CN109721531A - A kind of novel liposome kinase inhibitor - Google Patents

A kind of novel liposome kinase inhibitor Download PDF

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Publication number
CN109721531A
CN109721531A CN201711058134.9A CN201711058134A CN109721531A CN 109721531 A CN109721531 A CN 109721531A CN 201711058134 A CN201711058134 A CN 201711058134A CN 109721531 A CN109721531 A CN 109721531A
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compound
amino
carbonyl
alkyl
acid
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CN109721531B (en
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刘青松
刘静
梁小飞
李凤
胡晨
蒋宗儒
汪文亮
陈程
王蓓蕾
王黎
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Hefei Institutes of Physical Science of CAS
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Abstract

The present invention provides a kind of novel kinase inhibitor comprising the compound of formula (I) or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug.It is used to treat the illness by PI3K kinases or the mediation of PfPI4K kinase activation, especially malaria, the purposes and method of cancer and other cell proliferation disorders the present invention also provides the pharmaceutical composition for including formula (I) compound and using these compounds and composition.

Description

A kind of novel liposome kinase inhibitor
Technical field
This application involves the compound of a kind of novel kinase inhibitor, the pharmaceutical composition comprising these compounds, with And it is used to treat the illness by PI3K kinases or the mediation of PfPI4K kinase activation, especially malaria using these compounds and composition The purposes and method of disease, cancer and other cell proliferation disorders.
Background technique
The signal transduction that many viruses mediate the transport of host's lipid-metabolism, lipid film and lipid can generate shadow It rings.Phosphoinositide (phosphoinositide, PI) is a kind of phosphatide for participating in above several cell processes.Phosphatidylinositols is The basic framework of PI, in 5 hydroxyls of phosphatidylinositols, 3,4,5 hydroxyls can be obtained 7 in total after kinases reversibly phosphorylation Kind PIs, including phosphatidylinositols -3- phosphoric acid (phosphatidylinositol 3-phosphate, PI3P), phosphatidyl-4 Alcohol -4- phosphoric acid (phosphatidylinositol 4-phosphate, PI4P), phosphatidylinositols -5- phosphoric acid (phosphatidylinositol 5-phosphate, PI5P), phosphatidylinositols -3,4- diphosphate (phosphatidylinositol 3,4-biphosphate, PI (3,4) P2), phosphatidylinositols -3,5- diphosphate (phosphatidylinositol 3,5-bisphosphate, PI (3,5) P2), phosphatidylinositols -4,5- diphosphate (phosphatidylinositol 4,5-bisphosphate, PI (4,5) P2) and phosphatidylinositols -3,4,5- triphosphate (phosphatidylinositol 3,4,5-triphosphate, PI (3,4,5) P3).This 7 kinds of PIs can be carried out each other Conversion, different types of phosphatase and kinases participate in its process mutually converted.Distribution of these PIs in Subcellular membrane is respectively not It is identical.PI3P is distributed on early late endosomal, and PI4P is mainly distributed on golgiosome；PI(3,4)P2,PI(4,5)P2, PI (3,4,5) P3 is predominantly located at membrane plasmapheresis；PI (3,5) P2 is distributed mainly on cynapse excretion vesicles, also has on late endosomal a small amount of Distribution.
PIs is to be widely present in a kind of phosphatide negatively charged in cell membrane to be although content is lower in biomembrane Important component part in biomembrane.It is in the transport of permeability, vesica, the transfer of film, the cytoskeleton adjustment of film and signal It is played an important role in conduction path.
Recently the study found that phosphatidylinositols -4- kinases (phosphatidylinositol 4-kinases, PI4K) is For the major target of plasmodium falciparum, by selectively inhibiting the PI4K albumen of plasmodium falciparum, without inhibiting people's PI4K albumen can achieve the effect that treat malaria (Nature, 2013,504,248-253).
This patent relates generally to a kind of novel kinase inhibitor, its action target spot is mainly plasmodium falciparum PI4K (Plasmodium falciparum phosphatidylinositol 4-kinase, PfPI4K) and phosphatidylinositols -3- Kinases (phosphatidylinositol 3-kinases, PI3K), and there is no apparent inhibiting effect to the PI4K of people, thus Achieve the effect that treat malaria.Since the compound of this patent also has apparent inhibitory effect to PI3K albumen, thus can also use In the illness that treatment is mediated by PI3K.
Summary of the invention
The present invention relates to a kind of compound of formula (I) or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or Prodrug:
Wherein:
X is selected from CH or N；
A ring is selected from pyridyl group, pyrrole radicals, pyrrolopyridinyl, pyrazolyl, Pyrazolopyridine base, tetrahydro pyridyl, isoquinoline The nitrogen-atoms of quinoline base, phenyl and indyl, the A ring is optionally replaced by amino protecting group；
R1And R2It is each independently selected from H, C1-6Alkyl, halogen and C1-6Halogenated alkyl；
R3Selected from H, halogen, C1-6Alkyl and C1-6Alkoxy；
R4Selected from H, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkanoyl, C1-6Alkyl amino-carbonyl, C3-6 Cycloalkyl amino carbonyl, C1-6Alkyl amido, C1-6Alkyl amino C1-6Alkyl amido, amino C1-6Alkyl amino-carbonyl, benzene alkyl, Phenyl amino carbonyl, Phenylalkylamino carbonyl, pyridinylamino carbonyl and amino protecting group, above-mentioned substituent group optionally by Amino, hydroxyl or the halogen that amino, amino protecting group replace replace.
The A ring is selected from pyridin-3-yl, pyridin-4-yl, pyrroles -3- base, pyrrolo- [2,3-b] in a preferred aspect, Pyridine -5- base, pyrazoles -4- base, pyrazolo [3,4-b] pyridine -5- base, tetrahydropyridine -4- base, isoquinolin -4- base, phenyl and Indoles -2- base, the nitrogen-atoms of the A ring optionally by selected from valeryl, tertbutyloxycarbonyl, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl, Benzyl replaces the amino protecting group of methoxybenzyl, allyloxycarbonyl and trifluoroacetyl group.
Additionally preferably, R1And R2In at least one be H.
Additionally preferably, R3Selected from chlorine, methyl and methoxyl group.
In a preferred embodiment, R4Selected from C1-6Alkyl amino-carbonyl, C1-6Alkyl amido, C1-6Alkyl amino C1-6Alkane Acylamino-, amino C1-6Alkyl amino-carbonyl, phenyl amino carbonyl, Phenylalkylamino carbonyl and pyridinylamino carbonyl, on Substituent group is stated optionally to be replaced by amino, hydroxyl or halogen that amino, amino protecting group replace.It is further preferred that R4It is selected from Methylaminocarbonyl, ethyl aminocarbonyl, acetylamino, dimethylamino acetylamino, phenyl amino carbonyl, difluorophenyl amino Carbonyl, Benzylamino carbonyl and 2- pyridinylamino carbonyl.
It yet still another aspect, the present invention relates to the compound of formula (II) or its pharmaceutically acceptable salt, solvate, ester, acid, Metabolin or prodrug:
Wherein:
X is selected from CH or N；
R1And R2In at least one be H, another be selected from H, C1-6Alkyl, halogen and C1-6Halogenated alkyl；
R3Selected from H, halogen, C1-6Alkyl and C1-6Alkoxy；
R4The C replaced selected from H, optionally by amino1-6Alkyl amino-carbonyl, C1-6Alkyl amido, C1-6Alkyl amino C1-6 Alkyl amido, amino C1-6Alkyl amino-carbonyl, the phenyl amino carbonyl being optionally optionally substituted by halogen, Phenylalkylamino carbonyl, With pyridinylamino carbonyl.
Preferably, R1And R2In at least one be H, another be selected from H, methyl, 2- propyl, fluorine, chlorine and trifluoromethyl.
Additionally preferably, R3Selected from selected from chlorine, methyl and methoxyl group.
In other embodiments, R4Selected from methylaminocarbonyl, ethyl aminocarbonyl, acetylamino, dimethylamino second Acylamino-, phenyl amino carbonyl, difluorophenyl amino carbonyl, Benzylamino carbonyl and 2- pyridinylamino carbonyl.
On the other hand, the application provides a kind of pharmaceutical composition comprising at least one of therapeutically effective amount mentions herein The compound of confession or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug and pharmaceutically acceptable carrier Or excipient, and optional other therapeutic agents.
On the other hand, this application involves for inhibiting the active method of PI3K and/or PfPI4K and purposes, including application The compound of the present invention or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug or including chemical combination of the present invention The pharmaceutical composition of object.
On the other hand, this application involves for treating, preventing or improve by the disease of PI3K and/or PfPI4K mediation Method and purposes, it is of the invention including being applied to subject especially for treating, preventing or improving the method and purposes of malaria Compound or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug or the drug including the compounds of this invention Composition.
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 present invention is using mass spectrum, the NMR, HPLC, protein chemistry, life within the scope of art technology 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 the technical staff of field.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 in the present specification and discuss.
Term " alkyl " refers to aliphatic hydrocarbon groups, can be the alkyl of branch or straight chain.According to structure, alkyl be can be Monoradical or bivalent radical (i.e. alkylidene).In the present invention, alkyl is preferably the alkyl with 1-8 carbon atom, more excellent " low alkyl group " with 1-6 carbon atom is selected, even more preferably with the alkyl of 1-4 carbon atom.Typically alkyl includes But be not limited to methyl, ethyl, propyl, butyl, amyl, hexyl etc..It should be understood that " alkyl " that is mentioned herein includes that may be present The alkyl of all configurations and conformation, such as " propyl " that is mentioned herein includes n-propyl and isopropyl, " butyl " includes positive fourth Base, isobutyl group and tert-butyl, " amyl " include n-pentyl, isopropyl, neopentyl, tertiary pentyl and amyl- 3- base etc..
Term " alkoxy " refers to-O- alkyl, and wherein alkyl is as defined herein.Typically alkoxy includes but is not limited to Methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy, hexyloxy etc..
Term " naphthenic base " refers to monocycle or polycyclic group, only contains carbon and hydrogen.Naphthenic base includes having 3-12 ring former The group of son.According to structure, naphthenic base can be monoradical or bivalent radical (such as cycloalkylidene).In the present invention, ring Alkyl is preferably the naphthenic base with 3-8 carbon atom, more preferably with " low-grade cycloalkyl " of 3-6 carbon atom.Naphthenic base Example include but is not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclopentenyl, cyclohexene Base, cycloheptenyl and adamantyl.
Term " aromatic radical " refers to that planar rings have the pi-electron system of delocalization and contain 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, which can be, optionally to be replaced.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 monocycle or polycyclic (sharing the ring of the adjacent carbon atom pair) group of condensed ring.
The atom that terms used herein " aryl " refer to that each in fragrant basic ring constitutes ring is carbon atom.Aryl rings By five, six, seven, eight, nine or nine atomic buildings can be more than.Aryl, which can be, optionally to be replaced.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).
Term " heteroaryl " refers to include one or more ring hetero atoms selected from nitrogen, oxygen and sulphur in aryl.Containing N " heteroaryl Base " partially 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 is not limited to pyridyl group, imidazole radicals, pyrimidine radicals, pyrazolyl, Triazolyl, pyrazinyl, tetrazole radical, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrole radicals, quinoline Quinoline base, isoquinolyl, indyl, benzimidazolyl, benzofuranyl, indazolyl, indolizine base, phthalazinyl, pyridazinyl, iso-indoles Base, pteridyl, purine radicals, oxadiazoles base, thiadiazolyl group, furazanyl, benzofuraxan base, benzothienyl, benzothiazolyl, benzene And oxazolyl, quinazolyl, naphthyridines base and furopyridyl etc..
Term " alkyl (aryl) " or " aralkyl " refer to that alkyl defined herein is replaced by aryl defined herein.Non- limit The alkyl (aryl) of property processed includes benzyl, phenethyl etc..
