CN114685514A - 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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CN114685514A
CN114685514A CN202111622493.9A CN202111622493A CN114685514A CN 114685514 A CN114685514 A CN 114685514A CN 202111622493 A CN202111622493 A CN 202111622493A CN 114685514 A CN114685514 A CN 114685514A
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methyl
propyl
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butyl
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张英俊
刘辛昌
任青云
王猛
冀石龙
颜光华
雷斗兴
余国森
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Sunshine Lake Pharma Co Ltd
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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 preventing hepatitis B. Specifically, the invention relates to a compound shown in a general formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and application of the compound as a medicament, in particular application of the compound as a medicament for treating and/or preventing hepatitis B, wherein variables are defined 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. The invention also relates to compositions comprising these novel amidopyrrole compounds and other antiviral agents, and to their use for the treatment and/or prevention of Hepatitis B Virus (HBV) infections.
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 from 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) 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.
Thus, there is still a need for new compounds which can be effectively used as antiviral agents, in particular as agents 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 preventing 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, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,
Figure BDA0003438630010000011
wherein each R is5a、R5b、R5c、R5d、R5e、R2And R3Independently hydrogen, deuterium, F, Cl, Br, I, CN, SF5Amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C1-4Haloalkyl, trifluoromethoxy, methoxy, or ethoxy;
ring B is C6-10Aryl, 5-6 ring atoms,
Figure BDA0003438630010000012
(I-2) or
Figure BDA0003438630010000021
Wherein, said C6-10Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R6Substituted;
each R6Independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C (═ O) OC1-6Alkyl, -OC1-6alkylene-OC1-6Alkyl radical, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C2-6Alkenyl radical, C2-6Alkynyl or carboxyl C1-6Alkyl, wherein said amino, -C (═ O) OC1-6Alkyl, -OC1-6alkylene-OC1-6Alkyl radical, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C2-6Alkenyl radical, C2-6Alkynyl and carboxyl C1-6Each alkyl is independently unsubstituted or substituted with 1,2,3 or 4Rw1Substituted;
each R1a、R1b、R1、R4、RaAnd RbIndependently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C1-4A haloalkyl group;
each R2a、R2bAnd R2cIndependently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C1-4Haloalkyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C1-4Haloalkyl is each independently unsubstituted or substituted with 1,2,3 or 4Rw2Substituted;
each R3a、R3b、R3c、R4a、R4bAnd R4cIndependently is C1-6Alkyl radical, C6-10Aryl or heteroaryl of 5 to 6 ring atoms, wherein C is6-10Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4Rw3Substituted;
L1is a single bond, methylene or ethylene; wherein said methylene and ethylene are each independently unsubstituted or substituted with 1,2 or 3Rw4Substituted;
L2is a single bond or-NRb-；
Each Rw1、Rw2、Rw3、Rw4And Rw5Independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C (═ O) OC1-6Alkyl, amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, carboxyl C1-6Alkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
the ring A is cyclohexyl, monocyclic heterocyclic group consisting of 5-6 ring atoms, condensed bicyclic heterocyclic group consisting of 8-10 ring atoms or 6-10Bridged heterocyclic group consisting of ring atoms, wherein the cyclohexyl group, the monocyclic heterocyclic group consisting of 5 to 6 ring atoms, the fused bicyclic heterocyclic group consisting of 8 to 10 ring atoms and the bridged bicyclic heterocyclic group consisting of 6 to 10 ring atoms are each independently unsubstituted or substituted with 1,2,3,4, or 5RxSubstituted;
each RxIndependently is deuterium, ═ O, ═ S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH2、-C(＝O)OC1-6Alkyl, -C1-4alkylene-N (R)a)S(＝O)2C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkylene radical, C2-6Alkenyl radical, C2-6Alkynyl, carboxyl C1-6Alkyl or C1-6Haloalkyl, wherein said-CONH2、-C(＝O)OC1-6Alkyl, -C1-4alkylene-N (R)a)S(＝O)2C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkylene radical, C2-6Alkenyl radical, C2-6Alkynyl, carboxyl C1-6Alkyl and C1-6Haloalkyl is each independently unsubstituted or substituted with 1,2,3 or 4Rw5And (4) substituting.
In some embodiments, ring B of the present invention is phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, triazolyl, oxazolyl, thiazolyl, pyrimidinyl, pyridinyl, or a combination thereof,
Figure BDA0003438630010000022
Wherein said phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1,2,3 or 4R6Substituted;
wherein each oneR1a、R2a、R3a、R4a、R1b、R2b、R3b、R4b、R2c、R3c、R4cAnd R6Have the meaning as described in the present invention.
In some embodiments, each R described herein6Independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C (═ O) OC1-4Alkyl, -OC2-4alkylene-OC1-4Alkyl radical, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C2-4Alkenyl radical, C2-4Alkynyl or carboxyl C1-4Alkyl, wherein said amino, -C (═ O) OC1-4Alkyl, -OC2-4alkylene-OC1-4Alkyl radical, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C2-4Alkenyl radical, C2-4Alkynyl and carboxyl C1-4Each alkyl is independently unsubstituted or substituted with 1,2,3 or 4Rw1Wherein each R isw1Have the meaning as described in the present invention.
In some embodiments, each R described herein6Independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C (═ O) omethyl, -C (═ O) oethyl, -C (═ O) O n-propyl, -C (═ O) O isopropyl, -OCH2CH2CH2-OCH3、-OCH2CH2CH2-OCH2CH3、-OCH2CH2CH2CH2-OCH3、-OCH2CH2CH2CH2-OCH2CH3Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C1-4Haloalkyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, -OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCF3、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、C2-4Alkenyl radical, C2-4Alkynyl or carboxyl C1-4Alkyl, wherein said amino, -C (═ O) omethyl, -C (═ O) oethyl, -C (═ O) O n-propyl, -C (═ O) O isopropyl, -OCH2CH2CH2-OCH3、-OCH2CH2CH2-OCH2CH3、-OCH2CH2CH2CH2-OCH3、-OCH2CH2CH2CH2-OCH2CH3Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C1-4Haloalkyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, -OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、C2-4Alkenyl radical, C2-4Alkynyl and carboxyl C1-4Each alkyl is independently unsubstituted or substituted with 1,2,3 or 4Rw1Wherein each R isw1Have the meaning described in the present invention.
In some embodiments, each R described herein3a、R3b、R3c、R4a、R4bAnd R4cIndependently of one another, methyl, ethylN-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1,2,3 or 4Rw3Wherein each R isw3Have the meaning as described in the present invention.
In some embodiments, each R described hereinw1、Rw2、Rw3、Rw4And Rw5Independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C (═ O) OC1-4Alkyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C2-4Alkenyl radical, C2-4Alkynyl, carboxyl C1-4Alkyl radical, C1-4Haloalkyl or C1-4An alkoxy group.
In some embodiments, each R described hereinw1、Rw2、Rw3、Rw4And Rw5Independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C (═ O) omethyl, -C (═ O) oethyl, -C (═ O) O n-propyl, -C (═ O) O isopropyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and nitro2-4Alkenyl radical, C2-4Alkynyl, carboxyl C1-4Alkyl radical, C1-4Haloalkyl or C1-4An alkoxy group.
In some embodiments, ring a of the present invention is
Figure BDA0003438630010000031
Figure BDA0003438630010000041
Figure BDA0003438630010000042
Wherein the formula (II-1), the formula (II-2), the formula (II-3), the formula (II-4), the formula (II-5), the formula (II-6), the formula (II-7), the formula (II-8), the formula (II-9), the formula (II-10), the formula (II-11), the formula (II-12), the formula (II-13) and the formula (II-14) are each independently unsubstituted or substituted by 1,2,3,4 or 5RxWherein each R isxHave the meaning as described in the present invention.
In some embodiments, each R described hereinxIndependently is deuterium, ═ O, ═ S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH2、-C(＝O)OC1-4Alkyl, -C1-3alkylene-N (R)a)S(＝O)2C1-4Alkyl, hydroxy C1-4Alkyl, amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkylene radical, C2-4Alkenyl radical, C2-4Alkynyl, carboxyl C1-4Alkyl or C1-4Haloalkyl, wherein said-CONH2、-C(＝O)OC1-4Alkyl, -C1-3alkylene-N (R)a)S(＝O)2C1-4Alkyl, hydroxy C1-4Alkyl, amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkylene radical, C2-4Alkenyl radical, C2-4Alkynyl, carboxyl C1-4Alkyl and C1-4Haloalkyl is each independently unsubstituted or substituted with 1,2,3 or 4Rw5Wherein each R isaAnd Rw5Have the meaning as described in the present invention.
In some embodiments, each R described hereinxIndependently is deuterium, ═ O, ═ S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH2-C (═ O) omethyl, -C (═ O) oethyl, -C (═ O) O N-propyl, -C (═ O) O isopropyl, -methylene-N (R) (═ O) O isopropyl, -methyl, -N (R) methyl, -O (O) ethyl, -O (O) propyl, -methyl, -O (O) propyl, -O (O) methyl, -O (O) propyl, -O (O) propyl, O) methyl, -O (O) propyl, -O (O) propyl, O) O (O) propyl, O (O) propyl, O) propyl, and/O (O) propyl, O) methyl, and/O (O) methyl, and/O) and (O) methyl, and O (O) methyl, and O) N (O) methyl, and O) N (O) methyla)S(＝O)2Methyl, -methylene-N (R)a)S(＝O)2Ethyl, -methylene-N (R)a)S(＝O)2N-propyl, -methylene-N (R)a)S(＝O)2Isopropyl, -methylenemethyl-N (R)a)S(＝O)2N-butyl, -methylene-N (R)a)S(＝O)2Isobutyl, -ethylene-N (R)a)S(＝O)2Methyl, -ethylene-N (R)a)S(＝O)2Ethyl, -ethylene-N (R)a)S(＝O)2N-propyl, -ethylene-N (R)a)S(＝O)2Isopropyl, -ethylene-N (R)a)S(＝O)2N-butyl, -ethylene-N (R)a)S(＝O)2Isobutyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-n-butyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, 1-butoxymethyl, methoxymethyl, ethoxyethyl, 1-propoxyethyl, 2-propoxyethyl, 1-butoxyethyl, C2-4Alkenyl radical, C2-4Alkynyl, carboxyl C1-4Alkyl or C1-4Haloalkyl, wherein said-CONH2-C (═ O) omethyl, -C (═ O) oethyl, -C (═ O) O N-propyl, -C (═ O) O isopropyl, -methylene-N (R) (═ O) O isopropyl, -methyl, -N (R) methyl, -O (O) ethyl, -O (O) propyl, -methyl, -O (O) propyl, -O (O) methyl, -O (O) propyl, -O (O) propyl, O) methyl, -O (O) propyl, -O (O) propyl, O) O (O) propyl, O (O) propyl, O) propyl, and/O (O) propyl, O) methyl, and/O (O) methyl, and/O) and (O) methyl, and O (O) methyl, and O) N (O) methyl, and O) N (O) methyla)S(＝O)2Methyl, -methylene-N (R)a)S(＝O)2Ethyl, -methylene-N (R)a)S(＝O)2N-propyl, -methylene-N (R)a)S(＝O)2Isopropyl, -methylene-N (R)a)S(＝O)2N-butyl, -methylene-N (R)a)S(＝O)2Isobutyl, -ethylene-N (R)a)S(＝O)2Methyl, -ethylene-N (R)a)S(＝O)2Ethyl, -ethylene-N (R)a)S(＝O)2N-propyl, -ethylene-N (R)a)S(＝O)2Isopropyl, -ethylene-N (R)a)S(＝O)2N-butyl, -ethylene-N (R)a)S(＝O)2Isobutyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-n-butyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy2-methyl-l-propoxy, 2-butoxy, methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, 1-butoxymethyl, methoxymethyl, ethoxyethyl, 1-propoxyethyl, 2-propoxyethyl, 1-butoxyethyl, C2-4Alkenyl radical, C2-4Alkynyl, carboxyl C1-4Alkyl and C1-4Haloalkyl is each independently unsubstituted or substituted with 1,2,3 or 4Rw5Wherein each R isaAnd Rw5Have 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 some embodiments, it comprises the structure of one of, or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,
Figure BDA0003438630010000051
Figure BDA0003438630010000061
Figure BDA0003438630010000071
Figure BDA0003438630010000081
Figure BDA0003438630010000091
Figure BDA0003438630010000101
Figure BDA0003438630010000111
Figure BDA0003438630010000121
Figure BDA0003438630010000131
Figure BDA0003438630010000141
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 the prevention, treatment or amelioration of 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 present invention relates to a method of preventing, treating or ameliorating an HBV condition in a patient, comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the present 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 an additional 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).
