CN108794486A - Condensed ring radical ketones derivant, preparation method and its application in medicine - Google Patents

Condensed ring radical ketones derivant, preparation method and its application in medicine Download PDF

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CN108794486A
CN108794486A CN201810418381.3A CN201810418381A CN108794486A CN 108794486 A CN108794486 A CN 108794486A CN 201810418381 A CN201810418381 A CN 201810418381A CN 108794486 A CN108794486 A CN 108794486A
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heterocycle
alkyl
aryl
heteroaryl
compound represented
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CN108794486B (en
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张国宝
陈友喜
黄智明
贺峰
陶维康
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Shanghai Hengrui Pharmaceutical Co Ltd
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The present invention relates to condensed ring radical ketones derivant, preparation method and its applications in medicine.Specifically, the present invention relates to condensed ring radical ketones derivant new shown in a kind of logical formula (I), preparation method and the pharmaceutical composition containing the derivative as well as therapeutic agents, especially as the purposes of TLR7 agonists, each substituent group of formula of (I) is identical as the definition in specification.

Description

Condensed ring radical ketones derivant, preparation method and its application in medicine
Technical field
The invention belongs to field of medicaments, it is related to condensed ring radical ketones derivant new shown in a kind of logical formula (I), its preparation side Method and the pharmaceutical composition containing the derivative as well as therapeutic agent, especially as the purposes of TLR7 agonists.
Background technology
Toll-like receptor (toll-like receptors；TLRs) it is a kind of key protein point for participating in congenital immunity Son.TLRs is the non-catalytic receptor of monomer cross-film, is usually expressed in sentry post cell such as macrophage and Dendritic Cells, can To identify the molecule of the structural conservation generated by microorganism.Once these microorganisms break through the physics screen such as skin or intestinal mucosa Barrier, will be identified, then immune cell activated response (Mahla, R S. et al., Front Immunol.4 by TLRs:248 (2013)).Why immune system has the ability of identification pathogenic microorganism extensively, is since Toll-like is immune in a way Receptor is widely present.
At least 10 kinds of different TLRs in mammals.The ligand of some this receptoroids and corresponding signal cascade are put It is accredited out greatly.TLR7 is the member of TLRs (TLRs 3,7,8 and 9) subgroup, is confined to the thin of the non-own nucleic acid of special detection The endosome compartment of born of the same parents.TLR7 by identify ssRNA antiviral defenses in terms of play a crucial role (Diebold S.S. etc., Science,2004:303,1529-1531；With Lund J.M. etc., PNAS, 2004:101,5598-5603).TLR7 is in the person It is upper that there is limited expression and distribution, and mainly expressed by B cell and plasmacytoid dendritic cells (pDC), and lower degree Pass through monocytes.Plasmacytoid DCs is unique group (peripheral blood of 0.2-0.8% of dendritic cells derived from lymph Monocyte (PBMCs)), it is in response to virus infection and secreting high levels interferon-' alpha ' (IFN α) and interferon-beta (IFN β) Initial I type interferon cellulations (Liu Y-J, Annu.Rev.Immunol., 2005:23,275-306).
Many diseases, obstacle are related with the exception of TLRs, such as melanoma, non-small cell lung cancer, hepatocellular carcinoma, substrate Cell cancer (basalcellcarcinoma), clear-cell carcinoma, myeloma, allergic rhinitis, asthma, chronic obstructive pneumonia (COPD), ulcerative colitis, liver fibrosis, HBV, flaviviridae (Flaviviridae) virus, HCV, HPV, RSV, SARS, The virus infection etc. of HIV or influenza.Therefore it is very promising with the agonist treatment relevant disease of TLRs.
Due to TLR7 and TLR8 very high homologies, TLR7 ligands are also in most cases TLR8 ligands.TLR8 is pierced Swash main induction and generates cell factor such as tumor necrosis factor α (TNF-α) and chemotactic factor (CF).Interferon-' alpha ' is treatment chronic type b One of the key agents of hepatitis or hepatitis C, and TNF-α is a kind of proinflammatory cytokine, excessive secretion may cause serious Side effect.So to the selectivity of TLR7 and TLR8 for exploitation TLR7 agonists for treating disease of viral infection to closing weight It wants.
At present have relevant TLR7 agonists patent application, as WO2005025583, WO2007093901, WO2008011406、WO2009091032、WO2010077613、WO2010133882、WO2011031965、 WO2012080730.But it is still necessary to the continue research and development safety and upper more effective TLR7 agonists for the treatment of.
In view of the above technical problems, it is lower to provide a kind of action concentration by the present invention, and selectivity is more preferable, and activation effect becomes apparent from Medical compounds, meanwhile, there is no inhibiting effect or inhibiting effect weak CYP and hERG, be safer and more effective TLR7 agonists.
Invention content
The purpose of the present invention is to provide a kind of logical formula (I) compounds represented：
Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof shape Formula or its pharmaceutical salt,
Wherein：
For singly-bound or double bond；
G2Selected from CH, N and O；And
Work as G2For CH or N when,For double bond；Work as G2For O when,For singly-bound；
G1For CR4Or N；
Ring A is selected from naphthenic base, heterocycle, aryl and heteroaryl；
X1Selected from alkylidene and S (O)m, wherein the alkylidene is optionally by selected from halogen, alkyl, alkoxy, alkyl halide One or more of base, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base and heterocycle substituent group is replaced；
L1Selected from-NR5-、-O-、-S-、-C(O)-、-S(O)m-、-N(R5)C(O)-、-C(O)N(R5)-、-N(R5)S (O)2-、-S(O)2N(R5)-and covalent bond；
R1Selected from hydrogen atom, alkyl, halogenated alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein Alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, aryl and the heteroaryl is each independently optionally by selected from alkyl, alcoxyl One in base, halogen, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl A or multiple substituent groups are replaced；
R2It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyl Alkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-C (O) R6、-C(O)OR6、-S(O)mR6、-NR7R8 With-C (O) NR7R8, wherein alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally by selected from alkane Base, alkoxy, halogen, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl One or more of substituent group replaced；
L2Selected from alkylidene or covalent bond, wherein the alkylidene is optionally by selected from halogen, alkyl, alkoxy, halogenated One or more of alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base and heterocycle substituent group is replaced；
R3Selected from hydrogen atom, alkyl, alkoxy, halogen, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, ring Alkyl, heterocycle, aryl, heteroaryl ,-C (O) R6、-C(O)OR6、-S(O)mR6、-NR7R8With-C (O) NR7R8, wherein described Naphthenic base, heterocycle, aryl and heteroaryl each independently optionally by selected from alkyl, alkoxy, halogen, halogenated alkyl, hydroxyl, Hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-C (O) R6、-C(O)OR6、-S(O)mR6、- NR7R8With-C (O) NR7R8One or more of substituent group replaced；
R4Selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, ring Alkyl, heterocycle, aryl and heteroaryl；
R5Selected from hydrogen atom, alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and heteroaryl；
R6Selected from hydrogen atom, alkyl, halogenated alkyl, amino, hydroxyl, naphthenic base, heterocycle, aryl and heteroaryl；
R7And R8It is identical or different, and it is each independently selected from hydrogen atom, alkyl, halogenated alkyl, naphthenic base, heterocycle, virtue Base and heteroaryl, wherein alkyl, naphthenic base, heterocycle, aryl and the heteroaryl each independently optionally by selected from alkyl, One or more in alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl A substituent group is replaced；
Alternatively, the R7And R8With heterocycle is formed together with the nitrogen-atoms being connected, wherein the heterocycle is except containing 1 Except a nitrogen-atoms, also optionally containing 1~2 identical or different hetero atom selected from N, O and S, and the heterocycle is appointed Choosing is by selected from alkyl, alkoxy, oxo base, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl Replaced with one or more of heteroaryl substituent group；
N is 0,1,2,3 or 4；And
M is 0,1 or 2.
In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein the ring A For phenyl or pyridyl group.
In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein the X1For Alkylidene.
In a preferred embodiment of the present invention, the logical formula (I) compound represented, to lead to formula (II) institute The compound shown：
Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof shape Formula or its pharmaceutical salt,
Wherein：
G2For CH or N；
G1、L1~L2、R1~R3With n as defined in logical formula (I).
In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein the G1For N。
In a preferred embodiment of the present invention, the logical formula (I) compound represented, for logical formula (III) Compound represented：
Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof shape Formula or its pharmaceutical salt,
Wherein：
G2For CH or N；
L2For alkylidene；
R7And R8With heterocycle is formed together with the nitrogen-atoms being connected, wherein the heterocycle remove containing 1 nitrogen-atoms it Outside, also optionally containing 1~2 identical or different hetero atom selected from N, O and S, and the heterocycle is optionally by selected from alkane In base, alkoxy, oxo base, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl One or more substituent groups replaced；
L1And R1As defined in logical formula (I).
In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein the L1 For-O-.
In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein the R1For Alkyl.
In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein the L2For Alkylidene.
The present invention typical compound include but not limited to：
Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof shape Formula or its pharmaceutical salt.
In a preferred embodiment of the present invention, a kind of general formula (IA) compound represented leads to formula (I) to prepare The intermediate of compound：
Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof shape Formula or its pharmaceutical salt,
Wherein：
For singly-bound or double bond；
W is amino protecting group；
Ring A, G1、G2、X1、L1~L2、R1~R3With n as defined in logical formula (I).
