CN116836176A - Artemisinin compound, preparation method and application thereof - Google Patents
Artemisinin compound, preparation method and application thereof Download PDFInfo
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- CN116836176A CN116836176A CN202210304827.6A CN202210304827A CN116836176A CN 116836176 A CN116836176 A CN 116836176A CN 202210304827 A CN202210304827 A CN 202210304827A CN 116836176 A CN116836176 A CN 116836176A
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- substituted
- unsubstituted
- oxygen
- sulfur
- nitrogen
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- -1 Artemisinin compound Chemical class 0.000 title claims abstract description 44
- 229960004191 artemisinin Drugs 0.000 title abstract description 11
- 229930101531 artemisinin Natural products 0.000 title abstract description 11
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 218
- 229910052760 oxygen Inorganic materials 0.000 claims description 128
- 239000001301 oxygen Substances 0.000 claims description 122
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 118
- 229910052717 sulfur Inorganic materials 0.000 claims description 118
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 113
- 239000011593 sulfur Chemical group 0.000 claims description 112
- 229910052757 nitrogen Inorganic materials 0.000 claims description 109
- 125000005842 heteroatom Chemical group 0.000 claims description 108
- 229910052736 halogen Inorganic materials 0.000 claims description 96
- 150000002367 halogens Chemical class 0.000 claims description 96
- 125000001424 substituent group Chemical group 0.000 claims description 59
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 57
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 42
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 37
- 125000004423 acyloxy group Chemical group 0.000 claims description 33
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 33
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 239000004973 liquid crystal related substance Substances 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims description 17
- 125000006413 ring segment Chemical group 0.000 claims description 17
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 125000004122 cyclic group Chemical group 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 8
- 238000006482 condensation reaction Methods 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- 201000006417 multiple sclerosis Diseases 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 7
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 7
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 6
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 5
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 4
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 4
- 125000005108 alkenylthio group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 125000005366 cycloalkylthio group Chemical group 0.000 claims description 4
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- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 150000002513 isocyanates Chemical group 0.000 claims description 3
- 150000002540 isothiocyanates Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 2
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 claims description 2
- 208000003250 Mixed connective tissue disease Diseases 0.000 claims description 2
- 241000721454 Pemphigus Species 0.000 claims description 2
- 206010039710 Scleroderma Diseases 0.000 claims description 2
- 208000004732 Systemic Vasculitis Diseases 0.000 claims description 2
- 206010047115 Vasculitis Diseases 0.000 claims description 2
- COEWIOVAZWGZBG-UHFFFAOYSA-N aminocarbamothioic s-acid Chemical compound NNC(O)=S COEWIOVAZWGZBG-UHFFFAOYSA-N 0.000 claims description 2
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
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- 238000011321 prophylaxis Methods 0.000 claims description 2
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- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 125000004429 atom Chemical group 0.000 claims 1
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims 1
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- 230000000694 effects Effects 0.000 abstract description 4
- 239000012074 organic phase Substances 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000011734 sodium Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229910004298 SiO 2 Inorganic materials 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 8
- 210000001744 T-lymphocyte Anatomy 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 229960002521 artenimol Drugs 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 6
- 229930016266 dihydroartemisinin Natural products 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- HNHVTXYLRVGMHD-UHFFFAOYSA-N n-butyl isocyanate Chemical compound CCCCN=C=O HNHVTXYLRVGMHD-UHFFFAOYSA-N 0.000 description 6
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
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- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
Abstract
The invention relates to an artemisinin compound shown in a formula (I), a preparation method and application thereof. The compound has novel structure and obvious autoimmune disease resisting effect.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to an artemisinin compound, a preparation method thereof, a pharmaceutical composition and application thereof in autoimmune diseases.
Background
Autoimmune diseases such as multiple sclerosis (Multiple sclerosis, MS), rheumatoid disease and lupus erythematosus have serious influence on human health, wherein the main incidence group of multiple sclerosis is young and strong of 20-40 years old, and the autoimmune diseases are one of the most important causes for causing noninvasive nervous system paralysis and disability of young people, have serious influence on the life quality of patients, and have serious threat to the physical and mental health of patients (Annu Rev Immunol,2005, 23:683-747). MS is a common central nervous system demyelinating disease characterized by inflammatory infiltrates, demyelination, axonal injury, neuronal signal disruption, and multifocal regions of immune cell infiltration. The pathogenesis of MS is not clear, and means for effectively treating MS are not known, most of clinically used medicines are immunosuppressants and interferons, the symptomatic medicines can only control further worsening of diseases, and obvious side effects exist in the immunosuppressants, so that the low immunity and infection can be caused after long-term administration. However, interferon causes endocrine disorders, which are costly to treat and require intramuscular injection, which is very cumbersome to administer. Finding new effective therapeutic targets and drugs becomes a hotspot and difficulty in the MS field (Lancet, 2008,372 (9648):1502-1517).
Research shows that CD4 + T cell (Th 1 and Th17 cell) -mediated autoimmunity has been considered as an important cause of initiation of MS, and Experimental Autoimmune Encephalomyelitis (EAE) has many pathological and histological similarities to MS, leading to paralysis, physiological and neurological problems. Th1 CD4 producing interferon-gamma (IFN-gamma) + Th17 CD4 of T cells and secreted interleukin-17 (IL-17A) + T cells play a critical role in the EAE model, and T cell polarization, leukocyte migration and infiltration into the central nervous system are very important steps in EAE pathogenesis (J Autoimmun,2018, 87:97-108). There is growing evidence that Th17, characterized by IL-17 production, has a role in the pathogenesis of MS that is not inferior to Th1, e.g., mice with small numbers of Th17 cells are not readily available with EAE (Exp Med,2005,201 (2): 233-240), and Th17 cells have been identified in brain tissue lesions of MS patients, etc. (Am J Pathol,2008,172 (1): 146-155). However, there is no specific drug for the treatment of MS, and most of the disclosed regulatory factors are transcription factors or cytokines (Nat Immunol 2009,10 (12): 1252-1259) capable of regulatingSmall molecule anti-MS drugs that control Th17 cell differentiation have not been reported, and this provides a solution for MS treatment.
Artemisinin is an antimalarial drug naturally occurring in plants of the genus Artemisia of the family Compositae, and artemisinin derivatives have also been found to have therapeutic effects on autoimmune diseases such as MS, rheumatoid arthritis, lupus, ulcerative colitis and the like. The artemisinin derivatives have great potential in the treatment of autoimmune diseases such as multiple sclerosis, and the development of the artemisinin small molecule candidate compounds with the effect of inhibiting Th17 differentiation has great significance in the treatment of multiple sclerosis.
Disclosure of Invention
In order to solve the defects in the prior art, one aim of the invention is to provide an artemisinin compound.
Another object of the present invention is to provide a method for preparing the above artemisinin compound.
It is a further object of the present invention to provide a pharmaceutical composition comprising the above artemisinin-based compound.
It is still another object of the present invention to provide the use of the above artemisinin compounds in the preparation of a medicament for the treatment or prevention of autoimmune diseases.
