WO2021104470A1 - Anti-hbv 1,7-naphthyridine compound - Google Patents
Anti-hbv 1,7-naphthyridine compound Download PDFInfo
- Publication number
- WO2021104470A1 WO2021104470A1 PCT/CN2020/132344 CN2020132344W WO2021104470A1 WO 2021104470 A1 WO2021104470 A1 WO 2021104470A1 CN 2020132344 W CN2020132344 W CN 2020132344W WO 2021104470 A1 WO2021104470 A1 WO 2021104470A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- group
- alkyl
- Prior art date
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- -1 1,7-naphthyridine compound Chemical class 0.000 title abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 97
- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 229910052731 fluorine Inorganic materials 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 238000002360 preparation method Methods 0.000 claims description 26
- 229910052794 bromium Inorganic materials 0.000 claims description 25
- 229910052801 chlorine Inorganic materials 0.000 claims description 25
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 24
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 22
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 20
- 229910052740 iodine Inorganic materials 0.000 claims description 19
- 241000700721 Hepatitis B virus Species 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000004429 atom Chemical group 0.000 claims description 15
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 108091036055 CccDNA Proteins 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 239000012071 phase Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000460 chlorine Substances 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- 125000001424 substituent group Chemical group 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 208000002672 hepatitis B Diseases 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 0 C*C1C=*CC1 Chemical compound C*C1C=*CC1 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 125000004404 heteroalkyl group Chemical group 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000005647 linker group Chemical group 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000004020 luminiscence type Methods 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000011002 quantification Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- CFJJZVMYMPQIRD-UHFFFAOYSA-N 3-bromoquinolin-7-ol Chemical group C1=C(Br)C=NC2=CC(O)=CC=C21 CFJJZVMYMPQIRD-UHFFFAOYSA-N 0.000 description 3
- YLDFTMJPQJXGSS-UHFFFAOYSA-N 6-bromo-2-naphthol Chemical compound C1=C(Br)C=CC2=CC(O)=CC=C21 YLDFTMJPQJXGSS-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 102000014150 Interferons Human genes 0.000 description 3
- 108010050904 Interferons Proteins 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
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- 125000003277 amino group Chemical group 0.000 description 3
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 238000012552 review Methods 0.000 description 1
- 210000003752 saphenous vein Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
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- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to the field of medicine, in particular to a new class of anti-HBV 1,7-naphthyridine compounds or pharmaceutically acceptable salts thereof, a preparation method thereof, and application thereof in the preparation of drugs for treating hepatitis B.
- hepatitis B virus hepatitis B virus
- HBv hepatitis B virus
- Hepatitis B virus is the pathogen that causes hepatitis B (hepatitis B for short) and belongs to the family of hepatotropic DNA viruses. After HBV adheres to the surface of liver cells, it enters the cell through viral endocytosis mediated by sodium ion-taurocholic acid transporter polypeptide (NTCP), releases the capsid in the cytoplasm, and enters the nucleus and transforms into a covalently closed loop DNA (cccDNA). All subgenomic RNA (sgRNA) and pregenomic RNA (pgRNA) are formed by cccDNA transcription.
- sgRNA subgenomic RNA
- pgRNA pregenomic RNA
- sgRNA After exiting the nucleus, sgRNA is translated into X protein and three other envelope proteins, and pgRNA is translated into core protein and viral polymerase. pgRNA and core protein self-assemble under the action of polymerase to form RNA that wraps the nucleocapsid. In the nucleocapsid, pgRNA is reverse-transcribed into negative-strand DNA, and the positive strand of DNA is further synthesized from this to form rcDNA.
- the rcDNA wrapped by nucleocapsid re-uncoated into the nucleus to further amplify the cccDNA; on the other hand, it recombines with the envelope protein and releases the cell through the endoplasmic reticulum to form a new HBV.
- cccDNA has a high degree of stability and is a template for HBV to replicate continuously. It exists in the form of minichromosomes in the nucleus of the host liver cell, and it is difficult to completely remove it with current treatment methods. This is also the main reason why hepatitis B is difficult to cure at present.
- nucleoside (acid) compounds and interferons. Nucleoside (acid) drugs, such as lamivudine, entecavir, tenofovir (ester), etc., can effectively inhibit HBV DNA replication, but these drugs cannot eliminate cccDNA, and the disease often rebounds after stopping the drug.
- Interferon drugs can partially activate the patient's immune system and inhibit hepatitis B virus through the body's autoimmune effect.
- these drugs have relatively large side effects and are not well tolerated by patients. What is more serious is the response rate of different populations to interferon therapy. Significant differences, but overall the response rate is low (usually less than 30%) (Nat. Rev. Gastro. Hepat. 8 (2011), 275-284).
- Existing clinical treatment programs have a low functional cure rate, and there is still a large unmet clinical need for hepatitis B treatment.
- the present invention provides a compound represented by formula (I') or a pharmaceutically acceptable salt thereof,
- R 1 is selected H, F, and C 1 ⁇ 3 alkyl group, the optionally substituted with 1, 2 or 3 R a;
- R 2 is selected from H, F, Cl, Br and CF 3 ;
- R 3 , R 4 , R 5 and R 6 are each independently selected from H, F, Cl, Br, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3 ⁇ 6-membered heterocycloalkyl, the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally selected by 1, 2, or 3 R b is substituted;
- L is selected from -O-, -S-, -SO 2 -, -N(R 7 )- and -C(R 7 ) 2 -;
- L 1 is selected from -C(R 7 ) 2 -;
- L 2 is selected from -C(R 7 ) 2 -;
- R 7 is each independently selected from H, F, Cl, Br, I, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, so The C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 heteroalkyl group and 3-6 membered heterocycloalkyl group are optionally substituted with 1, 2 or 3 R c ;
- T, T 1 , T 2 , and T 3 are independently selected from CR 8 and N;
- R 8 is selected from H, F, Cl, Br, I, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R d ;
- n is selected from 1, 2, 3 and 4;
- R 9 is each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl groups, the C 1-3 alkyl groups are optionally substituted with 1, 2 or 3 R e ;
- R a, R b, R c , R d and R e are each independently selected from F, Cl, Br, I, OH, CN, NH 2, COOH, CF 3, -CHF 2, -CH 2 F, -OCH 3 , CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -NHCH 3 , -N(CH 3 ) 2 and cyclopropyl;
- the C 1-6 heteroalkyl group and 3-6 membered heterocycloalkane each independently include 1, 2, 3, or 4 atoms or heteroatom groups independently selected from O, N, S, and NH.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- R 1 is selected H, F, and C 1 ⁇ 3 alkyl group, the optionally substituted with 1, 2 or 3 R a;
- R 2 is selected from H, F, Cl, Br and CF 3 ;
- R 3 , R 4 , R 5 and R 6 are each independently selected from H, F, Cl, Br, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3 ⁇ 6-membered heterocycloalkyl, the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally selected by 1, 2, or 3 R b is substituted;
- L is selected from -O-, -S-, -SO 2 -, -N(R 7 )- and -C(R 7 ) 2 -;
- L 1 is selected from -C(R 7 ) 2 -;
- L 2 is selected from -C(R 7 ) 2 -;
- R 7 is each independently selected from H, F, Cl, Br, I, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, so The C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 heteroalkyl group and 3-6 membered heterocycloalkyl group are optionally substituted with 1, 2 or 3 R c ;
- T, T 1 , T 2 , and T 3 are independently selected from CR 8 and N;
- R 8 is selected from H, F, Cl, Br, I, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R d ;
- n is selected from 1, 2, 3 and 4;
- R 9 is each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl groups, the C 1-3 alkyl groups are optionally substituted with 1, 2 or 3 R e ;
- R a, R b, R c , R d and R e are each independently selected from F, Cl, Br, I, OH, CN, NH 2, COOH, CF 3, -CHF 2, -CH 2 F, -OCH 3 , CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -NHCH 3 , -N(CH 3 ) 2 and cyclopropyl;
- the C 1-6 heteroalkyl group and 3-6 membered heterocycloalkane each independently include 1, 2, 3, or 4 atoms or heteroatom groups independently selected from O, N, S, and NH.
- R 1 is selected from H, F and CH 3, said optionally substituted with 1, 2 or 3 R a.
- R 1 is selected from H and CH 3 .
- R 1 is selected from H.
- R 2 is selected from Cl.
- R 3 , R 4 , R 5 and R 6 are each independently selected from H.
- R 7 is selected from H, F, Cl, Br, I, -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl, the -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl are optionally substituted with 1, 2 or 3 R c .
- the above-mentioned R 7 is selected from H, F, Cl, Br, I, CF 3 , -CHF 2 , -CH 2 F, -OCH 3 , CH 3 , -CH 2 CH 3 , -CH (CH 3 ) 2 , -NHCH 3 , -N(CH 3 ) 2 and cyclopropyl.
- the aforementioned L is selected from -O-, -S-, -SO 2 -, -NH- and -CH 2 -.
- the above-mentioned L is selected from -O-.
- the aforementioned L 1 is selected from -CH 2 -, -CHF- and -CF 2 -.
- the aforementioned L 2 is selected from -CH 2 -, -CHF- and -CF 2 -.
- the above-mentioned R 8 is selected from H, F, Cl, Br, I, -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl, the -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl are optionally substituted with 1, 2 or 3 Rd .
- R 8 is selected from H.
- R 9 is independently selected from H.
- the above-mentioned compound is selected from
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , T, T 1 , T 2 , T 3 , L 1 , L 2 and m are as defined in the present invention.
- the above-mentioned compound is selected from
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are as defined in the present invention.
- the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof, and the compound is selected from
- the present invention also provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating hepatitis B virus.
- the present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt in the preparation of a medicine for inhibiting the activity of cccDNA.
- the compound of the present invention exhibits significant cccDNA inhibitory activity on HepDES19 cell lines, and exhibits low clearance and high plasma exposure in mouse pharmacokinetic studies.
- the compounds of the present invention can be used for diseases caused by HVB infection, such as the treatment of hepatitis B.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
- a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
- the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid.
- Certain specific compounds of the present invention contain basic and acidic functional groups
- the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods.
- such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
- enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
- cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
- diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror-image relationship.
- wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key And straight dashed key
- the term “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refers to one of the isomers or pairs of
- the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
- the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
- optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide pure The desired enantiomer.
- the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
- the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
- the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
- deuterium can be substituted for hydrogen to form deuterated drugs.
- the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
- deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
- substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
- Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
- any variable such as R
- its definition in each case is independent.
- the group can optionally be substituted with up to two Rs, and R has independent options in each case.
- combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond, and -C 0 alkyl-A means that the structure is actually -A.
- the substituent can be bonded with any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. .
- substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
- a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
- the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
- Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
- any one or more sites of the group can be connected to other groups through chemical bonds.
- the chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Said.
- the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
- the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
- the wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms.
- the number of atoms in a ring is generally defined as the number of ring members.
- “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
- C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
- the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
- C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
- C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
- Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- heteroalkyl by itself or in combination with another term means a stable linear or branched alkyl group or combination thereof composed of a certain number of carbon atoms and at least one heteroatom or heteroatom group.
- the heteroatoms are selected from B, O, N, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized.
- the heteroalkyl is a C 1-6 heteroalkyl; In other embodiments, the heteroalkyl is a heteroalkyl C 1- 3.
- heteroatom or heteroatom group can be located in any internal position of the heteroalkyl group, including the position of attachment of the alkyl group to the rest of the molecule.
- alkoxy "alkylamino” and “alkylthio” (or thioalkoxy) are customary expressions and refer to those connected to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively.
- Alkyl group is customary expressions and refer to those connected to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively.
- Up to two heteroatoms can be continuous
- C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
- Examples of C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms.
- a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
- the 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group.
- Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazo
- C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, where n and m are natural numbers, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, such as C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.
- n-membered to n+m-membered means that the number of atoms in the ring is from n to n+m.
- a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, and a 7-membered ring.
- 3-12 membered ring includes 3-6 membered ring, 3- 9-membered ring, 5-6 membered ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, 6-10 membered ring, etc.; in particular, C 0 represents not present.
- leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction).
- representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as methanesulfonate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
- protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
- Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldi
- hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
- Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
- alkyl groups such as methyl, ethyl, and tert-butyl
- acyl groups such as alkanoyl groups (such as acetyl)
- arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
- the solvent used in the present invention is commercially available.
- DMF stands for N,N-dimethylformamide
- Na 2 CO 3 stands for sodium carbonate
- K 2 CO 3 stands for potassium carbonate
- EtOAc stands for ethyl acetate
- THF stands for tetrahydrofuran
- MeOH stands for methanol
- DCM stands for dichloromethane
- DMSO stands for dimethyl sulfoxide
- EtOH stands for ethanol
- CH 3 CN stands for acetonitrile
- TFA stands for trifluoroacetic acid
- DIPEA stands for N,N-diisopropylethylamine
- Tf stands for trifluoromethanesulfonate
- Pd(PPh 2 )Cl 2 stands for bistriphenylphosphorus palladium dichloride
- CO 2 stands for carbon dioxide
- LCMS stands for liquid chromatography mass spectrometry
- MS stands for mass spectrometry
- HPLC stands for liquid chromatography
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the field.
- SXRD single crystal X-ray diffraction
- the cultured single crystal is collected with the Bruker D8 venture diffractometer to collect the diffraction intensity data
- the light source is CuK ⁇ radiation
- the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration
- the present invention will be described in detail through the following examples, but it is not meant to impose any disadvantageous restriction on the present invention.
