CN108794485A - A kind of toll samples receptor modulators, its pharmaceutical composition, preparation method and purposes - Google Patents
A kind of toll samples receptor modulators, its pharmaceutical composition, preparation method and purposes Download PDFInfo
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- CN108794485A CN108794485A CN201810404456.2A CN201810404456A CN108794485A CN 108794485 A CN108794485 A CN 108794485A CN 201810404456 A CN201810404456 A CN 201810404456A CN 108794485 A CN108794485 A CN 108794485A
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- 0 *=C(c(nc12)c[n]1c(cccc1)c1nc2N)NCC(N)=O Chemical compound *=C(c(nc12)c[n]1c(cccc1)c1nc2N)NCC(N)=O 0.000 description 8
- CETCFGUZSIARLS-UHFFFAOYSA-N CC(C)c1c(C(N(CC2)CC2O)=O)nc2[n]1c(nccc1)c1nc2 Chemical compound CC(C)c1c(C(N(CC2)CC2O)=O)nc2[n]1c(nccc1)c1nc2 CETCFGUZSIARLS-UHFFFAOYSA-N 0.000 description 1
- CSIOVWJYANMJKV-UHFFFAOYSA-N CC(C)c1c(C(NCCO)=O)nc2[n]1c1ncccc1nc2 Chemical compound CC(C)c1c(C(NCCO)=O)nc2[n]1c1ncccc1nc2 CSIOVWJYANMJKV-UHFFFAOYSA-N 0.000 description 1
- ARFNBTOMNXXODC-UHFFFAOYSA-N CN(C)CCN=C Chemical compound CN(C)CCN=C ARFNBTOMNXXODC-UHFFFAOYSA-N 0.000 description 1
- FLVFPAIGVBQGET-UHFFFAOYSA-N CN(CC1)CC1O Chemical compound CN(CC1)CC1O FLVFPAIGVBQGET-UHFFFAOYSA-N 0.000 description 1
- RXYPXQSKLGGKOL-UHFFFAOYSA-N CN1CCN(C)CC1 Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
Abstract
The invention belongs to medicinal chemistry arts, and in particular to one kind has the compound of toll sample regulation effects, preparation method and the usage.The present invention provides following Formula X compound represented.Formula X compound can be used as toll sample receptor modulators, and activity is higher.In addition, the compounds of this invention has the characteristics that high-efficiency low-toxicity, anti-drug resistance, there is clinical value.Also, the compounds of this invention synthesis step is simple, therefore has larger economic use value.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to one kind have toll sample regulation effects compound, its
Pharmaceutical composition, Preparation method and use.
Background technology
Toll-like receptor (Toll-like receptors, TLR) is to participate in one kind of nospecific immunity (innate immunity)
Key protein molecule, and connect the bridge of nospecific immunity and specific immunity.TLR is single cross-film non-catalytic
Protein can identify the molecule with conserved structure from microorganism.When the physical barriers of microorganism breakthrough body, such as
Whens skin, mucous membrane etc., TLR can identify them and body is activated to generate immune cell responses.Toll-like receptor is characterized in that
The main transmembrane protein that the extracellular structural domain rich in leucine and the cytoplasm containing conservative region extend.Inherent immunity system can
Pathogen relevant molecule mould is monitored and identifies by expressing these TLR on the cell surface of certain form of immunocyte
Type.The generation of cell factor and the up-regulation of costimulatory molecules on the identification activation phagocyte of foreign aid's pathogen.This leads to T cell
The adjusting of behavior.Wherein TLR4 not only can recognize that the pathogen of external source, also recognizable endogenous material and degradation product.Recently it studies
It was found that TLR also has identification and adjustment effect in acquired immune system, or even may also be played in cancer immunosurveillance
Certain effect.
Toll-like receptor after birth outskirt mainly exercises identification receptor and combines shape with other accessory receptors (co-receptor)
At the function of receptor complex.(IL-1R is mediated the cytoplasmic domain of Toll-like receptor with IL-1R family member's cytoplasmic domains very high homology
Signal transducting system and mechanism it is similar with drosophila), which is known as Toll-IL-1 receptor domains (Toll-IL-1receptor
Domain, TIR structural domain).There is TIR the thermophilic same sex to interact (homophilic interaction), thereby raise down
The signaling molecule containing TIR is swum, signal complex is formed.But the two extracellular portion is uncorrelated, TLR after birth outskirts are to have 17
The repetitive sequence (Leucine rich repeats, LRRs) of~31 leucines enrichment, and all contain 3 extracellular fragments and assist
Albumen, that is, MD-1, MD-2 and RP105 participates in the identification to disease associated molecule pattern (PAMP)；And the knot that IL-1R is Ig samples
Structure, in mammals, there is also the domains TIR, such as 2 kinds of signals to receive albumen, the receiving in the domains MyD88 and TIR for some plasmosins
Sub- albumen (TIR domain-containing adaptor protein, TIRAP), the two acts as in TIR signal transductions
With.Currently, the Toll-like receptor family member being had been found that in most of mammal and the mankind has ten one to ten five kinds.Its
Middle understanding more clearly has TLR2, TLR4, TLR5 and TLR9.The equivalent form of the certain TLR found in the mankind is simultaneously not present
In all mammals.For example, a kind of gene that coding is similar to the protein of TLR10 in the mankind is present in mouse, but
It is that the expression goes out over and damaged by a kind of retrovirus in certain site.On the other hand, TLR11, TLR12 of mouse expression
It is not presented in the mankind with TLR13.Other mammals can express the TLR not found in the mankind.
TLR monitors such as the eyes of the innate immunity and identifies a variety of different disease associated molecule patterns (PAMP), be machine
Body resists first of barrier of infectious diseases.Wherein TLR4 not only can recognize that the pathogen of external source, also recognizable endogenous object
Matter and degradation product.Also, Toll-like receptor has recognition reaction in acquired immunity.The strongest antigen presentation of body is thin
Born of the same parents --- dendritic cells can express TLR.By the thin of TLR identifications LPS, GpG-DNA, peptide glycan, lipoprotein and mycobacterium
There is cell wall components etc. the molecule of PAMP, dendritic cells to be activated and ripe, provide the costimulatory signal of acquired immunity.Therefore
TLR is the bridge that microbe composition causes dendritic cells to activate.
Therefore, improved high-efficiency low-toxicity, anti-drug resistance or the toll sample receptors with clinical value are researched and developed
Conditioning agent has larger social effect.
