CN104844566B - A kind of kinase inhibitor of new structure - Google Patents

A kind of kinase inhibitor of new structure Download PDF

Info

Publication number
CN104844566B
CN104844566B CN201410757626.7A CN201410757626A CN104844566B CN 104844566 B CN104844566 B CN 104844566B CN 201410757626 A CN201410757626 A CN 201410757626A CN 104844566 B CN104844566 B CN 104844566B
Authority
CN
China
Prior art keywords
compound
methyl
synthesis
alkyl
base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201410757626.7A
Other languages
Chinese (zh)
Other versions
CN104844566A (en
Inventor
刘青松
刘静
王强
刘飞扬
王蓓蕾
王傲莉
王文超
胡晨
陈程
赵铮
吴宏
王黎
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hefei Zhongke bio Pharmaceutical Technology Co., Ltd.
Original Assignee
Hefei Zhongke Bio Pharmaceutical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hefei Zhongke Bio Pharmaceutical Technology Co Ltd filed Critical Hefei Zhongke Bio Pharmaceutical Technology Co Ltd
Priority to CN201410757626.7A priority Critical patent/CN104844566B/en
Publication of CN104844566A publication Critical patent/CN104844566A/en
Application granted granted Critical
Publication of CN104844566B publication Critical patent/CN104844566B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Abstract

The present invention provides a kind of compound or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin, composition of medicine or prodrug of Azaindole kinase inhibitors formula (I).These compounds individually can be used for prevention at least one other therapeutic agent or treat the disease, obstruction and illness, autoimmune disease be either affected by it or being directed to tyrosine kinase activity that are adjusted by tyrosine kinase activity, especially cancer and other cell proliferation disorders.

