WO2021204258A1 - 作为乙肝表面抗原抑制剂的氮杂双环化合物 - Google Patents
作为乙肝表面抗原抑制剂的氮杂双环化合物 Download PDFInfo
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- WO2021204258A1 WO2021204258A1 PCT/CN2021/086205 CN2021086205W WO2021204258A1 WO 2021204258 A1 WO2021204258 A1 WO 2021204258A1 CN 2021086205 W CN2021086205 W CN 2021086205W WO 2021204258 A1 WO2021204258 A1 WO 2021204258A1
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- 0 C*(C)N(CC1)CC1OC Chemical compound C*(C)N(CC1)CC1OC 0.000 description 10
- FQDAJFFCUYOXOI-UHFFFAOYSA-N CC(C)(C)N(CC1)CCN1S(C)(=O)=O Chemical compound CC(C)(C)N(CC1)CCN1S(C)(=O)=O FQDAJFFCUYOXOI-UHFFFAOYSA-N 0.000 description 1
- OILJIEKQCVHNMM-UHFFFAOYSA-N CC(C)(C)N1CCOCC1 Chemical compound CC(C)(C)N1CCOCC1 OILJIEKQCVHNMM-UHFFFAOYSA-N 0.000 description 1
- ZVPDOQPRMJWPPR-UHFFFAOYSA-N CC(C)(C)c1nc(F)cc(N(C)CCOC)c1 Chemical compound CC(C)(C)c1nc(F)cc(N(C)CCOC)c1 ZVPDOQPRMJWPPR-UHFFFAOYSA-N 0.000 description 1
- IFOZTCATGKLXJR-UHFFFAOYSA-N CC(C)(C)c1nc(F)cc(NCCOC)c1 Chemical compound CC(C)(C)c1nc(F)cc(NCCOC)c1 IFOZTCATGKLXJR-UHFFFAOYSA-N 0.000 description 1
- LQMMFVPUIVBYII-UHFFFAOYSA-N CC1OCCNC1 Chemical compound CC1OCCNC1 LQMMFVPUIVBYII-UHFFFAOYSA-N 0.000 description 1
- IQAKNWUPMXHDIZ-UHFFFAOYSA-N CCCC(C1)c2nc(-c3ncccc3)ncc2CN1c1nc(F)cc(N(C)C)c1 Chemical compound CCCC(C1)c2nc(-c3ncccc3)ncc2CN1c1nc(F)cc(N(C)C)c1 IQAKNWUPMXHDIZ-UHFFFAOYSA-N 0.000 description 1
- NVJBCEUBOOPSKB-UHFFFAOYSA-N CCCC(C1)c2nc(-c3ncccn3)ncc2CN1c1nc(F)cc(N(C2)CC2OC)c1 Chemical compound CCCC(C1)c2nc(-c3ncccn3)ncc2CN1c1nc(F)cc(N(C2)CC2OC)c1 NVJBCEUBOOPSKB-UHFFFAOYSA-N 0.000 description 1
- UZFKZDQQQNZECH-UHFFFAOYSA-N CCS(c1cc(C)nc(F)c1)(=O)=O Chemical compound CCS(c1cc(C)nc(F)c1)(=O)=O UZFKZDQQQNZECH-UHFFFAOYSA-N 0.000 description 1
- CJNJXUIROPVPQK-UHFFFAOYSA-N CN(C)N1CC(C2)OC2C1 Chemical compound CN(C)N1CC(C2)OC2C1 CJNJXUIROPVPQK-UHFFFAOYSA-N 0.000 description 1
- PDTGGAIHOGHKCK-UHFFFAOYSA-N CN(C)c1cc(N2C3c4cnc(-c5ncccc5)nc4CC2CCC3)nc(F)c1 Chemical compound CN(C)c1cc(N2C3c4cnc(-c5ncccc5)nc4CC2CCC3)nc(F)c1 PDTGGAIHOGHKCK-UHFFFAOYSA-N 0.000 description 1
- PDTGGAIHOGHKCK-IFXJQAMLSA-N CN(C)c1cc(N2[C@H]3c4cnc(-c5ncccc5)nc4C[C@@H]2CCC3)nc(F)c1 Chemical compound CN(C)c1cc(N2[C@H]3c4cnc(-c5ncccc5)nc4C[C@@H]2CCC3)nc(F)c1 PDTGGAIHOGHKCK-IFXJQAMLSA-N 0.000 description 1
- YDOGEBDDNZDNJY-UHFFFAOYSA-N CN(CC1)CCN1S(C)(=O)=O Chemical compound CN(CC1)CCN1S(C)(=O)=O YDOGEBDDNZDNJY-UHFFFAOYSA-N 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N CN1CCOCC1 Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- XTGDPTZKVFPDCN-UHFFFAOYSA-N COC(C1)CN1c1cc(N2C3c4cnc(-c5ncccn5)nc4CC2CCC3)nc(F)c1 Chemical compound COC(C1)CN1c1cc(N2C3c4cnc(-c5ncccn5)nc4CC2CCC3)nc(F)c1 XTGDPTZKVFPDCN-UHFFFAOYSA-N 0.000 description 1
- XTGDPTZKVFPDCN-IFXJQAMLSA-N COC(C1)CN1c1cc(N2[C@H]3c4cnc(-c5ncccn5)nc4C[C@@H]2CCC3)nc(F)c1 Chemical compound COC(C1)CN1c1cc(N2[C@H]3c4cnc(-c5ncccn5)nc4C[C@@H]2CCC3)nc(F)c1 XTGDPTZKVFPDCN-IFXJQAMLSA-N 0.000 description 1
- WSILTRVMAQBBLL-LCSKWRJPSA-N COCCCOc1cc(N2C3(C4)C4CC[C@@H]2c2cnc(-c4ncccc4)nc2C3)nc(F)c1 Chemical compound COCCCOc1cc(N2C3(C4)C4CC[C@@H]2c2cnc(-c4ncccc4)nc2C3)nc(F)c1 WSILTRVMAQBBLL-LCSKWRJPSA-N 0.000 description 1
- VDACMFSVLARMRH-HRAATJIYSA-N COCCCOc1cc(N2[C@H]3c4cnc(-c5ncccc5)nc4C[C@@H]2CCC3)nc(F)c1 Chemical compound COCCCOc1cc(N2[C@H]3c4cnc(-c5ncccc5)nc4C[C@@H]2CCC3)nc(F)c1 VDACMFSVLARMRH-HRAATJIYSA-N 0.000 description 1
- OVORPYUFYCLHSF-UHFFFAOYSA-N CS(C)N(CCC1)S1(=O)=O Chemical compound CS(C)N(CCC1)S1(=O)=O OVORPYUFYCLHSF-UHFFFAOYSA-N 0.000 description 1
- DRKDESYZPJWZHJ-UHFFFAOYSA-N CS(N(CC1)CCN1c1cc(N2C3c4cnc(-c5ncccn5)nc4CC2CCC3)nc(F)c1)(=O)=O Chemical compound CS(N(CC1)CCN1c1cc(N2C3c4cnc(-c5ncccn5)nc4CC2CCC3)nc(F)c1)(=O)=O DRKDESYZPJWZHJ-UHFFFAOYSA-N 0.000 description 1
- DRKDESYZPJWZHJ-OXJNMPFZSA-N CS(N(CC1)CCN1c1cc(N2[C@H]3c4cnc(-c5ncccn5)nc4C[C@@H]2CCC3)nc(F)c1)(=O)=O Chemical compound CS(N(CC1)CCN1c1cc(N2[C@H]3c4cnc(-c5ncccn5)nc4C[C@@H]2CCC3)nc(F)c1)(=O)=O DRKDESYZPJWZHJ-OXJNMPFZSA-N 0.000 description 1
- LVNGQWVNUCNHSI-KDOFPFPSSA-N Cc(cc1)cnc1-c1ncc([C@H](CCC[C@@H]2C3)N2c2nc(F)cc(F)c2)c3n1 Chemical compound Cc(cc1)cnc1-c1ncc([C@H](CCC[C@@H]2C3)N2c2nc(F)cc(F)c2)c3n1 LVNGQWVNUCNHSI-KDOFPFPSSA-N 0.000 description 1
- MIAHZODQRPLKEX-UHFFFAOYSA-N Cc1cc(N(CC2)CCN2S(C)(=O)=O)cc(F)n1 Chemical compound Cc1cc(N(CC2)CCN2S(C)(=O)=O)cc(F)n1 MIAHZODQRPLKEX-UHFFFAOYSA-N 0.000 description 1
- PBPVBRWGXHOXMN-UHFFFAOYSA-N Cc1nc(F)cc(OC)c1 Chemical compound Cc1nc(F)cc(OC)c1 PBPVBRWGXHOXMN-UHFFFAOYSA-N 0.000 description 1
- RNEKVFZOBNKSAH-FWJOYPJLSA-N Fc1cc(N2C3c4cnc(-c5ncccc5)nc4C[C@H]2CCC3)nc(F)c1 Chemical compound Fc1cc(N2C3c4cnc(-c5ncccc5)nc4C[C@H]2CCC3)nc(F)c1 RNEKVFZOBNKSAH-FWJOYPJLSA-N 0.000 description 1
- RNEKVFZOBNKSAH-SUMWQHHRSA-N Fc1cc(N2[C@H]3c4cnc(-c5ccccn5)nc4C[C@@H]2CCC3)nc(F)c1 Chemical compound Fc1cc(N2[C@H]3c4cnc(-c5ccccn5)nc4C[C@@H]2CCC3)nc(F)c1 RNEKVFZOBNKSAH-SUMWQHHRSA-N 0.000 description 1
- ZOHVERGDIHQDLW-SWLSCSKDSA-N Fc1cc(N2[C@H]3c4cnc(-c5ncccn5)nc4C[C@@H]2CCC3)nc(F)c1 Chemical compound Fc1cc(N2[C@H]3c4cnc(-c5ncccn5)nc4C[C@@H]2CCC3)nc(F)c1 ZOHVERGDIHQDLW-SWLSCSKDSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
-
- 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
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
Definitions
- This application belongs to the field of medicinal chemistry, and relates to azabicyclic compounds as inhibitors of hepatitis B surface antigen.
- the present application specifically relates to the compound of formula I', its stereoisomers, its pharmaceutically acceptable salts, its preparation method, pharmaceutical compositions containing the compound, and its use as a medicament for the treatment of hepatitis B virus infection.
- hepatitis B virus is one of the world's health problems. There are about 400 million chronically infected people around the world, and they have a higher risk of liver cirrhosis and hepatocellular carcinoma. Currently, the incurable treatment of chronic viral hepatitis B can only be controlled, mainly limited to two types of agents (interferon and nucleoside analog/viral polymerase inhibitors).
- Hepatitis B surface antigen (HBsAg) quantification is a significant biomarker for prognosis and treatment response in chronic hepatitis B. Continuous exposure to HBsAg and other viral antigens can lead to the loss of HBV-specific T cells or cause progressive functional impairment.
- HBsAg has been reported to inhibit the function of immune cells such as monocytes, dendritic cells (DC) and natural killer (NK) cells through direct interaction.
- DC dendritic cells
- NK natural killer
- HBsAg disappearance and seroconversion are rarely observed in chronically infected patients, which is still the target of treatment.
- Current therapies such as nucleoside analogs are molecules that inhibit HBV DNA synthesis but do not reduce HBsAg levels.
- Studies have disclosed inhibitors that target the hepatitis B surface antigen, such as WO2016107832, WO2016177655, WO2018083106 and so on.
- At least one of X and Y is N, and the other is CH or N;
- A is selected from 5-6 membered heteroaryl, said A is optionally substituted with 1, 2 or 3 R 1 ;
- R 1 is selected from C 1-8 alkyl, C 1-8 alkoxy, halogen, C 3-7 cycloalkyl, 1-3 halo C 1-8 alkyl or 1-3 halo C 1 -8 alkoxy;
- p is selected from 1, 2, 3 or 4;
- L is selected from a single bond, -CO- or -SO 2 -;
- R 2 is selected from 6-10 membered aryl groups, 3-8 membered with 1-3 heteroaryl groups selected from N, O or S, or 3-8 membered with 1-3 selected from N, O or S Heterocycloalkyl, each of said R 2 is independently optionally substituted with 1 to 4 R 3;
- the R 4 is selected from halogen, -NO 2 , -CN, -C 1-8 alkyl, -C 3-7 cycloalkyl, -OH, -OC 1-8 alkyl, -OC 3-7 cycloalkane Group, -NH 2 , -NHC 1-8 alkyl, -N (C 1-8 alkyl) 2 , -SH, -SC 1-8 alkyl, -SC 3-7 cycloalkyl, -CO-C 1-8 alkyl, -COO-C 1-8 alkyl, -OCO-C 1-8 alkyl, -CONHC 1-8 alkyl, -CON (C 1-8 alkyl) 2 , -NHCO-C 1-8 alkyl, or -SO 2 C 1-8 alkyl.
- compositions which includes the compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof, and optionally further includes pharmaceutically acceptable excipients.
- Another aspect of the present application provides the use of the compound of the present application, its stereoisomers, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of hepatitis B virus infection.
- At least one of X and Y is N, and the other is CH or N;
- A is selected from 5-6 membered heteroaryl, said A is optionally substituted with 1, 2 or 3 R 1 ;
- R 1 is selected from C 1-8 alkyl, C 1-8 alkoxy, halogen, C 3-7 cycloalkyl, 1-3 halo C 1-8 alkyl or 1-3 halo C 1 -8 alkoxy;
- p is selected from 1, 2, 3 or 4;
- L is selected from a single bond, -CO- or -SO 2 -;
- R 2 is selected from 6-10 membered aryl groups, 3-8 membered with 1-3 heteroaryl groups selected from N, O or S, or 3-8 membered with 1-3 selected from N, O or S Heterocycloalkyl, each of said R 2 is independently optionally substituted with 1 to 4 R 3;
- the R 4 is selected from halogen, -NO 2 , -CN, -C 1-8 alkyl, -C 3-7 cycloalkyl, -OH, -OC 1-8 alkyl, -OC 3-7 cycloalkane Group, -NH 2 , -NHC 1-8 alkyl, -N (C 1-8 alkyl) 2 , -SH, -SC 1-8 alkyl, -SC 3-7 cycloalkyl, -CO-C 1-8 alkyl, -COO-C 1-8 alkyl, -OCO-C 1-8 alkyl, -CONHC 1-8 alkyl, -CON (C 1-8 alkyl) 2 , -NHCO-C 1-8 alkyl, or -SO 2 C 1-8 alkyl.
- the X is N and Y is CH, X is CH and Y is N, or both X and Y are N. In some aspects, both X and Y are N.
- the A is selected from 5-6 membered heteroaryl groups containing 1-4 atoms selected from N, O or S, and the A is optionally substituted with 1, 2 or 3 R 1 .
- the A is selected from in Represents a single bond or a double bond, T is selected from C or N, U, V, W and Z are each independently selected from CH, N, O or S, optionally one of U, V and W is selected from a bond, so Said A is optionally substituted with 1, 2 or 3 R 1 .
- the A is selected from pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazine, pyridazinyl or pyrimidinyl, and the A is optionally Ground is replaced by 1, 2 or 3 R 1 .
- the A is selected from pyridyl or pyrimidinyl, and the A is optionally substituted with 1, 2, or 3 R 1 .
- the U, V, W, and Z are all CH, or U, V, and W are CH and Z is N. In some aspects, the U, V, and W are CH and Z is N. In some aspects, one of the U, V, and W is selected from a bond, and the other is selected from CH, N, O, or S.
- the R 1 is selected from C 1-6 alkyl, C 1-6 alkoxy, F, Cl, Br, 1-3 F, Cl or Br substituted C 1-6 alkyl, Or 1-3 C 1-6 alkoxy substituted with F, Cl or Br. In some embodiments, the R 1 is selected from C 1-4 alkyl, C 1-4 alkoxy, F, Cl, Br, 1-3 F, Cl or Br substituted C 1-4 alkyl, Or 1-3 C 1-4 alkoxy substituted with F, Cl or Br.
- p is selected from 2 or 3. In some aspects, p is selected from 2. In some aspects, p is selected from 3.
- L is selected from single bonds.
- the R 2 is selected from 6-8 membered aryl groups, 4-6 membered containing 1-3 heteroaryl groups selected from N, O or S, or 4-6 membered containing 1-3 selected From N, O or S heterocycloalkyl, the substituents of R 2 are as described in this application.
- the R 2 is selected from phenyl, naphthyl, 4-6 membered with 1-2 heteroaryl groups selected from N, O or S, or 4-6 membered with 1-2 heteroaryl groups selected from N, O or S heterocycloalkyl, the substituent of R 2 is as described in this application.
- the R 2 is selected from phenyl, 4-6 membered containing 1-2 heteroaryl groups selected from N, or 4-6 membered containing 1-2 heterocycloalkanes selected from N or O
- the substituents of R 2 are as described in this application.
- the R 2 is selected from phenyl, pyridyl, or morpholinyl, and the substituent of R 2 is as described in this application.
- the R 2 is selected from pyridyl, and the substituents of R 2 are as described in this application.
- the R 3 is selected from F, Cl, Br, -NO 2 , -CN, -C 1-6 alkyl, -C 3-6 cycloalkyl, -OH, -OC 1-6 alkane Group, -OC 3-6 cycloalkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -SH, -SC 1-6 alkyl, -SC 3- 6 cycloalkyl, -CO-C 1-6 alkyl, -COO-C 1-6 alkyl, -OCO-C 1-6 alkyl, -CONHC 1-6 alkyl, -CON(C 1-6 Alkyl) 2 , -NHCO-C 1-6 alkyl, or 4-6 membered heterocycloalkyl containing 1-3 selected from N, O or S, said -C 1-6 alkyl, -C 3-6 cycloalkyl, -OC 1-6 alkyl, or 4-6 member
- the R 3 is selected from F, Cl, Br, -NO 2 , -CN, -C 1-4 alkyl, -C 3-6 cycloalkyl, -OH, -OC 1-4 alkane Group, -OC 3-6 cycloalkyl, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -SH, -SC 1-4 alkyl, -SC 3- 6 cycloalkyl, -CO-C 1-4 alkyl, -COO-C 1-4 alkyl, -OCO-C 1-4 alkyl, -CONHC 1-4 alkyl, -CON(C 1-4 Alkyl) 2 , -NHCO-C 1-4 alkyl, or 4-6 membered heterocycloalkyl containing 1-3 selected from N, O or S, said -C 1-4 alkyl, -C 3-6 cycloalkyl, -OC 1-4 alkyl, -OH,
- the R 3 is selected from F, Cl, Br, -C 1-4 alkyl, -C 3-6 cycloalkyl, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , OH, -OC 1-4 alkyl, -OC 3-6 cycloalkyl, azetidinyl, azetidinyl, azetidinyl, or 4
- the -6 member contains 2 heterocycloalkyl groups selected from N, O or S, the -C 1-4 alkyl group, -C 3-6 cycloalkyl group, -NHC 1-4 alkyl group, -N (C 1-4 alkyl) 2 , -OC 1-4 alkyl, or -OC 3-6 cycloalkyl are each independently optionally substituted with 1-3 R 4 , the azetidinyl, nitrogen The heterocyclopentyl group, azetidine group, or
- the R 3 is selected from halogen, -NO 2 , -CN, -C 1-8 alkyl, -C 3-7 cycloalkyl, -OH, -OC 1-8 alkyl, -OC 3-7 cycloalkyl, -NH 2 , -NHC 1-8 alkyl, -N(C 1-8 alkyl) 2 , -SH, -SC 1-8 alkyl, -SC 3-7 cycloalkyl , -CO-C 1-8 alkyl, -COO-C 1-8 alkyl, -OCO-C 1-8 alkyl, -CONHC 1-8 alkyl, -CON (C 1-8 alkyl) 2 , -NHCO-C 1-8 alkyl, or 3-8 membered heterocycloalkyl containing 1-3 selected from N, O or S; the -C 1-8 alkyl, -C 3-7 ring Alkyl, -OC 1-8 alkyl, -OC 1-8 alky
- the R 4 is selected from halogen, -NO 2 , -CN, -C 1-8 alkyl, -C 3-7 cycloalkyl, -OH, -OC 1-8 alkyl, -OC 3-7 cycloalkyl, -NH 2 , -NHC 1-8 alkyl, -N(C 1-8 alkyl) 2 , -SH, -SC 1-8 alkyl, -SC 3-7 cycloalkyl , -CO-C 1-8 alkyl, -COO-C 1-8 alkyl, -OCO-C 1-8 alkyl, -CONHC 1-8 alkyl, -CON (C 1-8 alkyl) 2 Or -NHCO-C 1-8 alkyl.
