CN108456216B - Sulfonyl hydrazide compound and application thereof - Google Patents

Sulfonyl hydrazide compound and application thereof Download PDF

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CN108456216B
CN108456216B CN201810150536.XA CN201810150536A CN108456216B CN 108456216 B CN108456216 B CN 108456216B CN 201810150536 A CN201810150536 A CN 201810150536A CN 108456216 B CN108456216 B CN 108456216B
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CN108456216A (en
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王喆
王晓光
卢涔宾
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Shanghai Longwood Biopharmaceuticals Co Ltd
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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    • 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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a sulfonyl hydrazide compound and application thereof as a medicament for treating hepatitis B. Specifically, the invention discloses a compound which can be used as an HBV inhibitor and has a structure shown in a chemical formula A, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, a hydrate or a solvate thereof, and the definition of each group is shown in the specification. The invention also relates to a pharmaceutical composition containing the compound and application thereof in treating hepatitis B.

Description

Sulfonyl hydrazide compound and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a sulfonyl hydrazide compound for treating hepatitis B and application thereof.
Background
Hepatitis B Virus (HBV) is a enveloped, partially double-stranded DNA (dsdna), virus of the Hepadnaviridae family (Hepadnaviridae). Its genome comprises 4 overlapping reading frames: the pronuclear/nuclear gene, the polymerase gene, the UM and S genes (which encode the three envelope proteins), and the X gene. Before infection, the partially double-stranded DNA genome is converted in the host cell nucleus (open circular DNA, rcDNA) into covalently closed circular DNA (cccdna) and the viral mRNA is transcribed. Once shelled, the pregenomic rna (pgrna), which also encodes the core protein and Pol, serves as a template for reverse transcription, which regenerates the portion of the dsDNA genome (rcDNA) in the nucleocapsid.
HBV causes epidemics in parts of asia and africa, and it is endemic in china. HBV has infected approximately 20 million people worldwide, of which approximately 3.5 million develop into chronic infectious diseases. The virus causes hepatitis b disease and chronic infectious diseases are associated with a high increased risk of development of cirrhosis and liver cancer.
Transmission of hepatitis b virus results from exposure to infectious blood or body fluids, while viral DNA is detected in saliva, tears, and urine of chronic carriers with high titers of DNA in serum.
While there is currently an effective and well-tolerated vaccine, the options for direct treatment are currently limited to interferon and the following antiviral drugs; tenofovir, lamivudine, adefovir, entecavir and telbivudine.
In addition, heteroaryl dihydropyrimidine (HAPs) has been identified as a class of HBV inhibitors in tissue culture as well as in animal models (Weber et al, Antiviral Res. 54: 69-78).
WO 2013/006394 (disclosed in 2013 on month 10) and WO 2013/096744 (disclosed in 2013 on month 6 on day 27) also disclose sulfamoyl-arylamides that are involved in anti-HBV activity.
However, problems of toxicity, mutagenicity, lack of selectivity, poor therapeutic effect, poor bioavailability, and difficulty in synthesis are encountered in these direct HBV antiviral agents.
Therefore, there is a need in the art to develop HBV inhibitors with advantages such as high potency, lower toxicity, etc.
Disclosure of Invention
The invention aims to provide a compound which can be used as an HBV inhibitor and has a novel structure.
In a first aspect of the present invention, there is provided a compound represented by formula a, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
Figure BDA0001579804270000021
wherein the content of the first and second substances,
R1selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C3-C10Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from N, S and O, substituted or unsubstituted C6-C10Aryl, and substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O; the R is1Wherein said substitution means being substituted with one or more (e.g. 1,2,3, 4 or 5) substituents selected from the group consisting of: -OH, halogen, C1-C6Alkyl, halogenated C1-C6Alkyl radical, C1-C6Alkoxy, -O-;
x is a divalent group selected from the group consisting of: CR2R3or-CR2＝CR3-; wherein R is2And R3Each independently selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3-C10Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from N, S and O, substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, C1-3alkyl-R7、-C(＝O)OC1-4An alkyl group; wherein said R7Is selected from the followingGroup (2): halogen, C1-C3Alkyl, substituted or unsubstituted 5-10 membered heteroaryl having 1-2 heteroatoms selected from N, S and O, 3-7 membered heterocycloalkyl having 1-3 heteroatoms selected from N, S and O, and-NR9R10Wherein, said R9And R10Each independently selected from: H. c1-C3Alkyl, and halogenated C1-C3An alkyl group;
alternatively, the first and second electrodes may be,
the R is2And R3Together with the adjacent C atom, form a substituted or unsubstituted 3-7 membered heterocycloalkyl having 1-3 heteroatoms selected from N, S and O, wherein the substitution of said 3-7 membered heterocycloalkyl means substitution with one or more (e.g., 1,2,3, 4, or 5) substituents selected from the group consisting of: -OH, halogen, methoxy, ethoxy, -O-, -C (═ O) OC1-4Alkyl, benzyl, C1-4Alkyl, halogenated C1-4An alkyl group, a carboxyl group,
and, said R2And R3Wherein said substitution means being substituted with one or more (e.g. 1,2,3, 4 or 5) substituents selected from the group consisting of: -OH, halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, -OH substituted C1-C6Alkyl radical, C1-C6Alkoxy, -C (═ O) OC1-4An alkyl group;
y is substituted or unsubstituted C1-C7Alkylene or C2-C7An alkenylene group; in said Y, said substitution means being substituted with one or more (e.g. 1,2,3, 4 or 5) substituents selected from the group consisting of: c1-C4Alkyl radical, C1-C4Haloalkyl, halogen, -OH (preferably C)1-C4Alkyl or-OH);
w is selected from the group consisting of: -SO2-、-CO-；
Ring C is a substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O; in the ring C, the substitution means being substituted with one or more (e.g., 1,2,3, 4, or 5, etc.) substituents selected from the group consisting of: c1-C3Alkyl (thanPreferably methyl), C1-C3Haloalkyl, C3-C4Cycloalkyl, -CN or halogen;
ring B is substituted or unsubstituted C6-C10Aryl, or substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O; in the ring B, the substitution means being substituted with one or more (e.g., 1,2,3, 4, or 5) substituents selected from the group consisting of: c1-C3Alkyl radical, C1-C3Haloalkyl, C3-C4Cycloalkyl, -CN or halogen;
Ra、Rb、Rcand RdIs a substituent at any position on the ring B, each of which is independently selected from the group consisting of: H. halogen, -CN, hydroxy, amino, C1-C6 carboxy, - (C ═ O) -substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C1-C8Alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from N, S and O, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O; in the Ra, Rb, Rc, Rd, the "substituted" means substituted with one or more (e.g., 1,2,3, 4, or 5, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, C1-C3 carboxy, C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O;
n is 0, 1 or 2;
p is 0, 1 or 2;
"- - -" in- -X- - - -Y- - -represents a bond or is absent;
wherein, when "- - -" represents a bond, Z is selected from the group consisting of: NH, O or none;
when "- - -" indicates absent, X and Y are both absent, and Z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR9R10、OR9Or H.
In another preferred embodiment, the "- - -" represents a single bond, a double bond or is absent.
In another preferred embodiment, the compound is a compound selected from the group consisting of:
Figure BDA0001579804270000031
wherein R is1X, Y, Z, W, Ring C, Ring B, Ra, Rb, Rc, Rd, n, p are as defined above.
In another preferred embodiment, in the compound represented by the formula A-1, when N is 2, - (N)2(R1) -represents the following structure: -NH-N (R)1)-。
In another preferred embodiment, R1Is H, unsubstituted C1-C10Alkyl, C substituted by-OH, -O-or halogen1-C10An alkyl group.
In another preferred embodiment, for R1When the substituent is-O-, it means R1Wherein both hydrogens on the carbon atom are simultaneously replaced by an oxygen, i.e. a C ═ O group is formed.