In one aspect, the present invention provides an artemisinin compound represented by the following formula (I), or a stereoisomer, a pharmaceutically acceptable salt or a solvate thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 is halogen, substituted or unsubstituted C1-C20 straight-chain or branched-chain or cyclic hydrocarbon group, substituted or unsubstituted C1-C20 straight-chain or branched-chain or cyclic hydrocarbon oxy group, substituted or unsubstituted C1-C20 straight-chain or branched-chain or cyclic hydrocarbon thio group, substituted or unsubstituted 3-20 membered heterocyclic oxy group containing 1-6 hetero atoms selected from oxygen, nitrogen and sulfur, substituted or unsubstituted 3-20 membered heterocyclic thio group containing 1-6 hetero atoms selected from oxygen, nitrogen and sulfur, Wherein the substituted substituent is selected from the group consisting of hydroxy, C1-C20 alkyl, halogen, amino (-NH) 2 ) C1-C20 alkanoylamino, C1-C20 haloalkyl, C1-C20 hydroxyalkyl, C1-C20 alkanoyloxy;
in particular, R 1 Is halogen, substituted or unsubstituted C1-C10 straight or branched alkyl, or cyclic alkyl, substituted or unsubstituted C2-C10 straight or branched alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 straight or branched alkoxy, substituted or unsubstituted C2-C10 straight or branched alkenyloxy, substituted or unsubstituted C3-C10 cycloalkyloxy, substituted or unsubstituted C1-C10 straight or branched alkylthio, substituted or unsubstituted C2-C10 straight or branched alkenylthio, substituted or unsubstituted C3-C10 cycloalkylthio, substituted or unsubstituted 3-20 membered oxygen heterocyclic oxy containing 1, 2, 3 or 4 oxygen atoms, substituted or unsubstituted 3-20 membered oxygen heterocyclic thio containing 1, 2, 3 or 4 oxygen atoms,wherein the substituted substituent is selected from the group consisting of hydroxy, C1-C10 alkyl, halogen, amino (-NH) 2 ) C1-C10 alkanoylamino, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, C1-C10 alkanoyloxy;
more particularly, R 1 Is halogen, substituted or unsubstituted C1-C10 straight-chain or branched alkyl, or cyclic alkyl, substituted or unsubstituted C2-C10 straight-chain or branched alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 straight-chain or branched alkoxy, substituted or unsubstituted C2-C10 straight-chain or branched alkenyloxy, substituted or unsubstituted C3-C10 cycloalkyloxy, substituted or unsubstituted C1-C10 straight-chain or branched alkylthio, substituted or unsubstituted C2-C10 straight-chain or branched alkenylthio, substituted or unsubstituted C3-C10 cycloalkylthio, substituted or unsubstituted C1-or 2 oxygen atom-containing 57-membered oxacycloalkanyloxy, substituted or unsubstituted 5-7-membered oxacycloalkanylthio containing 1 or 2 oxygen atoms,wherein the substituted substituent is selected from the group consisting of hydroxy, C1-C6 alkyl, halogen, amino (-NH) 2 ) C1-C6 alkanoylamino, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkanoyloxy;
R 5 each independently selected from the group consisting of substituted or unsubstituted C1-C20 straight or branched alkyl, substituted or unsubstituted C3-C20 cyclic alkyl, substituted or unsubstituted 3-C20 membered heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted C2-C20 straight or branched alkenyl, said substituted substituents selected from the group consisting of hydroxy, nitro, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, halogen, amino (-NH) 2 ) C1-C10 alkanoylamino, C1-C10 alkanoyloxy, R 6 OC (=O) -, 3-10 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur, 5-20 membered heterospirocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, 5-20 membered heterofused cyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, unsubstituted or substituted with a moiety selected from hydroxy, nitro, amino (-NH) 2 ) Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted C6-C20 aryl, or two adjacent substituents together with the attached ring atom form a 3-10 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur;
in particular, R 5 Each independently selected from the group consisting of substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C3-C10 cyclic alkyl, substituted or unsubstituted 3-10 membered heterocyclyl containing 1-6 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-6 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, substituted or unsubstituted C2-C10 straight or branched chain alkenyl, said substituted substituents selected from the group consisting of hydroxy, nitro, C1-C6 alkyl, C1-C6 alkoxyC1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogen, amino (-NH) 2 ) C1-C6 alkanoylamino, C1-C6 alkanoyloxy, R 6 OC (=O) -, 3-7 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur, 5-10 membered heterospirocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, 5-20 membered heterobicyclic heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, unsubstituted or substituted with a moiety selected from hydroxy, nitro, amino (-NH) 2 ) Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted C6-C10 aryl, or two adjacent substituents together with the attached ring atom form a 5-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from oxygen, nitrogen, sulfur;
more particularly, R 5 Each independently selected from the group consisting of substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C3-C10 cyclic alkyl, substituted or unsubstituted 3-10 membered heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur (e.g.)) Substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted C2-C10 straight or branched alkenyl, said substituted substituents being selected from hydroxy, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogen, amino (-NH) 2 ) C1-C6 alkanoylamino, C1-C6 alkanoyloxy, R 6 OC (=O) -, a 3-7 membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from oxygen, nitrogen, sulfur (e.g.)>) 5-10 membered heterospirocyclic groups containing 1-3 heteroatoms selected from oxygen, nitrogen, sulfur, < ->Unsubstituted or substituted by a member selected from hydroxy, nitro, amino (-NH) 2 ) Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl-substituted C6-C10 aryl, or two adjacent substituents are together with the ring atom to which they are attachedForming a 5-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from oxygen, nitrogen, sulfur;
R 6 is selected from C1-C20 straight-chain or branched alkyl, unsubstituted or substituted by hydroxy, nitro, amino (-NH) 2 ) A 5-to 20-membered heterobicyclic group containing 1 to 6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted by halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl;
in particular, R 6 Is selected from C1-C10 straight-chain or branched alkyl, unsubstituted or substituted by hydroxy, nitro, amino (-NH) 2 ) Substituted by substituents of halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl
R 2 Each independently selected from hydrogen, hydroxy, mercapto, halogen, trifluoromethyl;
or R is 1 、R 2 Together form oxo (=o);
R 3 、R 4 each independently methyl, hydrogen, hydroxy, halogen; preferably, the two are not hydrogen, hydroxyl and halogen at the same time; or (b)
R 2 、R 3 Together with the carbon atom to which it is attached, form a-c=c-double bond;
each a is independently oxygen or absent.
In some embodiments of the present invention, in some embodiments,
R 1 selected from halogen, trifluoromethyl; r is R 2 Selected from trifluoromethyl, hydrogen, hydroxy, mercapto, halogen, and R 1 And R is 2 Different;
R 3 、R 4 each independently is methyl, hydrogen, halogen, and both are not hydrogen, halogen at the same time; or (b)
R 2 、R 3 Together with the carbon atom to which it is attached, form a-c=c-double bond;
a is an oxygen atom or is absent.
In some embodiments of the present invention, in some embodiments,
R 1 selected from substituted C1-C20 straight or branched chains or ringsA linear hydrocarbon group, a substituted C1-C20 linear or branched or cyclic hydrocarbon oxy group, a substituted C1-C20 linear or branched or cyclic hydrocarbon thio group, a substituted 2-tetrahydrofuranyloxy group, a substituted 2-tetrahydropyranyloxy group; the substituted substituent is selected from hydroxy, C1-C20 alkyl, halogen, amino (-NH) 2 ) C1-C20 alkanoylamino, C1-C20 haloalkyl, C1-C20 alkanoyloxy;
R 2 hydrogen or halogen;
R 3 、R 4 each independently is methyl, hydrogen, hydroxy, halogen, and both are not simultaneously hydrogen, hydroxy, halogen;
a is an oxygen atom or is absent.
In some embodiments of the present invention, in some embodiments,
R 1 selected from the group consisting of
R 5 Each independently selected from the group consisting of substituted or unsubstituted C1-C20 straight or branched alkyl, substituted or unsubstituted C3-C20 cyclic alkyl, substituted or unsubstituted 3-C20 membered heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted C2-C20 straight or branched alkenyl, said substituted substituents selected from the group consisting of hydroxy, nitro, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, halogen, amino (-NH) 2 ) C1-C10 alkanoylamino, C1-C10 alkanoyloxy, R 6 OC (=O) -, 3-10 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur, 5-20 membered heterospirocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, 5-20 membered heterofused cyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, unsubstituted or substituted with a moiety selected from hydroxy, nitro, amino (-NH) 2 ) Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted C6-C20 aryl, or two adjacent substituents together with the attached ring atom form a 3-10 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur;
in particular, R 5 Each independently selected from the group consisting of substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C3-C10 cyclic alkyl, substituted or unsubstituted 3-10 membered heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur (e.g.)) Substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted C2-C10 straight or branched alkenyl, said substituted substituents being selected from hydroxy, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogen, amino (-NH) 2 ) C1-C6 alkanoylamino, C1-C6 alkanoyloxy, R 6 OC (=O) -, a 3-7 membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from oxygen, nitrogen, sulfur (e.g.)>) A 5-to 10-membered heterospirocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur,Unsubstituted or substituted by a member selected from hydroxy, nitro, amino (-NH) 2 ) Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted C6-C10 aryl, or two adjacent substituents together with the attached ring atom form a 5-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from oxygen, nitrogen, sulfur;
R 6 is selected from C1-C20 straight-chain or branched alkyl, unsubstituted or substituted by hydroxy, nitro, amino (-NH) 2 ) Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted 5-to 20-membered heterobicyclic ring containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur;
in particular, R 6 Is selected from C1-C10 straight-chain or branched alkyl, unsubstituted or substituted by hydroxy, nitro, amino (-NH) 2 ) Substituted by substituents of halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl
R 2 Selected from hydrogen or halogen;
R 3 、R 4 each independently is methyl, hydrogen, or halogen, and both are not hydrogen, halogen at the same time;
a is selected from oxygen atoms or is absent.
