CN114805362A - Novel amide pyrrole compound and application thereof in medicines - Google Patents

Novel amide pyrrole compound and application thereof in medicines Download PDF

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CN114805362A
CN114805362A CN202210070695.5A CN202210070695A CN114805362A CN 114805362 A CN114805362 A CN 114805362A CN 202210070695 A CN202210070695 A CN 202210070695A CN 114805362 A CN114805362 A CN 114805362A
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butyl
compound
methyl
ethyl
radical
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任青云
刘辛昌
张英俊
王猛
冀石龙
余国森
颜光华
雷斗兴
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Sunshine Lake Pharma Co Ltd
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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
    • 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
    • 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
    • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • 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
    • C07D207/32—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/323—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • 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
    • C07D207/32—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

The invention relates to a novel amide pyrrole compound and application thereof in medicaments, in particular to application of the amide pyrrole compound as a medicament for treating and/or preventing hepatitis B virus infection or diseases caused by the hepatitis B virus infection. In particular, the invention relates to a compound shown as a general formula (I) or a stereoisomer, a tautomer, an oxynitride, a solvate and a metabolic product thereofA substance, a pharmaceutically acceptable salt or a prodrug, and the use thereof in the preparation of medicaments, in particular the use as medicaments for the treatment and/or prevention of hepatitis B virus infection or diseases caused by hepatitis B virus infection, wherein the variables are defined as in the specification.

Description

Novel amide pyrrole compound and application thereof in medicines
Technical Field
The invention belongs to the field of medicine. In particular to a novel amide pyrrole compound and application thereof as a medicament, in particular to application as a medicament for treating and/or preventing hepatitis B virus infection or diseases caused by hepatitis B virus infection. The invention also relates to a composition containing the novel amide pyrrole compound and/or other antiviral agents, and application of the composition in treating and/or preventing Hepatitis B Virus (HBV) infection or diseases caused by the hepatitis B virus infection.
Background
Hepatitis b virus belongs to the hepadnaviridae family. It can cause acute and/or persistent progressive chronic disease. Hepatitis b virus also causes many other clinical manifestations in pathological morphology-in particular chronic inflammation of the liver, cirrhosis and canceration of hepatocytes. Estimated by the world health organization, there are 20 million people worldwide infected with HBV, about 3.5 million people with chronic infection, and about 100 million people per year die of liver failure, cirrhosis, and primary hepatocellular carcinoma (HCC) due to HBV infection.
The current treatment for Chronic Hepatitis B (CHB) is mainly antiviral treatment. Interferon alpha (IFN- α) and pegylated IFN- α and 5 nucleoside (acid) analogs (lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil) were approved by the U.S. Food and Drug Administration (FDA) for clinical treatment. Interferon is an anti-HBV drug approved by FDA for the first time, and it has a virus-removing effect mainly through direct antiviral action and immune response induction, but its application is limited due to its low response rate, various side effects, high price and limitations of therapeutic subjects. The anti-HBV common point of the nucleoside (acid) drugs is that the nucleoside (acid) drugs act on virus DNA polymerase specifically, so that the nucleoside (acid) drugs have strong effect of inhibiting virus replication, and the tolerance of patients to the drugs is better than that of interferon. However, the wide long-term use of nucleotide drugs can induce the mutation of DNA polymerase to form drug resistance, which leads to the continuous emergence of drug-resistant strains, and the treatment can not achieve ideal curative effect.
Therefore, there is still a need for new drugs that can be effectively used as drugs for the treatment and/or prevention of hepatitis B.
Disclosure of Invention
The invention relates to novel amide pyrrole compounds and application thereof in preparing medicaments for treating and/or preventing HBV infection or diseases caused by HBV infection. In particular, the invention relates to a novel amide pyrrole compound and a pharmaceutically acceptable composition thereof, and the compound has the advantages of good solubility, good stability, basically no induction effect on liver drug enzymes, less toxicity and the like, and particularly has very good pharmacokinetic properties. The compound can effectively inhibit HBV infection and has good application prospect in the aspect of HBV resistance.
In one aspect, the invention relates to a compound of formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
Figure BDA0003482027340000011
wherein R is 1 Is C 1-6 Alkyl radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl radical, C 5-10 Aryl or heteroaryl of 5 to 10 ring atoms, wherein said C 1-6 Alkyl radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl radical, C 5-10 Aryl and heteroaryl of 5 to 10 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w1 Substitution;
each R 2 And R 3 Independently hydrogen, deuterium, F, Cl, Br, I, CN, amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 Haloalkyl, methoxy or ethoxy;
each R 4 、R a 、R b And R c Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C 1-4 A haloalkyl group;
ring A is
Figure BDA0003482027340000021
Wherein X is N or CR 10 (ii) a Y is O or S;
each R 11 And R 11a Independently hydrogen, deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C (═ O) O-methyl, -C (═ O) O-ethyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl radical, C 1-4 Haloalkyl or C 1-4 An alkoxy group;
each n1 and n2 is independently 1,2,3, or 4;
each R 5 、R 6 、R 7 、R 8 、R 9 And R 10 Independently is H, deuterium, CN, -C (═ O) OR 1a 、-C(＝O)NR 1b R 1c 、-C(＝O)R、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 6-10 Aryl or heteroaryl of 5 to 6 ring atoms, wherein C is 1-6 Alkyl radical, C 1-6 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 6-10 Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w2 Substitution;
each R 1a Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C 1-4 Haloalkyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C 1-4 Haloalkyl is each independently unsubstituted or substituted with 1,2,3 or 4R w1 Substitution;
each R 1b And R 1c Independently hydrogen, deuterium, -S (═ O) 2 C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl or heterocyclyl consisting of 4 to 6 ring atoms, or R 1b And R 1c Together with the nitrogen atom to which they are attached form a heterocyclic group of 3 to 7 ring atoms in which said-S (═ O) 2 C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl, heterocyclyl consisting of 4 to 6 ring atoms and heterocyclyl consisting of 3 to 7 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w3 Substitution;
each R is independently C 1-6 Alkyl radical, C 3-6 Cycloalkyl or heterocyclyl consisting of 3 to 7 ring atoms, in which said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl and heterocyclyl consisting of 3 to 7 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w4 Substitution;
each R w1 Independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -SF 6 -C (═ O) O-methyl, -C (═ O) O-ethyl, -C (═ O) O-n-propyl, -C (═ O) O-isopropyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C (═ O) O-isopropyl, n-butyl 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl, -CH 2 F、-CH 2 Cl、-CF 3 、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Phenyl, -OCF 3 、C 2-4 Haloalkoxy or C 1-4 Alkoxy, wherein the phenyl is optionally substituted with 1,2,3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, and ethoxy;
each R w2 、R w3 And R w4 Independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C (═ O) OC 1-6 Alkyl radical, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 2-6 Alkenyl radical, C 2-6 Alkynyl, carboxyl C 1-6 Alkyl radical, C 6-12 Aryl or heteroaryl of 5 to 6 ring atoms, wherein said amino, -C (═ O) OC 1-6 Alkyl radical, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 2-6 Alkenyl radical, C 2-6 Alkynyl, carboxyl C 1-6 Alkyl radical, C 6-12 Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w1 And (4) substitution.
In some embodiments, R 1 Is C 1-4 Alkyl radical, C 2-4 Alkynyl, C 2-4 Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, heteroaryl of 5 to 6 ring atoms or heteroaryl of 7 to 10 atoms, wherein C is 1-4 Alkyl radical, C 2-4 Alkynyl, C 2-4 Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, heteroaryl of 5 to 6 ring atoms and heteroaryl of 7 to 10 atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w1 Substitution;
wherein each R is w1 Have the meaning as described in the present invention. In some embodiments, R 1 Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, ethenyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl or isoquinolyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-alkynylbutyl, propargyl, or isoquinolyl, 2-alkynylbutyl, 3-alkynylbutyl, ethenyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolinyl, and isoquinolinyl, each independently unsubstituted or substituted with 1,2,3, or 4R w1 Substitution;
wherein each R is w1 Have the meaning as described in the present invention.
In some embodiments, each R is 5 、R 6 、R 7 、R 8 、R 9 And R 10 Independently is H, deuterium, CN, -C (═ O) OR 1a 、-C(＝O)NR 1b R 1c -C (═ O) R, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-butyl, isopropyl, methyl, isopropyl, or isopropyl,Sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CF 3 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, 1-alkynbutyl, 2-alkynbutyl, 3-alkynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, 1-alkynbutyl, 2-alkynbutyl, 3-alkynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently being unsubstituted or substituted by 1,2,3 or 4R w2 Substitution;
wherein each R is 1a 、R 1b 、R 1c R and R w2 Have the meaning as described in the present invention.
In some embodiments, each R is 1b And R 1c Independently hydrogen, deuterium, -S (═ O) 2 C 1-4 Alkyl radical, C 1-4 Alkyl radical, C 2-4 Alkynyl, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl or heterocyclyl consisting of 4 to 6 ring atoms, or R 1b And R 1c Together with the nitrogen atom to which they are attached form a heterocyclic group of 3 to 6 ring atoms in which said-S (═ O) 2 C 1-4 Alkyl radical, C 1-4 Alkyl radical, C 2-4 Alkynyl, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl, heterocyclyl consisting of 4 to 6 ring atoms and heterocyclyl consisting of 3 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w3 Substitution;
wherein each R is w3 Have the meaning as described in the present invention.
In some embodiments, each R is 1b And R 1c Independently hydrogen, deuterium, -S (═ O) 2 -methyl, -S (═ O) 2 -ethyl, -S (═ O) 2 -n-propyl, -S (═ O) 2 -isopropyl, -S (═ O) 2 -n-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein said-S (═ O) 2 -methyl, -S (═ O) 2 -ethyl, -S (═ O) 2 -n-propyl, -S (═ O) 2 -isopropyl, -S (═ O) 2 -n-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, ethenyl, propenyl, allyl, cyclopropylCyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl each independently unsubstituted or substituted by 1,2,3, or 4R w3 Substitution; or R 1b And R 1c Together with the nitrogen atom to which they are attached form an aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl group, wherein said aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstituted or substituted with 1,2,3 or 4R w3 Substitution;
wherein each R is w3 Have the meaning as described in the present invention.
In some embodiments, each R is independently C 1-4 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or heterocyclyl consisting of 3 to 6 ring atoms, wherein said C is 1-4 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and heterocyclyl consisting of 3 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w4 Substitution;
wherein each R is w4 Have the meaning as described in the present invention.
In some embodiments, each R is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinylIndependently of each other, is unsubstituted or substituted by 1,2,3 or 4R w4 Substitution;
wherein each R is w4 Have the meaning as described in the present invention.
In some embodiments, each R is w2 、R w3 And R w4 Independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C (═ O) OC 1-4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、C 1-4 Alkoxy radical, C 1-4 Haloalkoxy, C 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said amino, -C (═ O) OC 1-4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、C 1-4 Alkoxy radical, C 1-4 Haloalkoxy, C 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently unsubstituted or substituted with 1,2,3 or 4R w1 Substitution;
wherein each R is w1 Have the meaning as described in the present invention.
In another aspect, the invention also provides a pharmaceutical composition comprising the compound of the invention and pharmaceutically acceptable excipients.
In some embodiments, the pharmaceutical composition of the present invention further comprises an additional anti-HBV agent.
In some embodiments, the pharmaceutical composition of the invention, wherein the other anti-HBV agent is an HBV polymerase inhibitor, an immunomodulator, or an interferon.
In some embodiments, the pharmaceutical composition of the invention, wherein the other anti-HBV agent is lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, alfafenone, Alloferon, simon, cladribine, emtricitabine, famciclovir, interferon, calamin CP, intefine, interferon alpha-1 b, interferon alpha-2 a, interferon beta-1 a, interferon alpha-2, interleukin-2, mefenate, nitazoxanide, peginterferon alpha-2 a, ribavirin, roscovitine-a, cezopyran, Euforavac, azapril, Phosphazid, heplisv, interferon alpha-2 b, levamisole, or propafege.
In another aspect, the invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating a viral disease in a patient.
In some embodiments, the use of the invention, wherein the viral disease is hepatitis b virus infection or a disease caused by hepatitis b virus infection.
In still other embodiments, the use of the present invention, wherein the disease caused by hepatitis b virus infection is liver cirrhosis or hepatocellular carcinoma.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for preventing, treating or ameliorating hepatitis b disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition of the invention.
Another aspect of the invention relates to a method of preventing, treating or ameliorating HBV disorders in a patient, comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the invention.
Another aspect of the invention relates to a method of preventing, treating or ameliorating HBV disorders in a patient, comprising administering to the patient a pharmaceutically acceptable effective amount of a pharmaceutical composition comprising a compound of the invention.
Another aspect of the invention relates to the use of a compound of the invention for the preparation of a medicament for the prevention or treatment, and lessening the severity, of an HBV disorder in a patient.
Another aspect of the present invention relates to the use of a pharmaceutical composition comprising a compound of the present invention for the preparation of a medicament for preventing or treating HBV disorders in a patient, and reducing the severity thereof.
Another aspect of the present invention relates to a method of inhibiting HBV infection comprising contacting a cell with a compound or pharmaceutical composition of the present invention in an amount effective to inhibit HBV. In other embodiments, the method further comprises contacting the cell with another anti-HBV therapeutic agent.
Another aspect of the present invention relates to a method of treating HBV disease in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In still other embodiments, the method further comprises administering to the patient in need of treatment a therapeutically effective amount of another anti-HBV agent.
Another aspect of the present invention relates to a method of inhibiting HBV infection in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In still other embodiments, the method further comprises administering to the patient in need of treatment a therapeutically effective amount of an additional anti-HBV agent.
Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I) or formula (II).
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.
Detailed description of the invention
Definitions and general terms
The invention will be described in detail in the literature corresponding to the identified embodiments, and the examples are accompanied by the graphic illustrations of structural formulae and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which may be included in the field of the present invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein which can be used in the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that may be used to distinguish or contradict the present application, including, but in no way limited to, the definition of a term, the usage of a term, the technology described, or the scope as controlled by the present application.
The following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are described in the periodic table of elements, CAS version and handbook of chemicals, 75, th ed, 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausaltio: 1999, and "March's Advanced Organic Chemistry," by Michael B.Smith and Jerry March, John Wiley Chemistry&Sons, New York, 2007, the entire contents of which are hereby incorporated by reference.
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those of the general formula above, or as specifically exemplified, subclassed, and encompassed by the invention.
In each part of this specification, substituents for the compounds of the present invention are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C 1-6 Alkyl "means in particular independently disclosed methyl, ethyl, C 3 Alkyl radical, C 4 Alkyl radical, C 5 Alkyl and C 6 An alkyl group.
The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl groups may independently be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 12 carbon atoms, in other embodiments, the alkyl group contains 1 to 10 carbon atoms, in other embodiments, the alkyl group contains 1 to 8 carbon atoms, in other embodiments, the alkyl group contains 1 to 6 carbon atoms, in other embodiments, the alkyl group contains 1 to 4 carbon atoms, and in other embodiments, the alkyl group contains 1 to 3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH) 3 ) Ethyl (Et-CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) 2-methylpropyl or isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) 1-methylpropyl or sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) T-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH)) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein C-C in at least one position is sp 2 Double bonds, wherein the alkenyl groups may be independently unsubstituted or substituted with one or more substituents as described herein, include the "cis", "trans" or "Z", "E" isomers, specific examples of which include, but are not limited to, vinyl (-CH ═ CH) 2 ) Propenyl (-CH ═ CHCH) 3 ) Allyl (-CH) 2 CH＝CH 2 ) And the like, wherein the alkenyl group can be independently unsubstituted or substituted with one or more substituents described herein.
The term "alkynyl" denotes a straight or branched chain containing 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atomsWherein at least one position of C-C is an sp triple bond, and specific examples include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH) 2 C ≡ CH), propynyl (-C ≡ C-CH) 3 ) 1-alkynylbutyl (-CH) 2 CH 2 C ≡ CH), 2-alkynylbutyl (-CH) 2 C≡CCH 3 ) 3-alkynylbutyl (-C [ identical to ] CCH 2 CH 3 ) And the like, wherein the alkynyl group can be independently unsubstituted or substituted with one or more substituents described herein.
The term "haloalkyl" or "haloalkoxy" denotes an alkyl group, wherein alkyl and alkoxy have the meaning as described herein. Examples include, but are not limited to, difluoroethyl (-CH) 2 CHF 2 ,-CF 2 CH 3 ,-CHFCH 2 F) Trifluoroethyl (-CH) 2 CF 3 ,-CF 2 CH 2 F,-CFHCHF 2 ) Trifluoromethyl (-CF) 3 ) Trifluoromethoxy (-OCF) 3 ) Fluorovinyl (-CH. CHF, -CF. CH) 2 ) And the like.
The term "carboxyalkyl" denotes an alkyl group substituted with 1 or 2 carboxy substituents, wherein "carboxy" is-COOH and alkyl has the meaning described herein. Examples include, but are not limited to, -CH 2 COOH、-CH 2 CH 2 COOH、-CH 2 CH 2 CH 2 COOH、-CH 2 CH 2 CH 2 CH 2 COOH, etc.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In some embodiments, alkoxy groups contain 1 to 8 carbon atoms; in other embodiments, the alkoxy group contains 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Of alkoxy groupsExamples include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentyloxy (n-pentyloxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyloxy (-OCH (CH)) 3 )CH 2 CH 2 CH 3 ) 3-pentyloxy (-OCH (CH)) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH)) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And so on.
The term "M-M 1 Or "M-M" consisting of ring atoms 1 "consisting of atoms" means that the cyclic group consists of M-M 1 And the ring atoms comprise carbon atoms and/or heteroatoms such as O, N, S, P. For example, "heteroaryl of 6 to 10 atoms" means that it includes heteroaryl of 6, 7,8, 9 or 10 ring atoms.
The terms "carbocycle", "carbocyclyl" or "carbocyclic" are used interchangeably herein and all refer to a non-aromatic carbocyclic ring system containing from 3 to 14 ring carbon atoms that is saturated or contains one or more units of unsaturation. In some embodiments, the number of carbon atoms is 3 to 12; in other embodiments, the number of carbon atoms ranges from 3 to 10; in other embodiments, the number of carbon atoms is from 3 to 8; in other embodiments, the number of carbon atoms is from 3 to 6; in other embodiments, the number of carbon atoms is from 5 to 6; in other embodiments, the number of carbon atoms is from 5 to 8. In other embodiments, the number of carbon atoms is from 6 to 8. Such "carbocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems, and also includes polycyclic ring systems in which the carbocyclic ring may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the atom groups or points of attachment are on the carbocyclic ring. Bicyclic carbocyclyl includes bridged bicyclic carbocyclyl, fused bicyclic carbocyclyl and spirobicyclic carbocyclyl, and a "fused" bicyclic ring system contains two rings that share 2 contiguous ring atoms. The bridged bicyclic group includes two rings that share 3 or 4 adjacent ring atoms. Spiro ring systems share 1 ring atom. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Bridging carbocyclyl groups include, but are not limited to, bicyclo [2.2.2] octyl, bicyclo [2.2.1] heptyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, and the like.