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.
- Step B Dissolve A-2 (1.75 g, 10.79 mmol) in N,N-dimethylformamide (40 mL), cool the solution to 0 degrees Celsius, and add oxalyl chloride (1.78 g, 14.03 mmol) .
- the reaction mixture was naturally heated to 25 degrees Celsius, and after stirring for 1 hour, methanol (5 mL) and water (50 mL) were added, and the mixture was extracted with 90 mL of ethyl acetate (30 mL/time, 3 times).
- the combined organic phase was dried over anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure to obtain A-3.
- Step C Add A-3 (3 g, 16.61 mmol), pyridine (6.57 g, 83.06 mmol), and N,N-diisopropylethylamine (4.72 g, 36.55 mmol) to dichloromethane in sequence (250 ml), after cooling to 0 degrees Celsius, add trifluoroacetic anhydride (37.50 g, 132.90 mmol). After the reaction mixture was naturally heated to 25 degrees Celsius, it was stirred for 3 hours. Then water (200 ml) was added, and extraction was performed with 600 ml of dichloromethane (200 ml/time, 3 times of extraction).
- 1 H NMR 400 MHz, CDCl 3
- Step B To a solution of ethyl (cis)-3-hydroxycyclobutyrate (B-3, 5 g, 34.68 mmol) in toluene (150 ml) was added N, N-diisopropylethylamine (8.96 g , 69.36 mmol) and B-2 (17.83 g, 69.36 mmol). The reaction mixture was stirred at 90 degrees Celsius for 12 hours. Then water (300 mL) and ethyl acetate (100 mL) were added to extract and separate the layers. The organic phase was washed once with 100 ml of saturated brine, and then dried over anhydrous sodium sulfate.
- the preparation of Intermediate E refers to the preparation process of Intermediate B, and the compound (cis)-3-hydroxycyclobutyric acid ethyl ester (B-3) in step B is replaced with 3-hydroxybicyclo[1.1.1]pentane- Methyl 1-carboxylate (E-1).
- the preparation of intermediate E refers to the preparation process of intermediate B, and the compound (cis)-3-hydroxycyclobutyric acid ethyl ester (B-3) in step B is replaced with 3-hydroxy-1-methylcyclobutyl ester ( F-1).
- Step A Dissolve 1-1 (200 mg, 896.60 ⁇ mol) and Intermediate B (247.67 mg, 986.26 ⁇ mol) in acetonitrile (3 mL), then add potassium carbonate (185.87 mg, 1.34 mmol) and potassium iodide (14.88 mg, 89.66 micromolar). Under the protection of nitrogen, the reaction mixture was stirred at 85 degrees Celsius for 12 hours. Then water (20 mL) was added, and extraction was performed with 40 mL ethyl acetate (20 mL/time, extraction twice). The organic phase was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product 1-2, which was directly used in the next reaction.
- Step B Dissolve 1-2 (280 mg, crude product, 711.98 micromolar) and bipartanol borate (216.96 mg, 854.37 micromolar) in anhydrous dioxane (5 mL), and then add Potassium acetate (139.75 mg, 1.42 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (51.10 mg, 71.2 micromoles). Under the protection of nitrogen, the reaction mixture was stirred at 100°C for 12 hours. Then water (20 mL) was added, and extraction was performed with 40 mL ethyl acetate (20 mL/time, extraction twice).
- Step C Dissolve 1-3 (60 mg, 136.26 micromoles) and Intermediate A (42.6 mg, 136.26 micromoles) in anhydrous tetrahydrofuran (6 mL) and water (1 mL), then add sodium carbonate (28.88) Mg, 272.52 micromoles) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (11.13 mg, 13.63 micromoles). Under the protection of nitrogen, the reaction mixture was stirred at 75 degrees Celsius for 3 hours. Then water (30 mL) was added, and extraction was performed with 40 mL of ethyl acetate (20 mL/time, extraction twice).
- Step D Add 1-4 (20 mg, 41.93 micromoles) to a mixed solvent of water (1 mL), methanol (1 mL) and tetrahydrofuran (1 mL), and then add lithium hydroxide monohydrate (4.4 mg, 104.83 micromolar). The reaction mixture was stirred at 25 degrees Celsius for 2 hours. After adjusting the pH to about 3 with hydrochloric acid (1 mol/L, 10 mL), it was concentrated under reduced pressure.
- the preparation of compound 3 refers to the preparation process of compound 1, replacing intermediate B in step A with intermediate D. Separation and purification by preparative HPLC (column: Shim-pack C18 150 ⁇ 25mm ⁇ 10 ⁇ m; mobile phase: phase A: 0.225% aqueous formic acid; phase B: acetonitrile; elution gradient: 48% to 68%; 10 minutes) to obtain compound 3 .
- the preparation of compound 4 refers to the preparation process of compound 1, replacing intermediate B in step A with intermediate E.
- preparative HPLC column: Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; mobile phase: phase A: 0.05% ammonia solution; phase B: acetonitrile; elution gradient: 5% to 35%; 10 minutes) to obtain compound 4.
- Step A Preparation of Intermediate 7-5 Referring to the preparation process of Compound 1, the compound 6-bromo-2-naphthol (1-1) in Step A is replaced with 3-bromo-7-hydroxyquinoline (5- 1) Replace Intermediate B with Intermediate F.
- the crude compound 7 was purified by high performance liquid chromatography (column: Unisil 3-100C18, 150 ⁇ 50mm ⁇ 3 ⁇ m; mobile phase: phase A: 0.225% aqueous formic acid, phase B: acetonitrile; elution gradient: 30%-50% , 10 minutes) to obtain compound 7.
- the HepDES19 cell line contains a 1.1-unit-length HBV genome, and the transcription of pgRNA is controlled by tetracycline. In the absence of tetracycline, the transcription of pgRNA is induced, but because the very short leader sequence before the HBeAg start codon interferes with the promoter, pgRNA cannot produce HBV e antigen (HBeAg). Only after the formation of cccDNA, the missing leader sequence and promoter mutation can be restored, and then HBeAg can be synthesized. Therefore, HBeAg can be used as a surrogate marker for cccDNA.
- the HBeAg content of HepDES19 cell culture supernatant was detected by enzyme-linked immunosorbent assay (ELISA) to evaluate the compound's inhibitory effect on HBV.
- ELISA enzyme-linked immunosorbent assay
- DMEM/F12 medium source: Gibco Cat.11330057
- 10% fetal bovine serum Fetal Bovine Serum, FBS, source: Clontech
- 100unis/mL 100 ⁇ g/mL penicillin/streptomycin (Penicillin/streptomycin)
- Source: Hyclone 2mM GlutaMAX (source: Gibco), 1% non-essential amino acid solution (MEM NEAA, source: Gibco), 0.1mM aminoglycoside antibiotic (Geneticin, source: Gibco), 1 ⁇ g/mL tetracycline hydrochloride (Tetracycline) Hydrochloride, source: Sigma), subcultured and expanded according to the ratio of 1/3, then planted HepDES19 into a T150 culture flask at a cell density of 4 ⁇ 10 6 cells, replaced with a tetracycline-free medium and cultured for 8 days, and finally The cells were collected and cryopreserved in liquid nitrogen (1 ⁇ 10 7
- HepDES19 cells Resuscitate HepDES19 cells, plant HepDES19 cells in a 96-well plate (6 ⁇ 10 4 cells/well), and incubate overnight at 37 degrees Celsius and 5% CO 2.
- the compound was diluted to a total of 8 concentrations in 3-fold serial dilutions. Compounds of different concentrations were added to the culture wells, and the wells were duplicated. The final concentration of DMSO in the culture broth is 0.5%.
- the culture medium in the culture well was collected, and the content of hepatitis B virus HBeAg was determined by ELISA. After aspirating the culture medium in the culture wells, add Celltiter-Glo reagent to each well of the 96-well plate, and the microplate reader detects the chemiluminescence value of each well to detect cell viability.
- ELISA measures the content of hepatitis B virus HBeAg.
- the specific steps refer to the product manual. The steps are briefly described as follows: Take 50 microliters of sample and standard substance into the reaction plate, and then add 50 microliters of enzyme conjugate to each well, shake and mix. Incubate at 37 degrees Celsius for 60 minutes, then wash the plate with washing solution 6 times, then add 50 microliters of luminescent substrate to each well, mix well, and react for 10 minutes in the dark at room temperature. Finally, check the chemiluminescence intensity with a microplate reader.
- %Inh. (1-HBeAg value in sample/DMSO control HBeAg value) ⁇ 100.
- % Cell viability (sample luminescence value-medium control luminescence value) / (DMSO control luminescence value-medium control luminescence value) ⁇ 100%.
- the compound of the present invention has good anti-HBV activity in vitro.
- This experiment aims to evaluate the pharmacokinetic behavior of the compound after a single intravenous injection or oral gavage in mice.
- the compound is formulated as a clear solution of 0.2 mg/mL, and the vehicle: 5% DMSO/5% dodecyl hydroxystearate (solutol)/90% water; orally administered by gavage, the compound is formulated as 0.3 mg /mL suspension, solvent: 0.5% sodium carboxymethyl cellulose/0.2% Tween 80/99.3% water.
- the sample collection schedule is as follows:
- the concentration of the compound in plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS).
- the retention time of the compound and the internal standard (diclofenac), the collection of chromatograms, and the integration of the chromatograms are processed by the software Analyst (Applied Biosystems), and the data statistics are processed by the software Watson LIMS (Thermo Fisher Scientific) or Analyst (Applied Biosystems).
- the unit of the analyte concentration in the sample is ng/mL, with 3 significant digits reserved, and all values expressed in percentage (such as% deviation and% coefficient of variation, etc.) are kept to one decimal place.
- Each calibration curve contains at least 6 concentration levels.
- the preparation of calibration standards requires stock solutions from different sources from the quality control samples.
- the standard sample should be rejected in the regression analysis.
- the rejected calibration standards should be less than 25%, and each calibration curve contains at least 6 calibration standards that meet the acceptance criteria. If the lower limit of quantification and upper limit of quantification need to be rejected, the upper and lower limit of quantification of the analysis batch will be increased and lowered accordingly.
- the non-compartmental model of WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process the plasma concentration, and the linear logarithmic ladder method was used to calculate the pharmacokinetic parameters.
- the pharmacokinetic parameters to be calculated include but are not limited to (data permitted) T 1/2 , Vd ss , CL, AUC 0-24h in the intravenous administration (iv) group; oral administration (po) group C max , T max , AUC 0-24h , bioavailability (F%).
- mice The pharmacokinetic parameters of the examples of the present invention in mice are shown in Table 2 below.
- the compound of the present invention exhibits a lower clearance rate and a higher plasma exposure of the drug, and has good pharmacokinetic properties.
Abstract
Provided is a 1,7-naphthyridine compound, and specifically disclosed are a compound as shown in formula (I') and a pharmaceutically acceptable salt thereof.
Description
本申请主张如下优先权：This application claims the following priority:
CN201911201259.1，申请日2019年11月29日。CN201911201259.1, application date November 29, 2019.
本发明涉及药物领域，具体涉及一类新的抗HBV的1,7-萘啶类化合物或其药学上可接受的盐、其制备方法以及其在制备治疗乙型肝炎药物中的应用。The present invention relates to the field of medicine, in particular to a new class of anti-HBV 1,7-naphthyridine compounds or pharmaceutically acceptable salts thereof, a preparation method thereof, and application thereof in the preparation of drugs for treating hepatitis B.
世界卫生组织估计，全球乙型肝炎病毒(HBv)感染估计2.57亿人，导致每年约有65万人死亡(Nature Reviews Drug Discovery，18(2019)，827-844)。中国是乙肝大国，感染人口七千多万。长期感染HBV可导致肝衰竭、肝硬化和肝癌等恶性疾病。(World Health Organization,Hepatitis B:World Health Organization Fact Sheet(2016).)The World Health Organization estimates that hepatitis B virus (HBv) infects an estimated 257 million people worldwide, resulting in approximately 650,000 deaths each year (Nature Reviews Drug Discovery, 18 (2019), 827-844). China is a big country with hepatitis B, with more than 70 million infected people. Long-term infection with HBV can lead to malignant diseases such as liver failure, cirrhosis and liver cancer. (World Health Organization, Hepatitis B: World Health Organization Fact Sheet (2016).)
乙型肝炎病毒(hepatitis B virus,HBV)是引起乙型肝炎(简称乙肝)的病原体，属嗜肝DNA病毒科。HBV黏附到肝细胞表面后，通过钠离子-牛磺胆酸供转运多肽(NTCP)介导的病毒内吞作用进入细胞，在细胞质中将衣壳释放，rcDNA进入细胞核转化成共价闭合环状DNA(cccDNA)。所有次基因组的RNA(sgRNA)和前基因组的RNA(pgRNA)均由cccDNA转录形成。出细胞核后，sgRNA翻译成X蛋白和其他三个包膜蛋白，pgRNA翻译成核心蛋白和病毒聚合酶。pgRNA与核心蛋白在聚合酶的作用下发生自组装，形成包裹了核衣壳的RNA。在核衣壳内，pgRNA逆转录成负链的DNA，并由此进一步合成出DNA正链，形成rcDNA。核衣壳包裹的rcDNA一方面重新脱壳进入细胞核，进一步使cccDNA扩增；另一方面重新与包膜蛋白结合，通过内质网释放出细胞，形成新的HBV。Hepatitis B virus (HBV) is the pathogen that causes hepatitis B (hepatitis B for short) and belongs to the family of hepatotropic DNA viruses. After HBV adheres to the surface of liver cells, it enters the cell through viral endocytosis mediated by sodium ion-taurocholic acid transporter polypeptide (NTCP), releases the capsid in the cytoplasm, and enters the nucleus and transforms into a covalently closed loop DNA (cccDNA). All subgenomic RNA (sgRNA) and pregenomic RNA (pgRNA) are formed by cccDNA transcription. After exiting the nucleus, sgRNA is translated into X protein and three other envelope proteins, and pgRNA is translated into core protein and viral polymerase. pgRNA and core protein self-assemble under the action of polymerase to form RNA that wraps the nucleocapsid. In the nucleocapsid, pgRNA is reverse-transcribed into negative-strand DNA, and the positive strand of DNA is further synthesized from this to form rcDNA. On the one hand, the rcDNA wrapped by nucleocapsid re-uncoated into the nucleus to further amplify the cccDNA; on the other hand, it recombines with the envelope protein and releases the cell through the endoplasmic reticulum to form a new HBV.