General formula (IA) compound represented includes, but are not limited to：
Another aspect of the present invention relates to a kind of method preparing general formula (IA) compound represented, this method includes：
The compound of general formula (IB), the compound and R of general formula (IC)3- H occurs nucleophilic substitution and obtains general formula together (IA) compound；
Wherein：
For double bond；
G2For N；
W is amino protecting group；
X is halogen；
Ring A, G1、X1、L1~L2、R1~R3With n as defined in general formula (I A).
Another aspect of the present invention relates to a kind of method preparing general formula (IA) compound represented, this method includes：
The compound of general formula (ID) and ethyl acetate cyclization obtain the compound of general formula (IA)；
Wherein：
For double bond；
G2For CH；
W is amino protecting group；
Ring A, G1、X1、L1~L2、R1~R3With n as defined in general formula (I A).
Another aspect of the present invention relates to a kind of method preparing logical formula (I) compound represented, this method includes：
The compound of general formula (IA) sloughs protecting group and obtains the compound of logical formula (I)；
Wherein：
For singly-bound or double bond；
W is amino protecting group；
Ring A, G1、G2、X1、L1~L2、R1~R3With n as defined in logical formula (I).
Another aspect of the present invention relates to a kind of method preparing general formula (III-A) compound represented, this method includes：
The compound of general formula (III-B), the compound of general formula (III-C) andNucleophilic substitution occurs together to obtain To the compound of general formula (III-A)；
Wherein：
G2For N；
X is halogen；
W is amino protecting group；
L1~L2、R1And R7~R8As defined in logical formula (III).
Another aspect of the present invention relates to a kind of method preparing general formula (III-A) compound represented, this method includes：
The compound of general formula (III-D) and ethyl acetate cyclization obtain the compound of general formula (III-A)；
Wherein：
G2For CH；
W is amino protecting group；
L1~L2、R1And R7~R8As defined in logical formula (III).
Another aspect of the present invention relates to a kind of method preparing logical formula (III) compound represented, this method includes：
The compound of general formula (III-A) sloughs protecting group and obtains the compound of logical formula (III)；
Wherein：
W is amino protecting group；
G2、L1~L2、R1And R7~R8As defined in logical formula (III).
Another aspect of the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition contains the general formula of therapeutically effective amount (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer or its Form of mixtures or its pharmaceutical salt and one or more pharmaceutically acceptable carrier, diluent or excipient.
The invention further relates to compound shown in logical formula (I) or its tautomers, mesomer, racemic modification, right Reflect isomers, diastereoisomer, or mixtures thereof form or its pharmaceutical salt or prepared comprising its pharmaceutical composition For the purposes in the drug of exciting TLR7.
The invention further relates to compound shown in logical formula (I) or its tautomers, mesomer, racemic modification, right Reflect isomers, diastereoisomer, or mixtures thereof form or its pharmaceutical salt or prepared comprising its pharmaceutical composition The purposes in drug for treating infection caused by virus.
The invention further relates to compound shown in logical formula (I) or its tautomers, mesomer, racemic modification, right Reflect isomers, diastereoisomer, or mixtures thereof form or its pharmaceutical salt or prepared comprising its pharmaceutical composition The purposes in drug for treating or preventing tumour.
The invention further relates to a kind of methods of excitement TLR7 comprising by logical formula (I) compound represented or its mutually Tautomeric, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its is pharmaceutically acceptable The step of salt or pharmaceutical composition comprising it are contacted with TLR7.
The invention further relates to a kind of methods for treating infection caused by virus, and the method includes giving required trouble The logical formula (I) compound represented of person's therapeutically effective amount or its tautomer, mesomer, racemic modification, enantiomter, Diastereoisomer, or mixtures thereof form or its officinal salt or the pharmaceutical composition comprising it.
The invention further relates to a kind of methods treating or preventing tumour comprising gives required bacterium Logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereo-isomerism Body, or mixtures thereof form or its officinal salt or the pharmaceutical composition comprising it.
The invention further relates to a kind of logical formula (I) compound represented or its tautomer, mesomer, racemics Body, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt or the drug comprising it, be used as medicine Object.
The invention further relates to a kind of logical formula (I) compound represented or its tautomer, mesomer, racemics Body, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt or the drug comprising it, be used to swash Dynamic TLR7.
The invention further relates to a kind of logical formula (I) compound represented or its tautomer, mesomer, racemics Body, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt or the drug comprising it, be used to control Treat or prevent infection caused by virus.
The invention further relates to a kind of logical formula (I) compound represented or its tautomer, mesomer, racemics Body, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt or the drug comprising it, be used to control Treatment or pre- preventing tumor.
Heretofore described virus be preferably selected from dengue fever virus, yellow fever virus, west nile virus, japanese encephalitis virus, Tick-brone encephalitis virus, elder brother Tianjin virus, Murray valley encephalitis virus, St. Louis encephalitis virus, msk haemorrhagia fever virus, cattle disease Viral diarrhea virus, zika virus, HIV, HBV, HCV, HPV, RSV, SARS and influenza virus, are more preferably selected from HBV and HCV.
Heretofore described tumour is preferably selected from melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal-cell carcinoma, kidney Cell cancer and myeloma.
Pharmaceutical composition containing active constituent can be suitable for oral form, such as tablet, dragee, pastille, water Or oil suspension, dispersible powder or particle, lotion, hard or soft capsule or syrup or elixir.It can be any according to this field Know that the method for preparing Pharmaceutical composition prepares Orally administered composition, such composition can contain it is one or more it is selected from the following at Point：Sweetener, corrigent, colorant and preservative, to provide pleasing and palatable pharmaceutical formulation.Tablet contain active constituent and The suitable nontoxic pharmaceutical excipient for preparing tablet for mixing.These excipient can be inert excipient, be granulated Agent, disintegrant, adhesive and lubricant,.These tablets can not be coated or can be by covering the taste of drug or in gastrointestinal tract Middle delay disintegration and absorption, thus the known technology for providing slow releasing function in a long time is coated.
Also wherein active constituent and inert solid diluent or in which active constituent and water-solubility carrier or oily solvent can be used Mixed Perle provides oral preparation.
Water slurry contains active material and the suitable excipient for preparing water slurry for mixing.Such excipient is Suspending agent, dispersant or wetting agent.Aqueous suspension can also contain one or more preservatives, one or more colorants, one Kind or a variety of corrigents and one or more sweeteners.
Oil suspension can active constituent be suspended in vegetable oil or mineral oil is formulated by making.Oil suspension can contain Thickener.Above-mentioned sweetener and corrigent can be added, to provide palatable preparation.These can be preserved by the way that antioxidant is added Composition.
The pharmaceutical composition of the present invention can also be the form of oil in water emulsion.Oil phase can be vegetable oil or mineral oil Or mixtures thereof.Suitable emulsifier can be naturally-produced phosphatide, and emulsion can also contain sweetener, corrigent, anti-corrosion Agent and antioxidant.Such preparation can also contain moderator, preservative, colorant and antioxidant.
The pharmaceutical composition of the present invention can be sterile injectable aqueous form.The acceptable solvent or molten that can be used Agent has water, ringer's solution and isotonic sodium chlorrde solution.Aseptic injection preparation can be that wherein active constituent is dissolved in the sterile of oil phase Oil-in-water microemulsion is injected to inject injection or micro emulsion in the blood flow of patient by a large amount of injections in part.It can alternatively, preferably pressing The mode of the compounds of this invention constant circulating concentration is kept to give solution and micro emulsion.To keep this constant density, the company of can be used Continuous intravenous delivery device.The example of this device is Deltec CADD-PLUS.TM.5400 type Iv pumps.
Pharmaceutical composition can be for intramuscular and the aseptic injection water of subcutaneous administration or the form of oil suspension.It can be by Know technology, the suspension is prepared with the suitable dispersant of those described above or wetting agent and suspending agent.Aseptic injection preparation can also It is the aseptic injectable solution or suspension prepared in the acceptable non-toxic diluent of parenteral or solvent.In addition, it is convenient to Use sterile fixed oil as solvent or suspension media.
The compounds of this invention can be given by the suppository form for rectally.It can be by by drug and at normal temperatures For solid but it is liquid in the rectum, thus can dissolves and discharge the suitable nonirritant excipient mixing of drug in the rectum To prepare these pharmaceutical compositions.Substance of this kind includes the poly- second of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, various molecular weight The mixture of the aliphatic ester of glycol and polyethylene glycol.
As it is well known to the skilled in the art, the dosage of drug depends on many factors, including but it is and non-limiting In following factor：The activity of particular compound used, the age of patient, the weight of patient, the health status of patient, patient row For, the combination etc. of the diet of patient, administration time, administering mode, the rate of excretion, drug；In addition, best therapeutic modality is such as The type of the pattern for the treatment of, the consumption per day of general formula compound (I) or pharmaceutical salt can be tested according to traditional therapeutic scheme Card.
Detailed description of the invention
Unless stated to the contrary, the term used in the specification and in the claims has following meanings.