The compound and the pharmaceutically acceptable composition thereof can effectively inhibit HBV infection.
Unless otherwise indicated, all stereoisomers, 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 isolated enantiomers of the compounds of formula (I).
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+(R14)4Salts 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+(R14)4Salts, e.g. R14Is H, C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl, 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., halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates.
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.
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 within the scope 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 terms, their usage, the techniques described, or the scope as controlled by the present application.
The following definitions shall apply unless otherwise indicated. Root of herbaceous plantFor the purposes of the present invention, the chemical elements are described in the periodic table of elements, CAS version and handbook of chemicals, 75,thed, 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito:1999, and "March's Advanced Organic Chemistry," by Michael B.Smith and Jerry March, John Wiley&Sons, New York, 2007, all of which are hereby incorporated by reference.
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds 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 "C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon radicals of 1 to 20 carbon atoms, wherein the alkyl radical 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)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) 2-methylpropyl or isobutyl (i-Bu, -CH)2CH(CH3)2) 1-methylpropyl or sec-butyl (s-Bu, -CH (CH)3)CH2CH3) T-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3) N-heptyl, n-octyl, and the like.
The term "carbonyl", whether used alone or in combination with other terms (such as "aminocarbonyl" or "acyloxy"), denotes- (C ═ O) -.
The term "alkylene" denotes a saturated divalent or polyvalent hydrocarbon radical resulting from the removal of two or more hydrogen atoms from a saturated straight or branched hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In some implementationsIn the scheme, the alkylene group contains 1 to 6 carbon atoms; in other embodiments, the alkylene group contains 1 to 4 carbon atoms; in still other embodiments, the alkylene group contains 1 to 3 carbon atoms; in still other embodiments, the alkylene group contains 1 to 2 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH)2-, ethylene (-CH)2CH2-, n-propylidene (-CH)2CH2CH2-), isopropylidene (-CH (CH)3)CH2-) and the like.
The terms "hydroxyalkyl" and "hydroxyalkoxy" mean an alkyl or alkoxy group, as the case may be, substituted with one or more hydroxy groups, where "hydroxyalkyl", "hydroxyalkylene" and "hydroxyalkyl" are used interchangeably, and such examples include, but are not limited to, hydroxymethyl (-CH)2OH), hydroxyethyl (-CH)2CH2OH,-CHOHCH3) Hydroxypropyl group (e.g., -CH)2CH2CH2OH,-CH2CHOHCH3,-CHOHCH2CH3) Hydroxy methoxy (-OCH)2OH), 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 sp2Double 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)2CH＝CH2) 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 monovalent hydrocarbon radical containing 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position of the C-C is a sp triple bond, wherein the alkynyl radical may independently be unsubstitutedOr substituted with one or more substituents described herein, specific examples include, but are not limited to, ethynyl (-C ≡ CH), propargyl (-CH)2C ≡ CH), propynyl (-C ≡ C-CH)3) 1-alkynylbutyl (-CH)2CH2C ≡ CH), 2-alkynylbutyl (-CH)2C≡CCH3) 3-alkynylbutyl (-C [ identical to ] CCH2CH3) And the like, wherein the alkynyl group can be independently unsubstituted or substituted with one or more substituents described herein.
The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms, wherein alkyl, alkenyl and alkoxy have the meaning described herein. Examples include, but are not limited to, difluoroethyl (-CH)2CHF2,-CF2CH3,-CHFCH2F) Trifluoroethyl (-CH)2CF3,-CF2CH2F,-CFHCHF2) Trifluoromethyl (-CF)3) Trifluoromethoxy (-OCF)3) Fluorovinyl (-CH. CHF, -CF. CH)2) And the like.
The term "carboxyalkyl" denotes an alkyl group substituted with one or 2 carboxy substituents, wherein alkyl and carboxy have the meaning described herein. Examples include, but are not limited to, -CH2COOH、-CH2CH2COOH、-CH2CH2CH2COOH、-CH2CH2CH2CH2COOH, 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.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-propoxy, n-PrO, n-propoxy, -OCH2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) 1-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-OCH (CH))2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2) 3-methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3) And so on.
The term "M-M1Or "M-M" consisting of ring atoms1"consisting of atoms" means that the cyclic group consists of M-M1And 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 term "cycloalkyl" refers to a monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring carbon atoms that is saturated, 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 term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged ring systems. 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 radical2-a 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 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 heterocycle consisting of 8-10 ring atomsA group; in some embodiments, heterocyclyl is a bridged bicyclic heterocyclyl consisting of 6-10 ring atoms; in other embodiments, heterocyclyl is a ring system of 3-8 ring atoms; 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 5-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 6-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-6 ring atoms; in other embodiments, 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 "fused bicyclic ring", "fused bicyclic group" and "fused ring group" are used interchangeably herein and all refer to monovalent or multivalent, saturated or partially unsaturated, nonaromatic ring systems in which two rings share a single bond. Such systems may contain independent or conjugated unsaturated systems, but the core structure does not contain aromatic or heteroaromatic rings (although aromatic groups may be substituted thereon).
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 C and B ') is referred to as a "fused bicyclic ring", while ring a' and ring B share a carbon atom, is referred to as a "spiro ring" or a "spirobicyclic ring". Each ring of the fused bicyclic group and spirobicyclic group can be a carbocyclic or heterocyclic group, and each ring is optionally substituted with one or more substituents described herein.
Figure BDA0003438630010000181
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 of said ring systemsOne ring containing 3 to 7 atoms and at least one ring containing 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 compounds like SO, SO2，PO，PO2In 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 ]]A thienyl group,
Figure BDA0003438630010000191
And the like. The fused heterobicyclic group is optionally substituted with one or more substituents described herein.
The term "bridged bicyclic group" denotes a saturated or partially unsaturated, nonaromatic bridged ring system, as shown in formula (b), i.e. ring A1 shares an alkyl or heteroalkyl chain with ring A2, wherein X3C, N, O, P, S; 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]Heptylalkyl, 2-methyl-diazabicyclo [2.2.1]Heptalkyl, and the like. The bridged bicyclic group is optionally substituted with one or more substituents described herein.
Figure BDA0003438630010000192
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, SO2，PO，PO2In 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]]Heptylalkyl, 2-thio-5-azabicyclo [2.2.1]]Heptylalkyl, 2-oxo-5-azabicyclo [2.2.1]Heptylalkyl, 2, 5-diazabicyclo [2.2.1]Heptylalkyl, 2-methyl-2, 5-diazabicyclo [2.2.1]A heptalkyl group,
Figure BDA0003438630010000193
And so on. The bridged bicyclic heterocyclic group is optionally substituted with one or more substituents described herein.
The term "aryl" denotes monocyclic, bicyclic, and tricyclic carbon ring systems containing 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 forming a 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" denotes a monocyclic, bicyclic or tricyclic ring system containing 5 to 16 ring atoms, wherein at least one ring system is aromatic and at least one ring system 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 to 14 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 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 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 heteroaryl consisting of 5 to 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.
Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers): for example, the R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and (Z), (E) conformers.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). 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, which can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as theseThe phosphate compound is obtained by phosphorylation of hydroxyl on the parent body. 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.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery,2008,7, 255-.
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 may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. 50: 50 is called a 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 converted to one another by low energy barriers. 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, or by other methods described in the literature, e.g. ion exchangeThe salts are obtained by the alternative method. Other pharmaceutically acceptable salts include adipates, malates, 2-hydroxypropionates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodiates, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurylsulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, embonate, pectinates, persulfates, 3-phenylpropionates, alginates, salts of alginic acid, salts of citric acid, malic acid, salts of lactic acid, lauryl sulfate, malic acid, malonic acid, salts of lactic acid, salts of lactic acid, salts of esters, salts of lactic acid, salts of esters, salts of acids, salts of lactic acid, salts of acids, salts of esters, salts of acids, salts of esters, salts of acids, salts of esters, salts of esters, salts of acids, salts of esters, salts of acids, salts of esters, salts of acids, salts of esters, salts of L, salts of acids, salts of esters, salts, Picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, pentanoates, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A 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 counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates 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, "of amino groupsBy "protecting group" is meant a substituent attached to an amino group to block or protect the functionality of the amino group in the compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (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-CH2CH2SO2Ph, 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。
Pharmaceutical compositions, formulations, administration of the compounds of the invention and uses of the compounds and pharmaceutical compositions
According to another aspect, a pharmaceutical composition of the invention is characterized by comprising a compound of formula (I), 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 comprises pharmaceutical preparations which, in addition to nontoxic, inert, pharmaceutically suitable adjuvants, also contain one or more compounds of the formula (I) according to the invention or pharmaceutical compositions thereof or one or more active ingredients compounds of the formula (I) or pharmaceutical compositions according to the invention.
The above pharmaceutical preparations may also contain other active pharmaceutical ingredients than the compounds of formula (I).
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) of the present invention, and further comprises pharmaceutically acceptable excipients, which, for example, as used herein, include any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target 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 proteins; 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 wax; 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, inhalation spray, 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, for example 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 ethyl alcohol; 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 adjuvant 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, preferably from 1 to 100mg, per 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, more preferably 1 to 50mg per 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, clevudine, emtricitabine, faprolivir, interferon, calamine CP, intefine, interferon alpha-1 b, interferon alpha-2 a, interferon beta-1 a, interferon alpha-2, interleukin-2, mevoxilate, nitazoxanide, polyethylene glycol interferon alpha-2 a, ribavirin, rosmarin-A, cizopran, Euforavac, azapril, Phosphazid, Heplissav, 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, liver cirrhosis and stem cell 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 only 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 strong 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 for the preparation of medicaments for the treatment and prophylaxis of viral diseases, in particular hepatitis b.
General synthetic methods
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), 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.
The examples described below, unless otherwise indicated, all temperatures are 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 CDC13,DMSO-d6,CD3OD or acetone-d6As solvent (reported in ppm) TMS (0ppm) or chloroform (7.25ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlets, singlet), d (doublets ), t (triplets, triplets), m (multiplets ), q (quatets, quartets), br (broadpeded, broad), dd (doublets of doublets, doublets), dt (doublets of triplets, doublets), br.s (broadpedsinglets, broad singlet), td (triple doublets). Coupling constant J, in Hertz (Hz).
Low resolution Mass Spectral (MS) data were measured by an Agilent6320 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 for analysis, and an ESI source for an LC-MS spectrometer.