在HBV的复制循环中，cccDNA有高度的稳定性，是HBV不断复制的模板。其在宿主肝细胞核内以微染色体的形式存在，目前的治疗手段难以将其彻底清除，这也是目前乙肝难以治愈的主要原因。目前被许可用于治疗慢性乙肝的常规药物只有核苷(酸)类化合物和干扰素两类。核苷(酸)类药物，如拉米夫定、恩替卡韦、替诺福韦(酯)等，能有效地抑制HBV DNA复制，但这类药物并不能清除cccDNA，停药后往往出现病情反弹。患者需长期用药，部分患者容易出现耐药现象。干扰素类药物能部分激活病人的免疫***，通过人体自身免疫作用抑制乙肝病毒，但这类药物副作用较大，患者耐受性不足，更为严重的是不同人群对干扰素治疗的应答率存在显著差异，但总体上看应答率较低(通常低于30％)(Nat.Rev.Gastro.Hepat.8(2011)，275-284)。现有的临床治疗方案功能性治愈率低，乙肝治疗仍然有很大未满足的临床需求。In the replication cycle of HBV, cccDNA has a high degree of stability and is a template for HBV to replicate continuously. It exists in the form of minichromosomes in the nucleus of the host liver cell, and it is difficult to completely remove it with current treatment methods. This is also the main reason why hepatitis B is difficult to cure at present. Currently, the only conventional drugs approved for the treatment of chronic hepatitis B are nucleoside (acid) compounds and interferons. Nucleoside (acid) drugs, such as lamivudine, entecavir, tenofovir (ester), etc., can effectively inhibit HBV DNA replication, but these drugs cannot eliminate cccDNA, and the disease often rebounds after stopping the drug. Patients need long-term medication, and some patients are prone to drug resistance. Interferon drugs can partially activate the patient's immune system and inhibit hepatitis B virus through the body's autoimmune effect. However, these drugs have relatively large side effects and are not well tolerated by patients. What is more serious is the response rate of different populations to interferon therapy. Significant differences, but overall the response rate is low (usually less than 30%) (Nat. Rev. Gastro. Hepat. 8 (2011), 275-284). Existing clinical treatment programs have a low functional cure rate, and there is still a large unmet clinical need for hepatitis B treatment.
发明内容Summary of the invention
本发明提供式(I’)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I') or a pharmaceutically acceptable salt thereof,
其中，among them,
E选自
E is selected from
R
1选自H、F和C
1～3烷基，所述任选被1、2或3个R
a取代；
R 1 is selected H, F, and C 1 ~ 3 alkyl group, the optionally substituted with 1, 2 or 3 R a;
R
2选自H、F、Cl、Br和CF
3；
R 2 is selected from H, F, Cl, Br and CF 3 ;
R
3、R
4、R
5和R
6分别独立地选自H、F、Cl、Br、CN、C
1～6烷基、C
3～6环烷基、C
1～6杂烷基和3～6元杂环烷基，所述C
1～6烷基、C
3～6环烷基、C
1～6杂烷基和3～6元杂环烷基任选被1、2或3个R
b取代；L选自-O-、-S-、-SO
2-、-N(R
7)-和-C(R
7)
2-；
R 3 , R 4 , R 5 and R 6 are each independently selected from H, F, Cl, Br, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3 ~ 6-membered heterocycloalkyl, the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally selected by 1, 2, or 3 R b is substituted; L is selected from -O-, -S-, -SO 2 -, -N(R 7 )- and -C(R 7 ) 2 -;
L
1选自-C(R
7)
2-；
L 1 is selected from -C(R 7 ) 2 -;
L
2选自-C(R
7)
2-；
L 2 is selected from -C(R 7 ) 2 -;
R
7分别独立地选自H、F、Cl、Br、I、C
1～6烷基、C
3～6环烷基、C
1～6杂烷基和3～6元杂环烷基，所述C
1～6烷基、C
3～6环烷基、C
1～6杂烷基和3～6元杂环烷基任选被1、2或3个R
c取代；
R 7 is each independently selected from H, F, Cl, Br, I, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, so The C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 heteroalkyl group and 3-6 membered heterocycloalkyl group are optionally substituted with 1, 2 or 3 R c ;
T、T
1、T
2、T
3分别独立地选自CR
8和N；
T, T 1 , T 2 , and T 3 are independently selected from CR 8 and N;
R
8选自H、F、Cl、Br、I、CN、C
1～6烷基、C
3～6环烷基、C
1～6杂烷基和3～6元杂环烷基，所述C
1～6烷基、C
3～6环烷基、C
1～6杂烷基和3～6元杂环烷基任选被1、2或3个R
d取代；
R 8 is selected from H, F, Cl, Br, I, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R d ;
m选自1、2、3和4；m is selected from 1, 2, 3 and 4;
R
9分别独立地选自H、F、Cl、Br、I和C
1～3烷基，所述C
1～3烷基任选被1、2或3个R
e取代；
R 9 is each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl groups, the C 1-3 alkyl groups are optionally substituted with 1, 2 or 3 R e ;
R
a、R
b、R
c、R
d和R
e分别独立地选自F、Cl、Br、I、OH、CN、NH
2、COOH、CF
3、-CHF
2、-CH
2F、-OCH
3、CH
3、-CH
2CH
3、-CH(CH
3)
2、-NHCH
3、-N(CH
3)
2和环丙基；
R a, R b, R c , R d and R e are each independently selected from F, Cl, Br, I, OH, CN, NH 2, COOH, CF 3, -CHF 2, -CH 2 F, -OCH 3 , CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -NHCH 3 , -N(CH 3 ) 2 and cyclopropyl;
所述C
1～6杂烷基和3～6元杂环烷分别独立地包含1、2、3或4个独立地选自O、N、S和NH的原子或杂原子团。
The C 1-6 heteroalkyl group and 3-6 membered heterocycloalkane each independently include 1, 2, 3, or 4 atoms or heteroatom groups independently selected from O, N, S, and NH.
本发明提供式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
其中，among them,
R
1选自H、F和C
1～3烷基，所述任选被1、2或3个R
a取代；
R 1 is selected H, F, and C 1 ~ 3 alkyl group, the optionally substituted with 1, 2 or 3 R a;
R
2选自H、F、Cl、Br和CF
3；
R 2 is selected from H, F, Cl, Br and CF 3 ;
R
3、R
4、R
5和R
6分别独立地选自H、F、Cl、Br、CN、C
1～6烷基、C
3～6环烷基、C
1～6杂烷基和3～6元杂环烷基，所述C
1～6烷基、C
3～6环烷基、C
1～6杂烷基和3～6元杂环烷基任选被1、2或3个R
b取代；L选自-O-、-S-、-SO
2-、-N(R
7)-和-C(R
7)
2-；
R 3 , R 4 , R 5 and R 6 are each independently selected from H, F, Cl, Br, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3 ~ 6-membered heterocycloalkyl, the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally selected by 1, 2, or 3 R b is substituted; L is selected from -O-, -S-, -SO 2 -, -N(R 7 )- and -C(R 7 ) 2 -;
L
1选自-C(R
7)
2-；
L 1 is selected from -C(R 7 ) 2 -;
L
2选自-C(R
7)
2-；
L 2 is selected from -C(R 7 ) 2 -;
R
7分别独立地选自H、F、Cl、Br、I、C
1～6烷基、C
3～6环烷基、C
1～6杂烷基和3～6元杂环烷基，所述C
1～6烷基、C
3～6环烷基、C
1～6杂烷基和3～6元杂环烷基任选被1、2或3个R
c取代；
R 7 is each independently selected from H, F, Cl, Br, I, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, so The C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 heteroalkyl group and 3-6 membered heterocycloalkyl group are optionally substituted with 1, 2 or 3 R c ;
T、T
1、T
2、T
3分别独立地选自CR
8和N；
T, T 1 , T 2 , and T 3 are independently selected from CR 8 and N;
R
8选自H、F、Cl、Br、I、CN、C
1～6烷基、C
3～6环烷基、C
1～6杂烷基和3～6元杂环烷基，所述C
1～6烷基、C
3～6环烷基、C
1～6杂烷基和3～6元杂环烷基任选被1、2或3个R
d取代；
R 8 is selected from H, F, Cl, Br, I, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R d ;
m选自1、2、3和4；m is selected from 1, 2, 3 and 4;
R
9分别独立地选自H、F、Cl、Br、I和C
1～3烷基，所述C
1～3烷基任选被1、2或3个R
e取代；
R 9 is each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl groups, the C 1-3 alkyl groups are optionally substituted with 1, 2 or 3 R e ;
R
a、R
b、R
c、R
d和R
e分别独立地选自F、Cl、Br、I、OH、CN、NH
2、COOH、CF
3、-CHF
2、-CH
2F、-OCH
3、CH
3、-CH
2CH
3、-CH(CH
3)
2、-NHCH
3、-N(CH
3)
2和环丙基；
R a, R b, R c , R d and R e are each independently selected from F, Cl, Br, I, OH, CN, NH 2, COOH, CF 3, -CHF 2, -CH 2 F, -OCH 3 , CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -NHCH 3 , -N(CH 3 ) 2 and cyclopropyl;
所述C
1～6杂烷基和3～6元杂环烷分别独立地包含1、2、3或4个独立地选自O、N、S和NH的原子或杂原子团。
The C 1-6 heteroalkyl group and 3-6 membered heterocycloalkane each independently include 1, 2, 3, or 4 atoms or heteroatom groups independently selected from O, N, S, and NH.
在本发明的一些方案中，上述R
1选自H、F和CH
3，所述任选被1、2或3个R
a取代。
In some aspects of the present invention, of R 1 is selected from H, F and CH 3, said optionally substituted with 1, 2 or 3 R a.
在本发明的一些方案中，上述R
1选自H和CH
3。
In some aspects of the present invention, the above-mentioned R 1 is selected from H and CH 3 .
在本发明的一些方案中，上述R
1选自H。
In some aspects of the present invention, the above-mentioned R 1 is selected from H.
在本发明的一些方案中，上述R
2选自Cl。
In some aspects of the present invention, the above-mentioned R 2 is selected from Cl.
在本发明的一些方案中，上述R
3、R
4、R
5和R
6分别独立地选自H。
In some aspects of the present invention, the above-mentioned R 3 , R 4 , R 5 and R 6 are each independently selected from H.
在本发明的一些方案中，上述R
7选自H、F、Cl、Br、I、-OCH
3、CH
3、-CH
2CH
3、-NHCH
3和环丙基，所述-OCH
3、CH
3、-CH
2CH
3、-NHCH
3和环丙基任选被1、2或3个R
c取代。
In some aspects of the present invention, the above-mentioned R 7 is selected from H, F, Cl, Br, I, -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl, the -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl are optionally substituted with 1, 2 or 3 R c .
在本发明的一些方案中，上述R
7选自H、F、Cl、Br、I、CF
3、-CHF
2、-CH
2F、-OCH
3、CH
3、-CH
2CH
3、-CH(CH
3)
2、-NHCH
3、-N(CH
3)
2和环丙基。
In some aspects of the present invention, the above-mentioned R 7 is selected from H, F, Cl, Br, I, CF 3 , -CHF 2 , -CH 2 F, -OCH 3 , CH 3 , -CH 2 CH 3 , -CH (CH 3 ) 2 , -NHCH 3 , -N(CH 3 ) 2 and cyclopropyl.
在本发明的一些方案中，上述L选自-O-、-S-、-SO
2-、-NH-和-CH
2-。
In some aspects of the present invention, the aforementioned L is selected from -O-, -S-, -SO 2 -, -NH- and -CH 2 -.
在本发明的一些方案中，上述L选自-O-。In some aspects of the present invention, the above-mentioned L is selected from -O-.
在本发明的一些方案中，上述L
1选自-CH
2-、-CHF-和-CF
2-。
In some aspects of the present invention, the aforementioned L 1 is selected from -CH 2 -, -CHF- and -CF 2 -.
在本发明的一些方案中，上述L
2选自-CH
2-、-CHF-和-CF
2-。
In some aspects of the present invention, the aforementioned L 2 is selected from -CH 2 -, -CHF- and -CF 2 -.
在本发明的一些方案中，上述R
8选自H、F、Cl、Br、I、-OCH
3、CH
3、-CH
2CH
3、-NHCH
3和环丙基，所述-OCH
3、CH
3、-CH
2CH
3、-NHCH
3和环丙基任选被1、2或3个R
d取代。
In some aspects of the present invention, the above-mentioned R 8 is selected from H, F, Cl, Br, I, -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl, the -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl are optionally substituted with 1, 2 or 3 Rd .
