WO2019223791A1 - 2,3-二氢-1h-吡咯嗪-7-甲酰胺类衍生物及其应用 - Google Patents
2,3-二氢-1h-吡咯嗪-7-甲酰胺类衍生物及其应用 Download PDFInfo
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- WO2019223791A1 WO2019223791A1 PCT/CN2019/088376 CN2019088376W WO2019223791A1 WO 2019223791 A1 WO2019223791 A1 WO 2019223791A1 CN 2019088376 W CN2019088376 W CN 2019088376W WO 2019223791 A1 WO2019223791 A1 WO 2019223791A1
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- 0 C*(C1)C1c(c(*)c(*)c(*C1CC1)c1*)c1NC(c1c(CCC2)[n]2c(C(C(N(*)C(CC2)(CC3)CCC23I)=O)=O)c1*)=O Chemical compound C*(C1)C1c(c(*)c(*)c(*C1CC1)c1*)c1NC(c1c(CCC2)[n]2c(C(C(N(*)C(CC2)(CC3)CCC23I)=O)=O)c1*)=O 0.000 description 10
- PLPMQIDBDDIILU-UHFFFAOYSA-N CC1(CCC(CC(O)=O)CC1)NC(C(c([n](CCC1)c1c1C(Nc(cc2)cc(F)c2F)=O)c1Cl)=O)=O Chemical compound CC1(CCC(CC(O)=O)CC1)NC(C(c([n](CCC1)c1c1C(Nc(cc2)cc(F)c2F)=O)c1Cl)=O)=O PLPMQIDBDDIILU-UHFFFAOYSA-N 0.000 description 3
- ATGMMYFLOBRAEV-UHFFFAOYSA-N CC(C(c1c(C)c(C(Nc(cc2F)ccc2F)=O)c2[n]1CCC2)=O)=O Chemical compound CC(C(c1c(C)c(C(Nc(cc2F)ccc2F)=O)c2[n]1CCC2)=O)=O ATGMMYFLOBRAEV-UHFFFAOYSA-N 0.000 description 1
- IRNPPQMSWACJQQ-UHFFFAOYSA-N CC(C)(C)OC(CC(CC1)CCC1(C#N)NC(C(c([n](CCC1)c1c1C(Cl)=O)c1Cl)=O)=O)=O Chemical compound CC(C)(C)OC(CC(CC1)CCC1(C#N)NC(C(c([n](CCC1)c1c1C(Cl)=O)c1Cl)=O)=O)=O IRNPPQMSWACJQQ-UHFFFAOYSA-N 0.000 description 1
- DCSIFMPCNGWEQS-UHFFFAOYSA-N CC(C)(C)OC(CC(CC1)CCC1(C)NC(C(c([n](CCC1)c1c1C(Nc(cc2F)cc(F)c2F)=O)c1Cl)=O)=O)=O Chemical compound CC(C)(C)OC(CC(CC1)CCC1(C)NC(C(c([n](CCC1)c1c1C(Nc(cc2F)cc(F)c2F)=O)c1Cl)=O)=O)=O DCSIFMPCNGWEQS-UHFFFAOYSA-N 0.000 description 1
- SNBGURLVYHVYEB-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCC1(C)C(OC)=O)=O Chemical compound CC(C)(C)OC(N(CC1)CCC1(C)C(OC)=O)=O SNBGURLVYHVYEB-UHFFFAOYSA-N 0.000 description 1
- YDVAFDALOGXWTO-UHFFFAOYSA-N CC(C)(CCC=O)[N+]([O-])=O Chemical compound CC(C)(CCC=O)[N+]([O-])=O YDVAFDALOGXWTO-UHFFFAOYSA-N 0.000 description 1
- OAHLAGQZPRQERJ-UHFFFAOYSA-N CC(CC1)(CCC1=COC)NC(OCc1ccccc1)=O Chemical compound CC(CC1)(CCC1=COC)NC(OCc1ccccc1)=O OAHLAGQZPRQERJ-UHFFFAOYSA-N 0.000 description 1
- PTSRMSIEIBUBHP-UHFFFAOYSA-N CC1(CCC(CC(O)=O)CC1)C(F)(F)F Chemical compound CC1(CCC(CC(O)=O)CC1)C(F)(F)F PTSRMSIEIBUBHP-UHFFFAOYSA-N 0.000 description 1
- GRJYVRRTLQKJJL-UHFFFAOYSA-N CC1(CCC(CC(OC)=O)CC1)NC(C(c([n](CCC1)c1c1C(Nc(cc2F)cc(F)c2F)=O)c1Cl)=O)=O Chemical compound CC1(CCC(CC(OC)=O)CC1)NC(C(c([n](CCC1)c1c1C(Nc(cc2F)cc(F)c2F)=O)c1Cl)=O)=O GRJYVRRTLQKJJL-UHFFFAOYSA-N 0.000 description 1
- BYWIDLQCJPXXPF-UHFFFAOYSA-N CC1(CCC(CCC(O)=O)CC1)NC(C(c([n](CCC1)c1c1C(Nc(cc2)cc(F)c2F)=O)c1Cl)=O)=O Chemical compound CC1(CCC(CCC(O)=O)CC1)NC(C(c([n](CCC1)c1c1C(Nc(cc2)cc(F)c2F)=O)c1Cl)=O)=O BYWIDLQCJPXXPF-UHFFFAOYSA-N 0.000 description 1
- GYIXUXQVQYKWJE-UHFFFAOYSA-N CC1(CCOCC1)NC(C(c([n](CCC1)c1c1C(Nc(cc2C#N)ccc2F)=O)c1Cl)=O)=O Chemical compound CC1(CCOCC1)NC(C(c([n](CCC1)c1c1C(Nc(cc2C#N)ccc2F)=O)c1Cl)=O)=O GYIXUXQVQYKWJE-UHFFFAOYSA-N 0.000 description 1
- JCKGKDAHTTVAEG-UHFFFAOYSA-N CC1(CCOCC1)NC(C(c([n](CCC1)c1c1C(OC)=O)c1Br)=O)=O Chemical compound CC1(CCOCC1)NC(C(c([n](CCC1)c1c1C(OC)=O)c1Br)=O)=O JCKGKDAHTTVAEG-UHFFFAOYSA-N 0.000 description 1
- NHWBTHWRFAAYDL-UHFFFAOYSA-N COC(c1c(CCC2)[n]2c(C(C(Cl)=O)=O)c1)=O Chemical compound COC(c1c(CCC2)[n]2c(C(C(Cl)=O)=O)c1)=O NHWBTHWRFAAYDL-UHFFFAOYSA-N 0.000 description 1
- MHQJNWSDFISCHW-UHFFFAOYSA-N COCC1(CCOCC1)C(OC)=O Chemical compound COCC1(CCOCC1)C(OC)=O MHQJNWSDFISCHW-UHFFFAOYSA-N 0.000 description 1
- RIXQXISSKCMVOH-UHFFFAOYSA-N COCC1(CCOCC1)NC(OCc1ccccc1)=O Chemical compound COCC1(CCOCC1)NC(OCc1ccccc1)=O RIXQXISSKCMVOH-UHFFFAOYSA-N 0.000 description 1
- LVNSGJXMEXMMPY-MRVPVSSYSA-N C[C@H](C(F)(F)F)NC(C(c([n](CCC1)c1c1C(Nc2ccnc(Cl)c2)=O)c1Cl)=O)=O Chemical compound C[C@H](C(F)(F)F)NC(C(c([n](CCC1)c1c1C(Nc2ccnc(Cl)c2)=O)c1Cl)=O)=O LVNSGJXMEXMMPY-MRVPVSSYSA-N 0.000 description 1
- IWGSFEYOVAVLFT-ZCFIWIBFSA-N C[C@H](C(F)(F)F)NC(C(c([n](CCC1)c1c1C(OC)=O)c1Cl)=O)=O Chemical compound C[C@H](C(F)(F)F)NC(C(c([n](CCC1)c1c1C(OC)=O)c1Cl)=O)=O IWGSFEYOVAVLFT-ZCFIWIBFSA-N 0.000 description 1
- IODUCUQJFMBGMZ-MLIRHYICSA-N C[C@](CC1)(CC[C@@H]1C(O)=O)NC(C(c([n](CCC1)c1c1C(Nc(cc2)cc(F)c2F)=O)c1Cl)=O)=O Chemical compound C[C@](CC1)(CC[C@@H]1C(O)=O)NC(C(c([n](CCC1)c1c1C(Nc(cc2)cc(F)c2F)=O)c1Cl)=O)=O IODUCUQJFMBGMZ-MLIRHYICSA-N 0.000 description 1
- YPIYTONAGSOAGD-IPDPSIFGSA-N C[C@]1(CC[C@@H](CC(O)=O)CC1)NC(C(c([n](CCC1)c1c1C(Nc(cc2F)cc(F)c2F)=O)c1Cl)=O)=O Chemical compound C[C@]1(CC[C@@H](CC(O)=O)CC1)NC(C(c([n](CCC1)c1c1C(Nc(cc2F)cc(F)c2F)=O)c1Cl)=O)=O YPIYTONAGSOAGD-IPDPSIFGSA-N 0.000 description 1
- BYWIDLQCJPXXPF-HTZSYRTJSA-N C[C@]1(CC[C@H](CCC(O)=O)CC1)NC(C(c([n](CCC1)c1c1C(Nc(cc2F)ccc2F)=O)c1Cl)=O)=O Chemical compound C[C@]1(CC[C@H](CCC(O)=O)CC1)NC(C(c([n](CCC1)c1c1C(Nc(cc2F)ccc2F)=O)c1Cl)=O)=O BYWIDLQCJPXXPF-HTZSYRTJSA-N 0.000 description 1
