layer, water (20mL × 2) and salt
Water (200mL) is washed, anhydrous sodium sulfate drying, solids removed by filtration, filtrate concentration, residue by silicagel column chromatography purification, eluting
Agent is ethyl acetate/petroleum ether (1:3) 7- (2- chloroethyls) -3- (2- chloropyrimide -4- bases) -1H- indole (54e), is obtained, is palm fibre
Color solid (0.30g, 50%).MS-ESI(m/z):292[M+1]+。
5- (2- chloropyrimide -4- bases) -1,2- pyrrolin [3,2,1-hi] indole (54f)
Under room temperature, to 7- (2- chloroethyls) -3- (2- chloropyrimide -4- bases) -1H- indole (54e) (33mg, 0.11mmol)
DMF (3ml) solution adds cesium carbonate (78mg, 0.22mmol), 60 DEG C of heating 10h.Mixture is cooled to room temperature, adds water and is quenched
(20ml), ethyl acetate extraction (20mL).Merge organic layer, water (20mL × 2) and saline (200mL) are washed, and anhydrous sodium sulfate is done
Dry, solids removed by filtration, filtrate is concentrated to give 5- (2- chloropyrimide -4- bases) -1,2- pyrrolin [3,2,1-hi] indole
(54f), be brown solid (0.30g, 100%).MS-ESI(m/z):256[M+1]+。
N- (5- ((4- (1,2- pyrrolin [3,2,1-hi] indole -5- bases) pyrimidine -2-base) amino) -2- ((2- (diformazans
Amino) ethyl) (methyl) amino) -6- methoxypyridine -3- bases) acrylamide (54)
The preparation of title compound 54 (5.0mg) according to 15 synthetic method, by 3- (2- chloropyrimide -4- bases) the fluoro- 1- of -7-
Methyl-1H-indole (15g) is substituted for 5- (2- chloropyrimide -4- bases) -1,2- pyrrolin [3,2,1-hi] indole (54f).MS-
ESI(m/z):513[M+1]+。
Embodiment 55
N- (5- ((4- (1,2- pyrrolin [3,2,1-hi] indole -5- bases) pyrimidine -2-base) amino) -2- ((2- (diformazans
Amino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (55)
The preparation of title compound (55) according to the synthetic method of embodiment 54, by N1- (5- iodo -6- methoxyl group -3- nitre
Yl pyridines -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15c) is substituted for N1- (4- iodo -5- methoxyl group -2- nitros
Phenyl)-N1,N2,N2- Trimethylethane -1,2- diamidogen (24a).MS-ESI(m/z):512[M+1]+。
Embodiment 56
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- methyl isophthalic acid H- indazole -1-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (56)
3- methyl isophthalic acids H- indazoles (56a)
Under room temperature, to ethane -1 of 1- (2- fluorophenyls) ethyl ketone (20g, 0.14mol), 2- glycol (70ml) solution adds water
Hydrazine (4.7ml, 0.15mol) is closed, this temperature 2h is kept, 150 DEG C is then heated to overnight.Mixture is cooled to room temperature, adds water
(200ml) it is quenched, dichloromethane extraction (200mL).Merge organic layer, water (200mL × 2) and saline (200mL) are washed, anhydrous sulfur
Sour sodium is dried, solids removed by filtration, filtrate concentration, and residue by silicagel column chromatography purification, eluant is ethyl acetate/petroleum ether
(1:20), obtain 3- methyl isophthalic acids H- indazoles (56a), be brown solid (7g, 37%).MS-ESI(m/z):133[M+1]+。
1- (2- chloropyrimide -4- bases) -3- methyl isophthalic acids H- indazoles (56b)
At 0 DEG C, sodium hydride is added to the DMF solution that is dried of 3- methyl isophthalic acids H- indazoles (56a) (1.1g, 8.3mmol), kept
This temperature 2h, is subsequently adding 2,4- dichloro pyrimidines (1.24g, 8.3mmol), and the mixture for obtaining is stirred overnight at room temperature.Add chlorine
Change aqueous ammonium (20ml) to be quenched, ethyl acetate extraction (50mL).Merge organic layer, water (50mL × 2) and saline (50mL) are washed,
Anhydrous sodium sulfate drying, solids removed by filtration, filtrate concentration, residue by silicagel column chromatography purification, eluant be ethyl acetate/
Petroleum ether (1:20), obtain 1- (2- chloropyrimide -4- bases) -3- methyl isophthalic acids H- indazoles (56b), be white solid (0.85g,