Invention content
To improve the above problem, the present invention provides lower Formula X compound represented, its stereoisomer, raceme, mutually variation
Structure body, isotopic label, nitrogen oxides, solvate or its pharmaceutically acceptable salt,
Wherein, A, B are identical or different, represent CR independently of one anotheraOr N；
E represents CRa, N or NRb；
D represents H, O, OH or NR4R5；
R1、R2It is identical or different, H, unsubstituted or optionally by one or more R is represented independently of one anothercThe following base of substitution
Group：C1-40Alkyl, C2-40Alkenyl, C2-40Alkynyl, C1-40Alkoxy, C3-20Naphthenic base, 3-20 circle heterocyclic rings base, C6-20Aryl, 5-20
Unit's heteroaryl；
R3Representative-NR4R5、-OR6；
R4、R5、R6It is identical or different, it is independently from each other H, it is unsubstituted or optionally by one or more RdUnder substitution
Row group：C1-40Alkyl, C2-40Alkenyl, C2-40Alkynyl, C3-20Naphthenic base, 3-20 circle heterocyclic rings base, C6-20Aryl, 5-20 member heteroaryls
Base；
Alternatively, R4And R5It is formed selected from unsubstituted or optionally by one or more R together with the nitrogen-atoms connected with iteIt takes
The following ring system in generation：3-20 circle heterocyclic rings base, 5-20 unit's heteroaryls；
Each Ra、RbIt is identical or different, H, unsubstituted or optionally by one or more R is represented independently of one anothercSubstitution
Following groups：C1-40Alkyl, C2-40Alkenyl, C2-40Alkynyl, C1-40Alkoxy, C3-20Naphthenic base, 3-20 circle heterocyclic rings base, C6-20Virtue
Base, 5-20 unit's heteroaryls；
Each Rc、Rd、ReIt is identical or different, be independently from each other-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-CN ,=O ,-
NO2, it is unsubstituted or optionally by one or more RgSubstituted following groups：-NH2、C1-40Alkyl, C1-40Alkyl oxy, C1-40Alkane
Base sulfenyl, C2-40Alkenyl, C2-40Alkenyl oxygroup, C2-40Enylsulfanyl, C2-40Alkynyl, C2-40Alkynyl oxygroup, C2-40Alkynyl sulfenyl,
C3-20Naphthenic base, C3-20Cycloalkyl oxy, C3-20Cycloalkylsulfanyl, 3-20 circle heterocyclic rings base, 3-20 circle heterocyclic ring bases oxygroup, 3-20 members
Heterocyclic thio, C6-20Aryl, C6-20Aryloxy, C6-20Artyl sulfo, 5-20 unit's heteroaryls, 5-20 unit's heteroaryls oxygroup, 5-
20 unit's heteroaryl sulfenyls；
Each RgIt is identical or different, it is independently from each other H, C1-40Alkyl, C2-40Alkenyl, C2-40Alkynyl, C3-20Cycloalkanes
Base, 3-20 circle heterocyclic rings base, C6-20Aryl, 5-20 unit's heteroaryls；
Represent singly-bound or double bond.
According to exemplary embodiment of the subject disclosure, A, B are identical or different, represent CH, C-C independently of one another1-8Alkyl or
N, the C1-8Alkyl is unsubstituted or is optionally replaced by one or more following groups：F or C1-8Alkyl；Such as A, B are identical or not
Together, N, CH, C-CF are represented independently of one another3；
According to exemplary embodiment of the subject disclosure, E represents CH, C-C1-8Alkyl, N or NH, the C1-8Alkyl is unsubstituted
Or optionally replaced by one or more following groups：F or C1-8Alkyl；Such as E represents CH, N or NH.
According to exemplary embodiment of the subject disclosure, R1、R2It is identical or different, represent independently of one another H, it is unsubstituted or appoint
Select the following groups replaced by one or more F：C1-8Alkyl, C1-8Alkoxy or C3-6Naphthenic base；
For example, R1、R2It is identical or different, H ,-CF are represented independently of one another3, methyl, ethyl, propyl, butyl, isobutyl group,
Methoxyl group, ethyoxyl, propoxyl group, n-butoxy, cyclobutyl or cyclopenta；
R3- NR can be represented4R5Or-OR6, wherein R4、R5、R6It is identical or different, it is independently from each other H or C1-8Alkyl,
The C1-8Alkyl can optionally be replaced by one or more following groups：-NH2、-NH-C1-8Alkyl ,-N (C1-8Alkyl)2、-OH、
=O, C1-8Alkyl；
Alternatively, R4And R5The following ring system of shape together with the nitrogen-atoms connected with it：3-8 circle heterocyclic ring bases, the 3-8 circle heterocyclic rings
Base can optionally be replaced by one or more following groups：-NH2,-OH or C1-8Alkyl；
For example, R3Represent following group：
Wherein,For the key in connection substitution site.
According to illustrative embodiment, it includes but not limited to following compound that the Formula X compound represented, which is selected from,：
The present invention also provides a kind of pharmaceutical compositions, and it includes the Formula X compound represented of therapeutically effective amount, its solid are different
In structure body, raceme, tautomer, isotopic label, nitrogen oxides, solvate or its pharmaceutically acceptable salt
It is a kind of, two kinds or more of.
Embodiment according to the present invention, described pharmaceutical composition also optionally include its pharmaceutically acceptable auxiliary material, example
Such as carrier, excipient；The auxiliary material be selected from one of the following, two or more：Disintegrant, glidant, lubricant, diluent
Or filler, adhesive, colorant.
The present invention also provides Formula X compound represented, its stereoisomer, raceme, tautomer, isotope labellings
A kind of, two kinds or more of use in medicine preparation in object, nitrogen oxides, solvate or its pharmaceutically acceptable salt
On the way.
Embodiment according to the present invention, the drug is for preventing or treating and the relevant disease of toll sample receptors.Example
Such as, the disease is selected from viral infection, tumour, depression, organ-graft refection or autoimmune disease.
According to the present invention, the virus infection for example, HIV, HBV, HCV infection.
According to the present invention, the tumour is selected from breast cancer, cutaneum carcinoma, carcinoma of urinary bladder, oophoroma, gastric cancer, prostate cancer, colon
Cancer, lung cancer, osteocarcinoma, the cancer of the brain, the carcinoma of the rectum, the cancer of the esophagus, tongue cancer, kidney, carcinoma of renal parenchyma, cervical carcinoma, carcinoma of uterine body, endometrium
Cancer, carcinoma of testis, uropoiesis cancer, melanotic cancer, astrocytes cancer, meningioma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute leaching
Bar property leukaemia, chronic lymphatic leukemia, acute myelogenous leukemia, chronic myelocytic leukemia, adult T-cell leukemia
Lymthoma, hepatocellular carcinoma, bronchiolar carcinoma, Huppert's disease, basal cell tumor, seminoma, rhabdomyosarcoma, cartilage meat
Tumor, muscle tumor or fibrosarcoma.
The present invention also provides preventing or treatment and the method for the relevant disease of toll sample receptors, including to needing such prevention
Or the patient for the treatment of gives the Formula X compound represented of therapeutically effective amount, its stereoisomer, raceme, tautomer, same
It is a kind of, two kinds or more of in the plain marker in position, nitrogen oxides, solvate or its pharmaceutically acceptable salt.
The present invention also provides the preparation methods of Formula X compound, include the following steps：
(1) synthesis of intermediate III：Compound I and compound II carries out that compound III is obtained by the reaction；
(2) synthesis of intermediate compound IV：The compound III that step (1) obtains carries out that compound IV is obtained by the reaction；
(3) synthesis of compound X：The compound IV and compound R that step (2) obtains3H reactions generate compound X；
Wherein A, B, D, E, R1、R2、R3With definition as described above；L is selected from leaving group, such as OTs, I, Br or Cl.
Preparation in accordance with the present invention, in step (1),
The reaction carries out at a temperature of 20 DEG C to 100 DEG C；
The solvent used in reaction is one, two, or more in alcohols solvent, ether solvent, aromatic hydrocarbon solvent；
Such as one, two, or more in ethyl alcohol, isopropanol, dioxane, tetrahydrofuran, toluene etc..
Preparation in accordance with the present invention, in step (2),
The reaction carries out at a temperature of 20 DEG C to 100 DEG C；
The reaction is basic hydrolysis or acid hydrolytic reaction, preferably basic hydrolysis；
One kind in sodium hydroxide, potassium hydroxide, lithium hydroxide etc. of the alkali that the basic hydrolysis uses, two kinds or more
It is a variety of；
Preparation in accordance with the present invention, in step (3),
The reaction carries out at a temperature of 20 DEG C to 100 DEG C；
The reaction carries out in the presence of condensing agent；The condensing agent is selected from EDCI.HCl (1- ethyls-(3- dimethyl
Aminopropyl) carbodiimide hydrochloride), HATU (2- (7- aoxidize benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids
Ester), BOP-Cl (bis- (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychlorides), one kind in DCC (N, N'- Dicyclohexylcarbodiimide),
Two or more；
The reaction carries out in the presence of base；The alkali be selected from triethylamine, diisopropylethylamine, N-methylmorpholine,
One, two, or more in DMAP.