In some embodiments, the compound of formula (I) is selected from compounds of formula (II):
Wherein, the liquid crystal display device comprises a liquid crystal display device,
A 1 is O or S;
R 7 a 3-20 membered heterocyclic group selected from H, a substituted or unsubstituted C3-C20 cyclic alkyl group, a substituted or unsubstituted 3-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted 5-20 membered heteroaryl group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur; the substituted substituent is selected from hydroxy, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, amino (-NH) 2 ) C1-C4 alkanoylamino and C1-C4 alkanoyloxy;
in particular, R 7 A 3-10 membered monocyclic heterocyclic group containing 1-4 hetero atoms selected from the group consisting of H, oxygen, nitrogen and sulfur, a 5-20 membered heterospiro group containing 1-6 hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur, and a 5-20 membered heterobicyclic group containing 1-6 hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur;
more particularly, R 7 Selected from the group consisting of
In some embodiments, the compound of formula (I) is selected from compounds of formula (III):
wherein, the liquid crystal display device comprises a liquid crystal display device,
A 1 is O or S;
R 8 selected from R 6 OC (=o) -, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 cyclic alkyl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted 5-20 membered heteroaryl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur; the substituted substituent is selected from hydroxy, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, amino (-NH) 2 ) C1-C4 alkanoylamino and C1-C4 alkanoyloxy;
in particular, R 8 Selected from R 6 OC (=O) -, unsubstituted or substituted by hydroxy, nitro, amino (-NH) 2 ) Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted phenyl;
R 6 is selected from C1-C10 straight-chain or branched alkyl, unsubstituted or substituted by hydroxy, nitro, amino (-NH) 2 ) Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted 5-to 20-membered heterobicyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur (e.gTherein A, R 2 、R 3 、R 4 The definition of (a) is as described above);
in particular, R 6 Is selected from C1-C4 straight-chain or branched alkyl, unsubstituted or substituted by hydroxy, nitro, amino (-NH) 2 ) Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted 5-to 20-membered heterobicyclic ring containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur;
more particularly, R 6 Selected from methyl group,
In some embodiments, the compound of formula (I) is selected from compounds of formula (IV):
wherein, the liquid crystal display device comprises a liquid crystal display device,
A 1 is O or S;
R 9 selected from the group consisting of substituted or unsubstituted 3-20 membered heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, wherein the substituted substituents are selected from hydroxy, C1-C4 alkyl, halogen, amino (-NH) 2 ) C1-C10 alkanoylamino, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C10 alkanoyloxy;
In particular, R 9 Selected from the group consisting of substituted or unsubstituted 2-tetrahydrofuranyl, substituted or unsubstituted 2-tetrahydropyranyl, substituted or unsubstitutedWherein the substituted substituent is selected from the group consisting of hydroxy, C1-C4 alkyl, halogen, amino (-NH) 2 ) C1-C6 alkanoylamino, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C6 alkanoyloxy.
In some embodiments, the compound of formula (I) is selected from compounds of formula (V):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 10 selected from the group consisting of substituted or unsubstituted C1-C20 straight or branched chain alkyl, substituted or unsubstituted C3-C20 cyclic alkyl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, said substituted substituents being selected from the group consisting of hydroxy, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, amino (-NH) 2 ) C1-C4 alkanoylamino, C1-C4 alkanoyloxy, or two adjacent substituents together with the attached ring atom form a 3-10 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur;
in particular,R 10 Selected from the group consisting of substituted or unsubstituted C1-C10 straight or branched alkyl, substituted or unsubstituted C3-C10 cyclic alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, said substituted substituents being selected from the group consisting of hydroxy, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, amino (-NH) 2 ) C1-C4 alkanoylamino, C1-C4 alkanoyloxy, or two adjacent substituents together with the attached ring atom form a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur.
In some embodiments, the compound of formula (I) is selected from compounds of formula (VI):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 11 selected from the group consisting of substituted or unsubstituted C3-C20 cyclic alkyl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, said substituted substituents being selected from the group consisting of hydroxy, nitro, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, amino (-NH) 2 ) C1-C4 alkanoylamino, C1-C4 alkanoyloxy, or two adjacent substituents together with the attached ring atom form a 3-10 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur;
in particular, R 10 Selected from the group consisting of a substituted or unsubstituted C3-C10 cyclic alkyl group, a substituted or unsubstituted nitrogen-containing 3-10 membered heterocyclic group, said substituted substituent being selected from the group consisting of hydroxy, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, amino (-NH) 2 ) C1-C4 alkanoylamino, C1-C4 alkanoyloxy.
In the present invention,
halogen means fluorine, chlorine, bromine or iodine.
"straight or branched or cyclic hydrocarbyl" includes straight or branched alkyl, straight or branched alkenyl, cycloalkyl, cycloalkenyl.
"alkyl" includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the like.
"alkoxy" refers to a group obtained by attaching oxygen to the terminal of the above alkyl group, for example, methoxy, ethoxy, n-propoxy, sec-butoxy, tert-butyl, n-hexyloxy, and the like.
"haloalkyl" refers to a group obtained by substituting one or more hydrogens on the above alkyl group with halogen, for example, trifluoromethyl and the like.
"hydroxyalkyl" refers to a group obtained by substituting one or more hydrogens on the alkyl group with hydroxyl groups, for example, hydroxymethyl and the like.
"cycloalkyl" refers to a monocyclic or polycyclic saturated alkyl group containing only carbon on the ring and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.
"amino" means-NH 2 。
"alkanoylamino" means an RC (=o) -N group wherein R is alkyl as described above.
"alkanoyloxy" means an RC (=o) -O group wherein R is alkyl as described above.
"aryl" refers to a monocyclic or polycyclic aromatic group containing only carbon in the ring, including, without limitation, phenyl, naphthyl, and the like.
"Heterocyclyl" means a saturated or unsaturated, mono-or polycyclic, non-aromatic group containing heteroatoms selected from oxygen, nitrogen, sulfur on the ring, including, without limitation, aziridinyl, azetidinyl, azepanyl, piperidinyl, oxetanyl, tetrahydrofuranyl, pyranyl, dihydropyranyl, tetrahydropyranyl, dioxolanyl, dioxanyl, piperazinyl, morpholinyl, benzodioxolanyl, Etc., but is not limited thereto.
"heterocyclyl" includes heterospirocyclic, heterofused cyclic, monocyclic heterocyclyl, and the like.
"Heterospirocyclic" means a saturated or unsaturated spirocyclic group containing heteroatoms selected from oxygen, nitrogen, sulfur in the ring, e.g
"Heterocyclyl" means a saturated or unsaturated, fused ring containing heteroatoms selected from oxygen, nitrogen, sulfur in the ring, e.g
"heteroaryl" refers to a monocyclic or polycyclic aromatic group containing heteroatoms selected from oxygen, nitrogen, sulfur in the ring, including, but not limited to, furyl, pyridyl, thienyl, thiazolyl, thiopyranyl, benzofuryl, benzothiazolyl, and the like.
"pharmaceutically acceptable salts" include salts with acids or bases; the acid comprises an inorganic acid and an organic acid; preferably, the inorganic acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid; preferably, the organic acid comprises formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, pamoic acid; the base includes hydroxides, carbonates, bicarbonates, etc. of sodium, potassium, calcium, aluminum, lithium and ammonium.
The compounds and pharmaceutically acceptable salts thereof according to the present application may have isomers or racemates, such as optical isomers (including diastereomers and enantiomers), atropisomers, geometric isomers (cis-trans isomers), conformational isomers, tautomers, and mixtures thereof, and the like, but are not limited thereto. These isomers are also included within the scope of the present application as defined in the claims.
All features or conditions defined in numerical ranges herein are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values within the range, particularly integer values. For example, a range description of "3 to 20" should be taken as having specifically disclosed all sub-ranges such as 3 to 15, 4 to 20, 4 to 15, 4 to 10, 5 to 20, 5 to 15, etc., particularly sub-ranges defined by all integer values, and should be taken as having specifically disclosed individual values such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, etc. within the ranges already disclosed. The foregoing explanation applies to all matters of the application throughout its entirety unless indicated otherwise, whether or not the scope is broad.
If an amount or other numerical value or parameter is expressed as a range, preferred range, or a series of upper and lower limits, then it is understood that any range consisting of any pair of the upper or preferred value for that range and the lower or preferred value for that range, whether or not those ranges are separately disclosed, is specifically disclosed herein.
The above embodiments are only exemplary embodiments of the present invention and are not intended to limit the present invention, the scope of which is defined by the claims. Various modifications and equivalent arrangements of this invention will occur to those skilled in the art, and are intended to be within the spirit and scope of the invention.