43%).MS-ESI(m/z):245[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- methyl isophthalic acid H- indazole -1-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (56)
The preparation of title compound 56 (8.0mg) according to the synthetic method of embodiment 15, by 3- (2- chloropyrimide -4- bases) -
The fluoro- 1- Methyl-1H-indoles (15g) of 7- are substituted for 1- (2- chloropyrimide -4- bases) -3- methyl isophthalic acids H- indazoles (56b).MS-ESI(m/
z):502[M+1]+。
Embodiment 57
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- methyl isophthalic acid H- indazole -1-
Base) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide (57)
The preparation of title compound 57 (5.0mg) according to the synthetic method of embodiment 23, by 3- (2- chloropyrimide -4- bases) -
1- Methyl-1H-indoles (1h) are substituted for 1- (2- chloropyrimide -4- bases) -3- methyl isophthalic acids H- indazoles (56b).MS-ESI(m/z):520
[M+1]+。
Embodiment 58
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl isophthalic acid H- indazole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (58)
1- (1- methyl isophthalic acid H- indazole -3- bases) ethyl ketone (58a)
The preparation method of title compound 58a is according to document：J.Heterocyclic Chem.,2013,50:E221.
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl isophthalic acid H- indazole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (58)
The preparation of title compound 58 according to the synthetic method of embodiment 25, by 1- (1- methyl indolizine -3- bases) ethyl ketone
(25d) it is substituted for 1- (1- methyl isophthalic acid H- indazole -3- bases) ethyl ketone (58a).MS-ESI(m/z):502[M+1]+。
Embodiment 59
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl isophthalic acid H- indazole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide (59)
N
2
- (2- (dimethylamino) ethyl) -6- methoxyl group-N
2
(4- (1- methyl isophthalic acid H- indazole -3- bases) is phonetic for-methyl-N5-
Pyridine -2- bases) -3- nitropyridines -2,5- diamidogen (59a)
The preparation of compound 59a according to the synthetic method of embodiment 25, by 1- (1- methyl indolizine -3- bases) ethyl ketone (25d)
It is substituted for 1- (1- methyl isophthalic acid H- indazole -3- bases) ethyl ketone (58a).MS-ESI(m/z):448[M+1]+。
N
2
- (2- (dimethylamino) ethyl) -6- methoxyl group-N
2
(4- (1- methyl isophthalic acid H- indazole -3- bases) is phonetic for-methyl-N5-
Pyridine -2- bases) pyridine -2,3,5- triamines (59b)
The preparation of title compound 59b according to the synthetic method of 15i, by N1- (5- iodo -6- methoxyl group -3- nitro pyrroles
Pyridine -2- bases)-N1,N2,N2- Trimethylethane -1,2- diamidogen (15h) is substituted for N2- (2- (dimethylamino) ethyl) -6- methoxies
Base-N2- methyl-N5- (4- (1- methyl isophthalic acid H- indazole -3- bases) pyrimidine -2-base) -3- nitropyridines -2,5- diamidogen (59a).MS-
ESI(m/z):447[M+1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl isophthalic acid H- indazole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide (59)
The preparation of title compound (59) according to the synthetic method of embodiment 23, by N2- (2- (dimethylamino) ethyl) -6-
Methoxyl group-N2- methyl-N5- (4- (1- methyl isophthalic acid H- indazole -3- bases) pyrimidine -2-base) pyridine -2,3,5- triamines (23b) is substituted for
N2- (2- (dimethylamino) ethyl) -6- methoxyl group-N2- methyl-N5- (4- (1- methyl isophthalic acid H- indazole -3- bases) pyrimidine -2-base) pyrrole
Pyridine -2,3,5- triamines (59b).MS-ESI(m/z):520[M+1]+。
Embodiment 60
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- Methylimidazole .s [1,5-a]
And pyridine -1- bases) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (60)
1- (3- Methylimidazole .s [1,5-a] and pyridine -1- bases) ethane -1- ketone (60a)
Synthetic method of the preparation of title compound 60a according to document：Journal of Chemical society.,