Description

A kind of kinase inhibitor of new structure
Technical field
The present invention relates to new compound and their tautomer and stereoisomer and its officinal salt, ester, acid, The composition and these noval chemical compounds of metabolin or prodrug, these new compounds and pharmaceutical acceptable carrier individually at least one Other therapeutic agent is preventing or is treating by the being either affected by it of tyrosine kinase activity adjusting or be directed to Purposes in the disease of tyrosine kinase activity, obstruction and illness, autoimmune disease, especially cancer and other cells Proliferative diseases.
Background technology
Tyrosine kinase is that γ-phosphoric acid is transferred to the kinases on protein-tyrosine residue on a kind of catalysis ATP, can be catalyzed more Kind substrate protein white matter tyrosine residue phosphorylation, plays an important roll in cell growth, multiplication, differentiation.Kinase function is abnormal It is of great significance in cancer, immune, nerve, metabolism and infectious diseases.About nearly 30 kinds different kinases conducts at present The drug of target spot, the overwhelming majority are used for treating cancer.Majority is to belong to carcinogenic RNA diseases in the protein tyrosine kinase found so far The oncoprotein of poison, can also be generated by the proto-oncogene of vertebrate.
Tyrosine kinase inhibitor can as the competitive inhibitor that atriphos (ATP) is combined with tyrosine kinase, Also the activity of tyrosine kinase as the analog of tyrosine, can be blocked, inhibits cell Proliferation, has developed to be several antitumor Drug.
The kinases encoded in human genome has 518 kinds, and almost each signal transduction process is required to pass through phposphate Cascade reaction (cascade) is got in touch with：Prompting, which inhibits kinase activity, can really eliminate the physiological reaction of cell.For example, suppression Oncogene BCR (Breakpoint cluster region)-ABL fusion proteins processed cause chronic myelogenous leukemia Key factor, tyrosine activity have apparent therapeutic potential.Although ATP-binding site has the conservative of height, can To develop the small molecule on pharmacological characteristic with apparent selectivity.Normal cell can usually be resistant to the inhibition of kinases, because This kills tumour cell for selectivity and provides a window treated.Such as Dasatinib treatments Imatinib is drug resistant slow Property myelogenous leukemia CML, can almost inhibit 9 kinases (and other multiple tyrosine kinase) of SRC families, but with tradition Cell chemotherapy compare, side effect or easily tolerance.Therefore, the exploitation of new kinase inhibitor is with important clinical meaning Justice.
The content of the invention
The present invention provides a kind of Azaindole kinase inhibitors, compound or its pharmaceutically acceptable salt, solvent including formula (I) Compound, ester, acid, metabolin or prodrug：
Wherein Z1, Z2, Z3, Z4 and Z5 are independently selected from CH or N；
X is selected from
R1 is selected from H, halogen, amino, nitro, hydroxyl, C1-C8 alkyl, C1-C8 halogenated alkyls, C1-C8 alkoxyl, C1-C8 Halogenated alkoxy, C1-C8 hydroxyalkyls, optionally by-NH- heteroaryls that 1-3 R6 group substitutes and are selecting C1-C8 alkyl aminos - Y- (C3-C8) heterocycle optionally substituted from the hetero atom (preferably N atoms) of N, O and S by R7 groups, wherein Y be selected from O, NH、S、(CH2)0-2, NH- (CO) and (CO)-NH；
R6 is selected from halogen, amino, nitro, hydroxyl, C1-C8 alkyl, C1-C8 halogenated alkyls, C1-C8 alkoxyl, C1-C8 halogen For alkoxy, C1-C8 hydroxyalkyls, C1-C8 alkyl aminos, aryl and heteroaryl；
R7 is selected from-(CO)-(C1-C8) alkyl ,-(CO)-(C2-C8) alkenyl ,-(CO)-(C2-C8) alkynyl ,-(CO)- (C3-C8) cycloalkyl ,-(CO)-(C1-C8) halogenated alkyl ,-(CO)-(C1-C8) hydroxyalkyl ,-(CO)-(C1-C8) alkyl ammonia Base ,-(CO)-(C1-C8) alkyl-N- [(C1-C8) alkyl]2,-(CO)-vinyl-(CH2)n- N- [(C1-C8) alkyl]2, appoint Choosing substituted by 1-3 R8 group-(CO)-aryl, optionally substituted by 1-3 R8 group-(CO)-heteroaryl, optionally by 1-3 - (CO)-(C3-C8) heterocycle of a R8 groups substitution ,-(CO)-(C1-C8) alkylaryl ,-(CO)-(C1-C8) alkyl heteroaryl Base ,-(SO2)-(C1-C8) alkyl ,-(SO2)-(C3-C8) cycloalkyl, optionally substituted by 1-3 R8 group-(SO2)-aryl, The heteroaryl that is optionally substituted by 1-3 R8 group,
R8 is selected from halogen, amino, nitro, hydroxyl, C1-C8 alkyl, C1-C8 halogenated alkyls, C1-C8 alkoxyl and C1-C8 Halogenated alkoxy；
R2 is selected from hydrogen, halogen, nitro, amino, hydroxyl, C1-C8 alkyl, C1-C8 halogenated alkyls, C1-C8 alkoxyl, C1- C8 halogenated alkoxies, C1-C8 hydroxyalkyls, C1-C8 alkyl aminos, aryl and heteroaryl；
R3 and R5 be each independently selected from hydrogen, C1-C8 alkyl, the aryl optionally substituted by 1-3 R9 group, optionally by 1- Heteroaryl, halogen, C1-C8 halogenated alkyls, C1-C8 alkoxyl, C1-C8 halogenated alkoxies ,-(CO)-of 3 R9 groups substitutions (C1-C8) alkyl ,-(CO)-(C1-C8) halogenated alkyl ,-(CH2)n- NH- (CO)-(C1-C8) alkyl ,-(CH2)n-NH-(CO)- (C1-C8) halogenated alkyl ,-(CH2)n- NH- (CO)-(C2-C8) alkenyl ,-(CH2)n- NH- (CO)-(C2-C8) alkynyl, fragrant oxygen Base, nitro, amino and hydroxyl；
R9 be selected from C1-C8 alkyl, aryl, heteroaryl ,-(CO)-(C1-C8) alkyl ,-(CO)-(C1-C8) cycloalkyl ,- (CO)-aryl ,-(CO)-heteroaryl ,-(SO2)-(C1-C8) alkyl ,-(SO2)-(C1-C8) cycloalkyl ,-(SO2)-(C1-C8) Aryl and-(SO2)-(C1-C8) heteroaryl；
R4 be selected from hydrogen, C1-C8 alkyl, optionally substituted by 1-3 R10 group-(CH2)n- (C3-C8) heterocycles ,- (CH2)n- NH- (CO)-(C1-C8) alkyl ,-(CH2)n- NH- (CO)-(C1-C8) halogenated alkyl ,-(CH2)n-NH-(CO)-(C2- C8) alkenyl ,-(CH2)n- NH- (CO)-(C2-C8) alkynyl ,-(CH2)n-NH-(SO2)-(C1-C8) alkyl ,-(CH2)n-NH- (SO2)-(C1-C8) halogenated alkyl ,-(CH2)n-NH-(SO2)-(C2-C8) alkenyl ,-(CH2)n-NH-(SO2)-(C2-C8) alkynes Base；With-(CH2)n- NH- (CO)-vinyl-(CH2)n- N- [(C1-C8) alkyl]2；
R10 be selected from C1-C8 alkyl, substituted by R11-(C1-C20) alkyl, substituted by R11-[(CH2)2-O-]m- (CH2)2- base, aryl, heteroaryl ,-(CO)-(C1-C8) alkyl ,-(CO)-(C1-C8) cycloalkyl ,-(CO)-aryl ,-(CO)- Heteroaryl ,-(SO2)-(C1-C8) alkyl ,-(SO2)-(C1-C8) cycloalkyl ,-(SO2)-(C1-C8) aryl ,-(SO2)-(C1- C8) heteroaryl；
R11 is selected from C1-C8 alkyl ,-NH- (CO)-(CH)n(the arbitrary site of the adamantyl is optionally for-adamantyl Substituted by one or more C1-C8 alkyl) and-N- [(C1-C8) alkyl]2；
Wherein n is each independently the integer of 0-6, and m is the integer of 1-6.
In one embodiment, Z1, Z2, Z3, Z4 and Z5 are CH.
In another embodiment, Z1And Z2It is CH for N and Z3, Z4 and Z5.
In a preferred embodiment, the present invention provides a kind of Azaindole kinase inhibitors, compound including formula (II) or Its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug：
Wherein R1、R2、R3、R4And R5As previously defined.
Compound involved in the present invention with chirality, configuration can be arbitrary configuration or the racemic modification of mixing.
The invention further relates to the pharmaceutical compositions including more than compound and the compound to prevent or treat by junket ammonia Kinase activity adjust disease that is either being affected by it or being directed to tyrosine kinase activity, obstruction and illness, from Method and purposes in body immunity disease.
Description of the drawings
Fig. 1 shows compound 26 to blood cell K562 (Fig. 1 a), mouse TEL-cKit-BaF3 cells (Fig. 1 b) and acute The influence of marrow leukaemia cell Kasumi-1 (Fig. 1 c) signal path.
Fig. 2 shows influence of the compound 26 to blood cell K562 Apoptosis.
Specific embodiment
Term
Unless otherwise defined, all scientific and technical terminologies used herein all have the skill with claimed theme fields Art personnel are commonly understood by identical meaning.
Unless otherwise indicated, the mass spectrum of the invention used in the range of art technology, NMR, HPLC, protein chemistry, life The conventional methods such as object chemistry, recombinant DNA technology and pharmacology.Unless provide specific definition, otherwise with analysis described herein The chemically relevant name of chemistry, synthetic organic chemistry and medicine and pharmaceutical chemistry etc. and laboratory operation and technology, are these Known to field technology personnel.In general, aforementioned techniques and step can be by well-known in the art and various one As conventional method described in document and more specific document implement, these documents are cited and discuss in the present specification.
" alkyl " refers to aliphatic hydrocarbon groups, can be the alkyl of branch or straight chain.According to structure, alkyl can be unit price Group or bivalent radical (i.e. alkylidene).In the present invention, alkyl is preferably " low alkyl group " with 1-8 carbon atom.Allusion quotation The alkyl of type includes but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, amyl, hexyl etc..
" alkoxy " refers to-O- alkyl, wherein alkyl as defined herein.Typical alkoxy includes but not limited to methoxy Base, ethyoxyl, propoxyl group, butoxy, amoxy, hexyloxy etc..
" alkoxyalkyl " refers to that alkyl defined herein is substituted by alkoxy defined herein.
Term " alkyl amino " refers to-N (alkyl)xHyGroup, wherein x and y are selected from x=1, y=1 and x=2, y=0.Work as x When=2, alkyl N atoms connected to them, which are combined together, can be optionally formed loop system.
" alkylaminoalkyl group " refers to that alkyl defined herein is substituted by alkyl amino defined herein.
Term " aromatic radical " refers to that planar rings have the pi-electron system of delocalization and containing 4n+2 pi-electron, and wherein n is Integer.Fragrant basic ring can be by five, six, seven, eight, nine or more than nine atomic buildings.Aromatic radical can optionally substitute.Art Language " aromatic radical " includes isocyclic aryl (such as phenyl) and heterocyclic aryl (or " heteroaryl " or " heteroaryl perfume base ") group (such as pyrrole Pyridine).The term includes polycyclic (ring for the sharing adjacent carbon atom pair) group of monocyclic or condensed ring.
Terms used herein " aryl " refers to that the atom that each in fragrant basic ring forms ring is carbon atom.Aryl rings It can be by five, six, seven, eight, nine or more than nine atomic buildings.Aryl can optionally substitute.The example of aryl include but It is not limited to phenyl, naphthalene, phenanthryl, anthryl, fluorenyl and indenyl.According to structure, aryl can be monoradical or bivalent radical (i.e. Arlydene).
" alkyl (aryl) " refers to that alkyl defined herein is substituted by aryl defined herein.Nonrestrictive alkyl (virtue Base) include benzyl, phenethyl etc..
Term " cycloalkyl " refers to monocyclic or polycyclic group, only contains carbon and hydrogen.Cycloalkyl includes having 3-8 annular atom Group.According to structure, cycloalkyl can be monoradical or bivalent radical (such as cycloalkylidene).In the present invention, cycloalkanes Base is preferably the cycloalkyl with 3-8 carbon atom, more preferably has " low-grade cycloalkyl " of 3-6 carbon atom.
" alkyl (cycloalkyl) " refers to that alkyl defined herein is substituted by cycloalkyl defined herein.Nonrestrictive alkyl (cycloalkyl) includes Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl etc..
Terms used herein " miscellaneous alkyl " refers to that one or more of alkyl defined herein skeletal chain atoms are Hetero atom, such as oxygen, nitrogen, sulphur, silicon, phosphorus or combination thereof.The hetero atom (one or more) can be located in miscellaneous alkyl Any position in portion or in the position that miscellaneous alkyl is connected with the rest part of molecule.
Term " heteroaryl " refers to that aryl includes one or more ring hetero atoms for being selected from nitrogen, oxygen and sulphur.Containing N " heteroaryls Base " partly refers to that at least one skeletal atom is nitrogen-atoms in aromatic radical middle ring.According to structure, heteroaryl can be monovalent radical Group or bivalent radical (i.e. inferior heteroaryl).The example of heteroaryl include but not limited to pyridyl group, imidazole radicals, pyrimidine radicals, pyrazolyl, Triazolyl, pyrazinyl, tetrazole radical, furyl, thienyl, isoxazolyls, thiazolyl, oxazolyls, isothiazolyl, pyrrole radicals, quinoline Quinoline base, isoquinolyl, indyl, benzimidazolyl, benzofuranyl, indazolyl, indolizine base, phthalazinyl, pyridazinyl, iso-indoles Base, pteridyl, purine radicals, oxadiazolyls, thiadiazolyl group, furyl, benzofuranyl, benzothienyl, benzothiazolyl, benzene Bing oxazolyls, quinazolyl, naphthyridines base and furopyridyl etc..
Terms used herein " Heterocyclylalkyl " refers to that one or more atoms for forming ring are to be selected from non-aromatic basic ring The hetero atom of nitrogen, oxygen and sulphur.Heterocycloalkyl ring can be by three, four, five, six, seven, eight, nine or more than nine atomic buildings.Heterocycle Alkyl ring can optionally substitute.The example of Heterocyclylalkyl includes but not limited to lactams, lactone, ring Asia glue, epithio generation Asia Amine, cyclic carbramates, tetrahydric thiapyran, 4H- pyrans, oxinane, piperidines, 1,3- bioxin, 1,3- dioxanes, Isosorbide-5-Nitrae-Er Evil English ,-dioxane of Isosorbide-5-Nitrae, piperazine, 1,3- thioxane, Isosorbide-5-Nitrae-oxathiin, Isosorbide-5-Nitrae-thioxane, tetrahydrochysene- Isosorbide-5-Nitrae-thiazine, 2H-1,2- oxazines, maleimide, succinimide, barbiturates, thiobarbituricacidα-, dioxopiperazine, Hydantoins, dihydrouracil, morpholine, trioxanes, hexahydro -1,3,5-triazines, thiophane, tetrahydrofuran, pyrrolin, pyrroles Alkane, imidazolidine, pyrrolidones, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3- dioxole, 1,3- dioxanes Pentane, 1,3- dithioles, 1,3- dithiolane, isoxazoline, isoxazole alkyl, oxazoline, oxazolidine, oxazolidines Ketone, thiazoline, thiazolidine and 1,3- oxathiolane.According to structure, Heterocyclylalkyl can be monoradical or bivalent radical (i.e. sub- Heterocyclylalkyl).
Term " alkyl (heteroaryl) " refers to that alkyl defined herein is substituted by heteroaryl defined herein.
Term " alkyl (Heterocyclylalkyl) " refers to that alkyl defined herein is substituted by Heterocyclylalkyl defined herein.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Term " halogenated alkyl ", " halogenated alkoxy " and " halogenated miscellaneous alkyl " include the knot of alkyl, alkoxy or miscellaneous alkyl Structure, wherein at least one hydrogen are replaced by halogen atom.In some embodiments, if two or more hydrogen atoms are put by halogen atom It changes, the halogen atom is same or different to each other.
Terms used herein " cyano " refers to formula-CN groups.
Term " ester group " refers to the chemical part with formula-COOR, and wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (being connected by ring carbon) (is connected) with heteroalicyclyl by ring carbon.
Term " optionally substituting " or " substituted " refer to that mentioned group can be by one or more additional groups Substitution, the additional group is each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, cyanogen Base, halogen, amide groups, nitro, halogenated alkyl, amino etc..
Terms used herein " tyrosine protein kinase (tyrosine protein kinase, TPK) " is a kind of catalysis Upper γ-the phosphoric acid of ATP is transferred to the kinases on protein-tyrosine residue, can be catalyzed a variety of substrate protein white matter tyrosine residue phosphoric acid Change, play an important roll in cell growth, multiplication, differentiation.
" inhibition ", " inhibition " or " inhibitor " of terms used herein kinases, refers to that phosphate transferase activity is pressed down System.
" metabolin " of compound disclosed herein is the derivative of the compound formed when the compound is metabolized.Art Language " active metabolite " refers to the biologically active derivatives of the compound formed when the compound is metabolized.Art used herein Language " is metabolized ", refers to the process of that predetermined substance (includes but not limited to hydrolysis and by enzymatic by organism transform summation Reaction, such as oxidation reaction).Therefore, enzyme can generate specific structure and be changed into compound.For example, Cytochrome P450 Various oxidations and reduction reaction are catalyzed, while the glucuronic acid molecule of diphosphate glucose sweet acid based transferase catalytic activation is extremely The conversion of aromatic alcohol, aliphatic alcohol, carboxylic acid, amine and free sulfydryl.The further information of metabolism can be from《The Pharmacological Basis ofTherapeutics》, the 9th edition, McGraw-Hill (1996) is obtained.It is disclosed herein The metabolin of compound can be by giving compound to host and analyzing tissue sample from the host or by by chemical combination Object with liver cell is incubated and analyzes gained compound to differentiate in vitro.Both approaches are all known in the art.One In a little embodiments, the metabolin of compound is to be formed by oxidation process and corresponding with corresponding hydroxy-containing compounds.One In a little embodiments, compound is metabolized as pharmaceutical active metabolite.Terms used herein " adjusting " refers to directly or indirectly It interacts with target, to change the activity of target, only for example, includes the work of intensifier target target activity, suppression target Property, limit target target activity or extend target activity.
Terms used herein " target protein " refers to the protein molecule that can be combined by selective binding compounds or portion Divide protein.In some embodiments, target protein is tyrosine kinase KIT (wild type or various mutation or its combination), ABL (wild type or various mutation or its combination), EGFR (wild type or various mutation or its combination), (wild type is various prominent by FLT3 Become or its combination), BLK (wild type or it is various mutation or its combination), VEGFR (wild type or it is various mutation or its combination), RET (wild type or various mutation or its combination), PDGFR (wild type or various mutation or its combination), (wild type is various prominent by MEK Become or its combination), BCR/ABL (wild type or it is various mutation or its combination), JAK (wild type or it is various mutation or its combination), BRAF (wild type or various mutation or its combination).
IC used herein50Refer to that the 50% of ceiling effect is obtained in the analysis of effect as measurement inhibits specific Test amount, concentration or the dosage of compound.