在本发明的一些方案中，上述R
8选自H。
In some aspects of the present invention, the above-mentioned R 8 is selected from H.
在本发明的一些方案中，上述R
9分别独立地选自H。
In some aspects of the present invention, the above-mentioned R 9 is independently selected from H.
在本发明的一些方案中，上述结构单元
选自
In some aspects of the present invention, the above-mentioned structural unit Selected from
在本发明的一些方案中，上述结构单元
选自
In some aspects of the present invention, the above-mentioned structural unit Selected from
在本发明的一些方案中，上述化合物选自In some aspects of the present invention, the above-mentioned compound is selected from
其中，among them,
R
1、R
2、R
3、R
4、R
5、R
6、R
9、T、T
1、T
2、T
3、L
1、L
2和m如本发明所定义。
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , T, T 1 , T 2 , T 3 , L 1 , L 2 and m are as defined in the present invention.
在本发明的一些方案中，上述化合物选自In some aspects of the present invention, the above-mentioned compound is selected from
其中，among them,
R
1、R
2、R
3、R
4、R
5、R
6和R
8如本发明所定义。
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are as defined in the present invention.
本发明提供下式化合物或其药学上可接受的盐，化合物选自The present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof, and the compound is selected from
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，化合物选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
本发明还提供上述化合物或其药学上可接受的盐在制备治疗乙型肝炎病毒药物中的应用。The present invention also provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating hepatitis B virus.
本发明还提供上述化合物或其药学上可接受的盐在制备抑制cccDNA的活性的药物中的应用。The present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt in the preparation of a medicine for inhibiting the activity of cccDNA.
本发明还有一些技术方案是由上述各变量任意组合而来。There are also some technical solutions of the present invention that are arbitrarily combined with the above-mentioned variables.
技术效果Technical effect
本发明化合物对HepDES19细胞株展现出显著的抑制cccDNA的活性，在小鼠药代动力学研究中，展现出低的清除和高的血浆暴露量。本发明化合物可用于因感染HVB所致疾病，如治疗乙型肝炎。The compound of the present invention exhibits significant cccDNA inhibitory activity on HepDES19 cell lines, and exhibits low clearance and high plasma exposure in mouse pharmacokinetic studies. The compounds of the present invention can be used for diseases caused by HVB infection, such as the treatment of hepatitis B.
定义和说明Definition and description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered uncertain or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts. When the compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, which can be converted into any base or acid addition salt.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体， 及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise specified, the term "cis-trans isomer" or "geometric isomer" is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise specified, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror-image relationship.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means right-handed, "(-)" means left-handed, and "(±)" means racemic.
除非另有说明，用楔形实线键
和楔形虚线键
表示一个立体中心的绝对构型，用直形实线键
和直形虚线键
表示立体中心的相对构型，用波浪线
表示楔形实线键
或楔形虚线键
或用波浪线
表示直形实线键
和直形虚线键
Unless otherwise specified, use wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key And straight dashed key
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise specified, the term "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in enantiomers" refers to one of the isomers or pairs of The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise specified, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。The optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide pure The desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(
3H)，碘-125(
125I)或C-14(
14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
The compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For another example, deuterium can be substituted for hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the event or condition described later may but does not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着 两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of. When the substituent is oxygen (i.e. =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (such as R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group can optionally be substituted with up to two Rs, and R has independent options in each case. In addition, combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR)
0-，表示该连接基团为单键，-C
0烷基-A表示该结构实际上是-A。
When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond, and -C 0 alkyl-A means that the structure is actually -A.
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R)
0表示该结构实际上是-A。
When the number of a substituent is 0, it means that the substituent is absent. For example, -A-(R) 0 means that the structure is actually -A.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。When a substituent is vacant, it means that the substituent is absent. For example, when X in A-X is vacant, it means that the structure is actually A.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two connected groups are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基的键可以交叉连接到一个环上的两一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
When the bond of a substituent can be cross-connected to two or more atoms on a ring, the substituent can be bonded with any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. . When the listed substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom. For example, a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。所述位点与其他基团连接的化学键可以用直形实线键
直形虚线键
或波浪线
表示。例如-OCH
3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
中的波浪线表示通过该苯基集团中的1和2位的碳原子与其他基团相连。
Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. The chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Said. For example , the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms.
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members. For example, "5-7 membered ring" refers to a "ring" in which 5-7 atoms are arranged around.
除非另有规定，术语“C
1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C
1-6烷基包括C
1-5、C
1-4、C
1-3、C
1-2、C
2-6、C
2-4、C
6和C
5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C
1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
Unless otherwise specified, the term "C 1-6 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
除非另有规定，术语“C
1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C
1-3烷基包括C
1-2和C
2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C
1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
Unless otherwise specified, the term "C 1-3 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
术语“杂烷基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烷基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)
2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)
2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂烷基为C
1-6杂烷基；在另一些实施方案中，所述杂烷基为C
1-
3杂烷基。杂原子或杂原子团可以位于杂烷基的任何内部位置，包括该烷基与分子其余部分的连接位置。但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。杂烷基的实例包括但不限于-OCH
3、-OCH
2CH
3、-OCH
2CH
2CH
3、-OCH
2(CH
3)
2、-CH
2-CH
2-O-CH
3、-NHCH
3、-N(CH
3)
2、-NHCH
2CH
3、-N(CH
3)(CH
2CH
3)、-CH
2-CH
2-NH-CH
3、-CH
2-CH
2-N(CH
3)-CH
3、-SCH
3、-SCH
2CH
3、-SCH
2CH
2CH
3、-SCH
2(CH
3)
2、-CH
2-S-CH
2-CH
3、-CH
2-CH
2、-S(＝O)-CH
3、-CH
2-CH
2-S(＝O)
2-CH
3。至多两个杂原子可以是连续的，例如-CH
2-NH-OCH
3。
The term "heteroalkyl" by itself or in combination with another term means a stable linear or branched alkyl group or combination thereof composed of a certain number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatoms are selected from B, O, N, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) 2 -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) 2 N(H)- and -S(=O)N( H)-. In some embodiments, the heteroalkyl is a C 1-6 heteroalkyl; In other embodiments, the heteroalkyl is a heteroalkyl C 1- 3. The heteroatom or heteroatom group can be located in any internal position of the heteroalkyl group, including the position of attachment of the alkyl group to the rest of the molecule. However, the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are customary expressions and refer to those connected to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. Alkyl group. Examples of heteroalkyl groups include, but are not limited to, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 (CH 3 ) 2 , -CH 2 -CH 2 -O-CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N( CH 3 ) -CH 3 , -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , -CH 2 -S-CH 2 -CH 3 , -CH 2- CH 2 , -S(=O)-CH 3 , -CH 2 -CH 2 -S(=O) 2 -CH 3 . Up to two heteroatoms can be continuous, for example -CH 2 -NH-OCH 3 .
除非另有规定，“C
3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C
3-6环烷基包括C
3-5、C
4-5和C
5-6环烷基等；其可以是一价、二价或者多价。C
3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。
Unless otherwise specified, "C 3-6 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent. Examples of C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
除非另有规定，术语“3-6元杂环烷基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-6元杂环烷基包括4-6元、5-6元、4元、5元和6元杂环烷基等。3-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms. Are heteroatoms independently selected from O, S and N, the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and carbon, nitrogen and sulfur heteroatoms can be optionally oxidized (ie C(=O), NO And S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings. In addition, for the "3-6 membered heterocycloalkyl group", a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule. The 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperazinyl Pyridyl and so on.
除非另有规定，C
n-n+m或C
n-C
n+m包括n至n+m个碳的任何一种具体情况，其中，n和m为自然数，例如C
1-12包括C
1、C
2、C
3、C
4、C
5、C
6、C
7、C
8、C
9、C
10、C
11、和C
12，也包括n至n+m中的任何一个范围，例如C
1-12包括C
1-3、C
1-6、C
1-9、C
3-6、C
3-9、C
3-12、C
6-9、C
6-12、和C
9-12等；同理，n元 至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等；特别地，C
0表示不存在。
Unless otherwise specified, C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, where n and m are natural numbers, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, such as C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc. ; Similarly, n-membered to n+m-membered means that the number of atoms in the ring is from n to n+m. For example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, and a 7-membered ring. , 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, including any range from n to n+m, for example, 3-12 membered ring includes 3-6 membered ring, 3- 9-membered ring, 5-6 membered ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, 6-10 membered ring, etc.; in particular, C 0 represents not present.
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as methanesulfonate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and so on. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxyl group. Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
本发明采用下述缩略词：DMF代表N,N-二甲基甲酰胺；Na
2CO
3代表碳酸钠；K
2CO
3代表碳酸钾；EtOAc代表乙酸乙酯；THF代表四氢呋喃；MeOH代表甲醇；DCM代表二氯甲烷；DMSO代表二甲基亚砜；EtOH代表乙醇；CH
3CN代表乙腈；TFA代表三氟乙酸；DIPEA代表N,N-二异丙基乙胺；Tf代表三氟甲磺酰基；Pd(PPh
2)Cl
2代表双三苯基磷二氯化钯；CO
2代表二氧化碳；LCMS代表液质联用色谱；MS代表质谱；HPLC代表液相色谱；SFC超临界流体色谱；po代表灌胃给药；iv代表静脉注射给药；T
1/2代表半衰期；Vd
ss代表稳态表观分布容积；CL代表清除率；AUC
0-24h代表给药后0～24小时血药浓度-时间曲线下面积；C
max代表最大血药浓度；T
max代表达到最大血药浓度的时间；F％代表口服生物利用度；mg代表毫克；μg代表微克；Kg代表千克；mL代表毫升；μL代表微升；nM代表钠摩尔/升；h代表小时；min代表分钟。
The present invention uses the following acronyms: DMF stands for N,N-dimethylformamide; Na 2 CO 3 stands for sodium carbonate; K 2 CO 3 stands for potassium carbonate; EtOAc stands for ethyl acetate; THF stands for tetrahydrofuran; MeOH stands for methanol DCM stands for dichloromethane; DMSO stands for dimethyl sulfoxide; EtOH stands for ethanol; CH 3 CN stands for acetonitrile; TFA stands for trifluoroacetic acid; DIPEA stands for N,N-diisopropylethylamine; Tf stands for trifluoromethanesulfonate Acyl; Pd(PPh 2 )Cl 2 stands for bistriphenylphosphorus palladium dichloride; CO 2 stands for carbon dioxide; LCMS stands for liquid chromatography mass spectrometry; MS stands for mass spectrometry; HPLC stands for liquid chromatography; SFC supercritical fluid chromatography; po Represents intragastric administration; iv represents intravenous administration; T 1/2 represents half-life; Vd ss represents steady-state apparent volume of distribution; CL represents clearance rate; AUC 0-24h represents blood drug concentration 0-24 hours after administration -Area under the time curve; C max represents the maximum plasma concentration; T max represents the time to reach the maximum plasma concentration; F% represents oral bioavailability; mg represents milligrams; μg represents micrograms; Kg represents kilograms; mL represents milliliter; μL Stands for microliters; nM stands for sodium moles/liter; h stands for hours; min stands for minutes.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型
The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the field. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with the Bruker D8 venture diffractometer to collect the diffraction intensity data, the light source is CuKα radiation, and the scanning method: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration
化合物依据本领域常规命名原则或者使用
软件命名，市售化合物采用供应商目录名称。
Compounds are based on conventional naming principles in the field or use The software is named, and the commercially available compounds use the supplier catalog name.
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail through the following examples, but it is not meant to impose any disadvantageous restriction on the present invention. The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.
中间体AIntermediate A
步骤A：将A-1(2.5克，17.11毫摩尔)溶于三氯甲烷(100毫升)中，随后加入间氯过氧苯甲酸(3.95克，18.30毫摩尔，80％纯度)。反应混合物在25摄氏度搅拌12小时后，减压浓缩。剩余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝50/1至20/1)后得到A-2。
1H NMR(400MHz,DMSO-d
6)δ＝11.43(br s,1H),8.21(d,J＝4.9Hz,1H),7.58-7.42(m,2H),7.24(br s,1H),6.46(d,J＝6.4Hz,1H)。
Step A: A-1 (2.5 g, 17.11 mmol) was dissolved in chloroform (100 mL), and then m-chloroperoxybenzoic acid (3.95 g, 18.30 mmol, 80% purity) was added. After the reaction mixture was stirred at 25 degrees Celsius for 12 hours, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1 to 20/1) to obtain A-2. 1 H NMR (400MHz, DMSO-d 6 )δ = 11.43 (br s, 1H), 8.21 (d, J = 4.9 Hz, 1H), 7.58-7.42 (m, 2H), 7.24 (br s, 1H), 6.46 (d, J=6.4 Hz, 1H).