Terms used herein " miscellaneous alkyl " refer to that one or more skeletal chain atoms in alkyl defined herein are miscellaneous Atom, such as oxygen, nitrogen, sulphur, silicon, phosphorus or their combination.The hetero atom (one or more) can be located inside miscellaneous alkyl Any position or in the position that miscellaneous alkyl is connected with the rest part of molecule.
Terms used herein " Heterocyclylalkyl " or " heterocycle " refer to one or more composition rings in non-aromatic basic ring Atom is the hetero atom selected from nitrogen, oxygen and sulphur.Heterocycloalkyl ring can be by three, four, five, six, seven, eight, nine or more than nine originals Son is constituted.Heterocycloalkyl ring, which can be, optionally to be replaced.The example of Heterocyclylalkyl includes but is not limited to lactams, lactone, ring Asia Amine, ring thioimines, cyclic carbramates, tetrahydric thiapyran, 4H- pyrans, oxinane, piperidines, 1,3- dioxin, 1,3- bis- are disliked Alkane, 1,4- dioxin, 1,4- dioxanes, piperazine, 1,3- thioxane, 1,4- oxathiin, 1,4- oxygen thia Hexamethylene, tetrahydro -1,4- thiazine, 2H-1,2- oxazines, maleimide, succinimide, barbiturates, thiobarbituricacidα-, Dioxopiperazine, hydantoins, dihydrouracil, morpholine, trioxane, hexahydro -1,3,5- triazine, thiophane, tetrahydrofuran, Pyrrolin, pyrrolidines, imidazolidine, pyrrolidones, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3- dioxole, 1, 3- dioxolane, 1,3- dithiole, 1,3- dithiolane, isoxazoline, isoxazole alkane, oxazoline, evil Oxazolidine, oxazolidone, thiazoline, thiazolidine and 1,3- oxathiolane.According to structure, Heterocyclylalkyl can be monoradical Or bivalent radical (i.e. sub- Heterocyclylalkyl).
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 set by halogen atom It changes, the halogen atom is same or different to each other.
Term " amino " refers to group-NH2。
Term " aminoacyl " refers to-CO-NH2。
Term " amide groups " or " acylamino- " refer to-NR-CO-R ', and wherein R and R ' are each independently hydrogen or alkyl.
Term " alkyl amino " refers to further by one or two alkyl-substituted amino-substituent, in particular to base Group-NRR ', wherein R and R ' is each independently selected from hydrogen or low alkyl group, and condition is that-NRR ' is not-NH2." alkyl amino " packet Include wherein-NH2Nitrogen connect at least one alkyl group compound group.The example of alkylamino group includes but unlimited In methylamino, ethylamino etc.." dialkyl amido " includes wherein-NH2Nitrogen connect at least two other alkyl groups Group.The example of dialkyl amino group includes but is not limited to dimethylamino, diethylamino etc..
Term " arylamino " and " ammonia diaryl base " refer to and are further replaced by the amino that one or two aryl replaces Base, in particular to group-NRR ', wherein R and R ' is each independently selected from hydrogen, low alkyl group or aryl, and wherein N is separately connected At least one or two aryl groups.
Term " cycloalkyl amino ", which refers to, further to be taken by the amino that one or two naphthenic base as defined herein replaces Dai Ji.
The term " aryl alkyl amino " of this paper refers to that wherein R is loweraralkyl and R ' is hydrogen, low alkyl group, aryl or low Group-the NRR ' of grade aralkyl.
Term " heteroaryl amino ", which refers to, further to be taken by the amino that one or two heteroaryl as defined herein replaces Dai Ji.
Term " alkylaminoalkyl group " refers to that alkyl defined herein is replaced by alkyl amino defined herein.
Term " aminoalkyl " refers to the alkyl substituent further replaced by one or more amino.
Term " hydroxyl " refers to formula-OH group.
Term " hydroxyalkyl " or " hydroxy alkyl " refer to the alkyl substituent further replaced by one or more hydroxyls.
Term " acyl group " refers to remaining monovalent radical after organic or inorganic oxyacid removes hydroxyl, general formula R-M (O)-, wherein M is usually C.
Term " carbonyl " is the organo-functional group (C=O) being formed by connecting by two kinds of atoms of carbon and oxygen by double bond.
Term " alkanoyl " or " alkyl-carbonyl " refer to further by an alkyl-substituted carbonyl.Typical alkanoyl packet Include but be not limited to acetyl group, propiono, bytyry, valeryl, caproyl etc..
Term " alkyl amino-carbonyl ", " cycloalkyl amino carbonyl ", " aromatic yl aminocarbonyl ", " Aralkylaminocarbonyl ", " heteroarylaminocarbonyl " refers respectively to carbonyl defined herein respectively by alkyl amino defined herein, cycloalkyl amino, virtue Base amino, aryl alkyl amino or heteroaryl amino replace.
Term " sulfuryl " or " sulfonyl " refer to the functional group after sulfonic acid loses hydroxyl, in particular to-S (=O)2Group.
Term " amino sulfuryl " or " amino-sulfonyl " refer to-S (=O)2-NH2Group.
Term " alkyl sulfuryl " or " alkyl sulphonyl " refer to-S (=O)2- R, wherein R is alkyl.
Term " optional " refers to that the one or more events described below may or may not occur, and the thing including generation Both part and the event not occurred.Term " optionally replacing " or " substituted " refer to that mentioned group can be by one or more A additional group replaces, and the additional group is respectively and independently selected from alkyl, naphthenic base, aryl, heteroaryl, heterocycle Base, hydroxyl, alkoxy, cyano, halogen, amide groups, nitro, halogenated alkyl, amino, mesyl, alkyl-carbonyl, alkoxy carbonyl Base, heteroaryl alkyl, hetercycloalkylalkyl, aminoacyl, amino protecting group etc..Wherein, amino protecting group is preferably selected from pivaloyl Base, tertbutyloxycarbonyl, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl, benzyl, to methoxybenzyl, allyloxycarbonyl and trifluoroacetyl group Deng.
" 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 ", refer to the process of predetermined substance by organism transform summation, including but not limited to hydrolysis and by enzymatic Reaction, such as oxidation reaction.Therefore, enzyme can produce specific structure and be changed into compound.For example, Cytochrome P450 is urged Change various oxidations and reduction reaction, while the glucuronic acid molecule of diphosphate glucose sweet acid based transferase catalytic activation is to virtue The conversion of aromatic, aliphatic alcohol, carboxylic acid, amine and free sulfydryl.The further information of metabolism can be from " The Pharmacological Basis of Therapeutics ", 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 that will change Object is closed to be incubated in vitro with liver cell and analyze gained compound to identify.Both methods is all known in the art.? In some embodiments, the metabolin of compound be by oxidation process formed and it is corresponding with corresponding hydroxy-containing compounds.? In some embodiments, compound is metabolized as pharmaceutical active metabolite.Terms used herein " adjusting ", refer to directly or It connects and interacts with target, to change the activity of target, for example only, activity, suppression target including enhancing target Activity, limit target target activity or the activity for extending target.
IC used herein50Refer to that the 50% of ceiling effect is obtained in the analysis for measuring such effect inhibits specific Test amount, concentration or the dosage of compound.
GI used herein50Drug concentration needed for referring to 50% growth inhibition of cell, i.e. drug make 50% cancer cell Growth is inhibited or controls, drug concentration at this time.
Azaindole kinase inhibitors of the invention
The present invention relates to a kind of compound of formula (I) or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or Prodrug:
Wherein, X is selected from CH or N；
A ring is selected from pyridyl group (such as pyridin-3-yl, pyridin-4-yl), pyrrole radicals (such as pyrroles -3- base), pyrrolo- pyrrole Piperidinyl (such as pyrrolo- [2,3-b] pyridine -5- base), pyrazolyl (such as pyrazoles -4- base), Pyrazolopyridine base (such as pyrazoles And [3,4-b] pyridine -5- base), tetrahydro pyridyl (such as tetrahydropyridine -4- base), isoquinolyl (such as isoquinolin -4- base), Aryl (such as phenyl) and indyl (such as indoles -2- base), the nitrogen-atoms of above-mentioned substituent group is optionally taken by amino protecting group Generation, A ring are particularly preferably pyridin-3-yl；
R1And R2It is each independently selected from H, C1-6Alkyl, halogen and C1-6Halogenated alkyl, preferably R1And R2In at least one It is H, is more preferably both H；
R3Selected from H, halogen, C1-6Alkyl and C1-6Alkoxy is preferably chosen from chlorine, methyl and methoxyl group；
R4Selected from H, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkanoyl, C1-6Alkyl amino-carbonyl, C3-6 Cycloalkyl amino carbonyl, C1-6Alkyl amido, C1-6Alkyl amino C1-6Alkyl amido, amino C1-6Alkyl amido, amino C1-6Alkyl Amino carbonyl, hydroxyl C1-6Alkyl amino-carbonyl, benzene alkyl, phenyl amino carbonyl, Phenylalkylamino carbonyl, pyridinylamino Carbonyl and amino protecting group, wherein amino is optionally replaced by amino protecting group, and above-mentioned substituent group is optionally protected by amino, amino It protects amino, hydroxyl or halogen that base replaces to replace, R4It is preferably chosen from C1-6Alkyl amino-carbonyl, C1-6Alkyl amido, C1-6Alkyl Amino C1-6Alkyl amido, amino C1-6Alkyl amino-carbonyl, phenyl amino carbonyl, Phenylalkylamino carbonyl and pyridyl group ammonia Base carbonyl is more preferably selected from methylaminocarbonyl, ethyl aminocarbonyl, acetylamino, dimethylamino acetylamino, phenylamino Base carbonyl, difluorophenyl amino carbonyl, Benzylamino carbonyl and 2- pyridinylamino carbonyl.
Amino protecting group of the present invention be selected from valeryl, tertbutyloxycarbonyl, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl, Benzyl, to methoxybenzyl, allyloxycarbonyl and trifluoroacetyl group.
The invention further relates to a kind of compound of formula (II) or its pharmaceutically acceptable salt, solvate, ester, acid, Metabolin or prodrug:
Wherein, X is selected from CH or N；
R1And R2At least one is H, another is selected from H, C1-6Alkyl, halogen and C1-6Halogenated alkyl is more preferably selected from H, methyl, 2- propyl, fluorine, chlorine and trifluoromethyl, most preferably R1And R2It is all H；
R3Selected from H, halogen, C1-6Alkyl and C1-6Alkoxy is preferably chosen from chlorine, methyl and methoxyl group；
R4The C replaced selected from H, optionally by amino1-6Alkyl amino-carbonyl, C1-6Alkyl amido, C1-6Alkyl amino C1-6 Alkyl amido, amino C1-6Alkyl amino-carbonyl, the phenyl amino carbonyl being optionally optionally substituted by halogen, Phenylalkylamino carbonyl, With pyridinylamino carbonyl, it is preferably chosen from methylaminocarbonyl, ethyl aminocarbonyl, acetylamino, diformazan Aminoacetylamino, phenyl amino carbonyl, difluorophenyl amino carbonyl, Benzylamino carbonyl and 2- pyridinylamino carbonyl.
Compound involved in the present invention containing chirality, configuration can be arbitrary configuration or mixed racemic modification.
