CN110437232B - Bicyclourea nucleocapsid inhibitor and pharmaceutical use thereof - Google Patents
Bicyclourea nucleocapsid inhibitor and pharmaceutical use thereof Download PDFInfo
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- CN110437232B CN110437232B CN201810422131.7A CN201810422131A CN110437232B CN 110437232 B CN110437232 B CN 110437232B CN 201810422131 A CN201810422131 A CN 201810422131A CN 110437232 B CN110437232 B CN 110437232B
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- 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
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- 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
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- 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
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- 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
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- 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
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- 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
Abstract
The present invention relates to a bicyclic nucleocapsid inhibitor and its use as a medicament for the treatment of 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
Technical Field
The invention belongs to the field of medicines, and particularly relates to an aryl-fused cyclic amide 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) have been identified as a class of HBV inhibitors in tissue culture as well as in animal models. 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 an HBV inhibitor with high potency and lower toxicity.
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,
wherein, the B ring is a substituted or unsubstituted 8-20 membered bicyclic fused ring structure; wherein said substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: halogen, -CN, hydroxy, amino, carboxyl, - (C ═ O) -substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl having 1 to 3 heteroatoms selected from the following group of N, S and O, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5-to 10-membered heteroaryl having 1 to 3 heteroatoms selected from the following group of N, S and O;
ring C is a substituted or unsubstituted 5-12 membered ring;
R1、R2each independently selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl (including monocyclic, fused, or bridged ring structures), substituted or unsubstituted 3-10 membered heterocyclyl (including monocyclic, fused, or bridged ring structures) having 1-3 heteroatoms selected from N, S and O, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group N, S and O;
or R1、R2Together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-10 membered heterocyclic group (including monocyclic, fused or bridged ring structures) having 1N and 0-3 heteroatoms selected from N, S and O;
R4、R5and R6Each independently is a substituent at any position on the C ring selected from the group consisting of: hydrogen, halogen, -CN, hydroxyl, amino, carboxyl, - (C ═ O) -substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl having 1 to 3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted C having 1 to 3 heteroatoms selected from the group consisting of N, S and O5-10 membered heteroaryl of a heteroatom selected from the group consisting of N, S and O;
x is NR9(ii) a Wherein R is9Is hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl; wherein "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -CN, hydroxyl, amino, carboxyl;
y is carbonyl (- (CO) -);
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, 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-C1-C6 alkyl, amino, carboxy, C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, unsubstituted or substituted with a substituent selected from the group consisting of: halogen, phenyl.
In another preferred embodiment, the compound is not a compound selected from the group consisting of:
in another preferred embodiment, the 3-10 membered heterocyclic group is selected from the group consisting of: monocyclic group, bicyclic group, condensed ring group, bridged ring group, spiro ring group.
In another preferred embodiment, the C ring is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-7 membered heteroaromatic ring.
In another preferred embodiment, the ring B is a five-membered ring.
In another preferred embodiment, the B ring is a five-membered and six-membered ring.
In another preferred embodiment, the ring B is a six-membered and six-membered ring.
In another preferred embodiment, the B ring is a five-membered and seven-membered ring.
In another preferred embodiment, the B ring is a saturated ring, a partially unsaturated ring or an aromatic ring.
In another preferred embodiment, the C ring is a 5-7 membered ring.
In another preferred embodiment, the C ring is a benzene ring.
In another preferred embodiment, each chiral center in the compound of formula I is independently R-or S-form.
In another preferred embodiment, R is4、R5And R6Each independently is a substituent at any position on the C ring selected from the group consisting of: hydrogen, halogen, -CN, hydroxy, amino, carboxy, substituted or unsubstituted C1-C8 alkyl.
In another preferred embodiment, the compound has the structure shown in formula I below:
wherein, W1Selected from the group consisting of: CR10R11、CR10O, S, or NR12；
W2Selected from the group consisting of: CR10Or N;
W3is CR10R11、CR10N or NR12；
n is 0, 1 or 2;
the dotted line is a bond or nothing;
R10and R11Each independently is a substituent selected from the group consisting of: hydrogen, halogen, -CN, hydroxyl, amino, carboxyl, - (C ═ O) -substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl having 1 to 3 heteroatoms selected from the following group N, S and O, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5 to 10-membered heterocycloalkyl having 1 to 3 heteroatoms selected from the following group N, S and OA membered heteroaryl group;
R12each independently is a substituent selected from the group consisting of: hydrogen, -CN, hydroxyl, amino, carboxyl, - (C ═ O) -substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl having 1 to 3 heteroatoms selected from the following group of N, S and O, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5-to 10-membered heteroaryl having 1 to 3 heteroatoms selected from the following group of N, S and O;
R3is one or more (preferably 1,2,3, 4 or 5) substituents on the fused ring structure selected from the group consisting of: H. halogen, -CN, hydroxyl, amino, carboxyl, - (C ═ O) -substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl having 1 to 3 heteroatoms selected from the following group of N, S and O, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5-to 10-membered heteroaryl having 1 to 3 heteroatoms selected from the following group of N, S and O.