In another preferred embodiment, R2Selected from the group consisting of: H. substituted or unsubstituted C1-C10Alkyl, -C (═ O) OC1-4Alkyl radical, C1-3alkyl-R7Substituted or unsubstituted C2-4Alkynyl, 3-7 membered heterocycloalkyl having 1-3 heteroatoms selected from N, S and O, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O.
In another preferred embodiment, R3Selected from the group consisting of: H. substituted or unsubstituted C1-C10Alkyl, preferably H, substituted or unsubstituted C1-C6Alkyl, more preferably H or methyl.
In another preferred embodiment, for "said R2And R3The case where a substituted or unsubstituted 3-7 membered heterocycloalkyl "having 1-3 heteroatoms selected from N, S and O is formed together with the adjacent C atom, when the substituent is-O-, means that two hydrogens on the carbon atoms in said 3-7 membered heterocycloalkyl are simultaneously substituted with one oxygen, i.e., a C ═ O group is formed.
In another preferred embodiment, ring C is a substituted or unsubstituted 5-or 6-membered heteroaryl, said substitution being by one or more (e.g., 1,2,3, 4, or 5, etc.) substituents selected from the group consisting of: methyl, -CN or halogen.
In another preferred embodiment, ring C is a substituted or unsubstituted 5-6 membered heteroaryl group containing 1 to 3N, in which ring C the substitution means is substituted with one or two substituents selected from the group consisting of: c1-C3Alkyl (preferably methyl), halogen, -CN.
In another preferred embodiment, ring B is phenyl or a substituted or unsubstituted 6 membered heteroaryl, preferably phenyl or pyridyl.
In another preferred embodiment, ring B is phenyl or 6-membered heteroaryl.
In another preferred embodiment, R isa、Rb、RcAnd RdEach independently selected from the group consisting of: H. halogen, -CHF2、-CF2-methyl, -CH2F、-CF3、-OCF3、-CN、-C3-C4Cycloalkyl, -C1-C4An alkyl group.
In another preferred embodiment, the ring C is
Figure BDA0001579804270000041
Wherein the content of the first and second substances,
R4is H, -C1-C3Alkyl (preferably methyl), -C3-C4A cycloalkyl group;
R6selected from H, methyl, -CN or halogen.
In another preferred embodiment, in formula A-1, Z is O or nothing.
In another preferred embodiment, R is7Is a substituted or unsubstituted 5-10 membered heteroaryl having 1-2 heteroatoms selected from N, S and O.
In another preferred embodiment, the compound of formula a is selected from the compounds listed in table 1.
In another preferred embodiment, the compound of formula a is selected from the compounds prepared in examples 1-49.
In a second aspect of the present invention there is provided a process for the preparation of a compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula a is a compound of formula IX-1, said process comprising the steps of:
Figure BDA0001579804270000051
in various forms, ring C, R1Ring B, Ra、Rb、RcAnd RdIs as defined in the first aspect of the invention;
z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR9R10、OR9Or H;
m is an integer of 0 to 8.
In a third aspect of the present invention, there is provided a process for the preparation of a compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula a is a compound of formula VIII-2, said process comprising the steps of:
Figure BDA0001579804270000052
in various forms, ring C, R1Ring B, Ra、Rb、RcAnd RdIs as defined in the first aspect of the invention;
z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR9R10、OR9Or H;
m is an integer of 0 to 8.
In a fourth aspect of the present invention, there is provided a process for the preparation of a compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula a is a compound of formula V-3, said process comprising the steps of:
Figure BDA0001579804270000061
in various forms, ring C, R1Ring B, Ra、Rb、RcAnd RdIs as defined in the first aspect of the invention;
z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR9R10、OR9Or H.
In a fifth aspect of the present invention, there is provided a process for the preparation of a compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula a is a compound of formula VI-4, said process comprising the steps of:
Figure BDA0001579804270000062
in various forms, ring C, R1Ring B, Ra、Rb、RcAnd RdIs as defined in the first aspect of the invention;
z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR9R10、OR9Or H.
In a sixth aspect of the present invention, there is provided a pharmaceutical composition comprising (1) a compound of the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (2) a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition further comprises other drugs for preventing and/or treating hepatitis B virus infection.
In another preferred embodiment, the other agent for preventing and/or treating hepatitis b virus infection may be selected from the group consisting of: immunomodulators (e.g., interferon-alpha (IFN-alpha), pegylated interferon-alpha) or stimulators of the innate immune system (e.g., Toll-like receptor 7 and/or 8 agonists).
In another preferred embodiment, the other agent for preventing and/or treating hepatitis b virus infection may be selected from the group consisting of: tenofovir, lamivudine, adefovir, entecavir, telbivudine, or combinations thereof.
In a seventh aspect of the invention, there is provided an intermediate compound of the formula:
Figure BDA0001579804270000071
wherein R1 and ring C are as defined in the first aspect of the invention;
z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR9R10、OR9Or H;
m is an integer of 0 to 8.
In an eighth aspect of the invention there is provided the use of an intermediate compound according to the seventh aspect of the invention for the preparation of a compound according to the first aspect of the invention.
In a ninth aspect of the present invention, there is provided the use of a compound according to the first aspect of the present invention, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the sixth aspect of the present invention, for the preparation of a medicament for the prophylaxis and/or treatment of hepatitis b virus infection.
In a tenth aspect of the present invention, there is provided a hepatitis b virus inhibitor comprising a compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
In an eleventh aspect of the present invention, there is provided a method for preventing and/or treating hepatitis b, comprising the steps of: administering to a patient in need thereof a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the sixth aspect of the invention.
In a twelfth aspect of the present invention, there is provided an in vitro method of inhibiting hepatitis b, comprising the steps of: contacting a compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, with hepatitis b virus, thereby inhibiting hepatitis b.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have conducted extensive and intensive studies and have found a novel class of compounds having an excellent therapeutic effect on hepatitis b. The compound has a novel mother nucleus in structure, particularly has a structural part of sulfonyl hydrazide, so that the compound not only has excellent anti-HBV activity, but also has the advantages of lower cytotoxicity (particularly to liver cells), more excellent pharmacokinetics, improved solubility and the like, and has better druggability. On this basis, the inventors have completed the present invention.
Definition of
As used herein, the term "alkyl" includes straight or branched chain alkyl groups. E.g. C1-C8Alkyl represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. E.g. C2-C6Alkenyl means a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.
As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. E.g. C2-C6Alkynyl means straight or branched chain alkynyl having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
As used herein, the term "C3-C10Cycloalkyl "refers to cycloalkyl groups having 3 to 10 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. It may also be in the form of a double ring, for example a bridged or spiro ring.
As used herein, the term "C1-C8Alkylamino "is defined as being substituted by C1-C8The amino group substituted by the alkyl can be mono-substituted or di-substituted; for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino and the like.
As used herein, the term "C1-C8Alkoxy "means a straight or branched chain alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.
As used herein, the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from N, S and O" refers to a saturated or partially saturated cyclic group having 3-10 atoms and wherein 1-3 atoms are heteroatoms selected from N, S and O. It may be monocyclic or may be in the form of a double ring, for example a bridged or spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
As used herein, the term "C6-C10Aryl "means an aryl group having 6 to 10 carbon atoms, e.g. phenyl orNaphthyl and the like.
As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from N, S and O. It may be a single ring or a condensed ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl and (1,2,4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
Unless specifically stated to be "substituted or unsubstituted", the groups of the present invention may be substituted with a substituent selected from the group consisting of: halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6Alkyl-amino, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, halo C1-C6Alkyl, halo C2-C6Alkenyl, halo C2-C6Alkynyl, halo C1-C6Alkoxy, allyl, benzyl, C6-C12Aryl radical, C1-C6alkoxy-C1-C6Alkyl radical, C1-C6Alkoxy-carbonyl, phenoxycarbonyl, C2-C6Alkynyl-carbonyl, C2-C6Alkenyl-carbonyl, C3-C6Cycloalkyl-carbonyl, C1-C6Alkyl-sulfonyl, and the like.
As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "halogenated" means substituted with an atom selected from F, Cl, Br, and I.
Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.
