CN109646442A - Acetate compounds are preparing the purposes in ring bird adenosine synzyme acetylation drug - Google Patents

Acetate compounds are preparing the purposes in ring bird adenosine synzyme acetylation drug Download PDF

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CN109646442A
CN109646442A CN201910086264.6A CN201910086264A CN109646442A CN 109646442 A CN109646442 A CN 109646442A CN 201910086264 A CN201910086264 A CN 201910086264A CN 109646442 A CN109646442 A CN 109646442A
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cgas
acetylation
unsubstituted
acid
substituted
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CN109646442B (en
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张学敏
周涛
何新华
李爱玲
李涛
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Biomedical Analysis Center of AMMS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract

The invention discloses acetate compounds shown in a kind of following formula I, its pharmaceutically acceptable salt or solvates to prepare the purposes in cGAS acetylation drug.

Description

Acetate compounds are preparing the purposes in ring bird adenosine synzyme acetylation drug
Technical field
The present invention relates to drug fields, are preparing in particular to acetate compounds shown in a kind of following formula I Purposes in ring bird adenosine synzyme acetylation drug.
Background technique
The appearance of DNA is usually considered the signal of microorganism infection or tissue damage, therefore cell by body in cytoplasm Matter DNA as a kind of danger signal can cause strong innate immune response (Annual review of immunology, 2011,29,185-214).The identification of cytoplasmic DNA is the important mechanisms of body defenses microorganism infection.cGAS(cyclic GMP-AMP Synthase, ring bird adenosine synzyme) it is main cytoplasmic DNA receptor, it can identify rapidly that DNA is stimulated And activate immune response.After in conjunction with DNA, the cGAS of activation can be catalyzed ATP and GTP and generate cyclic annular small molecule cGAMP (cyclic GMP-AMP) (Science, 2013,339,786-791；Science, 2013,339,826-830).CGAMP can be with Combined as second messenger and activate endoplasmic reticulum albumen matter STING (also referred to as MITA, MPYS, ERIS) (Nature, 2008, 455,674-678；Molecular and cellular biology, 2008,28,5014-5026；Proc Natl Acad Sci U S A, 2009,106,8653-8658；Immunity, 2008,29,538-550), STING can be with mediate downstream TBK1 With the activation of IRF3, and I type interferon (Science signaling, 2012,5, pe9) is generated.I type interferon is antiviral It is played an important role in reaction, it can induce expression (the Proc Natl of interferon-induced gene ISGs a series of Acad Sci USA, 2015,112, E5699-5705).
Other than microorganism infection, cellular damage or cellular endogenous retrovirus also can produce cytoplasm itself DNA (Current opinion in immunology, 2014,31,121-126；Nature reviews Immunology, 2016,16,207-219；Science, 2013,339,763-764).Metazoa has evolved DNA enzymatic, they can be removed Cell itself DNA, and then prevent immune response caused by the improper activation of cGAS.For example, TREX1 can degrade in cytoplasm DNA, in the autoimmune diseases such as AGS syndrome (Aicardi-Goutieres syndrome) and systemic loupus erythematosus Had found in patient TREX1 function missing (Current opinion in immunology, 2014,31,121-126； Annals of neurology, 1984,15,49-54；Nature reviews Immunology, 2015,15,429-440； Lancet, 2014,384,1878-1888).AGS syndrome patient accumulates in cytoplasm due to the mutation containing TREX1 gene Itself DNA, can be generated with chronic stimulation cGAS I type interferon (Nature genetics, 2006,38,917-920；Proc Natl Acad Sci USA, 2015,112, E5699-5705；Journal of immunology, 2015,195,1939- 1943；Cell, 2008,134,587-598).The excess interference element of generation can cause airframe systems inflammation and other itself Immune response (Current opinion in rheumatology, 2012,24,499-505).Trex1 meeting is knocked out in mouse Generate rely on cGAS-STING access serious autoimmune response (Proc Natl Acad Sci USA, 2015,112； Journal of immunology, 2015,195,1939-1943).These are research shows that inhibit cGAS to can be used for treating itself Autoimmune disease caused by DNA.However, the scarcity understood cGAS regulatory mechanism hinders the discovery of effective treatment means.