Compound described herein can be made into and/or be used as pharmaceutically acceptable salt.Pharmaceutically acceptable salt Type includes but is not limited to: (1) acid-addition salts, by by the free alkali form of compound and pharmaceutically acceptable inorganic acid reaction It is formed, described 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 benzoyl) benzoic acid, cortex cinnamomi Acid, mandelic acid, Loprazolam, ethane sulfonic acid, 1,2- ethionic acid, 2- ethylenehydrinsulfonic acid, 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' methylene bis-(3- hydroxyl Base -2- alkene -1- formic acid), 3- phenylpropionic acid, trimethylace tonitric, dodecyl sulphate, gluconic acid, glutamic acid, salicylic acid, hydroxyl Naphthoic acid, stearic acid, muconic acid etc.；(2) base addition salts, the shape when acid proton in parent compound is replaced by metal ion At, such as alkali metal ion (such as lithium, sodium, potassium), alkaline-earth metal ions (such as magnesium or calcium) or aluminium ion；Or with organic base or Inorganic base coordination.Acceptable organic base includes ethanol amine, diethanol amine, triethanolamine, trimethylamine, N- methyl glucose osamine, Etc..Acceptable inorganic base includes aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide etc..
Various method analyses and identification can be used in the corresponding ion balance of pharmaceutically acceptable salt, the method includes But be not limited to ion-exchange chromatography, ion chromatography, Capillary Electrophoresis, inductively coupled plasma body, atomic absorption spectrum, mass spectrum or Any combination of them.
Use at least one of following technology to recycle the salt: filtering, then filter with non-solvent precipitation, solvent evaporates, Or desivac is used in the case where aqueous solution.
Screening and characterize pharmaceutically acceptable salt, polymorphic and/or solvate can be used multiple technologies completion, described Technology includes but is 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 is not limited to IR Microscopy and Raman (Raman) microscopy.
Medical composition and its use of the invention
The application provides the pharmaceutical composition for being formulated for being administered by approach appropriate and mode, the pharmaceutical composition packet One or more compounds provided herein or its pharmaceutically acceptable salt, solvate, ester, acid, metabolism containing effective concentration Object or prodrug and pharmaceutically acceptable carrier or excipient, and optional other therapeutic agents.
The compound of the formula (I) or formula (II) of free form or salt form is hereinafter also known as " substance of the invention ", Due to their inhibiting effect to phosphatidyl-inositol 3-kinase, the formula (I) of free form or pharmaceutical acceptable salt or formula (II) Compound can be used for treating by one or more members of PI3K kinase families activation (including normal activity, especially excessively Activation) disease, the obstruction and illness that are mediated, for example (,) it is proliferative diseases, cancer, inflammatory disease or anaphylactia, obstructive Respiratory disease and/or the related illness with transplanting.
Since " substance of the invention " of free form or salt form is to the phosphatidylinositols 4- kinases of plasmodium falciparum The formula (I) of inhibiting effect, free form or pharmaceutical acceptable salt or the compound of formula (II) can be used for treating by PfPI4K kinases Disease, obstacle or the disease that the activation (including normal activity, especially overactivity) of one or more members of family is mediated Disease, such as pernicious malaria.
" treatment " of the invention can be therapeutic (such as symptomatic treatment) and/or preventative.
It is preferred for treating the purposes of proliferative diseases, the proliferative diseases are selected from benign or malignant tumour, including But it is not limited to: the cancer of the brain, kidney, liver cancer, adrenal, bladder cancer, breast cancer, lymph cancer, gastric cancer, stomach neoplasm, cancer of the esophagus, ovary Cancer, colorectal cancer, prostate cancer, cancer of pancreas, lung cancer, carcinoma of vagina, film gland cancer, thyroid cancer, neck cancer, CNS cancer, glioblastoma Tumor, myeloproliferative disease, sarcoma, spongioblastoma, Huppert's disease, human primary gastrointestinal cancers, H/N tumors, brain tumor, epidermis excessively increase Life, psoriasis, hyperplasia of prostate, tumor is formed, the tumor of epithelial character is formed, lymthoma or leukaemia.Other diseases include examining to step on Syndrome (Cowden syndrome), Lai Er meter -Du Baisi (Lhermitte-Dudos) disease and Bannayan-Zonana are comprehensive Simulator sickness or in which PI3K/PKB access are by the disease of abnormal activation.Preferably treat colorectal cancer, gastric cancer, breast cancer, lung cancer, liver Cancer, prostate cancer, film gland cancer, thyroid cancer, bladder cancer, kidney, brain tumor, neck cancer, CNS cancer, glioblastoma, myelosis Disease, leukaemia and lymph cancer.
Substance of the invention can be used for treating inflammatory or obstructive airway diseases, cause such as tissue damage, airway inflammation, The mitigation of bronchus overreact, remodeling or disease development.The inflammatory or obstructive airway diseases that the present invention is applicable in include any The asthma of type or cause, including endogenous (anallergic) asthma and exogenous (allergia) asthma, mild asthma, moderate are roared The asthma induced after asthma, severe asthma, bronchitic asthma, the asthma of exercise induced, occupational asthma and bacterium infection.It roars The treatment of asthma is also understood as including the treatment to individual, is, for example, less than the individual of 4 or 5 years old, shows wheezing symptoms, is examined Break and be or diagnosable for " wheezy infants (wheezy infant) ", this is the patient in a kind of fixed Major medical concern Classification, is typically now accredited as initial stage or asthma in early days.For convenience, referred to as " wheezy infants are comprehensive for this special asthma Simulator sickness ".
Prevention effect in treating asthma will appear as the reduction of paresthesia epilepsy frequency or the mitigation of severity, such as The reduction of acute asthma or bronchoconstrictor attack frequency or mitigation, lung function improvement or the air flue over-activity of severity change It is kind.Described effect is also embodied by the reduction to other symptom treatment demands, and other symptom treatments are used for or are directed at The treatment of paresthesia epilepsy, such as anti-inflammatory agent (such as corticosteroid) or bronchodilators are limited or stopped when it occurs.? It may be particularly evident to the prevention benefit of asthma in the individual for thering is " morning dipping (morning dipping) " to be inclined to." morning dipping " is one Kind of generally acknowledged Asthma Syndrome, usually accounts for significant proportion in asthma, it is characterized in that for example break out between about 4 to 6 points in the morning, That is, the farther away time breaking-out of any treatment for asthma symptoms usually applied before distance.
The other inflammatories or obstructive airway diseases and illness that the present invention is applicable in include acute lung injury (ALI), adult type/ Acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, air flue or lung disease (COPD, COAD or COLD), including it is slow Property bronchitis or expiratory dyspnea associated therewith, pulmonary emphysema, and controlled by other medicines treatment, particularly other Sucked medicines Air flue over-activity caused by treating deteriorates.The present invention is further adapted for treating the bronchitis of any type or cause, including for example anxious Property bronchitis, arachidic bronchitis, catarrhal bronchitis, fibrinous bronchitis, chronic bronchial Scorching or phthinoid bronchitis.Other inflammatories that the present invention is applicable in or the dirt that obstructive airway diseases include any type or cause (a kind of inflammatory is usually professional tuberculosis to lung, whether chronic or acute to be often accompanied by airway obstruction, and by repeating Sucking dust causes), including such as aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, iron heavy lung, silicosis, tabacism And byssinosis.
Substance of the invention is also used to treat the following diseases mediated by phosphatidyl-inositol 3-kinase, obstruction and illness: exhaling Desorption system disease, allergy, rheumatoid arthritis, osteoarthritis, wind-wetness syndrome, psoriasis, ulcerative colitis, office Allograft rejection after sex-limited ileitis, septic shock, proliferative disorders, atherosclerosis, transplanting is anti- It answers, diabetes, apoplexy, obesity or restenosis, leukaemia, mesenchymoma, thyroid cancer, systemic mast cell disease, acidophilia The anti-place of granulocytosis syndrome, fibre modification, rheumatoid arthritis, panarthritis, chorionitis, lupus erythematosus, graft Main disease, neurofibroma, pulmonary hypertension, Alzheimer disease, seminoma, dysgerminoma, mast cell tumor, lung cancer, Bronchiolar carcinoma, dysgerminoma, the formation of testis intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, mamillary/follicular Thyroid cancer, malignant lymphoma, non-Hodgkin lymphoma, 2 type Multiple Endocrine tumor formation, pheochromocytoma, thyroid cancer, Parathyroid hyperplasia/adenoma, colon cancer, colorectal adenomas, oophoroma, prostate cancer, spongioblastoma, brain tumor, evil Nerve glioma, cancer of pancreas, malignant pleural mesothelioma, hemangioblastoma, hemangioma, kidney, liver cancer, adrenal, wing Guang cancer, gastric cancer, the carcinoma of the rectum, carcinoma of vagina, cervical carcinoma, carcinoma of endometrium, Huppert's disease, neck and head tumor, tumor formed with And other Hypertrophic or proliferative diseases, or combinations thereof.
Substance of the invention can also be used in treatment illness relevant to eosinophils, such as eosinophilia, special It is not relevant to eosinophils airways disorders (such as being related to the lung tissue of ill eosinophils infiltration), including acidophilus is thin Born of the same parents are excessive, because it influences air flue and/or lung, and, for example, (special by loeffler syndrome, eosinophilic pneumonia, helminth It is not metazoa) infect (including tropical eosinophilia), bronchial aspergillosis, nodular polyarteritis (packet Include this syndrome of Qiu -), caused by eosinophilic granuloma or with the eosinophils relevant airways disorders parallel to its phase, With the illness relevant to eosinophils for influencing air flue caused by drug response.
Substance of the invention can also be used in treat skin inflammatory or allergic conditions, such as psoriasis, contact dermatitis, It is atopic dermatitis, alopecia circumscripta, erythema multiforme, dermatitis herpetiformis, chorionitis, hickie, allergic vasculitis, nettle rash, big Blister pemphigoid, lupus erythematosus, pemphigus (pemphisus), the inflammation of acquired epidermolysis bullosa and other skins Property or allergic conditions.
Substance of the invention can also be used to treat Other diseases or illness, especially with the disease or disease of inflammatory components Disease, such as the disease and illness for the treatment of eye, such as conjunctivitis, keratoconjunctivitis sicca and spring conjunctivitis；The disease of nose is influenced, Including allergic rhinitis；And it is directed to autoimmune response or there is autoimmunity sexual element or etiologic etiological inflammatory disease Disease, including autoimmune hematological illness (such as hemolytic anemia, alpastic anemia, pure red cell anaemia and Te Fa Property decrease of platelet), systemic loupus erythematosus, polychondritis, chorionitis, Wegner's granulomatosis, dermatomyositis, chronic work Dynamic property hepatitis, myasthenia gravis, Si-about syndrome, idiopathic sprue, autoimmune inflammatory enteropathy (such as ulcer Property colitis and regional enteritis), endocrine ophthalmopathy, Graves disease, sarcoidosis, pulmonary alveolitis, chronic allergic pneumonia, Multiple sclerosis, primary biliary cirrhosis, uveitis (anterior uveitis and rear uveitis), drying property Keratoconjunctivitis and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with not companion There is nephrotic syndrome, for example including idiopathic nephrotic syndrome or minute nephropathy).
Other can include septic shock, rheumatoid joint with the disease or illness of Substance treatment of the invention Allograft rejection reaction, apoplexy after inflammation, osteoarthritis, proliferative diseases such as cancer, atherosclerosis, transplanting, Obesity, restenosis, diabetes such as type-1 diabetes mellitus (juvenile-onset diabetes) and type-2 diabetes mellitus, diarrhea disease, part lack The retinopathy of blood/reperfusion injury, retinopathy such as diabetic retinopathy or induced by hyperbaric oxygen, and with eye Internal pressure increases or aqueous humor secretes the illness being characterized, such as glaucoma.
The validity of substance of the invention in terms of inhibiting inflammatory conditions such as airway inflammatory disease can be in animal model In be proven, such as the mouse or rat model of airway inflammation or other inflammatory conditions, such as such as Szarka, J.Immunol.Methods(1997)202:49-57；Renzi etc., Am.Rev.Respir.Dis. (1993) 148:932-939； Tsuyuki etc., J.Clin.1nvest. (1995) 96:2924-2931；With Cernadas etc., Am.J.Respir.Cell Mol.Biol. described in (1999) 20:1-8.