Low resolution Mass Spectral (MS) data were also determined by Agilent6120 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(CH3CN，0.1％HCOOH) B(H2O，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:
Figure BDA0003438630010000251
synthesis method
The following synthetic schemes set forth the experimental procedures for preparing the compounds disclosed in the present invention. Wherein each ring B, R5a、R5b、R5c、R5d、R5e、Rx、R1、R2、R3And R4Have the meaning as described in the present invention.
Synthesis scheme 1
Figure BDA0003438630010000252
The compounds of formula (a-6) can be prepared by the method described in scheme 1, wherein Y is O or S; x is chlorine or bromine. Compound (a-1) (obtainable by a method of synthesizing compound M in example 11 with reference to WO 2015132276) is reacted with compound (a-2) under basic conditions (e.g., sodium hydride, etc.) to give compound (a-3); then, the compound (a-3) is subjected to removal of the Boc protecting group under suitable conditions (e.g., trifluoroacetic acid) to give a compound (a-4) or a salt thereof; finally, compound (a-5) (obtained by the synthesis method of compound 42 described in WO2017156255, page 101) is subjected to condensation reaction with compound (a-4) or a salt thereof under suitable conditions (e.g., under HATU and DIPEA) to obtain compound (a-6).
Synthesis scheme 2
Figure BDA0003438630010000261
Compounds of formula (b-4) can be prepared by the methods described in scheme 2, wherein D is optionally substituted with 1,2,3,4, or 5RxSubstituted 4-7 ring atoms constituting a N-containing monocyclic heterocyclic group or 6-10 ring atoms constituting a N-containing bridged bicyclic heterocyclic group; x is chlorine or bromine. Condensation reaction of compound (a-5) with compound (b-1) under suitable conditions (e.g., under HATU and DIPEA) to produce compound (b-2); then, the compound (b-2) is subjected to removal of the Boc protecting group under suitable conditions (e.g., trifluoroacetic acid) to give a compound (b-3) or a salt thereof; finally, the compound (b-3) or a salt thereof is reacted with the compound (a-2) under basic conditions (e.g., potassium carbonate, etc.) to obtain the compound (b-4).
Synthesis scheme 3
Figure BDA0003438630010000262
Compounds of formula (b-4) can also be prepared by the methods described in FIG. 3, wherein D is optionally substituted with 1,2,3,4, or 5RxSubstituted 4-7 ring atoms constituting a N-containing monocyclic heterocyclic group or 6-10 ring atoms constituting a N-containing bridged bicyclic heterocyclic group; x is chlorine or bromine. Reacting the compound (a-2) with the compound (b-1) under basic conditions (e.g., potassium carbonate, etc.) to produce a compound (c-1); then, the compound (c-1) is subjected to removal of the Boc protecting group under suitable conditions (e.g., trifluoroacetic acid) to give a compound (c-2) or a salt thereof; finally, the compound (c-2) or a salt thereof is subjected to condensation reaction with the compound (a-5) under suitable conditions (e.g., such as under HATU and DIPEA) to obtain the compound (b-4).
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.
TABLE I, COMPOUND NUMBER AND STRUCTURE CORRESPONDING THEREFROM
Figure BDA0003438630010000271
Figure BDA0003438630010000281
Figure BDA0003438630010000291
Figure BDA0003438630010000301
Figure BDA0003438630010000311
Figure BDA0003438630010000321
Figure BDA0003438630010000331
Figure BDA0003438630010000341
Figure BDA0003438630010000351
Figure BDA0003438630010000361
Synthesis of Compound 1
Figure BDA0003438630010000362
Step 1: synthesis of Compound 1-1
Compound F1(1.5g,6.20mmol, obtained by reference to the synthesis of compound M in example 11 of WO 2015132276) was dissolved in DMF (20mL), sodium hydride (0.4g,10mmol,60 mass%) was added to the system at 0 ℃,1- (bromomethyl) -2-chloro-4-fluorobenzene (1.7g,7.6mmol) was slowly added to the reaction system after 1h of reaction, then the reaction was stirred at room temperature for 6h, water (5mL) was added to quench the reaction, DCM (10mL) and water (10mL) were added after which the aqueous phase was discarded, the organic phase was washed with water (10mL × 2), saturated brine (20mL), dried over anhydrous sodium sulfate, the solvent was dried by spinning, and the residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 10/1) to obtain a white solid (1.32g, 55%). MS (ESI, pos.ion) M/z 328.2[ M-56+ H ]]+。
Step 2: synthesis of Compound 1-2
Compound 1-1(650mg,1.69mmol) was dissolved in DCM (5mL), after which trifluoroacetic acid (3mL) was added, stirred at rt for 3h and concentrated under reduced pressure to give the title compound as a brown oil (673mg, 99%) which was directly dosed to the next step.
And step 3: synthesis of Compound 1
Compound F2(682mg,2.028mmol, see page 101 of WO2017156255, Synthesis of Compound 42), DIPEA (0.9mL,5mmol) and HATU (880mg,2.199mmol) were dissolved in DMF (20mL), and after stirring for ten minutes, Compound 1-2(673mg,1.69mmol) was added to the system, after stirring at room temperature for 21 hours, water (20mL) and DCM (20mL) were added, the organic layer was separated, and the organic layer was washed with dilute solution of each componentHydrochloric acid (1M,20mL × 1), sodium hydroxide solution (1M,20mL × 1) and saturated brine (20mL × 1) were washed, dried over anhydrous sodium sulfate, the solvent was spin-dried, and the residue was purified by column chromatography (PE/EA (V/V) ═ 1/2) to give the title compound as a white solid (737mg, 73%). MS (ESI, pos.ion) M/z 602.1[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ(ppm)10.46(s,1H),7.86(dd,J＝13.0,7.5Hz,1H),7.50–7.33(m,4H),7.27–7.19(m,1H),4.49–4.29(m,3H),3.85–3.63(m,2H),3.60(d,J＝3.6Hz,3H),3.46–3.38(m,1H),3.17–3.07(m,1H),3.06–3.00(m,1H),2.95–2.85(m,2H),2.83–2.70(m,1H),2.46(s,3H),2.25(d,J＝2.1Hz,3H).
Synthesis of Compound 2
The title product was prepared as a white solid (384mg, 51%) by substituting 2- (chloromethyl) -3, 4-dimethoxypyridine for 1- (bromomethyl) -2-chloro-4-fluorobenzene with reference to the synthesis of compound 1. MS (ESI, pos. ion) M/z 611.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ(ppm)10.49(s,1H),8.53(t,J＝7.2Hz,1H),7.92–7.82(m,1H),7.56(t,J＝5.5Hz,1H),7.49–7.33(m,2H),4.57(d,J＝10.6Hz,2H),4.41(dd,J＝40.6,11.8Hz,1H),4.10(d,J＝3.6Hz,3H),3.87(d,J＝6.9Hz,3H),3.83–3.65(m,2H),3.60(s,3H),3.55–3.37(m,2H),3.20–3.3.02(m,2H),2.95–2.69(m,2H),2.46(s,3H),2.25(s,3H).
Synthesis of Compound 3
Synthetic method for reference compound 1 was prepared by substituting 2- (chloromethyl) -3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine for 1- (bromomethyl) -2-chloro-4-fluorobenzene to give the desired product as a white solid (358mg, 44%). MS (ESI, pos. ion) M/z 663.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ(ppm)10.50(s,1H),8.71(s,1H),7.87(s,1H),7.58(s,1H),7.43(s,2H),5.16(s,2H),4.62(d,J＝9.3Hz,2H),4.41(dd,J＝38.9,10.4Hz,1H),3.96–3.64(m,2H),3.60(s,3H),3.55–3.35(m,2H),3.20–3.05(m,1H),3.02–2.75(m,3H),2.46(s,3H),2.25(s,6H).
Synthesis of Compound 4
A synthetic method for preparing a reference compound 1 by replacing 1- (bromomethyl) -2-chloro-4-fluorobenzene with 2- (chloromethyl) -4- (3-methoxypropoxy) -3-methylpyridine, and a target product is preparedThe material was a white solid (356mg, 44%). MS (ESI, pos. ion) M/z 653.3[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ(ppm)10.50(s,1H),8.74–8.58(m,1H),7.97–7.80(m,1H),7.60–7.53(m,1H),7.46–7.38(m,2H),4.62(d,J＝10.8Hz,2H),4.50–4.33(m,3H),3.88–3.65(m,2H),3.60(s,3H),3.51(s,3H),3.45–3.35(m,1H),3.26(s,3H),3.20–3.06(m,2H),3.02–2.72(m,2H),2.46(s,3H),2.30–2.17(m,6H),2.06(s,2H)
Synthesis of Compound 5
Figure BDA0003438630010000381
Compound F3 (i.e. (R) -methyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, obtained with reference to WO2015078391a1 example 11, the synthesis of compound W2) was substituted for 1- (bromomethyl) -2-chloro-4-fluorobenzene, with reference to the synthesis of compound 1, to afford the desired product as a yellow solid (351mg, 66%). MS (ESI, pos.ion) M/z 823.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ(ppm)10.46(d,J＝4.8Hz,1H),9.62(s,0.5H),9.05(d,J＝17.8Hz,0.5H),8.03–7.97(m,1H),7.95–7.81(m,2H),7.43(s,4H),7.25–7.13(m,1H),6.07–5.90(m,1H),4.70–4.59(m,1H),4.55–4.30(m,2H),3.90–3.68(m,3H),3.60(d,J＝6.4Hz,3H),3.55(d,J＝8.0Hz,3H),3.50–3.42(m,1H),3.28–3.07(m,2H),3.02–2.87(m,1H),2.85–2.72(m,1H),2.45(d,J＝5.6Hz,3H),2.30–2.17(m,3H).
Synthesis of Compound 6
Figure BDA0003438630010000382
Compound F4 (which was synthesized by substituting (R) -piperazine-2-carboxylic acid dihydrochloride for (S) -piperazine-2-carboxylic acid dihydrochloride, see synthesis method F1) and compound F3 for compound F1 and 1- (bromomethyl) -2-chloro-4-fluorobenzene, respectively, and compound 1, were synthesized to give the desired product as a yellow solid (350mg, 71%),). MS (ESI, pos. ion) M/z 823.0[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.69(d,J＝7.6Hz,1H),8.11(d,J＝17.3Hz,1H),7.85(d,J＝3.0Hz,1H),7.78–7.73(m,1H),7.46(dd,J＝2.9,1.5Hz,1H),7.28–7.23(m,2H),7.21–7.12(m,2H),6.95–6.88(m,1H),6.21(d,J＝2.2Hz,1H),4.44(dd,J＝17.7,6.4Hz,1H),4.18–4.10(m,1H),3.95(d,J＝17.6Hz,1H),3.71(d,J＝2.2Hz,3H),3.62(d,J＝2.4Hz,3H),3.56(d,J＝8.3Hz,2H),3.51–3.43(m,2H),3.02–2.86(m,1H),2.82(s,2H),2.70–2.60(m,1H),2.51(d,J＝1.6Hz,3H),2.42(d,J＝2.1Hz,3H).
Synthesis of Compound 7
Figure BDA0003438630010000391
Compound F5, which was obtained as a synthetic method according to example 39, step 1 to step 2 of reference WO2015144093a1, was substituted for 1- (bromomethyl) -2-chloro-4-fluorobenzene, reference compound 1 was synthesized to give the target product as a yellow solid (220mg, 53%). MS (ESI, pos. ion) M/z 823.1[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)8.98(d,J＝15.4Hz,1H),7.86(d,J＝3.0Hz,1H),7.76–7.68(m,1H),7.65–7.42(m,2H),7.39–7.33(m,1H),7.20–7.14(m,2H),7.02–6.88(m,1H),6.20–6.08(m,1H),4.85–4.55(m,3H),4.15–3.80(m,3H),3.72(d,J＝4.5Hz,3H),3.66–3.60(m,3H),3.30–3.10(m,3H),2.94–2.74(m,2H),2.51(d,J＝3.1Hz,3H),2.44–2.39(m,3H).