Advantageous effect
The compounds of this invention can be used as toll sample receptor modulators, and activity is adjusted with good TLR7/8.In addition, this
Invention compound has good cytotoxicity, suitable for medicinal, with clinical value.Also, the compounds of this invention synthesizes
Step is simple, therefore has good economic use value.
Term defines and explanation
Unless otherwise indicated, the group described in present specification and claims and term definition, including its work
For the defining of example, illustratively definition, preferred definition, the definition described in table, particular compound determines in embodiment
Justice etc. arbitrarily can be combined and be combined each other.Group definition after such combination and combination and compound structure, should
Belong in the range of present specification record.
Term " C1-40Alkyl " is interpreted as the preferred linear chain or branched chain saturation monovalent hydrocarbon for indicating to have 1~40 carbon atom
Base, preferably C1-10Alkyl."C1-10Alkyl " is interpreted as preferred indicate with 1,2,3,4,5,6,7,8,9 or 10 carbon atom
Linear chain or branched chain be saturated monovalent hydrocarbon.The alkyl be for example methyl, ethyl, propyl, butyl, amyl, hexyl, isopropyl,
Isobutyl group, sec-butyl, tertiary butyl, isopentyl, 2- methyl butyls, 1- methyl butyls, 1- ethyl propyls, 1,2- dimethyl propyls,
Neopentyl, 1,1- dimethyl propyls, 4- methyl amyls, 3- methyl amyls, 2- methyl amyls, 1- methyl amyls, 2- ethyl-butyls,
1- ethyl-butyls, 3,3- dimethylbutyls, 2,2- dimethylbutyls, 1,1- dimethylbutyls, 2,3- dimethylbutyls, 1,3- bis-
Methyl butyl or 1,2- dimethylbutyls etc. or their isomers.Particularly, the group have 1,2,3,4,5,6, a carbon
Atom (" C1-6Alkyl "), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl group, sec-butyl, tertiary butyl, more particularly,
The group has 1,2 or 3 carbon atom (" C1-3Alkyl "), such as methyl, ethyl, n-propyl or isopropyl.
Term " C2-40Alkenyl " is interpreted as the preferred monovalent hydrocarbon for indicating linear chain or branched chain, and it includes one or more double
Key and have 2~40 carbon atoms, preferably " C2-10Alkenyl "."C2-10Alkenyl " is interpreted as preferred expression linear chain or branched chain
Monovalent hydrocarbon it includes one or more double bonds and has 2,3,4,5,6,7,8,9 or 10 carbon atom, especially 2 or 3
Carbon atom (" C2-3Alkenyl "), it should be appreciated that in the case where the alkenyl includes more than one double bond, the double bond can mutually divide
From or conjugation.The alkenyl is such as vinyl, allyl, (E) -2- methyl ethylenes, (Z) -2- methyl ethylenes, (E) -
But-2-ene base, (Z)-but-2-ene base, (E)-but-1-ene base, (Z)-but-1-ene base, amyl- 4- alkenyls, (E)-amyl- 3- alkenyls,
(Z)-amyl- 3- alkenyls, (E)-amyl- 2- alkenyls, (Z)-amyl- 2- alkenyls, (E)-amyl- 1- alkenyls, (Z)-amyl- 1- alkenyls, hex- 5- alkene
Base, (E)-hex- 4- alkenyls, (Z)-hex- 4- alkenyls, (E)-hex- 3- alkenyls, (Z)-hex- 3- alkenyls, (E)-hex- 2- alkenyls, (Z)-
Hex- 2- alkenyls, (E)-hex- 1- alkenyls, (Z)-hex- 1- alkenyls, isopropenyl, 2- methyl propyl- 2- alkenyls, 1- methyl propyl- 2- alkene
Base, 2- methyl propyl- 1- alkenyls, (E) -1- methyl propyl- 1- alkenyls, (Z) -1- methyl propyl- 1- alkenyls, 3- methyl butyl- 3- alkenyls, 2-
Methyl butyl- 3- alkenyls, 1- methyl butyl- 3- alkenyls, 3- methyl but-2-enes base, (E) -2- methyl but-2-enes base, (Z) -2- methyl
But-2-ene base, (E) -1- methyl but-2-enes base, (Z) -1- methyl but-2-enes base, (E) -3- methyl but-1-enes base, (Z) -3-
Methyl but-1-ene base, (E) -2- methyl but-1-enes base, (Z) -2- methyl but-1-enes base, (E) -1- methyl but-1-enes base,
(Z) -1- methyl but-1-ene base, 1,1- dimethyl propylene -2- alkenyls, 1- ethyl propyl- 1- alkenyls, 1- propyl ethylenes base, 1- isopropyls
Vinyl.
Term " C2-40Alkynyl " is understood to mean that the monovalent hydrocarbon of linear chain or branched chain, and it includes one or more three keys simultaneously
And there is 2~40 carbon atoms, preferably " C2-C10Alkynyl ".Term " C2-C10Alkynyl " is interpreted as preferably indicating linear chain or branched chain
Monovalent hydrocarbon, it includes one or more three keys and there are 2,3,4,5,6,7,8,9 or 10 carbon atom, especially 2 or 3
A carbon atom (" C2-C3Alkynyl ").The alkynyl is such as acetenyl, propyl- 1- alkynyls, Propargyl, butyl- 1- alkynyls, butyl-
2- alkynyls, butyl- 3- alkynyls, amyl- 1- alkynyls, amyl- 2- alkynyls, amyl- 3- alkynyls, amyl- 4- alkynyls, hex- 1- alkynyls, hex- 2- alkynyls,
Hex- 3- alkynyls, hex- 4- alkynyls, hex- 5- alkynyls, 1- methyl Propargyl, 2- methyl butyl- 3- alkynyls, 1- methyl butyl- 3- alkynes
Base, 1- methyl butyl- 2- alkynyls, 3- methyl butyl- 1- alkynyls, 1- ethyls Propargyl, the amyl- 4- alkynyls of 3- methyl, 2- methyl are amyl-
The amyl- 4- alkynyls of 4- alkynyls, 1- methyl, the amyl- 3- alkynyls of 2- methyl, the amyl- 3- alkynyls of 1- methyl, the amyl- 2- alkynyls of 4- methyl, 1- methyl
The amyl- 1- alkynyls of amyl- 2- alkynyls, 4- methyl, the amyl- 1- alkynyls of 3- methyl, 2- ethyl butyl- 3- alkynyls, 1- ethyl butyl- 3- alkynyls, 1-
Ethyl butyl- 2- alkynyls, 1- propyl Propargyl, 1- isopropyls Propargyl, 2,2- dimethyl butyrate -3- alkynyls, 1,1- diformazans
Base butyl- 3- alkynyls, 1,1- dimethyl butyrate -2- alkynyls or 3,3- dimethyl butyrate -1- alkynyls.Particularly, the alkynyl be acetenyl,
Propyl- 1- alkynyls or Propargyl.
Term " C3-20Naphthenic base " is understood to mean that the monovalent monocyclic of saturation or bicyclic hydrocarbon ring, has 3~20 carbon
Atom, preferably " C3-10Naphthenic base ".Term " C3-10Naphthenic base " is understood to mean that the monovalent monocyclic of saturation or bicyclic hydrocarbon ring,
With 3,4,5,6,7,8,9 or 10 carbon atoms.The C3-10Naphthenic base can be monocycle alkyl, such as cyclopropyl, cyclobutyl, ring
Amyl, cyclohexyl, suberyl, cyclooctyl, cyclononyl or cyclodecyl or for example decahydronaphthalene naphthalene nucleus of bicyclic alkyl.