- XQKIRCPYKNQECZ-UHFFFAOYSA-N Cc(cc1)cc([F]CCc2cc([ClH]CCc(cc3F)cc([Fm](C)Cc(cc4C#N)ccc4F)c3F)ncc2)c1F Chemical compound Cc(cc1)cc([F]CCc2cc([ClH]CCc(cc3F)cc([Fm](C)Cc(cc4C#N)ccc4F)c3F)ncc2)c1F XQKIRCPYKNQECZ-UHFFFAOYSA-N 0.000 description 1
- DBGCWJAHTQNYDE-UHFFFAOYSA-N NC(C(c([n](CCC1)c1c1C(Nc(cc2F)cc(F)c2F)=O)c1Cl)=O)=O Chemical compound NC(C(c([n](CCC1)c1c1C(Nc(cc2F)cc(F)c2F)=O)c1Cl)=O)=O DBGCWJAHTQNYDE-UHFFFAOYSA-N 0.000 description 1
- FZAYYMAATCYCQA-UHFFFAOYSA-N O=C(C(Cl)=O)c([n](CCC1)c1c1C(Nc(cc2F)cc(F)c2F)=O)c1Cl Chemical compound O=C(C(Cl)=O)c([n](CCC1)c1c1C(Nc(cc2F)cc(F)c2F)=O)c1Cl FZAYYMAATCYCQA-UHFFFAOYSA-N 0.000 description 1
- VYQJBJUEHVDWIY-UHFFFAOYSA-N OC(C1CCC(CNC(C(c([n](CCC2)c2c2C(Nc(cc3F)ccc3F)=O)c2Cl)=O)=O)CC1)=O Chemical compound OC(C1CCC(CNC(C(c([n](CCC2)c2c2C(Nc(cc3F)ccc3F)=O)c2Cl)=O)=O)CC1)=O VYQJBJUEHVDWIY-UHFFFAOYSA-N 0.000 description 1
- BXBBBVZXFZCVRM-UHFFFAOYSA-N OC(CC(CC1)CCC1(C(F)(F)F)NC(C(c([n](CCC1)c1c1C(Nc(cc2F)cc(F)c2F)=O)c1Cl)=O)=O)=O Chemical compound OC(CC(CC1)CCC1(C(F)(F)F)NC(C(c([n](CCC1)c1c1C(Nc(cc2F)cc(F)c2F)=O)c1Cl)=O)=O)=O BXBBBVZXFZCVRM-UHFFFAOYSA-N 0.000 description 1
- NJGZYXPJPARJDI-WTIBDHCWSA-N OC(CC1CC(C2)[C@H]2CC1)=O Chemical compound OC(CC1CC(C2)[C@H]2CC1)=O NJGZYXPJPARJDI-WTIBDHCWSA-N 0.000 description 1
- YLYZKZARGFSKCI-UHFFFAOYSA-N OC(CC1CCC(CNC(C(c([n](CCC2)c2c2C(Nc(cc3)cc(F)c3F)=O)c2Cl)=O)=O)CC1)=O Chemical compound OC(CC1CCC(CNC(C(c([n](CCC2)c2c2C(Nc(cc3)cc(F)c3F)=O)c2Cl)=O)=O)CC1)=O YLYZKZARGFSKCI-UHFFFAOYSA-N 0.000 description 1
- FLFAQFGOCBNSGH-UHFFFAOYSA-N OC(CCC1CCC(CNC(C(c([n](CCC2)c2c2C(Nc(cc3)cc(F)c3F)=O)c2Cl)=O)=O)CC1)=O Chemical compound OC(CCC1CCC(CNC(C(c([n](CCC2)c2c2C(Nc(cc3)cc(F)c3F)=O)c2Cl)=O)=O)CC1)=O FLFAQFGOCBNSGH-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61P31/14—Antivirals for RNA viruses
-
- 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
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present application relates to a 2,3-dihydro-1H-pyrrolazine-7-carboxamide derivative as a nucleoprotein inhibitor, and its application in the preparation of a medicament for treating HBV-related diseases. Specifically, it relates to a compound represented by formula (II), a compound represented by formula (II-A), a compound represented by formula (II-B), a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable compound thereof. Accepted salts, and their use in the manufacture of a medicament for the treatment of HBV-related diseases.
- Hepatitis B is an inflammatory response caused by the invasion of the hepatitis B virus, which easily develops into liver fibrosis and cirrhosis, and is the direct cause of 80% of primary liver cancers worldwide.
- Hepatitis B is a worldwide medical problem. At present, there are no effective drugs for treating hepatitis B in the world. The nucleosides and interferons occupy the dominant position in the global hepatitis B drug market. The first-line drugs for hepatitis B treatment are mainly nucleoside drugs and interferons. However, it is expensive and easy to relapse, so it is imperative to develop a new type of anti-HBV drug.
- n 1 or 2;
- T 1 is selected from N and C (R 43 );
- R 2 is selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2 or 3 R b ;
- R 3 is selected from H, Cl, F, Br, I, OH, NH 2 , C 1-6 alkyl and C 1-3 alkoxy, said C 1-6 alkyl and C 1-3 alkoxy Optionally substituted with 1, 2 or 3 R c ;
- R 41 , R 42 , R 43 , R 44, and R 45 are each independently selected from H, Cl, F, Br, I, OH, NH 2 , CN, COOH, and C 1-3 alkyl, and the C 1- 3 alkyl is optionally substituted with 1, 2 or 3 Rd ;
- R 5 is selected from R 51 , C 3-10 cycloalkyl, and 3 to 6-membered heterocycloalkyl, wherein the C 3-10 cycloalkyl and 3 to 6-membered heterocycloalkyl is optionally 1, 2 Or 3 R 1 substitutions;
- R 51 is selected from C 1-10 alkyl and C 1-6 heteroalkyl, C 1-10 alkyl and the C 1-6 heteroalkyl optionally substituted with 1, 2, or 3 R e;
- R 1 is independently selected from H, Cl, F, Br, I, OH, NH 2 , CN, COOH, C 1-6 alkyl, -COO-C 1-6 alkyl, and -C 1-3 alkyl -COO-C 1-6 alkyl, wherein the C 1-6 alkyl, -COO-C 1-6 alkyl, and -C 1-3 alkyl-COO-C 1-6 alkyl are optionally 1 , 2 or 3 R a substitutions;
- R a is independently selected from Cl, F, Br, I, OH, NH 2 , CN, COOH, C 1-3 alkyl, and C 1-3 alkoxy, wherein C 1-3 is optionally 1 , 2 or 3 R substitutions;
- R b is independently selected from Cl, F, Br, I, OH, NH 2 , CN, and COOH;
- R c is independently selected from Cl, F, Br, I, OH, NH 2 , CN, COOH, and C 1-3 alkyl, wherein C 1-3 is optionally substituted by 1, 2 or 3 R;
- R d is independently selected from Cl, F, Br, I, OH, NH 2 , CN and COOH;
- R e is independently selected from Cl, F, Br, I, OH, NH 2 , CN and COOH;
- Each R is independently selected from Cl, F, Br, I, OH, NH 2, CN and of COOH;
- the C 1-6 heteroalkyl and 3- to 6-membered heterocycloalkyl respectively include 1, 2, 3 or 4 heteroatoms or heteroatoms independently selected from -NH-, -O-, -S- and N .