Synthesis of Compound 8
Step 1: synthesis of F6
Figure BDA0003438630010000392
Adding compound F1(10g,41.4mmol) and anhydrous toluene (200mL) into a reaction bottle in sequence, adding phosphorus pentasulfide (4.61g,20.7mmol) under the protection of nitrogen, heating to 115 ℃ for reaction, keeping the temperature for reaction for 6h, cooling to room temperature, adding water (100mL) and dichloromethane (200mL), extracting for layering, concentrating an organic layer, separating a concentrated residue by silica gel column chromatography (PE/EA (V/V) ═1/1) to yield a white solid (3.12g, 29.2%). MS (ESI, pos.ion) M/z 258.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)6.58(s,1H),4.37(d,J＝10.8Hz,1H),4.32–4.00(m,2H),3.96–3.84(m,1H),3.73(t,J＝9.5Hz,1H),3.28–3.18(m,1H),3.07–2.94(m,1H),2.84(s,1H),2.71(s,1H),1.47(s,9H)。
Step 2: synthesis of Compound 8
Reference to the synthesis of compound 1, substituting compound F6 for compound F1, gave the desired product as a white solid (40mg, 16%). MS (ESI, pos.ion) M/z 618.1[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)7.76–7.68(m,1H),7.58–7.46(m,2H),7.20–7.13(m,2H),7.04–6.97(m,1H),5.09–4.92(m,2H),4.75–4.58(m,2H),4.05–3.90(m,1H),3.75–3.60(m,2H),3.71(d,J＝6.2Hz,3H),3.30–3.18(m,2H),3.11–2.88(m,1H),2.73–2.65(m,1H),2.50(d,J＝6.7Hz,3H),2.41(d,J＝7.9Hz,3H)。
Synthesis of Compound 9
Figure BDA0003438630010000401
Step 1: synthesis of Compound 9-1
Compound F2(1.0g,3.0mmol) was dissolved in DMF (10mL), followed by the addition of DIPEA (1.6mL,8.7mmol) and HATU (2.4g,6.0mmol), stirring for two minutes, then piperazine-1-carboxylic acid tert-butyl ester (830mg,4.456mmol) was added to the system, stirring at room temperature for 13h, and then water (10mL) was added to quench the reaction. DCM (20mL) was then added, the layers were allowed to settle and the aqueous phase was extracted with DCM (20 mL). The organic phases were combined, washed twice with 1M dilute hydrochloric acid (20 mL. times.2), and dried over anhydrous sodium sulfate. The solvent was dried by rotation, and the obtained residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 1/1) to obtain the objective compound as a white solid (1.13g, 75%). MS (ESI, pos.ion) M/z 449.60[ M-56+ H]+。
Step 2: synthesis of Compound 9-2
Compound 9-1(371mg,0.74mmol) was dissolved in DCM (3mL), trifluoroacetic acid (5mL) was added, the reaction was stirred at room temperature for 1h, and then the solvent was dried by spinning to give the crude product (381mg, 100%) which was directly charged into the next step.
And step 3: synthesis of Compound 9
Compound F3(364mg,0.82mmol) and compound 9-2(381mg,0.74mmol) were dissolved in absolute ethanol (4mL) at room temperature, after which potassium carbonate (339mg,2.45mmol) was added and the reaction stirred at 40 ℃ for 4h, after which time it was filtered off over celite. The solid was washed with DCM (10mL), the solvent was dried by rotary evaporation, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 1/2) to give the title compound as a yellow solid (210mg, 37%). MS (ESI, pos. ion) M/z 768.3[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ(ppm)10.47(s,1H),9.69(s,1H),8.03(d,J＝3.1Hz,1H),7.95(d,J＝3.1Hz,1H),7.87(dd,J＝12.5,7.2Hz,1H),7.48–7.35(m,4H),7.17(td,J＝8.5,2.5Hz,1H),6.05(s,1H),4.08–3.88(m,2H),3.67(s,2H),3.61(s,3H),3.52(s,3H),3.42–3.36(m,2H),2.65(s,2H),2.59(d,J＝6.0Hz,2H),2.48(s,3H),2.28(s,3H).
Synthesis of Compound 10
Substituting 2- (chloromethyl) -4- (3-methoxypropoxy) -3-methylpyridine for compound F3, reference compound 9, the title product was prepared as a white solid (284mg, 80%). MS (ESI, pos. ion) M/z 598.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ(ppm)10.52(s,1H),8.55(d,J＝6.1Hz,1H),7.87(dd,J＝11.8,7.1Hz,1H),7.51–7.31(m,3H),4.31(t,J＝5.1Hz,2H),4.17(s,3H),3.74(s,3H),3.61(s,3H),3.55–3.43(m,5H),2.86(d,J＝21.9Hz,4H),2.47(s,3H),2.26(s,3H),2.19(s,3H),2.07–1.95(m,2H).
Synthesis of Compound 11
The title product was prepared as a white solid (52mg, 21%) by substituting 2- (chloromethyl) -3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine for compound F3, reference method for the synthesis of compound 9. MS (ESI, pos. ion) M/z 608.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)8.82(s,1H),8.70(d,J＝4.6Hz,1H),7.79–7.72(m,1H),7.34–7.30(m,1H),7.17–7.10(m,2H),4.62(q,J＝7.5Hz,2H),4.02(s,2H),3.85(s,2H),3.67(s,3H),3.56(s,2H),2.89–2.84(m,2H),2.82–2.76(m,2H),2.51(s,3H),2.34(s,6H).
Synthesis of Compound 12
Substituting (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester for piperazine-1-carboxylic acid tert-butyl ester with reference to the synthesis method of compound 9, the objective product was prepared as a yellow solid (280mg, 46%). MS (ESI, pos. ion) M/z 782.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)8.18(d,J＝19.7Hz,1H),7.90(d,J＝3.0Hz,1H),7.78–7.70(m,1H),7.64–7.60(m,1H),7.26–7.24(m,1H),7.23–7.12(m,2H),7.05–6.95(m,1H),6.19(d,J＝7.8Hz,1H),4.60–4.30(m,4H),4.05–3.97(m,1H),3.70(s,3H),3.63(s,3H),3.59–3.48(m,2H),3.17–2.96(m,2H),2.51(d,J＝4.0Hz,3H),2.40(d,J＝8.7Hz,3H),1.73–1.58(m,3H)
Synthesis of Compound 13
By reacting 2, 5-diazabicyclo [2.2.2]Octane-2-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester with reference to the synthesis method of compound 9, the desired product was prepared as a yellow solid (670mg, 95%). MS (ESI, pos. ion) M/z 794.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)7.87(d,J＝7.9Hz,1H),7.77–7.58(m,1H),7.49–7.30(m,2H),7.25–7.12(m,2H),7.08–6.81(m,2H),6.16(d,J＝9.7Hz,1H),4.96–4.73(m,2H),4.38–3.74(m,4H),3.72–3.65(m,3H),3.63(s,3H),2.63–2.36(m,6H),2.35–2.05(m,2H),1.35–1.25(m,2H),0.94–0.78(m,2H).
Synthesis of Compound 14
Reacting 3, 8-diazabicyclo [3.2.1 ]]Octane-3-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester, reference to the synthesis of compound 9, produced the desired product as a yellow solid (670mg, 95%). MS (ESI, pos. ion) M/z 794.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)8.10(d,J＝3.7Hz,1H),7.89(t,J＝3.0Hz,1H),7.79–7.70(m,1H),7.59(t,J＝2.7Hz,1H),7.36–7.30(m,1H),7.27–7.22(m,1H),7.21–7.11(m,1H),7.02-6.94(m,1H),6.22(d,J＝1.8Hz,1H),4.91–4.78(m,1H),4.32(dd,J＝16.5,5.3Hz,1H),4.22–4.07(m,2H),3.70(d,J＝1.5Hz,3H),3.62(s,3H),3.36–2.99(m,4H),2.49(d,J＝1.9Hz,3H),2.47–2.42(m,1H),2.40(s,3H),2.14–2.07(m,1H),1.30–1.25(m,1H),0.90–0.85(m,1H).
Synthesis of Compound 15
Compound F7 (which was obtained by the synthetic method referenced in WO2015078391, example 8, step 1 to step 2) was substituted for compound F3, with reference to the synthetic method of compound 9, to afford the target product as a yellow solid (570mg, 75%). MS (ESI, pos. ion) M/z 854.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)7.93–7.84(m,2H),7.78–7.71(m,1H),7.55(d,J＝2.9Hz,1H),7.44–7.37(m,1H),7.24–7.19(m,1H),7.15(dd,J＝9.8,7.5Hz,1H),7.03–6.98(m,1H),6.29(s,1H),4.95(q,J＝7.1Hz,1H),4.42(s,2H),4.25–4.17(m,2H),4.14–4.00(m,2H),3.80(s,2H),3.72(d,J＝2.5Hz,3H),3.28–3.10(m,4H),2.52(s,3H),2.42(s,3H),1.32(d,J＝7.1Hz,3H),1.28(t,J＝7.1Hz,3H).
Synthesis of Compound 16
Reacting (1R,4R) -2, 5-diazabicyclo [2.2.1]Octane-2-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester, reference to the synthesis of compound 9, produced the desired product as a yellow solid (150mg, 50%). MS (ESI, pos. ion) M/z 780.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.54(d,J＝13.3Hz,1H),8.04(d,J＝10.0Hz,1H),7.85–7.64(m,2H),7.41(dd,J＝14.7,3.1Hz,1H),7.29–7.25(m,1H),7.23–7.11(m,2H),6.98–6.89(m,1H),6.18(d,J＝5.4Hz,1H),5.01–4.36(m,1H),4.26(d,J＝17.4Hz,1H),4.14(d,J＝17.4Hz,1H),3.74–3.66(m,5H),3.58(d,J＝16.9Hz,3H),3.55–3.46(m,1H),3.14–2.97(m,2H),2.51(d,J＝16.6Hz,3H),2.43(d,J＝14.0Hz,3H),2.14(t,J＝9.7Hz,1H),1.95–1.85(m,1H).
Synthesis of Compound 17
Reacting (1S,4S) -2, 5-diazabicyclo [2.2.1]Octane-2-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester with reference to the synthesis method of compound 9, the desired product was prepared as a yellow solid (230mg, 77%). MS (ESI, pos. ion) M/z 780.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.62(d,J＝10.5Hz,1H),8.22(d,J＝16.2Hz,1H),7.84–7.51(m,2H),7.43(dd,J＝15.4,3.1Hz,1H),7.28–7.18(m,2H),7.17–7.09(m,2H),6.95–6.88(m,1H),6.20(d,J＝7.6Hz,1H),4.50–4.31(m,2H),4.00–3.80(m,2H),3.70(s,3H),3.65–3.42(m,5H),3.22–3.10(m,1H),3.03–2.90(m,1H),2.51(d,J＝18.3Hz,3H),2.44(d,J＝27.2Hz,3H),2.14–2.05(m,1H),1.87(dd,J＝16.7,10.3Hz,1H).