步骤B：将A-2(1.75克，10.79毫摩尔)溶于N，N-二甲基甲酰胺(40毫升)中，该溶液冷却到0摄氏度，加入草酰氯(1.78克，14.03毫摩尔)。反应混合物自然升温到25摄氏度，搅拌1小时后，加入甲醇(5毫升)，水(50毫升)，并用乙酸乙酯90毫升萃取(30毫升/次，萃取3次)。合并的有机相用无水硫酸钠干燥，过滤后，滤液减压浓缩得到A-3。
1H NMR(400MHz,DMSO-d
6)δ＝11.87-11.53(m,1H),8.20(d,J＝8.4Hz,1H),7.76(d,J＝8.4Hz,1H),7.37-7.25(m,1H),6.59(d,J＝7.0Hz,1H)。
Step B: Dissolve A-2 (1.75 g, 10.79 mmol) in N,N-dimethylformamide (40 mL), cool the solution to 0 degrees Celsius, and add oxalyl chloride (1.78 g, 14.03 mmol) . The reaction mixture was naturally heated to 25 degrees Celsius, and after stirring for 1 hour, methanol (5 mL) and water (50 mL) were added, and the mixture was extracted with 90 mL of ethyl acetate (30 mL/time, 3 times). The combined organic phase was dried over anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure to obtain A-3. 1 H NMR (400MHz, DMSO-d 6 ) δ = 11.87-11.53 (m, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.37-7.25 ( m, 1H), 6.59 (d, J=7.0 Hz, 1H).
步骤C：将A-3(3克，16.61毫摩尔)，吡啶(6.57克，83.06毫摩尔)，N，N-二异丙基乙胺(4.72克，36.55毫摩尔)依次加入到二氯甲烷(250毫升)中，冷到0摄氏度后，再向其中加入三氟乙酸酐(37.50克，132.90毫摩尔)。反应混合物自然升温到25摄氏度后，搅拌3小时。随后加入水(200毫升)，用二氯甲烷600毫升萃取(200毫升/次，萃取3次)。合并的有机相用无水硫酸钠干燥，过滤后，滤液减压浓缩。剩余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1至4/1)后得到中间体A。
1H NMR(400MHz,DMSO-d
6)δ＝8.76-8.65(m,1H),8.54-8.44(m,1H),8.28-8.16(m,1H),8.11-7.99(m,1H)。
Step C: Add A-3 (3 g, 16.61 mmol), pyridine (6.57 g, 83.06 mmol), and N,N-diisopropylethylamine (4.72 g, 36.55 mmol) to dichloromethane in sequence (250 ml), after cooling to 0 degrees Celsius, add trifluoroacetic anhydride (37.50 g, 132.90 mmol). After the reaction mixture was naturally heated to 25 degrees Celsius, it was stirred for 3 hours. Then water (200 ml) was added, and extraction was performed with 600 ml of dichloromethane (200 ml/time, 3 times of extraction). The combined organic phase was dried over anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1 to 4/1) to obtain Intermediate A. 1 H NMR (400MHz, DMSO-d 6 ) δ=8.76-8.65 (m, 1H), 8.54-8.44 (m, 1H), 8.28-8.16 (m, 1H), 8.11-7.99 (m, 1H).
中间体BIntermediate B
中间体B由下面的方法制备：Intermediate B is prepared by the following method:
步骤A：在零下20摄氏度下，将三氟甲磺酸酐(23.71克，84.02毫摩尔)滴加到吡啶(6.96克，88.03毫摩尔)和二氯甲烷的混合溶液中。加完后冷却至零下30摄氏度，然后加入2-溴乙醇(B-1， 10克，80.02毫摩尔)。反应混合物缓慢升温到0摄氏度，搅拌30分钟后过滤，滤液减压浓缩。剩余物在甲基叔丁基醚/石油醚(V/V＝1/1，100毫升)的混合溶剂中搅拌，然后过滤除去不溶物。滤液减压浓缩得到B-2。
1H NMR(400MHz,CDCl
3)δ＝4.75(t,J＝6.4Hz,2H),3.61(t,J＝6.3Hz,2H)。
Step A: Add trifluoromethanesulfonic anhydride (23.71 g, 84.02 mmol) to the mixed solution of pyridine (6.96 g, 88.03 mmol) and dichloromethane at minus 20 degrees Celsius. After the addition, it was cooled to minus 30 degrees Celsius, and then 2-bromoethanol (B-1, 10 g, 80.02 mmol) was added. The reaction mixture was slowly warmed to 0 degrees Celsius, stirred for 30 minutes and filtered, and the filtrate was concentrated under reduced pressure. The residue was stirred in a mixed solvent of methyl tert-butyl ether/petroleum ether (V/V=1/1, 100 ml), and then filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure to obtain B-2. 1 H NMR (400 MHz, CDCl 3 ) δ=4.75 (t, J=6.4 Hz, 2H), 3.61 (t, J=6.3 Hz, 2H).
步骤B：向(顺)-3-羟基环丁甲酸乙酯(B-3，5克，34.68毫摩尔)的甲苯(150毫升)溶液中加入N，N-二异丙基乙胺(8.96克,69.36毫摩尔)和B-2(17.83克，69.36毫摩尔)。反应混合物在90摄氏度搅拌12小时。然后加入水(300毫升)和乙酸乙酯(100毫升)，萃取分液。有机相用100毫升饱和食盐水洗涤一次，再用无水硫酸钠干燥。过滤后，滤液减压浓缩，剩余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝20/1至2/1)得到中间体B。
1H NMR(400MHz,CDCl
3)δ＝4.14(quin,J＝7.2Hz,2H),3.99-3.89(m,1H),3.68(t,J＝6.3Hz,2H),3.47-3.40(m,2H),2.69-2.57(m,1H),2.56-2.47(m,2H),2.31-2.19(m,2H),1.26(t,J＝7.2Hz,3H)。
Step B: To a solution of ethyl (cis)-3-hydroxycyclobutyrate (B-3, 5 g, 34.68 mmol) in toluene (150 ml) was added N, N-diisopropylethylamine (8.96 g , 69.36 mmol) and B-2 (17.83 g, 69.36 mmol). The reaction mixture was stirred at 90 degrees Celsius for 12 hours. Then water (300 mL) and ethyl acetate (100 mL) were added to extract and separate the layers. The organic phase was washed once with 100 ml of saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1 to 2/1) to obtain Intermediate B. 1 H NMR (400MHz, CDCl 3 ) δ = 4.14 (quin, J = 7.2 Hz, 2H), 3.99-3.89 (m, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.47-3.40 (m, 2H), 2.69-2.57 (m, 1H), 2.56-2.47 (m, 2H), 2.31-2.19 (m, 2H), 1.26 (t, J=7.2 Hz, 3H).
中间体CIntermediate C
中间体C由下面的方法制备：Intermediate C is prepared by the following method:
中间体C的制备参考中间体B的制备流程，将步骤B中的化合物(顺)-3-羟基环丁甲酸乙酯(B-3)替换成(顺)-3-羟基-1-甲基环丁酸甲酯(C-1)。
1H NMR(400MHz,CDCl
3)δ＝4.41(t,J＝6.1Hz,2H),4.14-4.02(m,1H),3.72-3.63(m,3H),3.54(t,J＝6.1Hz,2H),2.51-2.44(m,2H),2.28-2.21(m,2H),1.41(s,3H)。
For the preparation of Intermediate C, refer to the preparation process of Intermediate B, and replace the compound (cis)-3-hydroxycyclobutanoate (B-3) in step B with (cis)-3-hydroxy-1-methyl Methyl cyclobutyrate (C-1). 1 H NMR (400MHz, CDCl 3 ) δ = 4.41 (t, J = 6.1 Hz, 2H), 4.14-4.02 (m, 1H), 3.72-3.63 (m, 3H), 3.54 (t, J = 6.1 Hz, 2H), 2.51-2.44 (m, 2H), 2.28-2.21 (m, 2H), 1.41 (s, 3H).
中间体DIntermediate D
中间体D由下面的方法制备：Intermediate D is prepared by the following method:
中间体D的制备参考中间体B的制备流程，将步骤B中的化合物(顺)-3-羟基环丁甲酸乙酯(B-3)替换成(反)-3-羟基环丁甲酸乙酯(D-1)。
1H NMR(400MHz,CDCl
3)δ＝4.29-4.18(m,1H),3.69-3.67(m,3H),3.67-3.63(m,2H),3.45-3.38(m,2H),3.07-2.98(m,1H),2.54-2.45(m,2H),2.33-2.21(m,2H)。
For the preparation of Intermediate D, refer to the preparation process of Intermediate B, and replace the compound (cis)-3-hydroxycyclobutyrate (B-3) in step B with (trans)-3-hydroxycyclobutyrate ethyl ester (D-1). 1 H NMR (400MHz, CDCl 3 ) δ = 4.29-4.18 (m, 1H), 3.69-3.67 (m, 3H), 3.67-3.63 (m, 2H), 3.45-3.38 (m, 2H), 3.07-2.98 (m, 1H), 2.54-2.45 (m, 2H), 2.33-2.21 (m, 2H).
中间体EIntermediate E
中间体E由下面的方法制备：Intermediate E is prepared by the following method:
中间体E的制备参考中间体B的制备流程，将步骤B中的化合物(顺)-3-羟基环丁甲酸乙酯 (B-3)替换成3-羟基双环[1.1.1]戊烷-1-羧酸甲酯(E-1)。
1H NMR(400MHz,CDCl
3)δ＝3.79-3.76(m,2H),3.70(s,3H),3.47-3.43(m,2H),2.22(s,6H)。
The preparation of Intermediate E refers to the preparation process of Intermediate B, and the compound (cis)-3-hydroxycyclobutyric acid ethyl ester (B-3) in step B is replaced with 3-hydroxybicyclo[1.1.1]pentane- Methyl 1-carboxylate (E-1). 1 H NMR (400MHz, CDCl 3 ) δ=3.79-3.76 (m, 2H), 3.70 (s, 3H), 3.47-3.43 (m, 2H), 2.22 (s, 6H).
中间体FIntermediate F
中间体F由下面的方法制备：Intermediate F is prepared by the following method:
中间体E的制备参考中间体B的制备流程，将步骤B中的化合物(顺)-3-羟基环丁甲酸乙酯(B-3)替换成3-羟基-1-甲基环丁酯(F-1)。1H NMR(400MHz,CDCl
3)δ＝4.13-4.04(m,1H),3.70(d,J＝2.6Hz,3H),3.67(dt,J＝2.1,6.3Hz,2H),3.44(dt,J＝2.0,6.3Hz,2H),2.79-2.72(m,1H),2.49-2.41(m,1H),2.26-2.19(m,1H),1.99-1.90(m,1H),1.46-1.35(m,3H)。
The preparation of intermediate E refers to the preparation process of intermediate B, and the compound (cis)-3-hydroxycyclobutyric acid ethyl ester (B-3) in step B is replaced with 3-hydroxy-1-methylcyclobutyl ester ( F-1). 1H NMR(400MHz, CDCl 3 )δ=4.13-4.04(m,1H), 3.70(d,J=2.6Hz,3H), 3.67(dt,J=2.1,6.3Hz,2H), 3.44(dt,J =2.0,6.3Hz,2H),2.79-2.72(m,1H),2.49-2.41(m,1H),2.26-2.19(m,1H),1.99-1.90(m,1H),1.46-1.35(m ,3H).
实施例1Example 1
步骤A：将1-1(200毫克，896.60微摩尔)和中间体B(247.67毫克，986.26微摩尔)溶解在乙腈(3毫升)中，随后加入碳酸钾(185.87毫克，1.34毫摩尔)和碘化钾(14.88毫克，89.66微摩 尔)。氮气保护下，反应混合物在85摄氏度下搅拌12小时。然后加入水(20毫升)，用乙酸乙酯40毫升萃取(20毫升/次，萃取2次)。有机相用饱和食盐水(30毫升)洗涤，并用无水硫酸钠干燥。过滤后，滤液经减压浓缩得到粗产品1-2，直接用于下一步反应。Step A: Dissolve 1-1 (200 mg, 896.60 μmol) and Intermediate B (247.67 mg, 986.26 μmol) in acetonitrile (3 mL), then add potassium carbonate (185.87 mg, 1.34 mmol) and potassium iodide (14.88 mg, 89.66 micromolar). Under the protection of nitrogen, the reaction mixture was stirred at 85 degrees Celsius for 12 hours. Then water (20 mL) was added, and extraction was performed with 40 mL ethyl acetate (20 mL/time, extraction twice). The organic phase was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product 1-2, which was directly used in the next reaction.
步骤B：将1-2(280毫克，粗品，711.98微摩尔)和双联嚬哪醇硼酸酯(216.96毫克，854.37微摩尔)溶解在无水二氧六环(5毫升)中，随后加入醋酸钾(139.75毫克，1.42毫摩尔)和[1,1-双(二苯基膦基)二茂铁]二氯化钯(51.10毫克，71.2微摩尔)。氮气保护下，反应混合物在100摄氏度下搅拌12小时。然后加入水(20毫升)，用乙酸乙酯40毫升萃取(20毫升/次，萃取2次)。有机相用饱和食盐水(20毫升)洗涤，并用无水硫酸钠干燥。过滤后，滤液减压浓缩。剩余物用薄层色谱法分离纯化(展开剂：石油醚/乙酸乙酯＝5/2)得到化合物1-3。
1H NMR(400MHz,CDCl
3)δ＝8.31-8.27(m,1H),7.82-7.76(m,2H),7.72-7.69(m,1H),7.20-7.15(m,1H),7.13-7.11(m,1H),4.25-4.21(m,2H),4.18-4.10(m,3H),4.06-4.00(m,1H),3.82-3.78(m,2H),2.67-2.52(m,4H),2.34-2.24(m,3H),1.61-1.52(m,3H),1.32-1.21(m,9H)。
Step B: Dissolve 1-2 (280 mg, crude product, 711.98 micromolar) and bipartanol borate (216.96 mg, 854.37 micromolar) in anhydrous dioxane (5 mL), and then add Potassium acetate (139.75 mg, 1.42 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (51.10 mg, 71.2 micromoles). Under the protection of nitrogen, the reaction mixture was stirred at 100°C for 12 hours. Then water (20 mL) was added, and extraction was performed with 40 mL ethyl acetate (20 mL/time, extraction twice). The organic phase was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was separated and purified by thin layer chromatography (developing solvent: petroleum ether/ethyl acetate = 5/2) to obtain compound 1-3. 1 H NMR (400MHz, CDCl 3 ) δ = 8.31-8.27 (m, 1H), 7.82-7.76 (m, 2H), 7.72-7.69 (m, 1H), 7.20-7.15 (m, 1H), 7.13-7.11 (m,1H),4.25-4.21(m,2H),4.18-4.10(m,3H),4.06-4.00(m,1H),3.82-3.78(m,2H),2.67-2.52(m,4H) , 2.34-2.24 (m, 3H), 1.61-1.52 (m, 3H), 1.32-1.21 (m, 9H).