Term " 3-20 circle heterocyclic rings base " means the monovalent monocyclic of saturation or bicyclic hydrocarbon ring, and it includes 1-5 to be independently selected from N, O
With the hetero atom of S, preferably " 3-10 circle heterocyclic rings base ".Term " 3-10 circle heterocyclic rings base " means the monovalent monocyclic or dicyclic hydrocarbon of saturation
Ring, it is a that it includes 1-5, the preferably 1-3 hetero atoms for being selected from N, O and S.The heterocycle can pass through appointing in the carbon atom
One or nitrogen-atoms (if present) are connect with the rest part of molecule.Particularly, the heterocycle may include but not
It is limited to：4 membered rings, such as azetidinyl, oxetanyl；5 membered rings, such as tetrahydrofuran base, dioxa cyclopentenyl, pyrroles
Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl；Or 6 membered rings, as THP trtrahydropyranyl, piperidyl, morpholinyl, dithianyl,
Thio-morpholinyl, piperazinyl or trithiane base；Or 7 membered rings, such as Diazesuberane base.Optionally, the heterocycle can be
Benzo-fused.The heterocycle can be it is bicyclic, such as, but not limited to 5,5 membered rings, such as hexahydro cyclopentano [c] pyrroles -2
(1H)-basic ring or 5,6 membered bicyclics, such as hexahydropyrrolo simultaneously [1,2-a] pyrazine -2 (1H)-basic ring.The ring of nitrogen atom can be
Part is undersaturated, i.e., it can include one or more double bonds, such as, but not limited to 2,5- dihydro -1H- pyrrole radicals, 4H- [1,
3,4] thiadiazine base, 4,5- dihydro-oxazoles base or 4H- [Isosorbide-5-Nitrae] thiazinyl, alternatively, it can be benzo-fused, such as but not
It is limited to dihydro-isoquinoline base.According to the present invention, the heterocycle is no armaticity.
Term " C6-20Aryl " is interpreted as the preferred monovalence armaticity or partial aromatic for indicating to have 6~20 carbon atoms
The monocyclic, bicyclic or tricyclic hydrocarbon ring of property, preferably " C6-14Aryl ".Term " C6-14Aryl " be interpreted as it is preferred indicate with 6,7,
8,9,10,11,12, the 13 or 14 monovalence armaticity of carbon atom or monocyclic, bicyclic or tricyclic hydrocarbon rings of partial aromatic
(“C6-14Aryl "), especially the ring (" C with 6 carbon atoms6Aryl "), such as phenyl；Or xenyl, or there are 9
The ring (" C of carbon atom9Aryl "), such as indanyl or indenyl, or the ring (" C with 10 carbon atoms10Aryl "), such as
Tetrahydro naphthyl, ihydro naphthyl or naphthalene, or the ring (" C with 13 carbon atoms13Aryl "), such as fluorenyl, either
Ring (" C with 14 carbon atoms14Aryl "), such as anthryl.
Term " 5-20 unit's heteroaryls " is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring system：It has
There are 5~20 annular atoms and includes the 1-5 hetero atoms for being independently selected from N, O and S, such as " 5-14 unit's heteroaryls ".Term " 5-14
Unit's heteroaryl " is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring system：It has 5,6,7,8,9,10,11,
12, the carbon atom of 13 or 14 annular atoms, especially 5 or 6 or 9 or 10, and it includes 1-5, preferably 1-3 be respectively independently selected from N,
The hetero atom of O and S also, in addition can be benzo-fused at each occurrence.Particularly, heteroaryl is selected from thienyl, furan
It mutters base, pyrrole radicals, oxazolyls, thiazolyl, imidazole radicals, pyrazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, triazolyl, thiophene
Di azoly, thiophene -4H- pyrazolyls etc. and their benzo derivative, such as benzofuranyl, benzothienyl, benzoxazole
Base, benzoxazine, benzimidazolyl, benzotriazole base, indazolyl, indyl, isoindolyl etc.；Or pyridyl group, pyridazine
Base, pyrimidine radicals, pyrazinyl, triazine radical etc. and their benzo derivative, such as quinolyl, quinazolyl, isoquinolyl
Deng；Or azocine base, indolizine base, purine radicals etc. and their benzo derivative；Or cinnoline base, phthalazinyl, quinazolyl, quinoline
Quinoline base, naphthyridines base, pteridyl, carbazyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazine groups etc..
Unless otherwise indicated, heterocycle, heteroaryl or inferior heteroaryl include its all possible isomeric form, such as its position
Set isomers.Therefore, for some illustrative non-limiting examples, pyridyl group or sub-pyridyl group include pyridine -2- bases, sub- pyrrole
Pyridine -2- bases, pyridin-3-yl, sub- pyridin-3-yl, pyridin-4-yl and sub- pyridin-4-yl；Thienyl or sub- thienyl include thiophene
Pheno -2- bases, Asia thiophene -2- bases, thiene-3-yl and sub- thiene-3-yl.
It can according to known methods, such as by extraction, filtering or column chromatography come isolating target compound.
According to its molecular structure, the compound of the present invention can be chiral, it is thus possible to which there are various enantiomters
Form.Thus these compounds can exist with racemate form or optical active forms.The compound of the present invention or in which
Body can be by the way that well known to a person skilled in the art chemically or physically methods to be separated into enantiomter compound, or with this shape
Formula is for synthesizing.In the case of racemic amine, by being reacted with optically active resolution reagent, it is made non-right from mixture
Reflect isomers.The example of resolution reagent appropriate is optically active acid, such as R and the tartaric acid of S-shaped formula, diacetyl tartaric
Amino acid (such as the N- benzoyl proline of acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, N-protected appropriate
Or N- benzenesulfonyls proline) or various optically active camphorsulfonic acids.It (such as is fixed on by optically active resolution reagent
The derivative or chirality of dinitrobenzoyl phenylglycine, cellulose triacetate or other carbohydrate on silica gel spread out
Biochemical methacrylate polymers), it also can advantageously carry out chromatography Chiral Separation.Eluant, eluent appropriate for this purpose
It is aqueous or containing alcohol solvent mixture, for example, hexane/isopropyl alcohol/acetonitrile.
Pharmaceutically acceptable salt can be the present invention with enough alkalinity with nitrogen-atoms for example in chain or ring
Compound acid-addition salts, such as with following inorganic acid formed acid-addition salts：Such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydrogen iodine
Acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid or disulfate or the acid-addition salts formed with following organic acid：Such as formic acid,
Acetic acid, acetoacetate, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, hendecanoic acid, lauric acid, benzoic acid, bigcatkin willow
Acid, 2- (4- hydroxy benzoyls) benzoic acid, camphoric acid, cinnamic acid, pentamethylene propionic acid, didextrose acid, 3- hydroxyl -2- naphthalene first
Acid, niacin flutter acid, pectinic acid, persulfuric acid, 3- phenylpropionic acids, picric acid, pivalic acid, 2- ethylenehydrinsulfonic acids, itaconic acid, ammonia
Base sulfonic acid, trifluoromethanesulfonic acid, dodecyl sulphate, ethanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, 2- naphthalene sulfonic acids, naphthalene two
Sulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, algae
Acid, maleic acid, fumaric acid, D- gluconic acids, mandelic acid, ascorbic acid, glucoheptose, phosphoglycerol, aspartic acid, sulfosalisylic
Acid, hemisulfic acid or thiocyanic acid.