Synthesis of Compound 18
Substituting (S) -tert-butyl 2-methylpiperazine-1-carboxylate for tert-butyl piperazine-1-carboxylate with reference to the synthesis method of compound 9, the desired product was prepared as a yellow solid (290mg, 59%). MS (ESI, pos. ion) M/z 782.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.72(d,J＝10.0Hz,1H),7.86(t,J＝3.5Hz,1H),7.79–7.71(m,1H),7.67(s,1H),7.49–7.45(m,1H),7.31–7.27(m,1H),7.20–7.13(m,2H),6.95–6.88(m,1H),6.22(d,J＝5.2Hz,1H),4.35–4.26(m,1H),4.15(dd,J＝17.7,7.3Hz,1H),4.02(dd,J＝17.7,3.9Hz,1H),3.73(d,J＝4.8Hz,3H),3.62(d,J＝1.6Hz,3H),3.57–3.47(m,1H),3.45–3.33(m,1H),3.25–3.17(m,1H),3.15–3.08(m,1H),2.93–2.73(m,2H),2.54(d,J＝4.5Hz,3H),2.47(d,J＝3.0Hz,3H),1.28(d,3H).
Synthesis of Compound 19
Reacting a 3, 6-diazabicyclo [3.1.1 ]]Octane-6-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester reference was made to the synthesis of compound 9 to prepare the desired product as a yellow solid (360mg, 49%). MS (ESI, pos. ion) M/z 780.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.65(d,J＝5.4Hz,1H),7.95–7.82(m,2H),7.76–7.68(m,1H),7.46(d,J＝3.1Hz,1H),7.28–7.23(m,1H),7.20–7.10(m,2H),6.96–6.86(m,1H),6.18(d,J＝6.5Hz,1H),4.29–4.09(m,1H),4.05–3.94(m,1H),3.92–3.79(m,3H),3.74(d,J＝2.0Hz,3H),3.72–3.60(m,2H),3.50(d,J＝10.4Hz,3H),3.03–2.92(m,1H),2.59(d,J＝3.1Hz,3H),2.52(s,3H),1.78–1.69(m,2H).
Synthesis of Compound 20
Figure BDA0003438630010000421
Step 1: synthesis of Compound 20-1
Compound F3(608mg,1.37mmol), potassium carbonate (755mg, 5)46mmol) and tert-butyl (R) -3-methylpiperazine-1-carboxylate (410mg,2.05mmol) were dissolved in DMF (6mL), stirred at room temperature for 15h, ethyl acetate (10mL) and water (10mL) were added, the aqueous phase was discarded, the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, the solvent was spun off, and the residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 2/1) to give the title compound as a yellow solid (600mg, 78%). MS (ESI, pos. ion) m/z: 564.2[ M + H]+。
Step 2: synthesis of Compound 20-2
Compound 20-1(600mg,1.06mmol) was dissolved in DCM (14mL), trifluoroacetic acid (7mL) was added, the reaction was stirred at room temperature for 0.5h, and the solvent was dried by spinning to give a brown oil (615mg, 100%) which was directly used in the next step.
And step 3: synthesis of Compound 20
Compound F2(357mg,1.06mmol), DIPEA (0.7mL,4mmol) and HATU (554mg,1.38mmol) were dissolved in DCM (10mL), and after stirring for ten minutes, compound 20-2(615mg,1.06mmol) was added to the system, the reaction was stirred at room temperature for 15 hours, then water (20mL) was added and washed, the organic phase was washed with diluted hydrochloric acid (1M,20mL × 2), sodium hydroxide (1M,10mL) and saturated brine (10mL), respectively, and then dried over anhydrous sodium sulfate, then the solvent was spun off, and the obtained residue was purified by silica gel column chromatography (PE/EA (V/V) 1/1) to obtain the desired compound as a yellow solid (200mg, 24%). MS (ESI, pos. ion) M/z 782.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)8.15(s,1H),7.93–7.86(m,1H),7.79-7.71(m,1H),7.60(t,J＝3.4Hz,1H),7.36(dd,J＝14.2,7.5Hz,1H),7.27–7.22(m,1H),7.21–7.10(m,2H),7.05–6.98(m,1H),6.18(d,J＝7.7Hz,1H),5.02–4.82(m,1H),4.48–4.35(m,3H),4.01–3.74(m,4H),3.70(d,J＝2.4Hz,3H),3.64(s,3H),3.48–3.35(m,1H),2.51(d,J＝3.4Hz,3H),2.37(s,3H),1.60(dd,J＝34.2,5.5Hz,3H).
Synthesis of Compound 21
Reacting 3, 8-diazabicyclo [3.2.1 ]]Octane-3-carboxylic acid tert-butyl ester instead of (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester with reference to the synthesis method of compound 20, the objective product was prepared as a yellow solid (105mg, 25%). MS (ESI, pos.ion) m/z:794.3[M+H]+；1H NMR(400MHz,CDCl3) δ (ppm)8.39(d, J ═ 8.4Hz,1H), 7.93-7.87 (m,1H), 7.80-7.72 (m,1H),7.60(dd, J ═ 6.1,3.0Hz,1H), 7.47-7.38 (m,1H), 7.21-7.08 (m,2H),7.03(td, J ═ 8.4,2.3Hz,1H),6.16(s,1H), 4.71-4.48 (m,3H), 4.45-4.33 (m,2H), 4.22-4.12 (m,1H),3.89(d, J ═ 13.8Hz,1H),3.70(s,3H),3.63(d, J ═ 2.5Hz,3H), 3.59-3.55 (d, J ═ 13.8Hz,1H), 3.54 (d, 3.55H), 3.49 (d, 2.5H), 3.5H, 3.55(m, 2H), 3.5H, 3.5 (m, 3.5H), 3.55H), 3.5H), 3.49 (m, 3.5H), 3.5H, 2.5H, 3.5H, 2H, 3.8H, 2H), 3.5H, 2H, 1H, 2H, etc., 1H, 2H, 1H, 2H, 1H, 2H, 3, 2H, 3.5, 2H, 1H, 2H
Reference compound 20 synthesis procedure substituting (S) -tert-butyl 2-methylpiperazine-1-carboxylate for tert-butyl (R) -3-methylpiperazine-1-carboxylate yielded the desired product as a yellow solid (590mg, 78%). MS (ESI, pos. ion) M/z 782.2[ M + H ]]+；1H NMR(400MHz,CDCl3) δ (ppm)9.54(s,1H),7.82(dd, J ═ 12.1,9.0Hz,2H), 7.78-7.71 (m,1H),7.46(dd, J ═ 3.0,1.6Hz,1H), 7.23-7.13 (m,3H), 6.97-6.88 (m,1H),6.21(d, J ═ 1.8Hz,1H), 4.85-4.75 (m,1H), 4.58-4.52 (m,1H),4.08(dd, J ═ 17.1,2.3Hz,1H), 3.93-3.83 (m,2H),3.72(s,3H),3.60(d, J ═ 2.5Hz,3H), 3.58-3.53 (m,1H), 3.40-3.83 (m,2H),3.72(s,3H),3.60(d, J ═ 2.5Hz,3H), 3.58-3.53 (m, 3.65 (m,1H), 3.47, 3.7, 1H), 3.65 (m,1H), 3.47-4.7 (m,1H), 3.47H), 3.7, 1H),3.7 (m,1H), 3.47, 1H),3.7, 1H), 3.7.7, 1H),3.7, 1H, 4, 1H, 1H, 1H, 1H
Substitution of piperazine-1-carboxylic acid tert-butyl ester and compound F5 for (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester and compound F3, respectively, was made in reference to the synthetic procedure of compound 20 to give the desired product as a yellow solid (230mg, 50%). MS (ESI, pos. ion) M/z 768.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.56(s,1H),8.26(s,1H),7.85(d,J＝3.1Hz,1H),7.79–7.73(m,1H),7.47(d,J＝3.1Hz,1H),7.30–7.25(m,1H),7.18–7.12(m,2H),6.92(td,J＝8.3,2.5Hz,1H),6.21(s,1H),4.12(d,J＝17.2Hz,1H),3.93–3.81(m,3H),3.71(s,3H),3.61(s,3H),3.54(brs,2H),2.69(brs,2H),2.62(brs,2H),2.50(s,3H),2.41(s,3H).
Synthesis of Compound 24
Step 1: synthesis of compound F8:
Figure BDA0003438630010000431
compound F3(145.99g,328.1mmol), toluene (1200mL) and DDQ (82.0g,361.2mmol) were sequentially added to a dry reaction flask, the temperature was raised to 110 ℃ to react, the mixture was stirred at the same temperature for 1.5 hours, the temperature was lowered to room temperature, the reaction solution was washed with a 10% aqueous sodium hydroxide solution (500mL × 2) and a saturated saline solution (500mL × 2) in this order, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 3/1) to obtain a beige solid (80.2 g.55.2%).
Step 2: synthesis of Compound 24
Synthetic method for reference compound 20 was prepared by substituting piperazine-1-carboxylic acid tert-butyl ester and compound F8 for (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester and compound F3, respectively, to give the desired product as a brown solid (330mg, 78%). MS (ESI, pos. ion) M/z 766.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)8.09(d,J＝3.1Hz,1H),8.05(s,1H),7.78–7.71(m,1H),7.61(d,J＝3.1Hz,1H),7.41(dd,J＝8.5,5.9Hz,1H),7.27–7.20(m,2H),7.17–7.10(m,2H),4.03(s,2H),3.68(s,6H),3.64(s,2H),3.32(s,2H),2.61(brs,2H),2.52(s,2H),2.46(s,3H),2.37(s,3H).
Synthesis of Compound 25
Reacting 3, 6-diazabicyclo [3.1.1]Octane-6-carboxylic acid tert-butyl ester instead of (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester with reference to the synthesis method of compound 20, the objective product was prepared as a yellow solid (300mg, 44%). MS (ESI, pos. ion) M/z 780.3[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.51(d,J＝7.3Hz,1H),7.80(t,J＝2.8Hz,1H),7.78–7.67(m,2H),7.46(dd,J＝2.9,1.5Hz,1H),7.31–7.28(m,1H),7.22–7.13(m,3H),6.98–6.90(m,1H),6.21(d,J＝2.6Hz,1H),4.73–4.53(m,2H),4.35–4.08(m,2H),3.72(d,J＝1.0Hz,3H),3.61(d,J＝4.6Hz,3H),3.43–3.34(m,2H),3.32–3.21(m,2H),2.79–2.72(m,1H),2.64–2.58(m,1H),2.50(d,J＝3.3Hz,3H),2.47(s,3H).
Synthesis of Compound 26
Preparation of reference Compound 20 by substituting tert-butyl (R) -3-methylpiperazine-1-carboxylate with tert-butyl (S) -3- (hydroxymethyl) piperazine-1-carboxylateThe desired product was obtained as a yellow solid (430mg, 90%). MS (ESI, pos. ion) M/z 798.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.67(d,J＝11.1Hz,1H),8.23–8.00(m,1H),7.84(d,J＝3.0Hz,1H),7.79–7.66(m,1H),7.47(d,J＝2.9Hz,1H),7.27–7.22(m,1H),7.19–7.09(m,2H),6.97–6.87(m,1H),6.19(d,J＝7.4Hz,1H),4.45(d,J＝17.6Hz,1H),4.10–3.92(m,2H),3.87–3.72(m,2H),3.70(d,J＝6.4Hz,3H),3.62(d,J＝2.6Hz,3H),3.59–3.44(m,2H),3.23–3.12(m,1H),3.09–3.00(m,1H),2.87–2.77(m,1H),2.65(d,J＝12.7Hz,1H),2.50(d,J＝6.7Hz,3H),2.39(d,J＝4.0Hz,3H).