- the R 4 is selected from F, Cl, Br, -NO 2 , -CN, -C 1-6 alkyl, -C 3-6 cycloalkyl, -OH, -OC 1-6 alkane Group, -OC 3-6 cycloalkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -SH, -SC 1-6 alkyl, -SC 3- 6 cycloalkyl, -CO-C 1-6 alkyl, -COO-C 1-6 alkyl, -OCO-C 1-6 alkyl, -CONHC 1-6 alkyl, -CON(C 1-6 Alkyl) 2 , -NHCO-C 1-6 alkyl, or -S(O) 2 C 1-6 alkyl.
- the R 4 is selected from F, Cl, Br, -NO 2 , -CN, -C 1-4 alkyl, -C 3-6 cycloalkyl, -OH, -OC 1-4 alkane Group, -OC 3-6 cycloalkyl, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -SH, -SC 1-4 alkyl, -SC 3- 6 cycloalkyl, -CO-C 1-4 alkyl, -COO-C 1-4 alkyl, -OCO-C 1-4 alkyl, -CONHC 1-4 alkyl, -CON(C 1-4 Alkyl) 2 , -NHCO-C 1-4 alkyl, or -S(O) 2 C 1-4 alkyl.
- the R 4 is selected from F, Cl, Br, -NO 2 , -CN, -C 1-6 alkyl, -C 3-6 cycloalkyl, -OH, -OC 1-6 alkane Group, -OC 3-6 cycloalkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -SH, -SC 1-6 alkyl, -SC 3- 6 cycloalkyl, -CO-C 1-6 alkyl, -COO-C 1-6 alkyl, -OCO-C 1-6 alkyl, -CONHC 1-6 alkyl, -CON(C 1-6 Alkyl) 2 or -NHCO-C 1-6 alkyl.
- the R 4 is selected from F, Cl, Br, -NO 2 , -CN, -C 1-4 alkyl, -C 3-6 cycloalkyl, -OH, -OC 1-4 alkane Group, -OC 3-6 cycloalkyl, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -SH, -SC 1-4 alkyl, -SC 3- 6 cycloalkyl, -CO-C 1-4 alkyl, -COO-C 1-4 alkyl, -OCO-C 1-4 alkyl, -CONHC 1-4 alkyl, -CON(C 1-4 Alkyl) 2 or -NHCO-C 1-4 alkyl.
- the R 4 is selected from F, Cl, Br, -C 1-6 alkyl, -C 3-6 cycloalkyl, -OC 1-6 alkyl, or -OC 3-6 cycloalkane base.
- the R 4 is selected from F, -OCH 3 , cyclopropyl, or -S(O) 2 CH 3 .
- the R 4 is selected from halogen, -NO 2 , -CN, -C 1-8 alkyl, -C 3-7 cycloalkyl, -OH, -OC 1-8 alkyl, -OC 3-7 cycloalkyl, -NH 2 , -NHC 1-8 alkyl, -N(C 1-8 alkyl) 2 , -SH, -SC 1-8 alkyl, -SC 3-7 cycloalkyl , -CO-C 1-8 alkyl, -COO-C 1-8 alkyl, -OCO-C 1-8 alkyl, -CONHC 1-8 alkyl, -CON (C 1-8 alkyl) 2 , Or -NHCO-C 1-8 alkyl.
- the R 4 is selected from F, Cl, Br, -NO 2 , -CN, -C 1-6 alkyl, -C 3-6 cycloalkyl, -OH, -OC 1-6 alkane Group, -OC 3-6 cycloalkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -SH, -SC 1-6 alkyl, -SC 3- 6 cycloalkyl, -CO-C 1-6 alkyl, -COO-C 1-6 alkyl, -OCO-C 1-6 alkyl, -CONHC 1-6 alkyl, -CON(C 1-6 Alkyl) 2 , or -NHCO-C 1-6 alkyl.
- the R 4 is selected from F, Cl, Br, -NO 2 , -CN, -C 1-4 alkyl, -C 3-6 cycloalkyl, -OH, -OC 1-4 alkane Group, -OC 3-6 cycloalkyl, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -SH, -SC 1-4 alkyl, -SC 3- 6 cycloalkyl, -CO-C 1-4 alkyl, -COO-C 1-4 alkyl, -OCO-C 1-4 alkyl, -CONHC 1-4 alkyl, -CON(C 1-4 Alkyl) 2 , or -NHCO-C 1-4 alkyl.
- the R 4 is selected from F, Cl, Br, -C 1-6 alkyl, -C 3-6 cycloalkyl, -OC 1-6 alkyl, or -OC 3-6 cycloalkane base. In some schemes, the R 4 is selected from F, -OCH 3 , or cyclopropyl.
- the R 2 is selected from phenyl, The substituents of the groups are as described in this application. In some embodiments, the R 2 is selected from phenyl or The substituents of the groups are as described in this application.
- the R 3 is selected from F, Cl, -N(CH 3 ) 2 , -OCH 3 , -CF 3 ,
- the R 3 is selected from F, Cl, -N(CH 3 ) 2 , -OCH 3 , -CF 3 ,
- the R 2 is selected from
- the R 2 is selected from
- the R 2 is selected from
- this application includes the above-defined variables and their implementations, as well as any combination thereof.
- the compound of formula I', its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula II', its stereoisomer, or a pharmaceutically acceptable salt thereof,
- T is selected from C or N;
- U, V, W, and Z are each independently selected from CH, N, O, or S, and optionally one of U, V, and W is selected from a bond;
- q is selected from 0, 1, 2 or 3;
- the compound of formula I', its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula III', its stereoisomer, or a pharmaceutically acceptable salt thereof,
- the compound of formula I', its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula IV', its stereoisomer, or a pharmaceutically acceptable salt thereof,
- the compound of formula I', its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula V', its stereoisomer, or a pharmaceutically acceptable salt thereof,
- the compound of formula I', its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula VI', its stereoisomer, or a pharmaceutically acceptable salt thereof,
- the compound of formula I', its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof,
- A, X, Y, L and R 2 are as defined in this application.
- the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula II, its stereoisomer, or a pharmaceutically acceptable salt thereof,
- T is selected from C or N;
- U, V, W, and Z are each independently selected from CH, N, O, or S, and optionally one of U, V, and W is selected from a bond;
- q is selected from 0, 1, 2 or 3;
- X, Y, R 1 , L, R 2 , R 3 , and R 4 are defined as described in this application.
- the U, V, W, and Z are all CH, or U, V, and W are CH and Z is N. In some aspects, the U, V, and W are CH and Z is N.
- one of the U, V, and W is selected from a bond, and the other is selected from CH, N, O, or S.
- the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula III Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula IV Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula V Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof are selected from compounds of formula VI Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula VII Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula I, compound of formula II, compound of formula III, compound of formula IV, compound of formula V, compound of formula VI, compound of formula VII, stereoisomers thereof, or pharmaceutically acceptable salts thereof Structural units The stereoisomer of is selected from
- the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula IA Its stereoisomer, or its pharmaceutically acceptable salt or compound of formula IB Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula II, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula IIA Its stereoisomer, or its pharmaceutically acceptable salt or formula IIB compound Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula III, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula IIIA Its stereoisomer, or its pharmaceutically acceptable salt or compound of formula IIIB Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula IV, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula IVA Its stereoisomer, or its pharmaceutically acceptable salt or compound of formula IVB Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula V, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula VA Its stereoisomers, or pharmaceutically acceptable salts or compounds of formula VB Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula VI, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula VIA Its stereoisomer, or its pharmaceutically acceptable salt or compound of formula VIB Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula VII, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula VIIA Its stereoisomer, or its pharmaceutically acceptable salt or compound of formula VIIB Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- This application provides a compound of formula I', its stereoisomers, or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of formula (1), its stereoisomers, or a pharmaceutically acceptable salt thereof,
- rings A, X, Y, L and R 2 are the same as before.
- the A is selected from 6-membered heteroaryl groups containing 1-4 atoms selected from N, O or S, and the A is optionally substituted with 1, 2 or 3 R 1 . In some embodiments, the A is selected from 6-membered heteroaryl groups containing 1-2 N, and the A is optionally substituted with 1, 2, or 3 R 1 .
- the A is selected from Z is selected from CH or N, and said A is optionally substituted with 1, 2 or 3 R 1 .
- the A is selected from pyridyl or pyrimidinyl.
- the R 2 is selected from 6-8 membered aryl groups or 5-8 membered with 1-3 heteroaryl groups selected from N, O or S, and the substituents of R 2 are as described in this application. Narrated. In some embodiments, the R 2 is selected from phenyl or 5-6 membered containing 1-2 heteroaryl groups selected from N, O or S, and the substituent of R 2 is as described in this application. In some schemes, the R 2 is selected from 5-6 membered heteroaryl groups containing 1-2 N, and the substituents of R 2 are as described in this application. In some schemes, the R 2 is selected from 6-membered heteroaryl groups containing 1-2 N, and the substituents of R 2 are as described in this application. In some embodiments, the R 2 is selected from pyridyl, and the substituents of R 2 are as described in this application.
- the R 3 is selected from F, Cl, Br, -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -OC 1-4 alkyl, azetidine Group, or 4-7 members containing 2 heterocycloalkyl groups selected from N, O or S, the -NHC 1-4 alkyl group, -N(C 1-4 alkyl) 2 , -OC 1-4
- the alkyl group, azetidinyl group, or 4-7 membered heterocycloalkyl group containing 2 selected from N, O or S are each independently optionally substituted with 1 to 3 R 4.
- the R 4 is selected from F, Cl, Br, -C 1-4 alkyl, -OC 1-6 alkyl, or -S(O) 2 C 1-4 alkyl.
- the R 4 is selected from F, Cl, Br, -C 1-4 alkyl, -C 3-6 cycloalkyl, -OC 1-4 alkyl, -OC 3-6 cycloalkyl , Or -S(O) 2 C 1-4 alkyl.
- the R 4 is selected from F, -OCH 3 , or -S(O) 2 CH 3 .
- the R 2 is selected from The substituents of the groups are as described in this application.
- the R 3 is selected from F, -N(CH 3 ) 2 , -OCH 3 ,
- the R 2 is selected from
- the R 2 is selected from
- the compound of formula (1), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (1-2), its stereoisomer, or a pharmaceutically acceptable salt thereof Salt,
- T is selected from C or N;
- U, V, W, and Z are each independently selected from CH, N, O, or S, and optionally one of U, V, and W is selected from a bond;
- q is selected from 0, 1, 2 or 3;
- X, Y, R 1 , L, R 2 , R 3 , and R 4 are defined as described in this application.
- the U, V, W, and Z are all CH, or U, V, and W are CH and Z is N. In some aspects, the U, V, and W are CH and Z is N.
- one of the U, V, and W is selected from a bond, and the other is selected from CH, N, O, or S.
- the compound of formula (1), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from compounds of formula (1-3) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula (1), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from compounds of formula (1-4) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula (1), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from compounds of formula (1-5) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula (1), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from compounds of formula (1-6) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula (1), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from compounds of formula (1-7) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula (1), compound of formula (1-2), compound of formula (1-3), compound of formula (1-4), compound of formula (1-5), compound of formula (1-6 ) The structural unit of a compound, a compound of formula (1-7), its stereoisomer, or a pharmaceutically acceptable salt thereof The stereoisomer of is selected from
- the compound of formula (1), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (1-A) Its stereoisomer, or its pharmaceutically acceptable salt or formula (1-B) compound Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula (1-2), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (1-2A) Its stereoisomer, or its pharmaceutically acceptable salt or formula (1-2B) compound Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula (1-3), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (1-3A) Its stereoisomer, or its pharmaceutically acceptable salt or formula (1-3B) compound Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula (1-4), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (1-4A) Its stereoisomer, or its pharmaceutically acceptable salt or formula (1-4B) compound Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula (1-5), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (1-5A) Its stereoisomer, or its pharmaceutically acceptable salt or formula (1-5B) compound Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula (1-6), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (1-6A) Its stereoisomer, or its pharmaceutically acceptable salt or formula (1-6B) compound Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the compound of formula (1-7), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (1-7A) Its stereoisomer, or its pharmaceutically acceptable salt or formula (1-7B) compound Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the group definitions are as described in this application.
- the application provides the following compounds, stereoisomers, or pharmaceutically acceptable salts thereof:
- the application provides the following compounds, stereoisomers, or pharmaceutically acceptable salts thereof:
- compositions which includes the compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof, and optionally further includes pharmaceutically acceptable excipients.
- Another aspect of the present application provides the use of the compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of hepatitis B virus infection.
- Another aspect of the present application provides the use of the compound of the present application, its stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of hepatitis B virus infection.
- the present application provides the compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating hepatitis B virus infection.
- Another aspect of the present application provides a method for treating hepatitis B virus infection, which includes administering to a mammal in need of treatment, preferably a human, a therapeutically effective amount of the compound of the present application, its stereoisomer, its pharmaceutically acceptable salt, Or its pharmaceutical composition.
- the compound of the present application has good anti-hepatitis B virus activity.
- substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence of the specific atom is normal and the substituted compound is stable.
- oxo O
- oxo can occur on the C atom, such as forming -CO-; oxo can also occur on the S atom, such as forming -SO- or -SO 2 -.
- the term “optional” or “optionally” means that the event or situation described later can occur or not occur, and the description includes occurrence of said event or situation and non-occurrence of said event or situation.
- the ethyl group is "optionally" substituted by halogen, meaning that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), or polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ).
- CH 2 CH 3 unsubstituted
- monosubstituted such as CH 2 CH 2 F
- polysubstituted such as CHFCH 2 F, CH 2 CHF 2 etc.
- CF 2 CF 3 completely substituted
- C mn in this context means that the part has an integer number of carbon atoms in a given range.
- C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
- C 1-3 means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.
- any variable such as R
- its definition in each case is independent. For example, if a group is replaced by 2 Rs, then each R has independent options. Or, for example, if multiple groups are substituted by a certain R, the situation in which each group is substituted by R is independent of each other.
- linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
- the substituent can be bonded to any atom on the ring.
- the structural unit It means that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
- the structural unit including but not limited to
- halo or halogen refers to fluorine, chlorine, bromine and iodine.
- alkyl refers to a hydrocarbon group of the general formula C n H 2n+1.
- the alkyl group may be linear or branched.
- C 1 - 6 alkyl refers to (e.g., methyl, ethyl, n-propyl, isopropyl, alkyl containing 1 to 6 carbon atoms, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
- alkyl moiety ie, alkyl
- alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definition as described above.
- C 1 - 3 alkyl refers to an alkyl group containing 1-3 carbon atoms (e.g., methyl, ethyl, propyl and isopropyl).
- alkoxy refers to -O-alkyl
- cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3 to 10 membered ring.
- Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, diamond Alkyl, bicyclo[1.1.1]pent-1-yl, etc.
- C 3-4 cycloalkyl includes cyclopropyl and cyclobutyl.
- heterocycloalkyl refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocyclic ring is generally a 3 to 8 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and/or nitrogen.
- 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, sulfiethane, and azaethylenyl groups
- 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetane
- Examples of cyclic group, thiabutanyl, 5-membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine
- 6-membered heterocycloalkyl groups include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, Examples of 4-thiaxanyl, 1,4-dioxanyl
- aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
- aryl groups can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
- Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetralin and the like.
- heteroaryl refers to a monocyclic or condensed polycyclic ring system, which contains at least one ring atom selected from N, O, and S, the remaining ring atoms are C, and have at least one aromatic ring.
- Preferred heteroaryl groups have a single 3 to 8 membered ring, especially 5 to 8 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms.
- heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , Tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
- tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
- proton tautomers also called proton transfer tautomers
- proton migration such as keto-enol and imine-enamine isomerization.
- a specific example of a proton tautomer is the imidazole moiety, in which protons can migrate between two ring nitrogens.
- Valence tautomers include interconversion through the recombination of some bonding electrons.
- Certain compounds of this application may have asymmetric carbon atoms (stereocenters) or double bonds. Therefore, racemates, diastereomers, enantiomers, geometric isomers and individual isomers are all included in the scope of this application.
- the compounds of the present application may exist in specific geometric isomers or stereoisomers. This application envisions all such compounds, including tautomers, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers , Diastereomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, All of these fall within the scope of this application. 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 this application.
- 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 this application, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, 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 an appropriate 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 uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
- the present application also includes compounds of the present application that are the same as those described herein, but have one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature.
- isotopes that can be bound to the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
- isotope-labeled compounds of the application can be used in compound and/or substrate tissue distribution analysis. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred due to their ease of preparation and detectability. Positron emission isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
- PET positron emission tomography
- the isotopically-labeled compounds of the present application can be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing non-isotopically-labeled reagents with isotope-labeled reagents.
- substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations
- the following may be preferred, wherein the deuterium substitution may be partial or complete.
- Partial deuterium substitution refers to the substitution of at least one hydrogen with at least one deuterium. All compounds in such forms are included in the scope of this application.
- 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, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
- salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. can be mentioned. .
- pharmaceutical composition refers to a mixture of one or more of the compounds of the application or their salts and pharmaceutically acceptable excipients.
- the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to the organism.
- pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound.
- Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
- the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
- Typical routes for administering the compound of the present application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
- treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
- the effect can be therapeutic based on partial or complete stabilization or cure of the disease and/or side effects due to the disease.
- Treatment covers any treatment of a patient's disease, including: (a) inhibiting the symptoms of the disease, that is, preventing its development; or (b) alleviating the symptoms of the disease, that is, causing the disease or symptoms to degenerate.
- the term "effective amount” means (i) treatment or prevention of a specific disease, condition or disorder, (ii) reduction, amelioration or elimination of one or more symptoms of a specific disease, condition or disorder, or (iii) prevention or delay herein
- the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. Determined by its own knowledge and this disclosure.
- mammals such as primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, and poultry, etc.
- the therapeutic dose of the compound of the present application may be determined according to, for example, the following: the specific use of the treatment, the way of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician.
- the ratio or concentration of the compound of the present application in the pharmaceutical composition may not be fixed, depending on various factors, including dosage, chemical properties (for example, hydrophobicity), and route of administration.
- the compound of the present application can be provided by a physiologically buffered aqueous solution containing about 0.1-10% w/v of the compound for parenteral administration. Some typical dosage ranges are from about 1 ⁇ g/kg to about 1 g/kg body weight/day.
- the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight/day.
- the dosage is likely to depend on such variables, such as the type and degree of development of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation and its route of administration.
- the effective dose can be obtained by extrapolating the dose-response curve derived from the in vitro or animal model test system.
- the compounds of the present application 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 replacement manners, preferred implementation manners include but are not limited to the embodiments of the present application.
- the compounds of the present application can be prepared by those skilled in the art of organic synthesis by the following methods:
- DMF stands for N,N-dimethylformamide
- DCM stands for dichloromethane
- MeOH stands for methanol
- Pd 2 (dba) 3 stands for tris(benzylideneacetone) dipalladium
- EA stands for ethyl acetate
- Ru-phos stands for 2 -Dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl
- DMFDMA stands for N-dimethylformamide dimethyl acetal
- EtONa stands for sodium ethoxide
- TEA stands for triethylamine .
- Step A Add compound 1-1 (5g), N,N-dimethylformamide dimethyl acetal (3.3g), DMF (50mL) to the reaction flask in sequence, increase the temperature to 90°C and react for 3 hours and then cool To room temperature. After the solvent was removed by rotary evaporation, 2-pyrimidine formamidine hydrochloride (3.99 g), sodium ethoxide (3.43 g), and absolute ethanol (50 mL) were added to the reaction flask, and the reaction was refluxed for 3 hours. The reaction solution was spin-dried, 100 mL of water was added, and extraction was performed with ethyl acetate (100 mL*3).
- Step B Add compound 1-2 (3.4g), potassium hydroxide (4.9g), methanol (15mL) and water (15mL) to the microwave tube in sequence, and react in microwave at 100°C for 1 hour.
- the reaction solution was diluted with 50 mL of water and adjusted to pH 6 with dilute hydrochloric acid. After the solvent was removed by rotary evaporation, tetrahydrofuran (80 mL) and triethylamine (10 mL) were added. The mixture was stirred at room temperature for 1 hour and then filtered with suction. The filtrate was spin-dried to obtain compound 1-3. (1.3g).
- Step C Add compound 1-3 (500mg), 2,4,6-trifluoropyridine (278mg), cesium carbonate (2.042g), DMF (20mL) to the reaction flask in sequence, heat to 80°C and react for 8 hours
- the reaction solution was slowly poured into 50 mL of water, extracted with ethyl acetate (3*20 mL), the organic layers were combined, and the solvent was evaporated under reduced pressure.