1955,2834。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- Methylimidazole .s [1,5-a]
And pyridine -1- bases) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide (60)
The preparation of title compound 60 according to the synthetic method of embodiment 25, by 1- (1- methyl indolizine -3- bases) ethyl ketone
(25d) it is substituted for 1- (3- Methylimidazole .s [1,5-a] and pyridine -1- bases) ethane -1- ketone (60a).MS-ESI(m/z):502[M+
1]+。
Embodiment 61
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- Methylimidazole .s [1,5-a]
And pyridine -1- bases) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide (61)
N
2
- (2- (dimethylamino) ethyl) -6- methoxyl group-N
2
- methyl-N
5
- (4- (3- Methylimidazole .s [1,5-a] and pyridine-
1- yls) pyrimidine -2-base) pyridine -2,3,5- triamines (61a)
The preparation of title compound 61a according to the synthetic method of embodiment 25, by 1- (1- methyl indolizine -3- bases) ethyl ketone
(25d) it is substituted for 1- (3- Methylimidazole .s [1,5-a] and pyridine -1- bases) ethane -1- ketone (60a).MS-ESI(m/z):448[M+
1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- Methylimidazole .s [1,5-a]
And pyridine -1- bases) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide (61)
The preparation of title compound 61 according to the synthetic method of embodiment 23, by N2- (2- (dimethylamino) ethyl) -6- first
Epoxide-N2- methyl-N5- (4- (1- methyl isophthalic acid H- indazole -3- bases) pyrimidine -2-base) pyridine -2,3,5- triamines (23b) is substituted for
N2- (2- (dimethylamino) ethyl) -6- methoxyl group-N2- methyl-N5- (4- (3- Methylimidazole .s [1,5-a] and pyridine -1- bases) is phonetic
Pyridine -2- bases) pyridine -2,3,5- triamines.MS-ESI(m/z):520[M+1]+。
Cell propagation detection
By determining the inhibitory action that compound is bred to H1975 cells, detection compound is to L858R/T790M EGFR
Inhibitory action.In here experiment, the inhibitory action bred to H1975 cells by detection compound determines compound pair
The inhibitory action of L858R/T790M EGFR.H1975 cell culture is in the RPMI-1640 culture medium containing 40-80% hyclones
In.Take the H1975 cells in exponential phase to be seeded in 96 well culture plates by the density in 3000/ hole, 37 DEG C, 5%CO2Incubate
Educate overnight.In 96 orifice plates add variable concentrations (final concentration 10000,3333.3,1111.1,270.4,123.5,41.2,13.7,
4.6 and 1.5nM) compound, in 37 DEG C, 5%CO2Incubation 72 hours.Culture medium is discarded, the culture per the μ l MTS/100 μ l of hole 20
Base.After incubation 1.5h, 25 μ l 10%SDS terminating reactions are added per hole.The absorption at 490nm and 650nm is measured with microplate reader.
IC is calculated with GraphPad Prism5.050。
By determining the inhibitory action that compound is bred to A431 cells, suppression of the detection compound to Wild type EGFR is made
With.In here experiment, the inhibitory action bred to A431 cells by detection compound determines compound to Wild type EGFR
Inhibitory action.A431 cell culture is in the RPMI-1640 culture medium containing 40-80% hyclones.Take in exponential phase
H1975 cells be seeded in 96 well culture plates by the density in 3000/ hole, 37 DEG C, 5%CO2Overnight incubation.Add in 96 orifice plates
The compound of variable concentrations (final concentration 10000,3333.3,1111.1,270.4,123.5,41.2,13.7,4.6 and 1.5nM),
In 37 DEG C, 5%CO2Incubation 72 hours.Culture medium is discarded, per the μ l MTS/100 μ l culture medium of hole 20.After incubation 1.5h, add per hole
Enter 25 μ l 10%SDS terminating reactions.The absorption at 490nm and 650nm is measured with microplate reader.With GraphPad Prism 5.0
Calculate IC50。
The selected compounds of above-mentioned preparation are tested according to biological method specifically described herein.It the results are shown in Table 1.