- R a is selected from the group consisting of Cl, F, Br, I, OH, NH 2 , CN, and COOH.
- -OCH 3 other variables are as defined in this application.
- the R c is selected from the group consisting of Cl, F, Br, I, OH, NH 2 , CN, and COOH.
- Other variables are as defined in this application.
- R 1 is independently selected from H, Cl, F, Br, I, OH, and NH. 2 , CN, COOH, C 1-3 alkyl, -COO-C 1-3 alkyl, and -C 1-3 alkyl-COO-C 1-3 alkyl, wherein the C 1-3 alkyl, -COO-C 1-3 alkyl and -C 1-3 alkyl -COO-C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a, the other variables are as defined herein.
- R 1 is independently selected from H, Cl, F, Br, I, OH, and NH. 2, CN, COOH, CH 3 , Et, Wherein CH 3 , Et, Optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined herein.
- R 1 is independently selected from H, Cl, F, Br, I, OH, and NH. 2 , CN, COOH, CH 3 , CF 3 , Et, -CH 2 -COOH, -CH 2 -OCH 3 ,-(CH 2 ) 2 -COOH, Other variables are as defined in this application.
- R 2 is selected from H and C 1-3 alkyl, wherein C 1-3 Alkyl is optionally substituted with 1, 2 or 3 Rb , other variables are as defined herein.
- R 2 is selected from H, CH 3 and Et, and other variables are as defined in the present application.
- R 3 is selected from H, Cl, F, Br, I, OH, NH 2 and C. 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c and other variables are as defined herein.
- R 3 is selected from the group consisting of H, Cl, F, Br, I, OH, NH 2 , and CH. 3 , CF 3 and Et, other variables are as defined in this application.
- R 41 , R 42 , R 43 , R 44, and R 45 are each independently selected from H , Cl, F, Br, I , OH, NH 2, CN , and -COOH, other variables are as defined herein.
- R 51 is selected from C 1- 7 alkyl and C 1-6 heteroalkyl, the said C 1-7 alkyl and C 1-6 heteroalkyl is optionally substituted with 1, 2, or 3 R e, the other variables are as defined herein.
- R 51 is selected from C 1- 7 alkyl and C 1-3 heteroalkyl, the said C 1-7 alkyl and C 1-3 heteroalkyl is optionally substituted with 1, 2, or 3 R e, the other variables are as defined herein.
- R 51 is selected from methyl, ethyl, propyl, isopropyl, The methyl, ethyl, propyl, isopropyl, Optionally substituted with 1, 2, or 3 R e, the other variables are as defined herein.
- R 51 is selected from Other variables are as defined in this application.
- R 5 is selected from R 51 , C 3-8 cycloalkyl, and 5- to 6-membered heterocycles. Cycloalkyl, wherein the C 3-8 cycloalkyl and 5- to 6-membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R 1 , and other variables are as defined herein.
- R 5 is selected from R 51 , cyclohexane, tetrahydropyranyl, and piperidine.
- bicyclo [2.2.2] octyl wherein the cyclohexaneyl, tetrahydropyranyl, piperidinyl, and bicyclo [2.2.2] octyl are optionally substituted by 1, 2 or 3 R 1 instead, other variables are as defined in this application.
- R 5 is selected from R 51 .
- Other variables are as defined in this application.
- R 5 is selected from the group consisting of Other variables are as defined in this application.
- the compound of formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
- n 1 or 2;
- T 1 is selected from N and C (R 43 );
- R 2 is selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2 or 3 R b ;
- R 3 is selected from H, Cl, F, Br, I, OH, NH 2 , C 1-6 alkyl and C 1-3 alkoxy, said C 1-6 alkyl and C 1-3 alkoxy Optionally substituted with 1, 2 or 3 R c ;
- R 41 , R 42 , R 43 , R 44, and R 45 are each independently selected from H, Cl, F, Br, I, OH, NH 2 , CN, COOH, and C 1-3 alkyl, and the C 1- 3 alkyl is optionally substituted with 1, 2 or 3 Rd ;
- R 5 is selected from R 51 , C 3-10 cycloalkyl, and 3 to 6-membered heterocycloalkyl, wherein the C 3-10 cycloalkyl and 3 to 6-membered heterocycloalkyl is optionally 1, 2 Or 3 R 1 substitutions;
- R 51 is selected from C 1-7 alkyl and C 1-6 heteroalkyl, said C 1-7 alkyl and C 1-6 heteroalkyl optionally substituted with 1, 2 or 3 R e ;
- R 1 is selected from H, Cl, F, Br, I, OH, NH 2 , CN, COOH, C 1-6 alkyl, -COO-C 1-6 alkyl, and -C 1-3 alkyl-COO- C 1-6 alkyl, wherein the C 1-6 alkyl, -COO-C 1-6 alkyl and -C 1-3 alkyl-COO-C 1-6 alkyl are optionally substituted by 1, 2 or 3 R a substitutions;
- R a is independently selected from Cl, F, Br, I, OH, NH 2 , CN, COOH, C 1-3 alkyl, and C 1-3 alkoxy, wherein C 1-3 is optionally 1 , 2 or 3 R substitutions;
- R b is independently selected from Cl, F, Br, I, OH, NH 2 , CN, and COOH;
- R c is independently selected from Cl, F, Br, I, OH, NH 2 , CN, COOH, and C 1-3 alkyl, wherein C 1-3 is optionally substituted by 1, 2 or 3 R;
- R d is independently selected from Cl, F, Br, I, OH, NH 2 , CN and COOH;
- R e is independently selected from Cl, F, Br, I, OH, NH 2 , CN and COOH;
- Each R is independently selected from Cl, F, Br, I, OH, NH 2, CN and of COOH;
- the C 1-6 heteroalkyl and 3- to 6-membered heterocycloalkyl respectively include 1, 2, 3 or 4 heteroatoms or heteroatoms independently selected from -NH-, -O-, -S- and N .
- R a is selected from the group consisting of Cl, F, Br, I, OH, NH 2 , and CN. , COOH and -OCH 3 , other variables are as defined in this application.
- the R c is selected from the group consisting of Cl, F, Br, I, OH, NH 2 , and CN.
- COOH other variables are as defined in this application.
- R 1 is selected from H, Cl, F, Br, I, OH, and NH 2.
- CN COOH, C 1-3 alkyl, -COO-C 1-3 alkyl, and -C 1-3 alkyl-COO-C 1-3 alkyl, wherein the C 1-3 alkyl,- COO-C 1-3 alkyl and -C 1-3 alkyl -COO-C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a, the other variables are as defined herein.
- R 1 is selected from H, Cl, F, Br, I, OH, and NH 2. , CN, COOH, CH 3 and Et, wherein said CH 3 and Et are optionally substituted by 1, 2 or 3 R a , and other variables are as defined herein.
- R 1 is selected from H, Cl, F, Br, I, OH, and NH 2.
- CN COOH, CH 3 , Et, -CH 2 -COOH, -CH 2 -OCH 3 and-(CH 2 ) 2 -COOH, other variables are as defined in the present application.
- R 2 is selected from H and C 1-3 alkyl, wherein C 1 -3 alkyl is optionally substituted with 1, 2 or 3 Rb , other variables are as defined herein.
- R 2 is selected from H, CH 3 and Et, and other variables are as defined in the present application .
- R 3 is selected from H, Cl, F, Br, I, OH, and NH 2.
- C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c and other variables are as defined herein.
- R 3 is selected from H, Cl, F, Br, I, OH, and NH 2. , CH 3 , CF 3 and Et, other variables are as defined in this application.
- R 41 , R 42 , R 43 , R 44, and R 45 are independently selected. from H, Cl, F, Br, I, OH, NH 2, CN , and -COOH, other variables are as defined herein.
- R 51 is selected from C 1-6 alkyl and C 1-3 heteroalkyl. , said C 1-6 alkyl and C 1-3 heteroalkyl is optionally substituted with 1, 2, or 3 R e, the other variables are as defined herein.
- R 51 is selected from methyl, ethyl, propyl, isopropyl, The methyl, ethyl, propyl, isopropyl, Optionally substituted with 1, 2, or 3 R e, the other variables are as defined herein.
- R 51 is selected from Other variables are as defined in this application.
- R 5 is selected from R 51 , C 3-8 cycloalkyl, and 5-6. Heterocycloalkyl, wherein the C 3-8 cycloalkyl and 5- to 6-membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R 1 , and other variables are as defined herein.