Term " alkyl " refers to saturated aliphatic hydrocarbons group, is the linear chain or branched chain group for including 1 to 20 carbon atom, excellent Select the alkyl containing 1 to 12 carbon atom, the alkyl of further preferably 1 to 6 carbon atom.Non-limiting examples include methyl, Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- diformazans Base propyl, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls third Base, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethyl butyrates Base, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls, n-heptyl, 2- methyl oneself Base, 3- methylhexyls, 4- methylhexyls, 5- methylhexyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl Amyl, 3,3- dimethyl amyl groups, 2- ethylpentyls, 3- ethylpentyls, n-octyl, 2,3- dimethylhexanyls, 2,4- dimethyl oneself Base, 2,5- dimethylhexanyls, 2,2- dimethylhexanyls, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls, 2- ethylhexyls, 3- Ethylhexyl, 4- ethylhexyls, 2- methyl -2- ethylpentyls, 2- methyl -3- ethylpentyls, n-nonyl, 2- methyl -2- ethyls Hexyl, 2- methyl -3- ethylhexyls, 2,2- diethyl amyl groups, positive decyl, 3,3- diethylhexyls, 2,2- diethylhexyls, and Its various branched isomer etc..Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting embodiment include first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- Dimethyl propyl, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- ethyl -2- first Base propyl, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- diformazans Base butyl, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls etc..Alkyl can be with It is substitution or non-substituted, when substituted, substituent group can be substituted on any workable tie point, the substitution Base is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, Halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkanes Sulfenyl, heterocycle alkylthio group, oxo base, carboxyl or carboxylate.
Term " alkylidene " refers to the linear chain or branched chain aliphatic alkyl of saturation, and the same carbon with 2 from parent alkane is former Residue derived from two hydrogen atoms is removed on son or two different carbon atoms, is the straight chain for including 1 to 20 carbon atom Or branched group, preferably comprise 1 to 12 carbon atom, the alkylidene of further preferably 1 to 6 carbon atom.The non-limit of alkylidene Property example processed includes but not limited to methylene (- CH2), 1,1- ethylidene (- CH (CH3) -), 1,2- ethylidene (- CH2CH2)-、 1,1- propylidene (- CH (CH2CH3) -), 1,2- propylidene (- CH2CH(CH3) -), 1,3- propylidene (- CH2CH2CH2-)、1,4- Butylidene (- CH2CH2CH2CH2) etc..Alkylidene can be substitution or non-substituted, and when substituted, substituent group can be Be substituted on any workable tie point, the substituent group be preferably independently optionally chosen from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, heterocycle, aryl, heteroaryl, cycloalkyloxy, Heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base ,-C (O) R6、-C(O)OR6、-S(O)mR6、-NR7R8With-C (O) NR7R8One or more of substituent group replaced.
Term " alkenyl " refers to the alkyl compound containing carbon-carbon double bond in molecule, and wherein alkyl is as defined above.Alkene Base can be substitution or non-substituted, and when substituted, substituent group is preferably one or more following groups, is independently selected From hydrogen atom, alkyl, alkoxy, halogen, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, Aryl, heteroaryl ,-C (O) R6、-C(O)OR6、-S(O)mR6、-NR7R8With-C (O) NR7R8One or more of substituent group taken Generation.
Term " alkynyl " refers to the alkyl compound containing triple carbon-carbon bonds in molecule, and wherein alkyl is as defined above.Alkynes Base can be substitution or non-substituted, and when substituted, substituent group is preferably one or more following groups, is independently selected From hydrogen atom, alkyl, alkoxy, halogen, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, Aryl, heteroaryl ,-C (O) R6、-C(O)OR6、-S(O)mR6、-NR7R8With-C (O) NR7R8One or more of substituent group taken Generation.
Term " naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, cycloalkyl ring include 3 to 20 carbon atoms, preferably comprise 3 to 12 carbon atoms, include more preferably 3 to 6 carbon atoms, most preferably comprise 5 to 6 carbon originals Son.The non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, Cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc.；Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring.
Term " spiro cycloalkyl group " refers to the polycyclic moiety that a carbon atom (claiming spiro-atom) is shared between 5 to 20 yuan of monocycle, It can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more Preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spirocyclanes according to the number for sharing spiro-atom between ring and ring Base or more spiro cycloalkyl groups, preferably single spiro cycloalkyl group and double spiro cycloalkyl groups.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 Member/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl groups.The non-limiting examples of spiro cycloalkyl group include：
Term " cycloalkyl " refers to 5 to 20 yuan, each ring in system and shared a pair adjoined of other rings in system The full carbon polycyclic moiety of carbon atom, wherein one or more rings can contain one or more double bonds, but neither one ring has The pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.It can be divided into according to a group cyclic number double Ring, tricyclic, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl. The non-limiting examples of cycloalkyl include：
Term " bridge ring alkyl " refers to 5 to 20 yuan, and the full carbon that any two ring shares two carbon atoms being not directly connected is more Cyclic group can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.It can be divided into bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl according to a group cyclic number, it is excellent It is selected as bicyclic, tricyclic or Fourth Ring, more preferably bicyclic or tricyclic.The non-limiting examples of bridge ring alkyl include：
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being connected to precursor structure Ring together is naphthenic base, and non-limiting examples include indanyl, tetralyl, benzocyclohepta alkyl etc.；It is preferred that phenyl and ring Amyl, tetralyl.Naphthenic base can be it is optionally replacing or non-substituted, when substituted, substituent group be preferably one or Multiple following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl Base, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkane Sulfenyl, oxo base, carboxyl or carboxylate.
Term " heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, and it includes 3 to 20 rings Atom, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), but do not wrap The loop section of-O-O- ,-O-S- or-S-S- are included, remaining annular atom is carbon.3 to 12 annular atoms are preferably comprised, wherein 1~4 It is hetero atom；3 to 8 annular atoms are most preferably comprised, wherein 1~3 is hetero atom；5 to 6 annular atoms are most preferably comprised, In 1~2 or 1~3 be hetero atom.The non-limiting examples of monocyclic heterocycles base include pyrrolidinyl, imidazolidinyl, tetrahydrofuran Base, THP trtrahydropyranyl, tetrahydro-thienyl, glyoxalidine base, dihydrofuryl, pyrazoline base, pyrrolin base, piperidyl, Piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base etc., preferably THP trtrahydropyranyl, piperidyl, pyrrolidinyl.Multiring heterocyclic Include the heterocycle of loop coil, condensed ring and bridged ring.
Term " spiro heterocyclic radical " refers to the multiring heterocyclic that an atom (claiming spiro-atom) is shared between 5 to 20 yuan of monocycle Group, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom For carbon.It can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 Member, more preferably 7 to 10 yuan.Spiro heterocyclic radical is divided into single spiro heterocyclic radical, double according to the number for sharing spiro-atom between ring and ring Spiro heterocyclic radical or more spiro heterocyclic radicals, preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 Member/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting examples of spiro heterocyclic radical include：
Term " condensed hetero ring base " refers to 5 to 20 yuan, each ring in system and shared a pair adjoined of other rings in system The polycyclic heterocyclic group of atom, one or more rings can contain one or more double bonds, but neither one ring is with completely total The pi-electron system of yoke, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe miscellaneous original of (wherein m is integer 0 to 2) Son, remaining annular atom are carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to a group cyclic number can be divided into it is bicyclic, Tricyclic, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero rings Base.The non-limiting examples of condensed hetero ring base include：
Term " bridge heterocycle " refers to 5 to 14 yuan, and any two ring shares the polycyclic heterocycle of two atoms being not directly connected Group can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, one of them or Multiple annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom are carbon.Preferably 6 To 14 yuan, more preferably 7 to 10 yuan.It can be divided into bicyclic, tricyclic, Fourth Ring or polycyclic bridge heterocycle according to a group cyclic number, Preferably bicyclic, tricyclic or Fourth Ring, more preferably bicyclic or tricyclic.The non-limiting examples of bridge heterocycle include：
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein being connected to one with precursor structure The ring risen is heterocycle, and non-limiting examples include：
Deng.
Heterocycle can be it is optionally replacing or non-substituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo Base, carboxyl or carboxylate.
Term " aryl " refers to 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle (is namely shared The ring of adjacent carbon atoms pair) group, preferably 6 to 10 yuan, more preferable 5 to 6 yuan, such as phenyl and naphthalene.The aryl rings can To condense on heteroaryl, heterocycle or cycloalkyl ring, wherein being aryl rings, non-limit with the ring that precursor structure links together Property example processed includes：
Aryl can be substitution or non-substituted, and when substituted, substituent group is preferably one or more following groups, It is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, ring Alkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl or carboxylic acid Ester group.
Term " heteroaryl " refers to the heteroaromatic system comprising 1 to 4 hetero atom, 5 to 14 annular atoms, and wherein hetero atom selects From oxygen, sulphur and nitrogen.Heteroaryl is preferably 5 to 10 yuan, contains 1 to 3 hetero atom；More preferably 5 yuan or 6 yuan, contain 1 to 2 miscellaneous original Son；It is preferred that such as imidazole radicals, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrole radicals, tetrazole radical, pyridyl group, phonetic Piperidinyl, thiadiazoles, pyrazinyl etc., preferably imidazole radicals, pyrazolyl or pyrimidine radicals, thiazolyl；More preferable pyrazolyl.The heteroaryl Basic ring can be condensed on aryl, heterocycle or cycloalkyl ring, wherein be heteroaryl ring with the ring that precursor structure links together, Its non-limiting examples includes：
Heteroaryl can be it is optionally replacing or non-substituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl Or carboxylate.