Summary of the invention
An aspect of of the present present invention provides acetate compounds shown in Formulas I, its pharmaceutically acceptable salt or solvent It closes object and is preparing the purposes in cGAS acetylation drug:
Wherein Ar is phenyl or 6, and 7- dihydro -4H- thieno [3,2-c] pyridine -2- base, X is substituted or unsubstituted carbonyl Base, substituted or unsubstituted amine acyl group, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted amide groups, carboxyl, In the substituent group that contains be selected from C1-C6 oxyalkyl, containing 1 to 3 selected from N, O and S heteroatomic saturation or it is unsaturated 5 yuan or 6 circle heterocyclic ring bases, halogen atom.
Preferably, when Ar is phenyl, the structure of compound described in Formulas I can be indicated by Formula Il, wherein Y be oxygen or Nitrogen-atoms, R ' are hydrogen atom, substituted or unsubstituted C1-C8 alkyl, wherein the substituent group in the C1-C8 alkyl replaced is selected from and contains There are 1 to 3 selected from N, O and S heteroatomic saturation or unsaturated 5- or 6-membered heterocycle, C1-C6 oxyalkyl；
Or Y and R ' is formed together with the carbon atom for connecting them containing 1 to 3 heteroatomic saturation for being selected from N, O and S Or unsaturated 5- or 6-membered heterocycle.
It is further preferred that the structure of compound described in Formulas I can be indicated by Formula II when Ar is phenyl, wherein Y is oxygen Or nitrogen-atoms, R ' are hydrogen atom, substituted or unsubstituted C1-C3 alkyl, wherein the substituent group in the C1-C3 alkyl replaced selects From containing selected from 1 to 3 of N, O and S heteroatomic saturation or unsaturated 5- or 6-membered heterocycle, C1-C3 oxyalkyl.
Preferably, when Ar is 6,7- dihydro -4H- thieno [3,2-c] pyridine -2- base, the structure of compound described in Formulas I It can be indicated by Formula Il I, wherein R " is substituted or unsubstituted C1-C6 alkyl, wherein the substitution in the C1-C6 alkyl replaced Base is selected to be replaced containing 1 to 3 selected from N, O and S heteroatomic saturation or unsaturated 5- or 6-membered heterocycle, halogen atom The carbonyl that phenyl, C3-C6 naphthenic base replace.
It is further preferred that wherein R " is to replace when Ar is 6,7- dihydro -4H- thieno [3,2-c] pyridine -2- base Or unsubstituted methylene or ethylidene, wherein substituent group is selected from containing 1 to 3 selected from N, O and S heteroatomic saturation or not It is saturated the carbonyl that 5- or 6-membered heterocycle, the phenyl that halogen atom replaces, C3-C6 naphthenic base replace.
Preferably, the halogen atom is selected from fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.
Preferably, Formulas I compound represented according to the present invention is in following compound:
Another aspect of the invention provides a kind of cGAS acetylation pharmaceutical composition, contains the Formulas I as active constituent Shown compound, its pharmaceutically acceptable salt or solvate and pharmaceutically acceptable carrier.
CGAS acetylation pharmaceutical composition according to the present invention can be used for treating multiple sclerosis, lupus erythematosus, The genetic disease such as Aicardi-Goutieres syndrome etc. of tumour, cirrhosis, pulmonary fibrosis and cGAS overactivity Disease.
CGAS acetylation pharmaceutical composition according to the present invention can be made as several formulations form, including but not limited to Capsule, tablet, injection, suppository, infusion solution, liniment, emulsion etc..
Beneficial effect
Present invention firstly discovers that cGAS acetylation can inhibit cGAS to synthesize cGAMP, and then signal downstream can be inhibited The activation of access has treatment lupus erythematosus, multiple sclerosis, psoriasis etc. itself to inhibit the generation of I type interferon The effect of the diseases such as immunological diseases, tumour, liver fibrosis, pulmonary fibrosis provides a kind of completely new machine for the treatment of these diseases The therapeutic strategy of system；Compound shown in Formulas I provided by the invention has the function of acetylation cGAS, have treatment lupus erythematosus, The purposes of the diseases such as the autoimmune diseases such as multiple sclerosis, psoriasis, tumour, liver fibrosis, pulmonary fibrosis.