Substance of the invention is alternatively arranged as combination therapeutic agent for being applied in combination with other medicines substance, such as anti-inflammatory agent, branch Tracheaectasy medicine or antihistamine drug substances, especially for treating obstructive or airway inflammatory disease, as mentioned above Those of, such as the active synergist of these drug therapies or as dosage or potential pair needed for reducing these drugs The means of effect.Substance of the invention can mix in fixed drug composition with other medicines substance, or can be at it It is administered alone prior to, concurrently with, or after the application of its drug substance.The present invention include invention discussed above substance with it is anti-inflammatory The combination of medicine, bronchodilators or antihistamine drug substances, the substance of the invention and the drug substance can In identical or different pharmaceutical composition.Such anti-inflammatory agent includes steroids, and especially glucocorticosteroid is such as cloth Shrinkage porosite, beclomeasone propionate, Fluticasone Propionate, ciclesonide or furancarboxylic acid dish meter Ta Song and WO 0200679, WO 0288167, Compound described in WO 0212266 and WO 02100879, LTB4 antagonist are those of as described in US5451700, LTD4 Antagonist such as montelukast and zafirlukast, dopamine-receptor stimulant such as Cabergoline, bromocriptine, tired sharp Lip river and 4- hydroxyl 7- [2- [[2- [[3- (2- phenyl ethoxy)-propyl]-sulfonyl]-ethyl]-amino] ethyl] -2 (3H)-benzothiazolones and (hydrochloride is for its officinal salt- AstraZeneca) and PDE4 inhibitor is such as (GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH- 351591 (Schering-Plough), arofylline (AlmirallProdesfarma), PD189659 (Parke-Davis), AWD-12-281 (AstaMedica), CDC-801 (Celgene) and KW-4490 (Kyowa Hakko Kogyo) and WO 98/ Those of described in 18796 and WO 03/39544.Such bronchodilators includes anticholinergic drug or antimuscarinic drug, Especially Ipratropium Bromured, Oxitropium Bromide and tiotropium salt, there are also WO 01/04118, WO 02/51841, WO 02/ 53564、WO 03/00840、WO 03/87094、WO 04/05285、WO 02/00652、WO 03/53966、EP 424021、 Those of described in US 5171744, US 3714357 and WO 03/33495 and beta-2-adrenoceptor agonist is such as husky Butylamine alcohol, Terbutaline, salmeterol and Formoterol and its officinal salt and pct international patent announce WO 00/75114 Compound of formula I (free form or salt form or solvate form thereof) in (which is incorporated herein by reference), preferably The antihistamine drug substances of the compound combination treatment of embodiment include Cetirizine Hydrochloride, paracetamol, fumaric acid chlorine Maas fourth, fenazil, Loratadine, Desloratadine (desloratidine), diphenhydramine and hydrochloric acid Fexofenadine.This hair The combination of bright substance and steroids, β -2 agonist, PDE4 inhibitor or LTD4 antagonist can be used for for example treating COPD or spy It is not asthma.Substance of the invention and anticholinergic drug or antimuscarinic drug, PDE4 inhibitor, dopamine-receptor stimulant or The combination of LTB4 antagonist can be used for for example treating asthma or especially COPD.Substance and anti-inflammatory agent of the invention it is other useful Combination be with chemokine receptor anagonists such as CCR-l, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, The combination of the antagonist of CCR-8, CCR-9, CCR10, CXCRl, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5, institute State antagonist such as Schering-Plough antagonist SC-351125, SCH-55700 and SCH-D, Takeda antagonist such as N- [[4- [[[6,7- dihydro -2- (4- aminomethyl phenyl) -5H- benzo ring heptene -8- base] hydroxyl] amino] phenyl]-methyl] tetrahydro - N, N- dimethyl -2H- pyrans -4- ammonium chloride (TAK-770) and US6166037 (especially claim 18 and 19), WO 00/ CCR-5 antagonist described in 66558 (especially claims 8) and WO 00/66559 (especially claim 9).
Substance of the invention can be applied by any approach appropriate, such as be administered orally, such as with tablet or capsule Form is administered orally；Parenterally for example intravenous application；It is applied by sucking, such as controlling in inflammatory or obstructive airway diseases In treatment；Intranasal administration, such as in the treatment of allergic rhinitis；To topical application, such as in the treatment of atopic dermatitis In；Or rectal administration, such as in the treatment of inflammatory bowel disease.
The present invention also provides pharmaceutical composition, it includes free form or the compounds of this invention of pharmaceutical acceptable salt, Optionally and suitably pharmaceutical diluent or carrier.The composition can contain combination therapeutic agent, as described above Anti-inflammatory agent, bronchodilators or antihistamine.Conventional diluent or excipient and Galen can be used in such composition Known technology preparation in formulation art.Therefore, peroral dosage form may include tablets and capsules.
Formulations for topical administration can use cream, ointment, gelling agent or transdermal delivery system such as patch Form.Composition for inhalation may include aerosol or other aerosolizable preparations or dry powder formulations.
When composition includes aerosol formulation, the fluoro- alkane of such as hydrogen-(HFA) propellant such as HFA134a is preferably comprised Or HFA227 or these mixture, it can be containing one or more cosolvents known in the art such as ethyl alcohol (by weight extremely It is more 20%) and/or one or more surfactants such as oleic acid or three olease of sorbitan and/or one or more Filler such as lactose.When composition includes dry powder doses, preferably comprise for example with the present invention for being no more than 10 micron grain sizes Compound, optionally and such as lactose of the diluent or carrier with required particle diameter distribution, and help to prevent product property because The compound of dampness and variation.When composition includes spray formulation, preferably comprises and for example dissolve or be suspended in the medium The compounds of this invention, the medium contain water, cosolvent such as ethyl alcohol or propylene glycol and stabilizer, can be surface-active Agent.
The dosage of substance of the present invention used in the embodiment of this invention will be according to the specific illness, desired for example treated Effect and method of application difference and change.In general, the suitable dose being administered orally is 0.1 to 10 milligram/kg rank.
In embodiments of the present invention, when treating according to the present invention to patient, the amount of given drug is depended 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 1-1500mg/ days models It encloses.The required dosage is expressed as (or in a short time) one or be administered simultaneously or at interval appropriate in which can be convenient Divided dose, such as daily two, three, four doses or more divided agent.It will be appreciated by persons skilled in the art that although giving Dosage range is stated, but specific effective quantity can suitably be adjusted according to the case where patient and in conjunction with doctor diagnosed.
The preparation of compound
Using Standard synthetic techniques well known by persons skilled in the art or using methods known in the art be described herein Method combination, the compound of formula (I) and formula (II) can be synthesized.In addition, solvent given herein, temperature and other reaction items Part can change according to art technology.As further guidance, synthetic method below also can use.
The reaction can use in order, to provide compound described herein；Or they can be used for synthesizing segment, The segment is then added by method described herein and/or methods known in the art.
In some embodiments, it provided herein is PI3K and/or PfPI4K kinase inhibitor chemical combination described herein The preparation method and its application method of object.In some embodiments, following synthesis side can be used in compound described herein Case synthesis.It can be used and compound is synthesized by using selectable starting material appropriate with following similar methods.
Starting material for synthesizing compound described herein can be synthesized or can obtain from commercial source.Herein Technology well known by persons skilled in the art can be used to other related compounds with different substituents in the compound of description 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 modified by the reagent and condition being deemed appropriate by those skilled in the art, it is each in the molecule of offer to be incorporated herein Kind part.
If desired, routine techniques separation and purifying can be used in reaction product, including but not limited to filters, distills, knot The methods of brilliant, chromatography.Conventional method characterization, including physical constant and spectrum data can be used in these products.
The non-limiting embodiment of the compound of the present invention of preparation is referring to table 1.
The structure of 1. embodiment compound of table
Embodiment
Non-limiting embodiment in detail below is to be interpreted as being merely illustrative, not limit in any way originally It is open.Although without being described in further detail, it is believed that those skilled in the art can be based on description herein, completely benefit Use the disclosure.
Embodiment 1:(S)-(1- ((4- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) phenyl) amino) -3- methyl - 1- oxo butyl- 2- yl) t-butyl carbamate
(4- (5- amino -6- chloropyridine -3- base) phenyl) t-butyl carbamate (2): it is bromo- that 5- is added in round-bottomed flask 1,4- dioxane (8 milliliters), water (4 milliliters), (4- ((tert-butoxycarbonyl) is added in 2- chloropyridine -3- amine (219 milligrams) afterwards Amino) phenyl) boric acid (300 milligrams), Pd (PPh3)4(37 milligrams), potassium carbonate (300 milligrams).Reaction system is under protection of argon gas 80 degree are reacted 14 hours.After reaction, solvent evaporated, gains are extracted after being diluted with water with ethyl acetate system under reduced pressure It takes.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase obtains after evaporated under reduced pressure through filtering Crude product.Compound (2) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/MS:M+H 320.12.
(4- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) phenyl) t-butyl carbamate (3): in round-bottomed flask Pyridine (2 milliliters) is added in middle addition (4- (5- amino -6- chloropyridine -3- base) phenyl) t-butyl carbamate (240 milligrams) afterwards With benzene sulfonyl chloride (0.57 milliliter).Reaction system normal-temperature reaction 14 hours under protection of argon gas.After reaction, system is depressurizing Lower solvent evaporated, gains are extracted with ethyl acetate after being diluted with water.Organic phase is respectively with using nothing after water, saturated common salt water washing Aqueous sodium persulfate is dry.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Compound is obtained after the pressurized silica gel column chromatography purification of crude product (3), 460.11 LC/MS:M+H.
N- (5- (4- aminophenyl) -2- chloropyridine -3- base) benzsulfamide (4): ((6- is chloro- by 4- for addition in round-bottomed flask 5- (phenylsulfonyl-amido) pyridin-3-yl) phenyl) ethyl acetate (4 of hydrochloric acid is added in t-butyl carbamate (100 milligrams) afterwards Milliliter) and methanol (1 milliliter) solution.Reaction system normal-temperature reaction 0.5 hour.After reaction, system is evaporated molten under reduced pressure Agent obtains compound (4), LC/MS:M+H 360.06.
(S)-(1- ((4- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) phenyl) amino)-3- methyl-1-oxo Butyl- 2- yl) t-butyl carbamate (5): N- (5- (4- aminophenyl) -2- chloropyridine -3- base) benzene is added in round-bottomed flask N,N-dimethylformamide (2 milliliters), (tertbutyloxycarbonyl)-Valine (38 milligrams), 2- is added in sulfonamide (60 milligrams) afterwards (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester HATU (78 milligrams) and N, N- diisopropylethylamine (0.2 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.After reaction, system solvent evaporated under reduced pressure, Gains are extracted with ethyl acetate after being diluted with water.Organic phase is done after using water, saturated common salt water washing respectively with anhydrous sodium sulfate It is dry.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Compound (5) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/MS: M+H 559.18。
Embodiment 2:(S) -2- amino-N- (4- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) phenyl) -3- methyl Butyramide
(S)-(1- ((4- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) phenyl) ammonia is added in round-bottomed flask Base)-3- methyl-1-oxo butyl- 2- yl) t-butyl carbamate (50 milligrams) be added afterwards hydrochloric acid ethyl acetate (2 milliliters) and Methanol (1 milliliter) solution.Reaction system normal-temperature reaction 0.5 hour.After reaction, solvent evaporated obtains reality to system under reduced pressure Apply the compound (6) of example 2, LC/MS:M+H 459.13.