EC used herein50Refer to the dosage, concentration or the amount that measure compound, particular assay compound is caused to induce, The 50% maximum dose-dependant expressed of the specific reaction for stimulating or strengthening reacts.
The new kinase inhibitor of the present invention
The present invention provides a kind of Azaindole kinase inhibitors, compound or its pharmaceutically acceptable salt, solvent including formula (I) Compound, ester, acid, metabolin or prodrug：
Wherein Z1, Z2, Z3, Z4 and Z5 are independently selected from CH or N；
X is selected from
Wherein R1、R2、R3、R4And R5As previously defined.
In one embodiment, Z1, Z2, Z3, Z4 and Z5 are CH.
In another embodiment, Z1And Z2It is CH for N and Z3, Z4 and Z5.
In a preferred embodiment, the present invention provides a kind of Azaindole kinase inhibitors, compound including formula (II) or Its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug：
Wherein, R1 is selected from H, halogen, amino, nitro, hydroxyl, C1-C8 alkyl (preferably methyl, ethyl, propyl), C1-C8 Halogenated alkyl, C1-C8 alkoxyl, C1-C8 halogenated alkoxies, C1-C8 hydroxyalkyls, C1-C8 alkyl aminos, optionally by 1-3 R6 - NH- the heteroaryls (the preferred pyrimidine radicals of heteroaryl) and take up an official post in the hetero atom (preferably N atoms) selected from N, O and S that group substitutes - Y- (C3-C8) heterocycle (the preferred piperidyl of heterocycle, pyrrolidinyl, azetidinyl) substituted by R7 groups is selected, wherein Y is selected from O, NH, S, (CH2)0-2, NH- (CO) and (CO)-NH (preferably O)；
R6 is selected from halogen, amino, nitro, hydroxyl, C1-C8 alkyl, C1-C8 halogenated alkyls, C1-C8 alkoxyl, C1-C8 halogen For alkoxy, C1-C8 hydroxyalkyls, C1-C8 alkyl aminos, aryl and heteroaryl (preferably pyridyl group, particularly 2- pyridyl groups)；
It is (excellent that R7 is selected from-(CO)-(C1-C8) alkyl (preferably methyl, ethyl, propyl, butyl) ,-(CO)-(C2-C8) alkenyl Select vinyl, acrylic) ,-(CO)-(C2-C8) alkynyl (preferably acetenyl) ,-(CO)-(C3-C8) cycloalkyl (preferably ring third Base) ,-(CO)-(C1-C8) halogenated alkyl (preferably chloromethyl, Chloroethyl, trifluoroethyl) ,-(CO)-(C1-C8) hydroxyalkyl (preferably ethoxy) ,-(CO)-(C1-C8) alkylamino (preferably ethylamino) ,-(CO)-(C1-C8) alkyl-N- [(C1-C8) alkane Base]2,-(CO)-vinyl-(CH2)n- N- [(C1-C8) alkyl]2, optionally substituted by 1-3 R8 group-(CO)-aryl (virtue The preferred phenyl of base), optionally substituted by 1-3 R8 group-(CO)-heteroaryl (the preferred pyridyl group of heteroaryl, pyrimidine radicals, furans Base, quinolyl, quinazolyl, benzodioxole base) ,-(CO)-(C3-C8) that is optionally substituted by 1-3 R8 group it is miscellaneous Ring group (the preferred piperidyl of heterocycle) ,-(CO)-(C1-C8) alkylaryl ,-(CO)-(C1-C8) miscellaneous alkyl aryl ,-(SO2)- (C1-C8) alkyl (the preferred methyl of alkyl, ethyl, propyl) ,-(SO2)-(C3-C8) cycloalkyl (the preferred cyclopropyl of cycloalkyl), appoint Choosing substituted by 1-3 R8 group-(SO2)-aryl (the preferred phenyl of aryl), the heteroaryl optionally substituted by 1-3 R8 group (preferably purine radicals, pyrazolopyrimidine base, quinazolyl),
R8 is selected from halogen (preferably fluorine), amino, nitro, hydroxyl, C1-C8 alkyl (preferably methyl), C1-C8 halogenated alkyls (preferably trifluoromethyl), C1-C8 alkoxyl (preferably methoxyl group) and C1-C8 halogenated alkoxies；
It is halogenated that R2 is selected from hydrogen, halogen (preferably fluorine, chlorine), nitro, amino, hydroxyl, C1-C8 alkyl (preferably methyl), C1-C8 Alkyl (preferably trifluoromethyl), C1-C8 alkoxyl (preferably methoxyl group), C1-C8 halogenated alkoxies, C1-C8 hydroxyalkyls, C1-C8 Alkyl amino, aryl and heteroaryl；
R3 and R5 independently selected from hydrogen, C1-C8 alkyl (preferably methyl), the aryl optionally substituted by 1-3 R9 group, appoint Select heteroaryl (preferably 4-methylimidazole base), halogen (preferably fluorine, chlorine), the C1-C8 halogenated alkyls substituted by 1-3 R9 group (preferably trifluoromethyl), C1-C8 alkoxyl, C1-C8 halogenated alkoxies (preferably trifluoromethoxy) ,-(CO)-(C1-C8) alkane Base ,-(CO)-(C1-C8) halogenated alkyl (preferably halogenated methyl) ,-(CH2)n- NH- (CO)-(C1-C8) alkyl ,-(CH2)n-NH- (CO)-(C1-C8) halogenated alkyl ,-(CH2)n- NH- (CO)-(C2-C8) alkenyl ,-(CH2)n- NH- (CO)-(C2-C8) alkynyl, Fragrant oxygroup, nitro, amino and hydroxyl；
R9 is selected from C1-C8 alkyl (preferably methyl, ethyl), aryl, heteroaryl ,-(CO)-(C1-C8) alkyl (preferably second Base) ,-(CO)-(C1-C8) cycloalkyl ,-(CO)-aryl ,-(CO)-heteroaryl ,-(SO2)-(C1-C8) alkyl ,-(SO2)-(C1- C8) cycloalkyl ,-(SO2)-(C1-C8) aryl ,-(SO2)-(C1-C8) heteroaryl；
R4 be selected from hydrogen, C1-C8 alkyl (preferably methyl), optionally substituted by 1-3 R10 group-(CH2)n-(C3-C8) Heterocycle (the preferred nitrogen of heterocycle, oxygen and 5 yuan of rings of nitrogen oxa- and hexatomic ring) ,-(CH2)n- NH- (CO)-(C1-C8) alkyl ,- (CH2)n- NH- (CO)-(C1-C8) halogenated alkyl ,-(CH2)n- NH- (CO)-(C2-C8) alkenyl ,-(CH2)n-NH-(CO)-(C2- C8) alkynyl ,-(CH2)n-NH-(SO2)-(C1-C8) alkyl ,-(CH2)n-NH-(SO2)-(C1-C8) halogenated alkyl ,-(CH2)n- NH-(SO2)-(C2-C8) alkenyl ,-(CH2)n-NH-(SO2)-(C2-C8) alkynyl；-(CH2)n- NH- (CO)-vinyl-(CH2)n- N- [(C1-C8) alkyl]2；
R10 be selected from C1-C8 alkyl (preferably methyl, ethyl), substituted by R11-(C1-C20) alkyl, substituted by R11- [(CH2)2-O-]m-(CH2)2- base, aryl, heteroaryl ,-(CO)-(C1-C8) alkyl (preferably ethyl) ,-(CO)-(C1-C8) ring Alkyl ,-(CO)-aryl ,-(CO)-heteroaryl ,-(SO2)-(C1-C8) alkyl ,-(SO2)-(C1-C8) cycloalkyl ,-(SO2)- (C1-C8) aryl ,-(SO2)-(C1-C8) heteroaryl；
R11 is selected from C1-C8 alkyl ,-NH- (CO)-(CH)n(the arbitrary site of the adamantyl is optionally for-adamantyl Substituted by one or more C1-C8 alkyl) and-N- [(C1-C8) alkyl]2；
Wherein n is each independently the integer (the preferably integer of 0-2) of 0-6, and (preferably 1-4's is whole for the integer that m is 1-6 Number).
On the one hand, preferably provide herein and select following compound, the structure of these preferred compounds is as shown in table 1.
For each variable, any combination of above-mentioned group also among considering herein.It is appreciated that：It is carried herein Substituent group and substitute mode in the compound of confession can be made choice by those skilled in the art, in order to provide chemically stable And compound that techniques known in the art and technology set forth herein can be used to synthesize.
Described herein is new kinase inhibitor.The pharmaceutically acceptable salt, molten of this compound has been also described herein Agent compound, ester, acid, pharmaceutical active metabolite and prodrug.
In other or further embodiment, by compound described herein give after organism in need Its metabolism in vivo generates metabolin, and generated metabolin is subsequently used for generating desired effect, including desired therapeutic effect.
Compound described herein can be made into and/or be used as pharmaceutically acceptable salt.Pharmaceutically acceptable salt Type includes but not limited to：(1) acid-addition salts, by by the free alkali form of compound and pharmaceutically acceptable inorganic acid reaction It is formed, the inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid etc.；Or formed with organic acid reaction, it is described Organic acid for example acetic acid, propionic acid, caproic acid, pentamethylene propionic acid, hydroxyacetic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, Succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3- (4- hydroxy benzoyls) benzoic acid, Chinese cassia tree Acid, mandelic acid, Loprazolam, ethane sulfonic acid, 1,2- ethionic acids, 2- ethylenehydrinsulfonic acids, benzene sulfonic acid, toluenesulfonic acid, 4- methyl Bicyclic-[2.2.2] oct-2-ene -1- formic acid, 2- naphthalene sulfonic acids, butylacetic acid, glucoheptonic acid, 4,4 '-di-2-ethylhexylphosphine oxide-(3- hydroxyls Base -2- alkene -1- formic acid), 3- phenylpropionic acids, trimethylace tonitric, dodecyl sulphate, gluconic acid, glutamic acid, salicylic acid, hydroxyl Naphthoic acid, stearic acid, muconic acid etc.；(2) salt, the acid proton in parent compound are formed when being replaced by metal ion, example Such as alkali metal ion (such as lithium, sodium, potassium), alkaline-earth metal ions (such as magnesium or calcium) or aluminium ion；Or it is coordinated with organic base.It can The organic base of receiving includes ethanolamine, diethanol amine, triethanolamine, trimethylamine, N- methyl glucose osamines, etc..It is acceptable Inorganic base includes aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide etc..
The corresponding ion balance of pharmaceutically acceptable salt can analyze and be identified using various methods, the described method includes But be not limited to ion-exchange chromatography, ion chromatography, Capillary Electrophoresis, inductively coupled plasma, atomic absorption spectrum, mass spectrum or Any combination of them.
The salt is recycled using at least one of following technology：Filtering is then filtered, evaporation of the solvent with non-solvent precipitation, Or desivac is used in the case of aqueous solution.
Screening and characterize pharmaceutically acceptable salt, polymorphic and/or solvate can be completed using multiple technologies, described Technology includes but not limited to heat analysis, X-ray diffraction, spectrum, microscopy, elemental analysis.The various spectral techniques used Including but not limited to Raman, FTIR, UVIS and NMR (liquid and solid state).Various microscopies include but not limited to IR Microscopy and Raman (Raman) microscopy.
The pharmaceutical composition of the present invention
The application also provides pharmaceutical composition, and it includes the compound of at least one formula (I) or the pharmacy of the compound Acceptable salt, solvate, ester, acid, pharmaceutical active metabolite or prodrug and pharmaceutically acceptable carrier or excipient, And other therapeutic agents that person is optional.
Over the course for the treatment of, according to circumstances can individually or with one or more other therapeutic agents be applied in combination.It can be with By injecting, taking orally, sucking, at least one of rectum and transdermal administration by the medicament administration comprising the compounds of this invention to suffering from Person.Other therapeutic agents can be selected from following drug：Immunosuppressor (such as tacrolimus, encircle rhzomorph, rapamycin, first An Die ridges, cyclophosphamide, imuran, mercaptopurine, mycophenolate or FTY720), glucocorticoids medicine (such as prednisone, Cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, hydrogen hydroxyl prednisolone, times chlorine rice Pine, fludrocortisone acetate, percorten, aldosterone), non-steroidal anti-inflammatory drugs (such as salicylate, aryl alkanoic acid, 2- arylpropionic acids, N- aryl-anthranilic acids, examine former times class or sulphonanilid at former times health class), allergic reaction bacterin, antihistamine Medicine, anti-leukotriene medicine, beta-2-agonists, theophylline, anticholinergic agent or other selective kinase inhibitors (such as mTOR inhibitors, c- Met inhibitor) or her2 antibody-drugs.In addition, mentioned other therapeutic agents can also be rapamycin (Rapamycin), Gram azoles is for Buddhist nun (Crizotinib), tamoxifen, Raloxifene, Anastrozole, Exemestane, Letrozole, TrastuzumabTMIt is (bent appropriate Pearl monoclonal antibody), GleevecTM(Imatinib), taxolTM(taxol), cyclophosphamide, Lovastatin, U.S. promise tetracycline (Minosine), cytarabine, 5 FU 5 fluorouracil (5-FU), methotrexate (MTX) (MTX), taxotereTM(docetaxel), promise thunder MoralTM(Goserelin), vincristine, vincaleukoblastinum, nocodazole, Teniposide, Etoposide, gemzarTM(gemcitabine), angstrom Rich mycin (Epothilone), promise only sheet, camptothecine, daunorubicin (Daunonibicin), dactinomycin D, mitoxantrone, peace Acridine, Doxorubicin (adriamycin), epirubicin or idarubicin.Alternatively, other therapeutic agents can also be cell because Son such as G-CSF (granulocyte colony stimulating factor).Alternatively, other therapeutic agents can also be, and such as, but not limited to, CMF (ring phosphorus Amide, methotrexate (MTX) and 5 FU 5 fluorouracil), CAF (cyclophosphamide, adriamycin and 5 FU 5 fluorouracil), AC (sub- Baudrillards Mycin and cyclophosphamide), FEC (5 FU 5 fluorouracil, epirubicin and cyclophosphamide), ACT or ATC (adriamycin, ring phosphorus Amide and taxol) or CMFP (cyclophosphamide, methotrexate (MTX), 5 FU 5 fluorouracil and prednisone).
In embodiments of the present invention, when being treated according to the present invention to patient, the amount of given drug depends on Factors, such as specific dosage regimen, disease or implant treatment and its seriousness, subject in need for the treatment of or host Unique (such as weight), still, according to specific ambient conditions, including for example used specific drug, administration route, control The illness for the treatment of and the subject or host for the treatment of, administration dosage can routinely be determined by methods known in the art.In general, For the dosage that adult treatment uses, administration dosage is typically at 0.02-5000mg/ days, for example, about model of 1-1500mg/ days It encloses.The required dosage can easily be expressed as one or (or in a short time) that be administered simultaneously or at appropriate interval Divided dose, such as daily two, three, four doses or more divided agent.It will be appreciated by persons skilled in the art that it although gives State dosage range, but specific effective quantity can suitably be adjusted according to the situation of patient and with reference to doctor diagnosed.
The purposes of the drug of the present invention
The compound of formula (I) can include its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug or medicine Compositions inhibit it is a kind of for inhibit tyrosine kinase KIT (wild type or various mutation or its combination), ABL (wild type or It is various mutation or its combination), EGFR (wild type or it is various mutation or its combination), FLT3 (wild type or it is various mutation or its group Close), BLK (wild type or it is various mutation or its combination), VEGFR (wild type or it is various mutation or its combination), RET (wild types It is various mutation or its combination), PDGFR (wild type or it is various mutation or its combination), MEK (wild type or it is various mutation or its Combination), BCR/ABL (wild type or various mutation or its combination), JAK (wild type or various mutation or its combination), BRAF it is (wild Raw type or various mutation or its combination) activity.Formula (I) compound or its pharmaceutically acceptable salt, solvate, ester, acid, Metabolin or prodrug and pharmaceutically acceptable carrier or excipient can be used for treatment or prepare can be used for treatment a kind of or A variety of diseases selected from the group below：Solid tumor (including benign or especially malignant class), especially sarcoma, gastrointestinal stromal tumors (Gastrointestinal Stromal Tumors, GIST), acute myeloblastic leukemia (Acute Myeloblastic Leukemia, AML), chronic myelogenous leukemia (Chronic Myelogenous Leukemia, CML), to Abl tyrosine-kinases Inhibition of enzyme activity has influential leukaemia, celiothelioma, thyroid cancer (thyroid carcinoma), systematic mast cell Disease, hypereosinophilic syndrome (HES), fibre modification, rheumatoid arthritis, panarthritis, chorionitis, erythema wolf Sore, graft versus host disease(GVH disease) (graft-versus-host disease, GVHD), neurofibroma, pulmonary hypertension, alzheimer ' Silent disease, seminoma, argyraemia, dysgerminoma, mast cell tumor, lung cancer, bronchiolar carcinoma, dysgerminoma, testis Intraepithelial neoplasia formation, melanoma, breast cancer, neuroblastoma, mamillary/follicular thyroid cancer, malignant lymphoma, it is non-suddenly Strange gold lymthoma, 2 type Multiple Endocrine knurl formation, pheochromocytoma, thyroid cancer, parathyroid hyperplasia/adenoma, colon Cancer, colorectal adenomas, oophoroma, prostate cancer, spongioblastoma, brain tumor, glioblastoma, cancer of pancreas, evil Property mesothelioma of pleura, hemangioblastoma, hemangioma, kidney, liver cancer, adrenal, carcinoma of urinary bladder, stomach cancer, the carcinoma of the rectum, vagina Cancer, cervical carcinoma, carcinoma of endometrium, Huppert's disease, neck and head tumor；Knurl is formed and other Hypertrophic or proliferative diseases Disease or similar disease or its combination.Particularly preferably treatment gastrointestinal stromal tumor (Gastrointestinal Stromal Tumors, GIST), acute myeloblastic leukemia (Acute Myeloblastic Leukemia, AML), chronic myelogenous leukemia (Chronic Myelogenous Leukemia, CML), thyroid cancer (thyroid carcinoma) or similar disease or its Combination.Autoimmune disease includes but not limited to：Arthritis, rheumatic arthritis, osteoarthritis, lupus, rheumatoid close Save inflammation, inflammatory bowel disease, psoriasis arthropathica, osteoarthritis, Still disease (Still ' s disease), adolescent arthritis, Diabetes, myasthenia gravis, Hashimoto thyroiditis (Hashimoto ' s thyroiditis), Order thyroiditis (Ord ' s Hyroiditis), Graves disease (Graves ' disease), rheumatoid arthritis syndrome ( Syndrome), multiple sclerosis, Guillain-Barre syndrome (Guillain-Barr é syndrome), acute disseminated brain ridge Marrow inflammation, Addision's disease (Addison ' s disease), regarding property eye battle array it is twin-the twin syndrome of flesh battle array, ankylosing spondylitis, anti-phosphatide Antibody Syndrome, alpastic anemia, oneself immunity hepatitis, chylous diarrhea (coeliac disease), Gourde(G) Paasche are thorough comprehensive Simulator sickness (Goodpasture ' s syndrome), Idiopathic Thrombocytopenic Purpura, optic neuritis, chorionitis, primary courage Juice hepatic sclerosis, Reiter syndrome (Reiter ' s syndrome), takayasu's arteritis (Takayasu ' s arteritis), Temporal arteritis, warm type autoimmune hemolytic anemia, Wegner's granulomatosis (Wegener ' s granulomatosis), silver Consider disease, alopecia universalis, behcet disease (Behcet ' s disease), confirmed fatigue, familial dysautonomia, son to be worth doing Endometriosis, interstitial cystitis, neuromyotonia, chorionitis or Vulvodynia.
The preparation of compound
Using Standard synthetic techniques well known by persons skilled in the art or using methods known in the art with being described herein Method combination, the compound of formula (I) can be synthesized.In addition, solvent given herein, temperature and other reaction conditions can roots Change according to art technology.As further guidance, following synthetic method can also be utilized.