- the compound of Example 1-B 100 mg
- the compound of Example 1-A 80 mg
- Example 2-A (15 mg) and Example 2-B (15 mg) were separated in sequence.
- Example 1-B 50mg, 40% dimethylamine aqueous solution (0.8mL), DMF (1mL), cesium carbonate (1.5g) were added to the microwave tube in sequence, heated to 90°C for 1 hour in the microwave, and the reaction solution was slowly poured.
- Pour into 50mL water, extract with ethyl acetate (3*20mL), combine the organic layers, wash the organic layer with saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, distill the solvent under reduced pressure, and prepare the liquid phase of the crude product by high pressure After separation (YMC-TriartPrepC18-S chromatographic column; acetonitrile: water 30:70), Example 3 (14 mg) was prepared.
- Example 4 using 3-methoxyazetidine hydrochloride instead of the dimethylamine aqueous solution, Example 4 (50 mg) was prepared.
- Example 5 (50 mg) was prepared.
- Example 5-A (20 mg)
- Example 5-B (20 mg).
- Example 8 Into the microwave tube was added compound 1-3 (200mg), 5-bromo-1,2-difluoro-3-methoxybenzene (224mg), Pd 2 (dba) 3 (38mg), Ru-phos (20mg ), sodium tert-butoxide (241mg), 1,4-dioxane (5mL), replaced with nitrogen and reacted in microwave at 100°C for 2 hours.
- Example 9 using 1-bromo-3-methoxy-5-(trifluoromethyl)benzene instead of 5-bromo-1,2-difluoro-3-methoxybenzene, Example 9 ( 3.3mg). MS(ESI + ,[M+Na] + )m/z:414.5.
- Example 8 1-bromo-3-chloro-5-fluorobenzene was substituted for 5-bromo-1,2-difluoro-3-methoxybenzene to prepare Example 16 (15 mg).
- Step A According to step A of Example 1, using 2-pyridinecarboxamidine hydrochloride instead of 2-pyrimidinecarboxamidine hydrochloride, compound 17-2 was prepared. MS(ESI + ,[M+H] + )m/z:311.4.
- Step B According to step B of Example 1, compound 17-2 is substituted for compound 1-2 to prepare compound 17-3. MS(ESI + ,[M+Na] + )m/z:262.4.
- Step C According to step C of Example 1, compound 17-3 is substituted for compound 1-3 to prepare compound 17-4.
- Example 20 (80 mg) was prepared.
- Example 21 (70 mg) was prepared.
- Step A Add compound 24-1 (50g), N,N-dimethylformamide dimethyl acetal (29.9g) to the reaction flask in sequence, increase the temperature to 100°C and react for 7 hours, then cool to room temperature, and rotatably evaporate After removing the excess DMFDMA, continue to add 2-pyrimidine formamidine hydrochloride (33.9 g), sodium tert-butoxide (41.1 g), and absolute ethanol (500 mL) to the reaction flask, and react under reflux for 7 hours.
- 2-pyrimidine formamidine hydrochloride 33.9 g
- sodium tert-butoxide 41.1 g
- absolute ethanol 500 mL
- Step B Add compound 24-2 (43.0g) and dioxane hydrochloride solution (4.0M, 50mL) to the reaction flask in sequence. The reaction was carried out at room temperature for 16 hours, the pH of the reaction solution was adjusted to about 7 with TEA, filtered, and the filtrate was spin-dried to obtain compound 24-3 (28.0 g). MS(ESI + ,[M+H] + )m/z:253.99.
- Example 24 (100mg), 40% dimethylamine aqueous solution (0.615mL), DMF (2mL) were sequentially added to the microwave tube, heated to 90°C in the microwave for 1 hour, and the reaction solution was slowly poured into 50mL of water. Ester (3*20mL) was extracted, the organic layers were combined, the organic layer was washed with saturated sodium chloride aqueous solution, the organic phase was dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Example 24 (250mg), 3-fluoroazetidine hydrochloride (230mg), DMF (4 mL), and cesium carbonate (1.0g) were added to the microwave tube and heated to 90°C for 1 hour in order to react.
- the reaction solution was slowly poured into 50 mL of water, extracted with ethyl acetate (3*20 mL), the organic layers were combined, and the organic layers were washed with saturated aqueous sodium chloride solution.
- the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Step A Add 24-1 (20g), N,N-dimethylformamide dimethyl acetal (12.0g) to the reaction flask, increase the temperature to 100°C and react for 7 hours, then cool to room temperature, and remove by rotary evaporation. After excess DMFDMA was added to the reaction flask, 2-pyridinecarboxamidine hydrochloride (10.71g), sodium tert-butoxide (9.25g), absolute ethanol (200mL) were continuously added to the reaction flask, and the reaction was refluxed for 7 hours.
- Example 35A (100mg), 3-fluoroazetidine hydrochloride (183mg), DMF (1mL), and cesium carbonate (624mg) were sequentially added to the microwave tube and heated to 100°C for 2 hours.
- a multi-channel pipette was used to inoculate the cells on a 96-well plate (the 96-well plate was coated with 50 ⁇ g/mL Collagen I solution in advance), 100 ⁇ L/well. Place the inoculated orifice plate in a constant temperature CO 2 incubator for 24 hours.
- A means EC50 ⁇ 0.1 ⁇ M;
- B means 0.1 ⁇ M ⁇ EC50 ⁇ 1 ⁇ M;
Abstract
提供作为乙肝表面抗原抑制剂的氮杂双环化合物，具体涉及式I'化合物、其立体异构体、其药学上可接受的盐，其制备方法，含有该化合物的药物组合物，及其作为治疗乙型肝炎病毒感染的药物的用途。
Description
本申请属于医药化学领域，涉及作为乙肝表面抗原抑制剂的氮杂双环化合物。本申请具体涉及式I’化合物、其立体异构体、其药学上可接受的盐，其制备方法，含有该化合物的药物组合物，及其作为治疗乙型肝炎病毒感染的药物的用途。
目前乙型肝炎病毒(HBV)感染世界性的健康问题之一，其在全球大约有4亿慢性感染者，他们具有更高的肝硬化和肝细胞癌的风险。当前，针对慢性乙型病毒性肝炎不可治愈只能控制，主要限于两类药剂(干扰素和核苷类似物/病毒聚合酶的抑制剂)。
乙肝表面抗原(HBsAg)定量是用于慢性乙型肝炎中的预后和治疗响应的显著生物标志物。持续暴露于HBsAg和其他病毒抗原可以导致HBV-特异性T细胞缺失或导致进行性的功能受损。此外，HBsAg已被报道通过直接相互作用而抑制免疫细胞如单核细胞、树突细胞(DC)和自然杀伤(NK)细胞的功能。然而，在慢性感染患者中很少观察到HBsAg消失和血清转化，其仍然是治疗的目标。当前疗法如核苷类似物是抑制HBV DNA合成但不降低HBsAg水平的分子。已有研究公开以乙肝表面抗原为靶点的抑制剂，例如WO2016107832、WO2016177655、WO2018083106等。
本申请合成了一系列新型化合物，并对其进行研究。
发明内容
本申请提供式I’化合物、其立体异构体、或其药学上可接受的盐，
其中，X和Y中至少一个是N，另一个是CH或N；
A选自5-6元杂芳基，所述A任选地被1、2或3个R
1取代；
R
1选自C
1-8烷基、C
1-8烷氧基、卤素、C
3-7环烷基、1-3个卤代C
1-8烷基或1-3个卤代C
1-8烷氧基；
p选自1、2、3或4；
L选自单键、-CO-或-SO
2-；
R
2选自6-10元芳基、3-8元含有1-3个选自N、O或S的杂芳基、或3-8元含有1-3个选自N、O或S的杂环烷基，所述R
2各自独立地任选地被1-4个R
3取代；
所述R
3选自卤素、-NO
2、-CN、-C
1-8烷基、-C
3-7环烷基、-OH、-OC
1-8烷基、-OC
3-7环烷基、-NH
2、-NHC
1-8烷基、-N(C
1-8烷基)
2、-SH、-SC
1-8烷基、-SC
3-7环烷基、-CO-C
1-8烷基、-COO-C
1-8烷基、-OCO-C
1-8烷基、-CONHC
1-8烷基、-CON(C
1-8烷基)
2、-NHCO-C
1-8烷基、-S(＝O)C
1-6烷基、-S(＝O)
2C
1-6烷基或3-8元含有1-3个选自N、O或S的杂环烷基；所述-C
1-8烷基、-C
3-7环烷基、-OC
1-8烷基、-OC
3-7环烷基、-NHC
1-8烷基、-N(C
1-8烷基)
2、-SC
1-8烷基、-SC
3-7环烷基、-CO-C
1-8烷基、-COO-C
1-8烷基、-OCO-C
1-8烷基、-CONHC
1-8烷基、-CON(C
1-8烷基)
2、-NHCO-C
1-8烷基、-S(＝O)C
1-6烷基或-S(＝O)
2C
1-6烷基各自独立地任选地被1-3个R
4取代，所述3-8元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R
4取代或发生1-2个氧代；
所述R
4选自卤素、-NO
2、-CN、-C
1-8烷基、-C
3-7环烷基、-OH、-OC
1-8烷基、-OC
3-7环烷基、-NH
2、-NHC
1-8烷基、-N(C
1-8烷基)
2、-SH、-SC
1-8烷基、-SC
3-7环烷基、-CO-C
1-8烷基、-COO-C
1-8烷基、-OCO-C
1-8烷基、-CONHC
1-8烷基、-CON(C
1-8烷基)
2、-NHCO-C
1-8烷基、或-SO
2C
1-8烷基。
本申请另一方面提供药物组合物，其包括本申请的化合物、其立体异构体、或其药学上可接受的盐，任选地进一步包括药学上可接受的辅料。
本申请另一方面提供本申请的化合物、其立体异构体、或其药学上可接受的盐在制备治疗乙型肝炎病毒感染的药物中的用途。
本申请提供式I’化合物、其立体异构体、或其药学上可接受的盐，
其中，X和Y中至少一个是N，另一个是CH或N；
A选自5-6元杂芳基，所述A任选地被1、2或3个R
1取代；
R
1选自C
1-8烷基、C
1-8烷氧基、卤素、C
3-7环烷基、1-3个卤代C
1-8烷基或1-3个卤代C
1-8烷氧基；
p选自1、2、3或4；
L选自单键、-CO-或-SO
2-；
R
2选自6-10元芳基、3-8元含有1-3个选自N、O或S的杂芳基、或3-8元含有1-3个选自N、O或S的杂环烷基，所述R
2各自独立地任选地被1-4个R
3取代；
所述R
3选自卤素、-NO
2、-CN、-C
1-8烷基、-C
3-7环烷基、-OH、-OC
1-8烷基、-OC
3-7环烷基、-NH
2、-NHC
1-8烷基、-N(C
1-8烷基)
2、-SH、-SC
1-8烷基、-SC
3-7环烷基、-CO-C
1-8烷基、-COO-C
1-8烷基、-OCO-C
1-8烷基、-CONHC
1-8烷基、-CON(C
1-8烷基)
2、-NHCO-C
1-8烷基、-S(＝O)C
1-6烷基、-S(＝O)
2C
1-6烷基、或3-8元含有1-3个选自N、O或S的杂环烷基；所述-C
1-8烷基、-C
3-7环烷基、-OC
1-8烷基、-OC
3-7环烷基、-NHC
1-8烷基、-N(C
1-8烷基)
2、-SC
1-8烷基、-SC
3-7环烷基、-CO-C
1-8烷基、-COO-C
1-8烷基、-OCO-C
1-8烷基、-CONHC
1-8烷基、-CON(C
1-8烷基)
2、-NHCO-C
1-8烷基、-S(＝O)C
1-6烷基或-S(＝O)
2C
1-6烷基各自独立地任选地被1-3个R
4取代，所述3-8元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R
4取代或发生1-2个氧代；
所述R
4选自卤素、-NO
2、-CN、-C
1-8烷基、-C
3-7环烷基、-OH、-OC
1-8烷基、-OC
3-7环烷基、-NH
2、-NHC
1-8烷基、-N(C
1-8烷基)
2、-SH、-SC
1-8烷基、-SC
3-7环烷基、-CO-C
1-8烷基、-COO-C
1-8烷基、-OCO-C
1-8烷基、-CONHC
1-8烷基、-CON(C
1-8烷基)
2、-NHCO-C
1-8烷基、或-SO
2C
1-8烷基。
在一些方案中，所述X是N且Y是CH、X是CH且Y是N、或X和Y都是N。在一些方案中，所述X和Y都是N。
在一些方案中，所述A选自5-6元含有1-4个选自N、O或S原子的杂芳基，所述A任选地被1、2或3个R
1取代。在一些方案中，所述A选自
其中
表示单键或双键，T选自C或N，U、V、W和Z各自独立地选自CH、N、O或S，任选地U、V和W中之一选自键，所述A任选地被1、2或3个R
1取代。
在一些方案中，所述A选自吡唑基、咪唑基、恶唑基、噻唑基、三唑基、四唑基、吡啶基、吡嗪、哒嗪基或嘧啶基，所述A任选地被1、2或3个R
1取代。在一些实施方案中，所述A选自吡啶基或嘧啶基，所述A任选地被1、2或3个R
1取代。
在一些方案中，所述U、V、W和Z都是CH，或U、V和W是CH且Z是N。在一些方案中，所述U、V和W是CH且Z是N。在一些方案中，所述U、V和W中之一选自键，其他选自CH、N、O或S。
在一些方案中，所述R
1选自C
1-6烷基、C
1-6烷氧基、F、Cl、Br、1-3个F、Cl或Br取代的C
1-6烷基、或1-3个F、Cl或Br取代的C
1-6烷氧基。在一些方案中，所述R
1选自C
1-4烷基、C
1-4烷氧基、F、Cl、Br、1-3个F、Cl或Br取代的C
1-4烷基、或1-3个F、Cl或Br取代的C
1-4烷氧基。
在一些方案中，p选自2或3。在一些方案中，p选自2。在一些方案中，p选自3。
在一些方案中，L选自单键。
在一些方案中，所述R
2选自6-8元芳基、4-6元含有1-3个选自N、O或S的杂芳基、或4-6元含有1-3个选自N、O或S的杂环烷基，所述R
2的取代基如本申请所述。在一些方案中，所述R
2选自苯基、萘基、4-6元含有1-2个选自N、O或S的杂芳基、或4-6元含有1-2个选自N、O或S的杂环烷基，所述R
2的取代基如本申请所述。在一些方案中，所述R
2选自苯基、4-6元含有1-2个选自N的杂芳基、或4-6元含有1-2个选自N或O的杂环烷基，所述R
2的取代基如本申请所述。在一些方案中，所述R
2选自苯基、吡啶基、或吗啉基，所述R
2的取代基如本申请所述。在一些方案中，所述R
2选自吡啶基，所述R
2的取代基如本申请所述。
在一些方案中，所述R
3选自F、Cl、Br、-NO
2、-CN、-C
1-6烷基、-C
3-6环烷基、-OH、-OC
1-6烷基、-OC
3-6环烷基、-NH
2、-NHC
1-6烷基、-N(C
1-6烷基)
2、-SH、-SC
1-6烷基、-SC
3-6环烷基、-S(＝O)C
1-6烷基、-S(＝O)
2C
1-6烷基、-CO-C
1-6烷基、-COO-C
1-6烷基、-OCO-C
1-6烷基、-CONHC
1-6烷基、-CON(C
1-6烷基)
2、-NHCO-C
1-6烷基、或4-7元含有1-3个选自N、O或S的杂环烷基，所述-C
1-6烷基、-C
3-6环烷基、-OC
1-6烷基、-OC
3-6环烷基、-NHC
1-6烷基、-N(C
1-6烷基)
2、-SC
1-6烷基、-SC
3-6环烷基、-S(＝O)C
1-6烷基、-S(＝O)
2C
1-6烷基、-CO-C
1-6烷基、-COO-C
1-6烷基、-OCO-C
1-6烷基、-CONHC
1-6烷基、-CON(C
1-6烷基)
2、或-NHCO-C
1-6烷基各自独立地任选地被1-3个R
4取代，所述4-7元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R
4取代或发生1-2个氧代。
在一些方案中，所述R
3选自F、Cl、Br、-NO
2、-CN、-C
1-4烷基、-C
3-6环烷基、-OH、-OC
1-4烷基、-OC
3-6环烷基、-NH
2、-NHC
1-4烷基、-N(C
1-4烷基)
2、-SH、-SC
1-4烷基、-SC
3-6环烷基、-S(＝O)C
1-4烷基、-S(＝O)
2C
1-4烷基、-CO-C
1-4烷基、-COO-C
1-4烷基、-OCO-C
1-4烷基、-CONHC
1-4烷基、-CON(C
1-4烷基)
2、-NHCO-C
1-4烷基、或4-7元含有1-3个选自 N、O或S的杂环烷基，所述-C
1-4烷基、-C
3-6环烷基、-OC
1-4烷基、-OC
3-6环烷基、-NHC
1-4烷基、-N(C
1-4烷基)
2、-SC
1-4烷基、-SC
3-6环烷基、-S(＝O)C
1-4烷基、-S(＝O)
2C
1-4烷基、-CO-C
1-4烷基、-COO-C
1-4烷基、-OCO-C
1-4烷基、-CONHC
1-4烷基、-CON(C
1-4烷基)
2、或-NHCO-C
1-4烷基各自独立地任选地被1-3个R
4取代，所述4-7元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R
4取代或发生1-2个氧代。
在一些方案中，所述R
3选自F、Cl、Br、-C
1-4烷基、-C
3-6环烷基、-NH
2、-NHC
1-4烷基、-N(C
1-4烷基)
2、-SC
1-4烷基、-S(＝O)C
1-4烷基、-S(＝O)
2C
1-4烷基、OH、-OC
1-4烷基、-OC
3-6环烷基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、或4-7元含有2个选自N、O或S的杂环烷基，所述-C
1-4烷基、-C
3-6环烷基、-NHC
1-4烷基、-N(C
1-4烷基)
2、-SC
1-4烷基、-S(＝O)C
1-4烷基、-S(＝O)
2C
1-4烷基、-OC
1-4烷基、或-OC
3-6环烷基各自独立地任选地被1-3个R
4取代，所述氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、或4-7元含有2个选自N、O或S的杂环烷基各自任选地被1-3个R
4取代或发生1-2个氧代。
在一些方案中，所述R
3选自F、Cl、Br、-NO
2、-CN、-C
1-6烷基、-C
3-6环烷基、-OH、-OC
1-6烷基、-OC
3-6环烷基、-NH
2、-NHC
1-6烷基、-N(C
1-6烷基)
2、-SH、-SC
1-6烷基、-SC
3-6环烷基、-CO-C
1-6烷基、-COO-C
1-6烷基、-OCO-C
1-6烷基、-CONHC
1-6烷基、-CON(C
1-6烷基)
2、-NHCO-C
1-6烷基、或4-6元含有1-3个选自N、O或S的杂环烷基，所述-C
1-6烷基、-C
3-6环烷基、-OC
1-6烷基、-OC
3-6环烷基、-NHC
1-6烷基、-N(C
1-6烷基)
2、-SC
1-6烷基、-SC
3-6环烷基、-CO-C
1-6烷基、-COO-C
1-6烷基、-OCO-C
1-6烷基、-CONHC
1-6烷基、-CON(C
1-6烷基)
2、或-NHCO-C
1-6烷基各自独立地任选地被1-3个R
4取代，所述4-6元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R
4取代或发生1-2个氧代。
在一些方案中，所述R
3选自F、Cl、Br、-NO
2、-CN、-C
1-4烷基、-C
3-6环烷基、-OH、-OC
1-4烷基、-OC
3-6环烷基、-NH
2、-NHC
1-4烷基、-N(C
1-4烷基)
2、-SH、-SC
1-4烷基、-SC
3-6环烷基、-CO-C
1-4烷基、-COO-C
1-4烷基、-OCO-C
1-4烷基、-CONHC
1-4烷基、-CON(C
1-4烷基)
2、-NHCO-C
1-4烷基、或4-6元含有1-3个选自N、O或S的杂环烷基，所述-C
1-4烷基、-C
3-6环烷基、-OC
1-4烷基、-OC
3-6环烷基、-NHC
1-4烷基、-N(C
1-4烷基)
2、-SC
1-4烷基、-SC
3-6环烷基、-CO-C
1-4烷基、-COO-C
1-4烷基、-OCO-C
1-4烷基、-CONHC
1-4烷基、-CON(C
1-4烷基)
2、或-NHCO-C
1-4烷基各自独立地任选地被1-3个R
4取代，所述4-6元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R
4取代或发生1-2个氧代。
在一些方案中，所述R
3选自F、Cl、Br、-C
1-4烷基、-C
3-6环烷基、-NH
2、-NHC
1-4烷基、-N(C
1-4烷基)
2、OH、-OC
1-4烷基、-OC
3-6环烷基、氮杂环丁烷基、氮杂环戊烷基、 氮杂环己烷基、或4-6元含有2个选自N、O或S的杂环烷基，所述-C
1-4烷基、-C
3-6环烷基、-NHC
1-4烷基、-N(C
1-4烷基)
2、-OC
1-4烷基、或-OC
3-6环烷基各自独立地任选地被1-3个R
4取代，所述氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、或4-6元含有2个选自N、O或S的杂环烷基各自任选地被1-3个R
4取代或发生1-2个氧代。
在一些方案中，所述R
3选自卤素、-NO
2、-CN、-C
1-8烷基、-C
3-7环烷基、-OH、-OC
1-8烷基、-OC
3-7环烷基、-NH
2、-NHC
1-8烷基、-N(C
1-8烷基)
2、-SH、-SC
1-8烷基、-SC
3-7环烷基、-CO-C
1-8烷基、-COO-C
1-8烷基、-OCO-C
1-8烷基、-CONHC
1-8烷基、-CON(C
1-8烷基)
2、-NHCO-C
1-8烷基、或3-8元含有1-3个选自N、O或S的杂环烷基；所述-C
1-8烷基、-C
3-7环烷基、-OC
1-8烷基、-OC
3-7环烷基、-NHC
1-8烷基、-N(C
1-8烷基)
2、-SC
1-8烷基、-SC
3-7环烷基、-CO-C
1-8烷基、-COO-C
1-8烷基、-OCO-C
1-8烷基、-CONHC
1-8烷基、-CON(C
1-8烷基)
2、或-NHCO-C
1-8烷基各自独立地任选地被1-3个R
4取代，所述3-8元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R