The term "cycloalkyl" refers to a saturated, monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring carbon atoms, including monocyclic, bicyclic, or polycyclic fused, spiro, or bridged ring systems, having one or more points of attachment to the rest of the molecule. In some of these embodiments, cycloalkyl is spirobicycloalkyl of 6 to 10 atoms; in still other embodiments, cycloalkyl is a fused bicycloalkyl of 6 to 10 atoms; in other embodiments, cycloalkyl groups are ring systems containing from 3 to 10 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing from 3 to 8 ring carbon atoms; in other embodiments, cycloalkyl groups are ring systems containing from 3 to 7 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing from 5 to 8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing from 3 to 6 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 5 to 6 ring carbon atoms; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and the cycloalkyl groups can independently be unsubstituted or substituted with one or more substituents described herein.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic ring system containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen, and wherein the ring system has one or more attachment points to the remainder of the molecule. The term "heterocyclyl" includes monocyclic heterocyclyl, bicyclic or polycyclic fused heterocyclyl, spiro or bridged heterocyclic heterocyclyl, and also includes polycyclic ring systems in which the heterocyclic ring may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the radical or point of attachment is on the heterocyclic ring. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spiro bicyclic heterocyclic groups. Unless otherwise indicated, a-CH of a heterocyclic radical 2 -the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. In some embodiments, heterocyclyl is a ring system of 3-12 ring atoms; in some embodiments, heterocyclyl is a monocyclic heterocyclyl consisting of 4 to 7 ring atoms; in some embodiments, heterocyclyl is a monocyclic heterocyclyl consisting of 3-7 ring atoms; in some embodiments, heterocyclyl is a monocyclic heterocyclyl consisting of 4-6 ring atoms; in some embodiments, heterocyclyl is a monocyclic heterocyclyl consisting of 3-6 ring atoms; in some embodiments, heterocyclyl is a monocyclic heterocyclyl consisting of 5-6 ring atoms; in some embodiments, heterocyclyl is a fused bicyclic heterocyclyl consisting of 7-10 ring atoms; in some embodiments, heterocyclyl is a fused bicyclic heterocyclyl consisting of 8 to 10 ring atoms; in some embodiments, heterocyclyl is a bridged bicyclic heterocyclyl consisting of 6-10 ring atoms in other embodiments, heterocyclyl is a ring body consisting of 3-8 ring atomsIs a step of; in other embodiments, heterocyclyl is a ring system of 3-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-7 ring atoms; in other embodiments, heterocyclyl is a ring system of 5 to 8 ring atoms; in other embodiments, heterocyclyl is a ring system of 6-8 ring atoms; heterocyclyl is a ring system of 3 ring atoms; in other embodiments, heterocyclyl is a ring system of 4 ring atoms; in other embodiments, heterocyclyl is a ring system of 5 ring atoms; in other embodiments, heterocyclyl is a ring system of 6 ring atoms; in other embodiments, heterocyclyl is a ring system of 7 ring atoms; in other embodiments, heterocyclyl is a ring system of 8 ring atoms.
Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxetanyl, azepinyl, thietanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithienylalkyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 3H-indolylquinazinyl and N-pyridylurea. Examples of heterocyclic groups also include, 1, 1-dioxothiomorpholinyl; examples of the group in which the carbon atom on the ring is substituted with an oxo (═ O) group include, but are not limited to, pyrimidinedione group, 1,2, 4-thiadiazol-5 (4H) -one group, 1,2, 4-oxadiazol-5 (4H) -one group, 1H-1,2, 4-triazol-5 (4H) -one group and the like; examples in which the carbon atom on the ring is substituted with an ═ S group include, but are not limited to, 1,2, 4-oxadiazol-5 (4H) -thioketo, 1,3, 4-oxadiazol-2 (3H) -thioketo, and the like. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
The terms "spirocyclic", "spirobicyclic" or "spirobicyclic" are used interchangeably herein to refer to a monovalent or multivalent, saturated or partially unsaturated, nonaromatic ring system in which one ring is derived from a specific ring carbon atom on the other ring and both rings share only one atom.
For example, as described below for formula a-1, a saturated ring system (rings B and B ') is referred to as "fused bicyclic ring", while ring a' and ring B share a carbon atom and are referred to as "spiro" or "spirobicyclic ring". Each ring of the fused bicyclic and spirobicyclic groups can be a carbocyclyl or heterocyclyl and each ring is optionally substituted with one or more substituents described herein.
Figure BDA0003482027340000081
The term "fused bicyclic heterocyclyl" denotes a monovalent saturated or partially unsaturated nonaromatic fused ring system. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). Each ring in said ring system comprises 3-7 atoms and at least one ring comprises one or more heteroatoms, i.e. 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give compounds like SO, SO 2 ，PO，PO 2 In some embodiments, the fused bicyclic heterocyclic group is a fused bicyclic heterocyclic group consisting of 7 to 10 ring atoms; in some embodiments, a fused bicyclic heterocyclyl is a fused bicyclic heterocyclyl consisting of 8-10 ring atoms; examples include, but are not limited to, 3-azafused [3.1.0]Hexane, 3-azabicyclo [3.3.0]Octane, hexahydro-furan [3,4-c ]]Pyrrolyl, hexahydro-thiophen [3,4-c ]]Pyrrolyl, 3,4,5, 6-tetrahydro-cyclopentane [ c ]]Thienyl, and the like. Said fused heterobicyclic group being optionally substituted by one or moreSubstituted by the substituents described in the invention.
The term "bridged bicyclic group" denotes a saturated or partially unsaturated non-aromatic bridged ring system, as shown in formula b, i.e. ring a1 shares an alkyl or a heteroalkyl chain with ring a2, wherein j is 1,2,3 or 4. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or aromatic rings (although aromatics may be substituents thereon). Wherein each ring, such as A1 or A2, contains 3 to 7 atoms, examples of which include, but are not limited to, bicyclo [2.2.1] heptanyl, 2-methyl-diazabicyclo [2.2.1] heptanyl, and the like. The bridged bicyclic group is optionally substituted with one or more substituents described herein.
Figure BDA0003482027340000082
The term "bridged carbocyclyl" refers to a saturated or partially unsaturated nonaromatic bridged bicyclic ring system wherein each ring contains 3 to 7 carbon atoms, examples of which include, but are not limited to, bicyclo [2.2.1] heptanyl and the like. The bridged bicyclic group is optionally substituted with one or more substituents described herein.
The term "bridged bicyclic heterocyclyl" denotes a saturated or partially unsaturated, non-aromatic bridged bicyclic ring system wherein each ring contains 3 to 7 atoms and at least one ring contains one or more heteroatoms, i.e. 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give a structure like SO, SO 2 ，PO，PO 2 In some embodiments, bridged bicyclic heterocyclic groups are bridged bicyclic heterocyclic groups consisting of 6-10 ring atoms, examples of which include, but are not limited to, 2-oxo-5-azabicyclo [2.2.1]]Heptenyl, 2-thio-5-azabicyclo [2.2.1] s]Heptylalkyl, 2-oxo-5-azabicyclo [2.2.1]Heptylalkyl, 2, 5-diazabicyclo [2.2.1]Heptenyl, 2-methyl-2, 5-diazabicyclo [2.2.1]A heptalkyl group. The bridged bicyclic heterocyclic group is optionally substituted with one or more substituents described herein.
The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbon ring systems of 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 carbon atoms in the ring and one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring", e.g., aryl may include phenyl, naphthyl and anthracenyl. The aryl group can be independently unsubstituted or substituted with one or more substituents described herein.
The term "heteroaryl" may be used alone or as a majority of "heteroarylalkyl" or "heteroarylalkoxy" and refers to a monocyclic, bicyclic, or tricyclic ring system of 5 to 16 ring atoms, at least one of which is aromatic, and at least one of which contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 ring atoms, and one or more attachment points are attached to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a heteroaryl consisting of 5-14 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is heteroaryl consisting of 5 to 12 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 to 10 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 7 to 10 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 to 8 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is heteroaryl consisting of 5 to 7 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5-6 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is heteroaryl consisting of 5 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 6 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N.
In other embodiments, heteroaryl includes, but is not limited to, the following monocyclic groups: 2-furyl group, 3-furyl group, N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, pyridazinyl group (e.g., 3-pyridazinyl group), 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, tetrazolyl group (e.g., 5H-tetrazolyl group, 2H-tetrazolyl group), triazolyl group (e.g., 2-triazolyl group, 5-triazolyl group, 4H-1,2, 4-triazolyl, 1H-1,2, 4-triazolyl, 1,2, 3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bi-or tricyclic groups are also included, but are in no way limited to these groups: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), phenoxathiyl, dibenzoimidazolyl, dibenzofuranyl, or dibenzothienyl, and the like. The heteroaryl group is optionally substituted with one or more substituents described herein.
In addition, unless otherwise expressly indicated, the descriptions "… and … are each independently," "… and … are each independently" and "… and … are each independently" used throughout this document are interchangeable and should be broadly construed to mean that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.
The invention also needs to be explained
Figure BDA0003482027340000091
R in (1) 11 And R 11a Are each substituted on the pyrrole ring, i.e. R 11 May be substituted in the position of formula (I-1), R 11a Substitutions may be made at the positions of formula (I-2):
Figure BDA0003482027340000101
unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric (or conformational) isomers, such as the R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and conformational isomers of (Z), (E). accordingly, a single stereochemical isomer (e.g., enantiomer, diastereomer), or mixture of geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of the present invention.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I) or formula (II). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C) 1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。
Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "stereoschemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994. All stereoisomeric forms of the compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer can be an enantiomer, and a mixture of enantiomers is commonly referred to as a mixture of enantiomers. 50: the 50 enantiomer mixture is called racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
The term "tautomer" or "tautomeric form" means that isomers of structures of different energies may be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers that move through protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the descriptive pharmaceutical acceptable salts in detail in J. pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, which are formed by reaction with amino groups, or which are obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbic acidSalts, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and so on. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl radical) 4 A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
The term "protecting group" or "Pg" refers to a substituent that when reacted with another functional group, is typically used to block or protect a particular functionality. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups includeIncluding acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。
Description of the Compounds of the invention
The compound and the pharmaceutically acceptable composition thereof can effectively inhibit HBV infection.
In one aspect, the invention relates to a compound of formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
Figure BDA0003482027340000111
wherein R is 1 Is C 1-6 Alkyl radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl radical, C 5-10 Aryl or heteroaryl of 5 to 10 ring atoms, wherein said C 1-6 Alkyl radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl radical, C 5-10 Aryl and heteroaryl of 5 to 10 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w1 Substitution;
each R 2 And R 3 Independently hydrogen, deuterium, F, Cl, Br, I, CNAmino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 Haloalkyl, methoxy or ethoxy;
each R 4 、R a 、R b And R c Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C 1-4 A haloalkyl group;
ring A is
Figure BDA0003482027340000121
Wherein X is N or CR 10 (ii) a Y is O or S;
each R 11 And R 11a Independently hydrogen, deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C (═ O) O-methyl, -C (═ O) O-ethyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl radical, C 1-4 Haloalkyl or C 1-4 An alkoxy group;
each n1 and n2 is independently 1,2,3, or 4;
each R 5 、R 6 、R 7 、R 8 、R 9 And R 10 Independently is H, deuterium, CN, -C (═ O) OR 1a 、-C(＝O)NR 1b R 1c 、-C(＝O)R、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 6-10 Aryl or heteroaryl of 5 to 6 ring atoms, wherein C is 1-6 Alkyl radical, C 1-6 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 6-10 Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w2 Substitution;
each R 1a Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C 1-4 Haloalkyl groupWherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C are 1-4 Haloalkyl is each independently unsubstituted or substituted with 1,2,3 or 4R w1 Substitution;
each R 1b And R 1c Independently hydrogen, deuterium, -S (═ O) 2 C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl or heterocyclyl consisting of 4 to 6 ring atoms, or R 1b And R 1c Together with the nitrogen atom to which they are attached form a heterocyclic group of 3 to 7 ring atoms in which said-S (═ O) 2 C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl, heterocyclyl consisting of 4 to 6 ring atoms and heterocyclyl consisting of 3 to 7 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w3 Substitution;
each R is independently C 1-6 Alkyl radical, C 3-6 Cycloalkyl or heterocyclyl consisting of 3 to 7 ring atoms, in which said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl and heterocyclyl consisting of 3 to 7 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w4 Substitution;
each R w1 Independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -SF 6 -C (═ O) O-methyl, -C (═ O) O-ethyl, -C (═ O) O-n-propyl, -C (═ O) O-isopropyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C (═ O) O-isopropyl, n-butyl 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl, -CH 2 F、-CH 2 Cl、-CF 3 、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Phenyl, -OCF 3 、C 2-4 Haloalkoxy or C 1-4 Alkoxy, wherein the phenyl is optionally substituted with 1,2,3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, and ethoxy;
each R w2 、R w3 And R w4 Independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C (═ O) OC 1-6 Alkyl radical, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 2-6 Alkenyl radical, C 2-6 Alkynyl, carboxyl C 1-6 Alkyl radical, C 6-12 Aryl or heteroaryl of 5 to 6 ring atoms, wherein said amino, -C (═ O) OC 1-6 Alkyl radical, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 2-6 Alkenyl radical, C 2-6 Alkynyl, carboxyl C 1-6 Alkyl radical, C 6-12 Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w1 And (4) substitution.
In some embodiments, the invention relates to a compound of formula (II) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound of formula (II),
Figure BDA0003482027340000131
wherein each R is a 、R b 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 11 And n1 has the meaning stated in the present invention.
In some embodiments, R 1 Is C 1-4 Alkyl radical, C 2-4 Alkynyl, C 2-4 Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, heteroaryl of 5 to 6 ring atoms or heteroaryl of 7 to 10 atoms, wherein C is 1-4 Alkyl radical, C 2-4 Alkynyl, C 2-4 Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, heteroaryl of 5 to 6 ring atoms and heteroaryl of 7 to 10 atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w1 Substitution;
wherein each R is w1 Have the meaning described in the present invention. In some embodiments, R 1 Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, ethenyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl or isoquinolyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-alkynylbutyl, propargyl, or isoquinolyl, 2-alkynylbutyl, 3-alkynylbutyl, ethenyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolinyl, and isoquinolinyl, each independently unsubstituted or substituted with 1,2,3, or 4R w1 Substitution;
wherein each R is w1 Have the meaning as described in the present invention.
In some embodiments, each R is 5 、R 6 、R 7 、R 8 、R 9 And R 10 Independently is H, deuterium, CN, -C (═ O) OR 1a 、-C(＝O)NR 1b R 1c -C (═ O) R, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CF 3 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, 1-alkynbutyl, 2-alkynbutyl, 3-alkynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, and the like,Thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently being unsubstituted or substituted by 1,2,3 or 4R w2 Substitution;
wherein each R is 1a 、R 1b 、R 1c R and R w2 Have the meaning as described in the present invention.
In some embodiments, each R is 1b And R 1c Independently hydrogen, deuterium, -S (═ O) 2 C 1-4 Alkyl radical, C 1-4 Alkyl radical, C 2-4 Alkynyl, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl or heterocyclyl consisting of 4 to 6 ring atoms, or R 1b And R 1c Together with the nitrogen atom to which they are attached form a heterocyclic group of 3 to 6 ring atoms in which said-S (═ O) 2 C 1-4 Alkyl radical, C 1-4 Alkyl radical, C 2-4 Alkynyl, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl, heterocyclyl consisting of 4 to 6 ring atoms and heterocyclyl consisting of 3 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w3 Substitution;
wherein each R is w3 Have the meaning as described in the present invention.
In some embodiments, each R is 1b And R 1c Independently hydrogen, deuterium, -S (═ O) 2 -methyl, -S (═ O) 2 -ethyl, -S (═ O) 2 -n-propyl, -S (═ O) 2 -isopropyl, -S (═ O) 2 -n-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein said-S (═ O) 2 -methyl, -S (═ O) 2 -ethyl, -S (═ O) 2 -n-propyl, -S (═ O) 2 -isopropyl, -S (═ O) 2 -n-butyl, methyl, ethyl, n-propyl, isoPropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-alkynbutyl, 2-alkynylbutyl, 3-alkynylbutyl, ethenyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstituted or substituted by 1,2,3 or 4R w3 Substitution; or R 1b And R 1c Together with the nitrogen atom to which they are attached form an aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl group, wherein said aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstituted or substituted with 1,2,3 or 4R w3 Substitution;
wherein each R is w3 Have the meaning as described in the present invention.
In some embodiments, each R is independently C 1-4 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or heterocyclyl consisting of 3 to 6 ring atoms, wherein said C is 1-4 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and heterocyclyl consisting of 3 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w4 Substitution;
wherein each R is w4 Have the meaning as described in the present invention.
In some embodiments, each R is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, and piperazinyl is,Isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl, each independently, being unsubstituted or substituted by 1,2,3 or 4R w4 Substitution;
wherein each R is w4 Have the meaning as described in the present invention.
In some embodiments, each R is w2 、R w3 And R w4 Independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C (═ O) OC 1-4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、C 1-4 Alkoxy radical, C 1-4 Haloalkoxy, C 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said amino, -C (═ O) OC 1-4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、C 1-4 Alkoxy radical, C 1-4 Haloalkoxy, C 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently unsubstituted or substituted with 1,2,3 or 4R w1 Substitution;
wherein each R is w1 Have the meaning as described in the present invention.
In some embodiments, each R is w2 、R w3 And R w4 Independently is deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C (═ O) O-methyl, -C (═ O) O-ethyl, -C (═ O) O-n-propyl, -C (═ O) O-isopropyl, -C (═ O) O-n-butyl, -C (═ O) O-isobutyl, -C (═ O) O-sec-butyl, -C (═ O) O-tert-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF, n-butyl, C-CF-butyl, or a salt thereof 3 、-CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, -OCH 2 F、-OCF 3 、-OCH 2 Cl、-OCHF 2 、-OCHCl 2 、-OCH 2 CH 2 F、-OCH 2 CH 2 Cl、-OCH 2 CHF 2 、-OCH 2 CHCl 2 、-OCHFCH 2 F、-OCHClCH 2 Cl、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 CH 2 CH 3 、-OCH 2 CH 2 CH 2 F、-OCH 2 CH 2 CHF 2 、-OCH 2 CH 2 CF 3 、C 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said amino, -C (═ O) OC 1-4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, -OCH 2 F、-OCF 3 、-OCH 2 Cl、-OCHF 2 、-OCHCl 2 、-OCH 2 CH 2 F、-OCH 2 CH 2 Cl、-OCH 2 CHF 2 、-OCH 2 CHCl 2 、-OCHFCH 2 F、-OCHClCH 2 Cl、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 CH 2 CH 3 、-OCH 2 CH 2 CH 2 F、-OCH 2 CH 2 CHF 2 、-OCH 2 CH 2 CF 3 、C 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently unsubstituted or substituted with 1,2,3 or 4R w1 Substitution;
wherein each R is w1 Have the meaning as described in the present invention.
In another aspect, the invention encompasses structures of one of the following, or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,
Figure BDA0003482027340000151
Figure BDA0003482027340000161
Figure BDA0003482027340000171
Figure BDA0003482027340000181
Figure BDA0003482027340000191
Figure BDA0003482027340000201
Figure BDA0003482027340000211
Figure BDA0003482027340000221
Figure BDA0003482027340000231
Figure BDA0003482027340000241
Figure BDA0003482027340000251
Figure BDA0003482027340000261
Figure BDA0003482027340000271
Figure BDA0003482027340000281
Figure BDA0003482027340000291
Figure BDA0003482027340000301
Figure BDA0003482027340000311
Figure BDA0003482027340000321
Figure BDA0003482027340000331
Figure BDA0003482027340000341
in another aspect, the invention also provides a pharmaceutical composition comprising the compound of the invention and pharmaceutically acceptable excipients.
In some embodiments, the pharmaceutical composition of the present invention further comprises an additional anti-HBV agent.
In some embodiments, the pharmaceutical composition of the invention, wherein the other anti-HBV agent is an HBV polymerase inhibitor, an immunomodulator, or an interferon.
In some embodiments, the pharmaceutical composition of the invention, wherein the other anti-HBV agent is lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, alfafenone, Alloferon, simon, cladribine, emtricitabine, famciclovir, interferon, calamin CP, intefine, interferon alpha-1 b, interferon alpha-2 a, interferon beta-1 a, interferon alpha-2, interleukin-2, mefenate, nitazoxanide, peginterferon alpha-2 a, ribavirin, roscovitine-a, cezopyran, Euforavac, azapril, Phosphazid, heplisv, interferon alpha-2 b, levamisole, or propafege.
In another aspect, the invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating a viral disease in a patient.
In some embodiments, the use of the invention, wherein the viral disease is hepatitis b virus infection or a disease caused by hepatitis b virus infection.
In still other embodiments, the use of the present invention, wherein the disease caused by hepatitis b virus infection is liver cirrhosis or hepatocellular carcinoma.
In another aspect, the compounds of the present invention or the pharmaceutical compositions are used for the manufacture of a medicament for the prevention, treatment or alleviation of viral diseases in a patient.