Synthesis of Compound 27
Synthetic route to compound F9:
Figure BDA0003438630010000441
step 1: synthesis of Compound F9-1
Compound F9-0(5.0g,14.3mmol) was dissolved in tetrahydrofuran (50mL), cooled to-20 deg.C, sodium hydride (1.1g,28mmol, 60% mass) was slowly added thereto, and after 5min of reaction, iodomethane (1.3mL,21mmol) was added thereto, after the addition was completed, the reaction was slowly warmed to room temperature and continued for 5 h. The reaction was quenched by addition of water (20mL), extracted with ethyl acetate (20mL × 3), the organic phases were combined, the combined organic phases were washed with saturated brine (50mL), 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) ═ 3/1) to give the objective compound as a colorless oil (2.81g, 54%). MS (ESI, pos.ion) M/z 365.2[ M + H ]]+。
Step 2: synthesis of Compound F9
To a dry reaction flask were added compound F9-1(2.51g,6.89mmol), 10% Pd/C (251mg), and methanol (20mL) in that order, and the mixture was stirred at room temperature for 4h under a hydrogen atmosphere. Filtration, cake washing with dichloromethane (20mL), and concentration of the filtrate under reduced pressure gave the title compound as a white solid (1.58g, 99%). MS (ESI, pos.ion) M/z 231.2[ M + H ]]+。
Step (ii) of3: synthesis of Compound 27
Substituting compound F9 for tert-butyl (R) -3-methylpiperazine-1-carboxylate, reference to the synthesis of compound 20, gave the desired product as a yellow solid (350mg, 72%). MS (ESI, pos. ion) M/z 812.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.54(d,J＝4.7Hz,1H),8.63(s,0.5H),8.37(s,0.5H),7.84(dd,J＝4.1,3.3Hz,1H),7.80–7.71(m,1H),7.47(dd,J＝4.3,3.3Hz,1H),7.37–7.29(m,2H),7.20–7.11(m,2H),6.98–6.88(m,1H),6.18(d,J＝1.2Hz,1H),4.88–4.81(m,0.5H),4.53–4.48(m,0.5H),3.98–3.87(m,3H),3.84–3.78(m,1H),3.69(d,J＝4.5Hz,3H),3.61(s,3H),3.57–3.42(m,1H),3.32–3.19(m,4H),3.17–3.05(m,1H),2.97–2.70(m,1H),2.55–2.50(m,1H),2.49(d,J＝4.2Hz,3H),2.43–2.37(m,4H).
Synthesis of Compound 28
Referring to the synthesis method of compound 9, compound F9 was substituted for tert-butyl piperazine-1-carboxylate to prepare the desired product as a yellow solid (320mg, 80%). MS (ESI, pos. ion) M/z 812.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.69(d,J＝7.6Hz,1H),8.11(d,J＝17.3Hz,1H),7.87–7.83(m,1H),7.79-7.73(m,1H),7.46(dd,J＝2.9,1.5Hz,1H),7.28–7.22(m,2H),7.21–7.11(m,2H),6.96–6.87(m,1H),6.21(d,J＝2.2Hz,1H),4.44(dd,J＝17.7,6.4Hz,1H),4.15–4.02(m,1H),3.95(d,J＝17.6Hz,1H),3.71(d,J＝2.2Hz,3H),3.62(d,J＝2.4Hz,3H),3.58–3.42(m,5H),3.24(d,J＝31.5Hz,3H),3.02–2.85(m,2H),2.72–2.57(m,1H),2.51(d,J＝1.6Hz,3H),2.42(d,J＝2.1Hz,3H).
Synthesis of Compound 29
Reference compound 20 synthesis method substituting (R) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester for (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester prepared the title compound as a yellow solid (30mg, 7%). MS (ESI, pos. ion) M/z 798.2[ M + H ]]+。
Synthesis of Compound 30
Substituting (R) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester for piperazine-1-carboxylic acid tert-butyl ester, reference to the synthesis of compound 9, produced the desired product as a yellow solid (145mg, 16%).MS(ESI,pos.ion)m/z:798.2[M+H]+；1H NMR(400MHz,CDCl3)δ(ppm)8.93–8.73(m,1H),7.88(d,J＝2.6Hz,1H),7.85–7.73(m,1H),7.65–7.61(m,1H),7.37–7.26(m,2H),7.23–7.17(m,1H),7.13(dd,J＝18.2,9.0Hz,1H),7.05–6.98(m,1H),6.16(s,1H),4.55(d,J＝22.9Hz,2H),4.45–4.35(m,1H),4.30–4.20(m,1H),4.19–4.05(m,2H),3.93–3.74(m,2H),3.67(d,J＝3.1Hz,3H),3.63(d,J＝3.7Hz,3H),3.42–3.34(m,1H),3.31–3.22(m,1H),3.15–3.05(m,1H),2.52(d,J＝13.0Hz,3H),2.38(d,J＝3.9Hz,3H).
Synthesis of Compound 31
Figure BDA0003438630010000461
Step 1: synthesis of Compound 31-1
Compound F10(500mg,0.91mmol, obtained by reference to the synthesis method of example 1, step 1 in WO 2020135439) was dissolved in DCM (10mL), after which NBS (169mg,0.95mmol) was added portionwise to the system, the reaction was stirred at 40 ℃ for 3h and the solvent was dried off by spinning to give a yellow oil (550mg, 95.8%) which was directly used in the next step. MS (ESI, pos.ion) M/z 530.1[ M + H-100 ]]+。
Step 2: synthesis of Compound 31-2
Compound 31-1(550mg,0.87mmol), DIPEA (0.6mL,4mmol) and compound 9-2(450mg,0.87mmol) were dissolved in DCM (6mL) at room temperature, the reaction was stirred at room temperature for 15h, then water (10mL) and ethyl acetate (15mL) were added, the aqueous phase was extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, the solvent was dried by spin-drying, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 1/1) to give a yellow solid (520mg, 62.7%). MS (ESI, pos. ion) M/z 954.3[ M + H ]]+。
And step 3: synthesis of Compound 31-3
Compound 31-3(520mg,0.55mmol), sodium hydroxide (110mg,2.75mmol) were dissolved in methanol (6mL), water (2mL) and THF (4mL) at room temperature, after which the reaction was stirred at 70 ℃ for 10hThen, water (10mL) and ethyl acetate (15mL) were added, and the pH of the solution was adjusted to 4-5 with 1M dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, the organic phase was washed with saturated brine (30 mL. times.1), dried over anhydrous sodium sulfate, and the solvent was dried by spinning to give a yellow solid (330mg, 70.9%). MS (ESI, pos. ion) M/z 854.1[ M + H ]]+。
And 4, step 4: synthesis of Compound 31
After compound 31-3(330mg,0.39mmol) was dissolved in 1, 4-dioxane (3mL), a solution of 1, 4-dioxane hydrogen chloride (4mL,16mmol,4mol/L) was added and the reaction was stirred at room temperature for 18 h. The solvent was dried by rotary evaporation and the residue was chromatographed on silica gel (DCM/CH)3OH (V/V) ═ 25/1) purified to give a yellow solid (53mg, 18%). MS (ESI, pos. ion) M/z 754.1[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)8.39(s,1H),7.88(d,J＝2.7Hz,1H),7.72–7.64(m,1H),7.58(d,J＝2.8Hz,1H),7.27–7.22(m,2H),7.12(dd,J＝10.6,8.5Hz,2H),6.89–6.80(m,1H),6.11(s,1H),4.58–4.40(m,2H),3.88–3.75(m,2H),3.67(s,3H),3.62–3.40(m,6H),3.20–3.10(m,2H),2.49(s,3H),2.30(s,3H).
Synthesis of Compound 32
Figure BDA0003438630010000471
Step 1: synthesis of Compound 32-1
Compound F2(500mg,1.49mmol) and HATU (895mg,2.24mmol) were dissolved in DMF (5mL), to which DIPEA (578mg,4.46mmol) and (S) -1-tert-butyl 2-methylpiperazine-1, 2-dicarboxylate (363mg,1.49mmol) were added, respectively, and stirred at room temperature for 24 h. The reaction was quenched by the addition of water (20mL), extracted with dichloromethane (50mL), the organic layer was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, and dried by spinning, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 1/3) to give the title compound as a brown solid (650mg, 78%). MS (ESI, pos. ion) M/z 507.2[ M-56+ H]+。
Step 2: synthesis of Compound 32-2
Compound 32-1(600mg,1.07mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (5mL), and lithium hydroxide monohydrate (90mg,2.15mmol) was added thereto, followed by stirring at room temperature for 2 h. Water (100mL) was added thereto, extraction was performed with ethyl acetate (50 mL. times.2), the aqueous phase was adjusted to pH 3-4 with 1M hydrochloric acid, a large amount of solid precipitated, stirred for 30min and filtered, and the filter cake was dried to give the title compound as a brown solid (550mg, 94%). MS (ESI, pos.ion) M/z 493.2[ M-56+ H ]]+。
And step 3: synthesis of Compound 32-3
Compound 32-2(200mg,0.36mmol), HATU (212mg,0.55mmol) and DIPEA (95mg,0.73mmol) were dissolved in DMF (5mL), then ammonium chloride (39mg,0.73mmol) was added thereto, stirred at room temperature for 12h, water (20mL) was added thereto to quench the reaction, ethyl acetate (80mL) was added, the organic layer was washed with 1M dilute hydrochloric acid (50mL), saturated brine (50mL × 2), dried over anhydrous sodium sulfate, dried by spinning, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (V/V) ═ 20/1) to afford the title compound as a brown solid (150mg, 75%). MS (ESI, pos. ion) M/z 492.2[ M-56+ H]+。
And 4, step 4: synthesis of Compound 32-4
32-3(200mg,0.37mmol) was suspended in dichloromethane (2mL), to which trifluoroacetic acid (2mL) was slowly added and stirred at room temperature for 20 min. Direct spin-dry to give the title compound trifluoroacetate as a brown oil (200mg, 98%).
And 5: synthesis of Compound 32
Compound 32-4(200mg,0.36mmol) and DIPEA (140mg,1.08mmol) were dissolved in dichloromethane (10mL), compound F3(175mg,0.39mmol) was added thereto, stirred at room temperature for 16h, then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (V/V) ═ 20/1) to give the title compound as a yellow solid (180mg, 62%). MS (ESI, pos. ion) M/z 811.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.64–9.49(m,1H),8.58–8.26(m,1H),7.90–7.80(m,1H),7.78–7.70(m,1H),7.60–7.40(m,1H),7.35–7.25(m,1H),7.20–7.10(m,2H),7.03–6.85(m,2H),6.21–6.12(m,1H),6.00–5.83(m,1H),4.39–4.19(m,1H),3.96–3.72(m,1H),3.68(s,3H),3.65–3.52(m,5H),3.48–3.04(m,4H),2.87–2.54(m,1H),2.48(d,J＝3.9Hz,3H),2.37(d,J＝6.3Hz,3H).
Synthesis of Compound 33
Compound 32-2 was substituted for compound 32-3, reference to the synthesis of compound 32 from step 4 to step 5, to afford the desired product as a yellow solid (200mg, 69%). MS (ESI, pos. ion) M/z 812.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.00–8.71(m,1H),7.92(dd,J＝8.3,2.9Hz,1H),7.79–7.69(m,1H),7.65(t,J＝3.1Hz,1H),7.37–7.29(m,2H),7.19–7.07(m,2H),7.04–6.92(m,1H),6.22(s,1H),4.58(d,J＝16.5Hz,1H),4.38(dd,J＝29.4,16.7Hz,1H),4.27–3.96(m,2H),3.97–3.75(m,2H),3.70–3.51(m,8H),3.11–2.74(m,1H),2.46(d,J＝6.6Hz,3H),2.30(d,J＝5.0Hz,3H).