- R 5 is selected from R 51 , cyclohexane, tetrahydropyranyl, Piperidinyl and bicyclo [2.2.2] octyl, wherein the cyclohexaneyl, tetrahydropyranyl, piperidinyl, and bicyclo [2.2.2] octyl are optionally 1, 2, or 3
- R 1 is replaced, other variables are as defined in this application.
- R 5 is selected from R 51 .
- Other variables are as defined in this application.
- R 5 is selected from Other variables are as defined in this application.
- the compound of formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
- n 1 or 2;
- T 1 is selected from N and C (R 43 );
- R 2 is selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2 or 3 R b ;
- R 3 is selected from H, Cl, F, Br, I, OH, NH 2 , C 1-6 alkyl and C 1-3 alkoxy, said C 1-6 alkyl and C 1-3 alkoxy Optionally substituted with 1, 2 or 3 R c ;
- R 41 , R 42 , R 43 , R 44, and R 45 are each independently selected from H, Cl, F, Br, I, OH, NH 2 , CN, COOH, and C 1-3 alkyl, and the C 1- 3 alkyl is optionally substituted with 1, 2 or 3 Rd ;
- R 5 is selected from R 51 , C 3-6 cycloalkyl and 3 to 6 membered heterocycloalkyl, wherein the 5 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl are optionally 1, 2 Or 3 R 1 substitutions;
- R 51 is selected from C 1-6 alkyl and C 1-6 heteroalkyl, said C 1-6 alkyl and C 1-6 heteroalkyl optionally substituted with 1, 2 or 3 R e ;
- R 1 is selected from H, Cl, F, Br, I, OH, NH 2 , CN, COOH, C 1-6 alkyl, -COO-C 1-6 alkyl, and -C 1-3 alkyl-COO- C 1-6 alkyl, wherein the C 1-6 alkyl, -COO-C 1-6 alkyl and -C 1-3 alkyl-COO-C 1-6 alkyl are optionally substituted by 1, 2 or 3 R a substitutions;
- R a is independently selected from Cl, F, Br, I, OH, NH 2 , CN, COOH, C 1-3 alkyl, and C 1-3 alkoxy, wherein C 1-3 is optionally 1 , 2 or 3 R substitutions;
- R b is independently selected from Cl, F, Br, I, OH, NH 2 , CN, and COOH;
- R c is independently selected from Cl, F, Br, I, OH, NH 2 , CN, COOH, and C 1-3 alkyl, wherein C 1-3 is optionally substituted by 1, 2 or 3 R;
- R d is independently selected from Cl, F, Br, I, OH, NH 2 , CN and COOH;
- R e is independently selected from Cl, F, Br, I, OH, NH 2 , CN and COOH;
- Each R is independently selected from Cl, F, Br, I, OH, NH 2, CN and of COOH;
- the C 1-6 heteroalkyl and 3- to 6-membered heterocycloalkyl respectively include 1, 2, 3 or 4 heteroatoms or heteroatoms independently selected from -NH-, -O-, -S- and N .
- R a is selected from Cl, F, Br, I, OH, NH 2, CN , COOH and -OCH 3 , other variables are as defined in this application.
- R c is selected from the group consisting of Cl, F, Br, I, OH, NH 2 , and CN.
- COOH other variables are as defined in this application.
- R 1 is selected from the group consisting of H, Cl, F, Br, I, OH, and NH 2. , CN, COOH, C 1-3 alkyl, -COO-C 1-3 alkyl, and -C 1-3 alkyl-COO-C 1-3 alkyl, wherein the C 1-3 alkyl,- COO-C 1-3 alkyl and -C 1-3 alkyl -COO-C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a, the other variables are as defined herein.
- R 1 is selected from the group consisting of H, Cl, F, Br, I, OH, and NH 2. , CN, COOH, CH 3 and Et, wherein said CH 3 and Et are optionally substituted by 1, 2 or 3 R a , and other variables are as defined herein.
- R 1 is selected from the group consisting of H, Cl, F, Br, I, OH, and NH 2. , CN, COOH, CH 3 , Et, -CH 2 -COOH and -CH 2 -OCH 3 , and other variables are as defined in the present application.
- R 2 is selected from H and C 1-3 alkyl, wherein C 1 -3 alkyl is optionally substituted with 1, 2 or 3 Rb , other variables are as defined herein.
- R 2 is selected from H, CH 3 and Et, and other variables are as defined in the present application. .
- R 3 is selected from H, Cl, F, Br, I, OH, and NH 2.
- C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c and other variables are as defined herein.
- R 3 is selected from H, Cl, F, Br, I, OH, and NH 2. , CH 3 , CF 3 and Et, other variables are as defined in this application.
- R 41 , R 42 , R 43 , R 44, and R 45 are independently selected. from H, Cl, F, Br, I, OH, NH 2, CN , and -COOH, other variables are as defined herein.
- R 51 is selected from C 1-3 alkyl and C 1-3 heteroalkyl. , said C 1-3 alkyl and C 1-3 heteroalkyl is optionally substituted with 1, 2, or 3 R e, the other variables are as defined herein.
- R 51 is selected from methyl, ethyl, propyl, and isopropyl. said methyl, ethyl, propyl and isopropyl group optionally substituted with 1, 2, or 3 R e, the other variables are as defined herein.
- R 51 is selected from Other variables are as defined in this application.
- R 5 is selected from R 51 , C 5-6 cycloalkyl, and 5-6.
- 5-membered heterocycloalkyl wherein the 5- to 6-membered cycloalkyl and 5- to 6-membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R 1 , and other variables are as defined in the present application.
- R 5 is selected from R 51 , cyclohexane, tetrahydropyranyl, and Piperidinyl, wherein the cyclohexane, tetrahydropyranyl and piperidinyl are optionally substituted with 1, 2 or 3 R 1 , and other variables are as defined herein.
- R 5 is selected from R 51 .
- Other variables are as defined in this application.
- R 5 is selected from Other variables are as defined in this application.
- the compound of formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the compound of formula (I) or a pharmaceutically acceptable salt thereof,
- E 1 is selected from -O-, -S- and -NH-;
- R 1 is selected from H, Cl, F, Br, I, OH, NH 2 , CN, COOH, C 1-6 alkyl, -COO-C 1-6 alkyl, and -C 1-3 alkyl-COO- C 1-6 alkyl, wherein the C 1-6 alkyl, -COO-C 1-6 alkyl and -C 1-3 alkyl-COO-C 1-6 alkyl are optionally substituted by 1, 2 or 3 R a substitutions;
- R 2 is selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2 or 3 R b ;
- R 3 is selected from H, Cl, F, Br, I, OH, NH 2 , C 1-6 alkyl and C 1-3 alkoxy, said C 1-6 alkyl and C 1-3 alkoxy Optionally substituted with 1, 2 or 3 R c ;
- R 41 , R 42 , R 43 , R 44, and R 45 are each independently selected from H, Cl, F, Br, I, OH, NH 2 , CN, COOH, and C 1-3 alkyl, and the C 1- 3 alkyl is optionally substituted with 1, 2 or 3 Rd ;
- R a is selected from Cl, F, Br, I, OH, NH 2 , CN, COOH and C 1-3 alkyl, wherein C 1-3 is optionally substituted by 1, 2 or 3 R;
- R b is selected From Cl, F, Br, I, OH, NH 2 , CN and COOH;
- R c is selected from Cl, F, Br, I, OH, NH 2 , CN, COOH and C 1-3 alkyl, wherein said C 1-3 is optionally substituted by 1, 2 or 3 R;
- R d respectively is independently selected from Cl, F, Br, I, OH, NH 2, CN and of COOH;
- Each R is independently selected from Cl, F, Br, I, OH, NH 2, CN and COOH.
- R a is selected from Cl, F, Br, I, OH, NH 2 , CN, and COOH.
- Other variables are as defined in this application.
- the R c is selected from Cl, F, Br, I, OH, NH 2 , CN, and COOH.
- Other variables are as defined in this application.
- R 1 is selected from H, Cl, F, Br, I, OH, NH 2 , and CN. , COOH, C 1-3 alkyl, -COO-C 1-3 alkyl, and -C 1-3 alkyl-COO-C 1-3 alkyl, wherein the C 1-3 alkyl, -COO- C 1-3 alkyl and -C 1-3 alkyl -COO-C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a, the other variables are as defined herein.
- R 1 is selected from H, Cl, F, Br, I, OH, NH 2 , and CN. , COOH, CH 3 and Et, wherein said CH 3 and Et are optionally substituted with 1, 2 or 3 R a , and other variables are as defined herein.