As used herein, the term "tautomer" means that structural isomers having different energies may exceed the low energy barrier, thereby converting with each other. For example, proton tautomers (i.e., proton transmutations) include interconversion by proton shift, such as 1H-indazoles and 2H-indazoles. Valence tautomers include interconversion by recombination of some of the bonding electrons.
As used herein, the term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specific ratio.
As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.
Active ingredient
As used herein, "compound of the present invention" refers to a compound represented by formula (a), and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of the compound of formula (a).
As used herein, "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid.
Pharmaceutical compositions and methods of administration
Since the compound of the present invention has excellent inhibitory activity against Hepatitis B Virus (HBV), the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment (stabilization, alleviation or cure) of infection by hepatitis b virus or for the prevention and/or treatment (stabilization, alleviation or cure) of diseases associated with hepatitis b virus (e.g., hepatitis b, progressive hepatic fibrosis, inflammation and necrosis leading to liver cirrhosis, end-stage liver disease, ethyl liver cancer).
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0001579804270000101
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
When administered in combination, the pharmaceutical composition further comprises one or more (2, 3,4, or more) other pharmaceutically acceptable compounds (e.g., anti-HBV agents). One or more (2, 3,4, or more) of such other pharmaceutically acceptable compounds (e.g., anti-HBV agents) may be used simultaneously, separately or sequentially with a compound of the invention in the prevention and/or treatment of HBV infection or HBV-related disease.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The compounds of the present invention in table 1 were synthesized according to the synthesis methods of the compounds 10a, 20a, 30a, 40a, 50a, 60a, 70a and 80a of the present invention.
TABLE 1
Figure BDA0001579804270000121
Figure BDA0001579804270000131
Figure BDA0001579804270000141
Figure BDA0001579804270000151
Figure BDA0001579804270000161
Figure BDA0001579804270000171
The main advantages of the invention include:
1. the compound of the invention has novel structure and excellent effect of resisting hepatitis B virus infection.
2. The compounds of the present invention have very low toxicity to normal cells.
3. The compound and the pharmaceutical composition containing the compound as the main active ingredient can be used for preventing and/or treating hepatitis B virus infection.
4. The compound of the present invention and the pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for preventing and/or treating diseases associated with hepatitis b virus (e.g., hepatitis b, progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, ethyl liver cancer).
Description of the terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
The synthesis of compounds of type 10 is as follows:
example 1: synthesis of Compound 10a
Figure BDA0001579804270000181
Step 1:
Figure BDA0001579804270000182
dissolving compound 1(1.5g) and compound 2(0.5g) in acetonitrile (20mL), adding pyridine (1.5g) into the reaction system, raising the temperature to 85 ℃ for reaction for 2h, adding ethyl acetate (30mL) into the reaction system, adding water 30(mL), extracting with ethyl acetate (3 x 20mL), drying with anhydrous sodium sulfate, spin-drying the organic phase, and performing column chromatography to obtain compound 3(1.0 g). ESI-MS (366H + M)
Step 2:
Figure BDA0001579804270000183
dissolving compound 3(0.8g), vinyl boron anhydride pyridinium salt (0.75g) and potassium carbonate (1.8g) in dioxane (5mL) and water (0.5mL), adding palladium tetratriphenylphosphine (100mg) into the reaction system, raising the temperature of the system to 100 ℃, reacting for 8H under the protection of nitrogen, adding water (20mL) into the reaction system, extracting with ethyl acetate (3X 30mL), drying with anhydrous sodium sulfate, spin-drying the organic phase, and performing crude column chromatography to obtain compound 4(400mg), ESI-MS (M + H ═ 314)
And step 3:
Figure BDA0001579804270000184
dissolving the compound 4(400mg) in dichloromethane (800mL), adding a catalyst CAT-C (90mg) into a reaction system, reacting at 30 ℃ for 36 hours, adding water (600mL) into the reaction system, extracting with dichloromethane (3X 400mL), drying with anhydrous sodium sulfate, spin-drying an organic phase, and separating a crude product by column chromatography to obtain a yellow solid 5(120mg), ESI-MS, (M + H ═ 286)
And 4, step 4:
Figure BDA0001579804270000191
dissolving compound 5(120mg) in tetrahydrofuran (2.4mL), water (0.6mL) and methanol (0.6mL), adding lithium hydroxide monohydrate (83mg) to the reaction system at room temperature, reacting at 40 ℃ for 5H, adjusting the pH value of the system to 3-4 with 1N hydrochloric acid, extracting with ethyl acetate (3X 15mL), drying over anhydrous sodium sulfate, and spin-drying the organic phase to obtain yellow solid 6(50mg) ESI-MS, (M + H ═ 272)
And 5:
Figure BDA0001579804270000192
dissolving the compound 6(50mg), triethylamine (70mg) and 3, 4-difluoro-1-aniline (22mg) in dichloromethane (3mL), cooling the temperature to about 5 ℃, adding TBTU (70mg) into the reaction system, reacting at room temperature for 12h, adding water (15mL), extracting with dichloromethane (3X 20mL), drying over anhydrous sodium sulfate, spin-drying the organic phase, and performing column chromatography on the crude product (n-heptane: ethyl acetate ═ 1: 1) to obtain a compound 10a (10mg)
Example 2: synthesis of Compound 10b
Figure BDA0001579804270000193
Compound 6b was prepared according to example 1, steps 1-4, except that 1-allyl-1-cyclopropylhydrazine was used in place of 1-allyl-1-methylhydrazine in step 1.
According to step 5 of example 1, only compound 6b was used instead of compound 6, and the other conditions were unchanged, the target product 10b (11mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 1).
Example 3: synthesis of Compound 10c
Figure BDA0001579804270000201
Compound 6c was prepared according to example 1, steps 1-4, except that 1-allyl-1-isopropylhydrazine was used instead of 1-allyl-1-methylhydrazine in step 1.
According to step 5 of example 1, only compound 6c was used instead of compound 6, and the other conditions were unchanged, the target product 10c (6mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 2: 1).
Example 4: synthesis of Compound 10d
Figure BDA0001579804270000202
Compound 6d was prepared according to example 1, steps 1-4, except that 1- (1-allylhydrazino) ethanol was used in place of 1-allyl-1-methylhydrazine in step 1.
According to step 5 of example 1, only compound 6d was used instead of compound 6, and the other conditions were unchanged, the target product 10d (6mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 2: 1).
Example 5: synthesis of Compound 10e
Figure BDA0001579804270000203
Compound 6e was prepared according to example 1, steps 1-4, except that 1-allyl-1-isopropylhydrazine was used instead of 1-allyl-1-methylhydrazine in step 1.
According to step 5 of example 1, only compound 6e was used instead of compound 6, 3, 4-difluoro-1-aniline was used instead of 3-chloro-4-fluoro-1-aniline, and column chromatography was performed (n-heptane: ethyl acetate ═ 2: 1) for the objective product 10e (11mg) under other conditions.
Example 6: synthesis of Compound 10f
Figure BDA0001579804270000204
Compound 6f was prepared according to example 1, steps 1-4, except that 1-allyl-1-isopropylhydrazine was used instead of 1-allyl-1-methylhydrazine in step 1.
According to step 5 of example 1, only compound 6f was used instead of compound 6, 3, 4-difluoro-1-aniline was used instead of 3-cyano-4-fluoro-1-aniline, and column chromatography was performed (n-heptane: ethyl acetate ═ 2: 1) for the objective product 10f (8mg) under other conditions.
Example 7: synthesis of Compound 10g
Figure BDA0001579804270000211
Compound 6f was prepared according to example 1, steps 1-4, except that 2-methyl-1-allyl-1-isopropylhydrazine was used in place of 1-allyl-1-methylhydrazine in step 1.
According to step 5 of example 1, only compound 6f was used instead of compound 6, 3, 4-difluoro-1-aniline was used instead of 3-cyano-4-fluoro-1-aniline, and column chromatography was performed (n-heptane: ethyl acetate ═ 2: 1) for 10g (8mg) of the objective product, without changing other conditions.