Embodiment 3:(S)-(1- (5- (6- chloro- 5- (phenyl-sulfamide) pyridin-3-yl) -1H- pyrrolo- [2,3-b] pyrrole Pyridine-1- base)-3- methyl-1-oxo butyl- 2- yl) t-butyl carbamate
1- (bromo- 1H- pyrrolo- [2,3-b] pyridine -1- base of 5-) second -1- ketone (8): the bromo- 1H- of 5- is added in round-bottomed flask Anhydrous methylene chloride (80 milliliters), triethylamine (3.6 milliliters) is added in pyrrolo- [2,3-b] pyridine (5.0 grams) afterwards, then uses ice water Bath makes system be cooled to 0 degree.Then it is slowly added to chloroacetic chloride.Reaction system at room temperature, argon gas protection reaction 14 hours.Reaction After, solvent evaporated, gains are extracted with dichloromethane system after being diluted with water under reduced pressure.Organic phase with respectively with water, It is dry with anhydrous sodium sulfate after saturated common salt water washing.Organic phase obtains compound (8) after evaporated under reduced pressure, LC/MS:M+H through filtering 238.98。
1- (5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- base) -1H- pyrrolo- [2,3-b] pyridine - 1- yl) second -1- ketone (9): 1- (bromo- 1H- pyrrolo- [2,3-b] pyridine -1- base of 5-) second -1- ketone is added in round-bottomed flask 1,4- dioxane (80 milliliters), 4,4,4', 4', 5,5,5', two (1,3,2- bis- of 5'- prestox -2,2'- is added in (2.5g) afterwards Oxa- borine) (5.3g), PdCl2(dppf)2(257 milligrams) and potassium acetate (3.1g).Reaction system is heated under protection of argon gas 80 DEG C are reacted 14 hours.After reaction, solvent evaporated, gains are extracted after being diluted with water with ethyl acetate system under reduced pressure It takes.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase obtains after evaporated under reduced pressure through filtering Crude product.Compound (9) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/MS:M+H 287.16.
The chloro- 5- of 2- (1H- pyrrolo- [2,3-b] pyridine -5- base) pyridine -3- amine (10): it is bromo- that 5- is added in round-bottomed flask 1,4- dioxane (80 milliliters), water (15 milliliters), 1- (5- (4,4,5,5- tetramethyl is added in 2- chloropyridine -3- amine (1.5g) afterwards Base -1,3,2- dioxaborolane -2- base) -1H- pyrrolo- [2,3-b] pyridine -1- base) second -1- ketone (2.5g), Pd (PPh3)4(200 milligrams), potassium carbonate (2.5g).Reaction system is reacted 14 hours for 80 DEG C under protection of argon gas.After reaction, body Solvent evaporated, gains are extracted with ethyl acetate after being diluted with water under reduced pressure for system.Organic phase uses water, saturated common salt washing respectively It is dry with anhydrous sodium sulfate after washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure.After the pressurized silica gel column chromatography purification of crude product It obtains compound (10), LC/MS:M+H 245.06.
N- (the chloro- 5- of 2- (1H- pyrrolo- [2,3-b] pyridine -5- base) pyridin-3-yl) benzsulfamide (11): it is burnt in round bottom The chloro- 5- of 2- (1H- pyrrolo- [2,3-b] pyridine -5- base) pyridine -3- amine (300 milligrams) is added in bottle, pyridine (8 milliliters) is added afterwards With benzene sulfonyl chloride (0.25 milliliter).Reaction system normal-temperature reaction 14 hours under protection of argon gas.After reaction, system is depressurizing Lower solvent evaporated, gains are extracted with ethyl acetate after being diluted with water.Organic phase is respectively with using nothing after water, saturated common salt water washing Aqueous sodium persulfate is dry.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Compound is obtained after the pressurized silica gel column chromatography purification of crude product (11), 385.05 LC/MS:M+H.
(S)-(1- (5- (6- chloro- 5- (phenyl-sulfamide) pyridin-3-yl) -1H- pyrrolo- [2,3-b] pyridine -1- base) - 3- methyl-1-oxo butyl- 2- yl) t-butyl carbamate (12): N- (2- chloro- 5- (1H- pyrrolo- is added in round-bottomed flask [2,3-b] pyridine -5- base) pyridin-3-yl) N,N-dimethylformamide (3 milliliters), (uncle is added in benzsulfamide (80 milligrams) afterwards Butoxy carbonyl)-Valine (48 milligrams), HATU (95 milligrams) and N, N- diisopropylethylamine (0.25 milliliter).Reaction system It is stirred at room temperature under protection of argon gas 14 hours.After reaction, system under reduced pressure use after being diluted with water by solvent evaporated, gains Ethyl acetate extraction.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is filtered, and is subtracted Pressure obtains crude product after being evaporated.Compound (12) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/MS:M+H 584.18.
Embodiment 4:4- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) -5,6- dihydropyridine -1 (2H)-carboxylic acid uncle Butyl ester
The synthesis of 4 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M +1)+: 450.13.
Embodiment 5:N- (the chloro- 5- of 2- (1,2,3,6- tetrahydropyridine -4- base) pyridin-3-yl) benzenesulfonamide, hydrochloride
4- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) -5,6- dihydropyridine -1 is added in round-bottomed flask The ethyl acetate (3 milliliters) and methanol (1 milliliter) solution of hydrochloric acid is added in (2H)-carboxylic acid tert-butyl ester (100 milligrams) afterwards.Reaction system Normal-temperature reaction 0.5 hour.After reaction, solvent evaporated obtains the compound of embodiment 5, LC/MS:M+H to system under reduced pressure 350.08。
Embodiment 6:5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N- methylnicotinamide
5- (5- amino -6- chloropyridine -3- base)-N- methylnicotinamide: the bromo- 2- chloropyridine-of 5- is added in round-bottomed flask 3- amine (90 milligrams) be added afterwards 1,4- dioxane (4 milliliters), water (1 milliliter), N- methyl -5- (tetramethyl -1,3 4,4,5,5-, 2- dioxaborinate -2- base) niacinamide (135 milligrams), Pd (PPh3)4(16 milligrams), potassium carbonate (155 milligrams).Reaction system exists Lower 80 DEG C of argon gas protection are reacted 14 hours.After reaction, solvent evaporated, gains use second after being diluted with water to system under reduced pressure Acetoacetic ester extraction.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is filtered, decompression Crude product is obtained after being evaporated.5- (5- amino -6- chloropyridine -3- base)-N- methylnictotinyl is obtained after the pressurized silica gel column chromatography purification of crude product Amine, LC/MS:M+H 263.07.
5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N- methylnicotinamide: 5- (5- is added in round-bottomed flask Amino -6- chloropyridine -3- base) pyridine (2 milliliters) and benzene sulfonyl chloride (0.15 milli is added in-N- methylnicotinamide (41 milligrams) afterwards It rises).Reaction system normal-temperature reaction 14 hours under protection of argon gas.After reaction, system solvent evaporated under reduced pressure, gains It is extracted with ethyl acetate after being diluted with water.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.It is organic It is mutually filtered, crude product is obtained after evaporated under reduced pressure.The compound of embodiment 6, LC/MS:M are obtained after the pressurized silica gel column chromatography purification of crude product +H 403.06。
Embodiment 7:N- (5- (1- acetyl group -1H- pyrrolo- [2,3-b] pyridine -5- base) -2- chloropyridine -3- base) benzene sulphur Amide
The synthesis of the compound of embodiment 7 is completed by using the step of being similar to described in embodiment 3.MS(ESI)m/z (M+1)+: 427.07.
Embodiment 8:N- (the chloro- 5- of 2- (1- methyl-1 H- pyrazoles -4- base) pyridin-3-yl) benzsulfamide
The synthesis of the compound of embodiment 8 is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+: 349.05.
Embodiment 9:N- (the chloro- 5- of 2- (isoquinolin -4- base) pyridin-3-yl) benzsulfamide
The synthesis of the compound of embodiment 9 is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z (M+1)+: 396.06.
Embodiment 10:5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N, N- dimethyl nicotinamide
The synthesis of the compound of embodiment 10 is completed by using the step of being similar to described in embodiment 6.MS(ESI)m/ z(M+1)+: 417.08.
Embodiment 11:5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N- cyclopropyl niacinamide
The synthesis of the compound of embodiment 11 is completed by using the step of being similar to described in embodiment 6.MS(ESI)m/ z(M+1)+: 429.08.
Embodiment 12:N- tert-butyl -5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) niacinamide
The synthesis of the compound of embodiment 12 is completed by using the step of being similar to described in embodiment 6.MS(ESI)m/ z(M+1)+: 445.11.
Embodiment 13:5- (4- chloro- 3- (phenylsulfonyl-amido) phenyl)-N- methylnicotinamide
N- (the bromo- 2- chlorphenyl of 5-) benzsulfamide (26): the bromo- 2- chloroaniline (3.0g) of 5- is added in round-bottomed flask and adds afterwards Enter pyridine (15 milliliters) and benzene sulfonyl chloride (2.8g).Reaction system normal-temperature reaction 14 hours under protection of argon gas.After reaction, Solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase uses water, saturated salt solution respectively It is dry with anhydrous sodium sulfate after washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure.The pressurized silica gel column chromatography purification of crude product Compound (26) are obtained afterwards, LC/MS:M+H 345.93.
5- (4- chloro- 3- (phenylsulfonyl-amido) phenyl) niacin (27): N- (the bromo- 2- chlorobenzene of 5- is added in round-bottomed flask Base) benzsulfamide (690 milligrams) be added afterwards 1,4- dioxane (5 milliliters), water (5 milliliters), 5- (tetramethyl -1 4,4,5,5-, 3,2- dioxaborolanes -2- base) ethyl nicotinate (500 milligrams), Pd (PPh3)4(200 milligrams), potassium carbonate (570 milligrams). Reaction system is reacted 14 hours for 80 DEG C under protection of argon gas.After reaction, system solvent evaporated under reduced pressure, gains water It is extracted with ethyl acetate after dilution.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase warp It filters, crude product is obtained after evaporated under reduced pressure.Compound (27) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/MS:M+H 389.04。
5- (4- chloro- 3- (phenylsulfonyl-amido) phenyl)-N- methylnicotinamide (28): 5- (4- is added in round-bottomed flask Chloro- 3- (phenyl sulfonamido) phenyl) anhydrous tetrahydro furan (2 milliliters) is added in niacin (50 milligrams) afterwards, (140 in the least for oxalyl chloride Gram), n,N-Dimethylformamide (1 drop), reaction system reacts at room temperature 2 hours under protection of argon gas.Then, it is added into system Methylamine (360 milligrams) stirs 1 hour at room temperature.Solvent evaporated, gains use ethyl acetate after being diluted with water to system under reduced pressure Extraction.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is through filtering, after evaporated under reduced pressure Obtain crude product.Compound (28) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/MS:M+H 402.07.
Embodiment 14:N- methyl -5- (6- methyl -5- (phenylsulfonyl-amido) pyridin-3-yl) niacinamide
N- (5- bromine-2-methylpyridine -3- base) benzsulfamide (30): 5- bromine-2-methylpyridine-is added in round-bottomed flask Pyridine (10 milliliters) and benzene sulfonyl chloride (1.56g) is added in 3- amine (1.5g) afterwards.Reaction system normal-temperature reaction 14 under protection of argon gas Hour.After reaction, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase point It Yong not be dried after water, saturated common salt water washing with anhydrous sodium sulfate.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Crude product warp Compound (30) are obtained after pressurized silica gel column Chromatographic purification, LC/MS:M+H 326.99.
5- (6- methyl -5- (phenylsulfonyl-amido) pyridin-3-yl) niacin (31): (5- is bromo- by addition N- in round-bottomed flask 2- picoline -3- base) benzsulfamide (650 milligrams) be added afterwards 1,4- dioxane (5 milliliters), water (5 milliliters), 5- (4,4, 5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) methyl nicotinate (500 milligrams), Pd (PPh3)4(200 milligrams), carbonic acid Potassium (570 milligrams).Reaction system is reacted 14 hours for 80 DEG C under protection of argon gas.After reaction, system is evaporated molten under reduced pressure Agent, gains are extracted with ethyl acetate after being diluted with water.Organic phase is respectively with using anhydrous sodium sulfate after water, saturated common salt water washing It is dry.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Compound (31) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/ MS:M+H 370.09.