Synthesis of Compound 34
Substituting (2S,4S) -1-tert-butyl 2-methyl 4-aminopyrrolidine-1, 2-dicarboxylate for piperazine-1-carboxylic acid tert-butyl ester with reference to the synthesis of compound 9, the desired product was prepared as a yellow solid (72mg, 71%). MS (ESI, pos. ion) M/z 826.0[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.61(s,1H),7.83(d,J＝8.0Hz,1H),7.72(s,1H),7.67–7.57(m,2H),7.32–7.21(m,2H),7.15–7.01(m,3H),6.92–6.84(m,1H),6.14(d,J＝6.7Hz,1H),4.71–4.60(m,1H),4.35(d,J＝17.4Hz,1H),4.12(d,J＝17.4Hz,1H),3.74–3.61(m,4H),3.57(d,J＝4.7Hz,6H),3.18(d,J＝9.5Hz,1H),2.95(dd,J＝9.3,4.1Hz,1H),2.76–2.65(m,1H),2.29(s,3H),2.23(s,3H),2.18–2.08(m,1H).
Synthesis of Compound 35
Substituting (2R,4R) -methyl 4- ((tert-butoxycarbonyl) amino) pyrrolidine-2-carboxylate for tert-butyl (R) -3-methylpiperazine-1-carboxylate, reference to the synthesis of compound 20, produced the desired product as a yellow solid (60mg, 59%). MS (ESI, pos. ion) M/z 826.0[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.68(s,1H),7.82(d,J＝8.0Hz,1H),7.69–7.59(m,2H),7.55(s,1H),7.31–7.21(m,2H),7.16–7.03(m,3H),6.94–6.84(m,1H),6.15(d,J＝6.1Hz,1H),4.72–4.62(m,1H),4.36(d,J＝17.4Hz,1H),4.13(d,J＝17.5Hz,1H),3.78–3.64(m,4H),3.59(s,6H),3.19(d,J＝9.7Hz,1H),3.02–2.90(m,1H),2.78–2.66(m,1H),2.31(s,3H),2.25(s,3H),2.17–2.10(m,1H).
Synthesis of Compound 36
Adding compound 34(0.2g,0.24mmol) and tetrahydrofuran (5mL) in sequence into a dry reaction flask, stirring uniformly, adding a water (1mL) solution of lithium hydroxide monohydrate (20mg,0.48mmol), stirring at room temperature for 12h, adding water (10mL) and ethyl acetate (20mL) into the reaction solution, extracting and layering, washing the organic layer with saturated brine (20mL × 2), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate, separating the residue by silica gel column chromatography (DCM/CH)3OH (V/V) ═ 10/1) gave the desired product as a yellow solid (120mg, 61%). MS (ESI, pos. ion) M/z 812.1[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.01(s,1H),7.91–7.61(m,3H),7.35–7.20(m,2H),7.19–6.95(m,3H),6.11(d,J＝33.5Hz,1H),4.63(s,2H),3.91(d,J＝14.5Hz,1H),3.82–3.41(m,7H),3.27–3.09(m,1H),2.82–2.59(m,1H),2.36(s,3H),2.31–2.14(m,5H).
Synthesis of Compound 37
Compound 35 was substituted for compound 34, reference to the synthesis of compound 36, and the title product was prepared as a yellow solid (120mg, 68%). MS (ESI, pos. ion) M/z 812.1[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)8.99(s,1H),7.95–7.64(m,3H),7.35–7.23(m,2H),7.15–6.95(m,3H),6.15(s,1H),4.63(s,2H),3.91(d,J＝13.2Hz,1H),3.81–3.56(m,6H),3.54–3.41(m,1H),3.25–3.10(m,1H),2.66(s,1H),2.45–2.31(m,4H),2.29–2.19(m,4H).
Synthesis of Compound 38
Synthetic route to compound F11:
Figure BDA0003438630010000491
step 1: synthesis of Compound F11-1
Compound F11-0(1.35g,4.28mmol) and triethylamine (866mg,8.56mmol) were dissolved in dichloromethane (15mL), methanesulfonyl chloride (588mg,5.13mmol) was added thereto under ice-water bath, after addition, stirring was performed at room temperature for 15h, followed by concentration 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 white solid (1.21g, 72%). MS (ESI, pos.ion) M/z 416.1[ M + Na ]]+。
Step 2: synthesis of Compound F11-2
Compound F11-1(1.21g,3.07mmol) was dissolved in dichloromethane (10mL), to which was added trifluoroacetic acid (10mL), stirred at room temperature for 20h, and concentrated under reduced pressure to give the trifluoroacetate salt of the title compound as a brown oil (1.18g, 91.1%). MS (ESI, pos.ion) M/z 194.1[ M + H ]]+
And step 3: synthesis of Compound F11
Compound F11-2(1.10g,2.61mmol) was dissolved in dichloromethane (10mL), triethylamine (1.32g,13.0mmol) was added thereto, and (Boc) was slowly added thereto in an ice-water bath2O (513mg,2.35mmol) was added and the reaction was continued at this temperature for 14h, dried and the residue chromatographed on silica gel (DCM/MeOH (V/V) ═ 10/1) to give the title compound as a white solid (630mg, 82%). MS (ESI, pos. ion) M/z 294.2[ M + H ]]+。
And 4, step 4: synthesis of Compound 38
Substituting compound F11 for tert-butyl (R) -3-methylpiperazine-1-carboxylate, reference to the synthesis of compound 20, gave the title product as a yellow solid (130mg, 50%). MS (ESI, pos. ion) M/z 875.0[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.52(d,J＝63.3Hz,1H),8.60(d,J＝32.8Hz,1H),7.93–7.85(m,1H),7.76–7.63(m,1H),7.52–7.40(m,1H),7.33–7.24(m,2H),7.21–7.09(m,2H),7.00–6.88(m,2H),6.20–6.17(m,1H),4.98–4.42(m,1H),4.19–3.93(m,2H),3.88–3.79(m,1H),3.69–3.64(m,4H),3.60(d,J＝4.2Hz,3H),3.55–3.43(m,1H),3.12–3.02(m,1H),2.98–2.87(m,1H),2.84–2.65(m,2H),2.65–2.61(m,2H),2.58–2.47(m,4H),2.45–2.35(m,4H).
Synthesis of Compound 39
Figure BDA0003438630010000492
Substituting compound F11 for t-butyl piperazine-1-carboxylate, reference to the synthesis of compound 9, gave the desired product as a yellow solid (120mg, 51%). MS (ESI, pos. ion) M/z 875.0[ M + H ]]+；1H NMR(400MHz,CDCl3)δ(ppm)9.50(d,J＝6.6Hz,1H),8.62(d,J＝22.7Hz,1H),7.83(d,J＝2.7Hz,1H),7.75–7.66(m,1H),7.45(t,J＝3.4Hz,1H),7.31–7.23(m,2H),7.16–7.07(m,2H),6.97–6.85(m,1H),6.16(d,J＝8.9Hz,1H),5.97–5.51(m,1H),4.51–4.41(m,1H),4.22–3.97(m,2H),3.70–3.63(m,4H),3.59(s,3H),3.56–3.45(m,2H),3.37–3.29(m,2H),3.07–2.99(m,1H),2.97–2.88(m,4H),2.62–2.52(m,1H),2.46(d,J＝5.7Hz,3H),2.32(d,J＝5.7Hz,3H).
Biological assay
HepAD38 cells for evaluating compound cytotoxicity and HBV DNA replication inhibition activity (qPCR method)
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 was about 11-fold higher in HBV DNA yield 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
Virion DNA secreted by HepAD38 cells can be quantified by qPCR methods and the effect of compounds on viral replication detected therefrom.
In vitro cytotoxicity assay
Reviving HepAD38Digesting and counting the cells after the cells are well overgrown, and diluting the cells to be 1 × 10 by using DMEM/F-12K culture medium containing 10% FBS and 1% double antibody5PermL of the cell suspension, 100. mu.L/well of the cell suspension was seeded in a 96-well plate (the whole plate was filled), and the plate was incubated at 37 ℃ with 5% CO2And (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 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, discarding the old culture medium, adding a culture medium containing 10% CCK8 solution, incubating for 20-40min, detecting in an enzyme-labeling instrument to obtain OD value, deriving data to calculate inhibition rate, processing by a Graphpad Prism 5 software nonlinear regression model and drawing a curve to calculate CC of the compound50. The results are shown in Table 1.
In vitro anti-HBV Activity assay
After HepAD38 was recovered to ensure that the cells were in a good state, Tetracycline (final concentration of 300ng/ml) and G418 (final concentration of 400. mu.g/ml) were added to the medium, and the medium was digested after confluency without expressing the virus in the presence of Tetracycline, counted, diluted to 2X 10 with 10% FBS-containing DMEM/F-12K medium (containing Tetracycline at final concentration of 300ng/ml and G418 at final concentration of 400. mu.g/ml, 1% double antibody) to 1X 105The cell suspension was seeded in a 96-well plate (full plate) at 100. mu.L/well and incubated at 37 ℃ with 5% CO2And (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 a maximum concentration of 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 Q-PCR
Q-PCR is carried out by using a hepatitis B virus nucleic acid quantitative determination kit of a Shengxiang biological 48-person one-step method (PCR-fluorescent probe method), 2.5 mu L of supernatant is absorbed for Q-PCR, vortex mixing is carried out after reagent of the kit is melted before use, enzyme mixed liquor is placed on ice for standby after centrifugation, and the completion of the subsequent steps on the ice is ensured. 2.5. mu.L of sample release agent and 2.5. mu.L of test sample supernatant (experimental, control, standard curve) were added to each well of the Q-PCR plate. The copy number of the virus DNA in each well is obtained after QPCR reaction. Concentration-viral copy number was processed with Graphpad Prism 5 software and EC of compounds on viral replication was calculated by a four-parameter non-linear regression model50. The results are shown in Table 1.
Table 1: experimental results of in vitro anti-HBV activity and cytotoxicity of the compound
Compound (I) EC50(nM) CC50(μM)
1 55 N/A
2 157 98
3 45 N/A
4 190 N/A
5 120 ＞100
6 84 ＞100
8 131 N/A
9 29 ＞100
10 129 N/A
11 86 N/A
12 21 ＞100
13 145 ＞100
14 86 ＞100
16 46 ＞100
17 81 ＞100
18 20 ＞100
19 20 ＞100
20 48 ＞100
21 40 ＞100
22 80 ＞100
24 120 ＞100
25 152 ＞100
26 27 N/A
27 109 ＞100
28 58 ＞100
29 34 N/A
30 80 ＞100
32 55 62
34 167 ＞100
38 164 ＞100
Note that: N/A represents not measured
And (4) conclusion: the experimental result shows that the compound has better inhibitory activity to HBV and has small toxicity to cells.