In some embodiments, the compound is selected from the group consisting of compounds of the following structures:
in another aspect, the present invention provides a process for the preparation of a compound of formula I, said process being one of the following processes.
The method comprises the following steps:
taking a1 as a raw material, obtaining a fluoro product I-1 in the presence of a fluoro reagent,
therein, A, R 3 And R is 4 As defined above.
The fluoro reagent may be selected from: diethylaminosulfur trifluoride, tetrabutylammonium fluoride, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis tetrafluoroborate, N-fluoro bis benzenesulfonamide, but are not limited thereto.
The second method is as follows:
using a2 as raw material, and acid R 5 C (=O) OH to obtain condensation product I-2,
therein, A, R 3 、R 4 And R is 5 As defined above.
The acid is preferably, but not limited to, biotin, lipoic acid, monomethyl fumarate, maleic acid, ferulic acid, for example.
The condensation reaction may be carried out in the presence of a condensing agent. The condensing agent may be selected from: one or a combination of several of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), 1-Hydroxybenzotriazole (HOBT), or a condensation reagent of similar mechanism in the art may be used.
And a third method:
taking a3 as a raw material, and substituting isocyanate R 5 NCO or substituted isothiocyanate R 5 The NCS is subjected to condensation reaction to obtain a carbamate product or an aminothiocarbamate product I-3,
therein, A, R 3 、R 4 And R is 5 As defined above, A 1 And A 2 Each independently selected from oxygen or sulfur.
The substituted isocyanate or the substituted isothiocyanate is, for example, preferably n-butyl isocyanate, cyclopropyl isocyanate, p-trifluoromethoxyphenyl isocyanate, 1-adamantyl isocyanate, 1-naphthyl isocyanate, 3,4- (methylenedioxy) phenyl isocyanate, but is not limited thereto.
The condensation reaction may be carried out in the presence of a base. The usual bases may be: triethylamine, ammonia water, 4-dimethylaminopyridine, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, N-dimethylaminopyridine or a combination of several or similar mechanism agents.
The method four:
taking a3 as a raw material, and R 9 A 1 H is condensed to obtain an ether product I-4,
therein, A, R 3 、R 4 And R is 9 As defined above, the term "liquid" as used herein refers to,
A 1 selected from the group consisting of oxygen and sulfur,
the condensation reaction may be carried out in the presence of a condensing agent. The condensing agent is boron trifluoride diethyl etherate or a reagent of similar mechanism.
And a fifth method:
by reacting cyclic amine compoundsReaction with triphosgene (triphosgene) gives +.>Then carrying out condensation reaction with a3 to obtain a compound I-5,
therein, A, R 3 And R is 4 As aboveDefined herein, A 1 Selected from oxygen or sulfur.
Cyclic aminesA 3-20 membered, preferably 3-10 membered, mono-or polycyclic cyclic amine compound which may be substituted or unsubstituted, and which may be, for example, a monocycloalkylamine, a procycloamine or a spirocyclic amine, said cyclic amine ++>Optionally further comprising 1-5 heteroatoms selected from oxygen, nitrogen, sulfur. The substituted substituent is selected from hydroxy, nitro, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, halogen, amino (-NH) 2 ) C1-C10 alkanoylamino, C1-C10 alkanoyloxy, R 6 OC (=O) -, 3-10 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur, 5-20 membered heterospirocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, 5-20 membered heterofused cyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, unsubstituted or substituted with a moiety selected from hydroxy, nitro, amino (-NH) 2 ) Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted C6-C20 aryl, or two adjacent substituents together with the attached ring atom form a 3-10 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur; preferably the substituted substituents are selected from hydroxy, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogen, amino (-NH) 2 ) C1-C6 alkanoylamino, C1-C6 alkanoyloxy, R 6 OC (=O) -, a 3-7 membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from oxygen, nitrogen, sulfur (e.g.)>) 5-10 membered heterospirocyclic groups containing 1-3 heteroatoms selected from oxygen, nitrogen, sulfur, < ->Unsubstituted or substituted by a member selected from hydroxy, nitro, amino (-NH) 2 ) Halogen, C1-C4 alkylC1-C4 alkoxy, C1-C4 haloalkyl substituted C6-C10 aryl;
R 6 As defined above.
The condensation reaction may be carried out in the presence of a base. The base commonly used may be triethylamine or a reagent of similar mechanism.
The starting materials used in the present invention are commercially available or prepared according to known synthetic methods for similar compounds.
In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of one or more selected from the compounds according to the invention described above, stereoisomers, pharmaceutically acceptable salts and solvates thereof, and optionally, one or more pharmaceutical excipients.
In another aspect, the invention provides the use of the compound, stereoisomer, pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of an autoimmune disorder.
In another aspect, the present invention provides a method of treating or preventing an autoimmune disease, the method comprising administering to a subject in need thereof an effective amount of one or more selected from the compounds according to the invention described above, stereoisomers, pharmaceutically acceptable salts and solvates thereof, or a pharmaceutical composition described above.
The autoimmune disease may be at least one selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, ankylosing spondylitis, dermatomyositis, scleroderma, pemphigus, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, ulcerative colitis.
Advantageous effects
The compound has the following beneficial effects: novel structure and has the function of obviously resisting autoimmune diseases.
Detailed Description
For a further understanding of the present invention, the present invention is further illustrated below by reference to the following examples, which are described in order to illustrate only the features of the present invention in further detail and are not intended to limit the scope of the invention or the scope of the claims. Simple substitutions and modifications of the invention will occur to those skilled in the art, and are within the scope of the invention as defined by the appended claims.
EXAMPLE 1 Synthesis of Compound I1
200mg of trifluoromethyl substituted artemisinin and 5mL of methylene chloride are added into a 25mL three-necked flask, 184mg of diethylaminosulfur trifluoride (DAST) is added into the reaction solution at the temperature of 0 ℃, and the reaction is carried out for 10 hours after the temperature is raised to 25 ℃. 2mL of water was added to the mixture to separate the layers, and 2mL of saturated brine was added to the organic phase to separate the layers, followed by drying the organic phase over anhydrous sodium sulfate. The organic phase was concentrated by column chromatography (SiO 2 Petroleum ether ethyl acetate=50:1-10:1) to yield 130mg of product I1 as a white solid in 67.3% yield. 1 H NMR(400MHz,DMSO-d 6 ):δ5.83(d,J=2.7Hz,1H),2.75(ddt,J=32.7,13.3,6.0Hz,1H),2.23(ddd,J=14.7,12.9,4.0Hz,1H),2.06(ddd,J=14.7,4.8,2.9Hz,1H),1.87(ddt,J=13.1,6.3,3.4Hz,1H),1.33(s,3H),1.02(dd,J=7.3,1.7Hz,3H),0.91(d,J=6.4Hz,3H).ESI-MS m/z 355.2(M+H) + .
Example 2: synthesis of Compound I2
200mg of dihydroartemisinin, 172mg of biotin, 270mg of EDCI, 43mg of 4-Dimethylaminopyridine (DMAP) and 3mL of Dimethylformamide (DMF) are added to a 10-mL three-necked flask and reacted for 10 hours at 25 ℃. After 3mL of water and 10mL of methylene chloride were added, the layers were separated, 3mL of water was added to the organic phase, 3mL of saturated brine was added to the organic phase to separate the layers, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated by column chromatography (SiO 2 Petroleum ether ethyl acetate=10:1-2:1) to yield 255mg of white solid product I2 in 71.0% yield. 1 H NMR(400MHz,CDCl 3 ):δ5.81(d,J=9.8Hz,1H),5.45(s,1H),5.32(s,1H),4.55(s,1H),4.35(s,1H),3.18(s,1H),2.99–2.90(m,1H),2.82(d,J=12.8Hz,1H),2.62–2.32(m,4H),2.05(ddd,J=14.7,4.9,3.0Hz,1H),1.91(ddt,J=13.4,6.5,3.6Hz,1H),1.45(s,3H),0.98(d,J=5.9Hz,3H),0.86(d,J=7.1Hz,3H).ESI-MS m/z 533.2(M+Na) + .
Example 3: synthesis of Compound I3
The same procedure as in example 2 was followed except that lipoic acid was used instead of biotin, and the yield was 47.0%. 1 H NMR(400MHz,CDCl 3 ):δ5.81(d,J=9.9Hz,1H),5.45(s,1H),3.58(dq,J=8.3,6.4Hz,1H),3.24-3.08(m,2H),2.58(dqd,J=9.8,7.1,4.5Hz,1H),2.52-2.33(m,5H),2.05(ddd,J=14.6,4.9,3.0Hz,1H),1.97-1.88(m,2H),1.45(s,3H),0.98(d,J=6.0Hz,3H),0.86(d,J=7.1Hz,3H).ESI-MS m/z 495.2(M+Na) + .