步骤C：将1-3(60毫克，136.26微摩尔)和中间体A(42.6毫克，136.26微摩尔)溶解在无水四氢呋喃(6毫升)和水(1毫升)中，随后加入碳酸钠(28.88毫克，272.52微摩尔)和[1,1-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷复合物(11.13毫克，13.63微摩尔)。氮气保护下，反应混合物在75摄氏度下搅拌3小时。然后加入水(30毫升)，用乙酸乙酯40毫升萃取(20毫升/次，萃取2次)。有机相用饱和食盐水(20毫升)洗涤，并用无水硫酸钠干燥。过滤后，滤液减压浓缩。剩余物用薄层色谱法分离纯化(展开剂：石油醚/乙酸乙酯＝2/1)得到化合物1-4。MS(ESI)m/z：477[M+H
+]。
Step C: Dissolve 1-3 (60 mg, 136.26 micromoles) and Intermediate A (42.6 mg, 136.26 micromoles) in anhydrous tetrahydrofuran (6 mL) and water (1 mL), then add sodium carbonate (28.88) Mg, 272.52 micromoles) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (11.13 mg, 13.63 micromoles). Under the protection of nitrogen, the reaction mixture was stirred at 75 degrees Celsius for 3 hours. Then water (30 mL) was added, and extraction was performed with 40 mL of ethyl acetate (20 mL/time, extraction twice). The organic phase was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was separated and purified by thin layer chromatography (developing solvent: petroleum ether/ethyl acetate = 2/1) to obtain compound 1-4. MS(ESI) m/z: 477 [M+H + ].
步骤D：将1-4(20毫克，41.93微摩尔)加入到水(1毫升)、甲醇(1毫升)和四氢呋喃(1毫升)的混合溶剂中，随后加入一水合氢氧化锂(4.4毫克，104.83微摩尔)。反应混合物在25摄氏度下搅拌2小时，用盐酸(1摩尔/升，10毫升)将pH值调节至3左右后，减压浓缩。剩余物经高效液相制备色谱法纯化(分离柱：Phenomenex Synergi(规格：150毫米×25毫米，粒径：10微米)；流动相：水(0.225％甲酸)/乙腈；洗脱梯度：40％～70％，10分钟)得到化合物1(保留时间0.905min)。
1H NMR(400MHz，CD
3OD)δ＝8.69-8.64(m,1H),8.52-8.46(m,1H),8.43-8.38(m,1H),8.14-8.07(m,1H),7.93-7.84(m,3H),7.79-7.71(m,1H),7.35-7.30(m,1H),7.27-7.19(m,1H),4.28-4.22(m,2H),4.11-4.00(m,1H),3.85-3.79(m,2H),2.72-2.64(m,1H),2.62-2.52(m,2H),2.25-2.13(m,2H)。MS(ESI)m/z:449[M+H
+]。
Step D: Add 1-4 (20 mg, 41.93 micromoles) to a mixed solvent of water (1 mL), methanol (1 mL) and tetrahydrofuran (1 mL), and then add lithium hydroxide monohydrate (4.4 mg, 104.83 micromolar). The reaction mixture was stirred at 25 degrees Celsius for 2 hours. After adjusting the pH to about 3 with hydrochloric acid (1 mol/L, 10 mL), it was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (separation column: Phenomenex Synergi (specification: 150 mm × 25 mm, particle size: 10 microns); mobile phase: water (0.225% formic acid)/acetonitrile; elution gradient: 40% ~70%, 10 minutes) to give compound 1 (retention time 0.905 min). 1 H NMR (400MHz, CD 3 OD) δ = 8.69-8.64 (m, 1H), 8.52-8.46 (m, 1H), 8.43-8.38 (m, 1H), 8.14-8.07 (m, 1H), 7.93 7.84 (m, 3H), 7.79-7.71 (m, 1H), 7.35-7.30 (m, 1H), 7.27-7.19 (m, 1H), 4.28-4.22 (m, 2H), 4.11-4.00 (m, 1H) ), 3.85-3.79 (m, 2H), 2.72-2.64 (m, 1H), 2.62-2.52 (m, 2H), 2.25-2.13 (m, 2H). MS(ESI) m/z: 449 [M+H + ].
实施例2Example 2
参考化合物1的制备流程，将步骤A中的中间体B替换成中间体C。由制备HPLC(柱子：Phenomenex luna C18 150×25mm×10μm；流动相：A相：0.225％甲酸水溶液；B相：乙腈；洗脱梯度：47％～77％；11分钟)分离纯化得到化合物2。
1H NMR(400MHz,DMSO-d
6)δ＝8.79(d,J＝4.6Hz,1H),8.65-8.53(m,2H),8.17(d,J＝8.3Hz,1H),8.04-7.84(m,4H),7.41(br s,1H),7.25(d,J＝8.3Hz,1H),4.29-4.11(m,2H),3.71(br s,2H),2.25(br s,2H),2.20-2.09(m,2H),1.30(s,3H)。MS(ESI)m/z:463[M+H
+]。
Referring to the preparation process of compound 1, replace intermediate B in step A with intermediate C. By preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: phase A: 0.225% aqueous formic acid; phase B: acetonitrile; elution gradient: 47% to 77%; 11 minutes) to obtain compound 2. 1 H NMR(400MHz, DMSO-d 6 )δ=8.79(d,J=4.6Hz,1H), 8.65-8.53(m,2H), 8.17(d,J=8.3Hz,1H), 8.04-7.84( m, 4H), 7.41 (br s, 1H), 7.25 (d, J = 8.3 Hz, 1H), 4.29-4.11 (m, 2H), 3.71 (br s, 2H), 2.25 (br s, 2H), 2.20-2.09 (m, 2H), 1.30 (s, 3H). MS(ESI) m/z: 463 [M+H + ].
实施例3Example 3
化合物3的制备参考化合物1的制备流程，将步骤A中的中间体B替换成中间体D。由制备HPLC(柱子：Shim-pack C18 150×25mm×10μm；流动相：A相：0.225％甲酸水溶液；B相：乙腈；洗脱梯度：48％～68％；10分钟)分离纯化得到化合物3。
1H NMR(400MHz,DMSO-d
6)δ＝8.79(d,J＝5.4Hz,1H),8.63-8.56(m,2H),8.17(dd,J＝1.7,8.6Hz,1H),7.99-7.89(m,4H),7.41(d,J＝2.3Hz,1H),7.24(dd,J＝2.4,8.9Hz,1H),4.30-4.16(m,3H),3.74-3.70(m,2H),2.90-2.82(m,1H),2.52(d,J＝1.9Hz,1H),2.42-2.38(m,2H),2.21-2.08(m,2H)。MS(ESI)m/z:449[M+H
+]。
The preparation of compound 3 refers to the preparation process of compound 1, replacing intermediate B in step A with intermediate D. Separation and purification by preparative HPLC (column: Shim-pack C18 150×25mm×10μm; mobile phase: phase A: 0.225% aqueous formic acid; phase B: acetonitrile; elution gradient: 48% to 68%; 10 minutes) to obtain compound 3 . 1 H NMR(400MHz,DMSO-d 6 )δ=8.79(d,J=5.4Hz,1H),8.63-8.56(m,2H),8.17(dd,J=1.7,8.6Hz,1H),7.99- 7.89(m,4H),7.41(d,J=2.3Hz,1H),7.24(dd,J=2.4,8.9Hz,1H), 4.30-4.16(m,3H),3.74-3.70(m,2H) , 2.90-2.82 (m, 1H), 2.52 (d, J = 1.9 Hz, 1H), 2.42-2.38 (m, 2H), 2.21-2.08 (m, 2H). MS(ESI) m/z: 449 [M+H + ].
实施例4Example 4
化合物4的制备参考化合物1的制备流程，将步骤A中的中间体B替换成中间体E。由制备HPLC(柱子：Waters Xbridge 150×25mm×5μm；流动相：A相：0.05％氨水溶液；B相：乙腈；洗脱梯度：5％～35％；10分钟)分离纯化得到化合物4。
1H NMR(400MHz,DMSO-d
6)δ＝12.87-11.87(m,1H),9.54(d,J＝2.1Hz,1H),9.07(d,J＝1.6Hz,1H),8.84(d,J＝5.4Hz,1H),8.64(d,J＝8.8Hz,1H),8.16-8.01(m,2H),7.94(d,J＝8.7Hz,1H),7.51(d,J＝2.4Hz,1H),7.39(dd,J＝2.4,9.0Hz,1H),4.33(dd,J＝3.6,5.3Hz,2H),3.92-3.80(m,2H),2.15(s,6H)。MS(ESI)m/z:461[M+H
+]。
The preparation of compound 4 refers to the preparation process of compound 1, replacing intermediate B in step A with intermediate E. By preparative HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: phase A: 0.05% ammonia solution; phase B: acetonitrile; elution gradient: 5% to 35%; 10 minutes) to obtain compound 4. 1 H NMR (400MHz, DMSO-d 6 ) δ = 12.87-11.87 (m, 1H), 9.54 (d, J = 2.1 Hz, 1H), 9.07 (d, J = 1.6 Hz, 1H), 8.84 (d, J = 5.4Hz, 1H), 8.64 (d, J = 8.8Hz, 1H), 8.16-8.01 (m, 2H), 7.94 (d, J = 8.7Hz, 1H), 7.51 (d, J = 2.4Hz, 1H), 7.39 (dd, J=2.4, 9.0 Hz, 1H), 4.33 (dd, J=3.6, 5.3 Hz, 2H), 3.92-3.80 (m, 2H), 2.15 (s, 6H). MS (ESI) m/z: 461 [M+H + ].
实施例5Example 5
化合物5的制备参考化合物1的制备流程，将步骤A中的化合物6-溴-2-萘酚(1-1)替换成3-溴-7-羟基喹啉(5-1)。由高效液相制备色谱法纯化(柱子：3_Phenomenex Luna C18，75×30mm×3μm；流动相：A相：0.05％盐酸水溶液，B相：乙腈；洗脱梯度：21％～41％，7分钟)得到化合物5。
1H NMR(400MHz,DMSO-d
6)δ＝9.49(d,J＝1.3Hz,1H),8.97(s,1H),8.84(d,J＝5.4Hz,1H),8.67-8.60(m,1H),8.08-8.01(m,2H),7.93(dd,J＝1.3,8.6Hz,1H),7.48(s,1H),7.40-7.31(m,1H),4.35-4.24(m,2H),3.96(quin,J＝7.4Hz,1H),3.76-3.70(m,2H),2.55(s,2H),2.43-2.38(m,1H),2.06-1.96(m,2H)。MS(ESI)m/z：450[M+H
+]
Preparation of Compound 5 Referring to the preparation process of Compound 1, the compound 6-bromo-2-naphthol (1-1) in step A was replaced with 3-bromo-7-hydroxyquinoline (5-1). Purified by high performance liquid chromatography (column: 3_Phenomenex Luna C18, 75×30mm×3μm; mobile phase: phase A: 0.05% aqueous hydrochloric acid, phase B: acetonitrile; elution gradient: 21% to 41%, 7 minutes) Compound 5 was obtained. 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.49 (d, J = 1.3 Hz, 1H), 8.97 (s, 1H), 8.84 (d, J = 5.4 Hz, 1H), 8.67-8.60 (m, 1H), 8.08-8.01(m,2H),7.93(dd,J=1.3,8.6Hz,1H),7.48(s,1H),7.40-7.31(m,1H),4.35-4.24(m,2H) , 3.96 (quin, J = 7.4 Hz, 1H), 3.76-3.70 (m, 2H), 2.55 (s, 2H), 2.43-2.38 (m, 1H), 2.06-1.96 (m, 2H). MS(ESI)m/z: 450[M+H + ]
实施例6Example 6
化合物6的制备参考化合物1的制备流程，将步骤A中的化合物6-溴-2-萘酚(1-1)替换成3-溴-7-羟基喹啉(5-1)，将中间体B替换成中间体C。由高效液相制备色谱法纯化(柱子：Unisil 3-100C18，150×50mm×3μm；流动相：A相：0.225％甲酸水溶液，B相：乙腈；洗脱梯度：30％～50％，10分钟)得到化合物6。
1H NMR(400MHz,DMSO-d
6)δ＝9.49(d,J＝2.0Hz,1H),8.96(d,J＝1.8Hz,1H), 8.83(d,J＝5.4Hz,1H),8.63(d,J＝8.8Hz,1H),8.09-8.00(m,2H),7.93(d,J＝8.6Hz,1H),7.48(d,J＝2.0Hz,1H),7.34(dd,J＝2.3,8.9Hz,1H),4.35-4.24(m,2H),4.08(quin,J＝6.9Hz,1H),3.76-3.71(m,2H),2.69-2.65(m,2H),1.86-1.82(m,2H),1.32(s,3H)。MS(ESI)m/z：464[M+H
+]。
Preparation of compound 6 Referring to the preparation process of compound 1, the compound 6-bromo-2-naphthol (1-1) in step A was replaced with 3-bromo-7-hydroxyquinoline (5-1), and the intermediate B is replaced with intermediate C. Purified by high performance liquid chromatography (column: Unisil 3-100C18, 150×50mm×3μm; mobile phase: phase A: 0.225% aqueous formic acid, phase B: acetonitrile; elution gradient: 30%-50%, 10 minutes ) Compound 6 is obtained. 1 H NMR(400MHz,DMSO-d 6 )δ=9.49(d,J=2.0Hz,1H), 8.96(d,J=1.8Hz,1H), 8.83(d,J=5.4Hz,1H), 8.63 (d,J=8.8Hz,1H),8.09-8.00(m,2H),7.93(d,J=8.6Hz,1H),7.48(d,J=2.0Hz,1H),7.34(dd,J= 2.3,8.9Hz,1H),4.35-4.24(m,2H),4.08(quin,J=6.9Hz,1H),3.76-3.71(m,2H),2.69-2.65(m,2H),1.86-1.82 (m, 2H), 1.32 (s, 3H). MS (ESI) m/z: 464 [M+H + ].