Claims (13)

1. A compound which is a compound represented by formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of the compound represented by formula (I) or a prodrug thereof,
Figure FDA0003438622000000011
wherein each R is5a、R5b、R5c、R5d、R5e、R2And R3Independently hydrogen, deuterium, F, Cl, Br, I, CN, SF5Amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C1-4Haloalkyl, trifluoromethoxy, methoxy, or ethoxy;
ring B is C6-10Aryl, heteroaryl of 5 to 6 ring atoms,
Figure FDA0003438622000000012
Figure FDA0003438622000000013
Wherein, said C6-10Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R6Substituted;
each R6Independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C (═ O) OC1-6Alkyl, -OC1-6alkylene-OC1-6Alkyl radical, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C2-6Alkenyl radical, C2-6Alkynyl or carboxyl C1-6Alkyl, wherein said amino, -C (═ O) OC1-6Alkyl, -OC1-6alkylene-OC1-6Alkyl radical, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C2-6Alkenyl radical, C2-6Alkynyl and carboxyl C1-6Each alkyl is independently unsubstituted or substituted with 1,2,3 or 4Rw1Substituted;
each R1a、R1b、R1、R4、RaAnd RbIndependently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C1-4A haloalkyl group;
each R2a、R2bAnd R2cIndependently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C1-4Haloalkyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C1-4Haloalkyl is each independently unsubstituted or substituted with 1,2,3 or 4Rw2Substituted;
each R3a、R3b、R3c、R4a、R4bAnd R4cIndependently is C1-6Alkyl radical, C6-10Aryl or heteroaryl of 5 to 6 ring atoms, wherein C is6-10Aryl and heteroaryl of 5 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4Rw3Substituted;
L1is a single bond, methylene or ethylene; wherein said methylene and ethylene are each independently unsubstituted or substituted with 1,2 or 3Rw4Substituted;
L2is a single bond or-NRb-；
Each Rw1、Rw2、Rw3、Rw4And Rw5Independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C (═ O) OC1-6Alkyl, amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, carboxyl C1-6Alkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
ring A is cyclohexyl, 5-6 ringsA monocyclic heterocyclic group of atoms, a fused bicyclic heterocyclic group of 8 to 10 ring atoms or a bridged heterocyclic group of 6 to 10 ring atoms, wherein said cyclohexyl, monocyclic heterocyclic group of 5 to 6 ring atoms, fused bicyclic heterocyclic group of 8 to 10 ring atoms and bridged bicyclic heterocyclic group of 6 to 10 ring atoms are each independently unsubstituted or substituted with 1,2,3,4, or 5RxSubstituted;
each RxIndependently is deuterium, ═ O, ═ S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH2、-C(＝O)OC1-6Alkyl, -C1-4alkylene-N (R)a)S(＝O)2C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkylene radical, C2-6Alkenyl radical, C2-6Alkynyl, carboxyl C1-6Alkyl or C1-6Haloalkyl, wherein said-CONH2、-C(＝O)OC1-6Alkyl, -C1-4alkylene-N (R)a)S(＝O)2C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkylene radical, C2-6Alkenyl radical, C2-6Alkynyl, carboxyl C1-6Alkyl and C1-6Haloalkyl is each independently unsubstituted or substituted with 1,2,3 or 4Rw5And (4) substituting.
2. The compound of claim 1, wherein said ring B is phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, etc,
Figure FDA0003438622000000021
Wherein the phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, triazolyl, thiazolyl, triazolyl, and triazolyl,Thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently being unsubstituted or substituted by 1,2,3 or 4R6And (4) substitution.
3. A compound according to claim 1 or 2, each R6Independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C (═ O) OC1-4Alkyl, -OC2-4alkylene-OC1-4Alkyl radical, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C2-4Alkenyl radical, C2-4Alkynyl or carboxyl C1-4Alkyl, wherein said amino, -C (═ O) OC1-4Alkyl, -OC2-4alkylene-OC1-4Alkyl radical, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C2-4Alkenyl radical, C2-4Alkynyl and carboxyl C1-4Each alkyl is independently unsubstituted or substituted with 1,2,3 or 4Rw1And (4) substituting.
4. A compound according to claim 1 or 2, wherein each R is6Independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C (═ O) omethyl, -C (═ O) oethyl, -C (═ O) O n-propyl, -C (═ O) O isopropyl, -OCH2CH2CH2-OCH3、-OCH2CH2CH2-OCH2CH3、-OCH2CH2CH2CH2-OCH3、-OCH2CH2CH2CH2-OCH2CH3Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C1-4Haloalkyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, -OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCF3、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、C2-4Alkenyl radical, C2-4Alkynyl or carboxyl C1-4Alkyl, wherein said amino, -C (═ O) omethyl, -C (═ O) oethyl, -C (═ O) O n-propyl, -C (═ O) O isopropyl, -OCH2CH2CH2-OCH3、-OCH2CH2CH2-OCH2CH3、-OCH2CH2CH2CH2-OCH3、-OCH2CH2CH2CH2-OCH2CH3Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C1-4Haloalkyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, -OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、C2-4Alkenyl radical, C2-4Alkynyl and carboxyl C1-4Each alkyl is independently unsubstituted or substituted with 1,2,3 or 4Rw1And (4) substitution.
5. A compound according to claim 1 or 2, wherein each R is3a、R3b、R3c、R4a、R4bAnd R4cIndependently methyl, ethyl, n-propyl, isopropyl, n-butylPhenyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1,2,3 or 4Rw3And (4) substituting.
6. A compound according to claim 1 or 2, wherein each R isw1、Rw2、Rw3、Rw4And Rw5Independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C (═ O) OC1-4Alkyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C2-4Alkenyl radical, C2-4Alkynyl, carboxyl C1-4Alkyl radical, C1-4Haloalkyl or C1-4An alkoxy group.
7. The compound of claim 1 or 2, wherein ring a is
Figure FDA0003438622000000031
Figure FDA0003438622000000032
Figure FDA0003438622000000033
Wherein said formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), formula (II-12), formula (II-13) and formula (II-14) are each independently unsubstituted or substituted with 1,2,3,4, or 5RxAnd (4) substituting.
8. A compound according to claim 1 or 2, wherein each RxIndependently is deuterium, ═ O, ═ S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH2、-C(＝O)OC1-4Alkyl, -C1-3alkylene-N (R)a)S(＝O)2C1-4Alkyl, hydroxy C1-4Alkyl, amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkylene radical, C2-4Alkenyl radical, C2-4Alkynyl, carboxyl C1-4Alkyl or C1-4Haloalkyl, wherein said-CONH2、-C(＝O)OC1-4Alkyl, -C1-3alkylene-N (R)a)S(＝O)2C1-4Alkyl, hydroxy C1-4Alkyl, amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkylene radical, C2-4Alkenyl radical, C2-4Alkynyl, carboxyl C1-4Alkyl and C1-4Haloalkyl is each independently unsubstituted or substituted with 1,2,3 or 4Rw5And (4) substituting.
9. A compound according to claim 1 or 2, each RxIndependently deuterium, ═ O, ═ S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH2-C (═ O) omethyl, -C (═ O) oethyl, -C (═ O) O N-propyl, -C (═ O) O isopropyl, -methylene-N (R) (═ O) O isopropyl, -methyl, -N (R) methyl, -O (O) ethyl, -O (O) propyl, -methyl, -O (O) propyl, -O (O) methyl, -O (O) propyl, -O (O) propyl, O) methyl, -O (O) propyl, -O (O) propyl, O) O (O) propyl, O (O) propyl, O) propyl, and/O (O) propyl, O) methyl, and/O (O) methyl, and/O) and (O) methyl, and O (O) methyl, and O) N (O) methyl, and O) N (O) methyla)S(＝O)2Methyl, -methylene-N (R)a)S(＝O)2Ethyl, -methylene-N (R)a)S(＝O)2N-propyl, -methylene-N (R)a)S(＝O)2Isopropyl, -methylene-N (R)a)S(＝O)2N-butyl, -methylene-N (R)a)S(＝O)2Isobutyl, -ethylene-N (R)a)S(＝O)2Methyl, -ethylene-N (R)a)S(＝O)2Ethyl, -ethylene-N (R)a)S(＝O)2N-propyl, -ethylene-N (R)a)S(＝O)2Isopropyl, -ethylene-N (R)a)S(＝O)2N-butyl, -ethylene-N (R)a)S(＝O)2Isobutyl, hydroxymethyl,Hydroxyethyl, hydroxy-n-propyl, hydroxy-n-butyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, 1-butoxymethyl, methoxymethyl, ethoxyethyl, 1-propoxyethyl, 2-propoxyethyl, 1-butoxyethyl, C2-4Alkenyl radical, C2-4Alkynyl, carboxyl C1-4Alkyl or C1-4Haloalkyl, wherein said-CONH2-C (═ O) omethyl, -C (═ O) oethyl, -C (═ O) O N-propyl, -C (═ O) O isopropyl, -methylene-N (R) (═ O) O isopropyl, -methyl, -N (R) methyl, -O (O) ethyl, -O (O) propyl, -methyl, -O (O) propyl, -O (O) methyl, -O (O) propyl, -O (O) propyl, O) methyl, -O (O) propyl, -O (O) propyl, O) O (O) propyl, O (O) propyl, O) propyl, and/O (O) propyl, O) methyl, and/O (O) methyl, and/O) and (O) methyl, and O (O) methyl, and O) N (O) methyl, and O) N (O) methyla)S(＝O)2Methyl, -methylene-N (R)a)S(＝O)2Ethyl, -methylene-N (R)a)S(＝O)2N-propyl, -methylene-N (R)a)S(＝O)2Isopropyl, -methylene-N (R)a)S(＝O)2N-butyl, -methylene-N (R)a)S(＝O)2Isobutyl, -ethylene-N (R)a)S(＝O)2Methyl, -ethylene-N (R)a)S(＝O)2Ethyl, -ethylene-N (R)a)S(＝O)2N-propyl, -ethylene-N (R)a)S(＝O)2Isopropyl, -ethylene-N (R)a)S(＝O)2N-butyl, -ethylene-N (R)a)S(＝O)2Isobutyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-n-butyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, 1-butoxymethyl, methoxymethyl, ethoxyethyl, 1-propoxyethyl, 2-propoxyethyl, 1-butoxyethyl, C2-4Alkenyl radical, C2-4Alkynyl, carboxyl C1-4Alkyl and C1-4Haloalkyl is each independently unsubstituted or substituted with 1,2,3 or 4Rw5And (4) substituting.
10. The compound of claim 1, comprising the structure of one of:
Figure FDA0003438622000000041
Figure FDA0003438622000000051
Figure FDA0003438622000000061
Figure FDA0003438622000000071
Figure FDA0003438622000000081
Figure FDA0003438622000000091
Figure FDA0003438622000000101
Figure FDA0003438622000000111
Figure FDA0003438622000000121
Figure FDA0003438622000000131
Figure FDA0003438622000000132
or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, together with pharmaceutically acceptable excipients.
12. The pharmaceutical composition according to claim 11, further comprising other anti-HBV drugs, wherein the other anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator or an interferon, wherein the other anti-HBV drug is lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, alfafenone, Alloferon, simon interleukin, cladribine, emtricitabine, famciclovir, calamine CP, intefene, interferon alpha-1 b, interferon alpha-2 a, interferon beta-1 a, interferon alpha-2, interleukin-2, mefenate, nitazoxanide, peginterferon alpha-2 a, ribavirin, roscovarin-A, cionavir, Euforavac, amprenavir, Phosphazid, Heplivav, interferon alpha-2 b, levamisole or propafege.
13. Use of a compound of any one of claims 1-10 or a pharmaceutical composition of any one of claims 11-12 in the manufacture of a medicament for preventing, treating or ameliorating a viral disease in a patient, wherein the viral disease is hepatitis b virus infection or a disease caused by hepatitis b virus infection, wherein the disease caused by hepatitis b virus infection is cirrhosis or hepatocellular carcinoma.
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