In some embodiments, the compound of the present invention or the pharmaceutical composition is used, wherein the viral disease is hepatitis b virus infection or a disease caused by hepatitis b virus infection.
In still other embodiments, the use of the compound of the present invention or the pharmaceutical composition, wherein the disease caused by hepatitis b virus infection is liver cirrhosis or hepatocellular carcinoma.
Another aspect of the invention relates to a method of preventing, treating or ameliorating HBV disorders in a patient, comprising administering to the patient a pharmaceutically acceptable effective amount of a pharmaceutical composition comprising a compound of the invention.
In some embodiments, the method of the invention, wherein the viral disease is hepatitis b virus infection or a disease caused by hepatitis b virus infection.
In still other embodiments, the method of the present invention, wherein the disease caused by hepatitis B virus infection is liver cirrhosis or hepatocellular carcinoma.
In another aspect, the invention relates to the use of the compound or the pharmaceutical composition for the manufacture of a medicament for preventing, treating or alleviating hepatitis b disease in a patient.
Another aspect of the invention relates to a method of preventing, treating or ameliorating HBV disorders in a patient, comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the invention.
Another aspect of the invention relates to the use of a compound of the invention for the preparation of a medicament for the prevention or treatment, and lessening the severity, of an HBV disorder in a patient.
Another aspect of the present invention relates to the use of a pharmaceutical composition comprising a compound of the present invention for the preparation of a medicament for preventing or treating HBV disorders in a patient, and reducing the severity thereof.
In some embodiments, the patient is a mammal, and in other embodiments, the patient is a human. In other embodiments, the use further comprises contacting the cell with an anti-HBV therapeutic agent.
Another aspect of the present invention relates to a method of inhibiting HBV infection comprising contacting a cell with a compound or pharmaceutical composition of the present invention in an amount effective to inhibit HBV. In other embodiments, the method further comprises contacting the cell with another anti-HBV therapeutic agent.
Another aspect of the present invention relates to a method of treating HBV disease in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
In still other embodiments, the method further comprises administering to a patient in need of treatment a therapeutically effective amount of an additional anti-HBV therapeutic agent.
Another aspect of the present invention relates to a method of inhibiting HBV infection in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In still other embodiments, the method further comprises administering to the patient in need of treatment a therapeutically effective amount of an additional anti-HBV therapeutic agent.
Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I) or formula (II).
The invention also relates to the application of the compound and the pharmaceutically acceptable salt thereof in producing medical products for effectively inhibiting HBV infection and the application of the compound in producing medicaments for effectively inhibiting HBV infection. The compounds of the invention are also useful in the manufacture of a medicament for alleviating, preventing, controlling or treating a condition of hepatitis b in a patient.
Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention are within the scope of the present invention.
In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes materials or compositions which must be compatible chemically or toxicologically, with the other components comprising the formulation, and with the mammal being treated.
Salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of intermediates used in the preparation or purification of the compounds of formula (I) or formula (II) or isolated enantiomers of the compounds of formula (I) or formula (II).
If the compounds of the invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, and phosphoric acids, and the like. Or using organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid, and salicylic acid; pyranonic acids, such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, and the like, or combinations thereof.
If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium, N + (R 14 ) 4 Salts and alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary, N + (R 14 ) 4 Salts, e.g. R 14 Is H, C 1-4 Alkyl radical, C 6-10 Aryl radical, C 6-10 Aryl radical C 1-4 Alkyl, etc., and cyclic amines such as piperidine, morpholine, piperazine, etc., and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. Also included are suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, e.g. halidesCompound, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 Sulfonates and aromatic sulfonates.
Pharmaceutical compositions, formulations, administration of the compounds of the invention and uses of the compounds and pharmaceutical compositions
According to another aspect, the pharmaceutical composition of the present invention is characterized by comprising a compound represented by formula (I) or formula (II), a compound listed in the present invention, or a compound of the examples, and a pharmaceutically acceptable excipient. The compound in the pharmaceutical composition can effectively inhibit hepatitis B virus, and is suitable for treating diseases caused by virus, especially acute and chronic persistent HBV infection, chronic viral diseases caused by HBV can cause serious pathological changes, and chronic hepatitis B virus infection can cause cirrhosis and/or hepatocellular carcinoma in many cases.
For the compounds of the invention, the areas of disease treatment that may be mentioned are, for example: treatment of acute and chronic viral infections, which may lead to infectious hepatitis, e.g., hepatitis B virus infection. The compounds of the invention are particularly suitable for the treatment of chronic hepatitis B infections and acute and chronic hepatitis B virus infections.
The invention encompasses pharmaceutical preparations which, in addition to nontoxic, inert, pharmaceutically suitable adjuvants, also contain one or more compounds of the invention of the formula (I) or pharmaceutical compositions thereof.
The pharmaceutical preparation may contain other pharmaceutically active ingredients other than the compound represented by formula (I) or formula (II).
The compounds of the invention exist in free form or, where appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative that can be administered directly or indirectly in accordance with the needs of the patient, compounds described in other aspects of the invention, metabolites thereof, or residues thereof.
As described herein, the pharmaceutical composition of the present invention comprises any one of the compounds of formula (I) or formula (II) of the present invention, and further comprises pharmaceutically acceptable excipients, such as any solvent, solid excipient, diluent, binder, disintegrant, other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, and the like, as used herein, suitable for the specific intended dosage form. As described in the following documents: in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicates that different adjuvants can be used In The preparation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except insofar as any conventional adjuvant is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, their use is contemplated by the present invention.
Substances that may serve as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate esters; a wax; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphoric acid buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the coating material; a sweetener; a flavoring agent; a fragrance; preservatives and antioxidants.
Pharmaceutical compositions of the compounds of the invention may be administered in any of the following ways: oral administration, topical administration, rectal administration, nasal administration, topical administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or administration via an explanted reservoir. Preferred modes of administration are oral, intramuscular, intraperitoneal or intravenous.
The compounds of the present invention or pharmaceutical compositions thereof may be administered in unit dosage form. The administration dosage form can be liquid dosage form or solid dosage form. The liquid dosage forms can be true solutions, colloids, microparticles, and suspensions. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, clathrate, implant, patch, liniment, etc.
Oral tablets and capsules may contain excipients such as binding agents, for example syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants, such as potato starch; or acceptable humectants such as sodium lauryl sulfate. The tablets may be coated by methods known in the art of pharmacy.
Oral liquids may be in the form of suspensions of hydrated oils, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gelatin, hydrogenated edible fats and oils, emulsifying agents such as lecithin, sorbitan monooleate, gum arabic; or non-aqueous vehicles (which may include edible oils), such as almond oil, fats and oils such as glycerol, ethylene glycol, or ethanol; preservatives, e.g. methyl or propyl p-hydroxybenzoates, sorbic acid. Flavoring or coloring agents may be added if desired.
Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.
For parenteral administration, the liquid dosage form is usually prepared from the compound and a sterile excipient. The auxiliary material is preferably water. According to different selected adjuvants and drug concentrations, the compound can be dissolved in adjuvants or made into suspension solution, and can be dissolved in water for injection, filtered, sterilized and filled into sealed bottle or ampoule.
When applied topically to the skin, the compounds of the present invention may be formulated in the form of a suitable ointment, lotion, or cream in which the active ingredient is suspended or dissolved in one or more excipients which may be used in ointment formulations including, but not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions and creams adjuvants that may be used include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
In general, it has proven advantageous, both in human medicine and in veterinary medicine, to administer the active compounds according to the invention in a total amount of from about 0.5 to 500mg/kg of body weight, preferably from 1 to 100mg/kg of body weight, per 24 hours, if appropriate in divided single doses, in order to achieve the desired effect. The amount of active compound contained in a single dose is preferably about 1 to 80mg/kg body weight, more preferably 1 to 50mg/kg body weight, but may be varied from the above-mentioned dose, i.e., depending on the kind and body weight of the subject to be treated, the nature and severity of the disease, the type of preparation and the mode of administration of the drug, and the period or interval of administration.
The pharmaceutical composition provided by the invention also comprises an anti-HBV medicament. Wherein the anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator or an interferon.
The anti-HBV drugs include lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, alfafenone, Alloferon, simon interleukin, cladribine, emtricitabine, faprolivir, interferon, calamine CP, intefine, interferon alpha-1 b, interferon alpha-2 a, interferon beta-1 a, interferon alpha-2, interleukin-2, mevoxil, nitazoxanide, peginterferon alpha-2 a, ribavirin, rosmarin-A, xifurazol, Euforavac, azapril, Phosphazid, Heplivav, interferon alpha-2 b, levamisole or propafegermanium.
Another aspect of the present invention relates to the use of a compound or pharmaceutical composition of the present invention for the manufacture of a medicament for the prevention, treatment or amelioration of hepatitis B disease in a patient, which comprises administering to the patient a pharmaceutically acceptable effective amount. Hepatitis B disease refers to liver disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma. Acute hepatitis b virus infection may be asymptomatic or manifest as acute hepatitis symptoms. Patients with chronic viral infections have active disease and can develop cirrhosis and liver cancer.
The anti-HBV agent may be administered separately from a composition comprising a compound of the present invention as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the present invention to form a single composition. If administered as part of a multiple dosing regimen, the two active agents can be delivered to each other simultaneously, sequentially or over a period of time, to achieve the desired agent activity.
The amount of compound and pharmaceutical composition that can be combined with an adjuvant material to produce a single dosage form (those containing one pharmaceutical composition like that described herein) will vary depending on the indication and the particular mode of administration. Normally, the amount of the pharmaceutical composition of the invention will not exceed the amount of the composition normally administered containing as the only active agent. In another aspect, the amount of the presently disclosed pharmaceutical composition ranges from about 50% to 100% of the normal amount of the presently disclosed pharmaceutical composition, including the agent as the sole active therapeutic agent. In those compositions that are included, the compositions will act synergistically with the compounds of the present invention.
The compound of the invention shows stronger antiviral effect. The compounds have unexpected antiviral activity on HBV, and are suitable for treating various diseases caused by viruses, especially diseases caused by acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV can lead to a variety of syndromes of varying severity, and chronic hepatitis b virus infection is known to cause cirrhosis and/or hepatocellular carcinoma.
Examples of indications that can be treated with the compounds of the invention are: acute and chronic viral infections that can lead to infectious hepatitis, such as hepatitis b virus infection. Particularly preferred are chronic hepatitis B infection and acute hepatitis B virus infection.
The invention also relates to the use of the compounds and pharmaceutical compositions of the invention in the preparation of medicaments for the treatment and prevention of viral diseases, in particular hepatitis b.
General synthetic methods
In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I) or formula (II), unless otherwise indicated. The following synthetic schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
Examples are described below, unless otherwise indicated, all temperatures are set forth in degrees Celsius (. degree. C.). Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.
The column used silica gel column, silica gel (200-300 mesh) purchased from Qingdao oceanic plant. Nuclear magnetic resonance spectroscopy with CDC1 3 ,DMSO-d 6 ,CD 3 OD or acetone-d 6 TMS (0ppm) or chloroform (7.25ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet ), m (multiplet, multiplet), q (quatets, quartet), br (broadethylene, broad), dd (doublet of doublets, doublet), dt (doublet of triplets, double triplet), br. Coupling constant J, in Hertz (Hz).
Low resolution Mass Spectral (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.
Low resolution Mass Spectral (MS) data were also determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector applied for analysis, and an ESI source applied to the LC-MS spectrometer.
Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:
table 1: gradient elution conditions
Time (min) A(CH 3 CN，0.1％HCOOH) B(H 2 O，0.1％HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
The purity of the compounds was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm,10 min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.
The following acronyms are used throughout the invention:
MeOH methanol Pd 2 (dba) 3 Tris (dibenzylideneacetone) dipalladium
MeOH-d 4 /CD 3 OD deuterated methanol DMAP 4-dimethylaminopyridine
DCM,CH 2 Cl 2 Dichloromethane HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
CDC1 3 Deuterated chloroform
TFA trifluoroacetic acid h
(Boc) 2 Di-tert-butyl O-dicarbonate DIPEA N, N-diisopropylethylamine
NBS N-bromosuccinimide DMF N, N-dimethylformamide
DDQ 2, 3-dichloro-5, 6-dicyanobenzene jade THF tetrahydrofuran
PE Petroleum Ether DMSO dimethyl sulfoxide
EtOAc, EA Ethyl acetate DMSO-d 4 Deuterated dimethyl sulfoxide
EtOH t 1/2 Half life
Et 3 N, TEA Triethylamine AUC area under the curve for drug
mL, mL Vss steady state apparent distribution volume
Room temperature CL, clear clearance at RT, RT
Rt Retention time F, Absolute Bioavailabilitity bioavailability
LDA lithium diisopropylamide Dose
CDI N, N' -carbonyldiimidazole T max Time to peak
1atm 101.325kPa C max Maximum concentration
hr, ng/mL plasma concentration, time
Synthesis method
The following synthetic schemes set forth the experimental procedures for preparing the compounds disclosed in the present invention. Wherein each ring A, R b 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And X has the meaning as described in the present invention.
Synthesis scheme 1
Figure BDA0003482027340000401
The compound represented by the formula (A-4) can be prepared by the method described in Synthesis scheme 1. First, the compound (A-1) is subjected to Boc protection group removal under appropriate conditions (e.g., in the presence of trifluoroacetic acid, hydrochloric acid or the like) to produce a compound (A-2) or a salt thereof; then, the compound (A-2) or a salt thereof and the compound (A-3) are subjected to a condensation reaction to obtain a compound (A-4).
Synthesis scheme 2
Figure BDA0003482027340000402
The compound represented by the formula (b-4) can be prepared by the method described in synthetic scheme 2. Firstly, carrying out a ring-closing reaction on the compound (b-1) in the presence of isobutyl chloroformate to generate a compound (b-2); then, compound (b-2) is reacted with a reducing agent (e.g., NaBH) 4 Etc.) to produce a compound (b-3); and finally, closing the ring of the compound (b-3) under a proper condition (such as adding triethylamine and methanesulfonyl chloride, or DMAP and methanesulfonyl chloride and the like) to obtain a compound (b-4).
Synthesis scheme 3
Figure BDA0003482027340000403
The compound represented by the formula (C-1) can be prepared by the method described in Synthesis scheme 3. First, the compound (b-4) is subjected to Boc protection group removal under appropriate conditions (e.g., in the presence of trifluoroacetic acid, hydrochloric acid or the like) to produce a compound (b-5) or a salt thereof; then, the compound (b-5) or a salt thereof and the compound (A-3) are subjected to a condensation reaction to obtain a compound (C-1).
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Preparation examples
In the following preparation examples, the inventors described in detail the preparation of the compounds of the present invention by taking some of the compounds of the present invention as examples.
Synthesis of example 1
Figure BDA0003482027340000411
Step 1: synthesis of Compound 1-1
Compound F1(500mg,0.99mmol, prepared by the synthetic method referenced to ACS Med. chem. Lett.2017,8, page 969-974) was dissolved in dichloromethane (5mL), to which trifluoroacetic acid (5mL) was added, stirred at room temperature for 1h and directly spin-dried to give the title compound as a brown oil (500mg, 97%). MS (ESI, pos. ion) M/z 407.10[ M + H ]] + 。
Step 2: synthesis of Compound 1
Compound F2(500mg,1.49mmol, which was prepared with reference to the synthetic method of WO2017156255a1 compound 42) and HATU (893mg,2.23mmol) were dissolved in DMF (5mL), and DIPEA (578mg,4.46mmol) and compound 1-1(666mg,1.64mmol) were added thereto, respectively, stirred at room temperature for 15h, then water (50mL) was added thereto to quench the reaction, followed by extraction with dichloromethane (50mL), organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 1/1) to give the title compound as an off-white solid (420mg, 39%). MS (ESI, pos. ion) M/z 725.10[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.41(s,1H),9.22(d,J＝6.4Hz,1H),7.95(d,J＝3.2Hz,1H),7.91–7.86(m,1H),7.84(d,J＝3.2Hz,1H),7.50(dd,J＝8.6,6.3Hz,1H),7.46–7.37(m,3H),7.17(td,J＝8.4,2.5Hz,1H),6.04(s,1H),4.63–4.55(m,1H),4.46(d,J＝5.2Hz,2H),3.59(s,3H),3.52(s,3H),3.50–3.42(m,1H),3.31–3.25(m,1H),2.39(s,3H),2.20(s,3H).
Synthesis of example 2
Figure BDA0003482027340000421
Step 1: synthesis of Compound 2-1
To the reaction flask was added 2-bromo-4-fluoro-benzaldehyde (5.00g,24.6mmol), phenylboronic acid (3.60g,29.5mmol), tri-tert-butylphosphine tetrafluoroborate (736mg,2.46mmol), Pd 2 (dba) 3 (1.16g,1.23mmol), cesium carbonate (16.11g,49.44mmol) and 1, 4-dioxane (60mL) were reacted at 95 ℃ for 12h under nitrogen. The heating was turned off, the temperature was reduced to room temperature, suction filtration was carried out, and the filter cake was rinsed with ethyl acetate (50 mL). The filtrate was spun dry and petroleum ether (50mL) was added to the residue, stirred at room temperature for 30min, filtered, the filtrate was cooled to 5 ℃, filtered and the filtrate was spun dry to give a brown sticky mass (5.32g, 100%). MS (ESI, pos.ion) M/z 201.1[ M + H ]] + 。
Step 2: synthesis of Compound 2-2
F3(5.30g,14.0mmol, prepared by the method for synthesizing compound 4 in example 1 of WO 2017076286), compound 2-1(3.36g,16.8mmol), 2-thiazolecarboxamidine hydrochloride (3.14g,18.2mmol), 4-methylmorpholine (3.53g,34.9mmol) and THF (60mL) were added sequentially to a dry reaction flask and reacted at 60 ℃ for 24 h. And turning off the heating, and cooling to room temperature. The solvent was distilled off under reduced pressure, ethyl acetate (70mL) and water (50mL) were added to the residue, the layers were extracted, and the organic layer was washed with saturated brine (50mL) and dried over anhydrous sodium sulfate. Filtering, evaporating the solvent from the filtrate under reduced pressure, and separating the crude product by silica gel column chromatography (DCM/CH) 3 OH (V/V) ═ 30/1) purified to give a yellow solid (3.32g, 40.9%). MS (ESI, pos. ion) M/z 581.2[ M + H ]] + 。
And step 3: synthesis of Compounds 2-3
Compound 2-2(2.02g,3.48mmol), THF (30mL), and 4-methylmorpholine (711mg,7.03mmol) were added sequentially to a dry reaction flask, the temperature was reduced to 5 deg.C, then a solution of isobutyl chloroformate (608mg,4.45mmol) diluted with THF (15mL) was added slowly dropwise, the reaction was incubated for 12h, then water (30mL) was added, followed by extraction with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, spin dried, and the crude productPurification by silica gel column chromatography (PE/EA (V/V) ═ 2/1) gave a yellow solid (180mg, 9.2%). MS (ESI, pos. ion) M/z 563.2[ M + H ]] + 。
And 4, step 4: synthesis of Compounds 2-4
The compound 2-3(160mg,0.28mmol) and THF (6mL) were added sequentially in a dry reaction flask, and NaBH was added under ice bath 4 (34mg,0.86 mmol). After the addition, the reaction system was moved to room temperature for 6 h. Ethyl acetate (30mL) was added and the organic layer was washed successively with water (30mL) and saturated brine (30mL), dried over anhydrous sodium sulfate, and spin-dried to give a yellow foamy solid (158mg, 98.05%). MS (ESI, pos. ion) M/z 567.2[ M + H ]] + 。
And 5: synthesis of Compounds 2-5
Compound 2-4(158mg,0.28mmol), DCM (5mL) and DMAP (103mg,0.83mmol) were added sequentially to a dry reaction flask, dissolved with stirring, and methanesulfonyl chloride (70mg,0.60mmol) was added under ice-bath. The reaction mixture was allowed to cool to room temperature for 4 hours, and then methylene chloride (50mL) and water (40mL) were added to the mixture, followed by extraction to separate layers, and the organic layer was washed with dilute hydrochloric acid (30mL,1M) and saturated brine (30 mL. times.2), dried over anhydrous sodium sulfate, and spin-dried to obtain a yellow foaming solid (156mg, 100%). MS (ESI, pos. ion) M/z 549.2[ M + H ]] + 。
Step 6: synthesis of Compounds 2-6
In a dry reaction flask were added sequentially compound 2-5(156mg,0.28mmol), DCM (3mL) and trifluoroacetic acid (1mL), stirred at room temperature for 1h, then the solvent was evaporated under reduced pressure to give a yellow sticky mass (156mg, 99.44%). MS (ESI, pos. ion) M/z 449.4[ M + H ]] + 。
And 7: synthesis of Compound 2
The compounds 2 to 6(156mg,0.28mmol), DMF (5mL), DIPEA (191mg,1.45mmol), compound F2(104mg,0.31mmol) and HATU (163mg,0.42mmol) were added in this order to a dry reaction flask, reacted at room temperature for 12 hours, then ethyl acetate (30mL) and water (30mL) were added, the layers were separated by extraction, the organic layer was washed with dilute hydrochloric acid (30mL,1M) and saturated brine (30 mL. times.3) in this order, dried over anhydrous sodium sulfate, and spin-dried,the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 2/3) to give a beige solid (93mg, 43.7%). MS (ESI, pos. ion) M/z 767.2[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.87–7.76(m,2H),7.75–7.65(m,1H),7.58(d,J＝6.4Hz,2H),7.44–7.37(m,4H),7.20–7.10(m,2H),7.04–6.95(m,2H),5.70(s,1H),4.85–4.66(m,1H),4.50(s,2H),3.62(s,3H),3.60–3.52(m,1H),3.48(s,3H),3.16(dd,J＝18.1,6.2Hz,1H),2.31(d,J＝16.4Hz,6H).