Term:" alkoxy " refers to-O- (alkyl) and-O- (non-substituted naphthenic base), the wherein definition of alkyl and naphthenic base As described above.The non-limiting examples of alkoxy include：Methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, ring fourth oxygen Base, cyclopentyloxy, cyclohexyloxy.Alkoxy can be optionally replacing or non-substituted, and when substituted, substituent group is preferably One or more following groups, independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, One or more of cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl substituent group is replaced.
Term " amino protecting group " is in order to which amino remains unchanged when the other positions of molecule being made to be reacted, with being easy to slough Group amino is protected.Non-limiting embodiment includes tertbutyloxycarbonyl, acetyl group, benzyl, allyl and to methoxy Benzyl etc..These groups are optionally replaced by the 1-3 substituent group in halogen, alkoxy or nitro.The amino Protecting group is preferably to methoxybenzyl.
Term " halogenated alkyl " refers to alkyl and is replaced by one or more halogens, and wherein alkyl is as defined above.Term " hydroxyl Base " refers to-OH groups.
Term " hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, and wherein alkyl is as defined above.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " amino " refers to-NH2。
Term " cyano " refers to-CN.
Term " nitro " refers to-NO2。
Term " oxo base " refers to=O.
" optional " or " optionally " mean event described later or environment can with but need not occur, which includes The event or environment generation or not spot occasion.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group " But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more of group hydrogen atom, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this Field technology personnel, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take Generation.For example, amino or hydroxyl with free hydrogen may be unstable when being combined with the carbon atom with unsaturated (such as olefinic) key Fixed.
" pharmaceutical composition " indicate containing one or more compounds described herein or its physiologically/pharmaceutical salt or The mixture and other components such as physiology/pharmaceutical carrier and excipient of pro-drug and other chemical constituents.Medicine The purpose of compositions is the administration promoted to organism, and bioactivity is played in turn conducive to the absorption of active constituent.
" officinal salt " refers to the salt of the compounds of this invention, has safety when this kind of salt is used in the mammalian body and has Effect property, and there is due bioactivity.
M and R6~R8As defined in logical formula (I) compound.
The synthetic method of the compounds of this invention
In order to complete the purpose of the present invention, the present invention adopts the following technical scheme that：
Scheme one
The present invention lead to formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, Diastereoisomer, or mixtures thereof form or its pharmaceutical salt preparation method, include the following steps：
The first step, the compound of general formula (I-1) andUnder alkaline condition, nucleophilic substitution occurs and obtains general formula (I-2) compound；
Second step, under alkaline condition, cyclization obtains the change of general formula (IB) for the compound and carbamide compounds of general formula (I-2) Close object；
Third walks, the compound of general formula (IB), the compound and R of general formula (IC)3- H occurs nucleophilic substitution and obtains together To the compound of general formula (IA)；
4th step, the compound of general formula (IA) in acid condition, slough protecting group and obtain the compound of logical formula (I)；
Wherein：
The reagent for providing alkaline condition includes organic base and inorganic base, and the organic bases include but not limited to three second Amine, pyridine, 4-dimethylaminopyridine, N, N- diisopropylethylamine, n-BuLi, lithium diisopropylamine, double trimethyl silicon substrates Amido lithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and n-butanol sodium, the inorganic base include but not limited to sodium hydride, phosphorus Sour potassium, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide；
The reagent for providing acid condition includes but not limited to hydrogen chloride, the 1,4- dioxane solutions of hydrogen chloride, trifluoro Acetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, to benzene methanesulfonic acid, Me3SiCl and TMSOTf；
Above-mentioned reaction preferably carries out in a solvent, and solvent for use includes but not limited to：Acetic acid, methanol, ethyl alcohol, n-butanol, Toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide (DMSO), 1,4- dioxane, water, N, N- Dimethylformamide and its mixture；
For double bond；
G2For N；
W is amino protecting group, preferably to methoxybenzyl；
X is halogen, preferably chlorine or bromine；
Ring A, G1、X1、L1~L2、R1~R3With n as defined in logical formula (I).
Scheme two
The present invention lead to formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, Diastereoisomer, or mixtures thereof form or its pharmaceutical salt preparation method, include the following steps：
The first step, the compound of general formula (I-1) andUnder alkaline condition, nucleophilic substitution occurs and obtains general formula (I-2) compound；
Under alkaline condition, nucleophilic displacement of fluorine occurs for second step, the compound of general formula (I-2) and the compound of general formula (I-3) The compound of general formula (ID) is obtained by the reaction；
Third walks, and under alkaline condition, cyclization obtains the chemical combination of general formula (IA) for the compound and ethyl acetate of general formula (ID) Object；
4th step, the compound of general formula (ID) in acid condition, slough protecting group and obtain the compound of logical formula (I)；
Wherein：
The reagent for providing alkaline condition includes organic base and inorganic base, and the organic bases include but not limited to three second Amine, pyridine, 4-dimethylaminopyridine, N, N- diisopropylethylamine, n-BuLi, lithium diisopropylamine, double trimethyl silicon substrates Amido lithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and n-butanol sodium, the inorganic base include but not limited to sodium hydride, phosphorus Sour potassium, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide；
The reagent for providing acid condition includes but not limited to hydrogen chloride, the 1,4- dioxane solutions of hydrogen chloride, trifluoro Acetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, to benzene methanesulfonic acid, Me3SiCl and TMSOTf；
Above-mentioned reaction preferably carries out in a solvent, and solvent for use includes but not limited to：Acetic acid, methanol, ethyl alcohol, n-butanol, Toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide (DMSO), 1,4- dioxane, water, N, N- Dimethylformamide and its mixture；
For double bond；
G2For CH；
W is amino protecting group, preferably to methoxybenzyl；
X is halogen, preferably chlorine or bromine；
Ring A, G1、X1、L1~L2、R1~R3With n as defined in logical formula (I).
Scheme three
The present invention leads to formula (III) compound represented or its tautomer, mesomer, racemic modification, enantiomerism Body, diastereoisomer, or mixtures thereof form or its pharmaceutical salt preparation method, include the following steps：
The first step, the compound of general formula (III-1) andUnder alkaline condition, nucleophilic substitution occurs to be led to The compound of formula (III-2)；
Second step, under alkaline condition, cyclization obtains general formula (III- for the compound and carbamide compounds of general formula (III-2) B compound)；
Third walks, the compound of general formula (III-B), the compound and R of general formula (III-C)3Nucleophilic displacement of fluorine occurs together for-H The compound of general formula (III-A) is obtained by the reaction；
4th step, the compound of general formula (III-A) in acid condition, slough protecting group and obtain the chemical combination of logical formula (III) Object；
Wherein：
The reagent for providing alkaline condition includes organic base and inorganic base, and the organic bases include but not limited to three second Amine, pyridine, 4-dimethylaminopyridine, N, N- diisopropylethylamine, n-BuLi, lithium diisopropylamine, double trimethyl silicon substrates Amido lithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and n-butanol sodium, the inorganic base include but not limited to sodium hydride, phosphorus Sour potassium, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide；
The reagent for providing acid condition includes but not limited to hydrogen chloride, the 1,4- dioxane solutions of hydrogen chloride, trifluoro Acetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, to benzene methanesulfonic acid, Me3SiCl and TMSOTf；
Above-mentioned reaction preferably carries out in a solvent, and solvent for use includes but not limited to：Acetic acid, methanol, ethyl alcohol, n-butanol, Toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide (DMSO), 1,4- dioxane, water, N, N- Dimethylformamide and its mixture；
G2For N；
W is amino protecting group, preferably to methoxybenzyl；
X is halogen, preferably chlorine or bromine；
L1~L2、R1And R7~R8As defined in logical formula (III).
Scheme four
The present invention leads to formula (III) compound represented or its tautomer, mesomer, racemic modification, enantiomerism Body, diastereoisomer, or mixtures thereof form or its pharmaceutical salt preparation method, include the following steps：
The first step, the compound of general formula (III-1) andUnder alkaline condition, nucleophilic substitution occurs to be led to The compound of formula (III-2)；
Under alkaline condition, nucleophilic occurs for second step, the compound of general formula (III-2) and the compound of general formula (III-3) Substitution reaction obtains the compound of general formula (III-D)；
Third walks, and under alkaline condition, cyclization obtains general formula (III-A) for the compound and ethyl acetate of general formula (III-D) Compound；
4th step, the compound of general formula (III-D) in acid condition, slough protecting group and obtain the chemical combination of logical formula (III) Object；
Wherein：
The reagent for providing alkaline condition includes organic base and inorganic base, and the organic bases include but not limited to three second Amine, pyridine, 4-dimethylaminopyridine, N, N- diisopropylethylamine, n-BuLi, lithium diisopropylamine, double trimethyl silicon substrates Amido lithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and n-butanol sodium, the inorganic base include but not limited to sodium hydride, phosphorus Sour potassium, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide；
The reagent for providing acid condition includes but not limited to hydrogen chloride, the 1,4- dioxane solutions of hydrogen chloride, trifluoro Acetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, to benzene methanesulfonic acid, Me3SiCl and TMSOTf；
Above-mentioned reaction preferably carries out in a solvent, and solvent for use includes but not limited to：Acetic acid, methanol, ethyl alcohol, n-butanol, Toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide (DMSO), 1,4- dioxane, water, N, N- Dimethylformamide and its mixture；
G2For CH；
X is halogen, preferably chlorine or bromine；
W is amino protecting group, preferably to methoxybenzyl；
L1~L2、R1And R7~R8As defined in logical formula (III).