Since the compound of the present invention may be present multiple at salt site, " pharmaceutically acceptable salt " includes not only this
Invention compound wherein 1 includes wherein 2,3 or all at being formed on salt site at the salt formed on salt site
Salt.For this purpose, formula (I) compound and the radical ion (anion) or alkali at the acid needed for salt in " pharmaceutically acceptable salt "
Cation mole ratio can change in the larger context, such as can be 4:1~1:4, such as 3:1,2:1,1:1,1:2,1:3
Deng.
According to the present invention, pharmaceutically acceptable anion include selected from by inorganic acid or organic acid ionization generate it is cloudy from
Son." inorganic acid " includes but not limited to hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid.
" organic acid " includes but not limited to formic acid, acetic acid, acetoacetate, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptan
Acid, hendecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4- hydroxy benzoyls) benzoic acid, camphoric acid, cinnamic acid, ring penta
Alkane propionic acid, didextrose acid, 3- hydroxy-2-naphthoic acids, niacin, flutter acid, pectinic acid, persulfuric acid, 3- phenylpropionic acids, picric acid,
It is pivalic acid, 2- ethylenehydrinsulfonic acids, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulphate, ethanesulfonic acid, benzene sulfonic acid, right
Toluenesulfonic acid, methanesulfonic acid, 2- naphthalene sulfonic acids, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, third
Diacid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D- gluconic acids, mandelic acid, ascorbic acid, glucoheptose,
Phosphoglycerol, aspartic acid, sulfosalicylic acid, hemisulfic acid or thiocyanic acid.
Term " tautomer " refers to because of a certain atom is generated in the rapid movement in two positions in molecule functional group
Isomers.The compounds of this invention can express out tautomerism.Tautomeric compound there may be two or more can
The type mutually converted.The migration of prototropictautomer hydrogen atom of covalent bonding between two atoms.Change
Isomers generally exists with equilibrium form, attempts to generally produce a kind of mixture, physics and chemistry when detaching single tautomer
The mixture of matter and compound is consistent.The position of balance depends on the chemical characteristic of intramolecular.For example, in many aliphatic aldehydes
In ketone such as acetaldehyde, ketone type is dominant；And in phenol, enol form is dominant.The present invention includes all tautomerisms of compound
Form.
Term " effective quantity " or " therapeutically effective amount " refer to being enough to realize that intended application (includes but not limited to such as to give a definition
Disease treatment) compound of the present invention amount.Therapeutically effective amount can change depending on following factor：Intended application
The weight and age of (in vitro either in vivo) or the subject treated and disease symptom such as subject, disease symptom it is tight
Principal characteristic and administering mode etc. can be readily determined by those of ordinary skill in the art.Specific dosage will depend on it is following because
Element and change：Selected specific compound, based on dosage regimen, whether with other compound combinations administration, administration
Arrangement of time, the tissue being administered and the physical delivery system carried.
Term " auxiliary material " refers to pharmaceutically acceptable inert fraction.The example of categories of excipients includes without limitation adhesive, collapses
Solve agent, lubricant, glidant, stabilizer, filler and diluent etc..Excipient can enhance the operating characteristic of pharmaceutical preparation, i.e.,
Preparation is set to be more suitable for directly compressing by increasing mobility and/or adherence.Typical suitable for above-mentioned preparation pharmaceutically may be used
The example of the carrier of receiving is：Carbohydrate, such as lactose, sucrose, mannitol and sorbierite；Starch, such as cornstarch, cassava
Starch and potato starch；Cellulose and its derivates, such as sodium carboxymethylcellulose, ethyl cellulose and methylcellulose；Phosphorus
Sour calcium class, such as Dicalcium Phosphate and tricalcium phosphate；Sodium sulphate；Calcium sulfate；Polyvinylpyrrolidone；Polyvinyl alcohol；Stearic acid；Firmly
Resin acid alkali salt, such as magnesium stearate and calcium stearate；Stearic acid；Plant oil, such as peanut oil, cottonseed oil, sesame
Oil, olive oil and corn oil；Nonionic, cation and anionic surfactant；Ethylene glycol polymer；Aliphatic alcohols；And paddy
Object hydrolyze solid content and other nontoxic compatible fillers, adhesive, disintegrant, buffer, preservative, antioxidant,
The commonly used auxiliary material in pharmaceutical preparation such as lubricant, colorant.
Specific implementation mode
Further detailed description is done to technical scheme of the present invention below in conjunction with specific embodiment.The following example
It is merely illustrative the ground description and interpretation present invention, and is not necessarily to be construed as limiting the scope of the invention.It is all to be based on this hair
In the range of the technology that bright the above is realized is encompassed by the present invention is directed to protect.
Unless otherwise indicated, the raw materials and reagents used in following embodiment are commercial goods, or can be by
It is prepared by perception method.
Embodiment 1
The preparation of 2- (morpholinyl -4- carbonyls) imidazo [1,2-a] quinoxaline -4 (5H) -one
The first step：
By compound 1a (16.1g, 100mmol), 1b (19.5g, 100mmol) is dissolved in ethyl alcohol (200ml), is warming up to back
Stream, is stirred to react 8 hours, and TLC detection reactions are concentrated under reduced pressure, column chromatography for separation obtains off-white powder after completion of the reaction
20.3g, yield 79.0%.
Second step：
The compound 1c (20.0g, 77.7mmol) that the first step obtains is dissolved in ethyl alcohol (100ml) and water (100ml) mixes
In solvent, sodium hydroxide (6.2g, 155.5mmol) is added at room temperature, is stirred to react in 40 DEG C 6 hours, TLC detection reactions, instead
After answering, ethyl alcohol is removed under reduced pressure, remaining solution pours into the dilute hydrochloric acid of stirring, and solid, filtering is precipitated, and filter cake is washed with water
It washs, is dried to obtain off-white powder 14.8g, yield 83.1%.
Third walks：
Compound 1d (1.0g, 4.4mmol) that second step is obtained, morpholine (380mg, 4.4mmol), DIPEA (844mg,
It 6.5mmol) is dissolved in DMF (20ml), HATU (2.5g, 6.5mmol) is added at room temperature, reaction 8 hours, TLC inspections is stirred at room temperature
Reaction is surveyed, water (20ml) is added after completion of the reaction, reaction is quenched, ethyl acetate (50mlx2) is added and extracts, merges organic layer, it is dense
Contracting, column chromatography for separation obtain off-white powder 670mg, yield 51.5%, MS-ESI:M/z=299.3 [M+1].
Embodiment 2
The system of compound 2- shown in following formula (4- methyl piperidine base -1- carbonyls) imidazo [1,2-a] quinoxaline -4 (5H) -one
It is standby:Prepared by the method for reference implementation example 1, MS-ESI:M/z=312.3 [M+1].
Embodiment 3
The preparation of compound 2- shown in following formula (4- piperidyl -1- carbonyls) imidazo [1,2-a] quinoxaline -4 (5H) -one：
Prepared by the method for reference implementation example 1, MS-ESI:M/z=298.3 [M+1].
Embodiment 4
The system of compound 2- shown in following formula (3- methyl piperidine base -1- carbonyls) imidazo [1,2-a] quinoxaline -4 (5H) -one
It is standby：Prepared by the method for reference implementation example 1, MS-ESI:M/z=298.3 [M+1].
Embodiment 5
Compound N-shown in following formula (2- ethoxys) -4- oxo -4,5- glyoxalidine simultaneously [1,2-a] quinoxaline -2- formyls
The preparation of amine：Prepared by the method for reference implementation example 1, MS-ESI:M/z=273.3 [M+1].