4取代或发生1-2个氧代。
在一些方案中，所述R
4选自卤素、-NO
2、-CN、-C
1-8烷基、-C
3-7环烷基、-OH、-OC
1-8烷基、-OC
3-7环烷基、-NH
2、-NHC
1-8烷基、-N(C
1-8烷基)
2、-SH、-SC
1-8烷基、-SC
3-7环烷基、-CO-C
1-8烷基、-COO-C
1-8烷基、-OCO-C
1-8烷基、-CONHC
1-8烷基、-CON(C
1-8烷基)
2或-NHCO-C
1-8烷基。
在一些方案中，所述R
4选自F、Cl、Br、-NO
2、-CN、-C
1-6烷基、-C
3-6环烷基、-OH、-OC
1-6烷基、-OC
3-6环烷基、-NH
2、-NHC
1-6烷基、-N(C
1-6烷基)
2、-SH、-SC
1-6烷基、-SC
3-6环烷基、-CO-C
1-6烷基、-COO-C
1-6烷基、-OCO-C
1-6烷基、-CONHC
1-6烷基、-CON(C
1-6烷基)
2、-NHCO-C
1-6烷基、或-S(O)
2C
1-6烷基。
在一些方案中，所述R
4选自F、Cl、Br、-NO
2、-CN、-C
1-4烷基、-C
3-6环烷基、-OH、-OC
1-4烷基、-OC
3-6环烷基、-NH
2、-NHC
1-4烷基、-N(C
1-4烷基)
2、-SH、-SC
1-4烷基、-SC
3-6环烷基、-CO-C
1-4烷基、-COO-C
1-4烷基、-OCO-C
1-4烷基、-CONHC
1-4烷基、-CON(C
1-4烷基)
2、-NHCO-C
1-4烷基、或-S(O)
2C
1-4烷基。
在一些方案中，所述R
4选自F、Cl、Br、-NO
2、-CN、-C
1-6烷基、-C
3-6环烷基、-OH、-OC
1-6烷基、-OC
3-6环烷基、-NH
2、-NHC
1-6烷基、-N(C
1-6烷基)
2、-SH、-SC
1-6烷基、-SC
3-6环烷基、-CO-C
1-6烷基、-COO-C
1-6烷基、-OCO-C
1-6烷基、-CONHC
1-6烷基、-CON(C
1-6烷基)
2或-NHCO-C
1-6烷基。
在一些方案中，所述R
4选自F、Cl、Br、-NO
2、-CN、-C
1-4烷基、-C
3-6环烷基、-OH、-OC
1-4烷基、-OC
3-6环烷基、-NH
2、-NHC
1-4烷基、-N(C
1-4烷基)
2、-SH、-SC
1-4烷基、-SC
3-6 环烷基、-CO-C
1-4烷基、-COO-C
1-4烷基、-OCO-C
1-4烷基、-CONHC
1-4烷基、-CON(C
1-4烷基)
2或-NHCO-C
1-4烷基。
在一些方案中，所述R
4选自F、Cl、Br、-C
1-6烷基、-C
3-6环烷基、-OC
1-6烷基、或-OC
3-6环烷基。
在一些方案中，所述R
4选自F、-OCH
3、环丙基、或-S(O)
2CH
3。
在一些方案中，所述R
4选自卤素、-NO
2、-CN、-C
1-8烷基、-C
3-7环烷基、-OH、-OC
1-8烷基、-OC
3-7环烷基、-NH
2、-NHC
1-8烷基、-N(C
1-8烷基)
2、-SH、-SC
1-8烷基、-SC
3-7环烷基、-CO-C
1-8烷基、-COO-C
1-8烷基、-OCO-C
1-8烷基、-CONHC
1-8烷基、-CON(C
1-8烷基)
2、或-NHCO-C
1-8烷基。
在一些方案中，所述R
4选自F、Cl、Br、-NO
2、-CN、-C
1-6烷基、-C
3-6环烷基、-OH、-OC
1-6烷基、-OC
3-6环烷基、-NH
2、-NHC
1-6烷基、-N(C
1-6烷基)
2、-SH、-SC
1-6烷基、-SC
3-6环烷基、-CO-C
1-6烷基、-COO-C
1-6烷基、-OCO-C
1-6烷基、-CONHC
1-6烷基、-CON(C
1-6烷基)
2、或-NHCO-C
1-6烷基。
在一些方案中，所述R
4选自F、Cl、Br、-NO
2、-CN、-C
1-4烷基、-C
3-6环烷基、-OH、-OC
1-4烷基、-OC
3-6环烷基、-NH
2、-NHC
1-4烷基、-N(C
1-4烷基)
2、-SH、-SC
1-4烷基、-SC
3-6环烷基、-CO-C
1-4烷基、-COO-C
1-4烷基、-OCO-C
1-4烷基、-CONHC
1-4烷基、-CON(C
1-4烷基)
2、或-NHCO-C
1-4烷基。
在一些方案中，所述R
4选自F、Cl、Br、-C
1-6烷基、-C
3-6环烷基、-OC
1-6烷基、或-OC
3-6环烷基。在一些方案中，所述R
4选自F、-OCH
3、或环丙基。
在一些方案中，所述R
2选自苯基、
所述基团的取代基如本申请所述。在一些方案中，所述R
2选自苯基或
所述基团的取代基如本申请所述。
在一些方案中，所述R
3选自F、Cl、-N(CH
3)
2、-OCH
3、-CF
3、
-SCH
2CH
3、-S(＝O)CH
2CH
3、-S(＝O)
2CH
2CH
3、
在一些方案中，所述R
3选自F、Cl、-N(CH
3)
2、-OCH
3、-CF
3、
在一些方案中，所述R
3选自F、Cl、-N(CH
3)
2、-OCH
3、-CF
3、
-SCH
2CH
3、-S(＝O)CH
2CH
3、-S(＝O)
2CH
2CH
3、或
在一些方案中，所述R
3选自F、Cl、-N(CH
3)
2、-OCH
3、-CF
3、
在一些方案中，所述R
2选自
在一些方案中，所述R
2选自
在一些方案中，所述R
2选自
在一些方案中，本申请包含上述定义的变量及其实施方案，以及它们的任意组合。
在一些方案中，所述式I’化合物、其立体异构体、或其药学上可接受的盐选自式II’化合物、其立体异构体、或其药学上可接受的盐，
其中，
表示单键或双键；
T选自C或N；
U、V、W和Z各自独立地选自CH、N、O或S，任选地U、V和W中之一选自键；
q选自0、1、2或3；
p、X、Y、R
1、L、或R
2定义如本申请所述。
在一些方案中，所述式I’化合物、其立体异构体、或其药学上可接受的盐选自式III’化合物、其立体异构体、或其药学上可接受的盐，
在一些方案中，所述式I’化合物、其立体异构体、或其药学上可接受的盐选自式IV’化合物、其立体异构体、或其药学上可接受的盐，
在一些方案中，所述式I’化合物、其立体异构体、或其药学上可接受的盐选自式V’化合物、其立体异构体、或其药学上可接受的盐，
在一些方案中，所述式I’化合物、其立体异构体、或其药学上可接受的盐选自式VI’化合物、其立体异构体、或其药学上可接受的盐，
在一些方案中，所述式I’化合物、其立体异构体、或其药学上可接受的盐选自式I化合物、其立体异构体、或其药学上可接受的盐，
在一些方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐选自式II化合物、其立体异构体、或其药学上可接受的盐，
其中，
表示单键或双键；
T选自C或N；
U、V、W和Z各自独立地选自CH、N、O或S，任选地U、V和W中之一选自键；
q选自0、1、2或3；
X、Y、R
1、L、R
2、R
3、R
4定义如本申请所述。
在一些方案中，所述U、V、W和Z都是CH，或U、V和W是CH且Z是N。在一些方案中，所述U、V和W是CH且Z是N。
在一些方案中，所述U、V和W中之一选自键，其他选自CH、N、O或S。
在一些方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐选自式III化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐选自式IV化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐选自式V 化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐选自式VI化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐选自式VII化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式I化合物、式II化合物、式III化合物、式IV化合物、式V化合物、式VI化合物、式VII化合物、其立体异构体、或其药学上可接受的盐的结构单元
的立体异构体选自
在一些方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐选自式IA化合物
其立体异构体、或其药学上可接受的盐或式IB化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式II化合物、其立体异构体、或其药学上可接受的盐选自式IIA化合物
其立体异构体、或其药学上可接受的盐或式IIB化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式III化合物、其立体异构体、或其药学上可接受的盐选自式IIIA化合物
其立体异构体、或其药学上可接受的盐或式IIIB化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式IV化合物、其立体异构体、或其药学上可接受的盐选自式IVA化合物
其立体异构体、或其药学上可接受的盐或式IVB化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式V化合物、其立体异构体、或其药学上可接受的盐选自式 VA化合物
其立体异构体、或其药学上可接受的盐或式VB化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式VI化合物、其立体异构体、或其药学上可接受的盐选自式VIA化合物
其立体异构体、或其药学上可接受的盐或式VIB化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式VII化合物、其立体异构体、或其药学上可接受的盐选自式VIIA化合物
其立体异构体、或其药学上可接受的盐或式VIIB化合物
其立体异构体、或其药学上可接受的盐，其 中基团的定义如本申请所述。
本申请提供式I’化合物、其立体异构体、或其药学上可接受的盐，选自式(1)化合物、其立体异构体、或其药学上可接受的盐，
在一些方案中，所述A选自6元含有1-4个选自N、O或S原子的杂芳基，所述A任选地被1、2或3个R
1取代。在一些方案中，所述A选自6元含有1-2个N的杂芳基，所述A任选地被1、2或3个R
1取代。
在一些方案中，所述A选自
Z选自CH或N，所述A任选地被1、2或3个R
1取代。
在一些实施方案中，所述A选自吡啶基或嘧啶基。
在一些方案中，所述R
2选自6-8元芳基或5-8元含有1-3个选自N、O或S的杂芳基，所述R
2的取代基如本申请所述。在一些方案中，所述R
2选自苯基或5-6元含有1-2个选自N、O或S的杂芳基，所述R
2的取代基如本申请所述。在一些方案中，所述R
2选自5-6元含有1-2个N的杂芳基，所述R
2的取代基如本申请所述。在一些方案中，所述R
2选自6元含有1-2个N的杂芳基，所述R
2的取代基如本申请所述。在一些方案中，所述R
2选自吡啶基，所述R
2的取代基如本申请所述。
在一些方案中，所述R
3选自F、Cl、Br、-NO
2、-CN、-C
1-6烷基、-C
3-6环烷基、-OH、-OC
1-6烷基、-OC
3-6环烷基、-NH
2、-NHC
1-6烷基、-N(C
1-6烷基)
2、-SH、-SC
1-6烷基、-SC
3-6环烷基、-S(＝O)C
1-4烷基、-S(＝O)
2C
1-4烷基、或4-7元含有1-3个选自N、O或S的杂环烷基，所述-C
1-6烷基、-C
3-6环烷基、-OC
1-6烷基、-OC
3-6环烷基、-NHC
1-6烷基、-N(C
1-6烷基)
2、-SC
1-6烷基、-SC
3-6环烷基、-S(＝O)C
1-4烷基、或-S(＝O)
2C
1-4烷基各自独立地任选地被1-3个R
4取代，所述4-7元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R
4取代或发生1-2个氧代。
在一些方案中，所述R
3选自F、Cl、Br、-NO
2、-CN、-C
1-4烷基、-C
3-6环烷基、-OH、-OC
1-4烷基、-OC
3-6环烷基、-NH
2、-NHC
1-4烷基、-N(C
1-4烷基)
2、-SH、-SC
1-4烷基、-SC
3-6环烷基、-S(＝O)C
1-4烷基、-S(＝O)
2C
1-4烷基、或4-7元含有1-3个选自N、O或S的杂环 烷基，所述-C
1-4烷基、-C
3-6环烷基、-OC
1-4烷基、-OC
3-6环烷基、-NHC
1-4烷基、-N(C
1-4烷基)
2、-SC
1-4烷基、-SC
3-6环烷基、-S(＝O)C
1-4烷基、或-S(＝O)
2C
1-4烷基各自独立地任选地被1-3个R
4取代，所述4-7元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R
4取代或发生1-2个氧代。
在一些方案中，所述R
3选自F、Cl、Br、-NHC
1-4烷基、-N(C
1-4烷基)
2、-OC
1-4烷基、氮杂环丁烷基、或4-7元含有2个选自N、O或S的杂环烷基，所述-NHC
1-4烷基、-N(C
1-4烷基)
2、-OC
1-4烷基、氮杂环丁烷基、或4-7元含有2个选自N、O或S的杂环烷基各自独立地任选地被1-3个R
4取代。
在一些方案中，所述R
4选自F、Cl、Br、-C
1-4烷基、-OC
1-6烷基、或-S(O)
2C
1-4烷基。
在一些方案中，所述R
4选自F、Cl、Br、-C
1-4烷基、-C
3-6环烷基、-OC
1-4烷基、-OC
3-6环烷基、或-S(O)
2C
1-4烷基。
在一些方案中，所述R
4选自F、-OCH
3、或-S(O)
2CH
3。
在一些方案中，所述R
2选自
所述基团的取代基如本申请所述。
在一些方案中，所述R
3选自F、-N(CH
3)
2、
-OCH
3、
Cl、-CF
3、
-SCH
2CH
3、-S(＝O)CH
2CH
3、或-S(＝O)
2CH
2CH
3。
在一些方案中，所述R
3选自F、-N(CH
3)
2、
-OCH
3、
在一些方案中，所述R
2选自
在一些方案中，所述R
2选自
在一些方案中，所述式(1)化合物、其立体异构体、或其药学上可接受的盐选自式(1-2)化合物、其立体异构体、或其药学上可接受的盐，
其中，
表示单键或双键；
T选自C或N；
U、V、W和Z各自独立地选自CH、N、O或S，任选地U、V和W中之一选自键；
q选自0、1、2或3；
X、Y、R
1、L、R
2、R
3、R
4定义如本申请所述。
在一些方案中，所述U、V、W和Z都是CH，或U、V和W是CH且Z是N。在一些方案中，所述U、V和W是CH且Z是N。
在一些方案中，所述U、V和W中之一选自键，其他选自CH、N、O或S。
在一些方案中，所述式(1)化合物、其立体异构体、或其药学上可接受的盐选自式(1-3)化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式(1)化合物、其立体异构体、或其药学上可接受的盐选自式(1-4)化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式(1)化合物、其立体异构体、或其药学上可接受的盐选自式(1-5)化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式(1)化合物、其立体异构体、或其药学上可接受的盐选自式(1-6)化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式(1)化合物、其立体异构体、或其药学上可接受的盐选自式(1-7)化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式(1)化合物、式(1-2)化合物、式(1-3)化合物、式(1-4)化合物、式(1-5)化合物、式(1-6)化合物、式(1-7)化合物、其立体异构体、或其药学上可接受的盐的结构单元
的立体异构体选自
在一些方案中，所述式(1)化合物、其立体异构体、或其药学上可接受的盐选自式(1-A)化合物
其立体异构体、或其药学上可接受的盐或式(1-B)化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请 所述。
在一些方案中，所述式(1-2)化合物、其立体异构体、或其药学上可接受的盐选自式(1-2A)化合物
其立体异构体、或其药学上可接受的盐或式(1-2B)化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式(1-3)化合物、其立体异构体、或其药学上可接受的盐选自式(1-3A)化合物
其立体异构体、或其药学上可接受的盐或式(1-3B)化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式(1-4)化合物、其立体异构体、或其药学上可接受的盐选自式(1-4A)化合物
其立体异构体、或其药学上可接受的盐或式(1-4B)化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式(1-5)化合物、其立体异构体、或其药学上可接受的盐选自式 (1-5A)化合物
其立体异构体、或其药学上可接受的盐或式(1-5B)化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式(1-6)化合物、其立体异构体、或其药学上可接受的盐选自式(1-6A)化合物
其立体异构体、或其药学上可接受的盐或式(1-6B)化合物
其立体异构体、或其药学上可接受的盐，其中基团的定义如本申请所述。
在一些方案中，所述式(1-7)化合物、其立体异构体、或其药学上可接受的盐选自式(1-7A)化合物
其立体异构体、或其药学上可接受的盐或式(1-7B)化合物
其立体异构体、或其药学上可接受的盐，其 中基团的定义如本申请所述。
在一些方案中，本申请提供下述化合物、其立体异构体、或其药学上可接受的盐：
在一些方案中，本申请提供下述化合物、其立体异构体、或其药学上可接受的盐：
本申请另一方面提供药物组合物，其包括本申请的化合物、其立体异构体、或其药学上可接受的盐，任选地进一步包括药学上可接受的辅料。
本申请另一方面提供本申请的化合物、其立体异构体、或其药学上可接受的盐、或其药物组合物在制备治疗乙型肝炎病毒感染的药物中的用途。
本申请另一方面提供本申请的化合物、其立体异构体、或其药学上可接受的盐、或其药物组合物在治疗乙型肝炎病毒感染中的用途。
本申请另一方面提供用途治疗乙型肝炎病毒感染的本申请的化合物、其立体异构体、或其药学上可接受的盐、或其药物组合物。
本申请另一方面提供治疗乙型肝炎病毒感染的方法，包括对需要治疗的哺乳动物，优选人类，给予治疗有效量的本申请的化合物、其立体异构体、其药学上可接受的盐、或其药物组合物。
本申请的化合物具有良好的抗乙型肝炎病毒的活性。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术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，而应该按照本领域普通的含义去 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。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，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。
术语氧代(即＝O)指氧原子通过双键与被取代的原子相连。在非限制性的例子中，氧代可以发生在C原子上，例如形成-CO-；氧代也可以发生在S原子上，例如形成-SO-或-SO
2-。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH
2CH
3)、单取代的(如CH
2CH
2F)、多取代的(如CHFCH
2F、CH
2CHF
2等)或完全被取代的(CF
2CF
3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文中的C
m-n，是该部分具有给定范围中的整数个碳原子。例如“C
1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。例如C
1-3是指该基团可具有1个碳原子、2个碳原子、3个碳原子。
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。例如，如果一个基团被2个R所取代，则每个R都有独立的选项。或者例如，多个基团被某个R所取代，则其中每个基团被R取代的情况相互之间是独立的。
当一个连接基团的数量为0时，比如-(CH
2)
0-，表示该连接基团为共价键。
当其中一个变量选自共价键时，表示其连接的两个基团直接相连，比如A-L’-Z中L’代表共价键时表示该结构实际上是A-Z。
当一个取代基的键交叉连接到一个环上的两个原子时，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
表示其可在环己基或者环己二烯上的任意一个位置发生取代。又例如，结构单元
包括但不限于
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“烷基”是指通式为C
nH
2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C
1-
6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。又例如，术语“C
1-
3烷基”指含有1至3个碳原子的烷基(例如甲基、乙基、丙基和异丙基)。
术语“烷氧基”指-O-烷基。
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、二环[1.1.1]戊-1-基等。例如，C
3-4环烷基包括环丙基和环丁基。
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至8元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。优选为具有5或6个环原子的单环杂环烷基。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1,2,3,4-四氢化萘等。
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个3至8元环，尤其是5至8元环，或包含6至14个，尤其是6至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻 吩基、吲哚基、异吲哚基等。
本申请的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。
本申请的某些化合物可以具有不对称碳原子(立体中心)或双键。因此，外消旋体、非对映异构体、对映异构体、几何异构体和单个异构体都包括在本申请的范围之内。
当本申请的化合物含有烯属双键或其它几何不对称中心时，除非另有规定，它们包括E和Z几何异构体。
本申请的化合物可以存在特定的几何异构体或立体异构体形式。本申请设想所有的这类化合物，包括互变异构体、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，所有这些都属于本申请的范围之内。烷基等取代基中可以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申请的范围之内。
可以通过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。如果想得到本申请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)。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为
2H、
3H、
11C、
13C、
14C、
13N、
15N、
15O、
17O、
18O、
31P、
32P、
35S、
18F、
123I、
125I和
36Cl等。
某些同位素标记的本申请化合物(例如用
3H及
14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即
3H)和碳-14(即
14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如
15O、
13N、
11C和
18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即
2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代，所有这样的形式的化合物包含于本申请的范围内。
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。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状， 即，导致疾病或症状退化。
术语“有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
本申请中，术语“个体”包括人和动物，例如，哺乳动物(如灵长类动物，牛，马，猪，狗，猫，小鼠，大鼠，兔，山羊，绵羊以及禽类等)。
本申请化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本申请化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推，得到有效剂量。
本申请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申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.本申请引用的所有参考文献整体上并入本申请。
在一些实施方案中，本申请的化合物，例如通式IVA及IVB的化合物可以由有机合成领域技术人员通过以下方法来制备：
其中，Z或R
2的定义同本申请。
本申请采用下述缩略词：
DMF代表N，N-二甲基甲酰胺；DCM代表二氯甲烷；MeOH代表甲醇；Pd
2(dba)
3代表三(亚苄基丙酮)二钯；EA代表乙酸乙酯；Ru-phos代表2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯；DMFDMA代表N-二甲基甲酰胺二甲缩醛；EtONa代表乙醇钠；TEA是三乙胺。
实施例
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
实施例1(1_A和1_B)
步骤A：向反应瓶中依次加入化合物1-1(5g)，N,N-二甲基甲酰胺二甲基缩醛(3.3g)，DMF(50mL)，升温至90℃反应3小时后冷却至室温。，旋蒸除去溶剂后向反应瓶中加入2-嘧啶甲脒盐酸盐(3.99g)，乙醇钠(3.43g)，无水乙醇(50mL)，回流反应3小时。将反应液旋干后加水100mL，乙酸乙酯萃取(100mL*3)。合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥，抽滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离 (DCM:MeOH＝100:3)，制得化合物1-2(3.4g)。MS(ESI
+,[M+Na]
+)m/z:334.4.