Specific implementation mode
Embodiment
The structure of compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrum (MS).NMR displacements (δ) are with 10-6 (ppm) unit provides.The measurement of NMR is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometers, and measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3), OD inside it is designated as tetramethylsilane (TMS).
The measurement of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer:Thermo, model：Finnigan LCQ advantage MAX)。
The measurement of HPLC uses Agilent 1200DAD high pressure liquid chromatographs (Sunfire C18 150 × 4.6mm chromatographies Column) and Waters 2695-2996 high pressure liquid chromatographs (Gimini 150 × 4.6mm of C18 chromatographic columns).
Chiral HPLC, which measures, uses LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.)。
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, thin-layered chromatography (TLC) to make The specification that silica gel plate uses is 0.15mm~0.2mm, the specification that thin-layer chromatography isolates and purifies product use be 0.4mm~ 0.5mm。
It is carrier that column chromatography, which generally uses 200~300 mesh silica gel of Yantai Huanghai Sea silica gel,.
Chiral preparatory column chromatography uses Prep Star SD-1 (Varian Instruments Inc.) or SFC- multigram(Berger Instruments Inc.)。
Kinases average inhibition and IC50The measurement of value is with NovoStar microplate reader (German BMG companies).
The known starting material of the present invention may be used or be synthesized according to methods known in the art, or can purchase certainly ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, splendid remote chemical science and technology (Accela ChemBio Inc), up to the companies such as auspicious chemicals.
It can be carried out under argon atmospher or nitrogen atmosphere without specified otherwise, reaction in embodiment.
Argon atmospher or nitrogen atmosphere refer to the argon gas or nitrogen balloon that reaction bulb connects an about 1L volume.
Nitrogen atmosphere refers to the hydrogen balloon that reaction bulb connects an about 1L volume.
Pressure hydration reaction uses Parr 3916EKX types hydrogenation instrument and clear indigo plant QL-500 types hydrogen generator or HC2-SS Type hydrogenates instrument.
Hydrogenation usually vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.
Microwave reaction uses 908860 type microwave reactors of CEM Discover-S.
Without specified otherwise in embodiment, solution refers to aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature, is 20 DEG C~30 DEG C.
The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), reacts the system of used solvent Have：A：Dichloromethane and methanol system, B：N-hexane and ethyl acetate system, the volume ratio of solvent according to the polarity of compound not It is adjusted together.
Purifying compound use column chromatography the system of eluant, eluent and the solvent system of thin-layered chromatography include：A：Two Chloromethanes and methanol system, B：N-hexane and ethyl acetate system, the volume ratio of solvent it is different according to the polarity of compound and into Row is adjusted, and the alkalinity such as a small amount of triethylamine and acetic acid can also be added or acid reagent is adjusted.
Trifluoroacetate in embodiment may be used following universal method and obtain free alkali：Salt is molten with suitable solvent Solution is added suitable sodium bicarbonate solution and adjusts pH value to neutrality, is concentrated under reduced pressure, and residue is optionally purified to obtain free alkali.
Embodiment 1
5- amino -7- butoxy -1- (4- (pyrrolidin-1-yl methyl) benzyl) pyrimido [4,5-d] pyrimidine -2 (1H) -one
The first step
2- butoxy -4,6- dichloro pyrimidine -5- formaldehyde 1b
Phosphorus oxychloride (6.24g, 0.0407mol) is dissolved in 75mL tetrahydrofurans, is cooled to 0 DEG C, N, N- diformazans is added Base formamide (2.98g, 0.0407mol), after being stirred to react 1 hour, addition 2- butoxy pyrimidine -4,6- glycol 1a (5g, 0.0271mol is prepared using method disclosed in patent application " US20160075707 "), it is stirred to react 30 minutes, rises to Reaction 16 hours is stirred at room temperature.Reaction solution is concentrated under reduced pressure, and 50mL phosphorus oxychloride is added, and is cooled to 0 DEG C, and N, N- diisopropyls is added Ethamine (6.99g, 0.0542mol) is warming up to 60 DEG C and is stirred to react 2 hours.Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, gained 50mL water is added in residue, is extracted with ethyl acetate, organic phase is dried with anhydrous sodium sulfate, filtering, and filtrate decompression concentration is used The quick preparing instruments of CombiFlash obtain title compound 1b (2.89g, yield with eluant, eluent system B purifying gained residues： 42.8%).
MS m/z(ESI):249.1[M+1]
Second step
4- (bis- (4- methoxy-benzyls) amino) -2- butoxy -6- chlorine pyrimidine -5-formaldehydes 1c
Compound 1b (1.09g, 4.376mmol) is dissolved in 30mL tetrahydrofurans, bis- (4- methoxy-benzyls) amine are added Reaction 1 hour is stirred at room temperature in (1.24g, 4.814mmol) and triethylamine (663mg, 6.564mmol).Reaction solution silicagel column color Spectrometry obtains title compound 1c (1g, yield with eluant, eluent system B purifying gained residues：48.8%).
MS m/z(ESI):470.2[M+1]
Third walks
5- (bis- (4- methoxy-benzyls) amino) -7- butoxy pyrimido [4,5-d] (1H) -one of pyrimidine -2 1d
By compound 1c (100mg, 0.213mmol), urea (26mg, 0.426mmol) and potassium carbonate (59mg, It 0.426mmol) is dissolved in 1mL n,N-Dimethylformamide, 150 DEG C of microwave is stirred to react 15 minutes.Reaction solution is cooled to room Temperature is poured into 10mL water, is extracted with ethyl acetate (10mL × 2), is merged organic phase, is washed with 10mL saturated nacl aqueous solutions, Anhydrous sodium sulfate is dried, filtering, and filtrate decompression concentration is beaten with ethyl acetate, is filtered, and collects filter cake, and the above operation repeats 15 It is secondary, merge product, obtain crude title compound 1d (400mg), product directly carries out next step reaction without further purification.
MS m/z(ESI):476.2[M+1]
4th step
5- (bis- (4- methoxy-benzyls) amino) -7- butoxy -1- (4- (pyrrolidin-1-yl methyl) benzyl) pyrimido [4,5-d] pyrimidine -2 (1H) -one 1f
Bis- (bromomethyl) the benzene 1e (222mg, 0.842mmol) of Isosorbide-5-Nitrae-and potassium carbonate (174mg, 1.263mmol) are dissolved in Mixed solvent (the V/V=5 of 2.5mL acetonitriles and N,N-dimethylformamide:2) in, be added portionwise crude Compound 1d (200mg, 0.421mmol), after being stirred to react 2 hours, pyrrolidines (299mg, 4.211mmol) is added, is stirred to react 1 hour.In reaction solution 50mL water is added, is extracted with ethyl acetate (30mL × 3), merges organic phase, (20mL × 2) is washed with saturated nacl aqueous solution, Anhydrous sodium sulfate dry, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain Title compound 1f (200mg, yield：73.3%).
MS m/z(ESI):649.3[M+1]
5th step
5- amino -7- butoxy -1- (4- (pyrrolidin-1-yl methyl) benzyl) pyrimido [4,5-d] pyrimidine -2 (1H) -one 1
Compound 1f (200mg, 0.308mmol) is dissolved in 10mL trifluoroacetic acids, being warming up to 60 DEG C, to be stirred to react 20 small When.Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, and 30mL dichloromethane is added in gained residue, uses saturated sodium bicarbonate solution (20mL) is washed, and water phase is extracted with dichloromethane (20mL), is merged organic phase, is purified with solvent system A with thin-layered chromatography Gained residue obtains title compound 1 (46mg, yield：36.8%).
MS m/z(ESI):409.5[M+1]
1H NMR(400MHz,CD3OD):δ9.21(s,1H),7.37-7.51(m,4H),5.25(d,2H),4.38(t, 1H),4.18(t,1H),3.40-3.50(m,2H),3.05-3.15(m,2H),2.05-2.15(m,2H),1.90-2.00(m, 2H),1.56-1.72(m,2H),1.32-1.45(m,2H),0.88-0.96(m,3H)。
Embodiment 2
4- amino -2- butoxy -8- (4- (pyrrolidin-1-yl methyl) benzyl) pyrido [2,3-d] pyrimidine -7 (8H) -one
The first step
4- (bis- (4- methoxy-benzyls) amino) -2- butoxy -6- ((4- (pyrrolidin-1-yl methyl) benzyl) amino) is phonetic Pyridine -5- formaldehyde 2b
Compound 1c (200mg, 0.425mmol) is dissolved in 10mL n,N-Dimethylformamide, (4- (pyrroles is added Alkane -1- ylmethyls) phenyl) methylamine 2a (121.5mg, 0.638mmol, using well known method " Journal of Medicinal Chemistry, 2012,55 (23), 10387-10404 " are prepared) and potassium carbonate (118mg, 0.85mmol), it is warming up to 40 It DEG C is stirred to react 2 hours.Reaction solution is cooled to room temperature, and ethyl acetate is added, is washed with saturated nacl aqueous solution, organic phase nothing Aqueous sodium persulfate dry, filtering, filtrate decompression concentration, with the quick preparing instruments of CombiFlash with eluant, eluent system A purify obtained by it is residual Excess obtains title compound 2b (230mg, yield：87%).