Embodiment 6
The preparation of the amino of compound 4- shown in following formula-N- (2- amino-ethyls) imidazo [1,2-a] quinoxaline -2- formamides
The first step：
By compound 6a (16.0g, 100mmol), 1b (19.5g, 100mmol) is dissolved in ethyl alcohol (200ml), is warming up to back
Stream, is stirred to react 8 hours, and TLC detection reactions are concentrated under reduced pressure, column chromatography for separation obtains off-white powder after completion of the reaction
19.5g, yield 76.2%.
Second step：
The compound 6b (19.0g, 74.2mmol) that the first step obtains is dissolved in ethyl alcohol (100ml) and water (100ml) mixes
In solvent, sodium hydroxide (5.9g, 148.3mmol) is added at room temperature, is stirred to react in 40 DEG C 6 hours, TLC detection reactions, instead
After answering, ethyl alcohol is removed under reduced pressure, remaining solution pours into the dilute hydrochloric acid of stirring, and solid, filtering is precipitated, and filter cake is washed with water
It washs, is dried to obtain off-white powder 14.8g, yield 87.6%.
Third walks：
Compound 6c (1.0g, 4.4mmol), ethylenediamine (264mg, 4.4mmol), the DIPEA that second step is obtained
(844mg, 6.5mmol) is dissolved in DMF (20ml), and HATU (2.5g, 6.5mmol) is added at room temperature, and it is small that reaction 8 is stirred at room temperature
When, TLC detection reactions are added water (20ml) and reaction are quenched, ethyl acetate (50mlx2) is added and extracts, is associated with after completion of the reaction
Machine layer, concentration, column chromatography for separation obtain off-white powder 714mg, yield 60.1%, MS-ESI:M/z=271.3 [M+1].
Embodiment 7
The preparation of compound shown in following formula (4- aminooimidazoles simultaneously [1,2-a] quinoxaline -2- bases) (piperidin-1-yl) ketone：
Prepared by the method for reference implementation example 6, MS-ESI:M/z=297.3 [M+1].
Embodiment 8
Compound shown in following formula (4- aminooimidazoles simultaneously [1,2-a] quinoxaline -2- bases) (4- methyl piperidine -1- bases) ketone
It prepares：Prepared by the method for reference implementation example 6, MS-ESI:M/z=311.3 [M+1].
Embodiment 9
The preparation of compound shown in following formula (4- aminooimidazoles simultaneously [1,2-a] quinoxaline -2- bases) (morpholinyl) ketone：With reference to
Prepared by the method for embodiment 6, MS-ESI:M/z=298.3 [M+1].
Embodiment 10
Compound shown in following formula (4- aminooimidazoles simultaneously [1,2-a] quinoxaline -2- bases) (3- amino-pyrrolidine -1- bases) ketone
Preparation：Prepared by the method for reference implementation example 6, MS-ESI:M/z=297.3 [M+1].
Embodiment 11
Compound shown in following formula (4- aminooimidazoles simultaneously [1,2-a] quinoxaline -2- bases) (3- hydroxyl pyrrolidine -1- bases) ketone
Preparation：Prepared by the method for reference implementation example 6, MS-ESI:M/z=298.3 [M+1].
Embodiment 12
The amino of compound 4- shown in following formula-N- (2- amino -2- oxoethyls) imidazo [1,2-a] quinoxaline -2- formyls
The preparation of amine：Prepared by the method for reference implementation example 6, MS-ESI:M/z=285.3 [M+1].
Embodiment 13
The amino of compound 4- shown in following formula-N- (2- amino -1- oxopropan -2- bases) imidazo [1,2-a] quinoxaline -2-
The preparation of formamide：Prepared by the method for reference implementation example 6, MS-ESI:M/z=299.3 [M+1].
Embodiment 14
The amino of compound 4- shown in following formula-N- (2- amino -1- oxo-butanes -2- bases) imidazo [1,2-a] quinoxaline -2-
The preparation of formamide：Prepared by the method for reference implementation example 6, MS-ESI:M/z=3133 [M+1].
Embodiment 15
The amino of compound 4- shown in following formula-N- (1- amino -3- methyl-1s-oxo-butanes -2- bases) imidazo [1,2-a] quinoline
The preparation of quinoline -2- formamides：Prepared by the method for reference implementation example 6, MS-ESI:M/z=327.4 [M+1].
Embodiment 16
The amino of compound 4- shown in following formula-N- (1- amino -4- methyl-1s-oxo-pentane -2- bases) imidazo [1,2-a] quinoline
The preparation of quinoline -2- formamides：Prepared by the method for reference implementation example 6, MS-ESI:M/z=341.4 [M+1].
Embodiment 17
N- (2- amino-ethyls) -9- isobutyl group -6-o oxo -5,6- glyoxalidine simultaneously [1,2-a] pyrido [3,2-e] pyrrole
Piperazine -8- formamides
The first step：
By compound 17a (16.2g, 100mmol), 10b (25.1g, 100mmol) is dissolved in ethyl alcohol (200ml), is warming up to
Reflux, is stirred to react 8 hours, and TLC detection reactions are concentrated under reduced pressure, column chromatography for separation obtains off-white powder after completion of the reaction
22.2g, yield 70.7%.
Second step：
The compound 17b (22.0g, 70.0.0mmol) that the first step obtains is dissolved in ethyl alcohol (100ml) and water (100ml) is mixed
In bonding solvent, sodium hydroxide (5.6g, 140.0mmol) is added at room temperature, is stirred to react in 40 DEG C 6 hours, TLC detection reactions,
After completion of the reaction, ethyl alcohol is removed under reduced pressure, remaining solution pours into the dilute hydrochloric acid of stirring, and solid, filtering is precipitated, and filter cake is washed with water
It washs, is dried to obtain off-white powder 14.4g, yield 71.9%.
Third walks：
Compound 17c (1.0g, 3.5mmol), ethylenediamine (210mg, 3.5mmol), the DIPEA that second step is obtained
(677mg, 5.3mmol) is dissolved in DMF (20ml), and HATU (2.0g, 5.3mmol) is added at room temperature, and it is small that reaction 8 is stirred at room temperature
When, TLC detection reactions are added water (20ml) and reaction are quenched, ethyl acetate (50mlx2) is added and extracts, is associated with after completion of the reaction
Machine layer, concentration, column chromatography for separation obtain off-white powder 568mg, yield 49.4%, MS-ESI:M/z=329.4 [M+1].
Embodiment 18
Compound N-shown in following formula (2- (dimethylamino) ethyl) -9- isobutyl group -6- oxo -5,6- glyoxalidine is simultaneously
The preparation of [1,2-a] pyrido [3,2-e] pyrazine -8- formamides：Prepared by the method for reference implementation example 17, MS-ESI:m/z
=357.4 [M+1]
Embodiment 19
Compound N-shown in following formula (2- (dimethylamino) ethyl) -9- isobutyl-N-methyl -6- oxo -5,6- dihydros
The preparation of imidazo [1,2-a] pyrido [3,2-e] pyrazine -8- formamides：Prepared by the method for reference implementation example 17, MS-
ESI:M/z=371.4 [M+1].
Embodiment 20
The isobutyl group of compound 9- shown in following formula-N- (2- methoxy ethyls) -6- oxo -5,6- glyoxalidine is simultaneously [1,2-a]
The preparation of pyrido [3,2-e] pyrazine -8- formamides：Prepared by the method for reference implementation example 17, MS-ESI:M/z=344.4
[M+1]。
Embodiment 21
Compound N-shown in following formula (2- hydroxyethyls) -9- isobutyl group -6- oxo -5,6- glyoxalidine simultaneously [1,2-a] pyrrole
The preparation of pyridine simultaneously [3,2-e] pyrazine -8- formamides：Prepared by the method for reference implementation example 17, MS-ESI:M/z=330.4 [M
+1]。
Embodiment 22
The cyclobutyl of compound 9- shown in following formula -8- (piperazine -1- carbonyls) imidazo [1,2-a] pyrido [3,2-e] pyrazine -
The preparation of 6 (5H) -one：Prepared by the method for reference implementation example 17, MS-ESI:M/z=353.4 [M+1].