Table 1
| Embodiment | H1975IC50(nM) | A431IC50(nM) |
| 1 | 112 | >1000 |
| 15 | 156 | / |
| 16 | 193 | >1000 |
| 17 | 128 | 1213 |
| 18 | 183 | / |
| 19 | 76 | / |
| 20 | 48 | / |
| 21 | 69 | / |
| 23 | 184 | / |
| 24 | 219 | / |
| 25 | 219 | >1000 |
| 27 | 324 | >1000 |
| 32 | 190 | >1000 |
| 36 | 244 | 1193 |
| 38 | 183 | / |
| 41 | 350 | / |
| 50 | 476 | / |
| 51 | 348 | / |
| 53 | 452 | / |
| 54 | 481 | / |
Claims (24)
1. the compound shown at least one formula (I)：
And/or its at least one pharmaceutically acceptable salt,
Wherein：
Q is selected from aryl and heteroaryl；
X is selected from N and C；
Y is selected from N and C；
R1It is selected from：Hydrogen, C1-10Alkyl, C3-10Cycloalkyl, C3-10Cycloalkyl-C1-4Alkyl, heterocyclic radical and heterocyclic radical-C1-4Alkyl, its
In each alkyl, cycloalkyl and heterocyclic radical be unsubstituted or by least one, such as 1,2,3 or 4, be independently selected from R6aTake
Replace for base；
R1’Selected from hydrogen and halogen；
R2And R3It is respectively selected from：Hydrogen, halogen, hydroxyl, CN, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, C3-10Cycloalkyl, C3-10Ring
Alkyl-C1-4Alkyl, heterocyclic radical, heterocyclic radical-C1-4Alkyl, aryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl,
Wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl and heterocyclic radical are unsubstituted or by least one, such as 1,2,3 or 4, solely
It is vertical to be selected from R6aSubstituent group replace, wherein each aryl and heteroaryl are unsubstituted or by least one, such as 1,2,3 or 4
It is individual, it is independently selected from R6bSubstituent group replace；Or R2And R3Together with the carbon atom being connected with them cooperatively constitute one containing 0,
1st, 2 or 3 heteroatomic 5-6 yuan of rings for being independently selected from oxygen, sulfur and nitrogen, the ring can be unsubstituted or is selected from by 1 or 2
R6aSubstituent group replace；
Each R4Independently selected from：Hydrogen, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, C3-10Cycloalkyl ,-OR8、-NR7S(O)rR8、-
NO2,-halogen ,-S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C
(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-
NR7C(O)OR8、-NR7C(O)NR7R8With-CR7(N-OR8)；Wherein each C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl and C3-10Ring
Alkyl is unsubstituted or by least one, such as 1,2,3 or 4, is independently selected from R6aSubstituent group replace；
Each R5Independently selected from：Hydrogen, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, C3-10Cycloalkyl, C3-10Cycloalkyl-C1-4Alkane
Base, heterocyclic radical, heterocyclic radical-C1-4Alkyl, aryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl ,-OR8、-NR7S
(O)rR8、-NO2, halogen ,-S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC
(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8With-CR7(N-OR8), wherein each C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynes
Base, C3-10Cycloalkyl and heterocyclic radical are unsubstituted or by least one, such as 1,2,3 or 4, are independently selected from R6aSubstituent group
Replace；Each aryl and heteroaryl are unsubstituted or by least one, such as 1,2,3 or 4, are independently selected from R6bSubstituent group
Replace；
Each R6aIndependently selected from：C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, C3-10Cycloalkyl ,-OR8、-NR7S(O)rR8、-
NO2, halogen ,-S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-
(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-
(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O
(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)
(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC
(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8With-CR7(N-OR8)；
Each R6bIndependently selected from：R6a, aryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl；
Each R7With each R8Independently selected from：Hydrogen, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, cycloalkyl, cycloalkyl-C1-4Alkane
Base, heterocyclic radical, heterocyclic radical C1-4Alkyl, aryl, heteroaryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl；Wherein
Each alkyl, thiazolinyl, alkynyl, cycloalkyl and heterocyclic radical are unsubstituted or by least one, such as 1,2,3 or 4, independent choosing
From R6aSubstituent group replace, wherein each aryl and heteroaryl are unsubstituted or by least one, such as 1,2,3 or 4, solely
It is vertical to be selected from R6bSubstituent group replace；Or R7And R8Collectively form one together with the single or multiple atoms being connected with them together to contain
There is 0,1 or 2 extra heteroatomic 4-12 circle heterocycles for being independently selected from oxygen, sulfur and N, the ring can be unsubstituted or quilt
1 or 2 is selected from R6bSubstituent group replace；
Each R9With each R10Independently selected from：Hydrogen, C1-10Alkyl, C2-10Thiazolinyl, C2-10Alkynyl, cycloalkyl, cycloalkyl-C1-4Alkane
Base, heterocyclic radical, heterocyclic radical-C1-4Alkyl, aryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl；Or R9And R10One
Rise and collectively formed containing 0,1 or 2 miscellaneous original for being independently selected from oxygen, sulfur and nitrogen together with the single or multiple carbon atoms being connected with them
The 3-7 yuan of rings of son, the ring can be unsubstituted or by 1 or 2 selected from R6aSubstituent group replace；
M is independently selected from 0,1,2 and 3；
N is independently selected from 0,1,2 and 3；
Each r is independently selected from 1 and 2；
Each t is independently selected from 1,2 and 3.
2. at least one compound of claim 1, and/or its at least one pharmaceutically acceptable salt, wherein X is selected from N
And C, Y are selected from C.
3. at least one compound of any one of claim 1-2, and/or its at least one pharmaceutically acceptable salt, its
Middle X is selected from N, and Y is selected from C.
4. at least one compound of any one of claim 1-2, and/or its at least one pharmaceutically acceptable salt, its
Middle X and Y are C, also,
N=2, a R5It is (3R) -3- (dimethylamino) pyrroles -1- bases, (3S) -3- (dimethylamino) pyrroles -1- bases, 3- (diformazans
Amino) azetidin -1- bases, [2- (dimethylamino) ethyl]-(methyl) amino, [2- (methylamino) ethyl] (methyl) amino,
5- methyl -2,5- diaza spiros [3.4] certain herbaceous plants with big flowers -2- bases, (3aR, 6aR) -5- six-hydrogen of methyl-pyrroles [3,4-b] pyrroles -1 (2H) -
Base, 1- methyl isophthalic acids, 2,3,6- tetrahydropyridine -4- bases, 4- methylpiperazine-1-yls, 4- [2- (dimethylamino) -2- oxygen ethyls] piperazine
Piperazine -1- bases, methyl [2- (4- methylpiperazine-1-yls) ethyl] amino, methyl [2- (morpholine -4- bases) ethyl] amino, 1- amino -
1,2,3,6- tetrahydropyridine -4- bases or 4- [(2S) -2- aminopropionyls] piperazine -1- bases, another R5For methoxyl group or methyl,
R1、R1’And R2For hydrogen, and R3For hydrogen, fluorine, chlorine, methyl or cyano group when,
Q is not 4,5,6,7- nafoxidines [1,5-a] pyridin-3-yl, pyrazoles [1,5-a] pyridin-3-yl or 1H- indol-3-yls.
5. at least one compound of any one of claim 1-4, and/or its at least one pharmaceutically acceptable salt, its
Middle structural formula is
6. at least one compound of any one of claim 1-5, and/or its at least one pharmaceutically acceptable salt, its
Middle R1’Selected from hydrogen.