The synthesis of compounds of type 20 is as follows:
example 8: synthesis of Compound 20a
Figure BDA0001579804270000212
Step 11:
compound 10a (20mg) was dissolved in ethyl acetate (2mL), and then wet palladium on carbon (5mg) was added to the reaction system, and the mixture was reacted at 25 degrees under a hydrogen atmosphere for 3 hours, and the reaction solution was suction-filtered, and spin-dry column chromatography (n-heptane: ethyl acetate ═ 1: 1) was performed on target product 20a (7mg)
Example 9: synthesis of Compound 20b
Figure BDA0001579804270000213
According to step 11 of example 7, only compound 10b was used instead of compound 10a, and the other conditions were unchanged, the target product 20b (6mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 1).
Example 10: synthesis of Compound 20c
Figure BDA0001579804270000221
According to step 11 of example 7, only compound 10a was replaced with compound 10c, and the other conditions were unchanged, and column chromatography was performed (n-heptane: ethyl acetate ═ 1: 1) for target product 20c (7 mg).
Example 11: synthesis of Compound 20d
Figure BDA0001579804270000222
According to step 11 of example 7, only compound 10d was used instead of compound 10a, and the other conditions were unchanged, the target product 20d (8mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 1).
Example 12: synthesis of Compound 20e
Figure BDA0001579804270000223
According to step 11 of example 7, only compound 10e was used instead of compound 10a, and the other conditions were unchanged, and column chromatography was performed (n-heptane: ethyl acetate ═ 1: 1) for target product 20e (5 mg).
Example 13: synthesis of Compound 20f
Figure BDA0001579804270000224
According to step 11 of example 7, only compound 10f was used instead of compound 10a, and the other conditions were unchanged, and column chromatography was performed (n-heptane: ethyl acetate ═ 1: 1) for the target product 20f (10 mg).
The synthesis of compounds of type 30 is as follows:
example 14: synthesis of Compound 30a
Figure BDA0001579804270000231
Step 21:
Figure BDA0001579804270000232
compound 21(1.5g) and compound 22(0.6g) were dissolved in acetonitrile (20mL), pyridine (1.5g) was added to the reaction system, the temperature was raised to 85 ℃ for reaction for 2h, ethyl acetate (30mL) was added to the reaction system, water 30(mL) was added, ethyl acetate (3 × 20mL) was extracted, anhydrous sodium sulfate was dried, the organic phase was dried by spin drying, and crude column chromatography gave compound 23(0.9 g). ESI-MS (M + H367)
Step 22:
Figure BDA0001579804270000233
dissolving compound 23(0.8g), vinyl boron anhydride pyridinium salt (0.75g) and potassium carbonate (1.8g) in dioxane (5mL) and water (0.5mL), adding palladium tetratriphenylphosphine (100mg) into the reaction system, raising the temperature of the system to 100 ℃, reacting for 8H under the protection of nitrogen, adding water (20mL) into the reaction system, extracting with ethyl acetate (3X 30mL), drying with anhydrous sodium sulfate, spin-drying the organic phase, and performing crude column chromatography to obtain compound 24(350mg), ESI-MS (M + H ═ 315)
Step 23:
Figure BDA0001579804270000234
dissolving the compound 24(350mg) in dichloromethane (800mL), adding a catalyst CAT-C (90mg) into a reaction system, reacting at 30 ℃ for 36 hours, adding water (600mL) into the reaction system, extracting with dichloromethane (3X 400mL), drying with anhydrous sodium sulfate, spin-drying an organic phase, and separating a crude product by column chromatography to obtain a yellow solid 25(110mg), ESI-MS, (M + H ═ 287)
Step 24:
Figure BDA0001579804270000241
compound 25(110mg) was dissolved in tetrahydrofuran (2.4mL), water (0.6mL), and methanol (0.6mL), then lithium hydroxide monohydrate (83mg) was added to the reaction system at room temperature to react at 40 ℃ for 5H, then the pH of the system was adjusted to 3-4 with 1N hydrochloric acid, ethyl acetate (3 × 15mL) was extracted, dried over anhydrous sodium sulfate, and the organic phase was spin-dried to give ESI-MS (50mg) as a yellow solid (M + H ═ 273).
Step 25:
Figure BDA0001579804270000242
compound 26(50mg), triethylamine (70mg), 3, 4-difluoro-1-aniline (22mg) were dissolved in dichloromethane (3mL), the temperature was then decreased to about 5 ℃, TBTU (70mg) was added to the reaction system, the reaction was carried out at room temperature for 12 hours, water (15mL), dichloromethane (3 × 20mL) was added, dried over anhydrous sodium sulfate, the organic phase was spin-dried, and the crude product was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 1) to give compound 30a (12 mg).
Example 15: synthesis of Compound 30b
Figure BDA0001579804270000243
Compound 26b is prepared by reference to steps 21-24 of example 13, except that 1-allyl-1-cyclopropylhydrazine is used instead of 1-allyl-1-methylhydrazine in step 21.
According to step 25 of example 13, only compound 26b was used instead of compound 26, and the other conditions were unchanged, the target product 30b (9mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 1).
Example 16: synthesis of Compound 30c
Figure BDA0001579804270000244
Compound 26c is prepared by reference to steps 21 to 24 of example 13, except that 1-allyl-1-isopropylhydrazine is used in place of 1-allyl-1-methylhydrazine in step 21.
According to step 25 of example 13, only compound 26c was used instead of compound 26, and the other conditions were unchanged, the objective product 30c (6mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 1).
Example 17: synthesis of Compound 30d
Figure BDA0001579804270000251
Compound 26d is prepared by reference to steps 21-24 of example 13, except that 1- (1-allylhydrazino) ethanol is used in place of 1-allyl-1-methylhydrazine in step 21.
According to step 25 of example 13, only compound 26d was used instead of compound 26, and the other conditions were unchanged, the target product 30d (6mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 1).
Example 18: synthesis of Compound 30e
Figure BDA0001579804270000252
Compound 26e was prepared according to example 13, Steps 21-24, except that 1-allyl-1-isopropylhydrazine was used in place of 1-allyl-1-methylhydrazine in step 21.
According to step 25 of example 13, only compound 26e was used instead of compound 26, 3, 4-difluoro-1-aniline was used instead of 3-chloro-4-fluoro-1-aniline, and column chromatography was performed (n-heptane: ethyl acetate ═ 1: 1) for the objective product 30e (11mg) under other conditions.
Example 19: synthesis of Compound 30f
Figure BDA0001579804270000253
Compound 26f is prepared by reference to steps 21-24 of example 13, except that 1-allyl-1-isopropylhydrazine is used instead of 1-allyl-1-methylhydrazine in step 21.
According to step 25 of example 13, only compound 26f was used instead of compound 26, 3, 4-difluoro-1-aniline was used instead of 3-cyano-4-fluoro-1-aniline, and column chromatography was performed (n-heptane: ethyl acetate ═ 2: 1) for the objective product 30f (8mg) under other conditions.
The synthesis of compounds of type 40 is as follows:
example 20: synthesis of Compound 40a
Figure BDA0001579804270000261
Step 31:
compound 30a (20mg) was dissolved in ethyl acetate (2mL), and then wet palladium on carbon (5mg) was added to the reaction system, and the reaction was carried out at 25 degrees under a hydrogen atmosphere for 3 hours, followed by suction filtration of the reaction solution and spin-dry column chromatography (n-heptane: ethyl acetate ═ 1: 1) for target product 30a (7 mg).
Example 21: synthesis of Compound 40b
Figure BDA0001579804270000262
According to step 31 of example 19, only compound 30b was used instead of compound 30a, and the other conditions were unchanged, the target product 40b (6mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 1).
Example 22: synthesis of Compound 40c
Figure BDA0001579804270000263
According to step 31 of example 19, only compound 30c was used instead of compound 30a, and the other conditions were unchanged, and column chromatography was performed (n-heptane: ethyl acetate ═ 1: 1) for target product 40c (7 mg).