Embodiment 23
The cyclobutyl of compound 9- shown in following formula -8- (4- methyl piperazine -1- carbonyls) imidazo [1,2-a] pyrido [3,2-
E] pyrazine -6 (5H) -one preparation：Prepared by the method for reference implementation example 17, MS-ESI:M/z=367.4 [M+1].
Embodiment 24
The cyclobutyl of compound 9- shown in following formula -8- (morpholinyl -4- carbonyls) imidazo [1,2-a] pyrido [3,2-e] pyrrole
The preparation of piperazine -6 (5H) -one：Prepared by the method for reference implementation example 17, MS-ESI:M/z=354.4 [M+1].
Embodiment 25
Compound 8- shown in following formula (3- amino-pyrrolidine -1- carbonyls) -9- isobutyl groups imidazo [1,2-a] pyrido [3,
2-e] pyrazine -6 (5H) -one preparation：Prepared by the method for reference implementation example 17, MS-ESI:M/z=355.4 [M+1].
Embodiment 26
The cyclopenta of compound 9- shown in following formula -8- (3- hydroxyl pyrrolidine -1- carbonyls) imidazo [1,2-a] pyrido [3,
2-e] pyrazine -6 (5H) -one preparation：Prepared by the method for reference implementation example 17, MS-ESI:M/z=368.4 [M+1].
Embodiment 27
The preparation of (9- isopropylimdazoles simultaneously [1,2-a] pyrido [3,2-e] pyrazine -8- bases) (piperidin-1-yl) ketone
The first step
By compound 27a (14.6g, 100mmol), 27b (23.6g, 100mmol) is dissolved in ethyl alcohol (200ml), is warming up to
Reflux, is stirred to react 8 hours, and TLC detection reactions are concentrated under reduced pressure, column chromatography for separation obtains off-white powder after completion of the reaction
21.3g, yield 75.0%.
Second step
Compound 27c (21.0g, 73.9mmol) prepared by the first step is dissolved in ethyl alcohol (100ml) and water (100ml) mixes
In solvent, sodium hydroxide (5.9g, 147.8mmol) is added at room temperature, is stirred to react in 40 DEG C 6 hours, TLC detection reactions, instead
After answering, ethyl alcohol is removed under reduced pressure, remaining solution pours into the dilute hydrochloric acid of stirring, and solid, filtering is precipitated, and filter cake is washed with water
It washs, is dried to obtain off-white powder 12.3g, yield 65.0%.
Third walks
Compound 27d (1.0g, 3.9mmol), piperazine (336mg, 3.9mmol), DIPEA prepared by second step
(761mg, 5.9mmol) is dissolved in DMF (20ml), and HATU (2.2g, 5.9mmol) is added at room temperature, and it is small that reaction 8 is stirred at room temperature
When, TLC detection reactions are added water (20ml) and reaction are quenched, ethyl acetate (50mlx2) is added and extracts, is associated with after completion of the reaction
Machine layer, concentration, column chromatography for separation obtain off-white powder 712mg, yield 56.3%, MS-ESI:M/z=325.1 [M+1].
Embodiment 28
Compound shown in following formula (9- isopropylimdazoles simultaneously [1,2-a] pyrido [3,2-e] pyrazine -8- bases) (4- methyl
Piperidin-1-yl) ketone preparation：Prepared by the method for reference implementation example 27, MS-ESI:M/z=339.4 [M+1].
Embodiment 29
Compound shown in following formula (9- isopropylimdazoles simultaneously [1,2-a] pyrido [3,2-e] pyrazine -8- bases) (morpholinyl)
The preparation of ketone：Prepared by the method for reference implementation example 27, MS-ESI:M/z=326.4 [M+1].
Embodiment 30
Compound (3- amino-pyrrolidine -1- bases) shown in following formula (9- isopropylimdazoles simultaneously [1,2-a] pyrido [3,2-
E] pyrazine -8- bases) (morpholinyl) ketone preparation：Prepared by the method for reference implementation example 27, MS-ESI:M/z=325.4 [M
+1]。
Embodiment 31
Compound (3- hydroxyl pyrrolidine -1- bases) shown in following formula (9- isopropylimdazoles simultaneously [1,2-a] pyrido [3,2-
E] pyrazine -8- bases) (morpholinyl) ketone preparation：Prepared by the method for reference implementation example 27, MS-ESI:M/z=326.4 [M
+1]。
Embodiment 32TLR7 and TLR8 determination of activity
HEK-Blue people's TLR7 and TLR8 cell is used respectively.Pass through the Study of Activation pair by detecting NF-kB after processing
The stimulation of people TLR7 and TLR8 are pacified in the case where being fused to the control of INF-b minimal promoters of several NF-kB and AP-1 binding sites
Set SEAP reporters, stimulation people TLR7 and TLR8 cell 24 as a child after, pass through NF-kB promoters adjust report gene table
It reaches, the wavelength using Quanti Blue kits in 640nm measures cell culture supernatant SEAP reporter gene activities, leads to
It crosses and EC is measured based on active analysis50Value.
The result shows that EC of the embodiment 1-31 compounds to TLR850Value is between 83.2nM to 15 μM, to TLR7's
EC50Value is more than 100nM, and majority is between 300nM to 50 μM.Wherein, embodiment 2,5,9, the EC of 14-17 compounds50It is worth low
In 90nM, the selectivity to TLR8 is averagely about 49.6 times of TLR7.However, the EC of embodiment 4,12 and 21 compounds50It is higher than
200nM, the selectivity to TLR8 are averagely about 9.2 times of TLR7.
More than, embodiments of the present invention are illustrated.But the present invention is not limited to the above embodiments.It is all
Within the spirit and principles in the present invention, any modification, equivalent substitution, improvement and etc. done should be included in the guarantor of the present invention
Within the scope of shield.