Detailed description of the invention
Fig. 1 is acetylsalicylic acid (aspirin) acetylation cGAS protein immunoblotting test in embodiment 5 (westernblot) figure；
Fig. 2 is the comparison diagram that acetylsalicylic acid (aspirin) inhibits cGAS enzymatic activity in cell in embodiment 6；
Fig. 3 is the activation immunoblotting examination that acetylsalicylic acid (aspirin) inhibits cGAS access in cell in embodiment 7 Test (westernblot) figure；
Fig. 4 is compound and prasugrel acetylation cGAS the protein immunoblotting test of embodiment 4 in embodiment 8 (westernblot) figure；
Fig. 5 a and Fig. 5 b are respectively that the compound and prasugrel of embodiment 4 in embodiment 9 inhibit the test of cGAS enzymatic activity Comparison diagram.
Specific embodiment
Hereinafter, will be described in detail the present invention.Before doing so, it should be appreciated that in this specification and appended Claims used in term should not be construed as being limited to general sense and dictionary meanings, and inventor should allowed On the basis of the appropriate principle for defining term to carry out best interpretations, according to meaning corresponding with technical aspect of the invention and generally Thought explains.Therefore, description presented herein is not intended to limitation originally merely for the sake of the preferred embodiment for illustrating purpose The range of invention, it will thus be appreciated that without departing from the spirit and scope of the present invention, it can be obtained by it His equivalents or improved procedure.
The inventors found that cGAS acetylation can inhibit cGAS to synthesize cGAMP, and then can inhibit downstream The activation of signal path has treatment lupus erythematosus, multiple sclerosis, psoriasis etc. to inhibit the generation of I type interferon The effect of the diseases such as autoimmune disease, tumour, liver fibrosis, pulmonary fibrosis.Based on the discovery, the present inventor's screening The compound indicated out by Formulas I can be efficiently used for cGAS acetylation, and then realize the mesh of the diseases such as treatment lupus erythematosus 's.
The compound indicated according further to the Formulas I is developed preparing the purposes in cGAS acetylation drug, the present invention New pharmaceutical composition, wherein containing compound, its pharmaceutically acceptable salt or solvent shown in the Formulas I as active constituent Close object and pharmaceutically acceptable carrier.
" pharmaceutically acceptable salt " is the conventional nothing that formula (I) compound and inorganic acid or organic acid reaction are formed Malicious salt.For example, the conventional nontoxic salts can be made by formula (I) compound and inorganic acid or organic acid reaction, it is described inorganic Acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, amidosulfonic acid and phosphoric acid etc. and the organic acid include citric acid, tartaric acid, Lactic acid, pyruvic acid, acetic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, naphthalene sulfonic acids, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, apple Acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, flutters acid, hydroxymaleic acid, phenylacetic acid, benzene first at malonic acid Acid, salicylic acid, glutamic acid, ascorbic acid, para-anilinesulfonic acid, Aspirin and isethionic acid etc.；Or general formula (I) compound and propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, day Aspartic acid or glutamic acid form sodium salt, sylvite, calcium salt, aluminium salt or the ammonium salt formed again with inorganic base after ester；Or logical formula (I) Close methylamine salt, ethylamine salt or the ethanolamine salt that object and organic base are formed；Or logical formula (I) compound and lysine, arginine, bird Propylhomoserin forms the corresponding inorganic acid salt formed again with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid after ester or and first The corresponding acylate that acid, acetic acid, picric acid, methanesulfonic acid and ethanesulfonic acid are formed.
Term " pharmaceutically acceptable carrier " is to refer to deliver effective quantity active material of the present invention, do not interfere active matter The bioactivity of the matter and any preparation having no toxic side effect to host or patient or the representative carrier of mounting medium include Water, oil, vegetables and minerals, cream base, lotion base, ointment bases etc..These matrix include suspending agent, tackifier, transdermal rush Into agent etc..Their preparation is well known to the technical staff in cosmetic field or topical remedy field.Other letters about carrier Breath can refer to Remington:The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams&Wilkins (2005), the content of the document are incorporated herein by reference.
For drug or pharmacologically active agents, term " effective quantity " or " therapeutically effective amount " refer to nontoxic but can reach To the drug of desired effect or enough dosages of medicament.For the peroral dosage form in the present invention, a kind of active material in composition " effective quantity " refer to when being combined with active material another in the composition for the required dosage that achieves the desired results.Have The determination of effect amount varies with each individual, and age and ordinary circumstance depending on receptor also depend on specific active material, close in case Suitable effective quantity can be determined by those skilled in the art according to routine test.