Example 4: synthesis of Compound I4
The same procedure as in example 2 was followed except that monomethyl fumarate was used in place of biotin, giving a yield of 75.2%. 1 H NMR(400MHz,CDCl 3 ):δ6.89(dd,J=23.5,7.7Hz,2H),5.85(d,J=9.8Hz,1H),5.47(s,1H),3.82(d,J=4.6Hz,3H),2.63(ddt,J=14.4,11.3,5.6Hz,1H),2.38(td,J=14.0,4.0Hz,1H),2.09-2.01(m,1H),1.90(ddt,J=13.7,6.7,3.5Hz,1H),1.76(ddt,J=20.1,13.3,3.5Hz,2H),1.65(dt,J=13.6,4.4Hz,1H),1.58-1.45(m,1H),1.45-1.23(m,6H),1.10-0.99(m,1H),0.97(d,J=5.8Hz,3H),0.86(d,J=7.1Hz,3H).ESI-MS m/z 419.4(M+Na) + .
Example 5: synthesis of Compound I5
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Will be 900mg of dihydroartemisinin, 150mg of maleic acid, 512mg of EDCI, 740mg of HOBT, 80mg of DMAP and 20mL of dichloromethane are added to a 100mL three-necked flask, and the mixture is reacted for 10 hours at 25 ℃. 5mL of 1N hydrochloric acid was added to separate the layers, 5mL of water was added to separate the layers, 5mL of saturated brine was added to separate the layers, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated by column chromatography (SiO 2 Petroleum ether ethyl acetate=10:1-3:1) to give 140mg of product I5 as a white solid in 17.1% yield. 1 H NMR(400MHz,DMSO- d 6):δ6.96(s,2H),5.79(d,J=9.8Hz,2H),5.64(s,2H),2.52(p,J=1.9Hz,2H),2.41(ddd,J=9.7,7.2,4.3Hz,2H),2.21(td,J=14.0,3.9Hz,2H),2.08-1.99(m,2H),1.84(ddt,J=13.7,6.7,3.4Hz,2H),1.30(s,6H),0.91(d,J=6.4Hz,6H),0.84(d,J=7.1Hz,6H).ESI-MS m/z 671.3(M+Na) + .
Example 6: synthesis of Compound I8
200mg of dihydroartemisinin and 2mL of acetonitrile were added to a 10mL three-necked flask, and then 110mg of triethylamine and 77mg of n-butyl isocyanate were added to the reaction solution to react at 25℃for 10 hours. 2mL of 1N hydrochloric acid and 5mL of ethyl acetate were added to separate the layers, 2mL of water was added to separate the layers, 2mL of saturated brine was added to separate the layers, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated by column chromatography (SiO 2 Petroleum ether: acetone=10:1-4:1) to afford 150mg of product I8 as an oil in 53.6% yield. 1 H NMR(400MHz,CDCl 3 ):δ5.71(d,J=9.8Hz,1H),5.45(s,1H),4.92(t,J=5.8Hz,1H),3.19(qd,J=6.9,2.8Hz,2H),2.59–2.48(m,1H),2.38(ddd,J=14.6,13.4,4.0Hz,1H),2.03(ddd,J=14.6,4.9,3.0Hz,1H),1.89(ddt,J=13.6,6.8,3.6Hz,1H),1.44(s,3H),0.97(d,J=6.1Hz,3H),0.93(t,J=7.3Hz,3H),0.88(d,J=7.1Hz,3H).ESI-MS m/z 406.2(M+Na) + .
Example 7: synthesis of Compound I9
The same procedure as in example 6 was followed except that n-butyl isocyanate was replaced with cyclohexyl isocyanate, and the yield was 48.4%. 1 H NMR(400MHz,CDCl 3 ):δ5.71(d,J=9.8Hz,1H),5.46(s,1H),4.79(d,J=7.8Hz,1H),3.51(td,J=14.1,6.9Hz,2H),2.53(ddd,J=10.8,7.1,4.5Hz,1H),2.39(ddd,J=14.6,13.4,4.0Hz,1H),2.04(ddd,J=14.6,4.9,3.0Hz,1H),2.00-1.86(m,3H),1.45(s,3H),0.98(d,J=6.1Hz,3H),0.89(d,J=7.1Hz,3H).ESI-MS m/z 432.3(M+Na) + .
Example 8: synthesis of Compound I10
200mg of piperidine and 5mL of methylene chloride were charged into a 25mL three-necked flask, 231mg of triphosgene (triphosgene) was added to the reaction solution at 0℃and reacted at 25℃for 10 hours, followed by concentrating the dried reaction solution. 670mg of dihydroartemisinin, 730mg of triethylamine and 20mL of methylene chloride were added to the above-mentioned flask and reacted at 25℃for 10 hours. Then 3mL of 1N hydrochloric acid was added to the reaction mixture, and the mixture was allowed to stand for delamination. The organic phase was added with 5mL of saturated sodium chloride and allowed to stand for delamination. After drying the organic phase over anhydrous sodium sulfate, the organic phase was concentrated by column chromatography (SiO 2 Petroleum ether: acetone=30:1-4:1) to yield 350mg of product I10 as white solid in 38.3%. 1 H NMR(400MHz,Chloroform-d)δ5.69(d,J=9.8Hz,1H),5.44(s,1H),3.54-3.43(m,4H),2.66-2.51(m,1H),2.36(ddd,J=14.6,13.4,4.0Hz,1H),2.09-2.00(m,1H),1.88(ddt,J=13.5,6.7,3.7Hz,1H),1.81-1.45(m,12H),1.43(s,3H),1.39-1.19(m,2H),0.95(d,J=6.1Hz,3H),0.86(d,J=7.1Hz,3H).ESI-MS m/z 418.2(M+Na) + .
Example 9: synthesis of Compound I11
The same procedure as in example 8 was followed except that 8-azaspiro [4.5 ]]Decane was used instead of piperidine, yield 26.2%. 1 H NMR(400MHz,Chloroform-d)δ5.69(d,J=9.8Hz,1H),5.44(s,1H),3.55-3.35(m,4H),2.56(dqd,J=14.3,7.1,4.4Hz,1H),2.43-2.31(m,1H),2.02(ddd,J=14.7,4.9,3.0Hz,1H),1.87(ddt,J=13.5,6.6,3.6Hz,1H),1.73(ddq,J=22.1,16.5,3.4Hz,2H),1.61(dq,J=7.2,3.8Hz,5H),1.54-1.19(m,15H),1.01(td,J=13.6,13.1,3.5Hz,1H),0.95(d,J=6.1Hz,3H),0.85(d,J=7.1Hz,3H).ESI-MS m/z 450.22(M+H) + .
Example 10: synthesis of Compound I12
The same procedure as in example 6 was followed except that 1-adamantane isocyanate was used instead of n-butyl isocyanate, and the yield was 16.3%. 1 H NMR(400MHz,Chloroform-d)δ5.65(d,J=9.8Hz,1H),5.41(s,1H),4.76(s,1H),2.49(ddd,J=10.3,7.2,4.4Hz,1H),2.43-2.30(m,1H),2.06(dt,J=5.7,2.9Hz,3H),2.04-1.98(m,1H),1.93(d,J=2.9Hz,6H),1.87(ddd,J=13.5,6.5,3.4Hz,1H),1.80-1.68(m,1H),1.67-1.63(m,6H),1.63-1.45(m,2H),1.43(s,3H),1.35-1.20(m,4H),1.06-0.97(m,1H),0.95(d,J=6.0Hz,3H),0.86(d,J=7.2Hz,3H).ESI-MS m/z 484.1(M+Na) + .