N- methyl -5- (6- methyl -5- (phenylsulfonyl-amido) pyridin-3-yl) niacinamide (32): add in round-bottomed flask Enter 5- (6- methyl -5- (phenylsulfonyl-amido) pyridin-3-yl) niacin (50 milligrams) be added afterwards anhydrous tetrahydro furan (2 milliliters), Oxalyl chloride (140 milligrams), n,N-Dimethylformamide (1 drop), reaction system reacts at room temperature 2 hours under protection of argon gas.Then, Methylamine (360 milligrams) are added into system, stir 1 hour at room temperature.Solvent evaporated, gains are diluted with water system under reduced pressure After be extracted with ethyl acetate.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is passed through It filters, crude product is obtained after evaporated under reduced pressure.Compound (32) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/MS:M+H 383.12.
Embodiment 15:5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) -1H- pyrazolo [3,4-b] pyridine -1- first Tert-butyl acrylate
The synthesis of the compound of embodiment 15 is completed by using the step of being similar to described in embodiment 3.MS(ESI)m/ z(M+1)+: 486.10.
Embodiment 16:N- (the chloro- 5- of 2- (1H- pyrazolo [3,4-b] pyridine -5- base) pyridin-3-yl) benzsulfamide hydrochloric acid Salt
The synthesis of the compound of embodiment 16 is completed by using the step of being similar to described in embodiment 15.MS(ESI) m/z(M+1)+: 386.05.
Embodiment 17:3- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N-methyl-benzamide
The synthesis of the compound of embodiment 17 is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/ z(M+1)+: 402.07.
Embodiment 18:N- (the chloro- 5- of 2- (1H- pyrrolo- [2,3-b] pyridine -5- base) pyridin-3-yl) benzsulfamide
The synthesis of the compound of embodiment 18 is completed by using the step of being similar to described in embodiment 7.MS(ESI)m/ z(M+1)+: 385.05.
Embodiment 19:5- (6- fluoro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N- methylnicotinamide
N- (the bromo- 2- fluorine pyridin-3-yl of 5-) benzsulfamide (38): the bromo- 2- fluorine pyridine -3- amine of 5- is added in round-bottomed flask Pyridine (10 milliliters) and benzene sulfonyl chloride (1.5 milliliters) is added in (2.0g) afterwards.Normal-temperature reaction 20 is small under protection of argon gas for reaction system When.After reaction, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase difference It is dried with after water, saturated common salt water washing with anhydrous sodium sulfate.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Crude product is through adding Compound (38) are obtained after pressing silica gel column chromatography purification, LC/MS:M+H 330.96.
5- (6- fluoro- 5- (phenylsulfonyl-amido) pyridin-3-yl) ethyl nicotinate (39): N- (5- is added in round-bottomed flask Bromo- 2- fluorine pyridin-3-yl) 1,4- dioxane (1 milliliter), 5- (ethoxy carbonyl) pyrrole is added in benzsulfamide (331 milligrams) afterwards Pyridine -3- ylboronic acid (332 milligrams), PdCl2(dppf)2(81.6 milligrams), potassium acetate (294 milligrams).Reaction system is protected in argon gas Lower 100 DEG C are reacted 14 hours.After reaction, solvent evaporated, gains use ethyl acetate after being diluted with water to system under reduced pressure Extraction.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is through filtering, after evaporated under reduced pressure Obtain crude product.Compound (39) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/MS:M+H 402.09.
5- (6- fluoro- 5- (phenylsulfonyl-amido) pyridin-3-yl) niacin (40): 5- (the fluoro- 5- of 6- is added in round-bottomed flask (phenylsulfonyl-amido) pyridin-3-yl) ethyl alcohol (4 milliliters) and water (1 milliliter), reactant is added in ethyl nicotinate (100 milligrams) afterwards System reacts at room temperature 5 hours under protection of argon gas.Then, sodium hydroxide (360 milligrams) are added into system, it is small stirs 1 at room temperature When.Solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase uses water, saturation food respectively It is dry with anhydrous sodium sulfate after salt water washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure.The pressurized silica gel column chromatography of crude product Compound (40) are obtained after purification, LC/MS:M+H 383.12.
5- (6- fluoro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N- methylnicotinamide (41): it is added in round-bottomed flask Anhydrous tetrahydro furan (1 milliliter), methylamine is added in 5- (6- fluoro- 5- (phenylsulfonyl-amido) pyridin-3-yl) niacin (40 milligrams) afterwards Hydrochloride (14 milligrams), HATU (76 milligrams), N, N- diisopropylethylamine (0.1 milliliter).Reaction system room under protection of argon gas Temperature reaction 14 hours.Solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase is used respectively It is dry with anhydrous sodium sulfate after water, saturated common salt water washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Crude product is pressurized Compound (41) are obtained after silica gel column chromatography purification, LC/MS:M+H 387.09.
Embodiment 20:4- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N-methyl-benzamide
The synthesis of the compound of embodiment 20 is completed by using the step of being similar to described in embodiment 18.MS(ESI) m/z(M+1)+: 402.07.
Embodiment 21:4- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N- picoline acyl ammonia
The synthesis of the compound of embodiment 21 is completed by using the step of being similar to described in embodiment 6.MS(ESI)m/ z(M+1)+: 403.07.
Embodiment 22:N- (2- chloro- 5- (pyridin-3-yl) pyridin-3-yl) benzsulfamide
The synthesis of the compound of embodiment 22 is completed by using the step of being similar to described in embodiment 6.MS(ESI)m/ z(M+1)+: 346.04.
Embodiment 23:N- (2- chloro- 5- (pyridin-4-yl) pyridin-3-yl) benzsulfamide
The synthesis of the compound of embodiment 23 is completed by using the step of being similar to described in embodiment 6.MS(ESI)m/ z(M+1)+: 346.04.
Embodiment 24:N- (the chloro- 5- of 2- (6- methoxypyridine -3- base) pyridin-3-yl) benzsulfamide
The synthesis of the compound of embodiment 24 is completed by using the step of being similar to described in embodiment 6.MS(ESI)m/ z(M+1)+: 376.05.
Embodiment 25:N- (5- (1- benzyl -1H- pyrazoles -4- base) -2- chloropyridine -3- base) benzsulfamide
The synthesis of the compound of embodiment 25 is completed by using the step of being similar to described in embodiment 8.MS(ESI)m/ z(M+1)+: 425.09.
Embodiment 26:N- (the chloro- 5- of 2- (2- methoxypyridine -3- base) pyridin-3-yl) benzsulfamide
The synthesis of the compound of embodiment 26 is completed by using the step of being similar to described in embodiment 6.MS(ESI)m/ z(M+1)+: 376.05.
Embodiment 27:N- (5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) pyridin-3-yl) -2- (dimethylamino) Acetamide
N- (5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) pyridin-3-yl) acetamide (54): in round-bottomed flask 1,4- dioxane (5 milliliters), N- (5- is added in middle addition N- (the bromo- 2- chloropyridine -3- base of 5-) benzsulfamide (200 milligrams) afterwards (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) acetamide (165 milligrams), PdCl2 (dppf)2(47 milligrams) and potassium acetate (134 milligrams).Reaction system is heated to 80 DEG C under protection of argon gas and reacts 14 hours.Instead After answering, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase use respectively water, It is dry with anhydrous sodium sulfate after saturated common salt water washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure.The pressurized silica gel of crude product Compound (54) are obtained after column Chromatographic purification, LC/MS:M+H 403.07.
N- (5- (5- aminopyridine -3- base) -2- chloropyridine -3- base) benzsulfamide (55): N- is added in round-bottomed flask Methanol (5 milliliters) is added in (5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) pyridin-3-yl) acetamide (150 milligrams) afterwards With 6M hydrochloric acid solution (2 milliliters).Reaction system is heated to 80 DEG C under protection of argon gas and reacts 6 hours.After reaction, system exists It depressurizes lower solvent evaporated and obtains solid chemical compound (55).LC/MS:M+H 361.05.
N- (5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) pyridin-3-yl) -2- (dimethylamino) acetamide (56): after N- (5- (5- aminopyridine -3- base) -2- chloropyridine -3- base) benzsulfamide (35 milligrams) is added in round-bottomed flask Tetrahydrofuran (1 milliliter), 2- (dimethylamino) acetic acid (18 milligrams), HATU (67 milligrams) and N, N- diisopropylethylamine is added (0.1 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.After reaction, system solvent evaporated under reduced pressure, Gains are extracted with ethyl acetate after being diluted with water.Organic phase is done after using water, saturated common salt water washing respectively with anhydrous sodium sulfate It is dry.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Compound (56) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/ MS:M+H 446.11.
Embodiment 28:5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N-ethylnicotinamide
5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) ethyl nicotinate (57): N- (5- is added in round-bottomed flask Bromo- 2- chloropyridine -3- base) 1,4- dioxane (10 milliliters), 5- (4,4,5,5- tetramethyl-is added in benzsulfamide (1.0g) afterwards 1,3,2- dioxaborolanes -2- base) ethyl nicotinate (0.84g), PdCl2(dppf)2(0.23g) and potassium acetate (0.68g). Reaction system is heated to 80 DEG C under protection of argon gas and reacts 14 hours.After reaction, system solvent evaporated under reduced pressure, gained Object is extracted with ethyl acetate after being diluted with water.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Have Machine obtains crude product mutually through filtering after evaporated under reduced pressure.Compound (57) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/MS:M+H 418.07。
5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) niacin (58): 5- (the chloro- 5- of 6- is added in round-bottomed flask (phenylsulfonyl-amido) pyridin-3-yl) ethyl alcohol (5 milliliters) and 1M sodium hydroxide solution (5 millis are added in ethyl nicotinate (1.2g) afterwards It rises).Reaction system is heated to 80 DEG C under protection of argon gas and reacts 10 hours.After reaction, system solvent evaporated under reduced pressure, With 1M salt acid for adjusting pH to 3 after (50 milliliters) of water dilutions of gains.Sediment filtration drying obtains compound (58), LC/MS: M+H 390.03。
5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N-ethylnicotinamide (59): it is added in round-bottomed flask Tetrahydrofuran (1 milliliter), ethamine hydrochloric acid is added in 5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) niacin (50 milligrams) afterwards Salt (21 milligrams), HATU (99 milligrams) and N, N- diisopropylethylamine (0.11 milliliter).Reaction system room temperature under protection of argon gas Reaction 14 hours.After reaction, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Have Machine is mutually respectively with dry with anhydrous sodium sulfate after water, saturated common salt water washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure. Compound (59) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/MS:M+H 417.08.
Embodiment 29:2- (3- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) nicotinoyl amino) ethyl carbamic acid uncle Butyl ester
The synthesis of the compound of embodiment 29 is completed by using the step of being similar to described in embodiment 28.MS(ESI) m/z(M+1)+: 532.14.
Embodiment 30:(R) -2- (3- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) nicotinoyl amino) propylcarbamic first Tert-butyl acrylate
The synthesis of the compound of embodiment 30 is completed by using the step of being similar to described in embodiment 28.MS(ESI) m/z(M+1)+: 546.16.
Embodiment 31:5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N- (2- hydroxy-2-methyl propyl) nicotinoyl Amine
The synthesis of the compound of embodiment 31 is completed by using the step of being similar to described in embodiment 28.MS(ESI) m/z(M+1)+: 461.11.
