CN117126161A - Benzopyridine compound and preparation method and application thereof - Google Patents

Benzopyridine compound and preparation method and application thereof Download PDF

Info

Publication number
CN117126161A
CN117126161A CN202210557316.5A CN202210557316A CN117126161A CN 117126161 A CN117126161 A CN 117126161A CN 202210557316 A CN202210557316 A CN 202210557316A CN 117126161 A CN117126161 A CN 117126161A
Authority
CN
China
Prior art keywords
compound
alkyl
pharmaceutically acceptable
cancer
stereoisomer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202210557316.5A
Other languages
Chinese (zh)
Inventor
李瑛颖
冀斌
叶兆丰
杨子翊
陈明键
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Israel Hyde Artificial Intelligence Drug Research And Development Co ltd
Original Assignee
China Israel Hyde Artificial Intelligence Drug Research And Development Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by China Israel Hyde Artificial Intelligence Drug Research And Development Co ltd filed Critical China Israel Hyde Artificial Intelligence Drug Research And Development Co ltd
Priority to CN202210557316.5A priority Critical patent/CN117126161A/en
Publication of CN117126161A publication Critical patent/CN117126161A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The application provides a benzopyridine compound, a pharmaceutical composition, a preparation method and application thereof, and application thereof in treating hepatitis B or tumors, and also provides application of the compound shown in the general formula I or pharmaceutically acceptable salts, solvates, hydrates, crystal forms and stereoisomers thereof in preparing medicines for treating and/or preventing hepatitis B. The application also provides a pharmaceutical composition for use in the treatment and/or treatment of hepatitis B or a tumour comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, and optionally one or more additional therapeutic and/or prophylactic agents, and optionally one or more pharmaceutically acceptable salts, solvates, hydrates, crystalline forms, stereoisomers thereofA carrier.

Description

Benzopyridine compound and preparation method and application thereof
Technical Field
The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a benzopyridine compound, a pharmaceutical composition, a preparation method and application thereof.
Background
Hepatitis b is an infectious disease caused by Hepatitis B Virus (HBV) and is mainly a liver lesion. Clinically, it is mainly manifested by anorexia, nausea, epigastric discomfort, pain in liver region and hypodynamia. Some patients may have jaundice fever and liver large with liver function impairment. Some patients may become chronicized, even develop cirrhosis, and a few may develop liver cancer.
The treatment of hepatitis B is a long-term process, and the treatment aims to inhibit or eliminate HBV to the maximum extent, reduce inflammation necrosis of liver cells and hepatic fibrosis, delay and prevent disease progression, reduce and prevent liver decompensation, cirrhosis, hepatocellular carcinoma and complications thereof, thereby improving life quality and prolonging survival time.
There are many hepatitis b therapeutic drugs on the market at present, and antiviral treatment is mainly performed by using interferon or nucleoside analogues. For interferon, recombinant DNA leukocyte interferon (IFN-. Alpha.) can inhibit HBV replication. However, when interferon is used for treating hepatitis B, serious adverse reactions, including myelosuppression, influence on thyroid function, depression and the like are often accompanied.
Nucleoside analogs inhibit HBV production primarily by inhibiting reverse transcriptase activity during HBV replication, clinically useful drugs include: lamivudine, famciclovir, acyclovir, adefovir, entecavir, tenofovir, sodium phosphonoformate and the like, which have certain HBV inhibiting effect.
Although these reverse transcriptase inhibitors can effectively reduce HBV DNA level and control HBV level, they have no direct effect on HBV cccDNA and HBsAg clearance because the action target is RNA reverse transcription to DNA. Therefore, the single-drug treatment of nucleoside analogues has extremely low probability of seroconversion of HBsAg, and can not truly cure hepatitis B, and patients need to take medicines for a long time or even for a whole life.
Under the condition of taking the medicines for a long time, the problems of drug resistance, huge medical cost, serious side effects of the medicines and the like are heavy burden for hepatitis B patients. The key point is that at present, no medicine can completely remove viruses to cure hepatitis B. Therefore, there is an urgent need in the art to provide a new drug for treating hepatitis b, capable of eliminating HBsAg, and achieving a functional cure.