Example 23: synthesis of Compound 40d
Figure BDA0001579804270000264
According to step 31 of example 19, only compound 30d was used instead of compound 30a, and the other conditions were unchanged, the target product 40d (8mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 1).
Example 24: synthesis of Compound 40e
Figure BDA0001579804270000271
According to step 31 of example 19, only compound 30e was used instead of compound 30a, and the other conditions were unchanged, and column chromatography was performed (n-heptane: ethyl acetate ═ 1: 1) for target product 40e (5 mg).
Example 25: synthesis of Compound 40f
Figure BDA0001579804270000272
According to step 31 of example 19, only compound 30f was used instead of compound 30a, and the other conditions were unchanged, the target product 40f (10mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 1).
The synthesis of compounds of type 50 is as follows:
example 26: synthesis of Compound 50a
Figure BDA0001579804270000273
Step 41:
Figure BDA0001579804270000274
compound 41(0.5g) and compound 42(0.2g) were dissolved in acetonitrile (20mL), pyridine (0.5g) was added to the reaction system, the temperature was raised to 85 ℃ and the reaction was carried out for 2h, ethyl acetate (30mL) was added to the reaction system, water 30(mL) was added, ethyl acetate (3 × 20mL) was extracted, anhydrous sodium sulfate was dried, the organic phase was dried by spin drying, and crude column chromatography was carried out to obtain compound 43(0.2 g). ESI-MS (M + H410)
Step 42:
Figure BDA0001579804270000281
compound 43(0.2g) was dissolved in tetrahydrofuran (2.5mL), water (0.8mL), and methanol (0.8mL), then lithium hydroxide monohydrate (100mg) was added to the reaction system at room temperature for reaction at 40 ℃ for 5H, then the pH of the system was adjusted to 3-4 with 1N hydrochloric acid, ethyl acetate (3X 15mL) was extracted, dried over anhydrous sodium sulfate, and the organic phase was spin-dried to give ESI-MS as a yellow solid 44(80mg), (M + H. 396)
Step 43:
Figure BDA0001579804270000282
dissolving the compound 44(80mg), triethylamine (80mg) and 3, 4-difluoro-1-aniline (32mg) in dichloromethane (3mL), cooling the temperature to about 5 ℃, adding TBTU (90mg) into the reaction system, reacting at room temperature for 12H, adding water (15mL), extracting with dichloromethane (3X 20mL), drying with anhydrous sodium sulfate, spin-drying the organic phase, and performing column chromatography on the crude product to obtain a compound 45(30mg), ESI-MS (M + H-514)
Step 44:
Figure BDA0001579804270000283
compound 45(30mg) was dissolved in dichloromethane (1mL), followed by reaction with 4N hydrochloric acid (1mL) at room temperature for 2h, spin-drying dichloromethane, and column chromatography of the crude product (petroleum ether: ethyl acetate ═ 1:2) to give compound 50a (10mg)
Example 27: synthesis of Compound 50b
Figure BDA0001579804270000284
Compound 45b was prepared by referring to steps 41 to 43 of example 25 except that 1-tert-butoxycarbonyl-1-isopropylhydrazine was replaced with 1-tert-butoxycarbonyl-1-trifluoroisopropylhydrazine in step 41.
According to step 44 of example 25, only compound 45b was used instead of compound 45, and the other conditions were unchanged, the target product 50b (9mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 2).
Example 28: synthesis of Compound 50c
Figure BDA0001579804270000291
Compound 45c was prepared by referring to steps 41 to 43 of example 25 except that 1-tert-butoxycarbonyl-1-isopropylhydrazine was replaced with 1-tert-butoxycarbonyl-1-tert-butylhydrazine in step 41.
According to step 44 of example 25, only compound 45c was used instead of compound 45, and the other conditions were unchanged, the target product 50c (4mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 2).
Example 29: synthesis of Compound 50d
Figure BDA0001579804270000292
Compound 45d was prepared by referring to steps 41 to 43 of example 25, except that 1-tert-butoxycarbonyl-1-hydroxyisopropylhydrazine was used in place of 1-tert-butoxycarbonyl-1-isopropylhydrazine in step 41.
According to step 44 of example 25, only compound 45d was used instead of compound 45, and the other conditions were unchanged, the target product 50d (10mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 1).
Example 30: synthesis of Compound 50e
Figure BDA0001579804270000293
Compound 45e was prepared by referring to steps 41 to 43 of example 25 except that 1-tert-butoxycarbonyl-1-isopropylhydrazine was replaced with 1-tert-butoxycarbonyl-1-trifluoroisopropylhydrazine in step 41.
According to step 44 of example 25, only compound 45e was used instead of compound 45, 3, 4-difluoro-1-aniline was used instead of 3-chloro-4-fluoro-1-aniline, and column chromatography was performed (n-heptane: ethyl acetate ═ 1: 1) for the objective product 50e (11mg) under other conditions.
Example 31: synthesis of Compound 50f
Figure BDA0001579804270000294
Compound 45f was prepared by referring to steps 41 to 43 of example 25 except that 1-tert-butoxycarbonyl-1-isopropylhydrazine was replaced with 1-tert-butoxycarbonyl-1-trifluoroisopropylhydrazine in step 41.
According to step 44 of example 25, only compound 45f was used instead of compound 45, 3, 4-difluoro-1-aniline was used instead of 3-cyano-4-fluoro-1-aniline, and column chromatography was performed (n-heptane: ethyl acetate ═ 1: 1) for the objective product 50f (13mg) under other conditions.
The synthesis of compounds of class 60 is as follows:
example 32: synthesis of Compound 60a
Figure BDA0001579804270000301
Step 51:
Figure BDA0001579804270000302
compound 51(0.5g) and compound 52(0.2g) were dissolved in acetonitrile (20mL), pyridine (0.5g) was added to the reaction system, the temperature was raised to 85 ℃ for reaction for 2h, ethyl acetate (30mL) was added to the reaction system, water 30(mL) was added, ethyl acetate (3 × 20mL) was extracted, anhydrous sodium sulfate was dried, the organic phase was dried by spin drying, and crude column chromatography gave compound 53(0.2 g). ESI-MS (M + H411)
Step 52:
Figure BDA0001579804270000303
dissolving compound 53(0.2g) in tetrahydrofuran (2.5mL), water (0.8mL) and methanol (0.8mL), adding lithium hydroxide monohydrate (100mg) to the reaction system at room temperature, reacting at 40 ℃ for 5H, adjusting the pH of the system to 3-4 with 1N hydrochloric acid, extracting with ethyl acetate (3 × 15mL), drying over anhydrous sodium sulfate, and spin-drying the organic phase to obtain yellow solid 54(80mg) ESI-MS, (M + H ═ 397)
Step 53:
Figure BDA0001579804270000311
dissolving compound 54(80mg), triethylamine (80mg) and 3, 4-difluoro-1-aniline (32mg) in dichloromethane (3mL), cooling to about 5 ℃, adding TBTU (90mg) into the reaction system, reacting at room temperature for 12H, adding water (15mL), extracting with dichloromethane (3X 20mL), drying with anhydrous sodium sulfate, spin-drying the organic phase, and performing column chromatography to obtain compound 55(30mg) ESI-MS (M + H ═ 515)
Step 54:
Figure BDA0001579804270000312
compound 55(30mg) was dissolved in dichloromethane (1mL), followed by reaction with 4N hydrochloric acid (1mL) at room temperature for 2h, spin-drying dichloromethane, and column chromatography of the crude product (petroleum ether: ethyl acetate ═ 1:2) to give compound 60a (10mg)
Example 33: synthesis of Compound 60b
Figure BDA0001579804270000313
Compound 55b can be prepared by following steps 51 to 53 of example 31, except that 1-tert-butoxycarbonyl-1-isopropylhydrazine is replaced with 1-tert-butoxycarbonyl-1-trifluoroisopropylhydrazine in step 51.
According to step 54 of example 31, only compound 55b was used instead of compound 55, and the other conditions were unchanged, the target product 60b (9mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 2).