In another preferred example, when n ═ 2, the compound has the structure shown in formula a2 below:
in another preferred embodiment, R3Is one or more substituents on the fused ring structure selected from the group consisting of: H. halogen, -CN, hydroxy, amino, carboxy, - (C ═ O) -substituted or unsubstituted C1-C4 alkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylamino, C1-C4 alkoxy.
In another preferred embodiment, the compound is selected from the group consisting of formula A-1, A-2, A-3, or A-4:
W1is CR10R11S, O or NR12；W2Is CR10Or N; w3Is N or NR12；W4Is CR11Or (- (CO) -).
In another preferred embodiment, the compound has a structure selected from the group consisting of I, II, III, IV, V, VI, VII, VIII, IXX, XI:
wherein R is selected from the group consisting of: halogen, C1-C4 alkyl.
In another preferred embodiment, the C ring is a 5-7 membered ring.
In another preferred embodiment, the C ring is a saturated ring, a partially unsaturated ring or an aromatic ring.
In another preferred embodiment, R is1Is halogenated or C1-C4 alkyl substituted by hydroxyl, and the R is2Is H.
In another preferred embodiment, the compound is selected from the compounds described in table 1.
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising (1) 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; 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 third aspect of the present invention, there is provided a use of the 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 the pharmaceutical composition according to the second aspect of the present invention, for the preparation of a medicament for the prophylaxis and/or treatment of hepatitis b virus infection.
In a fourth 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 a fifth aspect of the present invention, there is provided a process for preparing 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, wherein the compound of formula a is represented by formula XIII-1, the process comprising the steps of:
reaction of a compound of formula A1 with a compound of formula A2 in an inert solvent affords a compound of formula A.
In another preferred embodiment, the compound of formula a is a compound of formula X-2, said method comprising the steps of:
in a sixth 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 second aspect of the invention.
In a seventh aspect of the present invention, there is provided a method for inhibiting hepatitis b virus in vitro, 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. 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 having 2 to 6 carbonsStraight or branched alkynyl groups of 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, for example, phenyl or naphthyl 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.
In another preferred embodiment, the B ring, C ring, X, Y, R1、R2、R4、R5And R6Each independently is a group corresponding to each compound in table 1.
Preferred compounds of the invention are shown in table 1:
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
) 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 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 by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
The following examples are each a synthesis of class 100 compounds:
EXAMPLE 1 Synthesis of Compound 100a
Step 1:
87(50mg) was dissolved in acetonitrile (3ml), and triethylamine (50mg) was added to the solution to react at 80 ℃ with 99(60 mg). After the reaction was completed, the reaction mixture was spun dry and then passed through a column (heptane: EA: 3:1)10 mg. ESI-MS (M + H451)
Following the synthesis procedure of example 1, the following 100 classes of compounds were synthesized:
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;
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
FL fluorescent dye 20. mu.l is mixed evenly 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:
[
FL]＝A504/78,000M-1；
[C150Bo]＝(A280-[
FL]x 1300M-1)/60,900M-1；
efficiency of fluorescent marking ═ 2
FL]/[C150Bo]；
Wherein the content of the first and second substances,
[
FL]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-1to representReciprocal of 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-1 MNaCl 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.
It can be seen that the compounds of the present application have excellent anti-hepatitis b virus activity.
The activity data for experiments one to three are shown in table 2:
TABLE 2
Wherein, in the second column of the table:
+ + + + + denotes IC50<1μM；
+ denotes IC501 to 100 μ M;
+ denotes IC50Is composed of>100μM。
In the third column of the table:
+ + + + + denotes EC50<0.1nM；
+ means EC50 0.1～100nM；
+ denotes EC50100-1000 nM;
+ denotes EC50Is composed of>1000nM。
It can be seen that the compounds of the present application have excellent anti-hepatitis b virus activity.