- R 1 is selected from H, Cl, F, Br, I, OH, NH 2 , and CN. , COOH, CH 3 and Et, other variables are as defined in this application.
- R 2 is selected from H and C 1-3 alkyl, wherein the C 1-3 Alkyl is optionally substituted with 1, 2 or 3 Rb , other variables are as defined herein.
- R 2 is selected from H, CH 3 and Et, and other variables are as defined in the present application.
- R 3 is selected from H, Cl, F, Br, I, OH, NH 2 and C. 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c and other variables are as defined herein.
- R 3 is selected from the group consisting of H, Cl, F, Br, I, OH, NH 2 , and CH. 3 and Et, other variables are as defined in this application.
- R 41 , R 42 , R 43 , R 44, and R 45 are each independently selected from H , Cl, F, Br, I , OH, NH 2, CN , and -COOH, other variables are as defined herein.
- the above-mentioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
- R 1 , R 2 , R 3 , R 41 , R 42 , R 43 , R 44 R 45 and R 51 are as defined in the present application.
- the application also provides a compound of the formula, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
- the above-mentioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
- the present application also provides a pharmaceutical composition
- a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of the above-mentioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the application also provides the application of the above compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for a nucleoprotein inhibitor.
- the application also provides the use of the above compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as a nucleoprotein inhibitor.
- the present application also provides a method for inhibiting nucleoprotein, which comprises administering a therapeutically effective amount of the above-mentioned compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, to a mammal, preferably a human, in need of the treatment or prevention. Its above pharmaceutical composition.
- the present application also provides the above-mentioned compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and its above-mentioned pharmaceutical composition for use as a nucleoprotein inhibitor.
- the above application is characterized in that the drug of the nucleoprotein inhibitor is a drug for treating or preventing a disease related to HBV infection.
- the present application also provides the use of the above compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease related to HBV infection.
- the application also provides the use of the above compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the treatment or prevention of diseases related to HBV infection.
- the present application also provides a method for treating a disease associated with HBV infection, which comprises administering a therapeutically effective amount of the above compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a mammal, preferably a human, in need of the treatment or prevention And its pharmaceutical composition.
- the present application also provides the above-mentioned compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and the above-mentioned pharmaceutical composition thereof for the treatment or prevention of diseases related to HBV infection.
- the compound of the present application has a significant inhibitory effect on HBV.
- the compounds of the present application show good pharmacokinetic properties in terms of absorption, distribution in the body, metabolism, etc., such as good targeting effect on the liver in the body.
- the compounds of the present application have little toxic and side effects.
- pharmaceutically acceptable refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.
- pharmaceutically acceptable salt refers to a salt of a compound of the present application, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found herein.
- base addition salts can be obtained by contacting a sufficient amount of a base with a neutral form of such compounds in a pure solution or a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
- acid addition salts can be obtained by contacting a sufficient amount of acid with a neutral form of such compounds in a pure solution or a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc .; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present application contain basic and acidic functional groups
- the compounds of the present application may exist in specific geometric or stereoisomeric forms.
- This application contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers Isomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomers or diastereomeric enriched mixtures, all of which belong to the present invention
- Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included within the scope of this application.
- enantiomers or “optical isomers” refer to stereoisomers in mirror image relationship to each other.
- cis-trans isomer or “geometric isomer” are caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.
- diastereomer refers to a stereoisomer in which a molecule has two or more centers of chirality and is in a non-mirror relationship between molecules.
- wedge solid line keys And wedge-shaped dotted keys Represents the absolute configuration of a solid center
- using straight solid line keys And straight dotted keys Represents the relative configuration of the solid center
- with wavy lines Represents a wedge solid line key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid line key And straight dotted keys
- the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2) Exists in the form of a mixture;
- the following formula (B) indicates that the compound exists as a single isomer of the formula (B-1) or (B-2) or in the form of both (B-1) and (B-2) The isomers exist as a mixture.
- the following formula (C) represents that the compound exists as a single isomer of the formula (C-1) or (C-2) or in the form of the two isomers of the formula (C-1) and the formula (C-2) It exists as a mixture.
- tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be quickly converted to each other. If tautomers are possible (eg in solution), the chemical equilibrium of the tautomers can be reached.
- proton tautomers also known as prototropic tautomers
- proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
- Valence tautomers include the recombination of some bonding electrons for mutual conversion.
- a specific example of the keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
- the terms “enriched with one isomer”, “enriched with isomers”, “enriched with one enantiomer” or “enantiomerically enriched” refer to one of the isomers or the The enantiomeric content is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or more 99.9%.
- the terms “isomer excess” or “enantiomeric excess” refer to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is 90% and the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
- Optically active (R)-and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide pure The desired enantiomer.
- a diastereomeric salt is formed with an appropriate optically active acid or base, and then by a conventional method known in the art Diastereomeric resolution is performed and the pure enantiomer is recovered.
- Diastereomeric resolution is performed and the pure enantiomer is recovered.
- the separation of enantiomers and diastereomers is usually accomplished by using chromatography that employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines) Formate).
- the compounds of the present application may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
- deuterated drugs can be replaced by heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have lower toxicity and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. Transformations of all isotopic compositions of the compounds of this application, whether radioactive or not, are included within the scope of this application.
- substituted refers to the replacement of any one or more hydrogen atoms on a specific atom with a substituent, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
- it means that two hydrogen atoms are substituted.
- Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
- any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
- R when any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
- the group may optionally be substituted with at most two R, and R in each case has independent options.
- combinations of substituents and / or variants are only permitted if such combinations result in stable compounds.
- substituents When a substituent is vacant, it means that the substituent does not exist.
- X in A-X indicates that the structure is actually A.
- substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be passed through any of the pyridine rings The carbon atom is attached to a substituted group.
- the intermediate linking group L is -MW-.
- -MW- can be connected to ring A and ring B in the same direction as the reading order from left to right. You can also connect ring A and ring B in the opposite direction from the reading order from left to right.
- the number of atoms on a ring is generally defined as the number of rings, for example, a "5-7 member ring” means a “ring” arranged around 5-7 atoms.
- 3-10 membered ring means a cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl group consisting of 3 to 10 ring atoms.
- the ring includes a single ring, and also includes a double ring or a multi-ring system such as a spiro ring, a parallel ring and a bridge ring.
- the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
- the 3-10 member ring includes 3-10 members, 3-9 members, 3-8 members, 3-7 members, 3-6 members, 3-5 members, 4-10 members, 4-9 members, 4- 8 yuan, 4-7 yuan, 4-6 yuan, 4-5 yuan, 5-10 yuan, 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6- 9 yuan, 6-8 yuan and 6-7 yuan ring, etc.
- the term "5- to 7-membered heterocycloalkyl” includes piperidinyl and the like, but does not include phenyl.
- ring also includes ring systems containing at least one ring, each of which "ring” independently meets the above definition.
- 5- to 6-membered ring means a cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aromatic group consisting of 5 to 6 ring atoms. Or heteroaryl.
- the ring includes a single ring, and also includes a double ring system such as a spiro ring, a parallel ring and a bridge ring. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
- the 5- to 6-membered ring includes a 5-membered, 6-membered ring, and the like.
- 5-6 membered ring includes, for example, phenyl, pyridyl, piperidinyl, and the like; on the other hand, the term “5- to 6-membered heterocycloalkyl” includes piperidinyl and the like, but does not include phenyl.
- ring also includes ring systems containing at least one ring, each of which "ring” independently meets the above definition.
- the terms “5- to 6-membered heteroaryl ring” and “5- to 6-membered heteroaryl group” are used interchangeably in this application, and the term “5 to 6-membered heteroaryl group” means from 5 to 6 ring atoms A monocyclic group consisting of a conjugated ⁇ -electron system.
- One, two, three, or four ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms.
- the nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) p , p is 1 or 2).
- the 5- to 6-membered heteroaryl group can be connected to the rest of the molecule through a heteroatom or a carbon atom.
- the 5- to 6-membered heteroaryl group includes 5- and 6-membered heteroaryl groups.
- Examples of the 5- to 6-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyryl) Oxazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1, 2,4
- alkyl is used to indicate a straight or branched chain saturated hydrocarbon group.
- the alkyl group is a C 1-12 alkyl group; in other embodiments , The alkyl group is a C 1-6 alkyl group; in other embodiments, the alkyl group is a C 1-3 alkyl group. It can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine).
- alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl And t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.
- C 1-10 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group consisting of 1 to 10 carbon atoms.