7. at least one compound of any one of claim 1-5, and/or its at least one pharmaceutically acceptable salt, its
Middle R1’Selected from fluorine.
8. at least one compound of any one of claim 1-7, and/or its at least one pharmaceutically acceptable salt, its
Middle R1Selected from hydrogen.
9. at least one compound of any one of claim 1-8, and/or its at least one pharmaceutically acceptable salt, its
Middle R2Selected from hydrogen.
10. at least one compound of any one of claim 1-9, and/or its at least one pharmaceutically acceptable salt, its
Middle R3Selected from hydrogen, halogen and C1-10Alkyl.
At least one compound of 11. claim 10, and/or its at least one pharmaceutically acceptable salt, wherein R3It is selected from
Hydrogen.
At least one compound of any one of 12. claim 1-11, and/or its at least one pharmaceutically acceptable salt,
Wherein Q is selected from heteroaryl.
At least one compound of 13. claim 12, and/or its at least one pharmaceutically acceptable salt, wherein Q is selected from
At least one compound of any one of 14. claim 1-13, and/or its at least one pharmaceutically acceptable salt,
Wherein R4Selected from hydrogen, C1-10Alkyl, halogen and cyano group, wherein C1-10Alkyl is unsubstituted or by least one, such as 1,2,3
Or 4, it is independently selected from R6aSubstituent group replace.
At least one compound of 15. claim 14, and/or its at least one pharmaceutically acceptable salt, wherein R4It is selected from
Hydrogen, methyl, halogen and cyano group, wherein methyl are unsubstituted or are independently selected from R by least one6aSubstituent group replace, more
R well6aFor fluorine.
At least one compound of 16. claim 1-15, and/or its at least one pharmaceutically acceptable salt, wherein R5It is independent
Selected from OR8, heterocyclic radical, NR7R8, wherein heterocyclic radical is unsubstituted or by least one, such as 1,2,3 or 4, is independently selected from
R6aSubstituent group replace.
At least one compound of 17. claim 16, and/or its at least one pharmaceutically acceptable salt, wherein R5Independent choosing
From methoxyl group, ethyoxyl, isopropoxy, piperazine -1- bases, 4- methylpiperazine-1-yls, methyl (2- (methylamino) ethyl) amino,
(2- (dimethylamino) ethyl) (methyl) amino, (2- (ethyl) (methyl) amino) ethyl) (methyl) amino and (methyl (2- (N-
Methyl vinyl amido) ethyl) amino).
18. at least one compounds, are selected from：
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (6- methoxyl group -2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -
2- yls) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (ethyl (methyl) amino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methyl-1H-indoles -
3- yls) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (6- methoxyl group -2- (methyl (2- (N- methylacetamidos) ethyl) amino) -5- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (6- ethyoxyl -2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -
2- yls) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- ethyoxyl -5- ((4- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (6- isopropoxy -2- (methyl (2- (N- methylacetamidos) ethyl) amino) -5- ((4- (1- Methyl-1H-indoles -
3- yls) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- isopropoxy -5- ((4- (1- Methyl-1H-indole -3-
Base) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (piperazine -1- bases) pyridine -
3- yls) acrylamide,
N- (6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (4- methyl piperidine -1-
Base) pyridin-3-yl) acrylamide,
N- (6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (piperidin-1-yl) pyridine -
3- yls) acrylamide,
N- (6- ethyoxyl -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (4- methyl piperidine -1-
Base) pyridin-3-yl) acrylamide,
N- (6- isopropoxy -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (piperidin-1-yl) pyrroles
Pyridine -3- bases) acrylamide,
N- (6- isopropoxy -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (4- methyl piperidine -1-
Base) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -
2- yls) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 6-) pyrimidine -
2- yls) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) pyrimidine -
2- yls) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 4-) pyrimidine -
2- yls) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((the fluoro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -
2- yls) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl)
(methyl) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((5- methyl -4- (1- methyl isophthalic acid H- Yin
Diindyl -3- bases) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (3- ((2- (dimethylamino) ethyl) (methyl) amino) -5- methoxyl group -6- ((4- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) pyridine -2- bases) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- bases)