The reaction can use in order, to provide compound described herein；Or they can be used for synthesizing segment, The segment is then added in by method described herein and/or methods known in the art.
In some embodiments, it provided herein is the preparation sides of tyrosine kinase inhibitor compound described herein Method and its application method.In some embodiments, compound described herein can use the scheme of following synthesis to synthesize.It can With use with following similar methods, by using appropriate selectable starting material, synthesize compound.
Starting material for synthesizing compound described herein can be synthesized or can be obtained from commercial source.Herein The compound of description can use technology well known by persons skilled in the art to other related compounds with different substituents And Material synthesis.The conventional method for preparing compound disclosed herein can come from reaction known in the art, and the reaction It can be changed by the reagent and condition thought fit by those skilled in the art, it is each in the molecule of offer to be incorporated herein Kind part.
If desired, reaction product can use routine techniques to separate and purify, including but not limited to filter, distill, knot The methods of crystalline substance, chromatography.These products can be characterized using conventional method, including physical constant and spectrum data.
The non-limiting example of the synthetic schemes of the compound of formula (I) is prepared referring to scheme I.
Scheme I
Using synthetic method described herein and those methods known in the art, obtained with good yield and purity Tyrosine kinase inhibitor disclosed herein.The compound prepared according to method disclosed herein passes through routine known in the art Method purifies, such as filtering, recrystallization, chromatography, distillation and combinations thereof.
Site on the aromatic moiety of the compound of formula (I) may be easy to that various metabolic responses occur, therefore appropriate Substituent group be introduced on aromatic ring structure, for example, only for example, halogen can reduce, this metabolism is reduced or eliminated Approach.
Embodiment
Non-limiting example in detail below is to be interpreted as being merely illustrative, not limit in any way originally It is open.Although need not be described in further detail, it is believed that those skilled in the art can be based on description herein, completely profit Use the disclosure.
The synthesis of the compounds of this invention intermediate
The synthesis of 3- trifluoromethyl -4- methyl-benzoic acid methyl compounds a
20mmol 3- trifluoromethyl -4- methyl-benzoic acids are dissolved in the round-bottomed flask equipped with 60mL methanol, add in catalysis The concentrated sulfuric acid of (3%mmol) is measured, reaction system is stirred at reflux overnight.Rotary Evaporators remove solvent, add in 30ml saturated carbons Then sour hydrogen sodium solution is extracted with ethyl acetate (2X50 milliliters), anhydrous sodium sulfate drying.Rotary Evaporators remove solvent and must produce Product 3- trifluoromethyl -4- methyl-benzoic acid methyl compound a (yields：96%).Exact Mass (calculated value)：218.06；MS (ESI)m/z(M+1)+：219.05.
The synthesis of 3- trifluoromethyls -4- bromomethyls-methyl benzoate compound b
It is respectively that 10mmol 3- trifluoromethyl -4- methyl-benzoic acid methyl compound a, 12mmolN- bromos succinyl is sub- Amine, 0.5mmol azodiisobutyronitriles add in round-bottomed flask, then add in 30 milliliters of carbon tetrachloride.Reaction system was stirred at reflux Night, Rotary Evaporators remove solvent, then add in 100 milliliters of saturated sodium bicarbonate solutions, are then extracted with ethyl acetate, and merge Organic phase is simultaneously dried with anhydrous sodium sulfate, the separated product 3- trifluoromethyls -4- bromomethyls-methyl benzoate of silica gel chromatographic column Close object b (yields：81%).Exact Mass (calculated value)：295.97；MS(ESI)m/z(M+1)+：296.99.
The synthesis of 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoro methyl benzoate compounds c
By 8mmol 3- trifluoromethyls -4- bromomethyls-methyl benzoate b, 10mmol 4- methyl piperazines and 15mmol carbon Sour potassium adds in round-bottomed flask, then adds in 20 milliliters of n,N-Dimethylformamide (DMF).Reaction 3 is stirred at room temperature in reaction system Hour.Rotary Evaporators remove solvent, and silica gel chromatograph post separation obtains product 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoros Methyl benzoic acid ester compounds c (yields：93%).Exact Mass (calculated value)：316.14；MS(ESI)m/z(M+1)+： 317.16。
The synthesis of 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethylbenzoic acid compounds d
6mmol4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoro methyl benzoate compounds c is dissolved in 20 milliliters The mixed solution of tetrahydrofuran and water (1: 1), and add in 18mmol lithium hydroxides.Reaction is stirred at room temperature overnight in reaction system, Then pH is adjusted to 7 with dilute hydrochloric acid, then with extracting n-butyl alcohol, merges organic phase and simultaneously dried with anhydrous sodium sulfate, Rotary Evaporators It removes solvent and obtains product 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethylbenzoic acid compound d (yields：91%). Exact Mass (calculated value)：302.12；MS(ESI)m/z(M+1)+：303.15.
The synthesis of tertiary butyl 4- (2- methyl-5-nitros phenoxy group) piperidines -1- carboxylate compounds e
5mmol 2- methyl-5-nitros phenol, 6mmol 1- tertbutyloxycarbonyls -4- methanesulfonyloxy groups piperidines and 10mmol Anhydrous potassium carbonates are sequentially added into 15 milliliters of anhydrous n,N-Dimethylformamide (DMF).Reaction system is in 85 Degree Celsius reaction overnight, be cooled to room temperature, reaction system is extracted with ethyl acetate, merge organic phase simultaneously done with anhydrous sodium sulfate It is dry.Rotary Evaporators remove solvent, and crude product obtains product tertiary butyl 4- (2- methyl-5-nitro benzene oxygen with silica gel chromatograph post separation Base) piperidines -1- carboxylate compound e (yields：89%).Exact Mass (calculated value)：336.17；MS(ESI)m/z(M+Na )+：359.20.
The synthesis of tertiary butyl 4- (2- methyl -5- amino-benzene oxygens) piperidines -1- carboxylate compounds f
4mmol tertiary butyls 4- (2- methyl-5-nitros phenoxy group) piperidines -1- carboxylate compounds e is dissolved in 20 milliliters of second In acetoacetic ester, the Pd/C (10%) of 0.05 equivalent is then added in.System reacted under an atmospheric pressure hydrogen environment 5 it is small when.Instead System is answered to be filtered with diatomite, collect filtrate and remove solvent obtain product tertiary butyl 4- (2- methyl -5- amino-benzene oxygens) piperidines - 1- carboxylate compound f (yields：96%).Exact Mass (calculated value)：306.19；MS(ESI)m/z(M+Na)+： 329.23。
N- (4- methyl -3- (piperidines -4- oxygroups) phenyl) -4- ((4- methylpiperazine-1-yls) methyl) -3- (trifluoromethyl) The synthesis of benzamide tri hydrochloride compound h
3mmol 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethylbenzoic acid compound d and 3mmol tertiary butyls 4- (2- methyl -5- amino-benzene oxygens) piperidines -1- carboxylates f is dissolved in 6 milliliters of n,N-Dimethylformamide (DMF), stirring 6mmol n,N-diisopropylethylamine (DIPEA) and 2- (7- azos benzotriazole)-N of 3.6mmol are sequentially added under state, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU).Reaction system be stirred at room temperature reaction 2 it is small when.Ethyl acetate extraction reaction System, merges organic phase, and anhydrous sodium sulfate drying removes solvent and obtains 4- (2- methyl -5- (4- (4- methylpiperazine-1-yls) first Base)-(trifluoromethyl) benzamido) ritalin -1- carboxylic acid tert-butyl esters) and compound g crude product, then add in 4M hydrochloric acid Simultaneously 3h is stirred at room temperature in ethyl acetate solution, filters solid and to be washed with ethyl acetate, then dry product N- (4- first Base -3- (piperidines -4- oxygroups) phenyl) three hydrochloric acid of -4- ((4- methylpiperazine-1-yls) methyl) -3- (trifluoromethyl) benzamide Salt h (two step yields：61%).Exact Mass (calculated value)：490.26；MS(ESI)m/z(M+H)+：491.27.
The synthetic method and route similar to intermediate h are taken, using different level-one aminated compounds and different carboxylics Acid compound can obtain a variety of condensation products by condensation reaction, and condensation product is through de- tertbutyloxycarbonyl protection reaction It can obtain various amine intermediates (below figure).
Using more than amine intermediate and different acyl chlorides (synthetic method of reference compound 26) and different carboxylic acids A variety of target products are obtained by the reaction in (synthetic method of reference compound 68) or electrophilic reagent.
4- (chloromethyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) benzoyl amination Close the synthesis of object j
6- methyl-N1- (4- (3 substitutions-pyridine) 2- substituted pyrimidines -) benzene -1,3- diamine compound i and 7mmol of 5mmol Triethylamine (Et3N) in 15mLN, dinethylformamide (DMF) is cooled to zero degrees celsius, under stirring, is added portionwise 4- (chloromethyl) chlorobenzoyl chlorides of 5.5mmol and be stirred to react under zero degrees celsius 1 it is small when.Reaction system is extracted with ethyl acetate It takes, merge organic phase and is dried with anhydrous sodium sulfate.Rotary Evaporators remove solvent, and residue silica gel chromatograph post separation must produce Product 4- (chloromethyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) benzamide compounds j (yield：93%).Exact Mass (calculated value)：429.14；MS(ESI)m/z(M+H)+：430.13.
4- (methyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) benzamide chemical combination The synthesis of object k
4mmol 4- (chloromethyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) benzene first Amide compound j, 4.4mmol sodium azide and 10 milliliters of n,N-Dimethylformamide add in round-bottomed flask, and reaction system is in room It is stirred to react under temperature overnight.Reaction system is extracted with ethyl acetate, and merges organic phase and is directly added into Pd/C (5%), and at one When the stirring under hydrogen reaction 6 of atmospheric pressure is small.Reaction system is filtered with diatomite, is collected organic phase and is removed solvent, crude product With silica gel chromatograph post separation (dichloromethane: methanol=10: 1) product 4- (methyl)-N- (4- methyl -3- ((4- (pyridine -3- Base) pyrimidine -2-base) amino) phenyl) benzamide (two step yields：66%).Exact Mass (calculated value)：410.19；MS (ESI)m/z(M+H)+：MS：411.18.
The synthetic method route similar with compound k is taken, following various amine intermediates can be obtained：
The amine intermediate and acyl chloride compound of more than figure, acid compounds or other electrophilic groups are as reaction Substrate using the synthetic route method similar to compound 26 and compound 68, can synthesize a variety of target compounds.
N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) -4- (piperazine -1- ylmethyls) benzene first The synthesis of amide compound 1
10mmol 4- (chloromethyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) are sequentially added in 100mL round-bottomed flasks Pyrimidine -2-base) amino) phenyl) benzamide compounds j, n,N-Dimethylformamide (DMF) 25mL, piperazine 30mmol.Reaction System is stirred at room temperature overnight, chloroform extraction, anhydrous sodium sulfate drying.Rotary Evaporators remove solvent, residue silica gel color Spectrum post separation obtains product N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) -4- (piperazine -1- Ji Jia Base) 1 (yield of benzamide compounds：86%), Exact Mass (calculated value)：479.24；MS(ESI)m/z(M+H)+：MS： 480.23。
4- ((4- (2- (2- (2- chloroethoxies) ethyoxyl) ethyl) piperazine -1- bases) methyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) and benzamide compounds m synthesis
50mL round-bottomed flasks sequentially add 8mmol N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) Phenyl) -4- (piperazine -1- ylmethyls) benzamide compounds 1, double (2- chloroethoxies) ethane of 30mmol 1,2-, 10mmol without Aqueous carbonate potassium and 20mLN, dinethylformamide (DMF).Reaction system is stirred to react overnight in 60 degrees Celsius, ethyl acetate Extraction, anhydrous sodium sulfate drying.Rotary Evaporators remove solvent, and residue obtains product 4- ((4- (2- with silica gel chromatograph post separation (2- (2- chloroethoxies) ethyoxyl) ethyl) piperazine -1- bases) methyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidines -2- Base) amino) phenyl) benzamide compounds m (yields：72%), Exact Mass (calculated value)：629.29；MS(ESI)m/z (M+H)+：MS：630.30.
4- ((4- (2- (2- (2- nitrine ethyoxyl) ethyoxyl) ethyl) piperazine -1- bases) methyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) benzamide compounds n synthesis
50mL round-bottomed flasks sequentially add 5mmol 4- ((4- (2- (2- (2- chloroethoxies) ethyoxyl) ethyl) piperazine -1- Base) methyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) benzamide compounds m, 5mmol Sodium azide and 15mLN, dinethylformamide (DMF).Reaction system is stirred to react overnight in 70 degrees Celsius, ethyl acetate Extraction, anhydrous sodium sulfate drying.Rotary Evaporators remove solvent, and residue obtains product 4- ((4- (2- with silica gel chromatograph post separation (2- (2- nitrine ethyoxyl) ethyoxyl) ethyl) piperazine -1- bases) methyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine - 2- yls) amino) phenyl) benzamide compounds n (yields：86%), Exact Mass (calculated value)：636.33；MS(ESI)m/ z(M+H)+：MS：637.32.
4- ((4- (2- (2- (2- amino ethoxies) ethyoxyl) ethyl) piperazine -1- bases) methyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) benzamide compounds o synthesis
25mL round-bottomed flasks sequentially add 4mmol 4- ((4- (2- (2- (2- nitrine ethyoxyl) ethyoxyl) ethyl) piperazine- 1- bases -) methyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) benzamide compounds n, Pd/C the and 15mL ethyl acetate of 5%mmol.Reaction system is stirred to react 6h, diatom in the hydrogen at room temperature of an atmospheric pressure Soil filtering, filtrate remove solvent with Rotary Evaporators, and residue obtains product 4- ((4- (2- (2- (2- ammonia with silica gel chromatograph post separation Base oxethyl) ethyoxyl) ethyl) piperazine -1- bases) methyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) ammonia Base) phenyl) benzamide compounds o (yields：82%), Exact Mass (calculated value)：610.34；MS(ESI)m/z(M+H )+：MS：611.35.
1. structural formula of compound of table
Embodiment 1
(4- methyl -3- (N- (4 (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) -4- (propine amide methyl) benzoyl The synthesis of amine compounds 1
With 0.05mmol 4- (methyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) benzene Formamide k reaction temperatures are down to zero degrees celsius, N- (4- methyl -3- (piperidines -4- oxygroups) phenyl) -4- ((4- first of 0.05mmol Base piperazine -1- bases) methyl) -3- (trifluoromethyl) benzamide tri hydrochloride h, 0.05mmol propiolic acids, 0.3mmol N, N- bis- Wopropyl ethyl amine (DIPEA) and 1 milliliter of n,N-Dimethylformamide (DMF) sequentially add 5 milliliters of round-bottomed flask, stir shape 2- (7- azos benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU) of 0.06mmol is added under state.Instead Answer system be stirred at room temperature reaction 2 it is small when.Ethyl acetate extracts reaction system, anhydrous sodium sulfate drying；Rotary Evaporators remove Solvent, crude product obtain 1 (yield of product objective product Compound with silica gel chromatograph post separation：38%).Exact Mass (are calculated Value)：462.18；MS(ESI)m/z(M+1)+：MS：463.19.
Embodiment 2
(E)-(4- (4- (dimethylamino) -2- acrylamides) methyl)-(4- methyl -3- (4- (3- pyridyl groups) pyrimidine -2- Base) amino) phenyl) and benzamide compound 2 synthesis
The step of synthesis of compound 2 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value)：521.25；MS(ESI)m/z(M+1)+：522.27.
Embodiment 3
(4- methyl -3- (N- (4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl)) -4 (- (vinylic sulfonamides first Base) benzamide compounds 3 synthesis
0.05mmol 4- (methyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) benzene first Amide k adds in 5 milliliters of round-bottomed flasks, then sequentially adds 1 milliliter of tetrahydrofuran (THF), triethylamine (Et3N)0.3mmol.It will Reaction system is cooled to zero degrees celsius, then adds in the vinylsulfonyl chloride of 0.08mmol and with being stirred to react 1 under zero degrees celsius Hour.Rotary Evaporators remove solvent, and residue directly obtains target product compound 3 (82%) with silica gel chromatograph post separation. Exact Mass (calculated value)：500.16；MS(ESI)m/z(M+1)+：501.17.
Embodiment 4
3- (2- chloro acetylaminos)-N- (4- methyl -3- ((4- (3- pyridyl groups) pyrimidine -2-) amino) phenyl) -5- (trifluoros Methyl) benzamide compound 4 synthesis
The step of synthesis of compound 4 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value)：540.12；MS(ESI)m/z(M+1)+：541.13.
Embodiment 5
3- (2- propine amide groups)-(4- methyl -3- (4- (3- pyridyl groups) pyrimidine -2-base) amino) phenyl) -5- (trifluoros Methyl) benzamide compound 5 synthesis
The step of synthesis of compound 5 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value)：516.15；MS(ESI)m/z(M+1)+：517.15.
Embodiment 6
3- (2- acrylamidos)-(4- methyl -3- (4- (3- pyridyl groups) pyrimidine -2-base) amino) phenyl) -5- (trifluoros Methyl) benzamide compound 6 synthesis
The step of synthesis of compound 6 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value)：518.17；MS(ESI)m/z(M+1)+：519.16.
Embodiment 7
3- (2- propionamido-s)-(4- methyl -3- (4- (3- pyridyl groups) pyrimidine -2-base) amino) phenyl) -5- (fluoroforms Base) benzamide compound 7 synthesis
The step of synthesis of compound 7 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value)：518.17；MS(ESI)m/z(M+1)+：521.20.
Embodiment 8
N- (3- ((1- Antiepilepsirin -4- bases) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) methyl) benzene The synthesis of benzamide compound 8
The step of synthesis of compound 8 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：476.28；MS(ESI)m/z(M+1)+：477.30.
Embodiment 9
N- (3- ((1- chloracetyls piperidin-4-yl) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) methyl) benzene The synthesis of formamide amine compounds 9