Disclosure of Invention
The application provides a benzopyridine compound, a pharmaceutical composition, a preparation method and application thereof, wherein the benzopyridine compound can be used for preventing and/or treating hepatitis B, can reduce the HBsAg level and the HBeAg level of hepatitis B, is expected to become a new hepatitis B therapeutic drug, and can also be used for treating and/or preventing lung cancer, gastric cancer, breast cancer, cervical cancer, tongue squamous carcinoma, oral squamous carcinoma, head and neck cancer, esophagus cancer, liver cancer, pancreatic cancer, kidney cancer, bladder cancer, soft tissue tumor of limbs, melanoma, skin cancer, lymphoma and other tumors.
In one aspect, the present application provides a compound, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, having a structure represented by formula I:
Wherein:
R 1 a 5-10 membered heteroaryl group selected from optionally substituted with one or more substituents selected from halogen, C1-4 alkyl, halo C1-4 alkyl, said heteroaryl group comprising 1 to 5 heteroatoms selected from N, O and S;
a is selected from-C (=O) NR 8 -、-NR 8 C(＝O)-、-S(＝O) 2 NR 8 -、-NR 8 S(＝O) 2 -、-C(＝O)O-、-OC(＝O)-、-S(＝O) 2 O-and-OS (=O) 2 -, wherein R is 8 Selected from C1-4 alkyl, H and halogenated C1-4 alkyl;
R 2 、R 3 and R is 4 Each independently selected from H, C1-4 alkyl and halogenated C1-4 alkyl;
R 5 、R 6 and R is 7 Each independently selected from C1-4 alkyl, H and halogenated C1-4 alkyl; and is also provided with
X and Y are each independently selected from C and N.
In one embodiment, R 1 Selected from:
wherein R is a And R is b Each independently selected from halogen and H.
In one embodiment, a is selected from-C (=o) NR 8 -、-NR 8 C(＝O)-、-S(＝O) 2 NR 8 -and-NR 8 S(＝O) 2 -, wherein R is 8 Selected from C1-4 alkyl and H.
In one embodiment, R 2 、R 3 And R is 4 Each independently selected from C1-4 alkyl.
In one embodiment, R 5 H.
In one embodiment, R 6 Selected from C1-4 alkyl.
In one embodiment, R 7 Selected from C1-4 alkyl.
In one embodiment, the compounds of the present application have a structure represented by formula II or formula III:
wherein each group is as defined above.
In another aspect, the application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the application (e.g., a compound of formula I, formula II, or formula III), or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, and optionally one or more additional therapeutic and/or prophylactic agents, and optionally one or more pharmaceutically acceptable carriers.
In one embodiment, the compounds of the application are selected from:
in one embodiment, the additional therapeutic and/or prophylactic agent is selected from interferon, pegylated interferon, or a nucleoside analog, and preferably wherein the nucleoside analog is selected from entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide.
In another aspect, the application provides the use of a compound of the application (e.g., a compound of formula I, formula II or formula III) or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of hepatitis b or a tumor.
In another aspect, the application provides a compound of the application (e.g., a compound of formula I, formula II, or formula III), or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, for use in the treatment and/or prevention of hepatitis b or a tumor.
In another aspect, the application provides a method of treating and/or preventing hepatitis b or a tumor, the method comprising administering to a subject in need thereof an effective amount of a compound of the application (e.g., a compound of formula I, formula II or formula III) or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof.
In one embodiment, the tumor is selected from lung cancer, stomach cancer, breast cancer, cervical cancer, tongue squamous carcinoma, oral squamous carcinoma, head and neck cancer, esophageal cancer, liver cancer, pancreatic cancer, kidney cancer, bladder cancer, soft tissue tumors of the extremities, melanoma, skin cancer, lymphoma, a compound of the application is selected from:
in another aspect, the present application provides a process for preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, comprising deprotecting a compound of formula I-1 to give a compound of formula I,
wherein PG is an amino protecting group, and the remaining groups are as defined above.
In some embodiments, pharmaceutically acceptable salts of the compounds of the present application or stereoisomers thereof include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinic acid, oxalate, thiocyanate, toluenesulfonate, and undecanoate.
In some embodiments, a compound of the application or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition or a medicament comprising the same is administered by a route selected from the group consisting of: oral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.
In some embodiments, the compounds described herein, or stereoisomers or pharmaceutically acceptable salts thereof, pharmaceutical compositions or medicaments comprising the same, are administered orally.
In some embodiments, the compounds of the application or stereoisomers or pharmaceutically acceptable salts thereof, pharmaceutical compositions or medicaments comprising the same are oral formulations. In some embodiments, the compounds described herein, or stereoisomers or pharmaceutically acceptable salts thereof, pharmaceutical compositions or medicaments comprising the same, are in the form of tablets or capsules.