Synthesis of example 3
Figure BDA0003482027340000431
Step 1: synthesis of Compound 3-1
Compound F1(613mg,1.21mmol) was dissolved in tetrahydrofuran (10mL), to which was added lithium hydroxide monohydrate (104mg,2.46mmol) and water (2mL), and stirred at 50 ℃ for 38 h. To this was added water (10mL), extracted with ethyl acetate (10mL), washed with water (10mL) and saturated brine (10mL), dried over anhydrous sodium sulfate, and dried by spinning, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 1/1) to give the title compound as a yellow solid (301mg, 51%). MS (ESI, pos. ion) M/z 493.20[ M + H ]] + 。
Step 2: synthesis of Compound 3-2
Propargylamine (25mg,0.45mmol) and HATU (225mg,0.56mmol) were dissolved in DMF (5mL), to which were added compound 3-1(230mg,0.47mmol) and DIPEA (181mg,1.40mmol), respectively, and stirred at room temperature for 19 h. To this were added dichloromethane (20mL) and water (20mL), the layers were separated and the organic phase was washed with dilute hydrochloric acid (1M,10mL), saturated sodium bicarbonate (10mL), water (10mL) and saturated brine (10mL), respectively, dried over anhydrous sodium sulfate and spin dried to give the title compound as a yellow solid (180mg, 73%). MS (ESI, pos. ion) M/z 530.20[ M + H ]] + 。
And step 3: synthesis of Compound 3-3
Compound 3-2(180mg,0.34mmol) was dissolved in dichloromethane (2mL), to which was addedTrifluoroacetic acid (2mL) was added, stirred at rt for 3h and spin dried directly to give the title compound as a brown oil (180mg, 97%). MS (ESI, pos. ion) M/z 430.10[ M + H ]] + 。
And 4, step 4: synthesis of Compound 3
Compound F2(100mg,0.30mmol) and HATU (140mg,0.35mmol) were dissolved in DMF (5mL), to which compound 3-3(180mg,0.33mmol) and DIPEA (116mg,0.90mmol) were added, respectively, and stirred at room temperature for 19 h. To this was added water (20mL), extracted with dichloromethane (20mL), and the organic phase was washed with dilute hydrochloric acid (1M,10mL), saturated sodium bicarbonate solution (10mL), water (10mL) and saturated brine (10mL), respectively, dried over anhydrous sodium sulfate, spun-dried, and the resulting residue was purified by silica gel column chromatography (EA) to give the title compound as a white solid (120mg, 54%). MS (ESI, pos. ion) M/z 748.10[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.39(s,1H),9.20(d,J＝5.9Hz,1H),7.98–7.73(m,4H),7.50–7.30(m,4H),7.16(td,J＝8.4,1.7Hz,1H),6.05(s,1H),4.55–4.37(m,2H),4.32(dd,J＝11.4,5.8Hz,1H),3.85(dd,J＝17.9,3.7Hz,1H),3.72(dd,J＝16.8,2.6Hz,1H),3.57(s,3H),3.42(dd,J＝17.1,6.9Hz,1H),3.06–2.96(m,2H),2.35(s,3H),2.17(s,3H).
Synthesis of example 4
Figure BDA0003482027340000441
Step 1: synthesis of Compound 4-1
Compound F4 (prepared by the synthetic method of example 1, fragment 4of WO2017156255a1, 500mg,1.97mmol), DIPEA (0.7mL,4mmol) and HATU (1.027g,2.57mmol) were dissolved in DCM (10mL), and after stirring for ten minutes, compound 1-1(1.03g,1.98mmol) was added to the reaction system. The reaction mixture was stirred at room temperature for 17h, then washed with dilute hydrochloric acid (1M,10mL) and sodium hydroxide solution (1M,10mL), the organic layer was spun dry, and the resulting residue was chromatographed on silica gel (DCM/CH) 3 OH (V/V) ═ 50/1) purified to give a brown solid (400mg, 31.6%). MS (ESI, pos. ion) M/z 642.2[ M + H ]] + 。
Step 2: synthesis of Compound 4-2
Compound 4-1(400mg,0.62mmol) was dissolved in ethanol (12mL) and THF (12mL), a solution of sodium hydroxide (99mg,2.48mmol) in water (4mL) was added, and the reaction was stirred at 70 ℃ for 2 h. The solvent was spun dry, water (10mL) and ethyl acetate (10mL) were added, the organic phase discarded, ethyl acetate (10mL) was added to the aqueous phase, and the pH of the solution was adjusted to about 3-4 with 1M dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (10 mL. times.2), and the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and spin-dried to give the title compound as a brown solid (225mg, 59%). MS (ESI, pos. ion) M/z 614.10[ M + H ]] + 。
And step 3: synthesis of Compound 4
Compound 4-2(225mg,0.38mmol), DIPEA (0.1mL,0.60mmol) and HATU (450mg,1.12mmol) were dissolved in DCM (6mL) and, after stirring for 10min, propynylamine (61mg,1.11mmol) was added to the system and the reaction stirred at room temperature for 16 h. The reaction system was washed with dilute hydrochloric acid (1M,10mL), sodium hydroxide solution (1M,10mL) and saturated brine (10mL), respectively, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated from the filtrate, and the resulting residue was separated by silica gel column chromatography (DCM/CH) 3 OH (V/V) ═ 50/1) purified to give a yellow solid (12mg, 5%). MS (ESI, pos. ion) M/z 651.15[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)9.19(d,J＝6.5Hz,1H),8.58(t,J＝5.7Hz,1H),7.95(d,J＝3.2Hz,1H),7.86(d,J＝3.2Hz,1H),7.49(dd,J＝8.7,6.3Hz,1H),7.40(dd,J＝8.9,2.6Hz,1H),7.17(td,J＝8.5,2.6Hz,1H),6.02(s,1H),4.61–4.53(m,1H),4.44(d,J＝5.1Hz,2H),4.01(dd,J＝5.6,2.4Hz,2H),3.52(s,3H),3.45(s,3H),3.40–3.35(m,1H),3.30–3.25(m,1H),3.13(t,J＝2.4Hz,1H),2.33(s,3H),2.15(s,3H).
Synthesis of example 5
Figure BDA0003482027340000451
Step 1: synthesis of Compound 5-1
Compound F3(11.70g,30.8mmol), 2-chloro-4-fluorobenzaldehyde (5.24g,32.4mmol), thiazolecarboxamidine hydrochloride (6.13g,35.4mmol) and N-methylmorpholine (8.6mL,77mmol) were dissolved in tetrahydrofuran (100mL) and reacted at 60 ℃ for 24 h. After the reaction is finished, the temperature is reduced to room temperature and the reaction solution is directly used for the next reaction.
Step 2: synthesis of Compound 5-2
The reaction solution from the previous step (i.e., tetrahydrofuran solution of compound 5-1) was cooled to 5 ℃ and a solution of isobutyl chloroformate (4.95mL,37.4mmol) in THF (20mL) was slowly added dropwise thereto, the reaction was incubated for 1h, then water (100mL) was added to quench the reaction, followed by extraction with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, the filtrate was concentrated, the resulting oil was dissolved in tetrahydrofuran (3.56mL) and ethyl acetate (21.9mL), n-heptane (66.4mL) was slowly added dropwise to precipitate a solid slowly, after the addition was completed, the temperature was lowered to 15 ℃ and stirring was carried out for 10 hours, the filtrate was filtered, and the filtrate was concentrated to purify the residue by silica gel column chromatography (PE/EA (V/V) ═ 1/1) to obtain the title compound as a yellow solid (3.75g, 23.1%). MS (ESI, pos. ion) M/z 521.0[ M + H ]] + 。
And step 3: synthesis of Compound 5-3
Sodium borohydride (0.15g,3.8mmol) was dissolved in water (2mL) and a solution of compound 5-2(1.00g,1.92mmol) in THF (10mL) was added dropwise over an ice bath and the reaction was allowed to stir at this temperature for a further 16 h. The reaction was quenched by the addition of water (20mL), extracted with ethyl acetate (20mL), washed successively with water (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (0.67g, 66%). MS (ESI, pos. ion) M/z 525.20[ M + H ]] + 。
And 4, step 4: synthesis of Compound 5-4
Compound 5-3(0.67g,1.3mmol) and DMAP (0.47g,3.8mmol) were dissolved in DCM (10mL), methanesulfonyl chloride (0.2mL,3mmol) was slowly added dropwise thereto under ice bath, and after completion of addition, the reaction was stirred at 35 ℃ with slow warming. The reaction was stopped and washed with dilute hydrochloric acid (1M,20 mL). The organic phase was washed with water (20mL) and saturated brine (20mL),dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 4/1) to give the title compound as a yellow solid (0.28g, 43%). MS (ESI, pos. ion) M/z 507.20[ M + H ]] + 。
And 5: synthesis of Compounds 5-5
Compound 5-4(0.28g,0.55mmol) was dissolved in DCM (10mL), TFA (0.5mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction was spin dried to give the title compound as a brown oil (280mg, 97%). MS (ESI, pos. ion) M/z 407.10[ M + H ]] + 。
Step 6: synthesis of Compound 5
Compound 5-5(0.29g,0.56mmol) was dissolved in DMF (10mL), then DIPEA (0.20g,1.6mmol), compound F2(0.22g,0.65mmol) and HATU (0.25g,0.66mmol) were added thereto, stirred at room temperature for 6h, then ethyl acetate (20mL) and water (50mL) were added to the system, the aqueous phase was extracted with ethyl acetate (20mL), the organic phases were combined, the organic phases were washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (PE/EA (V/V) 1/2) to give the title compound as a white solid (160mg, 40%). MS (ESI, pos. ion) M/z 725.20[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.83(d,J＝3.2Hz,1H),7.76–7.69(m,1H),7.44(s,1H),7.41(d,J＝3.2Hz,1H),7.34(dd,J＝8.6,6.1Hz,1H),7.22–7.12(s,4H),7.03(td,J＝8.3,2.6Hz,1H),6.21(s,1H),4.78–4.72(m,1H),4.62–4.53(m,2H),3.74(s,3H),3.65(s,3H),3.63–3.58(m,1H),3.38(dd,J＝18.2,6.6Hz,1H),2.44(s,3H),2.41(s,3H).
Synthesis of example 6
Figure BDA0003482027340000461
Step 1: synthesis of Compound 6-1
To a reaction flask was added compound F3(2.50g,6.59mmol, which was prepared by reference to the synthesis of compound 4 in example 1 of WO 2018196805), acetaldehydeAqueous solution (2.18g,19.80mmol, 40%), thiazolecarboxamidine hydrochloride (1.19g,7.27mmol), 4-methylmorpholine (1.68g,16.40mmol) and isopropanol (30mL), the reaction mixture was reacted at 80 ℃ for 6h, cooled to room temperature and then spun dry to give the title compound as a yellow oil (2.77g, 99%). MS (ESI, pos.ion) M/z:425.2[ M + H ]] + 。
Step 2: synthesis of Compound 6-2
Compound 6-1(2.70g,6.36mmol) and 4-methylmorpholine (1.29g,12.80mmol) were dissolved in tetrahydrofuran (30mL), cooled to 5 ℃, isobutyl chloroformate (1.01g,7.61mmol) was added dropwise, the reaction was incubated for 3h, then ethyl acetate (50mL) and water (50mL) were added, the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (EtOAc (V/V ═ 3/1)) to afford the title compound as a yellow solid (0.83g, 32%). MS (ESI, pos.ion) M/z 407.2[ M + H ]] + 。
And step 3: synthesis of Compound 6-3
Sodium borohydride (232mg,5.89mmol) was dissolved in water (1mL), a solution of compound 6-2(800mg,1.97mmol) in tetrahydrofuran (10mL) was added thereto under ice-water bath, reaction was completed for 1h, water (20mL) was added for dilution, and then extraction was performed with ethyl acetate (20mL), and the organic phase was washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid (650mg, 81%). MS (ESI, pos. ion) M/z 411.3[ M + H ]] + 。
And 4, step 4: synthesis of Compound 6-4
Compound 6-3(550mg,1.34mmol) and triethylamine (406mg,4.01mmol) were dissolved in dichloromethane (10mL), to which methanesulfonyl chloride (308mg,2.69mmol) was added under an ice-water bath, followed by warming to 35 ℃ for 2h, cooling and concentration under reduced pressure to give the title compound as a yellow solid (410mg, 78%). MS (ESI, pos.ion) M/z 393.2[ M + H ]] + 。
And 5: synthesis of Compounds 6-5
Compound 6-4(200mg,0.51mmol) was dissolved in dichloromethane (5mL), to which was added trifluoroacetic acid (5mL), stirred at room temperature for 2h, and spin-dried to give the title compound as a brown oil (200mg, 97%).
Step 6: synthesis of Compound 6
Compound F2(182mg,0.54mmol) and HATU (236mg,0.59mmol) were dissolved in DMF (5mL), to which DIPEA (191mg,1.47mmol) and compound 6-5(200mg,0.49mmol) were added in that order and stirred at room temperature for 22 h. Ethyl acetate (20mL) and water (20mL) were added, the organic phase was washed successively with 1M hydrochloric acid (20mL), saturated sodium bicarbonate (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, spun-dried, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (V/V) ═ 15/1) to give the title compound as a white solid (108mg, 36%). MS (ESI, pos. ion) M/z 611.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.96(d,J＝3.2Hz,1H),7.91–7.83(m,2H),7.46–7.37(m,2H),4.61–4.54(m,1H),4.52–4.44(m,1H),4.39(d,J＝5.8Hz,2H),3.65(s,3H),3.58(s,3H),3.31–3.23(m,2H),3.11(dd,J＝17.7,5.7Hz,1H),2.37(s,3H),2.18(s,3H),1.16(d,J＝6.4Hz,3H).
Synthesis of example 7
Figure BDA0003482027340000471
Step 1: synthesis of Compound 7-1
Compound 3-1(150mg,0.30mmol) was dissolved in dichloromethane (5mL) and then pyrrolidine (25mg,0.35mmol), HATU (140mg,0.37mmol) and DIPEA (120mg,0.93mmol) were added, stirred at room temperature for 4h, extracted with dichloromethane (20mL) and hydrochloric acid (1M,20mL), the organic phase was washed with saturated brine (25mL), dried over anhydrous sodium sulfate, filtered, and spun dried to afford the title compound as a yellow solid (160mg, 96%). MS (ESI, pos.ion) M/z 546.2[ M + H ]] + 。
Step 2: synthesis of Compound 7-2
Compound 7-1(160mg,0.29mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (0.1mL) was added, stirred at room temperature for 12h, the solvent was removed by rotary drying, and the residue was used for the next reaction.
And step 3: synthesis of Compound 7
Compound 7-2(160mg,0.29mmol) was dissolved in DMF (5mL), compound F2(120mg,0.36mmol), HATU (130mg,0.34mmol) and DIPEA (110mg,0.85mmol) were added, stirred at room temperature for 26h, ethyl acetate (25mL) and water (50mL) were added, extraction was performed for liquid separation, the aqueous phase was back-extracted with ethyl acetate (20mL × 2), the organic phases were combined, the combined organic phases were washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filter cake was purified by thin layer chromatography (PE/EA (V/V) ═ 1/6) to give a white solid (30mg, 13%). MS (ESI, pos. ion) M/z 764.2[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.67(s,1H),7.87(d,J＝3.2Hz,1H),7.82–7.72(m,1H),7.63(d,J＝7.6Hz,1H),7.43(d,J＝3.1Hz,1H),7.37(d,J＝8.8Hz,1H),7.32–7.29(m,1H),7.15–7.07(m,2H),6.98(td,J＝8.4,2.4Hz,1H),6.10(s,1H),4.76–4.69(m,1H),4.61–4.53(m,1H),4.48–4.41(m,1H),3.65(s,3H),3.30(s,3H),3.05–2.91(m,2H),2.35(s,3H),2.31(s,3H),1.89–1.69(m,5H).
Synthesis of example 8
Figure BDA0003482027340000481
Example 8 was prepared as an off-white solid (70mg, 33.50%) with reference to the synthesis of example 7. MS (ESI, pos. ion) M/z 724.1[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.42(s,1H),9.20(d,J＝5.9Hz,1H),7.92(d,J＝3.2Hz,1H),7.91–7.83(m,1H),7.80(d,J＝3.2Hz,1H),7.47–7.39(m,4H),7.18(td,J＝8.5,2.5Hz,1H),6.06(s,1H),4.52–4.39(m,2H),4.37–4.27(m,1H),3.58(s,3H),3.50–3.42(m,2H),3.08–2.95(m,1H),2.52(s,3H),2.37(s,3H),2.17(s,3H).
Synthesis of example 9
Figure BDA0003482027340000482
Example 9 was prepared as a yellow solid (110 m) by the synthetic method of reference example 7g,96.48％)。MS(ESI,pos.ion)m/z:780.2[M+H] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.28(s,1H),7.87(d,J＝3.2Hz,1H),7.78–7.66(m,1H),7.58(d,J＝7.5Hz,1H),7.44(d,J＝3.2Hz,1H),7.34–7.29(m,2H),7.20–7.09(m,2H),6.99(td,J＝8.3,2.5Hz,1H),6.09(s,1H),4.77–4.69(m,1H),4.63–4.53(m,1H),4.53–4.45(m,1H),3.66(s,3H),3.55–3.40(m,4H),3.39–3.14(m,4H),2.91(dd,J＝16.4,6.8Hz,1H),2.75(dd,J＝16.3,5.1Hz,1H),2.36(s,3H),2.32(s,3H).