The various dosage forms of pharmaceutical composition of the invention can be prepared according to the customary preparation methods of pharmaceutical field.Its preparation is matched Lead to formula (I) compound comprising 0.05-200mg in the unit dose of side, it is preferable that include in the unit dose of pharmaceutical formulation 0.1mg-100mg leads to formula (I) compound.
The compound of the present invention and pharmaceutical composition can pass through mammal clinical use, including humans and animals The administration route of mouth, nose, skin, lung or gastrointestinal tract etc..It is most preferably oral.Best preferably daily dose is 0.01-200mg/ Kg weight, disposably takes or 0.01-100mg/kg weight part vic.Which kind of ineffective instructions of taking, personal best agent Depending on amount should be according to specific treatment.It is to gradually increase dosage until finding most suitable since low dose under normal conditions Dosage.
Following embodiment is enumerated only as the example of embodiment of the present invention, does not constitute any limit to the present invention System, it will be appreciated by those skilled in the art that modification in the range of without departing from essence and design of the invention each falls within the present invention Protection scope.Unless stated otherwise, material used in the following embodiment, reagent and instrument etc. are unless otherwise specified Commercially available product.
The synthesis of 1. 2- of embodiment ((2- morpholine ethyl) aminoacyl) phenol acetic ester
Acetylsalicylic acid (3.6g, 20mmol) is added in anhydrous dimethyl formamide (50ml), HOBt is added (8.3g, 22mmol), EDCI (22mmol, 4.2g) are then stirred at room temperature 2 hours, addition 2- morpholine ethamine (2.9g, 20mmol), room temperature reaction is kept overnight.Second day, decompression steamed dimethylformamide, and residue is extracted with dichloromethane 100ml × 3 merge organic phase, wash 50ml × 3 with saturated aqueous ammonium chloride, anhydrous sodium sulfate is dried overnight.Column chromatography (eluant, eluent is petroleum ether: ethyl acetate=3:1~1:1) obtains off-white powder 5.5g.Yield 94%.1H NMR(400MHz, DMSO-d6):8.80(br s,1H),8.06(d,1H),7.88-7.90(m,2H),7.34(m,1H),3.52-3.54(d,2H), 3.60-3.64(m,4H),2.42-2.46(m,6H),2.39(s,3H).
The synthesis of 2. 2- of embodiment (morpholine -4- acyl group) phenol acetic ester
Other than reaction starting material is different, synthetic method is the same as embodiment 1.Yield 90%.1H NMR(400MHz,DMSO- d6):8.06(d,1H),7.88-7.90(m,2H),7.34(m,1H),3.50-3.54(m,4H),3.61-3.64(m,4H), 2.39(s,3H).
3. 2- of embodiment ((2- methoxy ethyl) acyl group) phenol acetic ester
Other than reaction starting material is different, synthetic method is the same as embodiment 1.Yield 96%.1H NMR(400MHz,DMSO- d6):8.06(d,1H),7.88-7.90(m,2H),7.34(m,1H),3.71(d,2H),3.30(s,3H),3.28(d,2H), 2.39(s,3H).
4. 5- of embodiment (thiophene -2- ylmethyl) -4,5,6,7- thiophane simultaneously [3,2-c] pyridine -2- yl acetate
Tetrahydrothieno pyridines hydrochloride (3.5g, 20mmol) is dissolved in methylene chloride (30ml), triethylamine is added (4.8g, 48mmol) is stirred 2 hours, is added 2- bromomethyl thiophene (3.5g, 20mmol), is warming up to 45 DEG C and is reacted 6 hours.Drop It warms to room temperature, is added with stirring ammonium chloride saturated solution, take organic layer, 100ml × 3 are extracted with dichloromethane in water phase.It is associated with Machine phase, anhydrous sodium sulfate are dried overnight.Column chromatography for separation obtains light yellow oil, is dissolved in ethyl acetate and is cooled to 0 DEG C, hydrochloric ethyl acetate solution is slowly added dropwise, white solid is precipitated.It filters, obtains 3.9g, yield 66%.1H NMR (400MHz,DMSO-d6):11.8(br s,1H),7.72(d,1H),7.49(d,1H),7.46(d,1H),7.17(m,1H), 4.69(s,2H),4.19(s,2H),3.72-3.37(m,2H),3.29-3.09(m,2H)。
5. acetylsalicylic acid (aspirin Aspirin) acetylation cGAS of embodiment test