- the C 1-10 alkyl includes but is not limited to C 1-10 , C 1-9 , C 1-8 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1- 2 , C 2-6 , C 2-4 , C 10 , C 8 , C 7 , C 6 and C 5 alkyl, etc .; it may be monovalent (such as methyl), divalent (such as methylene) or Multivalent (such as methine).
- C 1-12 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, heptyl, octyl and the like.
- C 1-6 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
- the C 1-6 alkyl group include but are not limited to C 1-5, C 1-4, C 1-3 , C 1-2, C 2- 6, C 2-4, C 6 and C 5 alkyl group ; It can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
- C 1-6 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.
- C 1-3 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes, but is not limited to, C 1-2 and C 2-3 alkyl groups, and the like; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methyl).
- Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- heteroalkyl itself or in combination with another term means a stable straight or branched chain alkyl radical group or a combination thereof composed of a certain number of carbon atoms and at least one heteroatom or heteroatom group.
- the heteroatoms are selected from B, O, N, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized.
- the heteroalkyl is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl is C 1-3 heteroalkyl.
- a heteroatom or heteroatom group can be located at any internal position of the heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkane (Oxy) is a customary expression and refers to those alkyl groups which are each connected to the rest of the molecule through an oxygen, amino or sulfur atom.
- Up to two heteroatoms
- alkoxy refers to those alkyl groups that are each connected to the rest of the molecule through one oxygen atom.
- C 1-6 alkoxy includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy.
- the alkoxy group is a C 1-3 alkoxy group. Examples of alkoxy include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy and S- Pentyloxy.
- C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are connected to the rest of the molecule through one oxygen atom.
- the C 1-3 alkoxy group includes, but is not limited to, C 1-2 , C 2-3 , C 3 and C 2 alkoxy, and the like.
- Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- C n-n + m or C n -C n + m includes any specific case of n to n + m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , and also include any range from n to n + m, for example, C 1-12 includes C 1- 3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.
- n yuan to n + m means that the number of atoms on the ring is n to n + m.
- 3-12-membered rings include 3-, 4-, 5-, 6-, 7-, 8-, and 9-membered rings.
- 10-membered ring, 11-membered ring, and 12-membered ring including any range from n to n + m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring Ring, 5-7 member ring, 6-7 member ring, 6-8 member ring, and 6-10 member ring, etc.
- cycloalkyl includes any stable cyclic alkyl group including monocyclic, bicyclic, or tricyclic systems, where bicyclic and tricyclic systems include spiro, paracyclic, and bridged rings.
- the cycloalkyl is C 3-8 cycloalkyl; in other embodiments, the cycloalkyl is C 3-6 cycloalkyl; in other embodiments, the cycloalkyl Cycloalkyl is C 5-6 cycloalkyl. It can be univalent, bivalent, or multivalent.
- C 3-10 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 10 carbon atoms, which includes monocyclic, bicyclic, and tricyclic systems, where bicyclic and tricyclic systems include a spiro ring, and Ring and bridge ring.
- the C 3-10 cycloalkyl includes, but is not limited to, C 3-8 , C 3-6 , C 3-5 , C 4-10 , C 4-8 , C 4-6 , C 4-5 , C 5 -8 or C 5-6, etc .; it can be monovalent, bivalent, or multivalent.
- Examples of C 3-10 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] bicyclooctane, [ 4.4.0] dicyclodecane and the like.
- C 3-8 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, which includes monocyclic and bicyclic systems, where bicyclic systems include spiro, paracyclic and bridged rings.
- the C 3-8 cycloalkyl includes, but is not limited to, C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 cycloalkyl Etc; it can be univalent, bivalent or multivalent.
- C 3-8 cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] dicyclooctane, and the like.
- heterocycloalkyl itself or in combination with other terms respectively represents a cyclic “heteroalkyl", which includes monocyclic, bicyclic, and tricyclic systems, where bicyclic and tricyclic systems include spiro, Parallel ring and bridge ring.
- a heteroatom may occupy the position of attachment of the heterocycloalkyl to the rest of the molecule.
- the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl; in other embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl.
- heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophene 2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl , Dithiaalkyl, isoxazolidinyl, isothiazolidinyl, 1,2-
- the term "3-6 membered heterocycloalkyl" itself or in combination with other terms respectively represents a saturated cyclic group composed of 3 to 6 ring atoms, and 1, 2, 3 or 4 ring atoms are independently selected from Heteroatoms of O, S and N, the rest are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) p , where p is 1 or 2 ). It includes single ring and double ring systems, where the double ring system includes a spiro ring, a parallel ring and a bridge ring.
- the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the rest of the molecule.
- the 3- to 6-membered heterocycloalkyl includes, but is not limited to, 4- to 6-membered, 5- to 6-membered, 4-, 5-, and 6-membered heterocycloalkyl.
- 3- to 6-membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazyl, isoxazolidinyl, isothiazolyl,
- the term "4- to 6-membered heterocycloalkyl" itself or in combination with other terms indicates a saturated cyclic group consisting of 4 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are independently selected Heteroatoms of O, S and N, the rest are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) p , where p is 1 or 2 ). It includes single ring and double ring systems, where the double ring system includes a spiro ring, a parallel ring and a bridge ring.
- the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the rest of the molecule.
- the 4- to 6-membered heterocycloalkyl includes, but is not limited to, 5- to 6, 4-, 5-, and 6-membered heterocycloalkyl.
- 4- to 6-membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazyl, isoxazolidinyl, isothiazolyl,
- the term "5- to 6-membered heterocycloalkyl" itself or in combination with other terms indicates a saturated cyclic group consisting of 5 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are independently selected Heteroatoms of O, S and N, the rest are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) p , where p is 1 or 2 ). It includes single ring and double ring systems, where the double ring system includes a spiro ring, a parallel ring and a bridge ring.
- a heteroatom may occupy a connection position between the heterocycloalkyl group and the rest of the molecule.
- the 5- to 6-membered heterocycloalkyl includes 5- and 6-membered heterocycloalkyl.
- Examples of 5- to 6-membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.) , Tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1 -Piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithiaalkyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl,
- pharmaceutically acceptable carrier refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and having no toxic side effects on the host or patient.
- Representative carriers include water, oil, Vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine.
- excipient generally refers to a carrier, diluent, and / or vehicle required to formulate an effective pharmaceutical composition.
- treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
- prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, particularly when Such mammals are susceptible to the disease state but have not yet been diagnosed as having the disease state.
- the term "effective amount” or “therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect.
- the "effective amount” of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
- the determination of an effective amount varies from person to person, depends on the age and general situation of the recipient, and also depends on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art based on routine tests.
- active ingredient refers to a chemical entity that can effectively treat a target disorder, disease, or condition.
- 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 familiar to those skilled in the art. Equivalent alternatives. Preferred implementations include, but are not limited to, the examples of this application.
- aq stands for water
- HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate
- EDC stands for N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
- m-CPBA stands for 3-chloroperoxybenzoic acid
- eq stands for equivalent, equivalent
- CDI stands for Carbonyl diimidazole
- DCM stands for dichloromethane
- PE stands for petroleum ether
- DIAD diisopropyl azodicarboxylate
- DMF stands for N, N-dimethylformamide
- DMSO stands for dimethyl sulfoxide
- EtOAc stands for ethyl acetate EtOH represents ethanol
- MeOH represents methanol
- CBz represents benzyloxy
- FIG. 1 HBV DNA levels in plasma
- FIG. 1 HBV DNA levels in the liver.
- Diisopropylamine (49.91g, 493.22mmol, 69.71mL, 1.2eq) was dissolved in tetrahydrofuran (1000mL), and then n-butyllithium (2.5M, 197.29mL, 1.2eq) was added at -78 ° C, and after stirring for 0.5 hours- Compound 4-1 (100 g, 411.02 mmol, 1 eq) was added at 78 ° C, and stirring was continued for 0.5 hours, and iodomethane (58.34 g, 411.02 mmol, 25.59 mL, 1 eq) was added at -78 ° C. The reaction was stirred at 25 ° C for 16 hours.
- reaction solution was poured into 1 L of a saturated ammonium chloride solution to quench it, extracted with ethyl acetate (500 mL * 4), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4-2.
- compound 1-5 (55.01 mg, 477.64 ⁇ mol, 1.2 eq) was added to a bottle containing dichloroethane (3 mL), and then O- (7-azabenzotriazole-1- ) -N, N, N ', N'-tetramethylurea hexafluorophosphate (227.02mg, 597.05 ⁇ mol, 1.5eq) and N, N-diisopropylethylamine (154.33mg, 1.19mmol, 207.99 ⁇ L, 3eq) was added to the reaction system. After the reaction was performed at 0 ° C.