Example 11: synthesis of Compound I14
The same procedure as in example 6 was followed except that 3,4- (methylenedioxy) phenyl isocyanate was used instead of n-butyl isocyanate, to give a yield of 37.9%. 1 H NMR(400MHz,Chloroform-d)δ7.19(s,1H),7.09(s,1H),6.70(t,J=7.7Hz,2H),5.91(s,2H),5.75(d,J=9.8Hz,1H),5.49(s,1H),2.69-2.54(m,1H),2.37(td,J=14.0,3.9Hz,1H),2.02(d,J=14.7Hz,2H),1.96-1.85(m,1H),1.85-1.56(m,3H),1.57-1.17(m,6H),1.05(d,J=14.5Hz,1H),0.96(d,J=5.9Hz,3H),0.93(d,J=7.2Hz,3H).ESI-MS m/z 470.0(M+Na) +
Example 12: synthesis of Compound I15
Step1: 1000mg of dihydroartemisinin, 100mg of 10% palladium on carbon and 20mL of methylene chloride are added to a 50mL three-necked flask, hydrogen is replaced three times, and the reaction is carried out for 10 hours at 40 ℃. The palladium on carbon was filtered through celite and the organic phase was concentrated by column chromatography (SiO 2 Petroleum ether: ethyl acetate=50:1-10:1) to afford 450mg of intermediate 1 in 48.5% yield.
Step2: the same procedure as in example 6 was followed except that cyclohexyl isocyanate was used instead of n-butyl isocyanate, and the yield was 38.3%. 1 H NMR(400MHz,DMSO-d 6 )δ7.15(d,J=7.9Hz,1H),5.49(d,J=8.0Hz,1H),5.33(s,1H),3.31-3.14(m,1H),2.32(td,J=7.4,4.2Hz,1H),1.73(dddd,J=32.1,16.0,7.7,3.7Hz,7H),1.62-1.44(m,2H),1.41(s,3H),1.16(ddt,J=21.6,15.9,12.5Hz,6H),1.02-0.87(m,1H),0.84(dd,J=6.9,3.2Hz,6H).ESI-MS m/z 415.8(M+Na) + .
Example 13: synthesis of Compound I17
100mg of dimethyl dihydroartemisinin and 3mL of methylene chloride are added into a 10mL three-necked flask, 0.1mL of boron trifluoride diethyl etherate solution is slowly added dropwise into the reaction solution at-25 ℃ and the reaction is carried out for 10h at-25 ℃.1mL of a saturated sodium bicarbonate solution was added to separate the layers, and 1mL of a saturated brine was added to separate the layers, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated by column chromatography (SiO 2 Petroleum ether ethyl acetate=500:1-100:1) to afford 50mg of product I17 as a white solid in 52.2% yield. 1 H NMR(400MHz,CDCl 3 )δ5.89(s,1H),5.76(s,1H),5.37(d,J=12.3Hz,1H),4.80(s,1H),4.68(s,1H),2.36(tdd,J=13.6,6.6,3.9Hz,2H),2.02(dt,J=13.4,3.5Hz,3H),1.95-1.71(m,4H),1.55(s,3H),1.45(s,3H),1.43(d,J=5.1Hz,3H),1.39(d,J=3.1Hz,3H),1.02-0.85(m,12H).ESI-MS m/z 596.4(M+NH 4 ) + .
EXAMPLE 14 Synthesis of Compound I18
200mg of mercaptodihydroartemisinin, 194mg of ferulic acid, 176mg of EDCI, 40mg of DMAP and 5mL of DMF are added into a 25mL three-necked flask and reacted for 3h at 25 ℃. 10mL of ethyl acetate and 2mL of 1N hydrochloric acid were added to separate the layers, 5mL of water was added to separate the layers, 5mL of saturated brine was added to separate the layers, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated by column chromatography (SiO 2 Petroleum ether acetone=10:1-2:1) to give 125mg of product I18 as a white solid in 39.3% yield. 1 H NMR(400MHz,CDCl 3 ):δ7.55(d,J=15.7Hz,1H),7.09(dd,J=8.3,1.9Hz,1H),7.02(d,J=1.9Hz,1H),6.92(d,J=8.2Hz,1H),6.56(d,J=15.8Hz,1H),5.53(d,J=11.4Hz,1H),5.43(s,1H),3.94(s,3H),2.73(ddd,J=11.2,7.3,4.0Hz,1H),2.37(td,J=13.9,4.0Hz,1H),2.02(dd,J=14.7,4.5Hz,1H),1.96-1.84(m,1H),1.76(t,J=7.0Hz,1H),1.42(s,3H),0.97(d,J=6.2Hz,3H),0.92(d,J=7.2Hz,3H).ESI-MS m/z 499.2(M+Na)+.
EXAMPLE 15 Synthesis of Compound I19
200mg of mercaptodihydroartemisinin, 220mg of monomethyl fumarate, 412mg of DCC, 80mg of DMAP and 5mL of LDCM were added to a 25mL three-necked flask and reacted at 25℃for 10 hours. 2mL of 1N hydrochloric acid was added to separate the layers, 2mL of water was added to separate the layers, 2mL of saturated brine was added to separate the layers, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated by column chromatography (SiO 2 Petroleum ether acetone=10:1-4:1) to yield 148mg of product I19 as a white solid in 53.8% yield. 1 H NMR(400MHz,CDCl 3 ):δ7.07(d,J=15.7Hz,1H),6.78(d,J=15.7Hz,1H),5.51(d,J=11.5Hz,1H),5.42(s,1H),3.84(s,3H),2.74(ddd,J=11.4,7.3,4.2Hz,1H),2.38(td,J=14.0,4.0Hz,1H),2.19(s,1H),2.04(ddd,J=14.6,4.9,2.9Hz,1H),1.91(ddd,J=13.9,6.8,3.5Hz,1H),1.43(s,3H),,0.99(d,J=6.3Hz,3H),0.91(d,J=7.2Hz,3H).ESI-MS m/z 435.2(M+Na) + .
Example 16: synthesis of Compound I20
200mg of mercaptodihydroartemisinin, 280mg of lipoic acid, 220mg of EDCI, 40mg of DMAP and 5mL of DMF are added into a 25mL three-necked flask and reacted for 10h at 25 ℃. 10mL of ethyl acetate and 2mL of 1N hydrochloric acid were added to separate the layers, 5mL of water was added to separate the layers, 5mL of saturated brine was added to separate the layers, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated by column chromatography (SiO 2 Petroleum ether acetone=10:1-5:1) to give 180mg of product I20 as an oil in 55.2% yield. 1 H NMR(400MHz,CDCl 3 ):δ5.41(s,1H),5.39(s,1H),3.58(p,J=6.5Hz,1H),3.30-3.11(m,3H),2.52-2.33(m,2H),2.19(s,2H),2.14-1.99(m,1H),1.99-1.86(m,2H),1.84-1.66(m,4H),1.43(s,3H),0.98(d,J=6.3Hz,3H),0.89(d,J=7.2Hz,3H).ESI-MS m/z 511.2(M+Na) + .
Pharmacological experiments
1. Purpose of experiment
The study was first conducted by CD4 + Detection of compound pair CD4 by T cell in vitro differentiation system + Inhibitory Activity of T cells towards Th17 differentiation.
2. Experimental method
2.1 CD4 + T cell isolation and in vitro differentiation
Magnetic beads (Invitrogen; 11415D) isolation of CD4 from spleen of 7-8 week C57BL/6 mice + T cells, 6X 10 5 Cells/well were inoculated into 96-well plates, cultured by adding 200. Mu.L of 1640 complete medium containing 10% FBS, 2mM L-glutamine and 50. Mu.M. Beta. -mercaptoethanol, and activated by adding anti-CD 3 (2. Mu.g/ml; BD Pharmingen) and anti-CD 28 (2. Mu.g/ml; BD Pharmingen) antibodies. For Th17 cell differentiation, anti-IL-4 (10. Mu.g/ml) and anti-IFN-gamma (10. Mu.g/ml, B) were added in additionTh17 "cytokine cocktail" including IL-6 (30 ng/ml), TGF-. Beta.1 (3 ng/ml), IL-23 (10 ng/ml), TNF-. Alpha.10 ng/ml, and IL-1β (10 ng/ml) was added in addition to D Bioscience, 551216) antibodies. Different concentrations of compounds were added with cytokines and after 3 days of culture the culture supernatants and cells were collected and evaluated for their effect on differentiation of the various T cell subtypes.
2.2 cell staining and flow analysis
In vitro CD4 + T differentiation test cells were stimulated with PMA (50 ng/ml; sigma-Aldrich), ionomycin (750 ng/ml; sigma-Aldrich) and brefeldin A (5. Mu.g/ml; sigma-Aldrich) for 5 hours at 37 ℃. The cells were resuspended in fixative, fixed in the dark for 30min, and then centrifuged to remove fixative. Cells were resuspended and stained for intracellular IL-17A (BioLegend, 506904, 1:100). The Flow analysis was a BD FACS Verse system and was performed using Flow Jo V10 software. The results are shown in Table 1.