Example 34: synthesis of Compound 60c
Figure BDA0001579804270000314
A compound 55c was obtained by referring to steps 51 to 53 of example 31, except that 1-tert-butoxycarbonyl-1-isopropylhydrazine was replaced with 1-tert-butoxycarbonyl-1-tert-butylhydrazine in step 51.
According to step 54 of example 31, only compound 55c was used instead of compound 55, and the other conditions were unchanged, the target product 60c (7mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 2).
Example 35: synthesis of Compound 60d
Figure BDA0001579804270000321
Compound 55d can be prepared by steps 51 to 53 in example 31, except that 1-tert-butoxycarbonyl-1-isopropylhydrazine is replaced with 1-tert-butoxycarbonyl-1-hydroxyisopropylhydrazine in step 41.
According to step 54 of example 31, only compound 55d was used in place of compound 55, and the other conditions were unchanged, the target product 60d (11mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 1).
Example 36: synthesis of Compound 60e
Figure BDA0001579804270000322
Compound 55e was prepared by following steps 51 to 53 of example 31, except that 1-tert-butoxycarbonyl-1-isopropylhydrazine was replaced with 1-tert-butoxycarbonyl-1-trifluoroisopropylhydrazine in step 51.
According to step 54 of example 31, only compound 55e was used instead of compound 55 and 3, 4-difluoro-1-aniline was used instead of 3, 4-difluoro-1-aniline, and column chromatography was performed (n-heptane: ethyl acetate ═ 1: 1) on the target product 60e (10mg) under the same conditions.
Example 37: synthesis of Compound 60f
Figure BDA0001579804270000323
A compound 55f was obtained by referring to steps 51 to 53 of example 31, except that 1-tert-butoxycarbonyl-1-isopropylhydrazine was replaced with 1-tert-butoxycarbonyl-1-trifluoroisopropylhydrazine in step 51.
According to step 54 of example 31, only compound 55f was used instead of compound 55 and 3, 4-difluoro-1-aniline was used instead of 3-cyano-4-fluoro-1-aniline under otherwise unchanged conditions, and column chromatography was performed (n-heptane: ethyl acetate ═ 1: 1) for target product 60f (9 mg).
The synthesis of compounds of class 70 is as follows:
example 38: synthesis of Compound 70a
Figure BDA0001579804270000331
Step 61:
Figure BDA0001579804270000332
A) dissolving the compound 61(300mg) in concentrated hydrochloric acid (1.35mL), cooling to-5 ℃, uniformly stirring, then dropwise adding an aqueous solution of sodium nitrite (100mg) into the reaction system, and stirring for 0.5 h.
B) Tin dichloride (729mg) was dissolved in concentrated hydrochloric acid and dissolved down to 0 ℃ with stirring.
C) The reaction liquid A) is dripped into the reaction liquid B), the reaction system is controlled to be about 0 ℃, and 0 ℃ reacts for 0.5h after dripping.
Water (15mL) was added to the reaction system, extracted with ethyl acetate (3X 20mL) and dried to give 62(250mg) as a yellow solid which was directly subjected to the next reaction. ESI-MS (204 ═ M + H)
Step 62:
Figure BDA0001579804270000333
dissolving crude 62(250mg) and isopropyl oxazolidinone (200mg) in acetonitrile (5mL), adding triethylamine (400mg) to the reaction system, raising the temperature of the system to 85 ℃, reacting for 8H, adding water (10mL) to the reaction system, extracting with ethyl acetate (3X 20mL), drying over anhydrous sodium sulfate, spin-drying the organic phase, and subjecting the crude product to column chromatography to obtain ESI-MS (M + H325) as a white solid
And step 63:
Figure BDA0001579804270000341
dissolving compound 63(0.2g) in tetrahydrofuran (4mL), water (1mL) and methanol (1mL), adding lithium hydroxide monohydrate (150mg) into the reaction system at room temperature, reacting at 40 ℃ for 5H, adjusting the pH value of the system to 3-4 with 1N hydrochloric acid, extracting with ethyl acetate (3X 15mL), drying over anhydrous sodium sulfate, and spin-drying the organic phase to obtain yellow solid 64(80mg) ESI-MS (M + H311)
Step 64:
Figure BDA0001579804270000342
dissolving compound 64(90mg), triethylamine (80mg) and 3, 4-difluoro-1-aniline (32mg) in dichloromethane (3mL), cooling to about 5 ℃, adding TBTU (90mg) into the reaction system, reacting at room temperature for 12h, adding water (15mL), extracting with dichloromethane (3X 20mL), drying with anhydrous sodium sulfate, spin-drying the organic phase, and subjecting the crude product to column chromatography (petroleum ether: ethyl acetate 1:3) to obtain compound 70a (10mg)
Example 39: synthesis of Compound 70b
Figure BDA0001579804270000343
Compound 64b was prepared according to steps 61-63 of example 38, except that in step 62, the isopropyl oxazolidinone was replaced with trifluoroisopropyl oxazolidinone.
According to step 64 of example 38, only compound 64b was used instead of compound 64, and the other conditions were unchanged, the title product 70b (5mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 3).
Example 40: synthesis of Compound 70c
Figure BDA0001579804270000344
Compound 64c was prepared according to steps 61-63 of example 38, except that tert-butyl oxazolidinone was used in place of isopropyl oxazolidinone in step 62.
According to step 64 of example 38, only compound 64c was used instead of compound 64, and the other conditions were unchanged, the title product 70c (6mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 3).
Example 41: synthesis of Compound 70d
Figure BDA0001579804270000351
Compound 64d is prepared by reference to steps 61-63 of example 38, except that in step 62 hydroxyisopropyloxazolidinone is used instead of isopropyloxazolidinone.
According to step 64 of example 38, only compound 64d was used in place of compound 64, and the other conditions were unchanged, the title product 70d (5mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 3).
Example 42: synthesis of Compound 70e
Figure BDA0001579804270000352
Compound 64e was prepared according to steps 61-63 of example 38, except that in step 62, the isopropyl oxazolidinone was replaced with trifluoroisopropyl oxazolidinone.
According to step 64 of example 38, only compound 64e was used instead of compound 64, 3, 4-difluoro-1-aniline was used instead of 3, 4-difluoro-1-aniline, and column chromatography was performed (n-heptane: ethyl acetate ═ 1:3) for target product 70e (8mg) under the same conditions.
Example 43: synthesis of Compound 70f
Figure BDA0001579804270000353
Compound 64f is prepared by reference to steps 61-63 of example 38, except that in step 61, the isopropyl oxazolidinone is replaced with trifluoroisopropyl oxazolidinone.
According to step 64 of example 38, only compound 64f was used instead of compound 64, 3, 4-difluoro-1-aniline was used instead of 3-cyano-4-fluoro-1-aniline, and column chromatography was performed (n-heptane: ethyl acetate ═ 1:3) for the objective product 70f (11mg) under other conditions.
The synthesis of compounds of class 80 is as follows:
example 44: synthesis of Compound 80a
Figure BDA0001579804270000361
Step 71:
Figure BDA0001579804270000362
D) dissolving the compound 71(300mg) in concentrated hydrochloric acid (1.35mL), cooling to-5 ℃, uniformly stirring, then dropwise adding an aqueous solution of sodium nitrite (100mg) into the reaction system, and stirring for 0.5 h.
E) Tin dichloride (729mg) was dissolved in concentrated hydrochloric acid and dissolved down to 0 ℃ with stirring.
F) The reaction liquid A) is dripped into the reaction liquid B), the reaction system is controlled to be about 0 ℃, and 0 ℃ reacts for 0.5h after dripping.