实施例7Example 7
步骤A：中间体7-5的制备参考化合物1的制备流程，将步骤A中的化合物6-溴-2-萘酚(1-1)替换成3-溴-7-羟基喹啉(5-1)，将中间体B替换成中间体F。Step A: Preparation of Intermediate 7-5 Referring to the preparation process of Compound 1, the compound 6-bromo-2-naphthol (1-1) in Step A is replaced with 3-bromo-7-hydroxyquinoline (5- 1) Replace Intermediate B with Intermediate F.
步骤B：中间体7-5经由SFC拆分(柱子：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相：二氧化碳；B相：50％甲醇+0.05％乙二胺的乙腈溶液)，得到化合物6(保留时间＝1.216分钟)和化合物7粗品(保留时间＝1.083分钟)。化合物7粗品经高效液相制备色谱法纯化(柱子：Unisil 3-100C18，150×50mm×3μm；流动相：A相：0.225％甲酸水溶液，B相：乙腈；洗脱梯度：30％～50％，10分钟)得到化合物7。
1H NMR(400MHz,DMSO-d
6)δ＝9.49(d,J＝1.9Hz,1H),8.97(d,J＝1.8Hz,1H),8.84(d,J＝5.4Hz,1H),8.63(d,J＝8.6Hz,1H),8.09-8.01(m,2H),7.93(d,J＝8.6Hz,1H),7.48(d,J＝2.0Hz,1H),7.35(dd,J＝2.3,8.9Hz,1H),4.34-4.25(m,2H),4.16(quin,J＝7.2Hz,1H),3.76-3.70(m,2H),2.31-2.22(m,2H),2.20-2.11(m,2H),1.30(s,3H)。MS(ESI)m/z：464[M+H
+]。
Step B: Intermediate 7-5 was resolved by SFC (column: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: phase A: carbon dioxide; phase B: 50% methanol + 0.05% ethylenediamine in acetonitrile ) To obtain compound 6 (retention time=1.216 minutes) and crude compound 7 (retention time=1.083 minutes). The crude compound 7 was purified by high performance liquid chromatography (column: Unisil 3-100C18, 150×50mm×3μm; mobile phase: phase A: 0.225% aqueous formic acid, phase B: acetonitrile; elution gradient: 30%-50% , 10 minutes) to obtain compound 7. 1 H NMR(400MHz,DMSO-d 6 )δ=9.49(d,J=1.9Hz,1H), 8.97(d,J=1.8Hz,1H), 8.84(d,J=5.4Hz,1H), 8.63 (d,J=8.6Hz,1H),8.09-8.01(m,2H),7.93(d,J=8.6Hz,1H),7.48(d,J=2.0Hz,1H),7.35(dd,J= 2.3,8.9Hz,1H),4.34-4.25(m,2H),4.16(quin,J=7.2Hz,1H),3.76-3.70(m,2H),2.31-2.22(m,2H),2.20-2.11 (m, 2H), 1.30 (s, 3H). MS (ESI) m/z: 464 [M+H + ].
实验例1：应用HepDES19细胞评价化合物抗HBV活性Experimental Example 1: Using HepDES19 cells to evaluate the anti-HBV activity of the compound
该方法主要用于cccDNA抑制剂的筛选。HepDES19细胞系包含一个1.1单位长度的HBV基因组，pgRNA的转录由四环素控制。在没有四环素的情况下，pgRNA的转录被诱导，但由于HBeAg起始密码子前的非常短的前导序列干扰了启动子，因此pgRNA不能产生HBV e抗原(HBeAg)。只有在cccDNA形成后，缺失的前导序列和启动子突变才能恢复，进而合成HBeAg。因此，HBeAg可以作为cccDNA的替代标记。This method is mainly used for the screening of cccDNA inhibitors. The HepDES19 cell line contains a 1.1-unit-length HBV genome, and the transcription of pgRNA is controlled by tetracycline. In the absence of tetracycline, the transcription of pgRNA is induced, but because the very short leader sequence before the HBeAg start codon interferes with the promoter, pgRNA cannot produce HBV e antigen (HBeAg). Only after the formation of cccDNA, the missing leader sequence and promoter mutation can be restored, and then HBeAg can be synthesized. Therefore, HBeAg can be used as a surrogate marker for cccDNA.
1.实验目的：1. The purpose of the experiment:
通过酶联免疫吸附测定(ELISA)检测HepDES19细胞培养上清的HBeAg含量，来评价化合物对HBV的抑制作用。The HBeAg content of HepDES19 cell culture supernatant was detected by enzyme-linked immunosorbent assay (ELISA) to evaluate the compound's inhibitory effect on HBV.
2.实验方法：2. Experimental method:
2.1 HepDES19细胞扩增。2.1 Expansion of HepDES19 cells.
将HepDES19细胞在DMEM/F12培养液(来源：Gibco Cat.11330057)，10％胎牛血清(Fetal Bovine Serum，FBS，来源：Clontech)，100unis/mL 100μg/mL盘尼西林/链霉素(Penicillin/streptomycin，来源：Hyclone)，2mM GlutaMAX(来源：Gibco)，1％非必需氨基酸溶液(MEM NEAA，来源：Gibco)，0.1mM氨基糖甙抗生素(Geneticin，来源：Gibco)，1μg/mL盐酸四环素(Tetracycline hydrochloride，来源：Sigma)中培养，按照1/3的比例传代并扩增，然后将HepDES19按4×10
6细胞密度种到T150培养瓶中，更换为不含四环素的培养基培养8天，最后收集细胞并液氮冷冻保存(1×10
7细胞/支)。2.2检测HepDES19细胞培养上清HBeAg
Put HepDES19 cells in DMEM/F12 medium (source: Gibco Cat.11330057), 10% fetal bovine serum (Fetal Bovine Serum, FBS, source: Clontech), 100unis/mL 100μg/mL penicillin/streptomycin (Penicillin/streptomycin) , Source: Hyclone), 2mM GlutaMAX (source: Gibco), 1% non-essential amino acid solution (MEM NEAA, source: Gibco), 0.1mM aminoglycoside antibiotic (Geneticin, source: Gibco), 1μg/mL tetracycline hydrochloride (Tetracycline) Hydrochloride, source: Sigma), subcultured and expanded according to the ratio of 1/3, then planted HepDES19 into a T150 culture flask at a cell density of 4×10 6 cells, replaced with a tetracycline-free medium and cultured for 8 days, and finally The cells were collected and cryopreserved in liquid nitrogen (1×10 7 cells/branch). 2.2 Detection of HepDES19 cell culture supernatant HBeAg
复苏HepDES19细胞，种HepDES19细胞到96孔板中(6×10
4细胞/孔)，在37摄氏度，5％CO
2培养过夜。第二天，稀释化合物，3倍梯度稀释共8个浓度。将不同浓度化合物加入到培养孔中，双复孔。培养液中DMSO的终浓度为0.5％。第七天收取培养孔中的培养液，ELISA测定乙肝病毒HBeAg的含量。吸出培养孔中的培养液后，96孔板中每孔加入Celltiter-Glo试剂，酶标仪检测各孔的化学发光值，检测细胞活力。
Resuscitate HepDES19 cells, plant HepDES19 cells in a 96-well plate (6×10 4 cells/well), and incubate overnight at 37 degrees Celsius and 5% CO 2. On the second day, the compound was diluted to a total of 8 concentrations in 3-fold serial dilutions. Compounds of different concentrations were added to the culture wells, and the wells were duplicated. The final concentration of DMSO in the culture broth is 0.5%. On the seventh day, the culture medium in the culture well was collected, and the content of hepatitis B virus HBeAg was determined by ELISA. After aspirating the culture medium in the culture wells, add Celltiter-Glo reagent to each well of the 96-well plate, and the microplate reader detects the chemiluminescence value of each well to detect cell viability.
ELISA测定乙肝病毒HBeAg的含量，具体步骤参照该产品说明书，步骤简述如下：取50微升样品和标准品分别加入到反应板中，再每孔分别加入50微升酶结合物，震荡混匀，37摄氏度温浴60分钟，然后用洗液洗板6次，再每孔加入50微升发光底物，混匀，室温避光反应10分钟，最后用酶标仪检测化学发光强度。ELISA measures the content of hepatitis B virus HBeAg. The specific steps refer to the product manual. The steps are briefly described as follows: Take 50 microliters of sample and standard substance into the reaction plate, and then add 50 microliters of enzyme conjugate to each well, shake and mix. Incubate at 37 degrees Celsius for 60 minutes, then wash the plate with washing solution 6 times, then add 50 microliters of luminescent substrate to each well, mix well, and react for 10 minutes in the dark at room temperature. Finally, check the chemiluminescence intensity with a microplate reader.
2.3数据分析2.3 Data analysis
计算抑制百分比(％Inh)：Calculate the percentage of inhibition (%Inh):
％Inh.＝(1–样品中的HBeAg值/DMSO对照HBeAg值)×100。%Inh.=(1-HBeAg value in sample/DMSO control HBeAg value)×100.
％细胞活力＝(样品发光值–培养基对照发光值)/(DMSO对照发光值–培养基对照发光值)×100％。% Cell viability = (sample luminescence value-medium control luminescence value) / (DMSO control luminescence value-medium control luminescence value) × 100%.
计算EC
50和CC
50：用GraphPad Prism软件计算化合物的EC
50和CC
50值。
Calculation of EC 50 and CC 50 : GraphPad Prism software was used to calculate the EC 50 and CC 50 values of the compound.
3.实验结果3. Experimental results
EC
50和CC
50实验结果如下表1所示。
The experimental results of EC 50 and CC 50 are shown in Table 1 below.
表1 HepDES19细胞评价化合物抗HBV活性实验结果Table 1 Experimental results of HepDES19 cell evaluation compound anti-HBV activity
| 化合物Compound | HBeAg EC 50(μM) HBeAg EC 50 (μM) | CC 50(μM) CC 50 (μM) |
| 化合物1Compound 1 | 0.0120.012 | >10>10 |
| 化合物2Compound 2 | 0.0620.062 | >10>10 |
| 化合物3Compound 3 | 0.0020.002 | >10>10 |
| 化合物5Compound 5 | 0.0120.012 | >10>10 |
| 化合物7Compound 7 | 1.1591.159 | >10>10 |
结论：本发明化合物在体外具有良好的抗HBV活性。Conclusion: The compound of the present invention has good anti-HBV activity in vitro.
实验例2：小鼠药代动力学研究Experimental example 2: Mouse pharmacokinetic study
本实验旨在评价化合物在小鼠体内单次静脉注射或口服灌胃给药后的药代动力学行为。静脉注射给药，化合物配制成0.2mg/mL的澄清溶液，溶媒：5％DMSO/5％十二羟基硬脂酸脂(solutol)/90％水；口服灌胃给药，化合物配制成0.3mg/mL的混悬液，溶媒：0.5％羧甲基纤维素钠/0.2％吐温80/99.3％水。This experiment aims to evaluate the pharmacokinetic behavior of the compound after a single intravenous injection or oral gavage in mice. For intravenous injection, the compound is formulated as a clear solution of 0.2 mg/mL, and the vehicle: 5% DMSO/5% dodecyl hydroxystearate (solutol)/90% water; orally administered by gavage, the compound is formulated as 0.3 mg /mL suspension, solvent: 0.5% sodium carboxymethyl cellulose/0.2% Tween 80/99.3% water.
样品采集时间表如下：The sample collection schedule is as follows:
P：血浆(Plasma)；抗凝剂：K2-EDTA。P: Plasma; anticoagulant: K2-EDTA.
通过隐静脉穿刺方式在规定的时间采集(或其他合适的采血位点)全血样品(每组约0.03mL)，并在试验记录中记录实际采血时间。采集时间点可接受的误差为给药1小时内时间点±1分钟，其他时间点的为理论时间±5％。所有血样立即转移至贴有标签的含K2-EDTA的商品化离心管中。血样采集后，4摄氏度，3200g离心10分钟吸取上清血浆，迅速至于干冰中，保持-20摄氏度或更低温度，用于LC-MS/MS分析。Collect whole blood samples (approximately 0.03 mL per group) at a prescribed time (or other suitable blood collection sites) by saphenous vein puncture, and record the actual blood collection time in the test record. The acceptable error of the collection time point is the time point within 1 hour of administration ± 1 minute, and the other time point is the theoretical time ± 5%. All blood samples were immediately transferred to labeled commercial centrifuge tubes containing K2-EDTA. After the blood sample is collected, the supernatant plasma is collected by centrifugation at 3200g for 10 minutes at 4 degrees Celsius, quickly placed in dry ice, and kept at -20 degrees Celsius or lower for LC-MS/MS analysis.