Pyrimidine -2-base) amino) phenyl) -2- fluoropropene amide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl indolizine -3- bases) pyrimidine -
2- yls) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl indolizine -3- bases) pyrimidine -
2- yls) amino) phenyl) acrylamide,
N- (5- ((4- (1- cyano group indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (1- cyano group indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -4- methoxyphenyls) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizine -3- bases) pyrimidine -2-base) amino) -6- first
Epoxide pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizine -3- bases) pyrimidine -2-base) amino) -4- first
Phenyl) acrylamide,
N- (5- ((4- (1- chlorine indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -
6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (1- chlorine indolizine -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -
4- methoxyphenyls) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- methyl indolizine -1- bases) pyrimidine -
2- yls) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- methyl indolizine -1- bases) pyrimidine -
2- yls) amino) phenyl) acrylamide,
N- (5- ((4- (3- cyano group indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (3- cyano group indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -4- methoxyphenyls) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizine -1- bases) pyrimidine -2-base) amino) -6- first
Epoxide pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizine -1- bases) pyrimidine -2-base) amino) -4- first
Phenyl) acrylamide,
N- (5- ((4- (3- chlorine indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -
6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (3- chlorine indolizine -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -
4- methoxyphenyls) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- Methyl-1H-indole -1- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- Methyl-1H-indole -1- bases)
Pyrimidine -2-base) amino) phenyl) acrylamide,
N- (6- methoxyl group -5- ((4- (3- Methyl-1H-indole -1- bases) pyrimidine -2-base) amino) -2- (4- methyl piperazine -1-
Base) pyridin-3-yl) acrylamide,
N- (4- methoxyl group -5- ((4- (3- Methyl-1H-indole -1- bases) pyrimidine -2-base) amino) -2- (4- methyl piperazine -1-
Base) phenyl) acrylamide,
N- (5- ((4- (3- cyano-1 H-indol -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (3- cyano-1 H-indol -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -4- methoxyphenyls) acrylamide,
N- (5- ((4- (1- chlorine imidazoles [1,5-a] and pyridin-3-yl) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) second
Base) (methyl) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (1- chlorine imidazoles [1,5-a] and pyridin-3-yl) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) second
Base) (methyl) amino) -4- methoxyphenyls) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- (trifluoromethyl) imidazoles [1,5-
A] and pyridin-3-yl) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- (trifluoromethyl) imidazoles [1,5-
A] and pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methylimidazole .s [1,5-a] and pyrrole
Pyridine -3- bases) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- (Methylimidazole. [1,5-a] and
Pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- Methylimidazole .s [1,5-a] and pyrrole
Pyridine -3- bases) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide,
N- (5- ((4- (1,2- pyrrolin [3,2,1-hi] indole -5- bases) pyrimidine -2-base) amino) -2- ((2- (diformazan ammonia
Base) ethyl) (methyl) amino) -6- methoxypyridine -3- bases) acrylamide,
N- (5- ((4- (1,2- pyrrolin [3,2,1-hi] indole -5- bases) pyrimidine -2-base) amino) -2- ((2- (diformazan ammonia
Base) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- methyl isophthalic acid H- indazole -1- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- methyl isophthalic acid H- indazole -1- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl isophthalic acid H- indazole -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (1- methyl isophthalic acid H- indazole -3- bases)
Pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- Methylimidazole .s [1,5-a] and pyrrole
Pyridine -1- bases) pyrimidine -2-base) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6- methoxyl group -5- ((4- (3- Methylimidazole .s [1,5-a] and pyrrole
Pyridine -1- bases) pyrimidine -2-base) amino) pyridin-3-yl) -2- fluoropropene amide,
With its pharmaceutically acceptable salt.
19. pharmaceutical compositions, comprising the arbitrary at least one described compound of claim 1-18 and/or its at least one pharmacy
Upper acceptable salt, and at least one pharmaceutically acceptable carrier.