Water (15mL) was added to the reaction system, extracted with ethyl acetate (3X 20mL) and dried to give yellow solid 72(250mg) which was directly subjected to the next reaction. ESI-MS (M + H205)
Step 72:
Figure BDA0001579804270000363
crude 72(250mg) and isopropyloxazolidinone (200mg) were dissolved in acetonitrile (5mL), triethylamine (400mg) was added to the reaction system, the temperature was raised to 85 ℃ and the reaction was carried out for 8 hours, water (10mL) was added to the reaction system, ethyl acetate (3X 20mL) was extracted, dried over anhydrous sodium sulfate, the organic phase was dried by rotary evaporation, and the crude product was subjected to column chromatography to give ESI-MS as a white solid (200mg), (M + H. 326)
Step 73:
Figure BDA0001579804270000364
dissolving compound 73(0.2g) in tetrahydrofuran (4mL), water (1mL) and methanol (1mL), adding lithium hydroxide monohydrate (150mg) into the reaction system at room temperature, reacting at 40 ℃ for 5H, adjusting the pH value of the system to 3-4 with 1N hydrochloric acid, extracting with ethyl acetate (3X 15mL), drying over anhydrous sodium sulfate, and spin-drying the organic phase to obtain yellow solid 74(80mg) ESI-MS (M + H ═ 312)
Step 74:
Figure BDA0001579804270000371
dissolving compound 74(90mg), triethylamine (80mg), and 3, 4-difluoro-1-aniline (32mg) in dichloromethane (3mL), cooling to about 5 ℃, adding TBTU (90mg) into the reaction system, reacting at room temperature for 12h, adding water (15mL), extracting with dichloromethane (3X 20mL), drying with anhydrous sodium sulfate, spin-drying the organic phase, and subjecting the crude product to column chromatography (petroleum ether: ethyl acetate 1:3) to obtain compound 80a (10mg)
Example 45: synthesis of Compound 80b
Figure BDA0001579804270000372
Compound 74b is prepared by reference to steps 71-73 of example 44, except that in step 72, trifluoroisopropyloxazolidinone is used in place of isopropyloxazolidinone.
According to step 74 of example 44, only compound 74b was used instead of compound 74, and the other conditions were unchanged, the title product 80b (5mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 3).
Example 46: synthesis of Compound 80c
Figure BDA0001579804270000373
Compound 74c can be prepared by reference to steps 71-73 of example 44, except that tert-butyl oxazolidinone is used in place of isopropyl oxazolidinone in step 72.
According to step 74 of example 44, only compound 74c was used instead of compound 74, and the other conditions were unchanged, the title product 80c (6mg) was subjected to column chromatography (n-heptane: ethyl acetate ═ 1: 3).
Example 47: synthesis of Compound 80d
Figure BDA0001579804270000381
Compound 74d is prepared by reference to steps 71-73 of example 44, except that hydroxyisopropyloxazolidinone is used in place of isopropyloxazolidinone in step 72.
According to step 74 of example 44, only compound 74d was used in place of compound 74 and the other conditions were unchanged, the title product 80d (5mg) was purified by column chromatography (n-heptane: ethyl acetate ═ 1: 3).
Example 48: synthesis of Compound 80e
Figure BDA0001579804270000382
Compound 74e was prepared by reference to steps 71-73 of example 44, except that in step 72, trifluoroisopropyloxazolidinone was used instead of isopropyloxazolidinone.
According to step 74 of example 44, only compound 74e was used instead of compound 74, 3, 4-difluoro-1-aniline was used instead of 3-chloro-4-fluoro-1-aniline, and column chromatography was performed (n-heptane: ethyl acetate ═ 1:3) for target product 80e (8mg) under the same conditions.
Example 49: synthesis of Compound 80f
Figure BDA0001579804270000383
Compound 74f was prepared by reference to steps 71-73 of example 44, except that in step 71, the isopropyl oxazolidinone was replaced with trifluoroisopropyl oxazolidinone.
According to step 74 of example 44, only compound 74f was used instead of compound 74, 3, 4-difluoro-1-aniline was used instead of 3-cyano-4-fluoro-1-aniline, and column chromatography was performed (n-heptane: ethyl acetate ═ 1:3) for target product 80f (11mg) under other conditions.
Biological examples- -anti-HBV Activity assay
Experiment one: in vitro anti-hepatitis B virus nucleocapsid assembly activity test method
Main reagents and raw materials:
c150 protein is expressed and purified by the pharmaceutical Mingkuda company;
Figure BDA0001579804270000384
purchased from semer feishell technologies.
Protein fluorescence labeling:
to each well of the 96-well plate, 150. mu.L of 2% w/v skim milk was added and incubated at room temperature for 2 hours. Sucking off the skimmed milk, washing with deionized water, drying, and storing at room temperature. The C150 protein (3 mg per tube) was desalted using a 5ml Hitrap desalting column. 50mM was added to the desalted C150 protein per tube
Figure BDA0001579804270000385
20 μ l of the fluorescent dye was mixed well and incubated overnight at 4 ℃ in the dark. The fluorescent dye not bound to C150 was removed by Sephadex G-25 gel filtration. The fluorescence labeling efficiency of C150 was calculated as follows:
Figure BDA0001579804270000391
Figure BDA0001579804270000392
Figure BDA0001579804270000393
wherein the content of the first and second substances,
Figure BDA0001579804270000394
indicates the concentration of the fluorescent label;
[ C150Bo ] indicates the concentration of the fluorescent-labeled protein;
a504 represents the absorbance at wavelength 504 nM;
a280 represents the absorbance at a wavelength of 280 nM;
M-1represents the reciprocal of the molar concentration.
Compound dilution:
compound stock was diluted to 6mM in DMSO and then to 600. mu.M in 50mM HEPES, followed by a further 3-fold serial dilution of 8 concentrations in 10% DMSO/50mM HEPES.
C150Bo was diluted to 2. mu.M with 50mM HEPES. Compounds were added to 96-well plates at 37.5 μ L C150Bo and 2.5 μ L of each concentration and mixed well and incubated for 15 minutes at room temperature. Mu.l of 750mM NaCl/50mM HEPES was added to the reaction wells at a final concentration of 150mM NaCl.
Control wells were assembled with 0% protein, and 10. mu.L of 50mM HEPES, NaCl at a final concentration of 0mM, was added.
100% protein assembly control wells, 10. mu.L of 5M NaCl/50mM HEPES, 1M NaCl final concentration.
The final DMSO concentration was 0.5%, the maximum final concentration of the compound was 30. mu.M, and the final concentration of C150Bo was 1.5. mu.M. Incubate at room temperature for 1 hour. The fluorescence signal was measured (excitation 485 nm; emission 535 nm).
Data analysis
% protein assembly [ 1- (sample fluorescence-1M NaCl fluorescence)/(0M NaCl fluorescence-1M NaCl fluorescence) ] × 100.
IC50The values were calculated by prism software, the equation is as follows:
Y＝Bottom+(Top-Bottom)/(1+10((LogIC50-X)*HillSlope))；
wherein the content of the first and second substances,
x represents the log of the concentration, Y represents the effect value, and Y fits to the top in sigmoid form starting from the bottom;
bottom represents the Bottom of the curve;
top indicates Top of the curve;
HillSlope denotes: absolute value of the maximum slope of the curve.
Experiment two: determination of anti-hepatitis B Virus Activity in HepG2.2.15 cells
The main reagents are as follows:
QIAamp 96DNA blood kit (12) (Qiagen, cat # 51162);
FastStart Universal Probe Master (Roche, cat # 04914058001);
cell-titer Glo detection reagent (Promega, cat # G7573).
Compound dilution: in vitro anti-HBV activity experiments and cytotoxicity experiments all compounds were serially diluted 3-fold at 8 concentrations. The final starting concentration of test compound was 30 μ M, the final starting concentration of reference compound GLS4 was 1 μ M, and the final concentration of DMSO was 0.5%.
HepG2.2.15 cell (4X 10)4Cells/well) to 96-well plates at 37 ℃, 5% CO2The culture was carried out overnight. The following day, fresh medium containing different concentrations of the compounds was added to the culture wells. On the fifth day, old culture medium was aspirated from the culture wells, and fresh culture medium containing different concentrations of compounds was added.
And eighthly, collecting the supernatant in the culture hole for extracting HBV DNA in the supernatant, and detecting the HBV DNA content in the HepG2.2.15 supernatant by qPCR. And after collecting the supernatant, adding a culture medium and a Cell-titer Glo reagent into the culture wells, and detecting chemiluminescence values of the wells by using an enzyme-labeling instrument.