化合物在血浆中的浓度由高效液相色谱-串联质谱(LC-MS/MS)进行测定。化合物和内标(双氯芬酸)的保留时间、色谱图采集和色谱图的积分采用软件Analyst(Applied Biosystems)进行处理，数据的统计采用软件Watson LIMS(Thermo Fisher Scientific)或Analyst(Applied Biosystems)进行处理。样品中分析物浓度单位为ng/mL，保留3位有效数字，所有以百分数表示的数值(如：％偏差和％变异系数等)均保留到小数点后一位。每条校正曲线至少包含6个浓度水平。校正标样的配制需采用和质控样品不同来源的储备液。校正标样算得的浓度与标示值的偏差超出±15.0％(定量下限超出±20.0％)回归分析中应拒绝该标样。被拒绝的校正标样应小于25％，且每条校正曲线至少包含6个符合接受标准的校正标样。如定量下限和定量上限校正标样需要拒绝时，该分析批的定量上限和下限将相应的提高和降低。The concentration of the compound in plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The retention time of the compound and the internal standard (diclofenac), the collection of chromatograms, and the integration of the chromatograms are processed by the software Analyst (Applied Biosystems), and the data statistics are processed by the software Watson LIMS (Thermo Fisher Scientific) or Analyst (Applied Biosystems). The unit of the analyte concentration in the sample is ng/mL, with 3 significant digits reserved, and all values expressed in percentage (such as% deviation and% coefficient of variation, etc.) are kept to one decimal place. Each calibration curve contains at least 6 concentration levels. The preparation of calibration standards requires stock solutions from different sources from the quality control samples. The deviation between the calculated concentration of the calibration standard sample and the labeled value exceeds ±15.0% (the lower limit of quantification exceeds ±20.0%). The standard sample should be rejected in the regression analysis. The rejected calibration standards should be less than 25%, and each calibration curve contains at least 6 calibration standards that meet the acceptance criteria. If the lower limit of quantification and upper limit of quantification need to be rejected, the upper and lower limit of quantification of the analysis batch will be increased and lowered accordingly.
采用WinNonlin
TMVersion 6.3(Pharsight,Mountain View,CA)药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数。需计算的药动学参数包含但不局限于(数据允许)静脉注射给药(iv)组的T
1/2、Vd
ss、CL、AUC
0-24h；口服灌胃给药(po)组的C
max、T
max、AUC
0-24h、生物利用度(F％)。
The non-compartmental model of WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process the plasma concentration, and the linear logarithmic ladder method was used to calculate the pharmacokinetic parameters. The pharmacokinetic parameters to be calculated include but are not limited to (data permitted) T 1/2 , Vd ss , CL, AUC 0-24h in the intravenous administration (iv) group; oral administration (po) group C max , T max , AUC 0-24h , bioavailability (F%).
本发明实施例在小鼠体内的药代动力学相关参数如下表2所示。The pharmacokinetic parameters of the examples of the present invention in mice are shown in Table 2 below.
表2小鼠药代动力学研究结果Table 2 Results of pharmacokinetic studies in mice
结论：本发明化合物在小鼠药代动力学研究中，展现较低的清除率和较高的药物血浆暴露量，具有良好的药代动力学性质。Conclusion: In the pharmacokinetic study of mice, the compound of the present invention exhibits a lower clearance rate and a higher plasma exposure of the drug, and has good pharmacokinetic properties.
Claims (22)
- 式(I’)所示化合物或其药学上可接受的盐，The compound represented by formula (I') or a pharmaceutically acceptable salt thereof,
其中，among them,E选自E is selected from
R 1选自H、F和C 1～3烷基，所述任选被1、2或3个R a取代； R 1 is selected H, F, and C 1 ~ 3 alkyl group, the optionally substituted with 1, 2 or 3 R a;R 2选自H、F、Cl、Br和CF 3； R 2 is selected from H, F, Cl, Br and CF 3 ;R 3、R 4、R 5和R 6分别独立地选自H、F、Cl、Br、CN、C 1～6烷基、C 3～6环烷基、C 1～6杂烷基和3～6元杂环烷基，所述C 1～6烷基、C 3～6环烷基、C 1～6杂烷基和3～6元杂环烷基任选被1、2或3个R b取代； R 3 , R 4 , R 5 and R 6 are each independently selected from H, F, Cl, Br, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3 ~ 6-membered heterocycloalkyl, the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally selected by 1, 2, or 3 R b replaces;L选自-O-、-S-、-SO 2-、-N(R 7)-和-C(R 7) 2-； L is selected from -O-, -S-, -SO 2 -, -N(R 7 )- and -C(R 7 ) 2 -;L 1选自-C(R 7) 2-； L 1 is selected from -C(R 7 ) 2 -;L 2选自-C(R 7) 2-； L 2 is selected from -C(R 7 ) 2 -;R 7分别独立地选自H、F、Cl、Br、I、C 1～6烷基、C 3～6环烷基、C 1～6杂烷基和3～6元杂环烷基，所述C 1～6烷基、C 3～6环烷基、C 1～6杂烷基和3～6元杂环烷基任选被1、2或3个R c取代； R 7 is each independently selected from H, F, Cl, Br, I, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, so The C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 heteroalkyl group and 3-6 membered heterocycloalkyl group are optionally substituted with 1, 2 or 3 R c ;T、T 1、T 2、T 3分别独立地选自CR 8和N； T, T 1 , T 2 , and T 3 are independently selected from CR 8 and N;R 8选自H、F、Cl、Br、I、CN、C 1～6烷基、C 3～6环烷基、C 1～6杂烷基和3～6元杂环烷基，所述C 1～6烷基、C 3～6环烷基、C 1～6杂烷基和3～6元杂环烷基任选被1、2或3个R d取代； R 8 is selected from H, F, Cl, Br, I, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R d ;m选自1、2、3和4；m is selected from 1, 2, 3 and 4;R 9分别独立地选自H、F、Cl、Br、I和C 1～3烷基，所述C 1～3烷基任选被1、2或3个R e取代； R 9 is each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl groups, the C 1-3 alkyl groups are optionally substituted with 1, 2 or 3 R e ;R a、R b、R c、R d和R e分别独立地选自F、Cl、Br、I、OH、CN、NH 2、COOH、CF 3、-CHF 2、-CH 2F、-OCH 3、CH 3、-CH 2CH 3、-CH(CH 3) 2、-NHCH 3、-N(CH 3) 2和环丙基； R a, R b, R c , R d and R e are each independently selected from F, Cl, Br, I, OH, CN, NH 2, COOH, CF 3, -CHF 2, -CH 2 F, -OCH 3 , CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -NHCH 3 , -N(CH 3 ) 2 and cyclopropyl;所述C 1～6杂烷基和3～6元杂环烷分别独立地包含1、2、3或4个独立地选自O、N、S和NH的原子或杂原子团。 The C 1-6 heteroalkyl group and 3-6 membered heterocycloalkane each independently include 1, 2, 3, or 4 atoms or heteroatom groups independently selected from O, N, S, and NH. - 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 1选自H、F和CH 3，所述任选被1、2或3个R a取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein, R & lt one selected from H, F and CH 3, said optionally substituted with 1, 2 or 3 R a.
- 根据权利要求2所述的化合物或其药学上可接受的盐，其中，R 1选自H和CH 3。 The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H and CH 3 .
- 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 2选自Cl。 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is selected from Cl.
- 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 3、R 4、R 5和R 6分别独立地选自H。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 , R 5 and R 6 are each independently selected from H.
- 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 7选自H、F、Cl、Br、I、-OCH 3、CH 3、-CH 2CH 3、-NHCH 3和环丙基，所述-OCH 3、CH 3、-CH 2CH 3、-NHCH 3和环丙基任选被1、2或3个R c取代。 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 7 is selected from H, F, Cl, Br, I, -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and Cyclopropyl, the -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl are optionally substituted with 1, 2 or 3 R c .
- 根据权利要求6所述的化合物或其药学上可接受的盐，其中，R 7选自H、F、Cl、Br、I、CF 3、-CHF 2、-CH 2F、-OCH 3、CH 3、-CH 2CH 3、-CH(CH 3) 2、-NHCH 3、-N(CH 3) 2和环丙基。 The compound or a pharmaceutically acceptable salt thereof according to claim 6, wherein R 7 is selected from H, F, Cl, Br, I, CF 3 , -CHF 2 , -CH 2 F, -OCH 3 , CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -NHCH 3 , -N(CH 3 ) 2 and cyclopropyl.
- 根据权利要求1或7所述的化合物或其药学上可接受的盐，其中，L选自-O-、-S-、-SO 2-、-NH·-和-CH 2-。 The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 7, wherein L is selected from -O-, -S-, -SO 2 -, -NH·- and -CH 2 -.
- 根据权利要求8所述的化合物或其药学上可接受的盐，其中，L选自-O-。The compound or a pharmaceutically acceptable salt thereof according to claim 8, wherein L is selected from -O-.
- 根据权利要求1或7所述的化合物或其药学上可接受的盐，其中，L 1选自-CH 2-、-CHF-和-CF 2-。 The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 7, wherein L 1 is selected from -CH 2 -, -CHF- and -CF 2 -.
- 根据权利要求1或7所述的化合物或其药学上可接受的盐，其中，L 2选自-CH 2-、-CHF-和-CF 2-。 The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 7, wherein L 2 is selected from -CH 2 -, -CHF- and -CF 2 -.
- 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 8选自H、F、Cl、Br、I、-OCH 3、CH 3、-CH 2CH 3、-NHCH 3和环丙基，所述-OCH 3、CH 3、-CH 2CH 3、-NHCH 3和环丙基任选被1、2或3个R d取代。 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 8 is selected from H, F, Cl, Br, I, -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and Cyclopropyl, the -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl are optionally substituted with 1, 2 or 3 Rd .
- 根据权利要求12所述的化合物或其药学上可接受的盐，其中，R 8选自H。 The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from H.
- 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 9分别独立地选自H。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 9 is independently selected from H.
- 根据权利要求1所述的化合物或其药学上可接受的盐，其中，结构单元选自
The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit
Selected from - 根据权利要求15所述的化合物或其药学上可接受的盐，其中，结构单元选自
The compound or a pharmaceutically acceptable salt thereof according to claim 15, wherein the structural unit
Selected from - 根据权利要求1～16任意一项所述的化合物或其药学上可接受的盐，其中，化合物选自The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein the compound is selected from
其中，among them,R 1、R 2、R 3、R 4、R 5、R 6、R 9、T、T 1、T 2、T 3、L 1、L 2和m如权利要求1～16所定义。 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , T, T 1 , T 2 , T 3 , L 1 , L 2 and m are as defined in claims 1-16. - 根据权利要求17所述的化合物或其药学上可接受的盐，其中，化合物选自The compound or a pharmaceutically acceptable salt thereof according to claim 17, wherein the compound is selected from
其中，among them,R 1、R 2、R 3、R 4、R 5、R 6和R 8如权利要求1～16所定义。 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are as defined in claims 1-16. - 下式化合物或其药学上可接受的盐，化合物选自The compound of the following formula or a pharmaceutically acceptable salt thereof, the compound is selected from
- 根据权利要求19所述的化合物或其药学上可接受的盐，其中，化合物选自The compound or a pharmaceutically acceptable salt thereof according to claim 19, wherein the compound is selected from
- 根据根据权利要求1～20任意一项所述的化合物或其药学上可接受的盐在制备治疗乙型肝炎病毒药物中的应用。The use of the compound according to any one of claims 1-20 or a pharmaceutically acceptable salt thereof in the preparation of a medicine for the treatment of hepatitis B virus.
- 根据根据权利要求1～20任意一项所述的化合物或其药学上可接受的盐在制备抑制cccDNA的活性的药物中的应用。The use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 in the preparation of a medicine for inhibiting the activity of cccDNA.
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|---|---|---|---|---|
| CN1829709A (en) * | 2003-08-01 | 2006-09-06 | 健亚生物科技公司 | Bicyclic imidazol derivatives against flaviviridae |
| US20090264426A1 (en) * | 2005-09-07 | 2009-10-22 | Shunji Sakuraba | Bicyclic aromatic substituted pyridone derivative |
| CN103140474A (en) * | 2010-07-02 | 2013-06-05 | 吉里德科学公司 | Napht- 2 -ylacetic acid derivatives to treat aids |
| WO2019204614A1 (en) * | 2018-04-19 | 2019-10-24 | Tvardi, Inc. | Stat3 inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829709A (en) * | 2003-08-01 | 2006-09-06 | 健亚生物科技公司 | Bicyclic imidazol derivatives against flaviviridae |
| US20090264426A1 (en) * | 2005-09-07 | 2009-10-22 | Shunji Sakuraba | Bicyclic aromatic substituted pyridone derivative |
| CN103140474A (en) * | 2010-07-02 | 2013-06-05 | 吉里德科学公司 | Napht- 2 -ylacetic acid derivatives to treat aids |
| WO2019204614A1 (en) * | 2018-04-19 | 2019-10-24 | Tvardi, Inc. | Stat3 inhibitors |
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