MS m/z(ESI):624.3[M+1]
Second step
4- (bis- (4- methoxy-benzyls) amino) -2- butoxy -8- (4- (pyrrolidin-1-yl methyl) benzyl) pyrido [2,3-d] pyrimidine -7 (8H) -one 2c
The tetrahydrofuran solution of the lithium hexamethyldisilazide of 1.2mL1M is placed in a reaction flask, is cooled to -78 DEG C, It is added dropwise to ethyl acetate (70.5mg, 0.8mmol), after being stirred to react 30 minutes, compound 2b prefabricated dropwise addition 10mL (250mg, Tetrahydrofuran solution 0.4mmol) is warmed to room temperature and is stirred to react 2 hours naturally.Saturated ammonium chloride solution is added in reaction solution, It is extracted with ethyl acetate (25mL), organic phase is dried with anhydrous sodium sulfate, is filtered, and silica gel column chromatography is used in filtrate decompression concentration With eluant, eluent system A purifying gained residues, title compound 2c (120mg, yield are obtained：47.2%).
MS m/z(ESI):648.3[M+1]
Third walks
4- amino -2- butoxy -8- (4- (pyrrolidin-1-yl methyl) benzyl) pyrido [2,3-d] pyrimidine -7 (8H) -one 2
Compound 2c (120mg, 0.185mmol) is dissolved in 5mL trifluoroacetic acids, being warming up to 60 DEG C, to be stirred to react 12 small When.Reaction solution is cooled to room temperature, be concentrated under reduced pressure, with high performance liquid chromatography purify obtained by residue, obtain title compound 2 (35mg, yield：46.37%).
MS m/z(ESI):408.2[M+1]
1H NMR(400MHz,CDCl3):δ7.55(d,1H),7.41(d,1H),7.28(s,1H),7.26(s,1H),6.46 (d,1H),5.57(s,2H),5.49(s,2H),4.37(t,2H),3.77(s,2H,),2.64-2.75(m,4H),1.81-1.90 (m,4H),1.71-1.77(m,2H),1.44-1.50(m,2H),0.93-0.95(m,3H)。
Test case：
Biological assessment
Test case 1, the compounds of this invention are to the measurement of people source TLR7 agonist activities
The compounds of this invention is to HEK-BlueTMHTLR7 surely turns the hTLR7 protein activations effect of plant cell expression using such as Lower determination of experimental method：
One, experiment material and instrument
1.DMEM (Gibco, 10564-029),
2. fetal calf serum (GIBCO, 10099),
3. trypan blue solution (Sigma, T8154-100ML),
3 multi-function microplate readers of 4.Flexstation (Molec μ lar Devices),
5.HEK-BlueTMHTLR7 cell lines (InvivoGen, hkb-hTLR7),
6.HEK-Blue detection reagents (InvivoGen, hb-det3),
Phosphate buffer 7. (PBS) pH7.4 (the Shanghai biotech inc Yuan Pei, B320).
Two, experimental procedure
It configures HEK-Blue and detects culture medium, HEK-Blue is taken to detect one bag of dry powder, 50ml is added and goes endotoxin water dissolution, 37 DEG C of incubators are placed into, are sterile filtered after ten minutes.Compound is first configured to the stoste of 20mM；It is diluted to most with pure DMSO again High concentration is 6x106NM, through 3 times of gradient dilutions, totally 10 points.
With culture medium first 20 times of above-mentioned prepared diluted chemical compound, the chemical combination after 20 μ l dilutions is then added per hole Object.Take HEK-BlueTMHTLR7 cells, first remove supernatant, add the PBS of 2-5ml preheatings, are put into incubator 1-2 minutes, gently Cell is beaten in featheriness, and Trypan Blue counts.Cell is resuspended with HEK-Blue detection culture mediums and adjusts a concentration of 2.2x 105It is a thin Born of the same parents/ml add 180 μ l cells to be added in 96 porocyte culture plates of 20 μ l drugs to above-mentioned, 37 DEG C, cultivate 6-16h.
Microplate reader is read, wavelength 620nm.Corresponding OD values are can get, drug is calculated through Graphpad Prism EC50Value.
The compounds of this invention can be measured people source TLR7 activations by above experiment, the EC measured50Value is shown in Table 1.
EC of 1 the compounds of this invention of table to people source TLR750。
Embodiment is numbered EC50(nM)
1 374
2 129
Conclusion：The compounds of this invention has preferable activation to people source TLR7.
Test case 2, the compounds of this invention are to the measurement of people source TLR8 agonist activities
The compounds of this invention is to HEK-BlueTMHTLR8 surely turns the hTLR8 protein activations effect of plant cell expression using such as Lower determination of experimental method：
One, experiment material and instrument
1.DMEM (Gibco, 10564-029),
2. fetal calf serum (GIBCO, 10099),
3. trypan blue solution (Sigma, T8154-100ML),
3 multi-function microplate readers of 4.Flexstation (Molec μ lar Devices),
5.HEK-BlueTMHTLR8 cell lines (InvivoGen, hkb-hTLR8),
6.HEK-Blue detection reagents (InvivoGen, hb-det3),
Phosphate buffer 7. (PBS) pH7.4 (the Shanghai biotech inc Yuan Pei, B320).
Two, experimental procedure
It configures HEK-Blue and detects culture medium, HEK-Blue is taken to detect one bag of dry powder, 50ml is added and goes endotoxin water dissolution, 37 DEG C of incubators are placed into, are sterile filtered after ten minutes.Compound is first configured to the stoste of 20mM；It is diluted to most with pure DMSO again High concentration is 6x106NM, then 3 times of gradient dilutions, totally 10 points；With culture medium first 20 times of diluted chemical compound, then per hole The compound after 20 μ l dilutions is added.
Take HEK-BlueTMHTLR8 cells, first remove supernatant, and the PBS 2-5ml of preheating are added, and are put into 1-2 points of incubator Clock, gently blows and beats cell, and Trypan Blue counts.Cell is resuspended with HEK-Blue detection culture mediums and adjusts a concentration of 2.2x 105 A cell/ml adds 180 μ l cells to be added in 96 porocyte culture plates of 20 μ l drugs to above-mentioned, 37 DEG C, cultivates 6-16h.
Microplate reader is read, wavelength 620nm.Corresponding OD values are can get, drug is calculated through Graphpad Prism EC50Value.
The compounds of this invention can be measured people source TLR8 activations by above experiment, the EC measured50Value is shown in Table 2.
EC of 2 the compounds of this invention of table to people source TLR850。
Embodiment is numbered EC50(μM)
1 13
2 >30
Conclusion：The compounds of this invention is weaker to people source TLR8 activations, illustrates that the compounds of this invention has choosing to TLR7 Selecting property.
Compound stimulation peripheral blood mononuclear cells (PBMC) secretes the measurement of IFN-α ability in test case 3, the present invention
Compound stimulation PBMC secretes IFN-α ability using following determination of experimental method in the present invention：
One, experiment material and instrument
1.RPMI 1640(Invitrogen,11875),
2.FBS(Gibco,10099-141),
3.Ficoll-Paque PREMIUM(GE,17-5442-02),
4. trypan blue solution (Sigma, T8154-100ML),
5.SepMateTM-50(Stemcell,15460),
6.Bright-LineTMBlood-counter system (Sigma, Z359629-1EA),
7.96 hole flat undersides (Corning, 3599),
8.96 hole v bottom plates (Corning, 3894),
9. people source IFN-α kit (cisbio, 6FHIFPEB),
10.PHERAStar multi-function microplate readers (BMG, PHERAStar).
Two, experimental procedure
Compound is diluted with pure DMSO, maximum concentration 5mM, 4 times of gradient dilutions, totally 9 points.Then 4 μ l compounds are taken, It is added in 1640 culture mediums of RMPI of the 196 μ l containing 10%FBS, mixing.Take 50 μ l to 96 new porocyte culture plates per hole.
All reagents equilibrate to room temperature, take 250ml culture bottles, 60ml blood and PBS+2%FBS are added thereto, gently Blow and beat mixing dilution.50ml PBMC separating pipe SepMateTM-50 are taken, 15ml lymphocyte separation mediums Ficoll-Paque is added Then blood after 30ml dilutions is added in PREMIUM.1200g is centrifuged 10 minutes, room temperature.Supernatant is taken, then 300g, centrifuges 8 points Clock.It is resuspended and is counted with 1640 culture mediums of RMPI containing 10%FBS, adjustment PBMC quantity to 3.33 × 106A cell/ml, takes 150 μ l are to being added in the tissue culture plate of compound, 37 DEG C, 5.0%CO2Incubator in cultivate for 24 hours.
Tissue culture plate is put into centrifuge, 1200rpm, room temperature centrifuges 10 minutes.150 μ l supernatants are taken out per hole.First The reagent in the IFN-α kit of people source is balanced to room temperature, anti-IFN-α-is prepared according to kit specification under the conditions of being protected from light Eu3+Cave-shaped conjugate (Cryptate conjugate) and anti-IFN-α-d2- conjugates, both with 1：40 ratio and knot Close buffer solution (conjugate Buffer) mixing.Then the supernatant that the centrifuging and taking of 16 μ l obtains is added per hole.2 are added per hole again Anti- IFN-α-the Eu that μ l have just been prepared3+Cave-shaped conjugate and anti-IFN-α-d2- conjugates, shake mixing, and room temperature is protected from light incubation 3h。
It is read with HTRF patterns on PHERAStar.We will stimulation generate minimum detection limit at least 3 times or more cells because Sub horizontal lowest concentration of drug, is defined as MEC (minimum effective concentration of the compound on the cell factor stimulation test Minimal Effective Concentration) value.