The step of synthesis of compound 9 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：498.24；MS(ESI)m/z(M+1)+：499.25.
Embodiment 10
N- (4- ((1- propioloyls piperidin-4-yl) oxygroup) -3- aminomethyl phenyls) -4- ((4- methylpiperazine-1-yls) methyl) The synthesis of benzamide compounds 10
The step of synthesis of compound 10 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value)：474.26；MS(ESI)m/z(M+1)+：475.28.
Embodiment 11
(4- methyl -3- (N- (4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) -4- propine amide groups benzamides The synthesis of compound 11
The step of synthesis of compound 11 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value)：448.16；MS(ESI)m/z(M+1)+：449.17.
Embodiment 12
(4- methyl -3- (N- (4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) -3- propine amide toluyls The synthesis of amine compounds 12
The step of synthesis of compound 12 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value)：462.18；MS(ESI)m/z(M+1)+：463.19.
Embodiment 13
(4- methyl -3- (N- (4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) -3- chloroacetamide toluyls The synthesis of amine compounds 13
The step of synthesis of compound 13 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：486.16；MS(ESI)m/z(M+1)+：487.17.
Embodiment 14
N- (3- ((1- acrylamide piperidines -3- bases) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) methyl) The synthesis of benzamide compounds 14
The step of synthesis of compound 14 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：476.28；MS(ESI)m/z(M+1)+：477.27.
Embodiment 15
3- (2- chloracetyls amido)-(4- methyl -3- (4- (3- pyridyl groups) pyrimidine -2-base) amino) phenyl) benzoyl amination Close the synthesis of object 15
The step of synthesis of compound 15 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：472.14；MS(ESI)m/z(M+1)+：473.15.
Embodiment 16
3- (2- acrylamidos)-(4- methyl -3- (4- (3- pyridyl groups) pyrimidine -2-base) amino) phenyl) benzoyl amination Close the synthesis of object 16
The step of synthesis of compound 16 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：450.18；MS(ESI)m/z(M+1)+：451.19.
Embodiment 17
N- (3- ((1- (acetyl group chlorine) pyrrolidin-3-yl)-phenoxy group)-(4)-(4- methylpiperazine-1-yls) methyl) benzene The synthesis of benzamide compound 17
The step of synthesis of compound 17 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：484.22；MS(ESI)m/z(M+1)+：485.23.
Embodiment 18
N- (3- ((1- (acryloyl group) pyrrolidin-3-yl)-phenoxy group)-(4)-(4- methylpiperazine-1-yls) methyl) benzene The synthesis of benzamide compound 18
The step of synthesis of compound 18 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：462.2；MS(ESI)m/z(M+1)+：463.27.
Embodiment 19
N- (3- ((1- (acetyl group chlorine) piperidin-4-yl) oxygroup)-p-methylphenyl) -3- propionamido-s -5- (trifluoromethyl) The synthesis of benzamide compounds 19
The step of synthesis of compound 19 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：525.16；MS(ESI)m/z(M+1)+：526.17.
Embodiment 20
N- (3- ((1- (2- chloracetyls) azepine butane -3- bases) oxygroup) -4- aminomethyl phenyls) -4- (4- methyl piperazines -1- Base) methyl) benzamide compounds 20 synthesis
The step of synthesis of compound 20 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：470.21；MS(ESI)m/z(M+1)+：471.23.
Embodiment 21
N- (3- ((1- (2- acryloyl groups) azepine butane -3- bases) oxygroup) -4- aminomethyl phenyls) -4- (4- methyl piperazines -1- Base) methyl) benzamide compounds 21 synthesis
The step of synthesis of compound 21 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：448.25；MS(ESI)m/z(M+1)+：449.25.
Embodiment 22
3- (4- methyl-1 H-imidazole-1-groups)-N- (4- methyl -3- ((1- nicotinoyl phenylpiperidines -4- bases) oxygen) phenyl) -5- The synthesis of (trifluoromethyl) benzamide compound 22
The step of synthesis of compound 22 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value)：563.21；MS(ESI)m/z(M+1)+：564.25.
Embodiment 23
3- (4-methylimidazole -1- bases)-(4- methyl -3- (1- nicotinoyl phenylpiperidines -4- bases) oxygen) phenyl) -5- (fluoroforms Base) benzamide compound 23 synthesis
The step of synthesis of compound 23 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：512.20；MS(ESI)m/z(M+1)+：513.21.
Embodiment 24
3- (4-methylimidazole -1- bases)-(4- methyl -3- (1- chloracetyls piperidin-4-yl) oxygen) phenyl) -5- (fluoroforms Base) benzamide compound 24 synthesis
The step of synthesis of compound 24 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：534.16；MS(ESI)m/z(M+1)+：535.18.
Embodiment 25
3- (4-methylimidazole -1- bases)-(4- methyl -3- (1- propine acylpiperidine -4- bases) oxygen) phenyl) -5- (fluoroforms Base) benzamide compound 25 synthesis
The step of synthesis of compound 25 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value)：510.19；MS(ESI)m/z(M+1)+：511.20.
Embodiment 26
N- (3- ((1- acrylic piperazinyl -4- bases) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 26 synthesis
N- (4- methyl -3- (piperidines -4- oxygroups) phenyl) -4- ((4- methylpiperazine-1-yls) methyl) -3- of 0.05mmol (trifluoromethyl) benzamide tri hydrochloride compound h adds in 5 milliliters of round-bottomed flasks, then sequentially adds tetrahydrofuran (THF) 1 Milliliter, triethylamine (Et3N)0.3mmol.Reaction system is cooled to zero degrees celsius, then adds in the acryloyl chloride of 0.08mmol And be stirred to react under zero degrees celsius 1 it is small when.Rotary Evaporators remove solvent, and residue must directly be produced with silica gel chromatograph post separation 26 (yield of product compound：86%).1H NMR (400MHz, DMSO-d6) δ (ppm) 10.35 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.92 (d, J=7.2Hz, 1H), 7.74 (s, 1H), 7.29 (d, J=8.0Hz, 1H), 7.13 (d, J=8.0Hz, 1H), 6.84 (m, 1H), 6.13 (d, J=16.4Hz, 1H), 5.69 (d, J=10.4Hz, 1H), 4.56 (m, 1H), 3.75-3.53 (m, 6H), 2.44 (brs, 8H), 2.23 (S, 3H), 2.14 (S, 3H), 1.95 (brs, 2H), 1.68 (brs, 2H) .Exact Mass (calculated value)：544.27；MS(ESI)m/z(M+H)+：545.26.
Embodiment 27
N- (3- ((1- chloracetyl piperazinyl -4- bases) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 27 synthesis
The step of synthesis of compound 27 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value)：566.23；MS(ESI)m/z(M+1)+：567.24.
Embodiment 28
4- ((2- chloroacetamides methyl)-(4- methyl -3- (4- (3- pyridyl groups) pyrimidine -2-base) amino) phenyl) -3- (three Methyl fluoride) benzamide compound 28 synthesis
The step of synthesis of compound 28 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：554.14；MS(ESI)m/z(M+1)+：555.16.
Embodiment 29
4- ((4 (2- (2- (2- (2- ((3R, 5R, 7R) 5- adamantane -1- bases) acetylamino) ethyoxyl) ethyoxyl) second Base) piperazine -1- bases) methyl)-N- (4- methyl-(4- (3- pyridyl groups) pyrimidinyl-amino) phenyl) benzamide compounds 29 Synthesis
5mL round-bottomed flasks sequentially add 0.3mmol 1- adamantane acetic acids, 0.3mmol (4- (4- (2- (2- (2- amino second Oxygroup) ethyoxyl) ethyl) -3-) methyl)-N- (4- methyl -3- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) benzene Benzamide compound o, 0.36mmol 2- (7- azos benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU), 0.45mmol n,N-diisopropylethylamine (DIPEA) and n,N-Dimethylformamide (DMF) 15mL.Reaction system Reaction 1h, ethyl acetate extraction, anhydrous sodium sulfate drying is stirred at room temperature.Rotary Evaporators remove solvent, residue silica gel Chromatography post separation obtains product 4- ((4 (2- (2- (2- (2- ((3R, 5R, 7R) 5- adamantane -1- bases) acetylamino) ethyoxyl) second Oxygroup) ethyl) piperazine -1- bases) methyl) (the production of-N- (4- methyl-(4- (3- pyridyl groups) pyrimidinyl-amino) phenyl) benzamide Rate：78%), Exact Mass (calculated value)：786.46；MS(ESI)m/z(M+1)+：787.49.
Embodiment 30
4- ((N- (2- (dimethylamino) ethyl) acrylamido) methyl)-(4- methyl -3- (4- (3- pyridyl groups) pyrimidine - 2- yls) amino) phenyl) and benzamide compound 30 synthesis
The step of synthesis of compound 30 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：535.27；MS(ESI)m/z(M+1)+：536.29.
Embodiment 31
N- (4- ((1- (2- chloracetyls) piperidin-4-yl) amino) -5- methylpyrimidine base -2- bases) -4- (4- methyl piperazines Piperazine -1- bases) methyl) benzamide compounds 31 synthesis
The step of synthesis of compound 31 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：499.25；MS(ESI)m/z(M+1)+：500.30.
Embodiment 32
4- ((4-6- (2- ((1S, 3S)-adamantane -1- bases) piperazine acetylamino) hexyl) -1- bases) methyl)-N- (4- first Base -3- ((4- (3- pyridyl groups) pyrimidine -2-base) amino) phenyl) benzamide compound 32 synthesis
The step of synthesis of compound 32 is by using similar to described in embodiment 29 is completed.Exact Mass (are calculated Value)：754.47；MS(ESI)m/z(M+1)+：755.47.
Embodiment 33
N- (3- ((1- acetylpiperazinyl -4- bases) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) methyl) - The synthesis of 3- (trifluoromethyl) benzamide compounds 33
The step of synthesis of compound 33 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：532.27；MS(ESI)m/z(M+1)+：533.29.
Embodiment 34
N-4- methyl -3- (N- (4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) -4- (propionamide methyl) benzoyl The synthesis of amine compounds 34
The step of synthesis of compound 34 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：466.55；MS(ESI)m/z(M+1)+：467.23.
Embodiment 35
N- (3- ((1- (2- chlorine propiono) piperidin-4-yl)-phenoxy group)-(4)-(4- methylpiperazine-1-yls) methyl) -3- The synthesis of (trifluoromethyl) benzamide compounds 35
The step of synthesis of compound 35 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：580.24；MS(ESI)m/z(M+1)+：581.26.
Embodiment 36
N- (the chloro- 3- of 4- ((1- (acetyl group chlorine) piperidin-4-yl) oxygroup) phenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 36 synthesis
The step of synthesis of compound 36 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：586.17；MS(ESI)m/z(M+1)+：587.21.
Embodiment 37
N- (the chloro- 3- of 4- ((1- (acryloyl group) piperidin-4-yl) oxygroup) phenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 37 synthesis
The step of synthesis of compound 37 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：564.21；MS(ESI)m/z(M+1)+：565.26.
Embodiment 38
N- (the chloro- 3- of 4- ((1- (propine acyl group) piperidin-4-yl) oxygroup) phenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 38 synthesis
The step of synthesis of compound 38 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：562.20；MS(ESI)m/z(M+1)+：563.21.
Embodiment 39
N- (3- ((1- propiono piperazinyl -4- bases) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) methyl) - The synthesis of 3- (trifluoromethyl) benzamide compounds 39
The step of synthesis of compound 39 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：546.28；MS(ESI)m/z(M+1)+：547.30.
Embodiment 40
N- (3- ((1- (acetyl group chlorine) piperidin-4-yl)-phenoxy group)-(4)-(4- methylpiperazine-1-yls) methyl) -3- nitre The synthesis of base benzamide compound 40
The step of synthesis of compound 40 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：543.22；MS(ESI)m/z(M+1)+：544.27.
Embodiment 41
N- (3- ((1- (acryloyl group) piperidin-4-yl)-phenoxy group)-(4)-(4- methylpiperazine-1-yls) methyl) -3- nitre The synthesis of base benzamide compound 41
The step of synthesis of compound 41 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：521.26；MS(ESI)m/z(M+1)+：522.30.
Embodiment 42
N- (the chloro- 3- of 4- (4- piperidines-oxygroup) phenyl) -4- (4- methylpiperazine-1-yls) methyl) benzamide (3- trifluoros Methyl) tri hydrochloride compound 42 synthesis
The step of synthesis of compound 42 is by using similar to described in intermediate h synthesis is completed.Exact Mass (meters Calculation value)：510.20；MS(ESI)m/z(M+1)+：511.22.
Embodiment 43
N- (4- methyl -3- (4- piperidines-oxygroup) phenyl) -4- (4- methylpiperazine-1-yls) methyl) benzamide (3- tri- Methyl fluoride) tri hydrochloride compound 43 synthesis
The step of synthesis of compound 43 is by using similar to described in intermediate h synthesis is completed.Exact Mass (meters Calculation value)：467.25；MS(ESI)m/z(M+1)+：468.31.
Embodiment 44
(1R, 3R, 5S, 7R) -3,5- dimethyl-N -s (2- (2- (2- (2- (4- (4- ((4- methyl -3- ((4- (pyridine -3- Base) pyrimidine -2-base) amino) phenyl) carbamyl) benzene) piperazine -1- bases -) ethyoxyl) ethyoxyl) ethyoxyl) ethyl) Buddha's warrior attendant The synthesis of alkane -1- benzamide compounds 44
The step of synthesis of compound 32 is by using similar to described in embodiment 29 is completed.Exact Mass (are calculated Value)：844.50；MS(ESI)m/z(M+1)+：845.53.
Embodiment 45
4- ((4- (1- ((3R, 5R, 7R)-adamantane -1- bases) -2- oxos -6,9, the tri- miscellaneous tetradecane -14- of oxygroup -3- of 12- Base) piperazine -1- bases) methyl)-(4- methyl -3- (4- (3- pyridin-2-yls) pyrimidine -2-base) amino) phenyl) benzamide compound 45 Synthesis
The step of synthesis of compound 45 is by using similar to described in embodiment 29 is completed.Exact Mass (are calculated Value)：830.48；MS(ESI)m/z(M+i)+：831.50.
Embodiment 46
(E)-N- (3- (1- (4- (dimethylamino) -2- alkene acyl) -4- piperidyls) oxygen) -4- aminomethyl phenyls) -4- (4- methyl Piperazine -1- bases) methyl) -3- (trifluoromethyl) benzamide compound 46 synthesis
The step of synthesis of compound 46 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value)：601.32；MS(ESI)m/z(M+1)+：602.32.
Embodiment 47
N- (3- ((the positive butyryl piperidin-4-yls of 1-) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) methyl) -3- The synthesis of (trifluoromethyl) benzamide compounds 47
The step of synthesis of compound 47 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：560.30；MS(ESI)m/z(M+1)+：561.32.
Embodiment 48
N- (3- ((1- methacryls piperidin-4-yl) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 48 synthesis
The step of synthesis of compound 48 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：558.28；MS(ESI)m/z(M+1)+：559.29.
Embodiment 49
N- (3- ((1- pivaloyl group acyls piperidin-4-yl) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 49 synthesis
The step of synthesis of compound 49 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：574.31；MS(ESI)m/z(M+I)+：575.32.
Embodiment 50
N- (3- ((1- cyclopropyl acyls piperidin-4-yl) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 50 synthesis
The step of synthesis of compound 50 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：558.28；MS(ESI)m/z(M+1)+：559.32.
Embodiment 51
N- (3- ((1- isobutyryl piperidines 4- yls) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) methyl) -3- The synthesis of (trifluoromethyl) benzamide compounds 51
The step of synthesis of compound 51 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：560.30；MS(ESI)m/z(M+1)+：561.33.
Embodiment 52
N- (3- ((2- crotonoyls piperidin-4-yl) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) methyl) -3- The synthesis of (trifluoromethyl) benzamide compounds 52
The step of synthesis of compound 52 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：558.28；MS(ESI)m/z(M+1)+：559.30.
Embodiment 53
N- (4- methoxyl groups -3- ((1- propionos piperidin-4-yl) oxygroup) phenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 53 synthesis
The step of synthesis of compound 53 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：562.28；MS(ESI)m/z(M+1)+：563.29.
Embodiment 54
N- (4- methoxyl groups -3- ((the positive bytyry piperidin-4-yls of 1-) oxygroup) phenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 54 synthesis
The step of synthesis of compound 54 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：576.29；MS(ESI)m/z(M+1)+：577.31.
Embodiment 55
N- (4- methoxyl groups -3- ((1- acryloylpiperidine -4- bases) oxygroup) phenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 55 synthesis
The step of synthesis of compound 55 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：560.26；MS(ESI)m/z(M+1)+：561.29.
Embodiment 56
N- (3- ((1- methacryls piperidin-4-yl) oxygroup) -4- methoxyphenyls) -4- ((4- methylpiperazine-1-yls) Methyl) -3- (trifluoromethyl) benzamide compounds 56 synthesis
The step of synthesis of compound 56 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：574.28；MS(ESI)m/z(M+1)+：575.30.
Embodiment 57
N- (3- ((1- mesylpiperazinyl -4- bases) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 57 synthesis
The step of synthesis of compound 57 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：568.23；MS(ESI)m/z(M+1)+：569.26.
Embodiment 58
N- (3- ((1- ethylsulfonyl piperazinyl -4- bases) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 58 synthesis
The step of synthesis of compound 58 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：582.25；MS(ESI)m/z(M+1)+：583.27.
Embodiment 59
N- (3- ((the positive fourth sulfonyl piperazinium base -4- bases of 1-) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 59 synthesis
The step of synthesis of compound 59 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：596.26；MS(ESI)m/z(M+1)+：597.28.
Embodiment 60
N- (3- ((1- Cyclopropylsulfonyl piperazinyl -4- bases) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) Methyl) -3- (trifluoromethyl) benzamide compounds 60 synthesis
The step of synthesis of compound 60 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：594.25；MS(ESI)m/z(M+1)+：595.26.
Embodiment 61
N- (3- ((1- benzoyl-piperazine base -4- bases) oxygroup)-p-methylphenyl) -4- ((4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compounds 61 synthesis
The step of synthesis of compound 61 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：594.28；MS(ESI)m/z(M+1)+：595-31.
Embodiment 62
N- (3- ((1- (7H- purine -6- bases) piperidin-4-yl)-phenoxy group)-(4)-(4- methylpiperazine-1-yls) methyl) - The synthesis of 3- (trifluoromethyl) benzamide compounds 62
The step of synthesis of compound 62 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：608.28；MS(ESI)m/z(M+1)+：609.30.
Embodiment 63
N- (3- (1- (1H- pyrazolopyrimidines) (3-D-4- yls) -4- piperidyls) oxygen) -4- aminomethyl phenyls) -4- (4- methyl Piperazine -1- bases) methyl) -3- (trifluoromethyl) benzamide compound 63 synthesis
The step of synthesis of compound 63 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：608.28；MS(ESI)m/z(M+1)+：609.31.
Embodiment 64
N- (4- methyl -3- (piperidines -4- oxygroups) phenyl) -4- ((4- methylpiperazine-1-yls) methyl) -3- (trifluoromethyl) The synthesis of benzamide tri hydrochloride compound 64
The step of synthesis of compound 64 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：490.26；MS(ESI)m/z(M+1)+：491.27.
Embodiment 65
N- (4- methyl -3- ((1- acryloylpiperidine -4- bases) oxygroup) phenyl) -4- ((4- methylpiperazine-1-yls) first Base) benzamide compounds 65 synthesis
The step of synthesis of compound 65 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：478.29；MS(ESI)m/z(M+1)+：479.31.
Embodiment 66