Claims (10)
1. lower Formula X compound represented, its stereoisomer, raceme, tautomer, isotopic label, nitrogen oxides,
Solvate or its pharmaceutically acceptable salt,
Wherein, A, B are identical or different, represent CR independently of one anotheraOr N；
E represents CRa, N or NRb；
D represents H, O, OH or NR4R5；
R1、R2It is identical or different, H, unsubstituted or optionally by one or more R is represented independently of one anothercSubstituted following groups：
C1-40Alkyl, C2-40Alkenyl, C2-40Alkynyl, C1-40Alkoxy, C3-20Naphthenic base, 3-20 circle heterocyclic rings base, C6-20Aryl, 5-20 members are miscellaneous
Aryl；
R3Representative-NR4R5、-OR6；
R4、R5、R6It is identical or different, it is independently from each other H, it is unsubstituted or optionally by one or more RdThe following base of substitution
Group：C1-40Alkyl, C2-40Alkenyl, C2-40Alkynyl, C3-20Naphthenic base, 3-20 circle heterocyclic rings base, C6-20Aryl, 5-20 unit's heteroaryls；
Alternatively, R4And R5It is formed selected from unsubstituted or optionally by one or more R together with the nitrogen-atoms connected with iteSubstitution
Following ring system：3-20 circle heterocyclic rings base, 5-20 unit's heteroaryls；
Each Ra、RbIt is identical or different, H, unsubstituted or optionally by one or more R is represented independently of one anothercWhat is replaced is following
Group：C1-40Alkyl, C2-40Alkenyl, C2-40Alkynyl, C1-40Alkoxy, C3-20Naphthenic base, 3-20 circle heterocyclic rings base, C6-20Aryl, 5-
20 unit's heteroaryls；
Each Rc、Rd、ReIt is identical or different, it is independently from each other-F ,-Cl ,-Br ,-I ,-OH ,-SH ,-CN ,=O ,-NO2、
It is unsubstituted or optionally by one or more RgSubstituted following groups：-NH2、C1-40Alkyl, C1-40Alkyl oxy, C1-40Alkyl sulfide
Base, C2-40Alkenyl, C2-40Alkenyl oxygroup, C2-40Enylsulfanyl, C2-40Alkynyl, C2-40Alkynyl oxygroup, C2-40Alkynyl sulfenyl, C3-20Ring
Alkyl, C3-20Cycloalkyl oxy, C3-20Cycloalkylsulfanyl, 3-20 circle heterocyclic rings base, 3-20 circle heterocyclic ring bases oxygroup, 3-20 circle heterocyclic ring bases
Sulfenyl, C6-20Aryl, C6-20Aryloxy, C6-20Artyl sulfo, 5-20 unit's heteroaryls, 5-20 unit's heteroaryls oxygroup, 5-20 members are miscellaneous
Artyl sulfo；
Each RgIt is identical or different, it is independently from each other H, C1-40Alkyl, C2-40Alkenyl, C2-40Alkynyl, C3-20Naphthenic base, 3-
20 circle heterocyclic ring bases, C6-20Aryl, 5-20 unit's heteroaryls；
Represent singly-bound or double bond.
2. compound according to claim 1, wherein A, B are identical or different, represent CH, C-C independently of one another1-8Alkyl
Or N, the C1-8Alkyl is unsubstituted or is optionally replaced by one or more following groups：F or C1-8Alkyl；For example, A, B it is identical or
Difference represents N, CH, C-CF independently of one another3；
E represents CH, C-C1-8Alkyl, N or NH, the C1-8Alkyl is unsubstituted or is optionally replaced by one or more following groups：F
Or C1-8Alkyl；For example, E represents CH, N or NH；
R1、R2It is identical or different, H, following groups that are unsubstituted or optionally being replaced by one or more F are represented independently of one another：
C1-8Alkyl, C1-8Alkoxy or C3-6Naphthenic base；
For example, R1、R2It is identical or different, H ,-CF are represented independently of one another3, methyl, ethyl, propyl, butyl, isobutyl group, methoxy
Base, ethyoxyl, propoxyl group, n-butoxy, cyclobutyl or cyclopenta；
R3Representative-NR4R5,-OR6Wherein R4、R5、R6It is identical or different, it is independently from each other H or C1-8Alkyl, the C1-8Alkyl
Can optionally it be replaced by one or more following groups：-NH2、-NH-C1-8Alkyl ,-N (C1-8Alkyl)2,-OH ,=O, C1-8Alkane
Base；
Alternatively, R4And R5The following ring system of shape together with the nitrogen-atoms connected with it：3-8 circle heterocyclic ring bases, the 3-8 circle heterocyclic rings base can
Optionally replaced by one or more following groups：-NH2,-OH or C1-8Alkyl；
For example, R3Represent following group：
Wherein,For the key in connection substitution site.
3. compound according to claim 1 or 2, wherein it includes but not limited to following compound that the compound, which is selected from,：
4. a kind of pharmaceutical composition, it includes claim 1-3 any one of them compound, its solid of therapeutically effective amount are different
In structure body, raceme, tautomer, isotopic label, nitrogen oxides, solvate or its pharmaceutically acceptable salt
It is a kind of, two kinds or more of.
5. pharmaceutical composition according to claim 4, wherein described pharmaceutical composition, which also optionally includes it, can pharmaceutically connect
The auxiliary material received, such as carrier, excipient；The auxiliary material be selected from one of the following, two or more：Disintegrant, glidant, profit
Lubrication prescription, diluent or filler, adhesive, colorant.
6. claim 1-3 any one of them compound, its stereoisomer, raceme, tautomer, isotope labelling
A kind of, two kinds or more of use in medicine preparation in object, nitrogen oxides, solvate or its pharmaceutically acceptable salt
On the way.
7. purposes according to claim 6, wherein the drug is for preventing or treating and the relevant disease of toll sample receptors
Disease；For example, the disease is selected from viral infection, tumour, depression, organ-graft refection or autoimmune disease.
8. the purposes described according to claim 6 or 7, wherein the virus infection for example, HIV, HBV, HCV infection；
Preferably, the tumour be selected from breast cancer, cutaneum carcinoma, carcinoma of urinary bladder, oophoroma, gastric cancer, prostate cancer, colon cancer, lung cancer,
Osteocarcinoma, the cancer of the brain, the carcinoma of the rectum, the cancer of the esophagus, tongue cancer, kidney, carcinoma of renal parenchyma, cervical carcinoma, carcinoma of uterine body, carcinoma of endometrium, carcinoma of testis,
Uropoiesis cancer, melanotic cancer, astrocytes cancer, meningioma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute lymphatic leukemia,
Chronic lymphatic leukemia, acute myelogenous leukemia, chronic myelocytic leukemia, adult T-cell leukemia-lymphoma, liver are thin
Born of the same parents' cancer, bronchiolar carcinoma, Huppert's disease, basal cell tumor, seminoma, rhabdomyosarcoma, chondrosarcoma, muscle tumor,
Or fibrosarcoma.
9. the preparation method of any one of the claim 1-3 compounds, includes the following steps：
(1) synthesis of intermediate III：Compound I and compound II carries out that compound III is obtained by the reaction；
(2) synthesis of intermediate compound IV：The compound III that step (1) obtains carries out that compound IV is obtained by the reaction；
(3) synthesis of compound X：The compound IV and compound R that step (2) obtains3H reactions generate compound X；
Wherein A, B, D, E, R1、R2、R3With any one of the claim 1-3 definition；L be selected from leaving group, such as OTs, I,
Br or Cl.
10. preparation method according to claim 9, wherein
In step (1),
The reaction carries out at a temperature of 20 DEG C to 100 DEG C；
Preferably, in step (2),
The reaction is basic hydrolysis or acid hydrolytic reaction；
One kind in sodium hydroxide, potassium hydroxide, lithium hydroxide etc. of the alkali that the basic hydrolysis uses, two or more
Kind；
Preferably, in step (3),
The reaction carries out in the presence of condensing agent；The condensing agent is selected from EDCI.HCl (1- ethyls-(3- dimethylaminos
Propyl) carbodiimide hydrochloride), HATU (2- (7- aoxidize benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester),
BOP-Cl (bis- (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychlorides), one kind in DCC (N, N'- Dicyclohexylcarbodiimide), two kinds
Or more；
The reaction carries out in the presence of base；The alkali is in triethylamine, diisopropylethylamine, N-methylmorpholine, DMAP
One, two, or more.
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| US10894797B2 (en) | 2018-09-18 | 2021-01-19 | Nikang Therapeutics, Inc. | Fused tricyclic ring derivatives as SRC homology-2 phosphatase inhibitors |
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| CN113416197A (en) * | 2021-08-25 | 2021-09-21 | 北京鑫开元医药科技有限公司 | Carboxamide derivative, preparation method, pharmaceutical composition and application |
| CN113416197B (en) * | 2021-08-25 | 2021-12-28 | 北京鑫开元医药科技有限公司 | Carboxamide derivative, preparation method, pharmaceutical composition and application |
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