- compound 1-9 (42.28mg, 327.49 ⁇ mol, 1.5eq) was added to a thumb flask containing dichloromethane (2mL), and then the reaction was cooled to 0 ° C, and O- (7-aza Benzotriazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate (107.92 mg, 283.82 ⁇ mol, 1.3 eq), N, N-diisopropylethylamine ( 84.65mg, 654.97 ⁇ mol, 114.08 ⁇ L, 3eq) were added to the reaction system.
- reaction solution was poured into 50 mL of a saturated ammonium chloride solution, and extracted with ethyl acetate (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 11-2.
- reaction solution was poured into 100 mL of a saturated ammonium chloride solution, followed by extraction with ethyl acetate (80 mL * 3).
- organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- titanium tetraisopropoxide (3.41g, 11.99mmol, 3.54mL, 1.2eq) was dissolved in ammonia / methanol (7M, 5.71mL, 4eq), and added dropwise at 30 ° C under the protection of nitrogen.
- Compound 12-1 (1 g, 9.99 mmol, 917.43 ⁇ L, 1 eq), stirred for 2 hours and cooled to -5 ° C.
- compound 12-2 (1.04 g, 10.49 mmol, 1.31 mL, 1.05 eq) was added dropwise and After stirring for 2 hours, the temperature was raised to 30 ° C and stirring was continued for 12 hours.
- compound 13-4 (1.3 g, 3.97 mmol, 1 eq) was dissolved in ethyl acetate (30 mL) and hydrochloric acid / ethyl acetate (4 mol / L, 10 mL, 10.08 eq) was added. Stir at 16 ° C for 16 hours. The reaction solution was directly concentrated to obtain compound 13-5.
- compound 13-7 (70 mg, 149.91 ⁇ mol, 1 eq) was dissolved in N, N-dimethylformamide (4 mL), and O- (7-azabenzotriazine was added under nitrogen protection at 30 ° C.
- reaction solution was poured into saturated ammonium chloride (200 mL), extracted with ethyl acetate (200 mL * 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
- Compound 13-6 was separated by SFC (chromatographic column: DAICELCHIRALCELOJ (250mm * 30mm, 10 ⁇ m); mobile phase [Neu-ETOH]; B%: 30% -30%, 9min). Compound 17-1 (SFC retention time 1.16min) and compound 18-1 (SFC retention time 1.7min) were obtained, and SFC analysis conditions (chromatographic column: Daicel OJ-3 chiral column, specification 0.46cm id * 5cm; Mobile phase: [A: carbon dioxide, B: chromatographic ethanol (0.05% isopropylamine)]; B%: 5% -40%; flow rate: 4 ml / min; 4 minutes; system back pressure: 100 bar).
- reaction solution was diluted with ethyl acetate (50 mL), and then washed with 0.5 M diluted hydrochloric acid (10 mL * 2).
- the organic phase was dried, filtered over anhydrous sodium sulfate, and concentrated under reduced pressure.
- MS (ESI) m / s: 578.2 [M + H] + .
- reaction solution was diluted with ethyl acetate (500 mL), and then filtered, and the mother liquor was concentrated under reduced pressure.
- reaction solution was poured into 0.5 mol / L dilute hydrochloric acid (10 mL), the aqueous phase was extracted with ethyl acetate (20 mL * 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- reaction solution was poured into dilute hydrochloric acid (0.5 mol / L, 50 mL), and the aqueous phase was extracted with ethyl acetate (20 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- reaction solution was poured into water (100 mL) and then extracted with ethyl acetate (50 mL * 2).
- organic phase was sequentially washed with a saturated aqueous sodium chloride solution (100 mL * 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- Dissolve compound 23-4 (150 mg, 745.61 ⁇ mol, 7.21e-1 eq) in dichloromethane (5 mL) at 26 ° C, and add sodium bicarbonate (434.37 mg, 5.17 mmol, 201.10 ⁇ L, 5 eq), slowly with stirring.
- a mixed solution of compound 11-7 (300 mg, 1.03 mmol, 1 eq) and dichloromethane (5 mL) was added dropwise. After the dropwise addition was completed, the reaction was stirred at 26 ° C for 0.5 hours.
- LCMS showed the formation of compound 23-5. Water (10 mL) was added to the reaction with stirring, and the mixture was allowed to stand and separate to obtain an organic phase.
- reaction solution was poured into 500 mL of saturated ammonium chloride, extracted with ethyl acetate (500 mL * 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain.
- the reaction solution was poured into dilute hydrochloric acid (0.5 mol / L, 20 mL), the aqueous phase was extracted with ethyl acetate (20 mL * 3), and the organic phase was dried and filtered over anhydrous sodium sulfate and concentrated under reduced pressure.
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Abstract
Description
试剂 | 供应商 | 体积(mL) |
F12培养基 | Invitrogen | 500 |
胎牛血清 | Invitrogen | 50 |
G418/遗传毒素 | Invitrogen | 1 |
潮霉素B | Invitrogen | 1 |
组成成分 | 细胞外液(mM) | 细胞内液(mM) |
NaCl | 145 | - |
KCl | 4 | 120 |
KOH | - | 31.25 |
CaCl 2 | 2 | 5.374 |
MgCl 2 | 1 | 1.75 |
Glucose | 10 | - |
Na 2ATP | - | 4 |
HEPES | 10 | 10 |
EGTA | - | 10 |
pH | 氢氧化钠调节pH为7.4 | 氢氧化钾调节pH为7.4 |
渗透压 | 295mOsm | 285mOsm |
供试样品 | hERG IC50(μM) |
化合物18 | >40 |
化合物25 | >40 |
化合物 | CC 50(μM) |
化合物18 | >50 |
化合物25 | >50 |
Claims (24)
- 式(Ⅱ)化合物或其药学上可接受的盐,其中,m为1或2;T 1选自N和C(R 43);R 2选自H和C 1-6烷基,其中所述C 1-6烷基任选被1、2或3个R b取代;R 3选自H、Cl、F、Br、I、OH、NH 2、C 1-6烷基和C 1-3烷氧基,所述C 1-6烷基和C 1-3烷氧基任选被1、2或3个R c取代;R 41、R 42、R 43、R 44和R 45分别独立地选自H、Cl、F、Br、I、OH、NH 2、CN、COOH和C 1-3烷基,所述C 1-3烷基任选被1、2或3个R d取代;R 5选自R 51、C 3-10环烷基和3~6元杂环烷基,其中,所述C 3-10环烷基和3~6元杂环烷基任选被1、2或3个R 1取代;R 51选自C 1-10烷基和C 1-6杂烷基,所述C 1-10烷基和C 1-6杂烷基任选被1、2或3个R e取代;R 1分别独立地选自H、Cl、F、Br、I、OH、NH 2、CN、COOH、C 1-6烷基、-COO-C 1-6烷基和-C 1-3烷基-COO-C 1-6烷基,其中所述C 1-6烷基、-COO-C 1-6烷基和-C 1-3烷基-COO-C 1-6烷基任选被1、2或3个R a取代;R a分别独立地选自Cl、F、Br、I、OH、NH 2、CN、COOH、C 1-3烷基和C 1-3烷氧基,其中所述C 1-3任选被1、2或3个R取代;R b分别独立地选自Cl、F、Br、I、OH、NH 2、CN和COOH;R c分别独立地选自Cl、F、Br、I、OH、NH 2、CN、COOH和C 1-3烷基,其中所述C 1-3任选被1、2或3个R取代;R d分别独立地选自Cl、F、Br、I、OH、NH 2、CN和COOH;R e分别独立地选自Cl、F、Br、I、OH、NH 2、CN和COOH;R分别独立地选自Cl、F、Br、I、OH、NH 2、CN和COOH;所述C 1-6杂烷基和3~6元杂环烷基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂 原子团。