(4- methyl -3- (N- (4- (pyridin-3-yl) pyrimidine -2-base) amino) phenyl) -3- (propionamide methyl) benzoyl The synthesis of amine compounds 66
The step of synthesis of compound 66 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：466.21；MS(ESI)m/z(M+1)+：467.24.
Embodiment 67
N- (4- methyl-(1- (2- carbonyl pyrimidines) 4- piperidyls) oxygen) phenyl)-(4- methyl piperazine base -1- bases) methyl) - The synthesis of benzamide (trifluoromethyl) compound 67
The step of synthesis of compound 67 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：596.27；MS(ESI)m/z(M+1)+：597.29.
Embodiment 68
N- (4- methyl -3- ((1- niacin piperidyl -4- bases) oxygroup) phenyl) -4- ((4- methylpiperazine-1-yls) methyl) - The synthesis of 3- (trifluoromethyl) benzamide compounds 68
N- (4- methyl -3- (piperidines -4- oxygroups) phenyl) -4- ((4- methylpiperazine-1-yls) methyl) -3- of 0.05mmol (trifluoromethyl) benzamide tri hydrochloride h, 0.05mmol niacin, 0.3mmol n,N-diisopropylethylamine (DIPEA) and 1 Milliliter n,N-Dimethylformamide (DMF) sequentially adds 5 milliliters of round-bottomed flask, and the 2- of 0.06mmol is added under stirring (7- azos benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU).Reaction 2 is stirred at room temperature in reaction system Hour.Ethyl acetate extracts reaction system, anhydrous sodium sulfate drying；Rotary Evaporators remove solvent, crude product silica gel chromatograph Post separation obtains 68 (yield of product compound：91%).1HNMR (400MHz, DMSO-d6) δ (ppm) 10.42 (s, 1H), 8.64 (s, 2H), 8.26-8.24 (m, 2H), 7.91-7.86 (m, 2H), 7.51-7.47 (m, 2H), 7.31 (d, J=7.6Hz, 1H), 7.13 (d, J=7.6Hz, 1H), 4.59 (m, 1H), 3.83-3.52 (m, 6H), 2.66 (brs, 8H), 2.37 (S, 3H), 2.15 (S, 3H), 1.98 (brs, 2H), 1.75 (brs, 2H) .Exact Mass (calculated value)：595.28；MS(ESI)m/z(M+H)+： 595.28。
Embodiment 69
(4- methyl -3- (N- (1- (3,3,3- trifluoro propiono) piperidin-4-yl) oxygroup) phenyl) -4- ((4- methyl piperazines Piperazine -1- bases) methyl) -3- (trifluoromethyl) benzamide compounds 69 synthesis
The step of synthesis of compound 69 is by using similar to described in embodiment 26 is completed.Exact Mass (are calculated Value)：600.25；MS(ESI)m/z(M+1)+：601.28.
Embodiment 70
(S)-tertiary butyl (1- (4- (2- methyl -5- (4- (4- methyl piperazine base -1- bases) methyl)-(trifluoromethyl) benzene first Acylamino-) benzene) piperidin-1-yl) -1- oxo -2- bases) carbamate compounds 70 synthesis
The step of synthesis of compound 70 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：661.35；MS(ESI)m/z(M+1)+：662.38.
Embodiment 71
(S)-tertiary butyl (3- (4- hydroxy phenyls) -1- (4- (2- methyl -5- (4- ((4- methylpiperazine-1-yls) methyl) - 3- (trifluoromethyl) benzamido) phenoxy group) piperidin-1-yl) -1- oxo -2- bases) carbamate compounds 71 synthesis
The step of synthesis of compound 71 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：753.37；MS(ESI)m/z(M+1)+：754.40.
Embodiment 72
(S)-N- (3- ((1- (2- aminopropionyls) piperidin-4-yl) oxygroup) -4- aminomethyl phenyls) -4- (4- methyl piperazines - 1- yls) methyl) -3- (trifluoromethyl) benzamide compounds 72 synthesis
The step of synthesis of compound 72 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：561.29；MS(ESI)m/z(M+1)+：562.31.
Embodiment 73
(S)-N- (3- ((1- (2- amino -3- (4- hydroxy phenyls) (piperidin-4-yl) oxygroup) -4- aminomethyl phenyls) -4- (4- Methylpiperazine-1-yl) methyl) -3- (trifluoromethyl) benzamide compounds 73 synthesis
The step of synthesis of compound 73 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：653.32；MS(ESI)m/z(M+1)+：654.36.
Embodiment 74
N- (4- methyl -3- ((2- methyl-1s-propiono piperidin-4-yl) oxygroup) phenyl) -4- ((4- methyl piperazines -1- Base) methyl) -3- (trifluoromethyl) benzamide compounds 74 synthesis
The step of synthesis of compound 74 is by using similar to described in embodiment 3 is completed.Exact Mass (are calculated Value)：560.30；MS(ESI)m/z(M+1)+：561.33.
Embodiment 75
N- (4- methyl -3- ((2- methyl-1s-benzoyl piperidine -4- bases) oxygroup) phenyl) -4- ((4- methyl piperazines -1- Base) methyl) -3- (trifluoromethyl) benzamide compounds 75 synthesis
The step of synthesis of compound 75 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：608.30；MS(ESI)m/z(M+1)+：609.31.
Embodiment 76
N- (4- methyl -3- ((2- methyl-1s-to methylbenzene acylpiperidine -4- bases) oxygroup) phenyl) -4- ((4- methyl piperazines Piperazine -1- bases) methyl) -3- (trifluoromethyl) benzamide compounds 76 synthesis
The step of synthesis of compound 76 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：608.30；MS(ESI)m/z(M+1)+：609.33.
Embodiment 77
N- (3- ((1- (the fluoro- 5- methyl benzoyls of 2-) piperidin-4-yl)-phenoxy group)-(4)-(4- methyl piperazines -1- Base) methyl) -3- (trifluoromethyl) benzamide compounds 77 synthesis
The step of synthesis of compound 77 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：626.29；MS(ESI)m/z(M+1)+：627.30.
Embodiment 78
N- (3- ((1- (3- trifluoromethylbenzoyl) piperidin-4-yl)-phenoxy group)-(4)-(4- methylpiperazine-1-yls) Methyl) -3- (trifluoromethyl) benzamide compounds 78 synthesis
The step of synthesis of compound 78 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：662.27；MS(ESI)m/z(M+1)+：663.29.
Embodiment 79
N- (3- ((1- (benzenesulfonyl) piperidin-4-yl)-phenoxy group)-(4)-(4- methylpiperazine-1-yls) methyl) -3- nitre The synthesis of base benzamide compound 79
The step of synthesis of compound 79 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：630.25；MS(ESI)m/z(M+1)+：631.28.
Embodiment 80
N- (3- (1- (2- furanylcarbonyls) 4- piperidyls) oxygen) -4- aminomethyl phenyls) -4- (4- methylpiperazine-1-yls) first Base) -3- (trifluoromethyl) benzamide compound 80 synthesis
The step of synthesis of compound 80 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：584.26；MS(ESI)m/z(M+1)+：585.28.
Embodiment 81
N- (4- methyl -3- ((1- pyridine -2- formyl piperidine -4- bases) oxygroup) phenyl) -4- ((4- methyl piperazines -1- Base) methyl) -3- (trifluoromethyl) benzamide compounds 81 synthesis
The step of synthesis of compound 81 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：595.28；MS(ESI)m/z(M+1)+：596.30.
Embodiment 82
N- (4- methyl -3- ((1- pyridine -4- formyl piperidine -4- bases) oxygroup) phenyl) -4- ((4- methyl piperazines -1- Base) methyl) -3- (trifluoromethyl) benzamide compounds 82 synthesis
The step of synthesis of compound 82 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：595.28；MS(ESI)m/z(M+1)+：596.31.
Embodiment 83
N- (4- methyl-(1- (3- carbonyls quinoline) -4- piperidyls) oxygen) phenyl)-(4- methylpiperazine-1-yls) methyl)-benzene The synthesis of formamide (trifluoromethyl) compound 83
The step of synthesis of compound 83 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：645.29；MS(ESI)m/z(M+1)+：646.29.
Embodiment 84
N- (4- methyl-(1- (5- pyrimidines-carbonyl) -4- piperidyls) oxygen) phenyl)-(4- methylpiperazine-1-yls) methyl) - The synthesis of benzamide (trifluoromethyl) compound 84
The step of synthesis of compound 84 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：596.27；MS(ESI)m/z(M+1)+：597.29.
Embodiment 85
N- (4- methyl -3- ((1- (quinazoline -2- bases) piperidin-4-yl) oxygroup) phenyl) -4- (4- methylpiperazine-1-yls) Methyl) benzamide (3- trifluoromethyls) compound 85 synthesis
The step of synthesis of compound 85 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：646.29；MS(ESI)m/z(M+1)+：647.32.
Embodiment 86
N- (3- ((1- (benzo [d] [1,3] dioxole -5- acyl groups) piperidin-4-yl) oxygroup) -4- methyl) benzene The synthesis of base-(4- (4- methylpiperazine-1-yls) methyl) benzamide -3- (trifluoromethyl) compound 86
The step of synthesis of compound 86 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：638.27；MS(ESI)m/z(M+1)+：639.28.
Embodiment 87
N- (3- ((1- (6- amino nicotinoyl base) piperidin-4-yl) oxygroup) -4- aminomethyl phenyls) -4- (4- methyl piperazines -1- Base) methyl) -3- (trifluoromethyl) benzamide compounds 87 synthesis
The step of synthesis of compound 87 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：646.29；MS(ESI)m/z(M+1)+：647.32.
Embodiment 88
N- (3- ((1- (2- aminopyrimidine -5- carboxyls) piperidin-4-yl)-phenoxy group)-(4)-(4- methylpiperazine-1-yls) Methyl) -3- (trifluoromethyl) benzamide compounds 88 synthesis
The step of synthesis of compound 88 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：610.29；MS(ESI)m/z(M+1)+：611.30.
Embodiment 89
(S)-N- (4- methyl -3- ((1- (2- hydrocinnamoyls) piperidin-4-yl) oxygroup) phenyl) -4- (4- methyl piperazines -1- Base) methyl) -3- (trifluoromethyl) benzamide compounds 89 synthesis
The step of synthesis of compound 89 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：622.31；MS(ESI)m/z(M+1)+：623.32.
Embodiment 90
N- (3- (1- (6,7- dimethoxyquinazoline -4- bases) 4- piperidyls) oxygen) -4- aminomethyl phenyls) -4- (4- methyl piperazines Piperazine -1- bases) methyl) -3- (trifluoromethyl) benzamide compound 90 synthesis
The step of synthesis of compound 90 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：678.31；MS(ESI)m/z(M+1)+：679.32.
Embodiment 91
(R)-N- (3- ((1- (2- methoxyl group -2- bases) piperidin-4-yl) oxygroup) -4- aminomethyl phenyls) -4- (4- methyl piperazines Piperazine -1- bases) methyl) -3- (trifluoromethyl) benzamide compounds 91 synthesis
The step of synthesis of compound 91 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：638.31；MS(ESI)m/z(M+1)+：639.32.
Embodiment 92
(S)-N- (3- ((1- (2- methoxyl group -2- bases) piperidin-4-yl) oxygroup) -4- aminomethyl phenyls) -4- (4- methyl piperazines Piperazine -1- bases) methyl) -3- (trifluoromethyl) benzamide compounds 92 synthesis
The step of synthesis of compound 92 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：638.31；MS(ESI)m/z(M+1)+：639.34.
Embodiment 93
(4- methyl -3- (N- (1- (2- (pyridin-3-yl) acetylamino) piperidin-4-yl) oxygroup) phenyl) -4- ((4- first Base piperazine -1- bases) methyl) -3- (trifluoromethyl) benzamide compounds 93 synthesis
The step of synthesis of compound 93 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：609.34；MS(ESI)m/z(M+1)+：610.32.
Embodiment 94
(4- methyl -3- (N- (1- (2- (pyridine -2- bases) acetylamino) piperidin-4-yl) oxygroup) phenyl) -4- ((4- first Base piperazine -1- bases) methyl) -3- (trifluoromethyl) benzamide compounds 94 synthesis
The step of synthesis of compound 94 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：609.34；MS(ESI)m/z(M+1)+：610.29.
Embodiment 95
N- (3- (1- (2- (dimethylamino) acetyl group) 4- piperidyls) oxygen) -4- aminomethyl phenyls)-(4- methyl piperazines -1- Base) methyl)-benzamide (trifluoromethyl) compound 95 synthesis
The step of synthesis of compound 95 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：575.31；MS(ESI)m/z(M+1)+：576.32.
Embodiment 96
N- (4- methyl-(1- (1-4- formylation piperidines alkane and its derivative) 4- piperidyls) oxygen) phenyl)-(4- methyl Piperazine -1- bases) methyl)-benzamide (trifluoromethyl) compound 96 synthesis
The step of synthesis of compound 96 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：615.34；MS(ESI)m/z(M+1)+：616.36.
Embodiment 97
N- (3- ((1- (2- hydroxypropanoyls) piperidin-4-yl)-phenoxy group)-(4)-(4- methylpiperazine-1-yls) methyl)- The synthesis of 3- (trifluoromethyl) benzamide compounds 97
The step of synthesis of compound 97 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：562.28；MS(ESI)m/z(M+1)+：563.28.
Embodiment 98
(S)-(3- (1- propionos piperidin-4-yl) oxygen) -4- aminomethyl phenyls) -4- (3- (dimethylamino) pyrrolidinyl) first Base) -3- (trifluoromethyl) benzamide compound 98 synthesis
The step of synthesis of compound 98 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：558.28；MS(ESI)m/z(M+1)+：559.29.
Embodiment 99
(S)-(3- (1- nicotinoyl phenylpiperidines -4- bases) oxygen) -4- aminomethyl phenyls) -4- (3- (dimethylamino) pyrrolidinyl) first Base) -3- (trifluoromethyl) benzamide compound 99 synthesis
The step of synthesis of compound 99 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：609.29；MS(ESI)m/z(M+1)+：610.30.
Embodiment 100
(R)-(3- (1- propionos piperidin-4-yl) oxygen) -4- aminomethyl phenyls) -4- (3- (dimethylamino) pyrrolidinyl) first Base) -3- (trifluoromethyl) benzamide compound 100 synthesis
The step of synthesis of compound 100 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：558.28；MS(ESI)m/z(M+1)+：559.29.
Embodiment 101
(R)-(3- (1- nicotinoyl phenylpiperidines -4- bases) oxygen) -4- aminomethyl phenyls) -4- (3- (dimethylamino) pyrrolidinyl) first Base) -3- (trifluoromethyl) benzamide compound 101 synthesis
The step of synthesis of compound 101 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value)：609.29；MS(ESI)m/z(M+1)+：610.30.
Embodiment 102
Influence of the Azaindole kinase inhibitors to growth of cancer cells
By testing influence of the Azaindole kinase inhibitors to the multiplication of cancer cell, we further have evaluated done compound Inhibit the selectivity of cancer cell multiplication.We have selected blood cell K562 and mouse pro B lymphocyte BaF3 in embodiment, more than it is thin Born of the same parents are purchased from ATCC.Mouse TEL-cKit-BaF3 (stablizing expression TEL-KIT activated protein kinases) is also selected, the cell is by this experiment Room is built, and construction method is：PCR expands mankind's KIT kinases region sequences respectively, and is inserted into the MSCV- with N-terminal TEL segments Puro carriers (Clontech), by retrovirus method, stabilization is transferred to mouse BaF3 cells, and remove IL-3 growths because Son finally obtains and relies on the cell line that KIT is transferred to albumen.
In embodiment by various concentration (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μ M, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, 10 μM) compound be added separately in above-mentioned cell, and be incubated 72 small When, with CCK8 (won purchased from shellfish, China) cell viability detection kit, by the reduction dehydrogenase in living cells to CCK8 into Row reduction obtains the stronger substance of UV absorption, is quantitative determined to detect number of viable cells with microplate reader reading.
Influence of the table 2 to cancer cell multiplication
Embodiment 103
Influence of the Azaindole kinase inhibitors to cell-signaling pathways
In blood cell K562 (expression Bcr-Abl chromosome translocation fusions carcinogenic protein) cell line, TEL-cKit-BaF3 (expressing K IT N822K are mutated by (stablizing expression TEL-KIT activated protein kinases) cell line and acute myeloid leukemia cells in children Kasumi-1 Gene, purchased from ATCC) on three plants of cells, by measuring many cellular biochemistry terminals and functional terminal, have evaluated chemical combination Object 26 is to Bcr-Abl chromosome translocations fusion protein in cell and other protein kinases closely related with the mutain The influence of Stat5, AKT, ErK, CrkL.With 0 μM of various concentration, 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM of change The Imatinib (Imatinib) and 0.1 μM of Dasatinib (Dasatinib) for closing 26,1 μM of object handle blood cell respectively K562 (expression Bcr-Abl chromosome translocation fusions carcinogenic protein) cell line, TEL-cKit-BaF3 (stablize expression TEL-KIT to live Change kinases) cell line and during small three plants of cells 2 of acute myeloid leukemia cells in children Kasumi-1 (expressing K IT N822K mutators) Afterwards, sample is collected.Compound 26 is measured to Bcr-AblY245, Stat5T694, AKT T308, AKT in this cell line The influence (Fig. 1) of S473, Erk T202/204, KIT Y719, KIT Y703, KIT Y823 phosphorylations.
Experimental result is as shown in Figure 1：At blood cell K562 (expression Bcr-Abl chromosome translocation fusions carcinogenic protein) In, compound 26 can substantially inhibit the phosphorylation (EC50 values are 161nM) of Bcr-Abl carcinogenic proteins, and under the albumen The signaling pathway protein Stat5 phosphorylations of trip also have apparent inhibitory action (EC50 values are 46nM).For with Bcr-Abl signals Tri- kinds of kinases of pathway associated protein AKT, ERK and CrkL, compound 26 also have and influence to a certain extent.These all illustrate compound 26 be to influence the chronic myelogenous leukemia of carrying Bcr-Abl carcinogenic proteins by inhibiting the phosphorylation of carcinogenic protein Bcr-Abl The cell Proliferation of cell cycling inhibiting.In TEL-cKit-BaF3 (stablize expression TEL-KIT activated protein kinases) cell line and acute myelogenous On leukaemia Kasumi-1 (expressing K IT N822K mutators) cell line, by measure many cellular biochemistry terminals and Functional terminal has evaluated compound 26 to c-kit kinases in cell and other albumen closely related with the mutain The influence of kinases AKT, ErK.It is the experimental results showed that no matter thin in TEL-cKit-BaF3 (stablizing expression TEL-KIT activated protein kinases) Born of the same parents strain or on acute myeloid leukemia cells in children Kasumi-1 (expressing K IT N822K mutators) cell line, compound 26 The phosphorylation of KIT kinases can substantially be inhibited, also have apparent shadow to the phosphorylation of associated signal paths protein kinase AKT and ERK It rings.This illustrates that compound 26 is to influence the Tel-ckit- of carrying KIT carcinogenic proteins by inhibiting the phosphorylation of KIT kinases The cell Proliferation of BaF3 and acute myeloid leukemia cells in children strain Kasumi-1.
Embodiment 104
Influence of the Azaindole kinase inhibitors to Apoptosis
In order to which the death for proving cell after medication is by apoptosis or necrosis, Bcr-Abl carcinogenic proteins are being carried In blood cell strain K562, pair DNA repair enzyme poly- adenosine closely related with Apoptosis in cell of compound 26 is had detected The influence of diphosphonic acid-ribose polymerase PARP, 3 protein cleavages of aspartic acid proteolytic enzyme Caspase containing cysteine. Handle blood cell K562 with 0 μM of various concentration, 0.1 μM, 0.3 μM, 1 μM, 3 μM of compound 26, then respectively when 24 is small, 48 it is small when after collect cell.With the medicine of Western Blot detection various concentrations in different time sections to the poly- adenosine of DNA repair enzymes The shadow of the shear protein of diphosphonic acid-ribose polymerase PARP and aspartic acid proteolytic enzyme Caspase 3 containing cysteine It rings.
Experimental result is as shown in Figure 2：At blood cell K562 (expression Bcr-Abl chromosome translocation fusions carcinogenic protein) In, effect 24 it is small when and 48 it is small when after, it can be seen that there is the poly- adenosine diphosphate of part DNA repair enzymes-ribose polymerase PARP Shearing.This demonstrate that compound 26 can cause the blood cell of expression Bcr-Abl chromosome translocation fusion carcinogenic proteins The apoptosis of K562.