The ability that the compounds of this invention stimulation PBMC secretes IFN-α is measured by above experiment, the MEC values measured It is shown in Table 3.
3 the compounds of this invention of table stimulates the MEC of PBMC secretion IFN-α
Embodiment is numbered MEC(nM)
1 16
2 10
Conclusion：From the active data that stimulation PBMC secretes IFN-α, the compounds of this invention can preferably cause IFN-α discharges.
Test case 4, the compounds of this invention are metabolized people's hepatomicrosome CYP3A4 midazolams the inhibition of the enzymatic activity in site Effect
The compounds of this invention is metabolized the enzymatic activity in site using following experiment side to people's hepatomicrosome CYP3A4 midazolams Method measures：
One, experiment material and instrument
1. phosphate buffer (PBS),
2.NADPH(Sigma N-1630),
3. people's hepatomicrosome (Corning Gentest),
4000 liquid matter double-purpose instruments (AB Sciex) of 4.ABI QTrap,
5.Inertsil C8-3 columns, 4.6 × 50mm, 5 μm (Di Ma companies of the U.S.),
6.CYP probe substrates (15 μM of midazolam, SIGMA UC429) and positive control inhibitor (ketoconazole, SIGMA K1003)。
Two, experimental procedure
The PBS buffer solution of 100mM is configured, it is molten with the particle liquid solution of buffer 2.5mg/ml and the NADPH of 5mM Liquid, with the compound working solutions (150,50,15,5,1.5,0.15,0.015,0 μM) of PBS gradient dilution 5X concentration.With PBS ladders The ketoconazole working solution (150,50,15,5,1.5,0.15,0.015,0 μM) of degree dilution 5X concentration.With PBS be diluted to 15 μM it is dense The midazolam working solution of degree.
The particle liquid solution of 2.5mg/ml, 15 μM of midazolam working solution, MgCl are taken respectively2Solution and compound work Liquid (150,50,15,5,1.5,0.15,0.015,0 μM, different reaction systems is arranged in each concentration) each 20 μ l are uniformly mixed. The ketoconazole of positive controls same concentrations replaces compound.Simultaneously by the NADPH solution of 5mM together in 37 DEG C of preincubates 5 Minute.It takes 20 μ l NADPH to be added in a hole after 5 minutes, starts reaction, be incubated 30 minutes.All samples of incubation set double samples This.30 minutes acetonitriles that 250 μ l containing the internal standards are added in backward all samples, mixing, 800rpm shake 10 minutes, then 3700rpm Centrifugation 10 minutes.The supernatant for taking 80 μ l is transferred to LC-MS/MS analyses.
The IC that drug is metabolized CYP3A4 midazolams in site is calculated through Graphpad Prism for numerical value50Value is shown in Table 4.
4 the compounds of this invention of table is metabolized CYP3A4 midazolams the IC in site50Value
Embodiment is numbered IC50(μM)
1 >30
2 8
Conclusion：The compounds of this invention does not have inhibiting effect to the midazolam metabolism site of people's hepatomicrosome CYP3A4, or Inhibiting effect is weaker, shows better safety, prompts to occur to be metabolized site based on CYP3A4 metabolism midazolams Metabolic drug interacts.
Test case 5, the compounds of this invention are to the inhibiting effect of people's hepatomicrosome CYP2D6 enzymatic activitys
The compounds of this invention uses following determination of experimental method to people's hepatomicrosome CYP2D6 enzymatic activitys：
One, experiment material and instrument
1. phosphate buffer (PBS),
2.NADPH(Sigma N-1630),
3. people's hepatomicrosome (Corning Gentest),
4000 liquid matter double-purpose instruments (AB Sciex) of 4.ABI QTrap,
5.Inertsil C8-3 columns, 4.6 × 50mm, 5 μm (Di Ma companies of the U.S.),
6.CYP probe substrates (20 μM of dextromethorphan, SIGMA Q0750) and positive control inhibitor (quinindium, SIGMA D9684)。
Two, experimental procedure
The PBS buffer solution of 100mM is configured, it is molten with the particle liquid solution of buffer 2.5mg/ml and the NADPH of 5mM Liquid, with the compound working solutions (150,50,15,5,1.5,0.15,0.015,0 μM) of PBS gradient dilution 5X concentration.With PBS ladders The quinindium working solution (150,50,15,5,1.5,0.15,0.015,0 μM) of degree dilution 5X concentration.With PBS be diluted to 20 μM it is dense The dextromethorphan working solution of degree.
The particle liquid solution of 2.5mg/ml, 20 μM of dextromethorphan working solution, MgCl are taken respectively2Solution and compound work Liquid (150,50,15,5,1.5,0.15,0.015,0 μM, different reaction systems is arranged in each concentration) each 20 μ l are uniformly mixed. The quinindium of positive controls same concentrations replaces compound.Simultaneously by the NADPH solution of 5mM together in 37 DEG C of preincubates 5 Minute, it takes 20 μ l NADPH to be added in a hole after 5 minutes, starts reaction, be incubated 30 minutes.All samples of incubation set double samples This.30 minutes acetonitriles that 250 μ l containing the internal standards are added in backward all samples, mixing, 800rpm shake 10 minutes.3700rpm is centrifuged 10 minutes.The supernatant for taking 80 μ l is transferred to LC-MS/MS analyses.
The IC that drug is metabolized CYP2D6 in site is calculated through Graphpad Prism for numerical value50Value is shown in Table 5.
5 the compounds of this invention of table is metabolized CYP2D6 the IC in site50Value
Embodiment is numbered IC50(μM)
1 24
Conclusion：The compounds of this invention does not have inhibiting effect to the enzymatic activity of people's hepatomicrosome CYP2D6, shows preferably Safety, prompt will not occur that metabolic drug interaction occurs based on CYP2D6.
Test case 6, the compounds of this invention are to the inhibiting effect of the enzymatic activity in people's hepatomicrosome CYP3A4 testosterone metabolisms site
The compounds of this invention surveys the enzymatic activity in people's hepatomicrosome CYP3A4 testosterone metabolisms site using following experimental method It is fixed：
One, experiment material and instrument
1. phosphate buffer (PBS),
2.NADPH(Sigma N-1630),
3. people's hepatomicrosome (Corning Gentest),
4000 liquid matter double-purpose instruments (AB Sciex) of 4.ABI QTrap,
5.Inertsil C8-3 columns, 4.6 × 50mm, 5 μm (Di Ma companies of the U.S.),
6.CYP probe substrates (testosterone/100 μM, SIGMA K1003) and positive control inhibitor (ketoconazole, Dr.Ehrenstorfer GmbH,C17322500)。
Two, experimental procedure
The PBS buffer solution of 100mM is configured, it is molten with the particle liquid solution of buffer 2.5mg/ml and the NADPH of 5mM Liquid, with the compound working solutions (150,50,15,5,1.5,0.15,0.015,0 μM) of PBS gradient dilution 5X concentration.With PBS ladders The ketoconazole working solution (150,50,15,5,1.5,0.15,0.015,0 μM) of degree dilution 5X concentration.With PBS be diluted to 50 μM it is dense The dextromethorphan working solution of degree.
The particle liquid solution of 2.5mg/ml, 50 μM of testosterone working solution, MgCl are taken respectively2Solution and compound working solutions (150,50,15,5,1.5,0.15,0.015,0 μM, different reaction systems is arranged in each concentration) each 20 μ l are uniformly mixed.Sun The ketoconazole of property control group same concentrations replaces compound.The NADPH solution of 5mM is divided in 37 DEG C of preincubates 5 together simultaneously Clock.It takes 20 μ l NADPH to be added in a hole after 5 minutes, starts reaction, be incubated 30 minutes.All samples of incubation set double samples This.30 minutes acetonitriles that 250 μ l containing the internal standards are added in backward all samples, mixing, 800rpm shake 10 minutes.3700rpm is centrifuged 10 minutes.The supernatant for taking 80 μ l is transferred to LC-MS/MS analyses.
IC of the drug to CYP3A4 testosterone metabolisms site is calculated through Graphpad Prism in numerical value50Value is shown in Table 6.
IC of 6 the compounds of this invention of table to CYP3A4 testosterone metabolisms site50Value
Embodiment is numbered IC50(μM)
1 >30
2 15
Conclusion：The compounds of this invention does not have inhibiting effect to the testosterone metabolism site to people's hepatomicrosome CYP3A4, performance Go out better safety, prompts the metabolic drug interaction that the testosterone metabolism site based on CYP3A4 will not occur.
Test case 7, the compounds of this invention are to the blocking effects of hERG potassium currents
1, experiment purpose
The compounds of this invention is tested to hERG on the stable cell line of transfection hERG potassium channels using system for automatic patch-clamp The blocking effect of potassium current.