A kind of 20. methods of the EGFR of regulation and control mutation, including claim 1-18 that effective dose is given to patient in need
Arbitrary at least one described compound and/or its at least one pharmaceutically acceptable salt.
The method that a kind of 21. treatments, improvement or prevention have the symptom of response to the EGFR of mutation inhibiting, including to having what this needed
Patient gives the arbitrary at least one described compound of claim 1-18 of effective dose and/or its and at least one pharmaceutically can connect
The salt received, it is alternative to combine with another medicine.
A kind of 22. methods of manufacture medicine, the medicine is used for treatment the symptom of response, including the medicine to the EGFR of mutation inhibiting
Thing contains at least one compound described in claim 1-18 and/or its at least one pharmaceutically acceptable salt.
A kind of 23. methods for treating cell proliferative disorder, including claim 1- that effective dose is given to patient in need
18 arbitrary at least one described compounds and/or its at least one pharmaceutically acceptable salt, it is alternative with another treatment
Drug regimen.
A kind of 24. methods of the medicine of manufacture treatment cell proliferative disorder, including the medicine contains described in claim 1-18
At least one compound and/or its at least one pharmaceutically acceptable salt.
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| SG11202108311RA (en) | 2019-02-26 | 2021-09-29 | Janssen Biotech Inc | Combination therapies and patient stratification with bispecific anti-egfr/c-met antibodies |
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| US11879013B2 (en) | 2019-05-14 | 2024-01-23 | Janssen Biotech, Inc. | Combination therapies with bispecific anti-EGFR/c-Met antibodies and third generation EGFR tyrosine kinase inhibitors |
| JP2023052711A (en) * | 2020-03-04 | 2023-04-12 | 国立研究開発法人理化学研究所 | Method for releasing compound |
| CA3224994A1 (en) * | 2021-06-22 | 2022-12-29 | Dana-Farber Cancer Institute, Inc. | (1h-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl-amino-phenyl--acrylamide inhibitors of egfr for use in the treatment of brain tumors |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102083800A (en) * | 2008-06-27 | 2011-06-01 | 阿维拉制药公司 | Heteroaryl compounds and uses thereof |
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111170998B (en) * | 2014-11-05 | 2023-04-11 | 益方生物科技(上海)股份有限公司 | Pyrimidine or pyridine compound, preparation method and medical application thereof |
-
2015
- 2015-06-12 CN CN201580031253.8A patent/CN106660993B/en active Active
- 2015-06-12 CN CN202010883613.XA patent/CN111875585B/en active Active
- 2015-06-12 CN CN202010883627.1A patent/CN111892579B/en active Active
- 2015-06-12 WO PCT/CN2015/081332 patent/WO2015188777A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102083800A (en) * | 2008-06-27 | 2011-06-01 | 阿维拉制药公司 | Heteroaryl compounds and uses thereof |
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
Non-Patent Citations (2)
| Title |
|---|
| RICHARD A. WARD,ET AL.: "Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)", 《J. MED. CHEM.》 * |
| 李仁利: "《药物构效关系》", 31 January 2004 * |
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| CN111303123B (en) * | 2020-03-31 | 2021-08-31 | 南京雷正医药科技有限公司 | 2- (2,4, 5-substituted anilino) pyrimidine compound and application thereof |
| CN115701429A (en) * | 2021-08-02 | 2023-02-10 | 上海和誉生物医药科技有限公司 | 4- (1H-indole-1-yl) pyrimidine-2-amino derivative and preparation method and application thereof |
| CN115701429B (en) * | 2021-08-02 | 2024-03-12 | 上海和誉生物医药科技有限公司 | 4- (1H-indol-1-yl) pyrimidine-2-amino derivative, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
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| CN111892579B (en) | 2023-07-25 |
| CN111892579A (en) | 2020-11-06 |
| CN111875585B (en) | 2023-06-23 |
| CN106660993B (en) | 2020-09-11 |
| WO2015188777A1 (en) | 2015-12-17 |
| CN111875585A (en) | 2020-11-03 |
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