Synthesis of example 10
Figure BDA0003482027340000491
Step 1: synthesis of Compound 10-1
Compound F6(5.00g,11.1mmol, obtained by reference to the method for the synthesis of compound 3 in example 1 of WO 2017076286) and ethyl D-lactate (2.63g,22.26mmol) were dissolved in toluene (30mL), reacted at 100 ℃ for 12h, and concentrated under reduced pressure to give a brown oil (5.10g, 99%). MS (ESI, pos. ion) M/z 366.2[ M-Boc + H] + 。
Step 2: synthesis of Compound 10-2
To a reaction flask were added compound 10-1(6.00g,12.9mmol), 2-chloro-4-fluorobenzaldehyde (2.15g,13.6mmol), thiazolecarboxamide hydrochloride (2.53g,14.8mmol), 4-methylmorpholine (3.6mL,32mmol) and tetrahydrofuran (50mL), reacted at 60 ℃ for 23h, cooled to room temperature and used for the next reaction. MS (ESI, pos. ion) M/z 625.2[ M + H ]] + 。
And step 3: synthesis of Compound 10-3
The reaction solution in the previous step was cooled to 5 ℃, isobutyl chloroformate (2.10g,15.4mmol) was added dropwise, the reaction was continued at 5 ℃ for 14h, ethyl acetate (100mL) and water (100mL) were added, the organic phase was washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 2/1) to give the title compound as a yellow solid (2.15g, 18%). MS (ESI, pos. ion) M/z 607.3[ M + H ]] + 。
And 4, step 4: synthesis of Compound 10-4
Sodium borohydride (130mg,3.30mmol) was dissolved in water (0.5mL), a solution of compound 10-3(1.00g,1.65mmol) in tetrahydrofuran (5mL) was added thereto under an ice-water bath, after the addition was completed, the reaction was continued for 1h under an ice bath, ethyl acetate (10mL) and water (10mL) were added, the organic phase was washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid (900mg, 89%). MS (ESI, pos. ion) M/z 611.1[ M + H ]] + 。
And 5: synthesis of Compound 10-5
Compound 10-4(900mg,1.47mmol) and triethylamine (450mg,4.45mmol) were dissolved in dichloromethane (10mL), methanesulfonyl chloride (338mg,2.95mmol) was added thereto under an ice-water bath, and after completion of the addition, the temperature was raised to 35 ℃ to react for 3 hours, and the reaction solution was washed with 1M hydrochloric acid (10mL) and saturated brine (10 mL. times.2) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid (620mg, 71%). MS (ESI, pos. ion) M/z 593.2[ M + H ]] + 。
Step 6: synthesis of Compound 10-6
Compound 10-5(250mg,0.42mmol) was dissolved in dichloromethane (5mL), to which was added trifluoroacetic acid (2mL), stirred at room temperature for 1h, and concentrated under reduced pressure to give the title compound as a brown oil (250mg, 98%).
And 7: synthesis of Compound 10
Compound F2(112mg,0.37mmol) and HATU (150mg,0.37mmol) were dissolved in DMF (5mL), to which DIPEA (120mg,0.93mmol) and compound 10-6(250mg,0.41mmol) were added in that order and stirred at room temperature for 3 h. Water (20mL) was added for dilution, followed by extraction with dichloromethane (20mL), the organic phase was washed successively with 1M hydrochloric acid (20mL), saturated aqueous sodium bicarbonate (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 1/1) to give the title compound as a yellow solid (140mg, 57%). MS (ESI, pos. ion) M/z 811.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.81(d,J＝3.2Hz,1H),7.77–7.67(m,2H),7.47–7.37(m,2H),7.35–7.29(m,1H),7.21–7.11(m,3H),6.95(td,J＝8.3,2.5Hz,1H),6.24(s,1H),4.96(q,J＝7.0Hz,1H),4.85–4.74(m,1H),4.65–4.49(m,2H),4.23–4.09(m,2H),3.78–3.70(m,1H),3.69(s,3H),3.32(dd,J＝18.3,6.3Hz,1H),2.39(s,3H),2.34(s,3H),1.34(d,J＝7.1Hz,3H),1.23(t,J＝7.1Hz,3H).
Synthesis of example 11
Figure BDA0003482027340000501
Step 1: synthesis of Compound 11-1
Compound F3(3.00g,7.91mmol), 2-chloro-4-fluoro-benzaldehyde (1.32g,8.32mmol), cyclopropylformamidine hydrochloride (1.05g,8.71mmol), 4-methylmorpholine (2.2mL,20mmol) and isopropanol (30mL) were added to a reaction flask, and the reaction was stirred at 80 ℃ for 16h and concentrated under reduced pressure to give the title compound as a brown oil (3.88g, 98.9%). MS (ESI, pos. ion) M/z 496.2[ M + H ]] + 。
Step 2: synthesis of Compound 11-2
Compound 11-1(3.88g,7.82mmol) and 4-methylmorpholine (1.58g,15.60mmol) were dissolved in tetrahydrofuran (30mL), cooled to 5 ℃, isobutyl chloroformate (1.28g,9.37mmol) was added slowly, and after dropwise addition, reaction was carried out at 5 ℃ for 32h, water (100mL) was added for dilution, followed by extraction with ethyl acetate (100mL), the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 4/1) to afford the title compound as a yellow solid (1.11g, 30%).
MS(ESI,pos.ion)m/z:478.1[M+H] + 。
And step 3: synthesis of Compound 11-3
Dissolving sodium borohydride (165mg,4.19mmol) in water (1mL), adding a tetrahydrofuran (10mL) solution of compound 11-2(1.00g,2.09mmol) in ice-water bath, reacting for 1.5h in ice bath, adding water (20mL), diluting, extracting with ethyl acetate (20mL), and collecting the organic phaseAnd brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid (720mg, 71%). MS (ESI, pos.ion) M/z 482.2[ M + H ]] + 。
And 4, step 4: synthesis of Compound 11-4
Compound 11-3(700mg,1.45mmol) and triethylamine (440mg,4.35mmol) were dissolved in dichloromethane (10mL), methanesulfonyl chloride (333mg,2.91mmol) was added thereto under an ice-water bath, after the addition, the temperature was raised to 35 ℃ to react for 19h, cooled to room temperature, the reaction solution was washed with 1M hydrochloric acid (10mL), water (10mL) and saturated brine (10mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid (520mg, 77%). MS (ESI, pos.ion) M/z 464.2[ M + H ]] + 。
And 5: synthesis of Compound 11-5
Compound 11-4(200mg,0.43mmol) was dissolved in dichloromethane (5mL), to which was added trifluoroacetic acid (5mL), stirred at room temperature for 0.5h, and concentrated under reduced pressure to give the title compound as a brown oil (200mg, 97%).
Step 6: synthesis of Compound 11
Compound F2(152mg,0.45mmol) and HATU (199mg,0.50mmol) were dissolved in DMF (5mL), to which DIPEA (160mg,1.23mmol) and compound 11-5(150mg,0.41mmol) were added and stirred at room temperature for 11 h. Water (20mL) was added to dilute the solution, and the solution was extracted with dichloromethane (20mL), the organic phase was washed successively with 1M hydrochloric acid (20mL), saturated aqueous sodium bicarbonate (20mL), and saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 1/1) to give the title compound as a yellow solid (110mg, 39%). MS (ESI, pos. ion) M/z 682.2[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.59(s,1H),8.09–7.98(m,1H),7.77–7.68(m,1H),7.25(d,J＝8.8Hz,1H),7.17–7.09(m,2H),7.06(dd,J＝8.5,2.3Hz,1H),6.88(td,J＝8.4,2.2Hz,1H),5.81(s,1H),4.89–4.75(m,1H),4.33–4.21(m,1H),3.96–3.86(m,1H),3.66(s,3H),3.64–3.58(m,1H),3.55(s,3H),3.23(dd,J＝18.2,6.9Hz,1H),2.38(s,3H),2.32(s,3H),1.59–1.50(m,1H),1.16–1.08(m,1H),0.86–0.79(m,1H),0.78–0.71(m,1H),0.60–0.51(m,1H).
Synthesis of example 12
Figure BDA0003482027340000521
Example 12 was prepared as a yellow solid (150mg, 55.6%) with reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 718.2[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.49(s 1H),7.89(d,J＝6.5Hz,1H),7.67–7.58(m,1H),7.43–7.31(m,5H),7.30–7.25(m,1H),7.19(d,J＝8.9Hz,1H),7.12–7.02(m,2H),6.96(td,J＝8.3,2.4Hz,1H),5.92(d,J＝30.2Hz,1H),4.68–4.57(m,1H),3.85–3.75(m,1H),3.69–3.61(m,1H),3.60(s,3H),3.57(s,3H),3.51(t,J＝9.1Hz,1H),3.40(dd,J＝18.4,4.5Hz,1H),2.33(s,3H),2.28(s,3H).
Synthesis of example 13
Figure BDA0003482027340000522
Example 13 was prepared as a yellow solid (150mg, 55.7%) with reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 719.3[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.63(s,2H),8.05–7.96(m,1H),7.76–7.65(m,2H),7.53(d,J＝6.3Hz,1H),7.37–7.30(m,2H),7.19–7.09(m,3H),6.98(td,J＝8.3,2.5Hz,1H),6.12(s,1H),4.72–4.67(m,1H),3.98–3.90(m,1H),3.68(s,3H),3.62(s,3H),3.60–3.50(m,2H),3.41(dd,J＝18.4,4.8Hz,1H),2.37(s,3H),2.30(s,3H).
Synthesis of example 14
Figure BDA0003482027340000531
Example 14 was prepared as a yellow solid (181mg, 80.4%) with reference to the synthesis of example 11. MS (ESI, pos. ion) M/z 682.2[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.06(d,J＝7.9Hz,1H),7.77–7.67(m,1H),7.52(d,J＝4.8Hz,1H),7.33–7.26(m,1H),7.21(d,J＝8.7Hz,1H),7.17–7.11(m,1H),7.08(dd,J＝8.6,2.4Hz,1H),6.96–6.89(m,1H),5.92(s,1H),4.70(d,J＝4.7Hz,1H),4.19–4.12(m,1H),4.09(d,J＝10.6Hz,1H),3.69(s,3H),3.59(s,3H),3.49(d,J＝18.2Hz,1H),3.39(dd,J＝18.5,6.7Hz,1H),2.40(s,3H),2.36(s,3H),1.60–1.51(m,1H),1.19–1.10(m,1H),0.88–0.79(m,2H),0.78–0.67(m,1H).
Synthesis of example 15
Figure BDA0003482027340000532
Example 15 was prepared by reference to the synthesis of example 6 as a yellow solid (130mg, 60.3%). MS (ESI, pos. ion) M/z 718.2[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.79(s,1H),7.71–7.62(m,1H),7.45–7.26(m,7H),7.18–7.09(m,3H),7.04–6.96(m,1H),6.13(s,1H),4.58(s,1H),3.89–3.79(m,1H),3.68(s,3H),3.61(s,3H),3.60–3.51(m,1H),3.48(d,J＝6.7Hz,1H),3.42(dd,J＝18.1,2.5Hz,1H),2.38(s,3H),2.32(s,3H).
Synthesis of example 16
Figure BDA0003482027340000541
Example 16 was prepared as a white solid (35mg, 14.46%) by reference to the synthesis of example 7.
MS(ESI,pos.ion)m/z:764.2[M+H] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.42(s,1H),9.17(d,J＝5.5Hz,1H),7.93(d,J＝3.1Hz,1H),7.91–7.83(m,1H),7.81(d,J＝3.0Hz,1H),7.65(s,1H),7.48–7.40(m,2H),7.38(dd,J＝8.8,2.4Hz,1H),7.23–7.14(m,1H),6.03(s,1H),4.44(d,J＝9.1Hz,1H),4.35–4.25(m,1H),3.58(s,3H),3.28(d,J＝7.6Hz,1H),2.92(d,J＝15.6Hz,1H),2.38(s,3H),2.17(s,3H),1.11(s,3H),0.41(s,3H).
Synthesis of example 17
Figure BDA0003482027340000542
Example 17 was prepared as a white solid (90mg, 25.7%) by reference to the synthesis of example 7. MS (ESI, pos. ion) M/z 858.2[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.75–8.29(m,1H),7.86(d,J＝3.0Hz,1H),7.72–7.65(m,1H),7.42(d,J＝3.1Hz,3H),7.37(s,1H),7.25–7.15(m,2H),7.14–7.06(m,1H),7.06–6.99(m,1H),6.96–6.88(m,1H),6.84–6.69(m,1H),6.67–6.53(m,1H),6.00(s,1H),4.52(d,J＝4.3Hz,1H),3.64(s,3H),3.58–3.46(m,1H),2.94–2.80(m,1H),2.34(s,3H),2.32(s,1H),2.30(s,3H),2.19(s,1H),2.04(s,1H),1.90–1.80(m,2H),1.79–1.67(m,4H).
Synthesis of example 18
Figure BDA0003482027340000551
Example 18 was prepared by reference to the synthesis of example 7 as a light yellow solid (90mg, 22%). MS (ESI, pos.ion) M/z 806.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.43(s,1H),9.18(d,J＝5.7Hz,1H),7.97–7.92(m,1H),7.88–7.79(m,2H),7.51–7.46(m,1H),7.46–7.42(m,1H),7.38(dd,J＝8.9,2.4Hz,1H),7.23–7.14(m,2H),6.08(s,1H),4.44(d,J＝10.6Hz,2H),4.37–4.27(m,1H),3.58(s,3H),3.45–3.41(m,1H),3.32–3.26(m,1H),3.04–2.93(m,1H),2.39(s,3H),2.16(s,3H),1.66–1.51(m,3H),1.46(d,J＝12.8Hz,1H),1.20–1.15(m,1H),1.14–1.02(m,2H),0.90–0.83(m,1H),0.79(d,J＝6.5Hz,3H).
Synthesis of example 19
Figure BDA0003482027340000552
Example 19 was prepared as a white solid (70mg, 20%) by the synthetic method of reference example 7. MS (ESI, pos. ion) M/z 856.30[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.43(s,1H),7.85(d,J＝3.0Hz,1H),7.77–7.69(m,1H),7.66(d,J＝7.5Hz,1H),7.42(d,J＝3.0Hz,1H),7.37–7.31(m,1H),7.27(s,2H),7.22(d,J＝2.4Hz,2H),7.11–6.98(m,2H),6.93(t,J＝7.1Hz,1H),6.04(s,1H),5.30(s,1H),4.71(s,1H),4.62–4.52(m,1H),4.45–4.37(m,1H),4.33(d,J＝11.5Hz,1H),3.88(d,J＝9.5Hz,1H),3.78–3.67(m,1H),3.64(s,3H),3.61–3.53(m,2H),2.99(t,J＝11.8Hz,1H),2.92–2.80(m,1H),2.75(dd,J＝15.8,4.6Hz,1H),2.34(s,3H),2.33(s,3H).
Synthesis of example 20
Figure BDA0003482027340000561
Example 20 was prepared as a white solid (70mg, 20%) by the synthetic method of reference example 7. MS (ESI, pos. ion) M/z 856.30[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.26(s,1H),7.85(d,J＝3.1Hz,1H),7.80–7.71(m,1H),7.43(d,J＝3.2Hz,1H),7.39–7.32(m,3H),7.31–7.27(m,4H),7.20–7.08(m,2H),7.00(t,J＝6.8Hz,1H),6.18(s,1H),5.62(br,1H),4.71–4.61(m,1H),4.60–4.53(m,1H),4.47–4.35(m,2H),3.72–3.55(m,5H),3.45–3.35(m,1H),3.27–3.17(m,2H),2.75–2.55(m 3H),2.36(s,3H),2.34(s,3H).
Synthesis of example 21
Figure BDA0003482027340000562
Example 21 was prepared as a white solid (0.16g, 48%) with reference to the synthesis of example 7. MS (ESI, pos. ion) M/z 750.20[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.41(s,1H),9.18(d,J＝5.5Hz,1H),7.93(d,J＝3.1Hz,1H),7.91–7.83(m,1H),7.81(d,J＝3.1Hz,1H),7.55(d,J＝3.5Hz,1H),7.48–7.41(m,2H),7.39(dd,J＝8.8,2.3Hz,1H),7.19(td,J＝8.4,2.3Hz,1H),6.06(s,1H),4.45(d,J＝9.2Hz,2H),4.37–4.20(m,1H),3.58(s,3H),2.95(d,J＝14.8Hz,1H),2.53(d,J＝8.8Hz,2H),2.38(s,3H),2.17(s,3H),0.52(d,J＝6.9Hz,2H),0.42–0.28(m,1H),0.29–0.19(m,1H).
Synthesis of example 22
Figure BDA0003482027340000571
Example 22 was prepared by reference to the synthesis of example 6 as a yellow solid (210mg, 75.2%). MS (ESI, pos. ion) M/z 719.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.41(s,1H),9.33(d,J＝4.6Hz,1H),8.82(d,J＝4.0Hz,1H),8.77(s,1H),8.10(d,J＝7.7Hz,1H),7.90–7.81(m,1H),7.77–7.68(m,1H),7.63(dd,J＝7.8,4.9Hz,1H),7.50–7.36(m,3H),7.13(td,J＝8.4,2.4Hz,1H),6.16(s,1H),4.49(d,J＝1.5Hz,1H),4.15–4.08(m,1H),3.79(d,J＝11.2Hz,2H),3.59(s,3H),3.57(s,3H),3.35(dd,J＝18.1,6.3Hz,1H),2.34(s,3H),2.18(s,3H).
Synthesis of example 23
Figure BDA0003482027340000572
Example 23 was prepared as a white solid (180mg, 59.9%) by reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 611.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.41(s,1H),9.21(d,J＝5.6Hz,1H),7.98(d,J＝3.2Hz,1H),7.88(d,J＝3.2Hz,1H),7.87–7.82(m,1H),7.49–7.36(m,2H),4.55(q,J＝6.3Hz,1H),4.50–4.43(m,1H),4.40(d,J＝11.7Hz,1H),4.34(dd,J＝11.8,5.2Hz,1H),3.65(s,3H),3.58(s,3H),3.28(d,J＝17.9Hz,1H),3.14(dd,J＝18.0,6.7Hz,1H),2.38(s,3H),2.20(s,3H),1.16(d,J＝6.4Hz,3H).
Synthesis of example 24
Figure BDA0003482027340000581
Example 24 was prepared as a white solid (150mg, 52.2%) by reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 673.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.42(s,1H),9.22(d,J＝6.2Hz,1H),7.96(d,J＝3.2Hz,1H),7.92–7.81(m,2H),7.48–7.40(m,2H),7.37–7.29(m,4H),7.27–7.20(m,1H),5.62(s,1H),4.57–4.41(m,3H),3.59(s,3H),3.56(s,3H),3.34–3.31(m,1H),3.23(dd,J＝18.0,4.9Hz,1H),2.38(s,3H),2.19(s,3H).
Synthesis of example 25
Figure BDA0003482027340000582
Example 25 was prepared as a white solid (530mg, 73.8%) with reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 673.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.38(s,1H),9.24(d,J＝4.5Hz,1H),8.12(d,J＝5.2Hz,2H),7.92–7.81(m,1H),7.49–7.37(m,4H),7.31–7.22(m,3H),5.65(s,1H),4.52(d,J＝10.6Hz,2H),4.42(dd,J＝11.8,5.2Hz,2H),3.60(s,3H),3.53(s,3H),3.26(dd,J＝17.9,6.3Hz,1H),2.28(s,3H),2.18(s,3H).
Synthesis of example 26
Figure BDA0003482027340000591
Example 26 was prepared by reference to the synthesis of example 6 as a yellow solid (120mg, 39.5%). MS (ESI, pos. ion) M/z 597.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.46(s,1H),9.20(d,J＝6.1Hz,1H),7.97(d,J＝3.2Hz,1H),7.92–7.83(m,2H),7.48–7.37(m,2H),4.50–4.40(m,2H),4.38–4.27(m,3H),3.64(s,3H),3.58(s,3H),3.20–3.14(m,2H),2.38(s,3H),2.20(s,3H).
Synthesis of example 27
Figure BDA0003482027340000601
Example 27 was prepared as an off-white solid (112mg, 53.80%) by reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 663.3[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.45(s,1H),9.21(d,J＝6.4Hz,1H),7.97(d,J＝3.2Hz,1H),7.92–7.81(m,2H),7.52(d,J＝15.6Hz,2H),7.44(d,J＝5.5Hz,2H),6.42(s,1H),5.56(s,1H),4.59–4.38(m,3H),3.63(s,3H),3.58(s,3H),3.44–3.39(m,1H),3.15(dd,J＝17.6,5.8Hz,1H),2.38(s,3H),2.19(s,3H).
Synthesis of example 28
Figure BDA0003482027340000611
Example 28 was prepared as an off-white solid (136mg, 65.3%) with reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 663.3[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.42(s,1H),9.19(d,J＝4.6Hz,1H),7.99(d,J＝3.1Hz,1H),7.93–7.83(m,2H),7.54(s,1H),7.48(d,J＝9.8Hz,1H),7.46–7.37(dd,J＝16.6,7.3Hz,2H),6.47(s,1H),5.55(s,1H),4.52(d,J＝11.6Hz,1H),4.48–4.42(m,1H),4.38(dd,J＝11.6,5.1Hz,1H),3.63(s,3H),3.56(s,3H),3.43(d,J＝18.1Hz,1H),3.20(dd,J＝18.0,6.5Hz,1H),2.30(s,3H),2.19(s,3H).