Claims (16)

1. the pharmaceutically acceptable salt of a kind of compound of following formula or the compound：
R7 is selected from H ,-(CO)-(C1-C8) alkyl ,-(CO)-(C2-C8) alkenyl ,-(CO)-(C2-C8) alkynyl ,-(CO)-(C3- C8) cycloalkyl ,-(CO)-(C1-C8) halogenated alkyl ,-(CO)-(C1-C8) hydroxyalkyl ,-(CO)-(C1-C8) alkyl amino ,- (CO)-(C1-C8) alkyl-N- [(C1-C8) alkyl]2,-(CO)-vinyl-(CH2)n- N- [(C1-C8) alkyl]2, optional quilt The substitution of 1-3 R8 group-(CO)-phenyl, optionally substituted by 1-3 R8 group-(CO)-heteroaryl, the heteroaryl Selected from pyridyl group, pyrimidine radicals, furyl, quinolyl, quinazolyl and benzodioxole base, optionally by 1-3 R8 Group substitution-(CO)-piperidyl ,-(CO)-(C1-C8) alkyl phenyl ,-(CO)-(C1-C8) Alkylpyridyl ,-(SO2)- (C1-C8) alkyl ,-(SO2)-(C3-C8) cycloalkyl, optionally substituted by 1-3 R8 group-(SO2)-phenyl,Optionally by 1-3 The heteroaryl of a R8 groups substitution, the heteroaryl are selected from purine radicals, pyrazolopyrimidine base and quinazolyl；
It is halogenated that R8 is selected from halogen, amino, nitro, hydroxyl, C1-C8 alkyl, C1-C8 halogenated alkyls, C1-C8 alkoxyl and C1-C8 Alkoxy；
R2 is selected from halogen, C1-C8 alkyl and C1-C8 alkoxyl；
R3 and R5 be each independently selected from hydrogen, optionally by the alkyl-substituted imidazole radicals of 1-3 C1-C8, C1-C8 halogenated alkyls ,- (CH2)n- NH- (CO)-(C1-C8) alkyl and nitro；
R4 be selected from hydrogen and optionally by 1-3 C1-C8 it is alkyl-substituted-(CH2)n- (C3-C8) heterocycles；
Wherein n is each independently the integer of 0-2, and m is the integer of 1-4.
2. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein R7 is selected from H ,-(CO)-methyl ,-(CO)- Ethyl ,-(CO)-propyl ,-(CO)-butyl ,-(CO)-vinyl ,-(CO)-acrylic ,-(CO)-acetenyl ,-(CO)-ring third Base ,-(CO)-chloromethyl ,-(CO)-Chloroethyl ,-(CO)-trifluoroethyl ,-(CO)-ethoxy ,-(CO)-ethylamino ,- (CO)-methyl-N- (methyl)2,-(CO)-vinyl-(CH2)-N- (methyl)2, optionally substituted by 1-3 R8 group- (CO)-phenyl, optionally substituted by 1-3 R8 group-(CO)-heteroaryl, the heteroaryl be selected from pyridyl group, pyrimidine radicals, furan Mutter base, quinolyl, quinazolyl and benzodioxole base, optionally substituted by 1-3 R8 group-(CO)-piperidines Base, 2- hydrocinnamoyls ,-(CO)-picolyl ,-(SO2)-methyl ,-(SO2)-ethyl ,-(SO2)-propyl ,-(SO2)-ring third Base, optionally substituted by 1-3 R8 group-(SO2)-phenyl, Optionally substituted by 1-3 R8 group miscellaneous Aryl, the heteroaryl are selected from purine radicals, pyrazolopyrimidine base and quinazolyl；
Wherein R8 is selected from amino, methyl and methoxyl group.
3. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein R7 be selected from-(CO)-(C2-C8) alkenyl and Optionally substituted by amino-(CO)-heteroaryl, the heteroaryl is selected from pyridyl group, pyrimidine radicals, furyl, quinolyl, quinazoline Base and benzodioxole base.
4. compound as claimed in claim 3 or its pharmaceutically acceptable salt, wherein R7 is selected from-(CO)-vinyl ,-(CO)- Acrylic, optionally substituted by amino-(CO)-pyridyl group and optionally substituted by amino-(CO)-pyrimidine radicals.
5. compound or its pharmaceutically acceptable salt as any one of claim 1-4, wherein R2 is selected from C1-C8 alkane Base.
6. compound as claimed in claim 5 or its pharmaceutically acceptable salt, wherein R2 is methyl.
7. compound or its pharmaceutically acceptable salt as any one of claim 1-4, wherein R3 and R5 are each independent Ground is selected from hydrogen and C1-C8 halogenated alkyls.
8. compound as claimed in claim 7 or its pharmaceutically acceptable salt, wherein R3 and R5 be each independently selected from hydrogen and Trifluoromethyl.
9. compound or its pharmaceutically acceptable salt as any one of claim 1-4, wherein R4 is optionally by methyl Or ethyl substitution-(CH2)-piperazinyl.
10. compound as described in claim 1 or its pharmaceutically acceptable salt are the compounds selected from following table：
11. a kind of pharmaceutical composition, including the compound as any one of claim 1-10 or its is pharmaceutically acceptable Salt and pharmaceutically acceptable carrier or excipient and optional other therapeutic agents.
12. compound or its pharmaceutically acceptable salt as any one of claim 1-10 are preparing for inhibiting junket ammonia Purposes in the drug of kinase activity, the tyrosine kinase are selected from wild type or KIT, wild of various mutation or its combination Type or it is various mutation or its combination ABL, wild type or it is various mutation or its combination EGFR, wild type or it is various mutation or its It is the FLT3 of combination, wild type or BLK of various mutation or its combination, wild type or VEGFR of various mutation or its combination, wild Type or it is various mutation or its combination RET, wild type or it is various mutation or its combination PDGFR, wild type or it is various mutation or Its MEK combined, wild type or the BCR/ABL of various mutation or its combination, wild type or the JAK of various mutation or its combination, With wild type or the BRAF of various mutation or its combination.
13. the compound or its pharmaceutically acceptable salt as any one of claim 1-10 are being prepared for treating, in advance It is anti-or improve adjusted by tyrosine kinase activity disease that is either being affected by it or being directed to tyrosine kinase activity, Purposes in the drug of the subject of obstruction and illness.
14. purposes as claimed in claim 13, wherein the disease, obstruction and illness are selected from following proliferative diseases： Acute myeloblastic leukemia, chronic myelogenous leukemia, to wild type or it is various mutation or its combination ABL and wild type or various The BCR/ABL tyrosine kinase activities of mutation or its combination inhibit have influential leukaemia, mesenchymoma, thyroid cancer, system Property mast cell disease, hypereosinophilia syndrome, fibre modification, rheumatoid arthritis, panarthritis, chorionitis, It is lupus erythematosus, graft versus host disease(GVH disease), neurofibroma, pulmonary hypertension, Alzheimer disease, seminoma, argyraemia, asexual Cytoma, mast cell tumor, lung cancer, bronchiolar carcinoma, the formation of testis intraepithelial neoplasia, melanoma, breast cancer, neuroblast Knurl, malignant lymphoma, non-Hodgkin lymphoma, 2 type Multiple Endocrine knurl formation, pheochromocytoma, parathyroid hyperplasia/gland Knurl, colon cancer, colorectal adenomas, oophoroma, prostate cancer, spongioblastoma, brain tumor, glioblastoma, pancreas Gland cancer, malignant pleural mesothelioma, hemangioblastoma, hemangioma, kidney, liver cancer, adrenal, carcinoma of urinary bladder, stomach cancer, rectum Cancer, carcinoma of vagina, cervical carcinoma, carcinoma of endometrium, Huppert's disease, neck and head tumor or its combination.
15. purposes as claimed in claim 14, wherein the disease, obstruction and illness are selected from following proliferative diseases： Gastrointestinal stromal tumor, acute myeloblastic leukemia, chronic myelogenous leukemia, thyroid cancer or its combination.
16. purposes as claimed in claim 13, wherein the disease, obstruction and illness are selected from following autoimmune disease Disease：Rheumatic arthritis, osteoarthritis, lupus, rheumatoid arthritis, inflammatory bowel disease, psoriasis arthropathica, Si Dier Disease, adolescent arthritis, diabetes, myasthenia gravis, Hashimoto thyroiditis, Order thyroiditis, Graves disease, class wind Wet arthritis syndrome, multiple sclerosis, Guillain-Barre syndrome, acute diseminated encephalomyelitis, Addision's disease, regarding property Eye battle array it is twin-the twin syndrome of flesh battle array, ankylosing spondylitis, antiphospholipid antibody syndrome, alpastic anemia, autoimmune liver Inflammation, chylous diarrhea, goodpasture's syndrome, Idiopathic Thrombocytopenic Purpura, optic neuritis, chorionitis, primary biliary Property hepatic sclerosis, Reiter syndrome, takayasu's arteritis, temporal arteritis, warm type autoimmune hemolytic anemia, Wegener Swollen disease, psoriasis, alopecia universalis, behcet disease, confirmed fatigue, familial dysautonomia, mullerianosis, Interstitial cystitis, neuromyotonia or Vulvodynia.
CN201410757626.7A 2014-12-12 2014-12-12 A kind of kinase inhibitor of new structure Active CN104844566B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410757626.7A CN104844566B (en) 2014-12-12 2014-12-12 A kind of kinase inhibitor of new structure