- 根据权利要求1所示的化合物或其药学上可接受的盐,其中,R a选自Cl、F、Br、I、OH、NH 2、CN、COOH和-OCH 3。
- 根据权利要求1所示的化合物或其药学上可接受的盐,其中,R c选自Cl、F、Br、I、OH、NH 2、CN和COOH。
- 根据权利要求1或2所示的化合物或其药学上可接受的盐,其中,R 1分别独立地选自H、Cl、F、Br、I、OH、NH 2、CN、COOH、C 1-3烷基、-COO-C 1-3烷基和-C 1-3烷基-COO-C 1-3烷基,其中所述C 1-3烷基、-COO-C 1-3烷基和-C 1-3烷基-COO-C 1-3烷基任选被1、2或3个R a取代。
- 根据权利要求1所示的化合物或其药学上可接受的盐,其中,R 2选自H和C 1-3烷基,其中所述C 1-3烷基任选被1、2或3个R b取代。
- 根据权利要求7所示的化合物或其药学上可接受的盐,其中,R 2选自H、CH 3和Et。
- 根据权利要求1或3所示的化合物或其药学上可接受的盐,其中,R 3选自H、Cl、F、Br、I、OH、NH 2和C 1-3烷基,其中所述C 1-3烷基任选被1、2或3个R c取代。
- 根据权利要求9所示的化合物或其药学上可接受的盐,其中,R 3选自H、Cl、F、Br、I、OH、NH 2、CH 3、CF 3和Et。
- 根据权利要求1所示的化合物或其药学上可接受的盐,其中,R 41、R 42、R 43、R 44和R 45分别独立地选自H、Cl、F、Br、I、OH、NH 2、CN和-COOH。
- 根据权利要求1所示的化合物或其药学上可接受的盐,其中,R 51选自C 1-7烷基和C 1-3杂烷基,所述C 1- 7烷基和C 1-3杂烷基任选被1、2或3个R e取代。
- 根据权利要求1所示的化合物或其药学上可接受的盐,其中,R 5选自R 51、C 3-8环烷基和5~6元杂环烷基,其中,所述C 3-8环烷基和5~6元杂环烷基任选被1、2或3个R 1取代。
- 根据权利要求15所示的化合物或其药学上可接受的盐,其中,R 5选自R 51、环己烷基、四氢吡喃基、哌啶基和双环[2.2.2]辛烷基,其中,所述环己烷基、四氢吡喃基、哌啶基和双环[2.2.2]辛烷基任选被1、2或3个R 1取代。
- 一种药物组合物,包括权利要求1-22任一项所述化合物、或其立体异构体、或其药学上可接受的盐,任选地,还包括药学上可接受的载体。
- 用作核蛋白抑制剂的权利要求1~22任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐或权利要求23所述的药物组合物,任选的,其中所述核蛋白抑制剂是指治疗或预防HBV感染相关疾病的药物。
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CN (2) | CN113549079A (zh) |
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Cited By (9)
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WO2020156494A1 (zh) * | 2019-01-31 | 2020-08-06 | 正大天晴药业集团股份有限公司 | 含有吡咯并杂环的衣壳蛋白装配抑制剂 |
US11008346B2 (en) | 2014-06-11 | 2021-05-18 | VenatoRx Pharmaceuticals, Inc. | Beta-lactamase inhibitors |
US11014881B2 (en) | 2018-06-11 | 2021-05-25 | VenatoRx Pharmaceuticals, Inc. | Hepatitis B capsid assembly modulators |
WO2021098850A1 (zh) * | 2019-11-22 | 2021-05-27 | 正大天晴药业集团股份有限公司 | 一种核蛋白抑制剂的晶型及其应用 |
US11247965B2 (en) | 2017-12-11 | 2022-02-15 | VenatoRx Pharmaceuticals, Inc. | Hepatitis B capsid assembly modulators |
US11267826B2 (en) | 2017-05-26 | 2022-03-08 | VenatoRx Pharmaceuticals, Inc. | Penicillin-binding protein inhibitors |
WO2022095950A1 (zh) | 2020-11-05 | 2022-05-12 | 正大天晴药业集团股份有限公司 | 包含衣壳蛋白抑制剂和核苷类似物的药物组合 |
US11332485B2 (en) | 2017-05-26 | 2022-05-17 | VenatoRx Pharmaceuticals, Inc. | Penicillin-binding protein inhibitors |
US11597716B2 (en) | 2018-03-30 | 2023-03-07 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | N-heterocyclic five-membered ring-containing capsid protein assembly inhibitor, pharmaceutical composition thereof, and use thereof |
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US20230234968A1 (en) * | 2020-06-10 | 2023-07-27 | Medshine Discovery Inc. | Methyl-substituted benzobisoxazole compound and use thereof |
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- 2019-05-24 AU AU2019272481A patent/AU2019272481B2/en active Active
- 2019-05-24 KR KR1020207037156A patent/KR20210016402A/ko not_active Application Discontinuation
- 2019-05-24 EP EP19806616.9A patent/EP3805223A4/en active Pending
- 2019-05-24 JP JP2020565885A patent/JP7333342B2/ja active Active
- 2019-05-24 US US17/058,308 patent/US11891398B2/en active Active
- 2019-05-24 CN CN201980005380.9A patent/CN111247151B/zh active Active
- 2019-05-24 WO PCT/CN2019/088376 patent/WO2019223791A1/zh unknown
- 2019-05-24 SG SG11202011685QA patent/SG11202011685QA/en unknown
- 2019-05-24 CA CA3101373A patent/CA3101373A1/en active Pending
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WO2008154817A1 (fr) | 2007-06-18 | 2008-12-24 | Zhang, Zhongneng | Thiazolyl-dihydropyrimidines à substitution bromo-phényle |
WO2018039531A1 (en) * | 2016-08-26 | 2018-03-01 | Gilead Sciences, Inc. | Substituted pyrrolizine compounds and uses thereof |
Cited By (13)
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US11008346B2 (en) | 2014-06-11 | 2021-05-18 | VenatoRx Pharmaceuticals, Inc. | Beta-lactamase inhibitors |
US11267826B2 (en) | 2017-05-26 | 2022-03-08 | VenatoRx Pharmaceuticals, Inc. | Penicillin-binding protein inhibitors |
US11332485B2 (en) | 2017-05-26 | 2022-05-17 | VenatoRx Pharmaceuticals, Inc. | Penicillin-binding protein inhibitors |
US11247965B2 (en) | 2017-12-11 | 2022-02-15 | VenatoRx Pharmaceuticals, Inc. | Hepatitis B capsid assembly modulators |
US11597716B2 (en) | 2018-03-30 | 2023-03-07 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | N-heterocyclic five-membered ring-containing capsid protein assembly inhibitor, pharmaceutical composition thereof, and use thereof |
US11566001B2 (en) | 2018-06-11 | 2023-01-31 | VenatoRx Pharmaceuticals, Inc. | Hepatitis B capsid assembly modulators |
US11014881B2 (en) | 2018-06-11 | 2021-05-25 | VenatoRx Pharmaceuticals, Inc. | Hepatitis B capsid assembly modulators |
WO2020156494A1 (zh) * | 2019-01-31 | 2020-08-06 | 正大天晴药业集团股份有限公司 | 含有吡咯并杂环的衣壳蛋白装配抑制剂 |
CN113365999A (zh) * | 2019-01-31 | 2021-09-07 | 正大天晴药业集团股份有限公司 | 含有吡咯并杂环的衣壳蛋白装配抑制剂 |
CN113365999B (zh) * | 2019-01-31 | 2023-04-14 | 正大天晴药业集团股份有限公司 | 含有吡咯并杂环的衣壳蛋白装配抑制剂 |
WO2021098850A1 (zh) * | 2019-11-22 | 2021-05-27 | 正大天晴药业集团股份有限公司 | 一种核蛋白抑制剂的晶型及其应用 |
CN114728973A (zh) * | 2019-11-22 | 2022-07-08 | 正大天晴药业集团股份有限公司 | 一种核蛋白抑制剂的晶型及其应用 |
WO2022095950A1 (zh) | 2020-11-05 | 2022-05-12 | 正大天晴药业集团股份有限公司 | 包含衣壳蛋白抑制剂和核苷类似物的药物组合 |
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EP3805223A1 (en) | 2021-04-14 |
CN113549079A (zh) | 2021-10-26 |
JP7333342B2 (ja) | 2023-08-24 |
PH12020552017A1 (en) | 2021-06-28 |
CN111247151B (zh) | 2021-08-10 |
EP3805223A4 (en) | 2021-12-22 |
US20220204510A1 (en) | 2022-06-30 |
SG11202011685QA (en) | 2020-12-30 |
US11891398B2 (en) | 2024-02-06 |
JP2021525267A (ja) | 2021-09-24 |
CA3101373A1 (en) | 2019-11-28 |
KR20210016402A (ko) | 2021-02-15 |
AU2019272481A1 (en) | 2020-12-17 |
AU2019272481B2 (en) | 2024-03-21 |
CN111247151A (zh) | 2020-06-05 |
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