Drawings
FIG. 1 shows the result of the inhibition of IAP by HTCP 81-05.
FIG. 2 shows the EC50 results of HTCP81-05 against MDA-MB-231.
FIG. 3 shows the IC50 results of HTCP81-02 on ME-180, hela, and UPCI-SCC-152.
FIG. 4 shows the IC50 results of HTCP81-05 versus ME-180.
Detailed Description
The application provides a benzopyridine compound, a pharmaceutical composition, a preparation method and application thereof, wherein the benzopyridine compound can be used for preventing and/or treating hepatitis B, can reduce the HBsAg level and the HBeAg level of hepatitis B, is expected to become a new hepatitis B therapeutic drug, and can also be used for treating and/or preventing lung cancer, gastric cancer, breast cancer, cervical cancer, tongue squamous carcinoma, oral squamous carcinoma, head and neck cancer, esophagus cancer, liver cancer, pancreatic cancer, kidney cancer, bladder cancer, soft tissue tumor of limbs, melanoma, skin cancer, lymphoma and other tumors.
Compounds or pharmaceutically acceptable salts, solvates, hydrates, crystal forms, stereoisomers thereof
The inventor provides a benzopyridine compound or pharmaceutically acceptable salt, solvate, hydrate, crystal form and stereoisomer thereof, wherein the compound has a structure shown in a general formula I:
wherein:
R 1 selected from 5-10 membered heteroaryl optionally substituted with one or more substituents selected from halogen, C1-4 alkyl, halo C1-4 alkyl, said heteroaryl comprising 1 to 5A heteroatom selected from N, O and S;
A is selected from-C (=O) NR 8 -、-NR 8 C(＝O)-、-S(＝O) 2 NR 8 -、-NR 8 S(＝O) 2 -、-C(＝O)O-、-OC(＝O)-、-S(＝O) 2 O-and-OS (=O) 2 -, wherein R is 8 Selected from C1-4 alkyl, H and halogenated C1-4 alkyl;
R 2 、R 3 and R is 4 Each independently selected from H, C1-4 alkyl and halogenated C1-4 alkyl;
R 5 、R 6 and R is 7 Each independently selected from C1-4 alkyl, H and halogenated C1-4 alkyl; and is also provided with
X and Y are each independently selected from C and N.
In one embodiment, R 1 Selected from:
wherein R is a And R is b Each independently selected from halogen and H.
In a preferred embodiment, R 1 Is that
In one embodiment, a is selected from-C (=o) NR 8 -、-NR 8 C(＝O)-、-S(＝O) 2 NR 8 -and-NR 8 S(＝O) 2 -, wherein R is 8 Selected from C1-4 alkyl and H.
In a preferred embodiment, a is selected from-C (=o) NH-, -NHC (=o) -, -S (=o) 2 NH-and-NHS (=O) 2 -。
In a more preferred embodiment, a is-C (=o) NH-, wherein the carbonyl end is bonded to R 1 And (5) connection.
In one embodiment, R 2 Selected from C1-4 alkyl; preferably, R 2 Is methyl. In one embodiment, R 3 Selected from C1-4 alkyl; preferably, R 3 Is methyl. In one embodiment, R 4 Selected from C1-4 alkyl; excellent (excellent)Optionally R 4 Is methyl.
In one embodiment, R 2 、R 3 And R is 4 Each independently selected from C1-4 alkyl. In a preferred embodiment, R 2 、R 3 And R is 4 Is methyl.
In one embodiment, R 5 H. In one embodiment, R 6 Selected from C1-4 alkyl; preferably, R 6 Is methyl. In one embodiment, R 7 Selected from C1-4 alkyl; preferably, R 7 Is methyl.
In one embodiment, R 5 Is H, and R 6 And R is 7 Each independently selected from C1-4 alkyl. In a preferred embodiment, R 5 Is H, and R 6 And R is 7 Is methyl.
In one embodiment, X is N and Y is C. In one embodiment, X is C and Y is N.
In one embodiment, the compound of formula I has a structure represented by formula II or formula III:
wherein each group is as defined above.