Synthesis of example 29
Figure BDA0003482027340000621
Example 29 was prepared as an off-white solid according to the synthetic method of example 6 (153mg, 76.1%). MS (ESI, pos. ion) M/z 663.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.40(s,1H),9.21(d,J＝4.6Hz,1H),7.98(d,J＝3.2Hz,1H),7.92–7.80(m,2H),7.47(s,1H),7.45–7.37(m,2H),6.31(d,J＝2.8Hz,1H),6.24(d,J＝3.0Hz,1H),5.67(s,1H),4.54(d,J＝11.6Hz,1H),4.45(d,J＝5.0Hz,1H),4.37(dd,J＝11.6,5.3Hz,1H),3.61(s,3H),3.56(s,3H),3.45(d,J＝18.0Hz,1H),3.28–3.13(m,1H),2.34(s,3H),2.20(s,3H).
Synthesis of example 30
Figure BDA0003482027340000631
Example 30 was prepared as an off-white solid (53mg, 60.1%) with reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 663.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.42(s,1H),9.22(d,J＝6.1Hz,1H),7.97(d,J＝3.2Hz,1H),7.91–7.83(m,2H),7.54(s,1H),7.47–7.39(m,2H),6.39–6.33(m,1H),6.23(d,J＝3.1Hz,1H),5.70(s,1H),4.60–4.38(m,3H),3.60(s,3H),3.58(s,3H),3.41(dd,J＝16.9,5.8Hz,1H),3.22(dd,J＝17.9,4.8Hz,1H),2.37(s,3H),2.18(s,3H).
Synthesis of example 31
Figure BDA0003482027340000641
Example 31 was prepared as a white solid (70mg, 25%) according to the synthetic method of example 3 (wherein compound 31-5 was prepared according to the synthetic method of compound 3-1). MS (ESI, pos. ion) M/z 650.20[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)10.39(s,1H),9.15(d,J＝6.0Hz,1H),7.94(d,J＝3.2Hz,1H),7.90–7.82(m,2H),7.46–7.40(m,2H),5.76(s,1H),4.52(q,J＝6.3Hz,1H),4.42–4.36(m,2H),4.33–4.25(m,2H),3.57(s,3H),3.42(d,J＝2.4Hz,2H),2.91(dd,J＝16.2,6.4Hz,1H),2.59–2.55(m,1H),2.36(s,3H),2.16(s,3H),1.92–1.69(m,4H),1.16(d,J＝6.5Hz,3H).
Synthesis of example 32
Figure BDA0003482027340000651
Example 32 was prepared as a white solid (85mg, 21%) by the synthetic method of reference example 3. MS (ESI, pos. ion) M/z 650.20[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)10.41(s,1H),9.19(d,J＝5.8Hz,1H),7.95(d,J＝3.1Hz,1H),7.91–7.82(m,2H),7.48–7.37(m,2H),4.50–4.32(m,3H),4.22(d,J＝9.3Hz,1H),3.59(s,3H),3.38(s,4H),2.81(dd,J＝16.1,6.3Hz,1H),2.72–2.65(m,1H),2.40(s,3H),2.23(s,3H),1.80(d,J＝6.6Hz,4H),1.19(d,J＝6.4Hz,3H).
Synthesis of example 33
Figure BDA0003482027340000652
Example 33 was prepared as a white solid (74mg, 26%) by reference to the synthesis of example 7. MS (ESI, pos. ion) M/z 666.20[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.40(s,1H),9.17(d,J＝6.2Hz,1H),7.94(d,J＝3.2Hz,1H),7.90–7.85(m,1H),7.83(d,J＝3.2Hz,1H),7.46–7.41(m,2H),4.47(q,J＝6.3Hz,1H),4.44–4.37(m,1H),4.36–4.25(m,2H),3.60(s,2H),3.58(d,J＝5.8Hz,6H),3.48–3.41(m,2H),2.86(dd,J＝16.1,6.5Hz,1H),2.54(d,J＝3.3Hz,1H),2.35(s,3H),2.16(s,3H),1.18(d,J＝6.5Hz,3H).
Synthesis of example 34
Figure BDA0003482027340000661
Example 34 was prepared as a white solid (90mg, 22%) by reference to the synthesis of example 7. MS (ESI, pos. ion) M/z 666.20[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.42(s,1H),9.21(d,J＝5.7Hz,1H),7.95(d,J＝3.0Hz,1H),7.91–7.81(m,2H),7.47–7.39(m,2H),4.48–4.31(m,3H),4.22(d,J＝10.6Hz,1H),3.59(s,3H),3.57(s,4H),3.55–3.51(m,2H),3.50–3.44(m,2H),2.80(dd,J＝16.1,6.2Hz,1H),2.65(d,J＝15.5Hz,1H),2.40(s,3H),2.23(s,3H),1.21(d,J＝6.4Hz,3H).
Synthesis of example 35
Figure BDA0003482027340000662
Step 1: synthesis of Compound 35-1
Compound 3-1(150mg,0.86mmol) was dissolved in DMF (5mL) and DIPEA (445mg, 3)44mmol), HATU (491mg,1.29mmol), stirring for 20min, addition of ammonium chloride (68mg,1.32mmol), stirring at room temperature for 23h, addition of dichloromethane (20mL), then washing with water (10mL × 5), drying of the organic phase with anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) ═ 1/2) to afford the title compound as a yellow solid (371mg, 88%). MS (ESI, pos.ion) M/z 492.3[ M + H ]] + 。
Step 2: synthesis of Compound 35-2
Compound 35-1(357mg,0.73mmol) was dissolved in DMF (5mL), pyridine (462mg,5.84mmol) and TFAA (613mg,2.92mmol) were added, stirred at room temperature for 2h, ethyl acetate (15mL) was added, then washed with water (10mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) ═ 3/1) to give the title compound as a light brown solid (216mg, 62%). MS (ESI, pos.ion) M/z 474.2[ M + H ]] + 。
And step 3: synthesis of Compound 35-3
Compound 35-2(216mg,0.46mmol) was dissolved in ethyl acetate (2mL), and ethyl acetate solution of hydrogen chloride (3mL,4mol/L) was added, stirred at room temperature for 2h, and concentrated under reduced pressure to give the title compound as a tan solid (190mg, 100%). MS (ESI, pos.ion) M/z 374.1[ M + H ]] + 。
And 4, step 4: synthesis of Compound 35
Compound F2(153mg,0.46mmol) and HATU (213mg,0.56mmol) were dissolved in DMF (10mL), then DIPEA (179mg,1.38mmol) was added, compound 35-3(190mg,0.46mmol) was added after stirring at room temperature for 10min, the reaction mixture was stirred at room temperature for 21h, ethyl acetate (20mL) was added for dilution, then washing with water (10mL × 5), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) ═ 1/1) to afford the title compound as an off-white solid (131mg, 41%). MS (ESI, pos. ion) M/z 692.0[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.42(s,1H),9.31(d,J＝5.8Hz,1H),8.01(d,J＝3.2Hz,1H),7.92(d,J＝3.2Hz,1H),7.91–7.83(m,1H),7.67–7.58(m,1H),7.51(dd,J＝8.7,2.7Hz,1H),7.48–7.38(m,2H),7.32(td,J＝8.5,2.6Hz,1H),5.92(s,1H),4.55(d,J＝10.3Hz,2H),4.52–4.45(m,1H),3.60(s,3H),3.23(dd,J＝16.9,6.6Hz,1H),2.90(dd,J＝17.0,2.9Hz,1H),2.41(s,3H),2.22(s,3H).
Synthesis of example 36
Figure BDA0003482027340000671
Step 1: synthesis of Compound 36-1
(3R) -4-benzyloxy-3- (tert-butoxycarbonylamino) -4-oxobutanoic acid (2.00g,6.19mmol) was dissolved in DCM (10mL), DMAP (1.19g,9.25mmol) was added, stirring at room temperature for 10min, then Meldrum's acid (0.94g,6.5mmol) was added, the temperature was reduced to 0 deg.C, and EDCI (1.87g,9.27mmol) in DCM (10mL) was added dropwise and stirring continued at 0 deg.C for 15 h. The reaction solution was washed with 1M hydrochloric acid (10 mL. times.3) and saturated brine (10 mL. times.1) in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow liquid (2.78g, 100%). MS (ESI, pos. ion) M/z 472.05[ M + Na ]] + 。
Step 2: synthesis of Compound 36-2
Compound 36-1 was dissolved in methanol (3mL) and toluene (8mL), the reaction was stirred for 23h at 70 ℃ and concentrated under reduced pressure, and the residue was used directly in the next reaction.
And step 3: synthesis of Compound 36-3
A reaction flask was charged with compound 36-2(2.35g,6.19mmol), 2-chloro-4-fluoro-benzaldehyde (1.05g,6.49mmol), 2-thiazolecarboxamidine hydrochloride (1.23g,7.11mmol, 94.6%), THF (20mL) and NMM (1.7mL,15mmol), stirred at 60 ℃ for 5h and cooled to room temperature for use in the next reaction.
And 4, step 4: synthesis of Compound 36-4
Cooling the reaction solution in the last step to 5 ℃, dropwise adding a THF (5mL) solution of isobutyl chlorobutyrate (0.98mL,7.4mmol), and stirring at 5 ℃ after dropwise addingThe reaction was stirred for 2h, diluted with ethyl acetate (30mL), washed with water (30mL × 1) and saturated brine (50mL × 1) in this order, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) ═ 3/1) to give the title compound as a yellow solid (0.7g, 22%). MS (ESI, pos. ion) M/z 521.20[ M + H ]] + 。
And 5: synthesis of Compound 36-5
Sodium borohydride (0.11g,2.8mmol) was dissolved in water (2mL), to which a solution of compound 36-4(0.70g,1.3mmol) in THF (10mL) was added dropwise under ice-bath, and the reaction was stirred at room temperature for 16 h. The reaction was quenched by the addition of water (20mL), extracted with ethyl acetate (20mL), and the organic phase was washed successively with water (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid (0.64g, 91%). MS (ESI, pos.ion) M/z 525.00[ M + H ]] + 。
Step 6: synthesis of Compound 36-6
Compound 36-5(0.64g,1.2mmol) and DMAP (0.45g,3.7mmol) were dissolved in DCM (10mL), methanesulfonyl chloride (0.19mL,2.5mmol) was slowly added dropwise thereto under ice bath, and after completion of addition, the reaction was stirred at 35 ℃ with slow warming for 20 h. The reaction mixture was washed with 1M hydrochloric acid (20mL), water (20mL) and saturated brine (20mL) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown solid (0.6g, 97%). MS (ESI, pos. ion) M/z 507.00[ M + H ]] + 。
And 7: synthesis of Compound 36-7
Compound 36-7(0.20g,0.39mmol) was dissolved in DCM (5mL), trifluoroacetic acid (0.5mL) was added, stirred at room temperature for 1.5h, concentrated under reduced pressure, and the residue was used directly in the next reaction.
And 8: synthesis of Compound 36
Compound 36-7(0.21g,0.40mmol) was dissolved in DMF (5mL), DIPEA (0.10g,0.77mmol), compound F2(0.16g,0.48mmol) and HATU (0.18g,0.47mmol) were added and stirred at room temperature for 24 h. Dilute with dichloromethane (20mL) and water (50mL) and reverse the aqueous phase with dichloromethane (20mL)After extraction, the organic phases were combined, washed with 1M hydrochloric acid (50mL), saturated sodium bicarbonate solution (50mL), and saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) ═ 1/1) to give a white solid (90mg, 30%). MS (ESI, pos. ion) M/z 724.90[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.42(s,1H),9.19(t,J＝30.4Hz,1H),7.97(d,J＝3.2Hz,1H),7.91–7.83(m,2H),7.56–7.47(m,1H),7.47–7.37(m,3H),7.18(td,J＝8.5,2.6Hz,1H),6.02(s,1H),4.65–4.53(m,1H),4.46(d,J＝5.2Hz,2H),3.57(s,3H),3.52(s,3H),3.49–3.41(m,1H),3.28(dd,J＝17.8,4.7Hz,1H),2.39(s,3H),2.20(s,3H).
Synthesis of example 37
Figure BDA0003482027340000691
Example 37 was prepared by the method of synthesis of reference example 36 as a white solid product (0.28g, 94%). MS (ESI, pos. ion) M/z 724.90[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.39(s,1H),9.31(d,J＝5.0Hz,1H),7.97(d,J＝3.2Hz,1H),7.91–7.83(m,2H),7.53(dd,J＝8.6,6.4Hz,1H),7.46–7.38(m,3H),6.98(td,J＝8.4,2.5Hz,1H),6.01(s,1H),4.56(d,J＝11.7Hz,1H),4.53–4.45(m,1H),4.34(dd,J＝11.7,5.2Hz,1H),3.62–3.46(m,7H),3.28(dd,J＝18.0,6.6Hz,1H),2.36(s,3H),2.22(s,3H).
Synthesis of example 38
Figure BDA0003482027340000692
Example 38 was prepared as a beige solid (206mg, 62.39%) by reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 715.1[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.84(d,J＝18.0Hz,2H),7.77–7.66(m,1H),7.59–7.38(m,2H),7.26–7.08(m,2H),4.71(s,2H),4.60–4.38(m,2H),3.73(s,3H),3.62(s,3H),3.22–3.06(m,1H),2.35(s,3H),2.28(s,3H),2.17–2.04(m,2H),1.87(d,J＝13.1Hz,1H),1.77–1.56(m,5H),1.46–1.30(m,2H).
Synthesis of example 39
Figure BDA0003482027340000701
Example 39 was prepared as an off-white solid (134mg, 35.14%) by reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 637.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.42(s,1H),9.17(d,J＝6.3Hz,1H),7.96(d,J＝3.2Hz,1H),7.91–7.82(m,2H),7.48–7.38(m,2H),4.45–4.33(m,3H),4.27(d,J＝6.7Hz,1H),3.66(s,3H),3.58(s,3H),3.40–3.35(m,1H),3.11(dd,J＝17.7,5.5Hz,1H),2.38(s,3H),2.18(s,3H),1.09–0.94(m,1H),0.45–0.19(m,4H).
Synthesis of example 40
Figure BDA0003482027340000702
Example 40 was prepared as an off-white solid (173mg, 57.31%) with reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 637.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.43(s,1H),9.21(d,J＝5.2Hz,1H),7.98(d,J＝3.2Hz,1H),7.91–7.81(m,2H),7.47–7.36(m,2H),4.49–4.40(m,2H),4.39–4.31(m,1H),4.16(d,J＝7.2Hz,1H),3.66(s,3H),3.58(s,3H),3.42–3.36(m,1H),3.15(dd,J＝18.0,6.7Hz,1H),2.40(s,3H),2.22(s,3H),1.10–0.98(m,1H),0.47–0.23(m,4H).
Synthesis of example 41
Figure BDA0003482027340000711
Example 41 was prepared as an off-white solid (168mg, 57.02%) with reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 679.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.42(s,1H),9.21(d,J＝6.2Hz,1H),7.97(d,J＝3.2Hz,1H),7.91–7.82(m,2H),7.48–7.39(m,3H),7.28(d,J＝2.2Hz,1H),7.09(d,J＝5.0Hz,1H),5.71(s,1H),4.59–4.39(m,3H),3.62(s,3H),3.58(d,J＝10.0Hz,3H),3.45–3.37(m,1H),3.18(dd,J＝17.7,5.4Hz,1H),2.39(s,3H),2.20(s,3H).
Synthesis of example 42
Figure BDA0003482027340000712
Example 42 was prepared as an off-white solid (157mg, 53.28%) by reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 679.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.38(s,1H),9.18(d,J＝4.6Hz,1H),7.99(d,J＝3.2Hz,1H),7.92–7.82(m,2H),7.47–7.39(m,2H),7.37–7.34(m,1H),7.32(s,1H),7.12(d,J＝4.9Hz,1H),5.69(s,1H),4.54(d,J＝11.6Hz,1H),4.49–4.42(m,1H),4.38(dd,J＝11.7,5.2Hz,1H),3.62(s,3H),3.55(s,3H),3.45(d,J＝17.9Hz,1H),3.22(dd,J＝18.0,6.6Hz,1H),2.29(s,3H),2.18(s,3H).
Synthesis of example 43
Figure BDA0003482027340000721
Example 43 was prepared as a beige solid (69mg, 8.3%) with reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 715.1[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.86(s,1H),7.78–7.64(m,1H),7.54(s,1H),7.46(s,1H),7.21–7.05(m,3H),4.87–4.75(m,1H),4.75–4.64(m,1H),4.61–4.40(m,2H),3.76(s,3H),3.71(s,3H),3.46(d,J＝18.1Hz,1H),3.34–3.18(m,1H),2.40(s,3H),2.37(s,3H),2.22–2.08(m,2H),1.90(d,J＝12.0Hz,1H),1.81–1.68(m,5H),1.46–1.41(m,1H).
Synthesis of example 44
Figure BDA0003482027340000722
Example 44 was prepared as a light yellow solid (93mg, 57.45%) by reference to the synthetic procedure of example 6. MS (ESI, pos. ion) M/z 677.3[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)9.05(d,J＝6.2Hz,1H),8.80(s,1H),7.90(d,J＝3.2Hz,1H),7.71–7.62(m,1H),7.49(d,J＝3.2Hz,1H),7.32-7.27(m,1H),7.14–7.05(m,2H),6.14(s,1H),4.84–4.76(m,1H),4.65(d,J＝12.6Hz,1H),4.55(dd,J＝12.6,4.7Hz,1H),4.13(s,3H),3.86(d,J＝13.3Hz,1H),3.73(s,3H),3.59(s,3H),3.23–3.15(m,2H),2.37(s,3H),2.31(s,3H).
Synthesis of example 45
Figure BDA0003482027340000731
A reaction flask was charged with a solution of compound 1 (i.e., compound of example 1) (500mg,0.69mmol), methanol (4mL), tetrahydrofuran (4mL), and sodium hydroxide (82.8mg,2.07mmol) in water (2mL), and the temperature was raised to 80 ℃ for reaction for 16 h. The reaction solution was spin-dried, and dichloromethane (50mL) and 1M (50mL) hydrochloric acid were added to dilute the solution, the layers were separated, the aqueous phase was back-extracted with dichloromethane (20mL × 2), the organic phases were combined, the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) ═ 2/3) to give a white solid (75mg, 15.1%). MS (ESI, pos. ion) M/z 711.20[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.97(s,2H),7.81(s,1H),7.70(s,1H),7.40(s,1H),7.28(s,2H),7.24–7.18(m,1H),7.13(d,J＝7.5Hz,1H),6.93(t,J＝10.0Hz,1H),6.05(s,1H),4.82(s,1H),4.62(d,J＝5.5Hz,1H),3.68(d,J＝19.2Hz,2H),3.61(s,2H),2.35(s,3H),2.28(s,3H).
Synthesis of example 46
Figure BDA0003482027340000732
Example 46 (starting from example 36) was prepared according to the synthesis method of example 45 as a white solid (46mg, 24.32%). MS (ESI, pos. ion) M/z 711.20[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.03(br,2H),7.82(d,J＝2.7Hz,1H),7.73–7.65(m,1H),7.40(d,J＝2.6Hz,1H),7.26–7.18(m,2H),7.18–7.07(m,2H),6.93(t,J＝8.0Hz,1H),6.01(s,1H),4.87(s,1H),4.64(d,J＝6.3Hz,2H),3.70(dd,J＝20.6,10.3Hz,1H),3.56(s,3H),3.23(d,J＝12.2Hz,1H),2.32(s,3H),2.25(s,3H).