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410757626.7A CN104844566B (en) 2014-12-12 2014-12-12 A kind of kinase inhibitor of new structure

Publications (2)

Publication Number Publication Date
CN104844566A CN104844566A (en) 2015-08-19
CN104844566B true CN104844566B (en) 2018-05-18

Family

ID=53844601

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410757626.7A Active CN104844566B (en) 2014-12-12 2014-12-12 A kind of kinase inhibitor of new structure

Country Status (1)

Country Link
CN (1) CN104844566B (en)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107286077B (en) * 2016-04-01 2021-04-02 合肥中科普瑞昇生物医药科技有限公司 Selective C-KIT kinase inhibitor
CN107663151B (en) * 2016-07-28 2021-11-26 江苏豪森药业集团有限公司 Intermediate synthesis method of flumatinib mesylate
TW201811766A (en) 2016-08-29 2018-04-01 瑞士商諾華公司 N-(pyridin-2-yl)pyridine-sulfonamide derivatives and their use in the treatment of disease
CN107805240A (en) * 2016-09-08 2018-03-16 中国科学院合肥物质科学研究院 A kind of new PDGFR kinase inhibitors and application thereof
ES2952061T3 (en) * 2016-11-02 2023-10-26 Mirdetect Gmbh Early detection of preliminary stages of testicular germ cell tumors
CN110283160B (en) * 2018-03-19 2022-04-29 中国科学院合肥物质科学研究院 PDGFR kinase inhibitor
EP3805219A4 (en) * 2018-06-06 2022-03-23 Gengle Therapeutics, Inc. Pyrazolopyrimidine derivative, use thereof and pharmaceutical composition
WO2021035788A1 (en) * 2019-08-29 2021-03-04 中国科学院合肥物质科学研究院 Pyrazole derivative and use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4288592A (en) * 1979-04-30 1981-09-08 American Cyanamid Company Process for preparing amides by reaction in presence of molecular sieve
WO2008144253A1 (en) * 2007-05-14 2008-11-27 Irm Llc Protein kinase inhibitors and methods for using thereof
WO2011090738A2 (en) * 2009-12-29 2011-07-28 Dana-Farber Cancer Institute, Inc. Type ii raf kinase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4288592A (en) * 1979-04-30 1981-09-08 American Cyanamid Company Process for preparing amides by reaction in presence of molecular sieve
WO2008144253A1 (en) * 2007-05-14 2008-11-27 Irm Llc Protein kinase inhibitors and methods for using thereof
WO2011090738A2 (en) * 2009-12-29 2011-07-28 Dana-Farber Cancer Institute, Inc. Type ii raf kinase inhibitors

Also Published As

Publication number Publication date
CN104844566A (en) 2015-08-19

Similar Documents

Publication Publication Date Title
CN104844566B (en) A kind of kinase inhibitor of new structure
CN106883213B (en) Dual inhibitor of EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase)
CN107286077B (en) Selective C-KIT kinase inhibitor
CN104829610B (en) A kind of novel cloth Shandong tyrosine kinase inhibitor
EP2755958B1 (en) Aminopyrimidine derivatives for use as modulators of kinase activity
EP3398950B1 (en) Novel kinase inhibitor against wild-type egfr and mutated egfr
CN103354809B (en) A kind of aryl urea compounds, its intermediate and application thereof
CN102958921B (en) A kind of carbamide compounds, its preparation method, its intermediate and application thereof
EP3640248B1 (en) Aminopyrimidine derivatives, preparation method therefor and use thereof
HUE031955T2 (en) Novel pyrrolopyrimidine compounds as inhibitors of protein kinases
CN103965120A (en) Quinoline and quinazoline derivative, preparation method, intermediate, composition and application
CN104854103B (en) There is the acyl amino compound cycloalkyl of the illness of reaction suitable for the regulation treated to dopamine D 3 receptor
CN109867676A (en) Compound derived from a kind of pyrrolopyrimidine, pharmaceutical composition with and application thereof
CN107922350A (en) New benzimidazole compound and its medical usage
CN110526941A (en) A kind of azolopyrimidines containing m-chloroaniline class substituent group, preparation method and applications
CN104876879B (en) A kind of BCR-ABL kinase inhibitors
JP2022521964A (en) New pan-RAF kinase inhibitor and its use
CN109942544B (en) Novel indazole derivative kinase inhibitor
CN111303024B (en) Quinoline-structured pan-KIT kinase inhibitor and application thereof
WO2021174581A1 (en) New use of indazole compound
CN110283160B (en) PDGFR kinase inhibitor
CN107033069A (en) A kind of novel cloth Shandong tyrosine kinase irreversible inhibitor
RU2789405C2 (en) Pan-kit kinase inhibitor having quinoline structure and its use
CN111138426B (en) Indazole kinase inhibitor and application thereof
CN107805240A (en) A kind of new PDGFR kinase inhibitors and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
EXSB Decision made by sipo to initiate substantive examination
SE01 Entry into force of request for substantive examination
C41 Transfer of patent application or patent right or utility model
TA01 Transfer of patent application right

Effective date of registration: 20151113

Address after: High tech Zone Hefei city Anhui province 230088 Wangjiang Road No. 860 B Innovation Center Room 1409

Applicant after: HEFEI TECHNOLOGY INNOVATION ENGINEERING INSTITUTE OF CAS

Address before: 230031 Shushan Lake Road, Anhui, China, No. 350, No.

Applicant before: Hefei Inst. of Matter Sciences, Chinese Academy of Sciences

C41 Transfer of patent application or patent right or utility model
TA01 Transfer of patent application right

Effective date of registration: 20160111

Address after: 1405-1, room 230088, building B, building 860, Wangjiang West Road, Hefei hi tech Zone, Anhui, China

Applicant after: Hefei Zhongke bio Pharmaceutical Technology Co., Ltd.

Address before: 1409, room 230088, building B, building 860, Wangjiang West Road, Hefei hi tech Zone, Anhui, China

Applicant before: HEFEI TECHNOLOGY INNOVATION ENGINEERING INSTITUTE OF CAS

GR01 Patent grant
GR01 Patent grant