步骤B：向微波管中依次加入化合物1-2(3.4g)，氢氧化钾(4.9g)，甲醇(15mL)和水(15mL)，微波100℃反应1小时。反应液加入50mL水稀释后用稀盐酸调pH至6，旋蒸除去溶剂后加入四氢呋喃(80mL)，三乙胺(10mL)，室温搅拌1小时后抽滤，滤液旋干后得化合物1-3(1.3g)。MS(ESI
+,[M+Na]
+)m/z:262.4.
步骤C：向反应瓶中依次加入化合物1-3(500mg)，2,4,6-三氟吡啶(278mg)，碳酸铯(2.042g)，DMF(20mL)，加热至80℃反应8小时后将反应液缓慢倒入50mL水中，用乙酸乙酯(3*20mL)萃取，合并有机层，减压蒸除溶剂，所得粗品经C18柱层析分离(乙腈：水＝40:60)，依次分离得到实施例1_B化合物(100mg)及实施例1_A化合物(80mg)。
实施例1_A：
1H NMR(500MHz,DMSO-d
6)δ8.97(s,1H),8.96(s,1H),8.86(s,1H),7.61(t,J＝4.9Hz,1H),6.80(d,J＝11.0Hz,1H),6.34(d,J＝8.7Hz,1H),5.45(d,J＝5.9Hz,1H),4.97-4.78(m,1H),3.37(dd,J＝18.1,4.7Hz,1H),2.87(d,J＝18.3Hz,1H),2.44-2.26(m,2H),2.06-2.01(m,1H),1.96-1.85(m,1H).MS(ESI
+,[M+Na]
+)m/z:375.4.
实施例1_B：
1H NMR(500MHz,DMSO-d
6)δ8.97(s,1H),8.96(s,1H),8.86(s,1H),7.62(t,J＝4.9Hz,1H),6.68(s,2H),5.44(d,J＝5.9Hz,1H),4.89(t,J＝6.0Hz,1H),3.38(dd,J＝18.3,4.6Hz,1H),2.88(d,J＝18.6Hz,1H),2.45-2.28(m,2H),2.09-2.01(m,1H),1.98-1.89(m,1H).MS(ESI
+,[M+Na]
+)m/z:375.4.
实施例2(2_A和2_B)
向微波管中依次加入化合物1_A(50mg)，40％二甲胺水溶液(0.8mL)，DMF(1mL)，碳酸铯(1.5g)，微波加热至90℃反应1小时后将反应液缓慢倒入50mL水中，用乙酸乙酯(3*20mL)萃取，合并有机层，用饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例2(40mg)。
实施例2：
1H NMR(500MHz,DMSO-d
6)δ8.95(d,J＝4.8Hz,2H),8.83(s,1H),7.61(t,J＝4.9Hz,1H),5.84(s,1H),5.62(s,1H),5.36(d,J＝5.6Hz,1H),4.81(t,J＝6.3Hz,1H),2.90(s,6H),2.76(d,J＝18.5Hz,1H),2.40–2.24(m,2H),2.01–1.81(m,2H),1.23(s,1H).MS(ESI
+,[M+Na]
+)m/z:400.5.
化合物2经高压制备液相分离(CHIRALART Cellulose-SB色谱柱；乙醇：正己烷＝20:80)，依次分离得到实施例2_A(15mg)及实施例2_B(15mg)。
实施例2_A：
1H NMR(500MHz,DMSO-d
6)δ8.95(d,J＝4.8Hz,2H),8.83(s,1H),7.61(t,J＝4.9Hz,1H),5.84(s,1H),5.62(s,1H),5.36(d,J＝5.6Hz,1H),4.81(t,J＝6.3Hz,1H),2.90(s,6H),2.76(d,J＝18.5Hz,1H),2.40–2.24(m,2H),2.01–1.81(m,2H),1.23(s,1H).MS(ESI
+,[M+Na]
+)m/z:400.5.
实施例2_B：
1H NMR(500MHz,DMSO-d
6)δ8.95(d,J＝4.8Hz,2H),8.83(s,1H),7.61(t,J＝4.9Hz,1H),5.84(s,1H),5.62(s,1H),5.36(d,J＝5.6Hz,1H),4.81(t,J＝6.3Hz,1H),2.90(s,6H),2.76(d,J＝18.5Hz,1H),2.40–2.24(m,2H),2.01–1.81(m,2H),1.23(s,1H).MS(ESI
+,[M+Na]
+)m/z:400.5.
实施例3
向微波管中依次加入实施例1_B(50mg)，40％二甲胺水溶液(0.8mL)，DMF(1mL)，碳酸铯(1.5g)，微波加热至90℃反应1小时后将反应液缓慢倒入50mL水中，用乙酸乙酯(3*20mL)萃取，合并有机层，用饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例3(14mg)。MS(ESI
+,[M+Na]
+)m/z:400.5.
实施例4(4_A和4_B)
根据实施例2，用3-甲氧基氮杂环丁烷盐酸盐替代二甲胺水溶液，制得实施例4(50mg)。
实施例4：
1H NMR(500MHz,DMSO-d
6)δ8.95(d,J＝4.8Hz,2H),8.82(s,1H),7.61(t,J＝4.9Hz,1H),5.65(d,J＝1.6Hz,1H),5.37(d,J＝1.4Hz,1H),5.32(d,J＝5.8Hz,1H),4.77(t,J＝6.0Hz,1H),4.31-4.25(m,1H),4.08-4.01(m,2H),3.71-3.64(m,2H),3.41-3.37(m,1H),3.21(s,3H),2.77(d,J＝18.6Hz,1H),2.39-2.20(m,2H),2.00-1.92(m,1H),1.84-1.88(m,1H).MS(ESI
+[M+H]
+)m/z:420.2.
实施例4经高压制备液相分离(CHIRALARTCellulose-SB色谱柱；乙醇：正己烷＝20:80)，依次分离得到实施例4_A(20mg)及实施例4_B(20mg)。
实施例4_A：
1H NMR(500MHz,DMSO-d
6)δ8.95(d,J＝4.8Hz,2H),8.82(s,1H),7.61(t,J＝4.9Hz,1H),5.65(d,J＝1.6Hz,1H),5.37(d,J＝1.4Hz,1H),5.32(d,J＝5.8Hz,1H),4.77(t,J＝6.0Hz,1H),4.31-4.25(m,1H),4.08-4.01(m,2H),3.71-3.64(m,2H),3.41-3.37(m,1H),3.21(s,3H),2.77(d,J＝18.6Hz,1H),2.39-2.20(m,2H),2.00-1.92(m,1H),1.84-1.88(m,1H).MS(ESI
+[M+H]
+)m/z:420.2.
实施例4_B：
1H NMR(500MHz,DMSO-d
6)δ8.95(d,J＝4.8Hz,2H),8.82(s,1H),7.61(t,J＝4.9Hz,1H),5.65(d,J＝1.6Hz,1H),5.37(d,J＝1.4Hz,1H),5.32(d,J＝5.8Hz,1H),4.77(t,J＝6.0Hz,1H),4.31-4.25(m,1H),4.08-4.01(m,2H),3.71-3.64(m,2H),3.41-3.37(m,1H),3.21(s,3H),2.77(d,J＝18.6Hz,1H),2.39-2.20(m,2H),2.00-1.92(m,1H),1.84-1.88(m,1H).MS(ESI
+[M+H]
+)m/z:420.2.
实施例5(5_A和5_B)
根据实施例2，用3-氟氮杂环丁烷盐酸盐替代二甲胺水溶液，制得实施例5(50mg)。
实施例5：
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.8Hz,2H),8.76(s,1H),7.41(t,J＝4.9Hz,1H),5.47-5.43(m,1H),5.35-5.34(m,1H),5.28(d,J＝1.5Hz,1H),5.25(d,J＝5.8Hz,1H),4.83(t,J＝6.1Hz,1H),4.23-4.09(m,2H),4.08-3.92(m,2H),3.73-3.60(m,1H),2.94(d,J＝18.6Hz,1H),2.49-2.39(m,2H),2.06-1.99(m,1H),1.93-1.85(m,1H).MS(ESI
+[M+Na]
+)m/z:430.3.
化合物5经高压制备液相分离(CHIRALARTCellulose-SB色谱柱；乙醇：正己烷＝20:80)，依次分离得到实施例5_A(20mg)及实施例5_B(20mg)。
实施例5_A：
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.8Hz,2H),8.76(s,1H),7.41(t,J＝4.9Hz,1H),5.47-5.43(m,1H),5.35-5.34(m,1H),5.28(d,J＝1.5Hz,1H),5.25(d,J＝5.8Hz,1H),4.83(t,J＝6.1Hz,1H),4.23-4.09(m,2H),4.08-3.92(m,2H),3.73-3.60(m,1H),2.94(d,J＝18.6Hz,1H),2.49-2.39(m,2H),2.06-1.99(m,1H),1.93-1.85(m,1H).MS(ESI
+[M+Na]
+)m/z:430.3.
实施例5_B：
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.8Hz,2H),8.76(s,1H),7.41(t,J＝4.9Hz,1H),5.47-5.43(m,1H),5.35-5.34(m,1H),5.28(d,J＝1.5Hz,1H),5.25(d,J＝5.8Hz,1H),4.83(t,J＝6.1Hz,1H),4.23-4.09(m,2H),4.08-3.92(m,2H),3.73-3.60(m,1H),2.94(d,J＝18.6Hz,1H),2.49-2.39(m,2H),2.06-1.99(m,1H),1.93-1.85(m,1H).MS(ESI
+[M+Na]
+)m/z:430.3.
实施例6
根据实施例2，用3-甲氧基氮杂环戊烷盐酸盐替代二甲胺水溶液，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例6(11.8mg)。
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.8Hz,2H),8.75(d,J＝1.5Hz,1H), 7.40(t,J＝4.8Hz,1H),5.48-5.44(m,1H),5.40(d,J＝1.5Hz,1H),5.24(t,J＝6.1Hz,1H),4.85(s,1H),4.0-4.03(m,1H),3.72-3.67(m,1H),3.41-3.35(m,2H),3.34(d,J＝3.1Hz,3H),3.38-3.24(m,2H),2.93(d,J＝18.6Hz,1H),2.51-2.40(m,2H),2.17-2.04(m,2H),2.00-1.83(m,2H).MS(ESI
+[M+Na]
+)m/z:456.4.
实施例7
根据实施例2，用异噻唑烷-1,1-二氧化物替代二甲胺水溶液，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例7(29mg)。
1H NMR(500MHz,Chloroform-d)δ8.98(d,J＝4.8Hz,2H),8.77(s,1H),7.39(t,J＝4.8Hz,1H),6.38(s,1H),5.85(d,J＝1.6Hz,1H),5.32(d,J＝6.0Hz,1H),4.85(t,J＝6.0Hz,1H),3.71(t,J＝6.7Hz,3H),3.37(t,J＝7.4Hz,2H),2.98(d,J＝18.7Hz,1H),2.55-2.38(m,4H),2.10-1.84(m,2H).MS(ESI
+[M+H]
+)m/z:454.3.
实施例8
向微波管中依次加入化合物1-3(200mg)，5-溴-1,2-二氟-3-甲氧基苯(224mg)，Pd
2(dba)
3(38mg)，Ru-phos(20mg)，叔丁醇钠(241mg)，1,4-二氧六环(5mL)，氮气置换后微波100℃反应2小时。反应液加水10mL，EA萃取(20mL*2),有机相合并，浓缩后硅胶柱层析分离(DCM:MeOH＝100:5)，制得实施例8(7mg)。
1H NMR(500MHz,DMSO-d
6)δ8.95(d,J＝4.9Hz,2H),8.87(s,1H),7.60(t,J＝4.8Hz,1H),6.60-6.50(m,2H),5.21(d,J＝5.7Hz,1H),4.73(t,J＝5.8Hz,1H),3.82(s,3H),3.39-3.34(m,1H),2.74(d,J＝18.7Hz,1H),2.41-2.26(m,2H),2.03-1.95(m,1H),1.94-1.86(m,1H).MS(ESI
+,[M+Na]
+)m/z:404.4.
实施例9
根据实施例8，用1-溴-3-甲氧基-5-(三氟甲基)苯替代5-溴-1,2-二氟-3-甲氧基苯，制得实施例9(3.3mg)。MS(ESI
+,[M+Na]
+)m/z:414.5.
实施例10
根据实施例8，用1-溴-3-氟-5-甲氧基苯替代5-溴-1,2-二氟-3-甲氧基苯，制得10(20mg)。MS(ESI
+[M+H]
+)m/z:364.5.
实施例11(11_A和11_B)
实施例8经高压制备液相分离(CHIRALARTCellulose-SB色谱柱；乙醇：正己烷＝20:80)，依次分离得到实施例11_A(15mg)及实施例11_B(15mg)。
实施例11_A：
1H NMR(500MHz,DMSO-d
6)δ8.95(d,J＝4.9Hz,2H),8.87(s,1H),7.60(t,J＝4.8Hz,1H),6.60-6.50(m,2H),5.21(d,J＝5.7Hz,1H),4.73(t,J＝5.8Hz,1H),3.82(s,3H),3.39-3.34(m,1H),2.74(d,J＝18.7Hz,1H),2.41-2.26(m,2H),2.03-1.95(m,1H),1.94-1.86(m,1H).MS(ESI
+,[M+Na]
+)m/z:404.4.
实施例11_B：
1H NMR(500MHz,DMSO-d
6)δ8.95(d,J＝4.9Hz,2H),8.87(s,1H),7.60(t,J＝4.8Hz,1H),6.60-6.50(m,2H),5.21(d,J＝5.7Hz,1H),4.73(t,J＝5.8Hz,1H),3.82(s,3H),3.39-3.34(m,1H),2.74(d,J＝18.7Hz,1H),2.41-2.26(m,2H),2.03-1.95(m,1H),1.94-1.86(m,1H).MS(ESI
+,[M+Na]
+)m/z:404.4.
实施例12
根据实施例2，用环丙基甲基胺替代二甲胺水溶液，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例12(15mg)。
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.9Hz,2H),8.75(s,1H),7.40(t,J＝4.8Hz,1H),5.54(s,1H),5.44(s,1H),5.20(d,J＝5.6Hz,1H),4.82(t,J＝5.9Hz,1H),4.31(s,1H),3.68(dd,J＝18.5,5.0Hz,1H),2.99–2.86(m,3H),2.58–2.27(m,2H),2.14–1.97(m,1H),1.95–1.83(m,1H),1.08–0.96(m,1H),0.70–0.43(m,2H),0.35–0.09(m,2H).MS(ESI
+,[M+H]
+)m/z:404.5.
实施例13
根据实施例2，用2-甲氧基乙胺替代二甲胺水溶液，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例13(35mg)。
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.8Hz,2H),8.74(s,1H),7.39(t,J＝4.8Hz,1H),5.58(d,J＝1.6Hz,1H),5.46(d,J＝1.6Hz,1H),5.21(d,J＝5.7Hz,1H),4.81(t,J＝6.0Hz,1H),4.52(t,J＝5.5Hz,1H),3.77–3.62(m,1H),3.53(t,J＝5.1Hz,2H),3.36(s,3H),3.29–3.18(m,2H),2.92(d,J＝18.6Hz,1H),2.57–2.33(m,2H),2.09–1.96(m,1H),1.94–1.80(m,1H).MS(ESI
+,[M+H]
+)m/z:408.4.
实施例14
根据实施例2，用吗啉替代二甲胺水溶液，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例14(32mg)。
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.9Hz,2H),8.76(s,1H),7.40(t,J＝4.8Hz,1H),5.76(s,1H),5.65(s,1H),5.26(d,J＝5.8Hz,1H),5.05–4.73(m,1H),3.78(t,J＝4.9Hz,4H),3.76–3.58(m,1H),3.30–3.10(m,4H),2.94(d,J＝18.6Hz,1H),2.58–2.38(m,2H),2.16–2.00(m,1H),2.00–1.81(m,1H).MS(ESI
+,[M+Na]
+)m/z:442.1.
实施例15
根据实施例2，用2-甲氧基乙醇替代二甲胺水溶液，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例15(30mg)。
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.9Hz,2H),8.75(s,1H),7.40(t,J＝4.8Hz,1H),6.00(s,1H),5.79(d,J＝1.7Hz,1H),5.24(d,J＝5.8Hz,1H),4.81(t,J＝6.1Hz,1H),4.23–3.95(m,2H),3.75–3.59(m,3H),3.42(s,3H),3.03–2.92(m,1H),2.57–2.37(m,2H),2.11–1.97(m,1H),1.95–1.84(m,1H).MS(ESI
+,[M+Na]
+)m/z:431.1.
实施例16
根据实施例8，用1-溴-3-氯-5-氟苯替代5-溴-1,2-二氟-3-甲氧基苯，制得实施例16(15mg)。
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.9Hz,2H),8.78(s,1H),7.40(t,J＝4.8Hz,1H),6.57(s,1H),6.51–6.34(m,2H),4.88(d,J＝5.9Hz,1H),4.66–4.54(m,1H),3.69–3.51(m,1H),2.93(dd,J＝18.7,1.0Hz,1H),2.64–2.37(m,2H),2.12–2.04(m,1H),1.99–1.86(m,1H).MS(ESI
+[M+H]
+)m/z:368.1.