Embodiment 32:N- (2- amino-ethyl) -5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) niacinamide hydrochloric acid Salt
The synthesis of the compound of embodiment 32 is completed by using the step of being similar to described in embodiment 28.MS(ESI) m/z(M+1)+: 468.07.
Embodiment 33:N- ((R) -1- amino propyl- 2- yl) -5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) nicotinoyl Amine hydrochlorate
The synthesis of the compound of embodiment 33 is completed by using the step of being similar to described in embodiment 28.MS(ESI) m/z(M+1)+: 482.08.
Embodiment 34:5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N- phenyl niacinamide
The synthesis of the compound of embodiment 34 is completed by using the step of being similar to described in embodiment 28.MS(ESI) m/z(M+1)+: 465.08.
Embodiment 35:N- benzyl -5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) niacinamide
The synthesis of the compound of embodiment 35 is completed by using the step of being similar to described in embodiment 28.MS(ESI) m/z(M+1)+: 479.10.
Embodiment 36:5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N- (4- fluorophenyl) niacinamide
The synthesis of the compound of embodiment 36 is completed by using the step of being similar to described in embodiment 28.MS(ESI) m/z(M+1)+: 483.07.
Embodiment 37:5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N- (3- fluorophenyl) niacinamide
The synthesis of the compound of embodiment 37 is completed by using the step of being similar to described in embodiment 28.MS(ESI) m/z(M+1)+: 483.07.
Embodiment 38:5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N- (pyridine -2- base) niacinamide
The synthesis of the compound of embodiment 38 is completed by using the step of being similar to described in embodiment 28.MS(ESI) m/z(M+1)+: 466.08.
Embodiment 39:N- (5- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 39 is completed by using the step of being similar to described in embodiment 27.MS(ESI) m/z(M+1)+: 403.07.
Embodiment 40:4- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl)-N- methyl-1 H- pyrroles's -2- formamide
The synthesis of the compound of embodiment 40 is completed by using the step of being similar to described in embodiment 28.MS(ESI) m/z(M+1)+: 391.07.
Embodiment 41:5- (5- (4- (tert-butyl) phenylsulfonyl-amido) -6- chloropyridine -3- base)-N- methylnicotinamide
The synthesis of the compound of embodiment 41 is completed by using the step of being similar to described in embodiment 6.MS(ESI)m/ z(M+1)+: 459.13.
Embodiment 42:N- (5- (4- chloro- 3- (phenylsulfonyl-amido) phenyl) pyridin-3-yl) acetamide
N- (5- (4- chloro- 3- (phenylsulfonyl-amido) phenyl) pyridin-3-yl) acetamide (80): it is added in round-bottomed flask 1,4- dioxane (1 milliliter), N- (5- (4,4,5,5- tetramethyl is added in N- (the bromo- 2- chlorphenyl of 5-) benzsulfamide (63 milligrams) afterwards Base -1,3,2- dioxaborinate -2- base) pyridin-3-yl) acetamide (50 milligrams), PdCl2(dppf)2(15 milligrams), potassium acetate (42 milligrams).Reaction system is reacted 14 hours for 80 DEG C under protection of argon gas.After reaction, system solvent evaporated under reduced pressure, Gains are extracted with ethyl acetate after being diluted with water.Organic phase is done after using water, saturated common salt water washing respectively with anhydrous sodium sulfate It is dry.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Compound (80) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/ MS:M+H 402.07.
Embodiment 43:N- (5- (6- fluoro- 5- (phenylsulfonyl-amido) pyridin-3-yl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 43 is completed by using the step of being similar to described in embodiment 39.MS(ESI) m/z(M+1)+: 387.09.
Embodiment 44:N- (5- (6- methyl -5- (phenylsulfonyl-amido) pyridin-3-yl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 44 is completed by using the step of being similar to described in embodiment 39.MS(ESI) m/z(M+1)+: 383.12.
Embodiment 45:5- (the chloro- 5- of 6- (4- (isopropyl) phenylsulfonyl-amido) pyridin-3-yl)-N- methylnicotinamide
The synthesis of the compound of embodiment 45 is completed by using the step of being similar to described in embodiment 41.MS(ESI) m/z(M+1)+: 445.11.
Embodiment 46:N- (5- (4- fluoro- 3- (phenylsulfonyl-amido) phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 46 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 386.10.
Embodiment 47:N- (5- (4- methyl -3- (phenylsulfonyl-amido) phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 47 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 382.12.
Embodiment 48:N- (5- (3- (phenylsulfonyl-amido) phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 48 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 368.11.
Embodiment 49:N- (5- (the chloro- 5- of 6- (2,6- difluorophenyl sulfonamido) pyridin-3-yl) pyridin-3-yl) acetyl Amine
The synthesis of the compound of embodiment 49 is completed by using the step of being similar to described in embodiment 39.MS(ESI) m/z(M+1)+: 439.05.
Embodiment 50:N- (5- (the chloro- 5- of 6- (2- fluorobenzene ylsulfonylamino) pyridin-3-yl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 50 is completed by using the step of being similar to described in embodiment 39.MS(ESI) m/z(M+1)+: 421.06.
Embodiment 51:N- (5- (4- methoxyl group -3- (phenylsulfonyl-amido) phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 51 is completed by using the step of being similar to described in embodiment 39.MS(ESI) m/z(M+1)+:398.12。
Embodiment 52:N- (5- (the chloro- 3- of 4- (2,6- difluorophenyl sulfonamido) phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 52 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 438.05.
Embodiment 53:N- (5- (the chloro- 3- of 4- (2- fluorobenzene ylsulfonylamino) phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 53 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 420.06.
Embodiment 54:N- (5- (4- methyl -3- (phenylsulfonyl-amido) phenyl) pyridin-3-yl) propionamide
N- (5- (5- aminopyridine -3- base) -2- aminomethyl phenyl) benzsulfamide (93): N- (5- is added in round-bottomed flask (4- methyl -3- (phenylsulfonyl-amido) phenyl) pyridin-3-yl) methanol (20 milliliters) and hydrochloric acid is added in acetamide (1.7 grams) afterwards (20 milliliters).Reaction system is reacted 4 hours for 80 DEG C under protection of argon gas.After reaction, solvent evaporated obtains system under reduced pressure To solid chemical compound (93).LC/MS:M+H 340.11.
N- (5- (4- methyl -3- (phenylsulfonyl-amido) phenyl) pyridin-3-yl) propionamide (94): add in round-bottomed flask Enter N- (5- (5- aminopyridine -3- base) -2- aminomethyl phenyl) benzsulfamide (30 milligrams) and propionic andydride (0.5 milliliter) is added afterwards.Instead System is answered to react 14 hours for 85 DEG C under protection of argon gas.After reaction, solvent evaporated, gains water are dilute under reduced pressure for system It is extracted with ethyl acetate after releasing.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is passed through It filters, crude product is obtained after evaporated under reduced pressure.Compound (94) are obtained after the pressurized silica gel column chromatography purification of crude product, LC/MS:M+H 396.14.
Embodiment 55:N- (5- (4- methyl -3- (phenylsulfonyl-amido) phenyl) pyridin-3-yl) pivaloyl amine
The synthesis of the compound of embodiment 55 is completed by using the step of being similar to described in embodiment 54.MS(ESI) m/z(M+1)+: 424.17.
Embodiment 56:N- (5- (4- methyl -3- (phenylsulfonyl-amido) phenyl) pyridin-3-yl) isobutyramide
The synthesis of the compound of embodiment 56 is completed by using the step of being similar to described in embodiment 54.MS(ESI) m/z(M+1)+: 410.16.
Embodiment 57:N- (5- (4- methyl -3- (phenylsulfonyl-amido) phenyl) pyridin-3-yl) butyramide
The synthesis of the compound of embodiment 57 is completed by using the step of being similar to described in embodiment 54.MS(ESI) m/z(M+1)+: 410.16.
Embodiment 58:N- (5- (4- methyl -3- (phenylsulfonyl-amido) phenyl) pyridin-3-yl) pentanamide
The synthesis of the compound of embodiment 58 is completed by using the step of being similar to described in embodiment 54.MS(ESI) m/z(M+1)+: 424.17.
Embodiment 59:2- (6- chloro- 5- (phenylsulfonyl-amido) pyridin-3-yl) -1H- indoles -1- carboxylic acid tert-butyl ester
The synthesis of the compound of embodiment 59 is completed by using the step of being similar to described in embodiment 4.MS(ESI)m/ z(M+1)+: 484.11.
Embodiment 60:N- (the chloro- 5- of 2- (1H- indoles -2- base) pyridin-3-yl) benzenesulfonamide, hydrochloride
The synthesis of the compound of embodiment 60 is completed by using the step of being similar to described in embodiment 5.MS(ESI)m/ z(M+1)+: 384.06.
Embodiment 61:N- (the chloro- 5- of 2- (4- (trifluoromethoxy) phenyl) pyridin-3-yl) benzsulfamide
The synthesis of the compound of embodiment 61 is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/ z(M+1)+: 429.03.
Embodiment 62:N- (5- (4- methyl -3- (3- methylphenyl sulfonamido) phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 62 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 396.14.
Embodiment 63:N- (5- (4- methyl -3- (3- trifluoromethyl-phenyl sulfonamido) phenyl) pyridin-3-yl) acetyl Amine
The synthesis of the compound of embodiment 63 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 450.11.
Embodiment 64:N- (5- (4- methyl -3- (4- methylphenyl sulfonamido) phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 64 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 396.14.
Embodiment 65:N- (5- (4- methyl -3- (2- methylphenyl sulfonamido) phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 65 is completed by using the step of being similar to described in embodiment 42.MS(ESI) M/z (M+1)+: 396.14.
Embodiment 66:N- (5- (3- (4- isopropyl-phenyl sulfonamido) -4- aminomethyl phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 66 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 424.17.
Embodiment 67:N- (5- (3- (3,4- Dichloro-phenyl sulfonamido) -4- aminomethyl phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 67 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 450.05.
Embodiment 68:N- (5- (4- methyl -3- (2- trifluoromethyl-phenyl sulfonamido) phenyl) pyridin-3-yl) acetyl Amine
The synthesis of the compound of embodiment 68 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 450.11.
Embodiment 69:N- (5- (3- (2,4- difluorophenyl sulfonamido) -4- aminomethyl phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 69 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 418.11.
Embodiment 70:N- (5- (3- (2,3- Dichloro-phenyl sulfonamido) -4- aminomethyl phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 70 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 450.05.
Embodiment 71:N- (5- (3- (the chloro- phenylsulfonyl-amido of 3-) -4- aminomethyl phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 71 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 416.09.
Embodiment 72:N- (5- (3- (2,5- Dimethvl-phenyl sulfonamido) -4- aminomethyl phenyl) pyridin-3-yl) acetyl Amine
The synthesis of the compound of embodiment 72 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 410.16.
Embodiment 73:N- (5- (3- (the chloro- phenylsulfonyl-amido of 2-) -4- aminomethyl phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 73 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 416.09.
Embodiment 74:N- (5- (3- (2,4- Dimethvl-phenyl sulfonamido) -4- aminomethyl phenyl) pyridin-3-yl) acetyl Amine
The synthesis of the compound of embodiment 74 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 410.16.
Embodiment 75:N- (5- (3- (3,4- difluorophenyl sulfonamido) -4- aminomethyl phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 75 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 418.11.
Embodiment 76:N- (5- (3- (the chloro- phenylsulfonyl-amido of 4-) -4- aminomethyl phenyl) pyridin-3-yl) acetamide
The synthesis of the compound of embodiment 76 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 416.09.
Embodiment 77:N- (5- (3- (3,4- Dimethvl-phenyl sulfonamido) -4- aminomethyl phenyl) pyridin-3-yl) acetyl Amine
The synthesis of the compound of embodiment 77 is completed by using the step of being similar to described in embodiment 42.MS(ESI) m/z(M+1)+: 410.16.