In one embodiment, the compounds of the application are selected from:
in a preferred embodiment, the compounds of the application are
In another aspect, the application provides the use of a compound, or a pharmaceutically acceptable salt, solvate, hydrate, crystal form, stereoisomer thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of hepatitis b or a tumour, wherein the compound has the structure of formula I:
wherein:
R 1 a 5-10 membered heteroaryl group selected from optionally substituted with one or more substituents selected from halogen, C1-4 alkyl, halo C1-4 alkyl, said heteroaryl group comprising 1 to 5 heteroatoms selected from N, O and S;
A is selected from-C (=O) NR 8 -、-NR 8 C(＝O)-、-S(＝O) 2 NR 8 -、-NR 8 S(＝O) 2 -、-C(＝O)O-、-OC(＝O)-、-S(＝O) 2 O-and-OS (=O) 2 -, wherein R is 8 Selected from C1-4 alkyl, H and halogenated C1-4 alkyl;
R 2 、R 3 and R is 4 Each independently selected from H, C1-4 alkyl and halogenated C1-4 alkyl;
R 5 、R 6 and R is 7 Each independently selected from C1-4 alkyl, H and halogenated C1-4 alkyl; and is also provided with
X and Y are each independently selected from C and N.
In one embodiment, the tumor is selected from lung cancer, stomach cancer, breast cancer, cervical cancer, tongue squamous carcinoma, oral squamous carcinoma, head and neck cancer, esophageal cancer, liver cancer, pancreatic cancer, renal cancer, bladder cancer, soft tissue tumor of extremities, melanoma, skin cancer, lymphoma.
In some embodiments, pharmaceutically acceptable salts of the compounds of the present application or stereoisomers thereof include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinic acid, oxalate, thiocyanate, toluenesulfonate, and undecanoate.
Compounds of formula (I)Or a pharmaceutically acceptable salt, solvate, hydrate, or crystalline form thereofProcess for preparing stereoisomers
The present application provides a general synthetic route for the synthesis of the compounds of the present application. The application provides a method for preparing a compound shown in a general formula I or pharmaceutically acceptable salt, solvate, hydrate, crystal form and stereoisomer thereof, which comprises the steps of deprotecting a compound shown in a formula I-1 to obtain the compound shown in the formula I,
wherein PG is an amino protecting group, preferably t-butoxycarbonyl (Boc) or p-methoxytrityl (MMT), the remaining groups being as defined above.
In an embodiment of the application, if a chiral carbon is present in the compound, the application includes isomers formed based on any of the stereoconfigurations of the chiral carbon, including, for example, racemates or any of the mirror image isomers. Moreover, the present application includes all other stereoisomers that may occur. That is, the compounds of the present application include all enantiomers, diastereomers, cis-trans isomers, racemates and the like.
Can be used hereinOr->Depicting the chemical bond of the compounds of the present application. Use->Depicted as bonds to asymmetric carbon atoms are meant to include all possible stereoisomers at that carbon atom (e.g., specific enantiomers A construct, a racemic mixture, etc.). Use-> Or->Depicted bonds to asymmetric carbon atoms are intended to indicate the presence of the stereoisomers shown. When present in the racemic mixture, +.>And->To define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
Stereoisomers of the compounds of the invention may be obtained by: reacting an optically active starting material under conditions that do not cause racemization or epimerization; or reacting the appropriate starting materials with "chiral auxiliary" which may then be removed at a suitable stage by derivatization; or the racemic or other mixtures obtained may be separated based on their different physicochemical properties by well-known means, for example, fractional crystallization or HPLC techniques. Enantiomers can also be obtained by separation using chiral chromatography columns.
The pharmaceutically acceptable salts of the compounds of the application or stereoisomers thereof may be formed by methods known in the art by reacting the N atom on the structure of the compound or stereoisomer thereof with an inorganic or organic acid. The mineral acids include, but are not limited to: hydrochloric acid, hydrobromic acid, semi-sulfuric acid, hydroiodic acid, and the like. The organic acids include, but are not limited to: acetic acid, adipic acid, alginic acid, aspartic acid, benzoic acid, benzenesulfonic acid, butyric acid, citric acid, camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid, digluconic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptanoic acid, glycerophosphate, heptanoic acid, caproic acid, 2-hydroxyethanesulfonic acid, lactic acid, malic acid, maleic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, oxalic acid, thiocyanic acid, toluenesulfonic acid, and undecanoic acid.
The present application encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.