TABLE 1 inhibitory Activity of artemisinin Compounds on Th17
From the data in Table 1 above, it can be seen that the compounds of the examples of the present application, except for I15 and I17, have a significantly reduced IL-17A content with increasing compound concentration, and exhibit a strong Th17 inhibitory activity, with the potential of being developed into anti-MULTIPLE SCLEROSIS drugs.
Claims (10)
1. A compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt or solvate thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
a is oxygen or absent;
R 1 is halogen, substituted or unsubstituted C1-C20 straight-chain or branched or cyclic hydrocarbon group, substituted or unsubstituted C1-C20 straight-chain or cyclic hydrocarbon groupBranched or cyclic hydrocarbyloxy, substituted or unsubstituted C1-C20 straight or branched or cyclic hydrocarbylthio, substituted or unsubstituted 3-20 membered heterocyclyloxy containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted 3-20 membered heterocyclylthio containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, Wherein the substituted substituents are selected from hydroxy, C1-C20 alkyl, halogen, -NH 2 C1-C20 alkanoylamino, C1-C20 haloalkyl, C1-C20 hydroxyalkyl, C1-C20 alkanoyloxy;
R 5 each independently selected from the group consisting of substituted or unsubstituted C1-C20 straight or branched alkyl, substituted or unsubstituted C3-C20 cyclic alkyl, substituted or unsubstituted 3-C20 membered heterocyclyl containing 1-6 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl containing 1-6 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, substituted or unsubstituted C2-C20 straight or branched alkenyl, said substituted substituents selected from the group consisting of hydroxy, nitro, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, halogen, -NH 2 C1-C10 alkanoylamino, C1-C10 alkanoyloxy, R 6 OC (=O) -, a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur, a 5-20 membered heterospiro group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, a 5-20 membered heterobicyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, unsubstituted or substituted with a moiety selected from hydroxy, nitro, -NH 2 Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted C6-C20 aryl, or two adjacent substituents together with the attached ring atom form a 3-10 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur;
R 6 Selected from C1-C20 straight-chain or branched alkyl, unsubstituted or substituted by hydroxy, nitro, -NH 2 Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkaneA 5-20 membered heterobicyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted with substituents of the group;
R 2 selected from hydrogen, hydroxy, mercapto, halogen, trifluoromethyl;
or R is 1 、R 2 Together, constitute = O;
R 3 、R 4 each independently methyl, hydrogen, hydroxy, halogen; or (b)
R 2 、R 3 Together with the carbon atoms to which they are attached form a-c=c-double bond.
2. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein,
R 1 is halogen, substituted or unsubstituted C1-C10 straight or branched alkyl, or cyclic alkyl, substituted or unsubstituted C2-C10 straight or branched alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 straight or branched alkoxy, substituted or unsubstituted C2-C10 straight or branched alkenyloxy, substituted or unsubstituted C3-C10 cycloalkyloxy, substituted or unsubstituted C1-C10 straight or branched alkylthio, substituted or unsubstituted C2-C10 straight or branched alkenylthio, substituted or unsubstituted C3-C10 cycloalkylthio, substituted or unsubstituted 3-20 membered oxygen heterocyclic oxy containing 1, 2, 3 or 4 oxygen atoms, substituted or unsubstituted 3-20 membered oxygen heterocyclic thio containing 1, 2, 3 or 4 oxygen atoms, Wherein the substituted substituents are selected from hydroxy, C1-C10 alkyl, halogen, -NH 2 C1-C10 alkanoylamino, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, C1-C10 alkanoyloxy;
R 5 each independently selected from the group consisting of substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C3-C10 cyclic alkyl, substituted or unsubstituted 3-10 membered heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted containing 1-6A 5-10 membered heteroaryl group selected from the group consisting of oxygen, nitrogen, sulfur heteroatoms, a substituted or unsubstituted C2-C10 straight or branched alkenyl group, said substituted substituent being selected from the group consisting of hydroxy, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogen, -NH 2 C1-C6 alkanoylamino, C1-C6 alkanoyloxy, R 6 OC (=O) -, 3-7 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur, 5-10 membered heterospirocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, 5-20 membered heterobicyclic heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, unsubstituted or substituted with a moiety selected from hydroxy, nitro, -NH 2 Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted C6-C10 aryl, or two adjacent substituents together with the attached ring atom form a 5-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from oxygen, nitrogen, sulfur;
R 6 Selected from C1-C10 straight-chain or branched alkyl, unsubstituted or substituted by hydroxy, nitro, -NH 2 Substituted by substituents of halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl
A is an oxygen atom or is absent.
3. The compound according to claim 2, or a stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein,
R 1 is halogen, substituted or unsubstituted C1-C10 straight-chain or branched alkyl, or cyclic alkyl, substituted or unsubstituted C2-C10 straight-chain or branched alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 straight-chain or branched alkoxy, substituted or unsubstituted C2-C10 straight-chain or branched alkenyloxy, substituted or unsubstituted C3-C10 cycloalkyloxy, substituted or unsubstituted C1-C10 straight-chain or branched alkylthio, substituted or unsubstituted C2-C10 straight-chain or branched alkenylthio, substituted or unsubstituted C3-C10 cycloalkylthio, substituted or unsubstituted 5-to 7-membered oxacycloalkanyloxy containing 1 or 2 oxygen atoms, substitutedOr unsubstituted 5-7 membered oxacycloalkanylthio containing 1 or 2 oxygen atoms,wherein the substituted substituents are selected from hydroxy, C1-C6 alkyl, halogen, -NH 2 C1-C6 alkanoylamino, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkanoyloxy;
R 5 each independently selected from the group consisting of substituted or unsubstituted C1-C10 straight or branched alkyl, substituted or unsubstituted C3-C10 cyclic alkyl, substituted or unsubstituted 3-10 membered heterocyclyl containing 1-6 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-6 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, substituted or unsubstituted C2-C10 straight or branched alkenyl, said substituted substituents selected from the group consisting of hydroxy, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogen, -NH 2 C1-C6 alkanoylamino, C1-C6 alkanoyloxy, R 6 OC (=O) -, a 3-7 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from oxygen, nitrogen and sulfur, a 5-10 membered heterospirocyclic group containing 1-3 heteroatoms selected from oxygen, nitrogen and sulfur,Unsubstituted or substituted by a member selected from hydroxy, nitro, -NH 2 Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted C6-C10 aryl, or two adjacent substituents together with the attached ring atom form a 5-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from oxygen, nitrogen, sulfur;
R 6 Selected from C1-C10 straight-chain or branched alkyl, unsubstituted or substituted by hydroxy, nitro, -NH 2 Substituted by substituents of halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl
A、R 2 、R 3 、R 4 As defined in claim 1.
4. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein,
R 1 selected from halogen, trifluoromethyl; r is R 2 Selected from trifluoromethyl, hydrogen, hydroxy, mercapto, halogen, and R 1 And R is 2 Different;
R 3 、R 4 each independently is methyl, hydrogen, halogen, and both are not hydrogen, halogen at the same time; or (b)
R 2 、R 3 Together with the carbon atom to which it is attached, form a-c=c-double bond;
a is an oxygen atom or is absent;
or alternatively
R 1 Selected from the group consisting of substituted C1-C20 linear or branched or cyclic hydrocarbyl, substituted C1-C20 linear or branched or cyclic hydrocarbyloxy, substituted C1-C20 linear or branched or cyclic hydrocarbylthio, substituted 2-tetrahydrofuranyloxy, substituted 2-tetrahydropyranyloxy; the substituted substituent is selected from hydroxy, C1-C20 alkyl, halogen, -NH 2 C1-C20 alkanoylamino, C1-C20 haloalkyl, C1-C20 alkanoyloxy;
R 2 hydrogen or halogen;
R 3 、R 4 each independently is methyl, hydrogen, hydroxy, halogen, and both are not simultaneously hydrogen, hydroxy, halogen;
A is an oxygen atom or is absent;
or alternatively
R 1 Selected from the group consisting of
R 5 Each independently selected from the group consisting of substituted or unsubstituted C1-C20 straight or branched chain alkyl, substituted or unsubstituted C3-C20 cyclic alkyl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfurA 5-20 membered heteroaryl, a substituted or unsubstituted C2-C20 straight or branched alkenyl, said substituted substituent being selected from the group consisting of hydroxy, nitro, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, halogen, -NH 2 C1-C10 alkanoylamino, C1-C10 alkanoyloxy, R 6 OC (=O) -, a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur, a 5-20 membered heterospiro group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, a 5-20 membered heterobicyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, unsubstituted or substituted with a moiety selected from hydroxy, nitro, -NH 2 Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted C6-C20 aryl, or two adjacent substituents together with the attached ring atom form a 3-10 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur;
In particular, R 5 Each independently selected from the group consisting of substituted or unsubstituted C1-C10 straight or branched alkyl, substituted or unsubstituted C3-C10 cyclic alkyl, substituted or unsubstituted 3-10 membered heterocyclyl containing 1-6 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-6 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, substituted or unsubstituted C2-C10 straight or branched alkenyl, said substituted substituents selected from the group consisting of hydroxy, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogen, -NH 2 C1-C6 alkanoylamino, C1-C6 alkanoyloxy, R 6 OC (=O) -, a 3-7 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from oxygen, nitrogen and sulfur, a 5-10 membered heterospirocyclic group containing 1-3 heteroatoms selected from oxygen, nitrogen and sulfur,Unsubstituted or substituted by a member selected from hydroxy, nitro, -NH 2 Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted C6-C10 aryl, or two adjacent substituents together with the attached ring atom form a 5-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from oxygen, nitrogen, sulfur;
R 6 selected from C1-C20 straight or branched alkyl groups,Unsubstituted or substituted by a member selected from hydroxy, nitro, -NH 2 A 5-to 20-membered heterobicyclic group containing 1 to 6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted by halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl;
in particular, R 6 Selected from C1-C10 straight-chain or branched alkyl, unsubstituted or substituted by hydroxy, nitro, -NH 2 Substituted by substituents of halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl
R 2 Selected from hydrogen or halogen;
R 3 、R 4 each independently is methyl, hydrogen, or halogen, and both are not hydrogen, halogen at the same time;
a is selected from oxygen atoms or is absent.
5. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein,
the compound of formula (I) is selected from the compounds of formula (II):
wherein, the liquid crystal display device comprises a liquid crystal display device,
A 1 is O or S;
R 7 a 3-20 membered heterocyclic group selected from H, a substituted or unsubstituted C3-C20 cyclic alkyl group, a substituted or unsubstituted 3-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted 5-20 membered heteroaryl group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur; the substituted substituent is selected from hydroxy, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, -NH 2 C1-C4 alkanoylamino and C1-C4 alkanoyloxy;
In particular, R 7 3-10 membered unit selected from H, containing 1-4 hetero atoms selected from oxygen, nitrogen and sulfurA cyclic heterocyclyl group, a 5-20 membered heterospirocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, a 5-20 membered heterobicyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur;
more particularly, R 7 Selected from the group consisting of
Or alternatively
The compound of formula (I) is selected from the compounds of formula (III):
wherein, the liquid crystal display device comprises a liquid crystal display device,
A 1 is O or S;
R 8 selected from R 6 OC (=o) -, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 cyclic alkyl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted 5-20 membered heteroaryl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur; the substituted substituent is selected from hydroxy, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, -NH 2 C1-C4 alkanoylamino and C1-C4 alkanoyloxy;
in particular, R 8 Selected from R 6 OC (=O) -, unsubstituted or substituted by hydroxy, nitro, -NH 2 Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted phenyl;
R 6 selected from C1-C10 straight-chain or branched alkyl, unsubstituted or substituted by hydroxy, nitro, -NH 2 Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl substituted 5-to 20-membered heterobicyclic ring containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur;
In particular, R 6 Selected from C1-C4 straight-chain or branched alkyl, unsubstituted or substituted by a group selected from hydroxy, nitro, -NH 2 1-6 hetero-groups selected from oxygen, nitrogen and sulfur, substituted by halogen, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 haloalkyl5-20 membered heterobicyclic group of atoms;
more particularly, R 6 Selected from methyl group,
Or alternatively
The compound of formula (I) is selected from the compounds of formula (IV):
wherein, the liquid crystal display device comprises a liquid crystal display device,
A 1 is O or S;
R 9 selected from substituted or unsubstituted 3-20 membered heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, wherein the substituted substituents are selected from hydroxy, C1-C4 alkyl, halogen, -NH 2 C1-C10 alkanoylamino, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C10 alkanoyloxy;
in particular, R 9 Selected from the group consisting of substituted or unsubstituted 2-tetrahydrofuranyl, substituted or unsubstituted 2-tetrahydropyranyl, substituted or unsubstitutedWherein the substituted substituents are selected from hydroxy, C1-C4 alkyl, halogen, -NH 2 C1-C6 alkanoylamino, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C6 alkanoyloxy.
Or alternatively
The compound of formula (I) is selected from the compounds of formula (V):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 10 selected from the group consisting of substituted or unsubstituted C1-C20 linear or branched alkyl groups, substituted or unsubstituted C3-C20 cyclic alkyl groups, and substituted or unsubstituted C3-C20 cyclic alkyl groups containing 1 to 6 members selected from the group consisting of oxygen, nitrogen, and sulfur 3-20 membered heterocyclyl of heteroatoms, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, said substituted substituents being selected from hydroxy, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, -NH 2 C1-C4 alkanoylamino, C1-C4 alkanoyloxy, or two adjacent substituents together with the attached ring atom form a 3-10 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur;
in particular, R 10 Selected from the group consisting of substituted or unsubstituted C1-C10 straight or branched alkyl, substituted or unsubstituted C3-C10 cyclic alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, said substituted substituents being selected from the group consisting of hydroxy, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, -NH 2 C1-C4 alkanoylamino, C1-C4 alkanoyloxy, or two adjacent substituents together with the attached ring atom form a 3-10 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur;
or alternatively
The compound of formula (I) is selected from the compounds of formula (VI):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 11 selected from the group consisting of substituted or unsubstituted C3-C20 cyclic alkyl, substituted or unsubstituted 3-20 membered heterocyclyl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl containing 1-6 heteroatoms selected from oxygen, nitrogen, sulfur, said substituted substituents being selected from the group consisting of hydroxy, nitro, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, -NH 2 C1-C4 alkanoylamino, C1-C4 alkanoyloxy, or two adjacent substituents together with the attached ring atom form a 3-10 membered monocyclic heterocyclyl containing 1-4 heteroatoms selected from oxygen, nitrogen, sulfur;
in particular, R 10 Selected from the group consisting ofA substituted or unsubstituted C3-C10 cyclic alkyl, a substituted or unsubstituted nitrogen-containing 3-10 membered heterocyclic group, said substituted substituent being selected from the group consisting of hydroxy, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halogen, -NH 2 C1-C4 alkanoylamino, C1-C4 alkanoyloxy.
6. A compound according to any one of claims 1 to 5, or a stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from compounds of the structure:
7. a process for preparing a compound according to any one of claims 1 to 6, which is one of the following processes.
The method comprises the following steps:
taking a1 as a raw material, obtaining a fluoro product I-1 in the presence of a fluoro reagent,
therein, A, R 3 And R is 4 As defined in the corresponding claims;
the second method is as follows:
using a2 as raw material, and acid R 5 C (=O) OH to obtain condensation product I-2,
therein, A, R 3 、R 4 And R is 5 As defined in the corresponding claims;
and a third method:
Taking a3 as a raw material, and substituting isocyanate R 5 NCO or substituted isothiocyanate R 5 The NCS is subjected to condensation reaction to obtain a carbamate product or an aminothiocarbamate product I-3,
therein, A, R 3 、R 4 And R is 5 A as defined in the corresponding claim 1 And A 2 Each independently selected from oxygen or sulfur;
the method four:
taking a3 as a raw material, and R 9 A 1 H is condensed to obtain an ether product I-4,
therein, A, R 3 、R 4 And R is 9 As defined in the accompanying claims and in the claims,
A 1 selected from the group consisting of oxygen and sulfur,
and a fifth method:
by reacting cyclic amine compoundsWith triphosgene to give->Then carrying out condensation reaction with a3 to obtain a compound I-5,
therein, A, R 3 And R is 4 A as defined in the corresponding claim 1 Selected from oxygen or sulfur.
8. A pharmaceutical composition comprising an effective amount of one or more selected from the group consisting of a compound according to any one of claims 1-6, stereoisomers, pharmaceutically acceptable salts and solvates thereof, and optionally, one or more pharmaceutical excipients.
9. Use of a compound according to any one of claims 1-6, a stereoisomer, a pharmaceutically acceptable salt or a solvate thereof, in the manufacture of a medicament for the treatment or prophylaxis of an autoimmune disease.
10. The use according to claim 9, wherein the autoimmune disease is at least one selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, ankylosing spondylitis, dermatomyositis, scleroderma, pemphigus, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, ulcerative colitis.
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