实施例17
步骤A：根据实施例1步骤A，用2-吡啶甲脒盐酸盐替代2-嘧啶甲脒盐酸盐，制得化合物17-2。MS(ESI
+,[M+H]
+)m/z:311.4.
步骤B：根据实施例1步骤B，用化合物17-2替代化合物1-2，制得化合物17-3。MS(ESI
+,[M+Na]
+)m/z:262.4.
步骤C：根据实施例1步骤C，用化合物17-3替代化合物1-3，制得化合物17-4。MS(ESI
+[M+H]
+)m/z:352.1.
步骤D：向微波管中依次加化合物入化合物17-4(200mg)，3-氟氮杂环丁烷盐酸盐(200mg)，碳酸铯(700mg)，DMF(1mL)，微波加热至90℃反应1小时后将反应液缓慢倒入50mL水中，用乙酸乙酯(3*20mL)萃取，合并有机层，用饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例17(40mg)。
1H NMR(500MHz,Chloroform-d)δ8.80(d,J＝5.0Hz,1H),8.64(s,1H),8.42(d,J＝8.0Hz,1H),7.82(t,J＝7.8,6.5,1.9Hz,1H),7.36(t,J＝8.8,4.5,1.9Hz,1H),5.34(s,1H),5.27(s,1H),5.20(d,J＝5.9Hz,1H),4.84–4.79(m,1H),4.24–4.06(m,2H),4.07–3.93(m,2H),3.66–3.58(m,1H),3.49(d,J＝5.2Hz,1H),2.87(d,J＝18.5Hz,1H),2.52–2.35(m,2H),2.06–1.96(m,1H),1.92–1.83(m,1H).MS(ESI
+[M+H]
+)m/z:407.2.
实施例18
根据实施例17，在步骤D中，用2-甲氧基乙醇替代3-氟氮杂环丁烷盐酸盐，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例 18(130mg)。
1H NMR(500MHz,Chloroform-d)δ8.80(ddd,J＝4.8,1.8,0.9Hz,1H),8.64(s,1H),8.42(d,J＝8.0Hz,1H),7.82(td,J＝7.7,1.8Hz,1H),7.39–7.32(m,1H),5.99(s,1H),5.78(d,J＝1.7Hz,1H),5.20(d,J＝5.9Hz,1H),4.80(t,J＝6.2Hz,1H),4.10–4.03(m,2H),3.73–3.67(m,2H),3.64–3.57(m,1H),3.42(s,3H),2.91-2.85(m,1H),2.51–2.35(m,2H),2.07–1.97(m,1H),1.92–1.82(m,1H).MS(ESI
+[M+H]
+)m/z:408.1.
实施例19
根据实施例17，在步骤D中，用二甲胺水溶液替代3-氟氮杂环丁烷盐酸盐，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例19(120mg)。
1H NMR(500MHz,Chloroform-d)δ8.80(ddd,J＝4.8,1.8,0.9Hz,1H),8.64(s,1H),8.42(d,J＝7.9Hz,1H),7.82(td,J＝7.8,1.8Hz,1H),7.36(ddd,J＝7.5,4.7,1.2Hz,1H),5.57(s,1H),5.50(s,1H),5.21(d,J＝5.8Hz,1H),4.84(t,J＝6.2Hz,1H),3.70–3.62(m,1H),2.92(s,6H),2.90–2.81(m,1H),2.51–2.37(m,2H),2.04–1.96(m,1H),1.90–1.83(m,1H).MS(ESI
+[M+H]
+)m/z:377.1.
实施例20(20_A和20_B)
根据实施例2，用2-甲氧基-N-甲基乙胺替代二甲胺水溶液，制得实施例20(80mg)。
实施例20：
1H NMR(500MHz,Chloroform-d)δ8.98(d,J＝4.8Hz,2H),8.75(s,1H), 7.39(t,J＝4.8Hz,1H),5.62(s,1H),5.52(s,1H),5.25(d,J＝5.9Hz,1H),4.91–4.82(m,1H),3.70(dd,J＝18.6,4.9Hz,1H),3.51–3.37(m,4H),3.31(s,3H),2.98–2.89(m,4H),2.54–2.38(m,2H),2.08–1.98(m,1H),1.95–1.84(m,1H).MS(ESI
+[M+H]
+)m/z:422.5.
实施例20经高压制备液相分离(CHIRALARTCellulose-SB色谱柱；乙醇：正己烷＝20:80)，依次分离得到实施例20_A(35mg)及实施例20_B(35mg)。
实施例20_A：
1H NMR(500MHz,Chloroform-d)δ8.98(d,J＝4.8Hz,2H),8.75(s,1H),7.39(t,J＝4.8Hz,1H),5.62(s,1H),5.52(s,1H),5.25(d,J＝5.8Hz,1H),4.84(t,J＝6.1Hz,1H),3.70(dd,J＝18.6,5.1Hz,1H),3.52–3.39(m,4H),3.31(s,3H),2.98–2.84(m,4H),2.56–2.38(m,2H),2.09–1.96(m,1H),1.96–1.82(m,1H).MS(ESI
+[M+H]
+)m/z:422.5.
实施例20_B：
1H NMR(500MHz,Chloroform-d)δ8.98(d,J＝4.8Hz,2H),8.75(s,1H),7.39(t,J＝4.8Hz,1H),5.62(t,J＝1.6Hz,1H),5.52(t,J＝1.4Hz,1H),5.25(d,J＝5.8Hz,1H),4.84(t,J＝6.1Hz,1H),3.83–3.61(m,1H),3.57–3.38(m,4H),3.31(s,3H),2.94(s,4H),2.54–2.31(m,2H),2.15–1.95(m,1H),1.95–1.84(m,1H).MS(ESI
+[M+H]
+)m/z:422.5.
实施例21(21_A和21_B)
根据实施例2，用乙硫醇替代二甲胺水溶液，制得实施例21(70mg)。
实施例21：
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.8Hz,2H),8.77(s,1H),7.40(t,J＝4.8Hz,1H),6.25(s,1H),6.04(s,1H),5.29(d,J＝6.0Hz,1H),4.95–4.76(m,1H),3.65(ddd,J＝18.7,5.3,1.7Hz,1H),2.98(d,J＝18.6Hz,1H),2.93(q,J＝7.4Hz,2H),2.59–2.35(m,2H),2.12–1.97(m,1H),1.97–1.83(m,1H),1.33(t,J＝7.4Hz,3H).MS(ESI
+[M+H]
+)m/z:395.1.
实施例21经高压制备液相分离(CHIRALARTCellulose-SB色谱柱；乙醇：正己烷 ＝20:80)，依次分离得到实施例21_A(30mg)及实施例21_B(30mg)。
实施例21_A：
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.9Hz,2H),8.77(s,1H),7.40(t,J＝4.8Hz,1H),6.25(s,1H),6.05(s,1H),5.29(d,J＝6.0Hz,1H),4.83(t,J＝6.2Hz,1H),3.75–3.53(m,1H),2.98(d,J＝18.6Hz,1H),2.93(q,J＝7.4Hz,2H),2.59–2.34(m,2H),2.10–1.99(m,1H),1.96–1.83(m,1H),1.33(t,J＝7.4Hz,3H).MS(ESI
+[M+H]
+)m/z:395.1.
实施例21_B：
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.9Hz,2H),8.77(s,1H),7.39(t,J＝4.8Hz,1H),6.25(s,1H),6.04(s,1H),5.29(d,J＝6.0Hz,1H),4.83(t,J＝6.2Hz,1H),3.70–3.59(m,1H),3.07–2.78(m,3H),2.57–2.37(m,2H),2.19–1.96(m,1H),1.96–1.77(m,1H),1.33(t,J＝7.4Hz,3H).MS(ESI
+[M+H]
+)m/z:395.1.
实施例22(22_A和22_B)
向茄型瓶中依次加入实施例21(120mg)，二氯甲烷20mL，冰浴下加入间氯过氧苯甲酸(68mg)，0℃反应1小时后将反应液缓慢倒入50mL饱和NaHCO
3水溶液中，二氯甲烷萃取(50mL*3)。合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥，抽滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(DCM:MeOH＝100:3)，制得实施例22化合物(127mg)。
实施例22：
1H NMR(500MHz,Chloroform-d)δ9.00(d,J＝4.8Hz,2H),8.81(s,1H),7.41(t,J＝4.8Hz,1H),6.81(d,J＝6.8Hz,1H),6.28–6.14(m,1H),5.44(dd,J＝16.0,5.7Hz,1H),4.94(s,1H),3.71–3.59(m,1H),3.05(d,J＝20.6Hz,1H),3.01–2.89(m,1H),2.79–2.62(m,1H),2.59–2.37(m,2H),2.18–2.05(m,1H),2.01–1.90(m,1H),1.25–1.16(m,3H).MS(ESI
+[M+H]
+)m/z:411.4.
实施例22经高压制备液相分离(CHIRALARTCellulose-SB色谱柱；乙醇：正己烷 ＝20:80)，依次分离得到实施例22_A(30mg)及实施例22_B(30mg)。
实施例22_A：
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.8Hz,2H),8.80(d,J＝1.0Hz,1H),7.40(t,J＝4.9Hz,1H),6.81(d,J＝6.7Hz,1H),6.19(ddd,J＝4.4,2.9,0.9Hz,1H),5.44(dd,J＝16.1,6.2Hz,1H),4.93(dd,J＝14.8,7.4Hz,1H),3.73–3.56(m,1H),3.16–3.01(m,1H),3.01–2.85(m,1H),2.80–2.64(m,1H),2.59–2.38(m,2H),2.12–2.03(m,1H),2.03–1.84(m,1H),1.26–1.16(m,3H).MS(ESI
+[M+H]
+)m/z:411.4.
实施例22_B：
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.8Hz,2H),8.80(d,J＝1.0Hz,1H),7.41(t,J＝4.8Hz,1H),6.81(d,J＝6.6Hz,1H),6.23–6.14(m,1H),5.51–5.37(m,1H),4.93(d,J＝6.8Hz,1H),3.70–3.59(m,1H),3.09–3.00(m,1H),3.00–2.90(m,1H),2.77–2.65(m,1H),2.56–2.38(m,2H),2.14–2.02(m,1H),1.99–1.88(m,1H),1.26–1.16(m,3H).MS(ESI
+[M+H]
+)m/z:411.4.
实施例23
向茄型瓶中依次加入实施例22(65mg)，二氯甲烷20mL，冰浴下加入间氯过氧苯甲酸(40mg)，0℃反应1小时后将反应液缓慢倒入50mL饱和NaHCO
3水溶液中，二氯甲烷萃取(50mL*3)。合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥，抽滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(DCM:MeOH＝100:3)，制得实施例23化合物(30mg)。
实施例23：
1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝4.8Hz,2H),8.81(s,1H),7.41(t,J＝4.8Hz,1H),6.92(s,1H),6.57(dd,J＝3.1,1.1Hz,1H),5.44(s,1H),4.93(s,1H),3.72–3.54(m,1H),3.14–3.03(m,3H),2.60–2.40(m,2H),2.20–2.07(m,1H),1.98–1.92(m,1H),1.27(t,J＝7.4Hz,3H).MS(ESI
+[M+H]
+)m/z:427.4.
实施例24(24_A和24_B)
步骤A：向反应瓶中依次加入化合物24-1(50g)，N,N-二甲基甲酰胺二甲基缩醛(29.9g)，升温至100℃反应7小时后冷却至室温，旋蒸除去过量DMFDMA后，向反应瓶中继续加入2-嘧啶甲脒盐酸盐(33.9g)，叔丁醇钠(41.1g)，无水乙醇(500mL)，回流反应7小时。将反应液旋干后加水500mL，乙酸乙酯萃取(300mL*3)，合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥，抽滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(DCM:MeOH＝100:3)，制得化合物24-2(43.0g)。MS(ESI
+,[M+H]
+)m/z:354.12.
步骤B：向反应瓶中依次加入化合物24-2(43.0g)，盐酸二氧六环溶液(4.0M,50mL)。室温反应16h，反应液用TEA调pH至7左右，过滤，滤液旋干后得化合物24-3(28.0g)。MS(ESI
+,[M+H]
+)m/z:253.99.
步骤C：向反应瓶中依次加入化合物24-3(28.0g)，2,4,6-三氟吡啶(8.1g)，碳酸铯(59.4g)，DMF(100mL)，加热至80℃反应14小时后将反应液缓慢倒入500mL冰水中，用乙酸乙酯(5*200mL)萃取，合并有机层，减压蒸除溶剂，所得粗品经C18柱层析分离(乙腈：水＝30:70)，分离得到实施例24(4.1g)。
实施例24：
1H NMR(500MHz,Chloroform-d)δ9.02(d,J＝4.8Hz,2H),8.76(s,1H),7.43(t,J＝4.8Hz,1H),6.25(d,J＝11.0,1.6Hz,1H),5.98–5.89(m,1H),5.73(s,1H),4.85(s,1H),3.62–3.50(m,1H),3.16(d,J＝19.1Hz,1H),2.18–2.07(m,1H),2.05–1.93(m,1H),1.88–1.81(m,1H),1.82–1.72(m,1H),1.71–1.63(m,1H),1.53–1.41(m,1H).MS(ESI
+,[M+H]
+)m/z:367.05.
将实施例24(4.1g)经过超临界流体色谱分离(CHIRALART Cellulose-SC色谱柱，甲醇：CO
2＝30:70)，先出峰的为实施例24_A(1.25g)，后出峰的为实施例24_B(1.18g)。
实施例24_A：
1H NMR(500MHz,Chloroform-d)δ9.02(d,J＝4.8Hz,2H),8.76(s,1H),7.43(t,J＝4.8Hz,1H),6.25(d,J＝11.0,1.6Hz,1H),5.98–5.89(m,1H),5.73(s,1H),4.85(s,1H),3.62–3.50(m,1H),3.16(d,J＝19.1Hz,1H),2.18–2.07(m,1H),2.05–1.93(m,1H),1.88–1.81(m,1H),1.82–1.72(m,1H),1.71–1.63(m,1H),1.53–1.41(m,1H).MS(ESI
+,[M+H]
+)m/z:367.05.
实施例24_B：
1H NMR(500MHz,Chloroform-d)δ9.02(d,J＝4.8Hz,2H),8.76(s,1H), 7.43(t,J＝4.8Hz,1H),6.25(d,J＝11.0,1.6Hz,1H),5.98–5.89(m,1H),5.73(s,1H),4.85(s,1H),3.62–3.50(m,1H),3.16(d,J＝19.1Hz,1H),2.18–2.07(m,1H),2.05–1.93(m,1H),1.88–1.81(m,1H),1.82–1.72(m,1H),1.71–1.63(m,1H),1.53–1.41(m,1H).MS(ESI
+,[M+H]
+)m/z:367.05.
实施例25(25_A和25_B)
向微波管中依次加入实施例24(100mg)，40％二甲胺水溶液(0.615mL)，DMF(2mL)，微波加热至90℃反应1小时后将反应液缓慢倒入50mL水中，用乙酸乙酯(3*20mL)萃取，合并有机层，用饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，所得粗品实施例25经高压制备液相分离(CHIRALARTCellulose-SB色谱柱；乙醇：正己烷＝20:80)，先出峰的为实施例25_A(20mg)，后出峰的为实施例25_B(20mg)。
实施例25_A：
1H NMR(500MHz,CDCl
3)δ9.01(d,J＝4.8Hz,2H),8.75(s,1H),7.42(t,J＝4.8Hz,1H),5.71(s,1H),5.67(s,1H),5.54(s,1H),4.88(s,1H),3.58(dd,J＝19.0,7.7Hz,1H),3.09(d,J＝19.0Hz,1H),2.97(s,6H),2.15(m,1H),2.07–1.98(m,1H),1.85(s,1H),1.81(dd,J＝13.6,1.8Hz,1H),1.73(d,J＝11.4Hz,1H),1.62(d,J＝14.1Hz,1H).MS(ESI
+,[M+H]
+)m/z:392.17.
实施例25_B：
1H NMR(500MHz,CDCl
3)δ9.01(d,J＝4.8Hz,2H),8.75(s,1H),7.42(t,J＝4.8Hz,1H),5.71(s,1H),5.67(s,1H),5.54(s,1H),4.88(s,1H),3.58(dd,J＝19.0,7.7Hz,1H),3.09(d,J＝19.0Hz,1H),2.97(s,6H),2.15(m,1H),2.07–1.98(m,1H),1.85(s,1H),1.81(dd,J＝13.6,1.8Hz,1H),1.73(d,J＝11.4Hz,1H),1.62(d,J＝14.1Hz,1H).MS(ESI
+,[M+H]
+)m/z:392.17.
实施例26(26_A和26_B)
向微波管中依次加入实施例24(250mg)，3-氟氮杂环丁烷盐酸盐(230mg)，DMF(4 mL)，碳酸铯(1.0g)微波加热至90℃反应1小时后将反应液缓慢倒入50mL水中，用乙酸乙酯(3*20mL)萃取，合并有机层，用饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，所得粗品经高压制备液相分离(CHIRALARTCellulose-SB色谱柱；乙醇：正己烷＝20:80)，先出峰的为26_A(40mg),后出峰的为26_B(60mg)。
实施例26_A：
1H NMR(500MHz,Chloroform-d)δ9.02(d,J＝4.8Hz,2H),8.75(s,1H),7.42(t,J＝4.8Hz,1H),5.70(s,1H),5.43(d,J＝1.6Hz,1H),5.30(s,1H),4.85(s,1H),4.25–4.17(m,2H),4.10–3.96(m,2H),3.72(q,J＝7.0Hz,1H),3.61–3.51(m,1H),3.11(d,J＝19.1Hz,1H),2.17–2.08(m,1H),2.07–1.92(m,1H),1.87–1.69(m,2H),1.49–1.38(m,1H),1.67–1.61(m,1H).MS(ESI+,[M+H]+)m/z:422.20.
实施例26_B：
1H NMR(500MHz,Chloroform-d)δ9.02(d,J＝4.8Hz,2H),8.75(s,1H),7.42(t,J＝4.8Hz,1H),5.70(s,1H),5.43(d,J＝1.6Hz,1H),5.30(s,1H),4.85(s,1H),4.26–4.14(m,2H),4.08–3.98(m,2H),3.72(q,J＝7.0Hz,1H),3.61–3.51(m,1H),3.11(d,J＝19.1Hz,1H),2.17–2.08(m,1H),2.05–1.95(m,1H),1.85–1.69(m,2H),1.49–1.38(m,1H),1.67–1.61(m,1H).MS(ESI
+,[M+H]
+)m/z:422.19.
实施例27(27_A和27_B)
根据实施例26，用N-甲基-2-甲氧基乙胺替代3-氟氮杂环丁烷盐酸盐，所得粗品实施例27经高压制备液相分离(CHIRALARTCellulose-SB色谱柱；乙醇：正己烷＝20:80)，先出峰的为实施例27_A(25mg),后出峰的为实施例27_B(25mg)。
实施例27_A：
1H NMR(500MHz,Chloroform-d)δ9.01(d,J＝4.9Hz,2H),8.75(s,1H),7.41(t,J＝4.8Hz,1H),5.72(t,J＝1.5Hz,1H),5.70(s,1H),5.55(d,J＝1.6Hz,1H),4.87(s,1H),3.62–3.54(m,1H),3.54–3.43(m,4H),3.34(s,3H),3.09(d,J＝19.1Hz,1H),2.99(s,3H),2.19–2.10(m,1H),2.06–1.96(m,1H),1.84–1.77(m,1H),1.77–1.70(m,1H),1.66–1.58(m,1H),1.49–1.37(m,1H).。MS(ESI
+,[M+H]
+)m/z:436.18.
实施例27_B：
1H NMR(500MHz,Chloroform-d)δ9.01(d,J＝4.9Hz,2H),8.75(s,1H),7.41(t,J＝4.8Hz,1H),5.72(t,J＝1.5Hz,1H),5.70(s,1H),5.55(d,J＝1.6Hz,1H),4.87(s,1H),3.62–3.54(m,1H),3.54–3.43(m,4H),3.34(s,3H),3.09(d,J＝19.1Hz,1H),2.99(s,3H),2.19–2.10(m,1H),2.06–1.96(m,1H),1.84–1.77(m,1H),1.77–1.70(m,1H),1.66–1.58(m,1H),1.49–1.37(m,1H).。MS(ESI
+,[M+H]
+)m/z:436.15.