The activity calculation formula is as follows:
Y＝Bottom+(Top-Bottom)/(1+10((LogIC50-X)*HillSlope))；
wherein the content of the first and second substances,
x represents the log of the concentration, Y represents the effect value, and Y fits to the top in sigmoid form starting from the bottom;
bottom represents the Bottom of the curve;
top represents the Top of the curve;
HillSlope denotes: absolute value of the maximum slope of the curve.
Experiment three: cytotoxicity assays
The cytotoxicity of test compounds was tested using HepG2 cells, which were incubated for 4 days in the presence of test compounds. Cell viability was assessed using the resazurin assay.
The results show that: the compound of the invention has good in vitro anti-hepatitis B virus nucleocapsid assembly activity and anti-hepatitis B virus activity and low cytotoxicity.
The activity data for experiments one to three are shown in table 2:
TABLE 2
Figure BDA0001579804270000401
Figure BDA0001579804270000411
In the table:
+ + + + + denotes IC50Or EC50<1μM；
+ denotes IC50Or EC501 to 100 μ M;
+ denotes IC50Or EC50Is composed of>100μM；
Wherein the control compound is:
Figure BDA0001579804270000421
(see WO2014184350A 1).
Experiment four: pharmacokinetic evaluation in rats
8 male Sprague-Dawley rats, 7-8 weeks old, weighing about 210g, divided into 2 groups of 4 rats each, given a single oral dose of 3mg/kg (a) control group: a positive control compound, or (b) a test group: table 2 individual compounds are compared for their pharmacokinetic differences.
Rats were fed with standard feed and given water. Fasting began 16 hours prior to the experiment. The drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the orbit at 0.083 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr and 24 hr post-dose.
The rats were briefly anesthetized after ether inhalation and 300 μ L of blood was collected from the orbit into a test tube. In the test tube there was 30. mu.L of 1% heparin salt solution. Before use, the tubes were dried overnight at 60 ℃. After completion of blood sample collection at a subsequent time point, rats were sacrificed after ether anesthesia.
Immediately after blood collection, the tubes were gently inverted at least 5 times to ensure mixing and then placed on ice. The blood samples were centrifuged at 5000rpm for 5 minutes at 4 ℃ to separate the plasma from the erythrocytes. Pipette out 100 μ L of plasma into a clean plastic centrifuge tube, indicating the name of the compound and the time point. Plasma was stored at-80 ℃ before analysis. The concentration of the compounds of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
As can be seen from the test results, the compound of the present invention has better pharmacokinetics in animals compared with the control group, and the compound of the present invention has the advantages of average increase of 15-100% in AUC and 10-100% in Cmax compared with the control group, thereby having better pharmacodynamics and therapeutic effects.
Experimental five solubility test
The compounds 10f, 60f and the positive control compound were tested for solubility change by dissolution assay.
Figure BDA0001579804270000422
Figure BDA0001579804270000431
Positive control compound
The test method comprises the following steps: at room temperature (20 ℃), 50mg of each of the compounds 10f, 60f and the positive control compound were added to 2mL of the corresponding solvent, and after stirring, the supernatant was taken and the solubility was measured by HPLC, the results are shown in the following table (unit: mg/mL):
solvent(s) 10f 60f Positive control compound
Deionized water 0.015 0.012 0.002
Methanol 3.1 3.0 2.2
Ethanol 2.5 2.2 1.8
Acetone (II) 2.9 2.5 2.0
Trichloromethane 1.2 1.0 0.8
Petroleum ether (boiling range: 60-90 deg.C) <0.001 <0.001 <0.001
As can be seen from the above table, the water solubility of the compounds 10f and 60f of the present invention is significantly increased, while the lipid solubility is decreased. Such solubility changes can have a beneficial effect on problems such as absorption of the drug in the body and choice of dosage form.
The results show that: the compound of the present invention has excellent in vitro anti-hepatitis B virus nucleocapsid assembly activity and anti-hepatitis B virus activity and lower cytotoxicity, and shows superior solubility and good pharmacokinetic properties to those of a reference compound.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (9)

1. A compound of formula A, or a pharmaceutically acceptable salt thereof,
Figure FDA0003370674920000011
the compound of the formula A has a structure shown as the following formula A-1 or A-2:
Figure FDA0003370674920000012
wherein the content of the first and second substances,
R1selected from the group consisting of: substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C3-C10A cycloalkyl group; the R is1Wherein said substitution means substitution with one or more substituents selected from the group consisting of: -OH, halogen;
w is selected from the group consisting of: -SO2-；
Ring C is a substituted or unsubstituted pyrrole or pyrazole ring; in the ring C, the substitution means being substituted with one or more substituents selected from the group consisting of: c1-C3Alkyl radical, C1-C3Haloalkyl, -CN, or halogen;
ring B is phenyl;
Ra、Rb、Rcand RdIs a substituent at any position on the ring B, each of which is independently selected from the group consisting of: H. halogen, -CN, substituted or unsubstituted C1-C8An alkyl group;
in the Ra, Rb, Rc, Rd, the "substituted" means substituted with one or more substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -CN;
and when the compound is a-2, n is 2 and p ═ 0; or n is 1 and p is 2; and Z is Cl;
when the compound is a-1, p ═ 0 and n ═ 2; and-X-Y-Z-together form-CH2-CH ═ CH-or (CH)2)3；
"- - -" represents a bond or is absent.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is
Figure FDA0003370674920000013
Wherein R is4Is H, -C1-C3An alkyl group; r6Selected from H, methyl, -CN or halogen.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R isa、Rb、RcAnd RdIs a substituent at any position on the ring B, each of which is independently selected from the group consisting of: H. halogen, -CN.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure FDA0003370674920000021
Figure FDA0003370674920000031
Figure FDA0003370674920000041
5. a process for preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: when the compound of formula a is of formula IX-1, the method comprises the steps of:
Figure FDA0003370674920000051
in various forms, ring C, R1Ring B, Ra、Rb、RcAnd RdIs as defined in claim 1;
z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, or H;
m is 0;
when the compound of formula a is a compound of formula VIII-2, the method comprises the steps of:
Figure FDA0003370674920000052
in various forms, ring C, R1Ring B, Ra、Rb、RcAnd RdIs as defined in claim 1;
z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, or H;
m is 0;
when the compound of formula a is a compound of formula V-3, the method comprises the steps of:
Figure FDA0003370674920000061
in various forms, ring C, R1Ring B, Ra、Rb、RcAnd RdIs as defined in claim 1;
z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, or H;
when the compound of formula a is of formula VI-4, the method comprises the steps of:
Figure FDA0003370674920000062
in various forms, ring C, R1Ring B, Ra、Rb、RcAnd RdIs as defined in claim 1;
z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, or H.
6. A pharmaceutical composition comprising (1) a compound of claim 1, or a pharmaceutically acceptable salt thereof; and (2) a pharmaceutically acceptable carrier.
7. An intermediate compound represented by the formula:
Figure FDA0003370674920000063
Figure FDA0003370674920000071
wherein R1 and ring C are as defined in claim 1;
z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, or H;
m is 0.
8. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for the preparation of a medicament for the prevention and/or treatment of hepatitis b virus infection.
9. An inhibitor of hepatitis b virus comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105102451A (en) * 2013-04-03 2015-11-25 爱尔兰詹森科学公司 N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
CN105452220A (en) * 2013-05-17 2016-03-30 爱尔兰詹森科学公司 Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
CN105980378A (en) * 2014-02-06 2016-09-28 爱尔兰詹森科学公司 Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
WO2017001655A1 (en) * 2015-07-02 2017-01-05 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis b

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105102451A (en) * 2013-04-03 2015-11-25 爱尔兰詹森科学公司 N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
CN105452220A (en) * 2013-05-17 2016-03-30 爱尔兰詹森科学公司 Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
CN105980378A (en) * 2014-02-06 2016-09-28 爱尔兰詹森科学公司 Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
WO2017001655A1 (en) * 2015-07-02 2017-01-05 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis b

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