Embodiment 78
External inhibitory activity (enzyme activity) measurement
External enzyme activity measuring compound is to I type kinase of PI3K family (PI3K α, PI3K β, PI3K δ, PI3K γ), III The IC of type kinase (VPS34) and the kinases (PfPI4K, PI4KB (source of people)) of PI4K family50Value.Protein kinase PI3K α, PI3K δ, PI3K γ, VPS34, PI4KB are purchased from Invitrogen (U.S.)；Protein kinase PI3K β is purchased from Sigma (U.S.)； PfPI4K is expressed by this laboratory, and steps are as follows for expression.It uses in Bac-to-Bac expression system (Thermo Fisher, the U.S.) Construct PfPI4K protein expression system.Recombinant baculovirus is constructed first according to Bac-to-Bac expression system operation instructions, Then mass propgation 1000mL SF9 cell (being purchased from U.S. ATC), by the recombinate shape virus infection SF9 cell of building, 72 is small When after with 1000 turns cell precipitation, ultrasonic lytic cell, with 12000 turns of 10 minutes collection supernatants is collected by centrifugation within 5 minutes.First make With his-beads preliminary purification, reuses FPLC protein purification instrument (AKTA, U.S. GE) and be further purified.Three kinds of substrate PIP2: PS, PI and PI:PS are purchased from Invitrogen (U.S.).
It takes respectively and is diluted to certain density 5.4 μ L of protein kinase PI3K α (final concentration of 0.16ng/ μ L), 5.4 μ of PI3K β L (final concentration of 6ng/ μ L), 5.4 μ L of PI3K δ (final concentration of 1ng/ μ L), 5.4 μ L of PI3K γ (final concentration of 5ng/ μ L), 5.4 μ L of VPS34 (final concentration of 1.2ng/ μ L), 5.4 μ L of PI4KB (final concentration of 5ng/ μ L) and 5.4 μ L of PfPI4K are (dense eventually Degree is 5ng/ μ L) reacting at room temperature 1h with each 1 μ L of the testing drug compound of gradient dilution respectively, (drug final concentration is respectively 10 μ M、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM、0.001μM)。
ATP and substrate PIP2:PS mixture totally 6 μ L (kinases are added into each reaction tube of above-mentioned I type kinase of PI3K family Final concentration of 50 μ of ATP in final concentration of 10 μM of ATP in PI3K α, PI3K beta response system, kinases PI3K δ, PI3K gamma reaction system M, substrate PIP2:PS final concentration are 50 μM), 37 DEG C of reaction 1h.Reaction buffer is 50mM HEPES (pH 7.5), 3mM MgCl2, 1mM EGTA, 100mM NaCl and 0.03%CHAPS.
ATP and substrate PI:PS mixture totally 6 μ L (final concentration are added into each reaction tube of above-mentioned III type kinase of PI3K family Respectively 50 μM and 100 μM), 37 DEG C of reaction 1h.Reaction buffer is 50mM Hepes (pH 7.5), 0.1%CHAPS and 1mM EGTA。
ATP and substrate PI:PS mixture totally 6 μ L (final concentration difference are added into above-mentioned each reaction tube of PI4K family kinase For 50 μM and 100 μM), 37 DEG C of reaction 1h.Reaction buffer is 20mM Tris (pH 7.5), 0.5mM EGTA and 0.4% Triton X-100。
5 μ L ADP-Glo are added in 384 orifice plates (Corning, the U.S.) in kinase solution after taking 5 μ L to reactTM (Promega, the U.S.) reagent reacts at room temperature 40min to terminate kinase reaction and run out of remaining ATP.
10 μ L kinase assay reagents are added, ADP is converted to ATP, uses luciferase/luciferin reaction detection of coupling Newly synthesized ATP is mapped after being read using Envision, calculates Graphpad 7.0IC50Value, experimental result are shown in Table 2.
The measurement result of 2. external inhibitory activity (enzyme activity) of table ("-" expression does not detect)
Continued 2.
IC50(μM) Embodiment 6 Embodiment 47
PIK3α 0.20 0.35
PIK3β 0.31 5.41
PIK3δ 0.33 >10
PIK3γ 0.22 >10
VPS34 0.20 4.14
PfPI4K 0.0015 0.0029
PI4KB (source of people) 1.42 >10
Embodiment 79
Plasmodium falciparum GI50 detection method
Giemsa stain (being purchased from sigma, the U.S.) is stand-by with distilled water 1:20 dilution, per secondary ready-to-use.Cracking Liquid contains 3x SYBR Green I (purchased from invitrogen, the U.S.), 1.5%triton-x-100.The red blood cell that will be uninfected by (separating in normal human blood) is transferred in 15ml centrifuge tube to be turned 5 minutes with 2000RPM, removes supernatant, precipitating is slowly added to The upper layer ficoll solution (Beijing, Suo Laibao) removes supernatant with 800g centrifugation 20 minutes.Leucocyte (is divided in normal human blood From) and ficoll reagent addition 10ml pbs, Washed Red Blood Cells 2 times, each 2000RPM turns 5 minutes.It sucks supernatant and leaves precipitating For use.3 bottom μ l cell precipitations are sucked out in the culture dish of culture parasitized erythrocyte, drop makes blood thin slice on glass slide, uses Giemsa stain dyes 19 minutes, and distilled water washes away dye liquor, counts infection rate.The red blood cell culture of infection is transferred to 15ml In disposable centrifuge tube.2000RPM turns 5 minutes, removes culture supernatant.The erythroprecipitin for mixing infection is added and is uninfected by Red blood cell adjusts infection rate 1.8~2.4%.Culture medium (U.S., Gibcol) is added in the red blood cell of infection, red Cell, which is overstock, is adjusted to 4.8~5%.The red cell suspension of infection is added in 96 orifice plates with 100 holes μ l/.Each hole sequentially adds 10,3,1,0.3,0.1,0.03,0.01,0.003,0 μM of drug final concentration, 3 holes of every piece of 96 orifice plates setting are overstock identical It is uninfected by 100 μ l of red blood cell.Candle cylinder cultivation culture 72 hours.After 72 hours, shakes 14 seconds, add on 96 orifice plate earthquake devices It is shaken again 10 seconds after entering 30 μ l of lysate.Room temperature is placed on shaking table 120 turns, 10 minutes.Envision reading, absorbing wavelength is about 497nm, transmitted wave are about 520nm, calculate GI with Graphpad 7.050Value.
Table 3

Claims (17)

1. the compound or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug of a kind of formula (I):
Wherein:
X is selected from CH or N；
A ring is selected from pyridyl group, pyrrole radicals, pyrrolopyridinyl, pyrazolyl, Pyrazolopyridine base, tetrahydro pyridyl, isoquinolin The nitrogen-atoms of base, phenyl and indyl, the A ring is optionally replaced by amino protecting group；
R1And R2It is each independently selected from H, C1-6Alkyl, halogen and C1-6Halogenated alkyl；
R3Selected from H, halogen, C1-6Alkyl and C1-6Alkoxy；
R4Selected from H, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkanoyl, C1-6Alkyl amino-carbonyl, C3-6Cycloalkanes Base amino carbonyl, C1-6Alkyl amido, C1-6Alkyl amino C1-6Alkyl amido, amino C1-6Alkyl amino-carbonyl, benzene alkyl, phenyl Amino carbonyl, Phenylalkylamino carbonyl, pyridinylamino carbonyl and amino protecting group, above-mentioned substituent group optionally by amino, Amino, hydroxyl or the halogen that amino protecting group replaces replace.
2. compound as described in claim 1 or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug, Wherein the A ring is selected from pyridin-3-yl, pyridin-4-yl, pyrroles -3- base, pyrrolo- [2,3-b] pyridine -5- base, pyrazoles -4- Base, pyrazolo [3,4-b] pyridine -5- base, tetrahydropyridine -4- base, isoquinolin -4- base, phenyl and indoles -2- base, the A ring Nitrogen-atoms optionally by selected from valeryl, tertbutyloxycarbonyl, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl, benzyl, to methoxybenzyl, The amino protecting group of allyloxycarbonyl and trifluoroacetyl group replaces.
3. compound as described in claim 1 or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug, Wherein R1And R2In at least one be H.
4. compound as described in claim 1 or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug, Wherein R3Selected from chlorine, methyl and methoxyl group.
5. compound as described in claim 1 or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug, Wherein R4Selected from C1-6Alkyl amino-carbonyl, C1-6Alkyl amido, C1-6Alkyl amino C1-6Alkyl amido, amino C1-6Alkyl amino Carbonyl, phenyl amino carbonyl, Phenylalkylamino carbonyl and pyridinylamino carbonyl, above-mentioned substituent group is optionally by amino, ammonia Amino, hydroxyl or the halogen that base protecting group replaces replace.
6. compound as claimed in claim 5 or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug, Wherein R4Selected from methylaminocarbonyl, ethyl aminocarbonyl, acetylamino, dimethylamino acetylamino, phenyl amino carbonyl, fluorine For phenyl amino carbonyl, Benzylamino carbonyl and 2- pyridinylamino carbonyl.
7. compound as described in claim 1 or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug, Wherein the compound has the structure of following formula (II):
Wherein:
X is selected from CH or N；
R1And R2In at least one be H, another be selected from H, C1-6Alkyl, halogen and C1-6Halogenated alkyl；
R3Selected from H, halogen, C1-6Alkyl and C1-6Alkoxy；
R4The C replaced selected from H, optionally by amino1-6Alkyl amino-carbonyl, C1-6Alkyl amido, C1-6Alkyl amino C1-6Alkane acyl ammonia Base, amino C1-6Alkyl amino-carbonyl, the phenyl amino carbonyl being optionally optionally substituted by halogen, Phenylalkylamino carbonyl and pyridine Base amino carbonyl.
8. compound as claimed in claim 7 or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug, Wherein R1And R2In at least one be H, another be selected from H, methyl, 2- propyl, fluorine, chlorine and trifluoromethyl.
9. compound as claimed in claim 7 or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug, Wherein R3Selected from selected from chlorine, methyl and methoxyl group.
10. compound as claimed in claim 7 or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug, Wherein R4Selected from methylaminocarbonyl, ethyl aminocarbonyl, acetylamino, dimethylamino acetylamino, phenyl amino carbonyl, fluorine For phenyl amino carbonyl, Benzylamino carbonyl and 2- pyridinylamino carbonyl.
11. compound as described in claim 1 or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug, Wherein the compound is the compound selected from following table.
12. a kind of pharmaceutical composition comprising such as compound of any of claims 1-11 or its is pharmaceutically acceptable Salt, solvate, ester, acid, metabolin or prodrug and pharmaceutically acceptable carrier or excipient, and it is optional other Therapeutic agent.
13. such as compound of any of claims 1-11 or its pharmaceutically acceptable salt, solvate, ester, acid, generation It thanks object or prodrug and is preparing the purposes in PI3K kinase inhibitor.
14. such as compound of any of claims 1-11 or its pharmaceutically acceptable salt, solvate, ester, acid, generation Thank to the purposes of object or prodrug in the PfPI4K kinase inhibitor that preparation is directed to plasmodium falciparum.
15. such as compound of any of claims 1-11 or its pharmaceutically acceptable salt, solvate, ester, acid, generation Object or prodrug are thanked in preparation for treating, preventing or improving the purposes in the drug by PI3K kinase mediated illness.
16. such as compound of any of claims 1-11 or its pharmaceutically acceptable salt, solvate, ester, acid, generation Object or prodrug are thanked in preparation for treating, preventing or improving the purposes in the drug by PfPI4K kinase mediated illness.
It by PfPI4K kinase mediated illness is malaria wherein described 17. purposes as claimed in claim 16.
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