实施例28
向微波管中依次加入实施例24_B(200mg)，甲醇(50uL)，DMF(2mL)，碳酸铯(0.6g)，微波加热至110℃反应2小时后将反应液缓慢倒入50mL水中，用乙酸乙酯(3*20mL)萃取，合并有机层，用饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例28(60mg)
实施例28：
1H NMR(500MHz,Chloroform-d)δ9.02(d,J＝4.9Hz,2H),8.75(s,1H),7.42(t,J＝4.9Hz,1H),6.03(t,J＝1.3Hz,1H),5.79(d,J＝1.6Hz,1H),5.71(s,1H),4.87(d,J＝6.3Hz,1H),3.81(s,3H),3.60–3.52(m,1H),3.12(d,J＝19.1Hz,1H),2.18–2.08(m,1H),2.04–1.94(m,1H),1.87–1.78(m,1H),1.78–1.70(m,1H),1.66–1.63(m,1H),1.52–1.39(m,1H).MS(ESI
+,[M+H]
+)m/z:379.12.
实施例29
根据实施例28，用2-甲氧基乙醇替代甲醇，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例29(39mg)。
实施例29：
1H NMR(500MHz,Chloroform-d)δ9.02(d,J＝4.8Hz,2H),8.75(s,1H),7.42(t,J＝4.8Hz,1H),6.09(s,1H),5.80(s,1H),5.69(s,1H),4.85(s,1H),4.15–4.10(m,2H),3.74–3.71(m,2H),3.59–3.51(m,1H),3.44(s,3H),3.11(d,J＝19.1Hz,1H),2.12– 2.08(m,1H),2.02–1.94(m,1H),1.85–1.77(m,1H),1.76–1.70(m,1H),1.67–1.60(m,1H),1.47–1.41(m,1H).MS(ESI
+,[M+H]
+)m/z:423.18.
实施例30
根据实施例28，用3-甲氧基丙醇替代甲醇，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例30(50mg)。
实施例30：
1H NMR(500MHz,CDCl
3)δ9.01(d,J＝4.8Hz,2H),8.75(s,1H),7.42(t,J＝4.8Hz,1H),6.04(s,1H),5.79(s,1H),5.70(s,1H),4.86(s,1H),4.07(t,J＝6.3Hz,2H),3.61–3.54(m,1H),3.52(t,J＝6.0Hz,2H),3.35(s,3H),3.11(d,J＝19.1Hz,1H),2.16–2.09(m,1H),2.04–2.00(m,2H),2.00–1.94(m,1H),1.83–1.80(m,1H),1.78–1.71(m,1H),1.66–1.60(m,1H),1.53–1.39(m,1H).MS(ESI
+,[M+H]
+)m/z:437.18.
实施例31
根据实施例28，用2-甲氧基乙胺替代甲醇，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例31(57mg)。
实施例31：
1H NMR(500MHz,Chloroform-d)δ9.01(d,J＝4.8Hz,2H),8.74(s,1H),7.41(t,J＝4.8Hz,1H),5.68(s,1H),5.66(s,1H),5.48(s,1H),4.84(s,1H),4.60–4.54(m,1H),3.57(d,J＝5.2Hz,2H),3.53(d,J＝7.7Hz,1H),3.38(s,3H),3.29(dd,J＝10.4,5.2Hz,2H),3.08(d,J＝19.0Hz,1H),2.19–2.09(m,1H),2.04–1.95(m,1H),1.82–1.76(m,1H),1.75–1.68(m,1H),1.65–1.59(m,1H),1.49–1.40(m,1H).MS(ESI
+,[M+H]
+)m/z:.422.19
实施例32
根据实施例28，用6-氧杂-3-氮杂-双环[3,1,1]庚烷盐酸盐替代甲醇，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例32(42mg)。
实施例32：
1H NMR(500MHz,Methanol-d
4)δ9.01(d,J＝4.9Hz,2H),8.80(s,1H),7.62(t,J＝4.9Hz,1H),5.99(s,1H),5.73(d,J＝18.4Hz,2H),4.97(d,J＝6.5Hz,1H),4.73(d,J＝6.5Hz,2H),3.65–3.42(m,5H),3.28–3.18(m,1H),3.02(d,J＝19.3Hz,1H),2.18–2.09(m,1H),2.09–1.97(m,1H),1.93(d,J＝8.9Hz,1H),1.88(d,J＝13.6Hz,1H),1.80(d,J＝13.4Hz,1H),1.68–1.58(m,1H),1.49–1.36(m,1H).MS(ESI
+,[M+H]
+)m/z:.446.18。
实施例33
根据实施例28，用3-氟氮杂环丁烷盐酸盐替代甲醇，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例33(60mg)。
实施例33：
1H NMR(500MHz,Chloroform-d)δ9.01(d,J＝4.8Hz,2H),8.75(s,1H),7.41(t,J＝4.8Hz,1H),5.69(s,1H),5.41(d,J＝1.7Hz,1H),5.29(d,J＝1.3Hz,1H),4.85(s,1H),4.40–4.25(m,1H),4.15–4.04(m,2H),3.82–3.76(m,2H),3.61–3.51(m,1H),3.33(s,3H),3.09(d,J＝19.0Hz,1H),2.19–2.07(m,1H),2.01–1.96(m,1H),1.84–1.76(m,1H),1.75–1.67(m,1H),1.66–1.56(m,1H),1.49–1.37(m,1H)..MS(ESI+,[M+H]
+)m/z:.434.17
实施例34
根据实施例28，用1-甲烷磺酰基哌嗪替代甲醇，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例34(30mg)。
实施例34：
1H NMR(500MHz,Chloroform-d)δ9.01(d,J＝4.8Hz,2H),8.76(s,1H),7.42(t,J＝4.8Hz,1H),5.87(s,1H),5.72(s,1H),5.69(s,1H),4.87(d,J＝7.0Hz,1H),3.56(dd,J＝19.1,7.7Hz,1H),3.47–3.39(m,4H),3.37–3.29(m,4H),3.11(d,J＝19.1Hz,1H),2.82(s,3H),2.19–2.06(m,1H),2.05–1.95(m,1H),1.89–1.80(m,1H),1.79–1.75(m,1H),1.67–1.60(m,1H),1.51–1.39(m,1H).MS(ESI+,[M+H]
+)m/z:.511.19
实施例35
步骤A：向反应瓶中依次加入24-1(20g)，N,N-二甲基甲酰胺二甲基缩醛(12.0g)，升温至100℃反应7小时后冷却至室温，旋蒸除去过量DMFDMA后向反应瓶中继续加入2-吡啶甲脒盐酸盐(10.71g)，叔丁醇钠(9.25g)，无水乙醇(200mL)，回流反应7小时。将反应液旋干后加水200mL，乙酸乙酯萃取(100mL*3)，合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥，抽滤，减压蒸除溶剂，所得粗品经硅胶柱层析分离(DCM:MeOH＝100:3)，制得35-2(20.0g)。MS(ESI
+,[M+H]
+)m/z:353.16.
步骤B：向反应瓶中依次加入35-2(20.0g)，盐酸甲醇溶液(4.0M,100mL)。室温反应 16h，体系直接过滤，滤饼用DCM 20mL洗涤，滤饼加入甲醇200ml，用三乙胺中和至pH＝7-8，体系浓缩，得到化合物35-3(11g)。MS(ESI
+,[M+H]
+)m/z:253.04.
步骤C：向反应瓶中依次加入35-3(11.0g)，2,4,6-三氟吡啶(7.0g)，碳酸铯(42.6g)，DMF(100mL)，加热至80℃反应14小时后将反应液缓慢倒入500mL冰水中，用乙酸乙酯(5*200mL)萃取，合并有机层，减压蒸除溶剂，所得粗品经C18柱层析分离(乙腈：水＝35:65)，得到实施例35(2.0g)，MS(ESI
+,[M+H]
+)m/z:366.13.
步骤D：将实施例35(2.0g)经过高压制备液相分离(CHIRALART Cellulose-SC色谱柱，甲醇：CO
2＝30:70)，先出峰的为35_A(0.9g)，后出峰的为35_B(0.65g)。
实施例36
向微波管中依次加入实施例35A(100mg)，3-氟氮杂环丁烷盐酸盐(183mg)，DMF(1mL)，碳酸铯(624mg)微波加热至100℃反应2小时，将反应液缓慢倒入50mL水中，用乙酸乙酯(3*20mL)萃取，合并有机层，用饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例36(40mg)
实施例36：
1H NMR(500MHz,Chloroform-d)δ8.83(ddd,J＝4.8,1.8,0.8Hz,1H),8.64(s,1H),8.47(dt,J＝7.9,1.1Hz,1H),7.89–7.83(m,1H),7.38(ddd,J＝7.5,4.8,1.2Hz,1H),5.65(s,1H),5.43(t,J＝1.6Hz,1H),5.29(d,J＝1.4Hz,1H),4.84(s,1H),4.29–4.13(m,2H),4.10–3.95(m,2H),3.59–3.44(m,1H),3.03(d,J＝19.0Hz,1H),2.16–2.07(m,1H),2.05–1.94(m,2H),1.84–1.77(m,1H),1.72–1.66(m,1H),1.66–1.57(m,1H),1.51–1.42(m,1H).MS(ESI+,[M+H]
+)m/z:421.19.
实施例37
根据实施例36，用二甲胺水溶液替代3-氟氮杂环丁烷盐酸盐，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例37(60mg)。
实施例37：
1H NMR(500MHz,Chloroform-d)δ8.84–8.80(m,1H),8.64(s,1H),8.50–8.45(m,1H),7.88–7.82(m,1H),7.41–7.35(m,1H),5.67–5.62(m,2H),5.53(d,J＝1.6Hz,1H),4.87(s,1H),3.58–3.49(m,1H),2.97(s,6H),2.19–2.09(m,1H),2.06–1.95(m,2H),1.84–1.75(m,1H),1.75–1.67(m,1H),1.65–1.57(m,1H),1.49–1.42(m,1H).MS(ESI+,[M+H]
+)m/z:391.13.
实施例38
根据实施例36，用3-甲氧基丙醇替代3-氟氮杂环丁烷盐酸盐，所得粗品经高压制备液相分离(YMC-TriartPrepC18-S色谱柱；乙腈：水＝30:70)，制得实施例38(52mg)。
实施例38：
1H NMR(500MHz,Chloroform-d)δ8.86–8.81(m,1H),8.64(s,1H),8.48(dd,J＝8.0,1.1Hz,1H),7.84(td,J＝7.7,1.8Hz,1H),7.42–7.35(m,1H),6.04(t,J＝1.3Hz,1H),5.78(d,J＝1.5Hz,1H),5.65(s,1H),4.85(s,1H),4.07(t,J＝6.3Hz,2H),3.51(dt,J＝13.7,6.9Hz,3H),3.35(s,3H),3.04(d,J＝19.0Hz,1H),2.15–2.07(m,1H),2.04–1.97(m,3H),1.85–1.76(m,1H),1.75–1.69(m,1H),1.64–1.59(m,1H),1.52–1.41(m,1H).MS(ESI+,[M+H]
+)m/z:436.16.
试验例1：
1)：体外抗HBV活性
往指数生长期状态良好的HepG2.2.15细胞中加入5mL PBS以清洗一遍，之后加入3mL胰酶，所得物放入细胞培养箱中进行消化。用显微镜观察，待细胞脱落时，弃掉2mL胰酶；放入37℃培养箱中消化5min，用显微镜观察细胞(是否为单个圆形，细胞间无粘连)，加入4mL完全培养基终止消化反应并进行重悬。形成单细胞悬浮液后，使用细胞计数仪对10μL细胞悬浮液计数。使用完全培养基稀释上述10μL细胞悬浮液，使得细胞密度至2*10
5个/mL。使用多道移液枪接种细胞于96孔板上(提前使用50μg/mL CollagenⅠ溶液包被96孔板)，100μL/孔。将接种后的孔板置恒温CO
2培养箱中培养24h。
给药处理
使用完全培养基将DMSO溶解的待测化合物稀释，5倍梯度，共8个浓度。将化合物加样于细胞中，每72h更换含化合物的新鲜培养基，化合物处理细胞6天。
HBV DNA检测
使用圣湘生物HBV DNA检测试剂盒进行检测。向八连管中每孔加入5μL细胞上清液，加入5μL核酸释放剂，室温放置10min后，加入PCR混合剂。用实时荧光定量PCR仪测定上清中HBV DNA，根据Ct值及IU计算抑制率，四参数法计算EC50。实验结果见表1。
HBsAg检测
使用北京科美HBsAg检测试剂盒进行检测。用PBS 20倍稀释细胞上清液，每孔加入50μL稀释后的上清液，再加入50μL酶反应液，37℃孵育60min。用洗涤液洗涤5次，加入发光底物反应液，放置5min，通过Tecan Spark酶标仪进行化学发光检测，根据检测数值，通过标准曲线计算出的含量(ng/ml)计算抑制率，四参数法计算EC50。实验结果见表1。
2)：细胞毒性检测
往指数生长期状态良好的HepG2.2.15细胞中加入5mL PBS以清洗一遍，之后加入3mL胰酶，所得物放入细胞培养箱中进行消化。用显微镜观察，待细胞脱落时，弃掉2mL胰酶；放入37℃培养箱中消化5min，用显微镜观察细胞(是否为单个圆形，细胞间无粘连)，加入4mL完全培养基终止消化反应并进行重悬。使用细胞计数仪计数，使用完全培养基稀释上述细胞液使得细胞密度至2*10
5个/mL。使用多道移液枪接种细胞于96孔板上(提前使用50μg/mL Collagen Ⅰ溶液包被96孔板)，100μL/孔。将接种后的孔板置恒温CO
2培养箱中培养24h。
给药处理
每隔3天，更换含化合物的新鲜培养基。对照孔中加入不含药物的DMSO浓度为0.5％的培养基，并设普通培养基的对照孔。给药处理6天后，于孔板中加CCK工作液(CCK和培养基比例为1比10)，110μL/孔。所述孔板于37℃放置30min后，用Tecan Spark酶标仪在450nm处检测其吸光值，计算抑制率，四参数法计算IC
50。
表1
| 化合物 | HBV DNA(EC50μM) | HBsAg(EC50nM) |
| 实施例2 | A | ++++ |
| 实施例3 | B | +++ |
| 实施例4 | B | +++ |
| 实施例5 | B | +++ |
| 实施例6 | B | +++ |
| 实施例7 | B | +++ |
| 实施例10 | B | |
| 实施例11_A | B | +++ |
| 实施例12 | B | +++ |
| 实施例13 | A | ++++ |
| 实施例14 | A | +++ |
| 实施例15 | A | +++ |
| 实施例17 | A | ++++ |
| 实施例18 | A | ++++ |
| 实施例19 | A | ++++ |
| 实施例20_A | A | ++++ |
| 实施例21_A | A | ++++ |
| 实施例22_A | B | +++ |
| 实施例23 | A | |
| 实施例25 | A | ++++ |
| 实施例26_A | A | ++++ |
| 实施例27_A | A | ++++ |
| 实施例28 | A | ++++ |
| 实施例29 | A | ++++ |
| 实施例30 | A | ++++ |
| 实施例31 | A | ++++ |
| 实施例32 | A | ++++ |
| 实施例33 | A | ++++ |
| 实施例34 | A | ++++ |
A表示EC50≤0.1μM；B表示0.1μM＜EC50≤1μM；
++++表示EC50≤0.1μM；+++表示0.1μM＜EC50≤1μM。
结果显示，本申请的化合物具有良好的体外抗HBV活性和HepG2.2.15细胞抑制活性。
Claims (23)
- 式I’化合物、其立体异构体、或其药学上可接受的盐，
其中，X和Y中至少一个是N，另一个是CH或N；A选自5-6元杂芳基，所述A任选地被1、2或3个R 1取代；R 1选自C 1-8烷基、C 1-8烷氧基、卤素、C 3-7环烷基、1-3个卤代C 1-8烷基或1-3个卤代C 1-8烷氧基；p选自1、2、3或4；L选自单键、-CO-或-SO 2-；R 2选自6-10元芳基、3-8元含有1-3个选自N、O或S的杂芳基、或3-8元含有1-3个选自N、O或S的杂环烷基，所述R 2各自独立地任选地被1-4个R 3取代；所述R 3选自卤素、-NO 2、-CN、-C 1-8烷基、-C 3-7环烷基、-OH、-OC 1-8烷基、-OC 3-7环烷基、-NH 2、-NHC 1-8烷基、-N(C 1-8烷基) 2、-SH、-SC 1-8烷基、-SC 3-7环烷基、-CO-C 1-8烷基、-COO-C 1-8烷基、-OCO-C 1-8烷基、-CONHC 1-8烷基、-CON(C 1-8烷基) 2、-NHCO-C 1-8烷基、-S(＝O)C 1-6烷基、-S(＝O) 2C 1-6烷基、或3-8元含有1-3个选自N、O或S的杂环烷基；所述-C 1-8烷基、-C 3-7环烷基、-OC 1-8烷基、-OC 3-7环烷基、-NHC 1-8烷基、-N(C 1-8烷基) 2、-SC 1-8烷基、-SC 3-7环烷基、-CO-C 1-8烷基、-COO-C 1-8烷基、-OCO-C 1-8烷基、-CONHC 1-8烷基、-CON(C 1-8烷基) 2、-NHCO-C 1-8烷基-S(＝O)C 1-6烷基或-S(＝O) 2C 1-6烷基各自独立地任选地被1-3个R 4取代，所述3-8元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R 4取代或发生1-2个氧代；所述R 4选自卤素、-NO 2、-CN、-C 1-8烷基、-C 3-7环烷基、-OH、-OC 1-8烷基、-OC 3-7环烷基、-NH 2、-NHC 1-8烷基、-N(C 1-8烷基) 2、-SH、-SC 1-8烷基、-SC 3-7环烷基、-CO-C 1-8烷基、-COO-C 1-8烷基、-OCO-C 1-8烷基、-CONHC 1-8烷基、-CON(C 1-8烷基) 2、-NHCO-C 1-8烷基、或-SO 2C 1-8烷基。 - 如权利要求1所述的化合物、其立体异构体、或其药学上可接受的盐，其为式I化合物、其立体异构体、或其药学上可接受的盐：
- 如权利要求1或2所述的化合物、其立体异构体、或其药学上可接受的盐，所述X是N且Y是CH、X是CH且Y是N、或X和Y都是N；或者，所述X和Y都是N。
- 如权利要求1-3任一项所述的化合物、其立体异构体、或其药学上可接受的盐，所述A选自5-6元含有1-4个选自N、O或S原子的杂芳基，所述A任选地被1、2或3个R 1取代；或者，所述A选自吡唑基、咪唑基、恶唑基、噻唑基、三唑基、四唑基、吡啶基、吡嗪基、哒嗪基或嘧啶基，所述A任选地被1、2或3个R 1取代；或者，所述A选自吡啶基或嘧啶基，所述A任选地被1、2或3个R 1取代。
- 如权利要求1-3任一项所述的化合物、其立体异构体、或其药学上可接受的盐，所述A选自其中
表示单键或双键，T选自C或N，U、V、W和Z各自独立地选自CH、N、O或S，任选地U、V和W中之一选自键，所述A任选地被1、2或3个R 1取代；
或者，所述U、V、W和Z都是CH，或U、V和W是CH且Z是N；或者，所述U、V和W是CH且Z是N；或者，所述U、V和W中之一选自键，其他选自CH、N、O或S。 - 如权利要求1-5任一项所述的化合物、其立体异构体、或其药学上可接受的盐，所述R 1选自C 1-6烷基、C 1-6烷氧基、F、Cl、Br、1-3个F、Cl、Br取代的C 1-6烷基、或1-3个F、Cl、Br取代的C 1-6烷氧基；或者，所述R 1选自C 1-4烷基、C 1-4烷氧基、F、Cl、Br、1-3个F、Cl、Br取代的C 1-4烷基、或1-3个F、Cl、Br取代的C 1-4烷氧基。
- 如权利要求1-6任一项所述的化合物、其立体异构体、或其药学上可接受的盐，所述L选自单键。
- 如权利要求1-7任一项所述的化合物、其立体异构体、或其药学上可接受的盐，所述R 2选自6-8元芳基、4-6元含有1-3个选自N、O或S的杂芳基、或4-6元含有1-3 个选自N、O或S的杂环烷基；或者，所述R 2选自苯基、萘基、4-6元含有1-2个选自N、O或S的杂芳基、或4-6元含有1-2个选自N、O或S的杂环烷基；或者，所述R 2选自苯基、4-6元含有1-2个选自N的杂芳基、或4-6元含有1-2个选自N或O的杂环烷基；或者，所述R 2选自苯基、吡啶基、或吗啉基；或者，所述R 2选自吡啶基；或者，所述R 2选自苯基、
或者，所述R 2选自苯基或
所述R 2的取代基如权利要求1所述；或者，所述R 2选自
或者，所述R 2选自
或者，所述R 2选自