Synthesis of example 47
Figure BDA0003482027340000741
Step 1: synthesis of Compound 47-1
A reaction flask was charged with compound F5(240mg,0.49mmol, which was prepared in reference to the synthesis of compound 3-1), ammonium chloride (27.52mg,0.51mmol), HATU (224mg,0.59mmol), DIPEA (127mg,0.98mmol) and DMF (6mL), and the reaction was stirred at room temperature for 5 h. Water (50mL) was added to dilute the mixture, followed by extraction with dichloromethane (25mL), aqueous phase was extracted with dichloromethane (10mL), the organic phases were combined, the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, the filtrate was spun dry, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) ═ 2/3) to give the product as a yellow solid (220mg, 91.3%). MS (ESI, pos.ion) M/z 492.3[ M + H ]] + 。
Step 2: synthesis of Compound 47-2
Compound 47-1 was dissolved in 1, 4-dioxane (4mL), HCl in 1.4-dioxane (4mL,4.01M/L) was added, the mixture was stirred at room temperature for 17h, and the reaction was spin-dried and used directly in the next step. MS (ESI, pos. ion) M/z 392.0[ M + H ]] + 。
And step 3: synthesis of Compound 47
Compound 47-2(0.19g,0.44mmol), compound F2(0.15g,0.44mmol), HATU (0.20g,0.53mmol), DIPEA (0.11g,0.88mmol) and DMF (10mL) were added to the reaction flask and stirred at room temperature for 7 h. Diluting with 1M hydrochloric acid (50mL), extracting with ethyl acetate (20mL), extracting the aqueous phase with ethyl acetate (20 mL. times.2), combining the organic phases, washing with saturated brine(50mL), dried over anhydrous sodium sulfate, filtered, the filtrate was spun dry, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) ═ 1/2) to give a pale yellow solid (44mg, 13.2%). MS (ESI, pos. ion) M/z 710.0[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.41(s,1H),9.21(d,J＝5.9Hz,1H),7.92(d,J＝3.1Hz,1H),7.86(dd,J＝13.1,7.7Hz,1H),7.80(d,J＝3.1Hz,1H),7.49–7.36(m,4H),7.26–7.16(m,1H),6.86(s,2H),6.06(s,1H),4.53–4.38(m,2H),4.33(dd,J＝11.8,5.9Hz,1H),3.58(s,3H),3.49–3.44(m,1H),3.05(dd,J＝17.1,3.0Hz,1H),2.37(s,3H),2.18(s,3H).
Synthesis of example 48
Figure BDA0003482027340000751
Compound 48-6(0.37g,0.51mmol, which was prepared by the synthetic method described in example 6) was dissolved in methanol (9mL) and THF (6mL), a solution of sodium hydroxide (0.10g,2.55mmol) in water (3mL) was added, stirred at room temperature for 6h, the reaction was dried, diluted with (50mL) water and then extracted with dichloromethane (50mL), the aqueous phase was extracted with dichloromethane (20mL), the organic phases were combined, the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, the filtrate was dried, the residue was added with ethyl acetate (10mL), slurried for 19h, filtered, the filter cake was washed with ethyl acetate (5mL), and dried by rotary evaporation at 50 ℃ to give a yellow solid (37mg, 9.47%). MS (ESI, pos. ion) M/z 717.1[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.48(s,1H),9.30(d,J＝6.4Hz,1H),8.11–8.05(m,2H),7.92(d,J＝8.1Hz,2H),7.90–7.85(m,1H),7.55(d,J＝8.1Hz,2H),7.48–7.39(m,2H),5.76(s,1H),4.65–4.58(m,1H),4.52–4.42(m,2H),3.59(s,6H),3.50–3.44(m,1H),3.26(dd,J＝17.8,5.2Hz,1H),2.39(s,3H),2.20(s,3H).
Synthesis of example 49
Figure BDA0003482027340000752
Example 49 reference may be made toPrepared by the synthetic method of example 48 as a light yellow solid (67mg, 16.07%). MS (ESI, pos. ion) M/z 717.1[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.37(s,1H),9.24(d,J＝4.6Hz,1H),7.99(d,J＝3.0Hz,1H),7.89(d,J＝2.9Hz,1H),7.83(d,J＝8.0Hz,2H),7.51(d,J＝8.1Hz,2H),7.45–7.37(m,2H),5.69(s,1H),4.56(d,J＝11.7Hz,1H),4.51–3.43(m,1H),4.38(dd,J＝11.6,5.1Hz,1H),3.58(s,3H),3.55(s,3H),3.46–3.43(m,1H),3.29–3.25(m,1H),2.31(s,3H),2.21(s,3H).
Synthesis of example 50
Figure BDA0003482027340000761
Step 1: synthesis of Compound 50-1
The reaction flask was charged with compound 3-1(500mg,1.01mmol), dichloromethane (15mL), methylsulfonamide (383mg,4.03mmol), EDCI (290mg,1.52mmol) and DMAP (185mg,1.52mmol) and the reaction mixture was stirred at room temperature for 13 h. The reaction solution was washed with 0.5M hydrochloric acid (15mL), the aqueous phase was back-extracted with dichloromethane (10mL), the organic phases were combined, the combined organic phase was washed with saturated brine (15mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol (V/V) ═ 20/1) to give a beige solid (325mg, 56.45%). MS (ESI, pos. ion) M/z 570.3[ M + H ]] + 。
Step 2: synthesis of Compound 50-2
The reaction flask was charged with compound 50-1(325mg,0.57mmol), ethyl acetate (3mL) and a solution of hydrogen chloride in ethyl acetate (6mL,4mol/L), the reaction mixture was stirred at room temperature for 16h, and the solvent was removed by concentration to give a yellow foamy solid (310mg, 100%).
And step 3: synthesis of Compound 50
A reaction flask was charged with compound 50-2(192mg,0.57mmol), HATU (260mg,0.68mmol), DMF (10mL) and DIPEA (223mg,1.73mmol), stirred at room temperature for 10min, then added with compound F2(310mg,0.57mmol), and the reaction mixture was allowed to mixThe reaction was carried out at room temperature for 16 h. EA (20mL) was added to dilute, then washed with saturated NaCl solution (20mL × 5), the organic phase was concentrated, and the residue was purified by thin layer chromatography (DCM/MeOH (V/V) ═ 10/1) to give a light carmine solid (57mg, 12.7%). MS (ESI, pos. ion) M/z 788.0[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)11.17(s,1H),10.46(s,1H),9.25(d,J＝6.2Hz,1H),8.00–7.76(m,3H),7.56–7.32(m,4H),7.20(t,J＝8.7Hz,1H),6.14(s,1H),4.59–4.33(m,3H),3.59(s,3H),3.54–3.47(m,1H),3.36(s,3H),3.16(dd,J＝17.4,4.3Hz,1H),2.38(s,3H),2.19(s,3H).
Synthesis of example 51
Figure BDA0003482027340000771
Step 1: synthesis of Compound 51-1
Formic acid (23mL,609.60mmol) is added into a reaction bottle, triethylamine (42mL,303mmol) is slowly added under the ice-water bath, after the stirring is uniform, 4-formylbenzonitrile (10.00g,76.26mmol) and Meldrum's acid (10.99g,76.26mmol) are added, and the temperature is raised to about 100 ℃ for reaction for about 16.5 h. The heating was turned off. The reaction system was cooled to about 5 ℃, water (120mL) was slowly added to precipitate a white solid, which was acidified with hydrochloric acid (6M,45mL) to pH 1-2, and stirred for 4h at about 5 ℃. Suction filtered, the filter cake was washed with water (20mL) and rotary evaporated at 50 ℃ for 1h to give the title compound as a white solid (11.21g, 83.91%). MS (ESI, pos.ion) M/z 176.1[ M + H ]] + 。
And 2, step: synthesis of Compound 51-2
The compound 51-1(12.77g,72.90mmol), formic acid (135mL), water (45mL) and Raney nickel (12.80g,149.44mmol) were added to a reaction flask, stirred and warmed to 105 ℃ for about 1.3h, and cooled to room temperature. Suction was applied and the filter cake was washed successively with methanol (100mL) and water (50 mL). The filtrate was concentrated until a large amount of solid precipitated, and the residue was diluted with water (150mL) and stirred at room temperature for an additional 4 h. Suction filtration, filter cake washing with water (100mL), 60 ℃ vacuum drying for 5h, white solid (9.43g, 72.6%). MS (ESI, pos.ion) M/z 179.2[ M + H ]] + 。
And step 3: synthesis of Compound 51-3
The reaction flask was charged with compound 51-2(3.00g,16.84mmol) and MeOH (15mL), thionyl chloride (3.1mL,42.73mmol) was added slowly under ice bath, the temperature was raised to 70 ℃ after addition for 1h, cooled to room temperature, and the solvent was concentrated to give a brown oil (3.36g, 103.8%). MS (ESI, pos.ion) M/z 193.3[ M + H ]] + 。
And 4, step 4: synthesis of Compound 51-4
A reaction flask was charged with compound 51-3(3.36g,17.48mmol), compound F3(6.73g,17.13mmol), 2-thiazolecarboxamidine hydrochloride (3.95g,19.21mmol, content 79.6%), isopropanol (15mL) and 4-methylmorpholine (4.42g,43.66mmol), and stirred at 80 ℃ for 5.5 h. Heating was turned off, cooled to room temperature, the solvent was removed by concentration, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol (V/V) ═ 20/1) to give a yellow solid (7.06g, 70.5%). MS (ESI, pos. ion) M/z 573.2[ M + H ]
And 5: synthesis of Compound 51-5
Compound 51-4(7.06g,12.33mmol), THF (30mL) and 4-methylmorpholine (2.49g,24.66mmol) were charged into a reaction flask, the temperature was reduced to about 5 ℃, a solution of isobutyl chloroformate (2.02g,14.80mmol) in THF (10mL) was added dropwise, the reaction was continued for 0.5h, and the mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) ═ 1/1) to give a yellow solid (1.77g, 25.9%). MS (ESI, pos. ion) m/z: 555.5[ M + H] + 。
Step 6: synthesis of Compound 51-6
Adding NaBH into a reaction bottle 4 (0.24g,6.38mmol) and water (5mL), a THF (10mL) solution of compound 51-5(1.77g,3.19mmol) was added with stirring in an ice bath, the reaction was continued for about 30min in an ice bath after the addition, ethyl acetate (20mL) and water (10mL) were added, the aqueous phase was discarded, and the organic phase was washed with saturated brine (20 mL. times.2), anhydrous Na 2 SO 4 Drying, suction filtration, filter cake washing with ethyl acetate (10mL), filtrate concentration to give yellow solid (1.59g, 89.2%). MS (ESI, pos. ion) M/z 559.1[ M + H ]] + 。
And 7: synthesis of Compound 51-7
A reaction flask was charged with compound 51-6(1.59g,2.85mmol), dichloromethane (20mL) and NMM (1mL,9.10mmol), and MsCl (0.65g,5.67mmol) was added under ice-water bath and heated to 35 ℃ for 4 h. The reaction mixture was washed with 1M hydrochloric acid (20mL), water (20mL) and saturated brine (20mL) in this order, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) ═ 3/1) to give a light brown solid (518mg, 33.6%). MS (ESI, pos. ion) M/z 541.1[ M + H ]] + 。
And 8: synthesis of Compound 51-8
The reaction flask was charged with compound 51-7(518mg,0.96mmol) and 1, 4-dioxane (6mL,4M) as hydrochloric acid and the reaction was stirred at room temperature for 2 h. Suction filtration was performed, the filter cake was washed with dioxane (5mL), and rotary evaporation was performed at 50 ℃ for 1h to give a light brown solid (437mg, 95.4%). MS (ESI, pos. ion) M/z 441.3[ M + H ]] + 。
And step 9: synthesis of Compound 51-9
Compound F2(333mg,0.99mmol), HATU (452mg,1.19mmol), DMF (10mL), DIPEA (0.5mL,3.02mmol) were added to a reaction flask, and the mixture was stirred at room temperature for 10min, and compound 51-8(437mg,0.99mmol) was added to the reaction flask for about 4.5 h. The reaction mixture was diluted with ethyl acetate (20mL), washed with saturated NaCl (20mL × 5), the organic phase was concentrated, and the resulting residue was purified by thin layer chromatography (petroleum ether/ethyl acetate (V/V) ═ 1/1) to give a tan solid (496mg, 66.0%). MS (ESI, pos.ion) M/z 759.0[ M + H ]] + 。
Step 10: synthesis of Compound 51
Adding 51-9(200mg,0.26mmol), THF (3mL) and MeOH (3mL) into a reaction bottle, adding a water (3mL) solution of NaOH (13mg,0.33mmol), stirring at room temperature for reaction for 4h, adding water (10mL) for dilution, washing with petroleum ether (10mL), acidifying the washed water phase with 6M hydrochloric acid to pH 6-7, continuing stirring at room temperature for 30min, performing suction filtration, transferring the filter cake into a reaction bottle, stirring with petroleum ether (6mL) and ethyl acetate (3mL) at room temperature for 1h, performing suction filtration, washing with a mixed solution of petroleum ether and ethyl acetate (3mL, V/V is 2/1), and finally performing thin-layer chromatography on the washed solutionPurification by chromatography (dichloromethane/methanol (V/V) ═ 10/1) gave a light brown solid (84mg, 43.4%). MS (ESI, pos. ion) M/z 745.0[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.46(s,1H),9.22(d,J＝6.3Hz,1H),7.96(d,J＝3.2Hz,1H),7.93–7.82(m,2H),7.49–7.37(m,2H),7.23(d,J＝7.8Hz,2H),7.16(d,J＝7.9Hz,2H),5.59(s,1H),4.59–4.39(m,3H),3.59(s,3H),3.57(s,3H),3.43–3.40(m,1H),3.25–3.19(m,1H),2.77(t,J＝7.7Hz,2H),2.48(t,J＝7.9Hz,2H),2.38(s,3H),2.20(s,3H).
Synthesis of example 52
Figure BDA0003482027340000791
Example 52 was prepared as an off-white solid (113mg, 58.36%) with reference to the synthesis of example 51. MS (ESI, pos. ion) M/z 745.0[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.36(s,1H),9.23(d,J＝4.9Hz,1H),7.98(d,J＝3.3Hz,1H),7.91–7.80(m,2H),7.47–7.36(m,2H),7.28(d,J＝7.7Hz,2H),7.08(d,J＝7.8Hz,2H),5.57(s,1H),4.56(d,J＝11.7Hz,1H),4.50–4.42(m,1H),4.41–4.32(m,1H),3.57(s,3H),3.56(s,3H),3.46(d,J＝18.0Hz,1H),3.24(dd,J＝18.2,6.9Hz,1H),2.77(t,J＝7.6Hz,2H),2.48(t,J＝7.9Hz,2H),2.34(s,3H),2.22(s,3H).
Synthesis of example 53
Figure BDA0003482027340000792
Example 53 was prepared according to the synthetic method of example 3 as an off-white solid (43mg, 36.41%) MS (ESI, pos.ion) M/z 622.1[ M + H.sub.] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.42(s,1H),9.11(d,J＝5.6Hz,1H),7.99–7.73(m,3H),7.50–7.33(m,2H),6.90(s,2H),4.47–4.24(m,4H),3.57(s,3H),3.43–3.39(m,1H),2.94(dd,J＝17.3,5.1Hz,1H),2.35(s,3H),2.17(s,3H),1.07–0.89(m,1H),0.45–0.19(m,4H).
Synthesis of example 54
Figure BDA0003482027340000801
Example 54 was prepared by the synthetic method of reference example 35 as a brown solid (88mg, 49.92%). MS (ESI, pos.ion) M/z 630.5[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.39(s,1H),9.26(d,J＝5.0Hz,1H),7.99(d,J＝3.0Hz,1H),7.90(d,J＝3.0Hz,1H),7.86(dd,J＝12.5,7.4Hz,1H),7.65(s,1H),7.46–7.36(m,2H),6.44(d,J＝7.0Hz,2H),5.66(s,1H),4.60–4.42(m,3H),3.58(s,3H),3.26(dd,J＝16.5,5.4Hz,1H),2.91(d,J＝16.8Hz,1H),2.39(s,3H),2.20(s,3H).
Synthesis of example 55
Figure BDA0003482027340000802
Example 55 was prepared according to the synthesis of example 45 as an off-white solid (91mg, 15.8%). MS (ESI, pos. ion) M/z 623.2[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)11.55(s,1H),9.66(s,1H),8.39(s,1H),7.95(d,J＝3.1Hz,1H),7.90–7.80(m,2H),7.48–7.29(m,2H),5.73(s,1H),4.43–4.31(m,3H),4.23(d,J＝6.9Hz,2H),3.48(s,3H),2.18(s,3H),2.04(s,3H),1.00-0.86(m,1H),0.36–0.16(m,4H).
Synthesis of example 56
Figure BDA0003482027340000803
Example 56 was prepared as a light brown solid (527mg, 74.68%) by reference to the synthesis of example 51. MS (ESI, pos.ion) M/z 759.0[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.40(s,1H),9.20(d,J＝6.3Hz,1H),7.96(d,J＝3.2Hz,1H),7.92–7.81(m,2H),7.51–7.37(m,2H),7.25(d,J＝7.7Hz,2H),7.17(d,J＝7.8Hz,2H),5.60(s,1H),4.61–4.39(m,3H),3.60(s,3H),3.58(s,6H),3.42(dd,J＝17.7,6.5Hz,1H),3.22(dd,J＝18.0,3.6Hz,1H),2.82(t,J＝7.7Hz,2H),2.61(t,J＝7.7Hz,2H),2.39(s,3H),2.21(s,3H).
Synthesis of example 57
Figure BDA0003482027340000811
Example 57 was prepared as a light brown solid by reference to the synthesis of example 51 (379mg, 66.60%). MS (ESI, pos.ion) M/z 759.0[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.36(s,1H),9.21(d,J＝4.8Hz,1H),8.07–7.94(m,1H),7.93–7.77(m,2H),7.42(d,J＝6.2Hz,2H),7.28(d,J＝7.6Hz,2H),7.07(d,J＝7.7Hz,2H),5.57(s,1H),4.56(d,J＝11.6Hz,1H),4.51–4.42(m,1H),4.41–4.31(m,1H),3.56(s,9H),3.47(d,J＝18.3Hz,1H),3.28–3.18(m,1H),2.80(t,J＝7.6Hz,2H),2.58(t,J＝7.9Hz,2H),2.33(s,3H),2.22(s,3H).
Synthesis of example 58
Figure BDA0003482027340000812
Example 58 was prepared by reference to the synthesis of example 48 as a light yellow solid (97mg, 40.22%). MS (ESI, pos.ion) M/z 731.1[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.39(s,1H),9.20(d,J＝6.3Hz,1H),8.02–7.81(m,5H),7.50(d,J＝8.0Hz,2H),7.47–7.37(m,2H),5.73(s,1H),4.64–4.40(m,3H),3.84(s,3H),3.59(s,3H),3.57(s,3H),3.43(dd,J＝17.8,7.0Hz,1H),3.24(dd,J＝18.1,5.0Hz,1H),2.39(s,3H),2.21(s,3H).
Synthesis of example 59
Figure BDA0003482027340000821
Example 59 was prepared by the synthetic method of reference example 49 as a light yellow solid (193mg, 53.90%). MS (ESI, pos. ion) M/z 731.5[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.32(s,1H),9.19(d,J＝4.9Hz,1H),7.99(d,J＝3.2Hz,1H),7.92–7.78(m,4H),7.54(d,J＝7.9Hz,2H),7.46–7.34(m,2H),5.69(s,1H),4.56(d,J＝11.8Hz,1H),4.47(d,J＝6.7Hz,1H),4.43–4.35(m,1H),3.82(s,3H),3.57(s,3H),3.55(s,3H),3.48(d,J＝18.6Hz,1H),3.29–3.21(m,1H),2.31(s,3H),2.19(s,3H).
Synthesis of example 60
Figure BDA0003482027340000822
Example 60 was prepared according to the synthetic method of example 6 as a yellow solid (180.9mg, 81.31%). MS (ESI, pos. ion) M/z 727.10[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ7.93-7.91(m,1H),7.75–7.71(m,1H),7.62(s,1H),7.57–7.54(m,1H),7.37–7.35(m,1H),7.18–7.15(m,1H),6.99–6.96(m,1H),6.06(s,1H),4.82–4.75(m,1H),4.73–4.68(m,1H),4.62–4.55(m,1H),3.70(s,3H),3.68(s,3H),3.64–3.60(m,1H),3.39–3.33(m,1H),3.34(s,1H),2.40(s,3H),2.36(s,3H).