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,
the compound of the formula A has a structure shown in a formula I:
wherein the content of the first and second substances,
ring C is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-7 membered heteroaromatic ring;
R1、R2each independently selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O; or R1、R2Together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-10 membered heterocyclic group having 1N and 0-3 heteroatoms selected from N, S and O;
R4、R5and R6Each independently is a substituent at any position on the C ring selected from the group consisting of: hydrogen, halogen, -CN, hydroxy, amino, carboxy, substituted or unsubstituted C1-C8 alkyl;
x is NR9(ii) a Wherein R is9Is hydrogen, substituted or unsubstituted C1-C8 alkyl; wherein, the "substituted" means substituted with one or more substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -CN, hydroxyl, amino, carboxyl;
y is carbonyl (- (CO) -);
W1selected from the group consisting of: CR10；
W2Selected from the group consisting of: n;
W3is CH2；
n is 0, 1 or 2;
R10is a substituent selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C8 alkyl;
R3is one or more substituents on the fused ring structure selected from the group consisting of: H. halogen, -CN, hydroxy, amino, carboxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl;
unless otherwise specified, the term "substituted" means substituted with one or more 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-C1-C6 alkyl, amino, carboxy, C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, unsubstituted or substituted with a substituent selected from the group consisting of: halogen, phenyl.
2. A compound of claim 1 wherein R is3Is H.
3. The compound of claim 1, wherein the compound has a structure selected from the group consisting of VII, IV, and VI:
wherein R is selected from the group consisting of: halogen, C1-C4 alkyl.
4. A compound of claim 1 wherein R is1Is halogenated or C1-C4 alkyl substituted by hydroxyl, and the R is2Is H.
5. The compound of claim 1, wherein said compound is selected from the group consisting of:
6. a pharmaceutical composition comprising (1) a compound of claim 1, or a pharmaceutically acceptable salt thereof; and (2) a pharmaceutically acceptable carrier.
7. 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.
8. An inhibitor of hepatitis b virus comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof.
9. A process for preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising the steps of:
reacting a compound of formula A-1 with a compound of formula A-2 in an inert solvent to provide a compound of formula A.
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| WO2006093518A2 (en) * | 2004-06-25 | 2006-09-08 | Apath, Llc | Thienyl compounds for treating virus-related conditions |
| WO2017198744A1 (en) * | 2016-05-20 | 2017-11-23 | F. Hoffmann-La Roche Ag | Novel pyrazine compounds with oxygen, sulfur and nitrogen linker for the treatment of infectious diseases |
| CN107735400A (en) * | 2015-07-02 | 2018-02-23 | 爱尔兰詹森科学公司 | Cyclisation sulfamoyl aryl amide derivatives and its purposes as the medicine for treating hepatitis B |
| WO2018039531A1 (en) * | 2016-08-26 | 2018-03-01 | Gilead Sciences, Inc. | Substituted pyrrolizine compounds and uses thereof |
| WO2018052967A1 (en) * | 2016-09-13 | 2018-03-22 | Arbutus Biopharma, Inc. | Substituted chromane-8-carboxamide compounds and analogues thereof, and methods using same |
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| US11591334B2 (en) * | 2017-05-04 | 2023-02-28 | Shanghai Longwood Biopharmaceuticals Co., Ltd. | Substituted pyrrolizines for the treatment of hepatitis B |
| CN110437232B (en) * | 2018-05-04 | 2022-04-12 | 上海长森药业有限公司 | Bicyclourea nucleocapsid inhibitor and pharmaceutical use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006093518A2 (en) * | 2004-06-25 | 2006-09-08 | Apath, Llc | Thienyl compounds for treating virus-related conditions |
| CN107735400A (en) * | 2015-07-02 | 2018-02-23 | 爱尔兰詹森科学公司 | Cyclisation sulfamoyl aryl amide derivatives and its purposes as the medicine for treating hepatitis B |
| WO2017198744A1 (en) * | 2016-05-20 | 2017-11-23 | F. Hoffmann-La Roche Ag | Novel pyrazine compounds with oxygen, sulfur and nitrogen linker for the treatment of infectious diseases |
| WO2018039531A1 (en) * | 2016-08-26 | 2018-03-01 | Gilead Sciences, Inc. | Substituted pyrrolizine compounds and uses thereof |
| WO2018052967A1 (en) * | 2016-09-13 | 2018-03-22 | Arbutus Biopharma, Inc. | Substituted chromane-8-carboxamide compounds and analogues thereof, and methods using same |
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