- 如权利要求1-8任一项所述的化合物、其立体异构体、或其药学上可接受的盐，所述R 3选自F、Cl、Br、-NO 2、-CN、-C 1-6烷基、-C 3-6环烷基、-OH、-OC 1-6烷基、-OC 3-6环烷基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-SH、-SC 1-6烷基、-SC 3-6环烷基、-S(＝O)C 1-6烷基、-S(＝O) 2C 1-6烷基、-CO-C 1-6烷基、-COO-C 1-6烷基、-OCO-C 1-6烷基、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCO-C 1-6烷基、或4-7元含有1-3个选自N、O或S的杂环烷基，所述-C 1-6烷基、-C 3-6环烷基、-OC 1-6烷基、-OC 3-6环烷基、-NHC 1-6烷基、-N(C 1-6烷基) 2、-SC 1-6烷基、-SC 3-6环烷基、-S(＝O)C 1-6烷基、-S(＝O) 2C 1-6烷基、-CO-C 1-6烷基、-COO-C 1-6烷基、-OCO-C 1-6烷基、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、或-NHCO-C 1-6烷基各自独立地任选地被1-3个R 4取代，所述4-7元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R 4取代或发生1-2个氧代；或者，所述R 3选自F、Cl、Br、-NO 2、-CN、-C 1-4烷基、-C 3-6环烷基、-OH、-OC 1-4烷基、-OC 3-6环烷基、-NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、-SH、-SC 1-4烷基、-SC 3-6环烷基、-S(＝O)C 1-4烷基、-S(＝O) 2C 1-4烷基、-CO-C 1-4烷基、-COO-C 1-4烷基、-OCO-C 1-4烷基、-CONHC 1-4烷基、-CON(C 1-4烷基) 2、-NHCO-C 1-4烷基、或4-7元含有1-3个选自N、O或S的杂环烷基，所述-C 1-4烷基、-C 3-6环烷基、-OC 1-4烷基、-OC 3-6环烷基、-NHC 1-4烷基、-N(C 1-4烷基) 2、-SC 1-4烷基、-SC 3-6环烷基、-S(＝O)C 1-4烷基、-S(＝O) 2C 1-4烷基、-CO-C 1-4烷基、-COO-C 1-4烷基、-OCO-C 1-4烷基、-CONHC 1-4烷基、-CON(C 1-4烷基) 2、或-NHCO-C 1-4烷基各自独立地任选地被1-3个R 4取代，所述4-7元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R 4取代或发生1-2个氧代；或者，所述R 3选自F、Cl、Br、-C 1-4烷基、-C 3-6环烷基、-NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、-SC 1-4烷基、-S(＝O)C 1-4烷基、-S(＝O) 2C 1-4烷基、OH、-OC 1-4烷基、-OC 3-6环烷基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、或4-7元含有2个选自N、O或S的杂环烷基，所述-C 1-4烷基、-C 3-6环烷基、-NHC 1-4烷基、-N(C 1-4烷基) 2、-SC 1-4烷基、-S(＝O)C 1-4烷基、-S(＝O) 2C 1-4烷基、-OC 1-4烷基、或-OC 3-6环烷基各自独立地任选地被1-3个R 4取代，所述氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、或4-7元含有2个选自N、O或S的杂环烷基各自任选地被1-3个R 4取代或发生1-2个氧代；或者，所述R 3选自F、Cl、Br、-NO 2、-CN、-C 1-6烷基、-C 3-6环烷基、-OH、-OC 1-6烷基、-OC 3-6环烷基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-SH、-SC 1-6烷基、-SC 3-6环烷基、-CO-C 1-6烷基、-COO-C 1-6烷基、-OCO-C 1-6烷基、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCO-C 1-6烷基、或4-6元含有1-3个选自N、O或S的杂环烷基，所述-C 1-6烷基、-C 3-6环烷基、-OC 1-6烷基、-OC 3-6环烷基、-NHC 1-6烷基、-N(C 1-6烷基) 2、-SC 1-6烷基、-SC 3-6环烷基、-CO-C 1-6烷基、-COO-C 1-6烷基、-OCO-C 1-6烷基、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、或-NHCO-C 1-6烷基各自独立地任选地被1-3个R 4取代，所述4-6元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R 4取代或发生1-2个氧代；或者，所述R 3选自F、Cl、Br、-NO 2、-CN、-C 1-4烷基、-C 3-6环烷基、-OH、-OC 1-4烷基、-OC 3-6环烷基、-NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、-SH、-SC 1-4烷基、-SC 3-6环烷基、-CO-C 1-4烷基、-COO-C 1-4烷基、-OCO-C 1-4烷基、-CONHC 1-4烷基、-CON(C 1-4烷基) 2、-NHCO-C 1-4烷基、或4-6元含有1-3个选自N、O或S的杂环烷基，所述-C 1-4烷基、-C 3-6环烷基、-OC 1-4烷基、-OC 3-6环烷基、-NHC 1-4烷基、-N(C 1-4烷基) 2、-SC 1-4烷基、-SC 3-6环烷基、-CO-C 1-4烷基、-COO-C 1-4烷基、-OCO-C 1-4烷基、-CONHC 1-4烷基、-CON(C 1-4烷基) 2、或-NHCO-C 1-4烷基各自独立地任选地被1-3个R 4取代，所述4-6元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R 4取代或发生1-2个氧代；或者，所述R 3选自F、Cl、Br、-C 1-4烷基、-C 3-6环烷基、-NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、OH、-OC 1-4烷基、-OC 3-6环烷基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、或4-6元含有2个选自N、O或S的杂环烷基，所述-C 1-4烷基、-C 3-6环烷基、-NHC 1-4烷基、-N(C 1-4烷基) 2、-OC 1-4烷基、或-OC 3-6环烷基各自独立地任选地被1-3个R 4取代，所述氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、或4-6元含有2个选自N、O或S的杂环烷基各自任选地被1-3个R 4取代或发生1-2个氧代；或者，所述R 3选自卤素、-NO 2、-CN、-C 1-8烷基、-C 3-7环烷基、-OH、-OC 1-8烷基、 -OC 3-7环烷基、-NH 2、-NHC 1-8烷基、-N(C 1-8烷基) 2、-SH、-SC 1-8烷基、-SC 3-7环烷基、-CO-C 1-8烷基、-COO-C 1-8烷基、-OCO-C 1-8烷基、-CONHC 1-8烷基、-CON(C 1-8烷基) 2、-NHCO-C 1-8烷基、或3-8元含有1-3个选自N、O或S的杂环烷基；所述-C 1-8烷基、-C 3-7环烷基、-OC 1-8烷基、-OC 3-7环烷基、-NHC 1-8烷基、-N(C 1-8烷基) 2、-SC 1-8烷基、-SC 3-7环烷基、-CO-C 1-8烷基、-COO-C 1-8烷基、-OCO-C 1-8烷基、-CONHC 1-8烷基、-CON(C 1-8烷基) 2、-NHCO-C 1-8烷基、各自独立地任选地被1-3个R 4取代，所述3-8元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R 4取代或发生1-2个氧代；或者，所述R 3选自F、Cl、-N(CH 3) 2、-OCH 3、-CF 3、
-SCH 2CH 3、-S(＝O)CH 2CH 3、-S(＝O) 2CH 2CH 3、
或者，所述R 3选自F、Cl、-N(CH 3) 2、-OCH 3、-CF 3、
-SCH 2CH 3、-S(＝O)CH 2CH 3、-S(＝O) 2CH 2CH 3、或
或者，所述R 3选自F、Cl、-N(CH 3) 2、-OCH 3、-CF 3、
- 如权利要求1-9任一项所述的化合物、其立体异构体、或其药学上可接受的盐，所述R 4选自F、Cl、Br、-NO 2、-CN、-C 1-6烷基、-C 3-6环烷基、-OH、-OC 1-6烷基、-OC 3-6 环烷基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-SH、-SC 1-6烷基、-SC 3-6环烷基、-CO-C 1-6烷基、-COO-C 1-6烷基、-OCO-C 1-6烷基、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCO-C 1-6烷基、或-S(O) 2C 1-6烷基；或者，所述R 4选自F、Cl、Br、-NO 2、-CN、-C 1-4烷基、-C 3-6环烷基、-OH、-OC 1-4烷基、-OC 3-6环烷基、-NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、-SH、-SC 1-4烷基、-SC 3-6环烷基、-CO-C 1-4烷基、-COO-C 1-4烷基、-OCO-C 1-4烷基、-CONHC 1-4烷基、-CON(C 1-4烷基) 2、-NHCO-C 1-4烷基、或-S(O) 2C 1-4烷基；或者，所述R 4选自F、Cl、Br、-C 1-6烷基、-C 3-6环烷基、-OC 1-6烷基、或-OC 3-6环烷基；或者，所述R 4选自F、-OCH 3、环丙基、或-S(O) 2CH 3；或者，所述R 4选自卤素、-NO 2、-CN、-C 1-8烷基、-C 3-7环烷基、-OH、-OC 1-8烷基、-OC 3-7环烷基、-NH 2、-NHC 1-8烷基、-N(C 1-8烷基) 2、-SH、-SC 1-8烷基、-SC 3-7环烷基、-CO-C 1-8烷基、-COO-C 1-8烷基、-OCO-C 1-8烷基、-CONHC 1-8烷基、-CON(C 1-8烷基) 2、或-NHCO-C 1-8烷基；或者，所述R 4选自F、Cl、Br、-NO 2、-CN、-C 1-6烷基、-C 3-6环烷基、-OH、-OC 1-6烷基、-OC 3-6环烷基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-SH、-SC 1-6烷基、-SC 3-6环烷基、-CO-C 1-6烷基、-COO-C 1-6烷基、-OCO-C 1-6烷基、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、或-NHCO-C 1-6烷基；或者，所述R 4选自F、Cl、Br、-NO 2、-CN、-C 1-4烷基、-C 3-6环烷基、-OH、-OC 1-4烷基、-OC 3-6环烷基、-NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、-SH、-SC 1-4烷基、-SC 3-6环烷基、-CO-C 1-4烷基、-COO-C 1-4烷基、-OCO-C 1-4烷基、-CONHC 1-4烷基、-CON(C 1-4烷基) 2、或-NHCO-C 1-4烷基；或者，所述R 4选自F、Cl、Br、-C 1-6烷基、-C 3-6环烷基、-OC 1-6烷基、或-OC 3-6环烷基；或者，所述R 4选自F、-OCH 3、或环丙基。
- 如权利要求1所述的化合物、其立体异构体、或其药学上可接受的盐，选自式(1)化合物、其立体异构体、或其药学上可接受的盐，
- 如权利要求11所述的化合物、其立体异构体、或其药学上可接受的盐，其中，所述A选自6元含有1-4个选自N、O或S原子的杂芳基，所述A任选地被1、2或3个R 1取代，或者，所述A选自6元含有1-2个N的杂芳基，所述A任选地被1、2或3个R 1取代，或者，所述A选自Z选自CH或N，所述A任选地被1、2或3个R 1取代；
或者，所述A选自吡啶基或嘧啶基。 - 如权利要求11所述的化合物、其立体异构体、或其药学上可接受的盐，其中，所述R 2选自6-8元芳基、4-6元含有1-3个选自N、O或S的杂芳基、或4-6元含有1-3个选自N、O或S的杂环烷基；或者，所述R 2选自苯基、萘基、4-6元含有1-2个选自N、O或S的杂芳基、或4-6元含有1-2个选自N、O或S的杂环烷基；或者，所述R 2选自苯基、4-6元含有1-2个选自N的杂芳基、或4-6元含有1-2个选自N或O的杂环烷基；或者，所述R 2选自苯基、吡啶基、或吗啉基；或者，所述R 2选自6-8元芳基或5-8元含有1-3个选自N、O或S的杂芳基；或者，所述R 2选自苯基或5-6元含有1-2个选自N、O或S的杂芳基；或者，所述R 2选自5-6元含有1-2个N的杂芳基；或者，所述R 2选自6元含有1-2个N的杂芳基；或者，所述R 2选自吡啶基；或者，所述R 2选自苯基、
或者，所述R 2选自
其中，所述R 2各自独立地任选地被1-4个R 3取代；或者，所述R 2选自
或者，所述R 2选自
- 如权利要求11所述的化合物、其立体异构体、或其药学上可接受的盐，其中，所述R 3选自F、Cl、Br、-NO 2、-CN、-C 1-6烷基、-C 3-6环烷基、-OH、-OC 1-6烷基、-OC 3-6环烷基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-SH、-SC 1-6烷基、-SC 3-6环烷基、-S(＝O)C 1-4烷基、-S(＝O) 2C 1-4烷基、或4-7元含有1-3个选自N、O或S的杂环烷基，所述-C 1-6烷基、-C 3-6环烷基、-OC 1-6烷基、-OC 3-6环烷基、-NHC 1-6烷基、-N(C 1-6烷基) 2、-SC 1-6烷基、-SC 3-6环烷基、-S(＝O)C 1-4烷基、或-S(＝O) 2C 1-4烷基各自独立地任选地被1-3个R 4取代，所述4-7元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R 4取代或发生1-2个氧代；或者，所述R 3选自F、Cl、Br、-NO 2、-CN、-C 1-4烷基、-C 3-6环烷基、-OH、-OC 1-4烷基、-OC 3-6环烷基、-NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、-SH、-SC 1-4烷基、-SC 3-6环烷基、-S(＝O)C 1-4烷基、-S(＝O) 2C 1-4烷基、或4-7元含有1-3个选自N、O或S的杂环烷基，所述-C 1-4烷基、-C 3-6环烷基、-OC 1-4烷基、-OC 3-6环烷基、-NHC 1-4烷基、-N(C 1-4烷基) 2、-SC 1-4烷基、-SC 3-6环烷基、-S(＝O)C 1-4烷基、或-S(＝O) 2C 1-4烷基各自独立地任选地被1-3个R 4取代，所述4-7元含有1-3个选自N、O或S的杂环烷基任选地被1-3个R 4取代或发生1-2个氧代；或者，所述R 3选自F、Cl、Br、-NHC 1-4烷基、-N(C 1-4烷基) 2、-OC 1-4烷基、氮杂环丁烷基、或4-7元含有2个选自N、O或S的杂环烷基，所述-NHC 1-4烷基、-N(C 1-4烷基) 2、-OC 1-4烷基、氮杂环丁烷基、或4-7元含有2个选自N、O或S的杂环烷基各自独立地任选地被1-3个R 4取代，或者，所述R 3选自F、-N(CH 3) 2、-OCH 3、
Cl、-CF 3、
-SCH 2CH 3、-S(＝O)CH 2CH 3、-S(＝O) 2CH 2CH 3，
或者，所述R 3选自F、-N(CH 3) 2、-OCH 3、
- 如权利要求11所述的化合物、其立体异构体、或其药学上可接受的盐，其中，所述R 4选自F、Cl、Br、-NO 2、-CN、-C 1-6烷基、-C 3-6环烷基、-OH、-OC 1-6烷基、-OC 3-6环烷基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、-SH、-SC 1-6烷基、-SC 3-6环烷基、-CO-C 1-6烷基、-COO-C 1-6烷基、-OCO-C 1-6烷基、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCO-C 1-6烷基、或-S(O) 2C 1-6烷基；或者，所述R 4选自F、Cl、Br、-NO 2、-CN、-C 1-4烷基、-C 3-6环烷基、-OH、-OC 1-4烷基、-OC 3-6环烷基、-NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、-SH、-SC 1-4烷基、-SC 3-6环烷基、-CO-C 1-4烷基、-COO-C 1-4烷基、-OCO-C 1-4烷基、-CONHC 1-4烷基、-CON(C 1-4烷基) 2、-NHCO-C 1-4烷基、或-S(O) 2C 1-4烷基；或者，所述R 4选自F、Cl、Br、-C 1-4烷基、-C 3-6环烷基、-OC 1-4烷基、-OC 3-6环烷基、或-S(O) 2C 1-4烷基；或者，所述R 4选自F、-OCH 3、环丙基、或-S(O) 2CH 3；或者，所述R 4选自F、Cl、Br、-C 1-4烷基、-OC 1-6烷基、或-S(O) 2C 1-4烷基；或者，所述R 4选自F、-OCH 3、或-S(O) 2CH 3。
- 如权利要求1所述的化合物、其立体异构体、或其药学上可接受的盐，选自式II’化合物、其立体异构体、或其药学上可接受的盐，
其中，表示单键或双键；
T选自C或N；U、V、W和Z各自独立地选自CH、N、O或S，任选地U、V和W中之一选自键；q选自0、1、2或3。 - 如权利要求1所述的化合物、其立体异构体、或其药学上可接受的盐，选自式III’、式IV’、式V’、式VI’化合物、其立体异构体、或其药学上可接受的盐，
其中，U、W和Z各自独立地选自CH、N、O或S，任选地U和W中之一选自键；q选自0、1、2或3。 - 如权利要求1、2或11所述的化合物、其立体异构体、或其药学上可接受的盐，选自式II或式(1-2)化合物、其立体异构体、或其药学上可接受的盐，
其中，表示单键或双键；
T选自C或N；U、V、W和Z各自独立地选自CH、N、O或S，任选地U、V和W中之一选自键；q选自0、1、2或3。 - 如权利要求1、2或11所述的化合物、其立体异构体、或其药学上可接受的盐，选自式III、式IV、式V、式VI、式VII、式(1-3)、式(1-4)、式(1-5)、式(1-6)或式(1-7)化合物、其立体异构体、或其药学上可接受的盐，
其中，U、W和Z各自独立地选自CH、N、O或S，任选地U和W中之一选自键；q选自0、1、2或3。 - 如权利要求1、2或11所述的化合物、其立体异构体、或其药学上可接受的盐，选自式IA、式IB、式IIA、式IIB、式IIIA、式IIIB、式IVA、式IVB、式VA、式VB、式VIA、式VIB、式VIIA、式VIIB、式(1-A)、式(1-B)、式(1-2A)、式(1-2B)、式(1-3A)、式(1-3B)、式(1-4A)、式(1-4B)、式(1-5A)、式(1-5B)、式(1-6A)、式(1-6B)、式(1-7A)或式(1-7B)化合物、其立体异构体、或其药学上可接受的盐
其中，表示单键或双键；
T选自C或N；U、V、W和Z各自独立地选自CH、N、O或S，任选地U、V和W中之一选自键；q选自0、1、2或3。 - 下述化合物、其立体异构体、或其药学上可接受的盐：
或者，以下化合物、其立体异构体、或其药学上可接受的盐：
- 药物组合物，其包括权利要求1-21任一项所述的化合物、其立体异构体、或其药学上可接受的盐。
- 权利要求1-21任一项所述的化合物、其立体异构体、或其药学上可接受的盐、或权利要求22所述的药物组合物在制备治疗乙型肝炎病毒感染的药物中的用途。
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| WO2016107832A1 (en) * | 2014-12-30 | 2016-07-07 | F. Hoffmann-La Roche Ag | Novel tetrahydropyridopyrimidines and tetrahydropyridopyridines for the treatment and prophylaxis of hepatitis b virus infection |
| CN107624113A (zh) * | 2015-05-04 | 2018-01-23 | 豪夫迈·罗氏有限公司 | 作为HBsAg(HBV表面抗原)和HBV DNA生成的抑制剂用于治疗乙型肝炎病毒感染的四氢吡啶并嘧啶和四氢吡啶并吡啶类化合物 |
| CN110088103A (zh) * | 2016-11-03 | 2019-08-02 | 豪夫迈·罗氏有限公司 | 用于治疗和预防乙型肝炎病毒感染的新的四氢吡啶并嘧啶化合物 |
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| WO2016107832A1 (en) * | 2014-12-30 | 2016-07-07 | F. Hoffmann-La Roche Ag | Novel tetrahydropyridopyrimidines and tetrahydropyridopyridines for the treatment and prophylaxis of hepatitis b virus infection |
| CN107624113A (zh) * | 2015-05-04 | 2018-01-23 | 豪夫迈·罗氏有限公司 | 作为HBsAg(HBV表面抗原)和HBV DNA生成的抑制剂用于治疗乙型肝炎病毒感染的四氢吡啶并嘧啶和四氢吡啶并吡啶类化合物 |
| CN110088103A (zh) * | 2016-11-03 | 2019-08-02 | 豪夫迈·罗氏有限公司 | 用于治疗和预防乙型肝炎病毒感染的新的四氢吡啶并嘧啶化合物 |
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