The aspirin (purchased from Beijing coupling science and technology) of the cGAS recombinant protein of purification and gradient concentration is existed HEPES (20mM), pH 7.5, MgCl2It is incubated for 2 hours altogether for 37 degrees Celsius in the solution of (5mM), sample-loading buffer, boiling water is added Boil sample 10 minutes.CGAS acetylation is detected with Western blot.By wide spectrum acetylation antibody test, the acetylation of cGAS is shown There is apparent gradient to increase.Prove that aspirin can be with one-step acylation cGAS.Fig. 1 is acetylsalicylic acid (aspirin) acetyl Change cGAS protein
6. acetylsalicylic acid of embodiment (aspirin) inhibits cGAS synthesis cGAMP test
After being broken up THP1 cell 72 hours with PMA, DMSO or aspirin (4mM) is added to handle cell 24 hours.Add HT- DNA (1 μ g/ml) is stimulated about 2 hours.After stimulation, cell is washed 2 times with PBS or physiological saline.It is cold that 800 μ l are added Extraction solution (volume ratio is methanol: acetonitrile: water=40:40:20), will be under cell scraper.Entire extract liquor is placed in refrigerator -20 to take the photograph Family name's degree stands 30 minutes.After extraction 30 minutes, 12000rpm, 4 degrees Celsius are centrifuged 10 minutes.Supernatant is taken, it is dry, use LC- MS/MRM detects cGAMP.The results show that aspirin processing can significantly inhibit the synthesis of cGAMP in cell.Fig. 2 is acetyl Salicylic acid (aspirin) inhibits cGAS enzymatic activity in cell
7. acetylsalicylic acid of embodiment (aspirin) inhibits interferon signal path activation experiment
After being broken up THP1 cell 72 hours with PMA, DMSO or 4mM aspirin is added to handle cell 24 hours.Add HSV-1 (MOI=10:1), different time points are stimulated.After stimulation, cell is washed 2 times with PBS or physiological saline.It is split with M2 cell Liquid is solved on ice after lytic cell 30 minutes, 12000rpm, 4 degrees Celsius are centrifuged 15 minutes.Supernatant is taken, sample-loading buffer is added, Boiling water boiling sample 10 minutes.With the Phosphorylation status of Western blot detection IRF3.The results show that aspirin processing can be significant The activation of IRF3 in cell caused by inhibiting HSV-1 to stimulate.Fig. 3 is that acetylsalicylic acid (aspirin) inhibits cGAS in cell logical The activation on road
8. 5- of embodiment (thiophene -2- ylmethyl) -4,5,6,7- thiophane simultaneously [3,2-c] pyridine -2- yl acetate (compound of embodiment 4) and prasugrel acetylation cGAS test
By the cGAS recombinant protein of purification and 5- (thiophene -2- ylmethyl) -4,5,6,7- thiophane simultaneously [3,2- C] pyridine -2- yl acetate (compound of embodiment 4,0.1mM) or prasugrel (0.1mM, purchased from Beijing coupling science and technology) It is added to HEPES (20mM) pH 7.5, MgCl2It is incubated for 2 hours altogether for 37 degrees Celsius in (5mM) solution, sample-loading buffer, boiling is added Boiling sample 10 minutes.CGAS acetylation is detected with Western blot.By wide spectrum acetylation antibody test, the acetyl of cGAS is shown Change dramatically increases.The compound and prasugrel for proving embodiment 4 can be with one-step acylation cGAS.Fig. 4 is the change of embodiment 4 Close object and prasugrel acetylation cGAS protein
The compound and prasugrel of 9. embodiment 4 of embodiment inhibit cGAS synthesis cGAMP test
By the Zhou-0312 or prasugrel HEPES of the cGAS recombinant protein of purification and gradient concentration (20mM) pH 7.5, MgCl2It is incubated for 2 hours altogether for 37 degrees Celsius in (5mM) solution.After add HT-DNA (0.2 μ g/ μ l), ATP (2mM), 37 degrees Celsius of GTP (2mM) are incubated for 2 hours altogether.The cold extraction solution of 4 times of volumes is added, and (volume ratio is methanol: acetonitrile =40:40).Entire extract liquor is placed in -2 degrees Celsius of refrigerator, stands 30 minutes.After extraction 30 minutes, 12000rpm, 4 is Celsius Degree centrifugation 10 minutes.Supernatant is taken, it is dry, cGAMP is detected with LC-MS/MRM.The results show that compound and the pula of embodiment 4 Gray can significantly inhibit the synthesis of cGAMP in cell.Fig. 5 a is that compound inhibition cGAS enzymatic activity Fig. 5 b of embodiment 4 is general Glug thunder inhibits cGAS enzymatic activity.