2, experimental method
2.1 experiment material and instrument
2.1.1 experiment material：
2.1.2 laboratory apparatus：
2.2 system for automatic patch-clamp experimental procedures
HEK293-hERG stable cell lines are according to 1:4 density is in MEM/EBSS culture mediums (10%FBS, 400 μ g/ml G418,1%MEM nonessential amino acid solution (100 ×), 1% sodium pyruvate solution) in carry out secondary culture, culture 48-72 it is small When within carry out system for automatic patch-clamp experiment.After experimental day digests cell with 0.25% pancreatin, cell is collected by centrifugation, with thin Extracellular fluid (140mM NaCl, 4mM KCl, 1mM MgCl2, 2mM CaCl2, 5mMD Dextrose Monohydrates, 10mM Hepes, pH7.4, Cell 298mOsmol) is resuspended, cell suspension is made.Cell suspension is placed on the cell bank of Patchliner instruments, Cell is added on chip (NPC-16) by Patchliner instruments using negative pressure controller, and negative pressure attracts individual cells in chip Aperture on.After forming full cell pattern, instrument will obtain hERG electric currents according to the hERG Current Voltage programs of setting, then Instrument automatically by low concentration to high concentration, carries out compound perfusion.Pass through HEAK Patchmaster, HEAK EPC10 diaphragms It is soft to clamp the data analysis that amplifier (Nanion) and Pathlinersoftware and Pathcontrol HTsoftware are provided Part, under each concentration of compound electric current and blank control electric current analyze.
2.3 test result
The compounds of this invention is measured the blocking effect of hERG potassium currents by above experiment, the IC measured50Value It is shown in Table 7.
IC of 7 the compounds of this invention of table to the blocking effect of hERG potassium currents50
Embodiment is numbered IC50(μM)
1 > 30
Conclusion：The compounds of this invention is weak to the inhibiting effect of hERG, and the side effect possibility caused by hERG accesses is small.

Claims (21)

1. a kind of logical formula (I) compound represented：
Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or Its pharmaceutical salt,
Wherein：
For singly-bound or double bond；
G2Selected from CH, N and O；And
Work as G2For CH or N when,For double bond；Work as G2For O when,For singly-bound；
G1For CR4Or N；
Ring A is selected from naphthenic base, heterocycle, aryl and heteroaryl；
X1Selected from alkylidene and S (O)m, wherein the alkylidene is optionally by selected from halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl One or more of base, hydroxyalkyl, cyano, amino, nitro, naphthenic base and heterocycle substituent group is replaced；
L1Selected from-NR5-、-O-、-S-、-C(O)-、-S(O)m-、-N(R5)C(O)-、-C(O)N(R5)-、-N(R5)S(O)2-、-S (O)2N(R5)-and covalent bond；
R1Selected from hydrogen atom, alkyl, halogenated alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein described Alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, aryl and heteroaryl are each independently optionally by selected from alkyl, alkoxy, halogen One or more in element, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl A substituent group is replaced；
R2It is identical or different, and be each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, Cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-C (O) R6、-C(O)OR6、-S(O)mR6、-NR7R8With-C (O)NR7R8, wherein alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally by selected from alkyl, alkane In oxygroup, halogen, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl One or more substituent groups are replaced；
L2Selected from alkylidene or covalent bond, wherein the alkylidene optionally by selected from halogen, alkyl, alkoxy, halogenated alkyl, One or more of hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base and heterocycle substituent group is replaced；
R3Selected from hydrogen atom, alkyl, alkoxy, halogen, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, Heterocycle, aryl, heteroaryl ,-C (O) R6、-C(O)OR6、-S(O)mR6、-NR7R8With-C (O) NR7R8, wherein the cycloalkanes Base, heterocycle, aryl and heteroaryl are each independently optionally by selected from alkyl, alkoxy, halogen, halogenated alkyl, hydroxyl, hydroxyl alkane Base, cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-C (O) R6、-C(O)OR6、-S(O)mR6、-NR7R8With- C(O)NR7R8One or more of substituent group replaced；
R4Selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, Heterocycle, aryl and heteroaryl；
R5Selected from hydrogen atom, alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and heteroaryl；
R6Selected from hydrogen atom, alkyl, halogenated alkyl, amino, hydroxyl, naphthenic base, heterocycle, aryl and heteroaryl；
R7And R8It is identical or different, and be each independently selected from hydrogen atom, alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and Heteroaryl, wherein alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally by selected from alkyl, alcoxyl One or more of base, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl take Replaced for base；
Alternatively, the R7And R8With heterocycle is formed together with the nitrogen-atoms being connected, wherein the heterocycle, which removes, contains 1 nitrogen Except atom, also optionally containing 1~2 identical or different hetero atom selected from N, O and S, and the heterocycle optionally quilt Selected from alkyl, alkoxy, oxo base, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and miscellaneous One or more of aryl substituent group is replaced；
N is 0,1,2,3 or 4；And
M is 0,1 or 2.
2. logical formula (I) compound represented according to claim 1, wherein the ring A is phenyl or pyridyl group.
3. logical formula (I) compound represented according to claim 1 or 2, wherein the X1For alkylidene.
4. logical formula (I) compound represented described in any one of claim 1 to 3, to change shown in logical formula (II) Close object：
Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or Its pharmaceutical salt,
Wherein：
G2For CH or N；
G1、L1~L2、R1~R3It is as defined in claim 1 with n.
5. logical formula (I) compound represented according to any one of claims 1 to 4, wherein the G1For N.
6. logical formula (I) compound represented according to any one of claims 1 to 5, to change shown in logical formula (III) Close object：
Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or Its pharmaceutical salt,
Wherein：
G2For CH or N；
L2For alkylidene；
R7And R8With heterocycle is formed together with the nitrogen-atoms being connected, wherein the heterocycle is in addition to containing 1 nitrogen-atoms, Also optionally containing 1~2 identical or different hetero atom selected from N, O and S, and the heterocycle optionally by selected from alkyl, In alkoxy, oxo base, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl One or more substituent groups are replaced；
L1And R1As defined in claim 1.
7. according to logical formula (I) compound represented according to any one of claims 1 to 6, wherein the L1For-O-.
8. logical formula (I) compound represented according to any one of claims 1 to 7, wherein the R1For alkyl.
9. according to logical formula (I) compound represented according to any one of claims 1 to 8, wherein the L2For alkylidene.
10. according to logical formula (I) compound represented according to any one of claims 1 to 9, it is selected from：
11. a kind of general formula (IA) compound represented：
Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or Its pharmaceutical salt,
Wherein：
For singly-bound or double bond；
W is amino protecting group；
Ring A, G1、G2、X1、L1~L2、R1~R3It is as defined in claim 1 with n.
12. general formula (IA) compound represented according to claim 11, is selected from：
13. a kind of method preparing general formula according to claim 11 (IA) compound represented, this method include：
The compound of general formula (IB), the compound and R of general formula (IC)3- H occurs nucleophilic substitution and obtains general formula (IA) together Compound；
Wherein：
For double bond；
G2For N；
W is amino protecting group；
X is halogen；
Ring A, G1、X1、L1~L2、R1~R3It is as defined in claim 11 with n.
14. a kind of method preparing general formula according to claim 11 (IA) compound represented, this method include：
The compound of general formula (ID) and ethyl acetate cyclization obtain the compound of general formula (IA)；
Wherein：
For double bond；
G2For CH；
W is amino protecting group；
Ring A, G1、X1、L1~L2、R1~R3It is as defined in claim 11 with n.
15. a kind of method preparing logical formula (I) compound represented according to claim 1, this method include：
The compound of general formula (IA) sloughs protecting group and obtains the compound of logical formula (I)；
Wherein：
For singly-bound or double bond；
W is amino protecting group；
Ring A, G1、G2、X1、L1~L2、R1~R3It is as defined in claim 1 with n.
16. a kind of pharmaceutical composition, described pharmaceutical composition contain therapeutically effective amount according to any one of claim 1~10 The logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereomeric are different Structure body, or mixtures thereof form or its pharmaceutical salt and one or more pharmaceutically acceptable carrier, diluent or tax Shape agent.
17. according to logical formula (I) compound represented according to any one of claims 1 to 10 or its tautomer, interior disappearing Revolve body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt or according to right It is required that purposes of the pharmaceutical composition in preparing the drug for excitement TLR7 described in 16.
18. according to logical formula (I) compound represented according to any one of claims 1 to 10 or its tautomer, interior disappearing Revolve body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt or according to right It is required that purposes of the pharmaceutical composition in preparing the drug for treating infection caused by virus described in 16.
19. purposes according to claim 18, wherein the virus is selected from：Dengue fever virus, yellow fever virus, Xi Niluo Virus, japanese encephalitis virus, tick-brone encephalitis virus, elder brother Tianjin virus, Murray valley encephalitis virus, St. Louis encephalitis virus, E Mu This gram of hemorrhagic fever viruse, bovine viral diarrhea virus, zika virus, HIV, HBV, HCV, HPV, RSV, SARS and influenza virus.
20. according to logical formula (I) compound represented according to any one of claims 1 to 10 or its tautomer, interior disappearing Revolve body, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt or according to right It is required that purposes of the pharmaceutical composition in preparing the drug for treating or preventing tumour described in 16.
21. purposes according to claim 20, wherein the tumour is selected from melanoma, non-small cell lung cancer, liver cell Cancer, basal-cell carcinoma, clear-cell carcinoma and myeloma.
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CN114075212A (en) * 2020-08-14 2022-02-22 江苏恒瑞医药股份有限公司 Fused tricyclic derivative, preparation method and application thereof in medicine
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