Synthesis of example 61
Figure BDA0003482027340000823
Example 61 was prepared by the synthetic method of reference example 6 as a yellowish solid (265.7mg, 85.74%). MS (ESI, pos. ion) M/z 727.10[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ7.85(d,J＝3.2Hz,1H),7.76–7.68(m,1H),7.46(s,1H),7.44(d,J＝3.2Hz,1H),7.21–7.17(m,1H),7.16-7.10(m,2H),6.98(dd,J＝16.7,8.1Hz,1H),6.02(s,1H),4.80–4.72(m,1H),4.65–4.54(m,2H),3.73(s,3H),3.68(s,3H),3.51(d,J＝18.3Hz,1H),3.34(dd,J＝18.3,6.6Hz,1H),2.43(s,3H),2.40(s,3H).
Synthesis of example 62
Figure BDA0003482027340000831
Example 62 reference exampleSynthetic method of 6 prepared as a light yellow solid (267.1mg, 90.42%). MS (ESI, pos.ion) M/z 773.10[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ7.81(d,J＝3.1Hz,1H),7.64(d,J＝8.9Hz,2H),7.55(s,1H),7.40(d,J＝3.1Hz,1H),7.27–7.22(m,2H),7.16(dd,J＝8.6,2.4Hz,1H),6.96(t,J＝8.2Hz,1H),6.19(s,1H),4.82–4.75(m,1H),4.64–4.54(m,2H),3.73(s,3H),3.68(d,J＝7.4Hz,1H),3.63(s,3H),3.33–3.27(m,1H),2.42(s,3H),2.39(s,3H).
Synthesis of example 63
Figure BDA0003482027340000832
Example 63 was prepared by reference to the synthesis of example 6 as a light yellow solid (116.6mg, 76.32%). MS (ESI, pos. ion) M/z 773.50[ M + H ]] + ； 1 H NMR(400MHz,CDCl 3 )δ7.82(d,J＝3.2Hz,1H),7.69(s,1H),7.52(s,1H),7.40(d,J＝3.5Hz,2H),7.19–7.14(m,2H),7.07–7.02(m,1H),6.99–6.93(m,1H),6.20(s,1H),4.80–4.75(m,1H),4.63–4.56(m,2H),3.74(s,3H),3.68(d,J＝7.8Hz,1H),3.63(s,3H),3.31(dd,J＝18.0,6.3Hz,1H),2.43(s,3H),2.41(s,3H).
Synthesis of example 64
Figure BDA0003482027340000833
Example 64 was prepared as an off-white solid by the synthetic method of reference example 6 (95.4mg, 83.88%). MS (ESI, pos. ion) M/z 732.0[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ9.24(d,J＝6.7Hz,1H),8.55(d,J＝8.4Hz,1H),8.24–8.20(m,1H),7.95(d,J＝3.4Hz,2H),7.85(d,J＝3.2Hz,1H),7.58–7.46(m,2H),7.43–7.39(m,1H),7.21–7.15(m,1H),6.03(s,1H),4.61–4.57(m,1H),4.48–4.44(m,2H),3.60(s,3H),3.52(s,3H),3.44(d,J＝7.3Hz,1H),2.40(s,3H),2.21(s,3H).
Synthesis of example 65
Figure BDA0003482027340000841
Example 65 was prepared as an off-white solid (152.3mg, 51.90%) with reference to the synthesis of example 6. MS (ESI, pos. ion) M/z 815.00[ M + H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ10.67(s,1H),9.29(d,J＝6.5Hz,1H),8.44(s,1H),7.96–7.92(m,2H),7.84(d,J＝3.2Hz,1H),7.63–7.59(m,2H),7.50(dd,J＝8.6,6.3Hz,1H),7.40(dd,J＝8.9,2.6Hz,1H),7.17(td,J＝8.5,2.6Hz,1H),6.03(s,1H),4.63–4.58(m,1H),4.46(d,J＝5.4Hz,2H),3.61(s,3H),3.51(s,3H),3.49–3.44(m,1H),3.32–3.26(m,1H),2.40(s,3H),2.23(s,3H).
Synthesis of example 66
Figure BDA0003482027340000842
Example 66 was prepared as an earthy yellow solid (211.8mg, 75.19%) by the synthetic method of reference example 6. MS (ESI, pos. ion) M/z 741.45[ M + H ]] + ； 1 H NMR(600MHz,DMSO-d 6 )δ10.40(s,1H),9.24(d,J＝5.9Hz,1H),8.02(d,J＝4.7Hz,1H),7.95(d,J＝2.0Hz,1H),7.84(s,1H),7.61(br,1H),7.53–7.47(m,1H),7.44–7.38(m,2H),7.18(t,J＝7.0Hz,1H),6.04(s,1H),4.59(d,J＝4.5Hz,1H),4.47(s,2H),3.59(s,3H),3.52(s,3H),3.47(dd,J＝17.8,7.0Hz,1H),2.40(s,3H),2.20(s,3H).
Synthesis of example 67
Figure BDA0003482027340000843
Example 67 was prepared by reference to the synthesis of example 6 as a light yellow solid (184.3mg, 65.48%). MS (ESI, pos. ion) M/z 689.3[ M + H ]] + ；1H NMR(400MHz,DMSO-d 6 )δ10.21(s,1H),9.22(d,J＝6.5Hz,1H),7.95(d,J＝3.2Hz,1H),7.84(d,J＝3.2Hz,1H),7.70(d,J＝7.9Hz,2H),7.49(dd,J＝8.6,6.3Hz,1H),7.40(dd,J＝8.9,2.5Hz,1H),7.34(t,J＝7.9Hz,2H),7.18(td,J＝8.4,2.5Hz,1H),7.10(t,J＝7.4Hz,1H),6.03(s,1H),4.62–4.55(m,1H),4.46(d,J＝5.1Hz,2H),3.59(s,3H),3.51(s,3H),3.49–3.40(m,1H),3.32–3.25(m,1H),2.39(s,3H),2.20(s,3H).
Biological assay
HepAD38 cells for evaluating HBV DNA replication inhibition activity (qPCR method) and cytotoxicity of the compound
HBV cell strain and culture condition
HepAD 38: ladner et al (Ladner, Otto et al 1997) ligated tetracycline-sensitive cytomegalovirus CMV promoter to the PBR322 plasmid and ligated into ptetHBV plasmid with ayw subtype HBV DNA, transfected HepG2 cells to obtain HepAD38 cell line, which yielded about 11-fold higher HBV DNA than HepG2.2.15 cells due to disruption of the pre-C region gene. The tetracycline can be used for regulating and controlling HBV replication, the time required by culture is only half of that of HepG2.2.15 cells, and the method is suitable for researching the HBV replication process and replication intermediate type and screening anti-HBV drugs. HepAD38 was cultured in DMEM/F-12K medium (containing Tetracycline at a final concentration of 300ng/mL and G418 at a final concentration of 400. mu.g/mL) containing 10% FBS and 1% double antibody.
In vitro cytotoxicity assay
Recovering HepAD38, digesting after cell state is well overgrown, counting, diluting with DMEM/F-12K medium containing 10% FBS and 1% double antibody to 1 × 10 5 The cell suspension was seeded in a 96-well plate (full plate) at 100. mu.L/well and incubated at 37 ℃ with 5% CO 2 And (5) incubating for 24h in an incubator. After 24h, the old medium was discarded and 200. mu.L of fresh DMEM/F-12K medium containing 2% FBS and 1% double antibody was added.
Compound formulation and cell treatment in vitro cytotoxicity experiments: compounds were dissolved in DMSO to 20mM, followed by 4-fold dilutions of 8 dilutions, with a maximum concentration of 20 mM. mu.L of serially diluted compound was added to each well of the above cell plate, with the highest final concentration tested being 100. mu.M (200-fold dilution). Staurosporine (Martensin, Selleck, CAS No.62996-74-1) was used as a positive control compound, with a maximum concentration of 1. mu.M. Negative control wells were loaded with 1 μ L DMSO to a final concentration of 0.5%.
After 72h, the old medium was discarded and 10% CCK8 was addedIncubating the culture medium in the solution for 20-40min, detecting in a microplate reader to obtain OD value, deriving data to calculate inhibition rate, processing by using Graphpad Prism 5 software nonlinear regression model, and drawing curve to calculate CC of the compound 50 . The results are shown in Table 2.
In vitro anti-HBV Activity assay
After HepAD38 was recovered until the cell status was good, Tetracycline (final concentration 300ng/mL) and G418 (final concentration 400. mu.g/mL) were added to the medium, the virus was not expressed in the presence of Tetracycline, digested after confluency, counted, diluted to 2X 10 with 10% FBS-containing DMEM/F-12K medium (containing Tetracycline at final concentration 300ng/mL and G418 at final concentration 400. mu.g/mL, 1% double antibody) to 1X 10 5 The cell suspension was seeded in a 96-well plate (full plate) at 100. mu.L/well and incubated at 37 ℃ with 5% CO 2 And (5) incubating for 24h in an incubator. After 24h, the old medium was discarded and 200. mu.L of fresh 2% FBS-containing and 1% double-resistant DMEM/F-12K medium was added.
Compound formulation and cell treatment in antiviral experiments: compounds were dissolved to 20mM in DMSO, further compounds were diluted to 800 μ M in DMSO, then 4-fold dilutions of 8 dilutions were made, with the highest concentration being 800 μ M. Add 1. mu.L of serially diluted compound per well to the above cell plate, with the highest final concentration tested being 4. mu.M (200-fold dilution). TDF (tenofovir disoproxil fumarate, Selleck, Cat S1400) was used as a positive control compound at a maximum concentration of 4. mu.M. Negative control wells were loaded with 1 μ L DMSO to a final concentration of 0.5%.
HBV DNA QPCR
The method comprises the steps of performing qPCR by using a hepatitis B virus nucleic acid quantitative determination kit of a Shengxiang biological 48-person one-step method (PCR-fluorescent probe method), sucking 2.5uL of supernatant for qPCR, performing qPCR before using, vortex and uniformly mixing reagents of the kit after melting, centrifuging, placing enzyme mixed liquor on ice for later use, and ensuring that the subsequent steps are finished on the ice. 2.5uL of sample release agent was added to each well of the qPCR plate and 2.5uL of sample supernatant was tested (experimental, control, standard curve). And obtaining the copy number of the virus DNA of each hole after qPCR reaction. Concentration-viral copy number was processed with Graphpad Prism 5 software and compounding was calculated by a four parameter non-linear regression modelEC of substance to virus replication 50 . The results are shown in Table 2.
Table 2: experimental results of in vitro anti-HBV activity and cytotoxicity of the compound
Figure BDA0003482027340000861
Figure BDA0003482027340000871
Note that: N/A indicates no detection
And (4) conclusion: the experimental result shows that the compound has better inhibitory activity to HBV and has small toxicity to cells.

Claims (16)

1. A compound which is a compound shown as a formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown as the formula (I),
Figure FDA0003482027330000011
wherein R is 1 Is C 1-6 Alkyl radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl radical, C 5-10 Aryl or heteroaryl of 5 to 10 ring atoms, wherein said C 1-6 Alkyl radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl radical, C 5-10 Aryl and heteroaryl of 5 to 10 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w1 Substitution;
each R 2 And R 3 Independently hydrogen, deuterium, F, Cl, Br, I, CN, amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 Haloalkyl, methoxy or ethoxy;
each R 4 、R a 、R b And R c Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C 1-4 A haloalkyl group;
ring A is
Figure FDA0003482027330000012
Wherein X is N or CR 10 (ii) a Y is O or S;
each R 11 And R 11a Independently hydrogen, deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C (═ O) O-methyl, -C (═ O) O-ethyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl radical, C 1-4 Haloalkyl or C 1-4 An alkoxy group;
each n1 and n2 is independently 1,2,3, or 4;
each R 5 、R 6 、R 7 、R 8 、R 9 And R 10 Independently is H, deuterium, CN, -C (═ O) OR 1a 、-C(＝O)NR 1b R 1c 、-C(＝O)R、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 6-10 Aryl or heteroaryl of 5 to 6 ring atoms, wherein C is 1-6 Alkyl radical, C 1-6 Haloalkyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 6-10 Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w2 Substitution;
each R 1a Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C 1-4 Haloalkyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C 1-4 Haloalkyl is each independently unsubstituted or substituted by 1,2,3 or 4R w1 Substitution;
each R 1b And R 1c Independently hydrogen, deuterium, -S (═ O) 2 C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl or heterocyclyl consisting of 4 to 6 ring atoms, or R 1b And R 1c Together with the nitrogen atom to which they are attached form a heterocyclic group of 3 to 7 ring atoms in which said-S (═ O) 2 C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl, heterocyclyl consisting of 4 to 6 ring atoms and heterocyclyl consisting of 3 to 7 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w3 Substitution;
each R is independently C 1-6 Alkyl radical, C 3-6 Cycloalkyl or heterocyclyl consisting of 3 to 7 ring atoms, in which said C is 1-6 Alkyl radical, C 3-6 Cycloalkyl and heterocyclyl consisting of 3 to 7 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w4 Substitution;
each R w1 Independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -SF 6 -C (═ O) O-methyl, -C (═ O) O-ethyl, -C (═ O) O-n-propyl, -C (═ O) O-isopropyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C (═ O) O-isopropyl, n-butyl 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl, -CH 2 F、-CH 2 Cl、-CF 3 、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Phenyl, -OCF 3 、C 2-4 Haloalkoxy or C 1-4 Alkoxy, wherein said phenyl is optionallySubstituted with 1,2,3 or 4 substituents independently selected from F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy and ethoxy;
each R w2 、R w3 And R w4 Independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C (═ O) OC 1-6 Alkyl radical, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 2-6 Alkenyl radical, C 2-6 Alkynyl, carboxyl C 1-6 Alkyl radical, C 6-12 Aryl or heteroaryl of 5 to 6 ring atoms, wherein said amino, -C (═ O) OC 1-6 Alkyl radical, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 2-6 Alkenyl radical, C 2-6 Alkynyl, carboxyl C 1-6 Alkyl radical, C 6-12 Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w1 And (4) substitution.
2. The compound of claim 1, wherein R 1 Is C 1-4 Alkyl radical, C 2-4 Alkynyl, C 2-4 Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, heteroaryl of 5 to 6 ring atoms or heteroaryl of 7 to 10 atoms, wherein C is 1-4 Alkyl radical, C 2-4 Alkynyl, C 2-4 Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, heteroaryl of 5 to 6 ring atoms and heteroaryl of 7 to 10 atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w1 And (4) substitution.
3. A compound according to claim 1 or 2, wherein R 1 Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, ethenyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclohexyl, or cyclohexyl,Cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolinyl, or isoquinolinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, Oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolinyl and isoquinolinyl are each independently unsubstituted or substituted by 1,2,3 or 4R w1 And (4) substitution.
4. A compound according to any one of claims 1 to 3, wherein each R is 5 、R 6 、R 7 、R 8 、R 9 And R 10 Independently is H, deuterium, CN, -C (═ O) OR 1a 、-C(＝O)NR 1b R 1c -C (═ O) R, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CF 3 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, 1-propargyl, 2-alkynylbutyl, 3-alkynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, 1-alkynbutyl, 2-alkynbutyl, 3-alkynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently being unsubstituted or substituted by 1,2,3 or 4R w2 And (4) substitution.
5. The compound of any one of claims 1-4, wherein each R 1b And R 1c Independently hydrogen, deuterium, -S (═ O) 2 C 1-4 Alkyl radical, C 1-4 Alkyl radical, C 2-4 Alkynyl, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl or heterocyclyl consisting of 4 to 6 ring atoms, or R 1b And R 1c Together with the nitrogen atom to which they are attached form a heterocyclic group of 3 to 6 ring atoms in which said-S (═ O) 2 C 1-4 Alkyl radical, C 1-4 Alkyl radical, C 2-4 Alkynyl, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl, heterocyclyl consisting of 4 to 6 ring atoms and 3 to 6 ringsThe heterocyclic groups of the atoms are each independently unsubstituted or substituted with 1,2,3 or 4R w3 And (4) substitution.
6. The compound of any one of claims 1-5, wherein each R 1b And R 1c Independently hydrogen, deuterium, -S (═ O) 2 -methyl, -S (═ O) 2 -ethyl, -S (═ O) 2 -n-propyl, -S (═ O) 2 -isopropyl, -S (═ O) 2 -n-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein said-S (═ O) 2 -methyl, -S (═ O) 2 -ethyl, -S (═ O) 2 -n-propyl, -S (═ O) 2 -isopropyl, -S (═ O) 2 -n-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstituted or substituted by 1,2,3 or 4R w3 Substitution; or R 1b And R 1c Together with the nitrogen atom to which they are attached form an aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl group, wherein said aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstitutedSubstituted or substituted by 1,2,3 or 4R w3 And (4) substitution.
7. The compound of any one of claims 1-6, wherein each R is independently C 1-4 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or heterocyclyl consisting of 3 to 6 ring atoms, wherein said C is 1-4 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and heterocyclyl consisting of 3 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R w4 And (4) substitution.
8. The compound of any one of claims 1-7, wherein each R is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, Tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstituted or substituted by 1,2,3 or 4R w4 And (4) substitution.
9. The compound according to any one of claims 1-8, each R w2 、R w3 And R w4 Independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C (═ O) OC 1-4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF 3 、-CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、C 1-4 Alkoxy radical, C 1-4 Haloalkoxy, C 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said amino, -C (═ O) OC 1-4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、C 1-4 Alkoxy radical, C 1-4 Haloalkoxy, C 2-4 Alkenyl radical, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently unsubstituted or substituted with 1,2,3 or 4R w1 And (4) substitution.
10. A compound comprising the structure of one of:
Figure FDA0003482027330000041
Figure FDA0003482027330000051
Figure FDA0003482027330000061
Figure FDA0003482027330000071
Figure FDA0003482027330000081
Figure FDA0003482027330000091
Figure FDA0003482027330000101
Figure FDA0003482027330000111
Figure FDA0003482027330000121
Figure FDA0003482027330000131
Figure FDA0003482027330000141
Figure FDA0003482027330000151
Figure FDA0003482027330000161
Figure FDA0003482027330000171
Figure FDA0003482027330000181
Figure FDA0003482027330000191
Figure FDA0003482027330000201
Figure FDA0003482027330000211
Figure FDA0003482027330000221
Figure FDA0003482027330000222
or a stereoisomer thereofA tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug.
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, and a pharmaceutically acceptable adjuvant.
12. The pharmaceutical composition of claim 11, further comprising an additional anti-HBV agent, wherein the additional anti-HBV agent is an HBV polymerase inhibitor, an immunomodulator, or an interferon.
13. The pharmaceutical composition of claim 11, further comprising an additional anti-HBV agent, wherein the additional anti-HBV agent is lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, alfafenone, Alloferon, simon, cladribine, emtricitabine, famciclovir, calamine CP, intefine, interferon alpha-1 b, interferon alpha-2 a, interferon beta-1 a, interferon alpha-2, interleukin-2, mevoxil, nitazoxanide, peginterferon alpha-2 a, ribavirin, roscovitine-a, cezopyran, Euforavac, april, phosziphad, Heplisav, interferon alpha-2 b, levamisole, or propafege.
14. Use of a compound of any one of claims 1-10 or a pharmaceutical composition of any one of claims 11-13 in the manufacture of a medicament for preventing, treating, or ameliorating a viral disease in a patient.
15. The use of claim 14, wherein the viral disease is hepatitis b virus infection or a disease caused by hepatitis b virus infection.
16. The use of claim 15, wherein the disease caused by hepatitis B virus infection is liver cirrhosis or hepatocellular carcinoma.
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JP7126947B2 (en) * 2016-03-09 2022-08-29 エモリー ユニバーシティー Elimination of hepatitis B virus by antiviral agents
CN108250121A (en) * 2016-12-28 2018-07-06 上海长森药业有限公司 Sulfonamide-arylamides and its medicinal usage for treating hepatitis B
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