The cGAS acetylation of the compound of 10. embodiment 1 of embodiment, embodiment 2 and embodiment 3 is tested
Experimental method calculates deacetylation percentage with embodiment 5, by comparing westernblot acetylation band, as a result It is listed in the table below in 1.
Table 1
Compound (1um) Deacetylation percentage
Embodiment 1 85%
Embodiment 2 80%
Embodiment 3 95%

Claims (10)

1. acetate compounds shown in Formulas I, its pharmaceutically acceptable salt or solvate are in preparation cGAS acetylation Purposes in drug:
Wherein Ar be phenyl or 6,7- dihydro -4H- thieno [3,2-c] pyridine -2- base, X be substituted or unsubstituted carbonyl, take Generation or unsubstituted amine acyl group, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted amide groups, carboxyl, wherein containing Substituent group be selected from C1-C6 oxyalkyl, containing selected from 1 to 3 of N, O and S heteroatomic saturation or unsaturated 5- or 6-membered miscellaneous Ring group, halogen atom.
2. purposes according to claim 1, which is characterized in that when Ar is phenyl, acetate compounds described in Formulas I Structure can indicate by Formula Il, and wherein Y is oxygen or nitrogen-atoms, and R ' is hydrogen atom, substituted or unsubstituted C1-C8 alkyl, The substituent group in C1-C8 alkyl wherein replaced is selected from containing 1 to 3 selected from N, O and S heteroatomic saturation or unsaturation 5 Member or 6 circle heterocyclic ring bases, C1-C6 oxyalkyl；
Or Y and R ' and the carbon atom for connecting them are formed together containing 1 to 3 selected from N, O and S heteroatomic saturation or not It is saturated 5- or 6-membered heterocycle,
3. purposes according to claim 2, which is characterized in that the R ' is hydrogen atom, substituted or unsubstituted C1-C3 alkane Base, wherein the substituent group in the C1-C3 alkyl replaced is selected from containing 1 to 3 heteroatomic saturation or insatiable hunger selected from N, O and S With 5- or 6-membered heterocycle, C1-C3 oxyalkyl.
4. purposes according to claim 1, which is characterized in that when Ar is 6,7- dihydro -4H- thieno [3,2-c] pyridine - When 2- base, the structure of acetate compounds described in Formulas I can be indicated by Formula Il I, and wherein R " is substituted or unsubstituted C1- C6 alkyl, wherein substituent group in the C1-C6 alkyl replaced be selected from containing 1 to 3 selected from N, O and S heteroatomic saturation or The carbonyl of phenyl, the substitution of C3-C6 naphthenic base that unsaturated 5- or 6-membered heterocycle, halogen atom replace,
5. purposes according to claim 4, which is characterized in that the R " is substituted or unsubstituted methylene or sub- second Base, wherein substituent group is selected from containing 1 to 3 selected from N, O and S heteroatomic saturation or unsaturated 5- or 6-membered heterocycle, halogen The carbonyl of phenyl, the substitution of C3-C6 naphthenic base that plain atom replaces.
6. purposes as claimed in any of claims 1 to 5, which is characterized in that the halogen atom be selected from fluorine, chlorine, Bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.
7. purposes according to claim 1, which is characterized in that acetate compounds shown in Formulas I are selected from following chemical combination In object:
8. a kind of cGAS acetylation pharmaceutical composition contains as active constituent according to claim 1 to any one of 7 Acetate compounds shown in the Formulas I, its pharmaceutically acceptable salt or solvate and pharmaceutically acceptable Carrier.
9. cGAS acetylation pharmaceutical composition according to claim 8, which is characterized in that described pharmaceutical composition is for treating The genetic disease of multiple sclerosis, lupus erythematosus, tumour, cirrhosis, pulmonary fibrosis and cGAS overactivity is (such as Aicardi-Goutieres syndrome) etc. diseases.
10. cGAS acetylation pharmaceutical composition according to claim 8, which is characterized in that the cGAS acetylation medicine group Several formulations form, including but not limited to capsule, tablet, injection, suppository, infusion solution, liniment, emulsion can be made as by closing object Deng.
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