Pharmaceutical composition
The application also provides a pharmaceutical composition comprising a compound of the application or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, and optionally one or more additional therapeutic and/or prophylactic agents, and optionally one or more pharmaceutically acceptable carriers. In one embodiment, the compounds of the present application have the structure shown in formula I:
Wherein:
R 1 a 5-10 membered heteroaryl group selected from optionally substituted with one or more substituents selected from halogen, C1-4 alkyl, halo C1-4 alkyl, said heteroaryl group comprising 1 to 5 heteroatoms selected from N, O and S;
a is selected from-C (=O) NR 8 -、-NR 8 C(＝O)-、-S(＝O) 2 NR 8 -、-NR 8 S(＝O) 2 -、-C(＝O)O-、-OC(＝O)-、-S(＝O) 2 O-and-OS (=O) 2 -, wherein R is 8 Selected from C1-4 alkyl, H and halogenated C1-4 alkyl;
R 2 、R 3 and R is 4 Each independently selected from H, C1-4 alkyl and halogenated C1-4 alkyl;
R 5 、R 6 and R is 7 Each independently selected from C1-4 alkyl, H and halogenated C1-4 alkyl; and is also provided with
X and Y are each independently selected from C and N.
In one embodiment, the compounds of the application are selected from:
in one embodiment, the additional therapeutic or prophylactic agent in the pharmaceutical composition is selected from interferon, pegylated interferon, or a nucleoside analog, and preferably wherein the nucleoside analog is selected from entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide.
In one embodiment, the pharmaceutically acceptable salts of the compounds of the present application or stereoisomers thereof include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinic acid, oxalate, thiocyanate, toluenesulfonate, and undecanoate.
In one embodiment, the additional therapeutic or prophylactic agent may be any one or more additional therapeutic or prophylactic agents as described in the "additional therapeutic or prophylactic agent" section below.
In one embodiment, the additional therapeutic or prophylactic agent may be selected from at least one of interferon, pegylated interferon, or a nucleoside analog.
In one embodiment, the nucleoside analog is selected from entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide.
In one embodiment, the application provides a pharmaceutical composition comprising a compound of formula I, formula II or formula III according to the application (e.g., compound HTCP 81-05) or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer and nucleoside analogue thereof, and a pharmaceutically acceptable carrier.
In one embodiment, the present application provides a pharmaceutical composition comprising a compound of formula I, formula II or formula III of the present application (e.g., compound HTCP 81-05) or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer and nucleoside analog selected from entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide, and a pharmaceutically acceptable carrier.
In the pharmaceutical composition of the present application, the compound of the present application or a pharmaceutically acceptable salt, solvate, hydrate, crystal form, stereoisomer and another therapeutic or prophylactic agent thereof may be formulated into one dosage form, or may be formulated into separate dosage forms, respectively, for sequential or simultaneous administration as a combined product.
In one embodiment, the pharmaceutical composition may be administered by a route selected from the group consisting of: oral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural. In one embodiment, the pharmaceutical composition is administered orally. In one embodiment, the pharmaceutical composition is administered by intravenous injection.
In one embodiment, the pharmaceutical composition is an oral formulation. In one embodiment, the pharmaceutical composition is in the form of a tablet or capsule.
Compounds or pharmaceutically acceptable salts, solvates, hydrates, crystal forms, stereoisomers thereofUses of (2)
The present application provides the use of a compound of formula I, formula II or formula III as defined above, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of hepatitis b, and for the treatment and/or prophylaxis of tumors.
In some embodiments, the tumor is selected from lung cancer, stomach cancer, breast cancer, cervical cancer, tongue squamous carcinoma, oral squamous carcinoma, head and neck cancer, esophageal cancer, liver cancer, pancreatic cancer, renal cancer, bladder cancer, soft tissue tumors of the extremities, melanoma, skin cancer, lymphoma.
In some embodiments, the compounds of the application are selected from:
in one embodiment, the present application provides the use of a compound of formula I, formula II or formula III as defined above, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, in the manufacture of a medicament for reducing the level of HBsAg of hepatitis b.
In one embodiment, the present application provides the use of a compound of formula I, formula II or formula III as defined above, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, in the manufacture of a medicament for reducing the level of HBeAg of hepatitis b.
In one embodiment, the present application provides the use of a compound of formula I, formula II or formula III as defined above, or a pharmaceutically acceptable salt, solvate, hydrate, crystal form, stereoisomer thereof, in the manufacture of a medicament for reducing HBV DNA levels.
In one embodiment, the present application provides the use of a compound of formula I, formula II or formula III as defined above, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of a tumor.
In one embodiment, the medicament further comprises one or more additional therapeutic or prophylactic agents. The one or more additional therapeutic or prophylactic agents may be any one or more additional therapeutic or prophylactic agents as described in the "additional therapeutic or prophylactic agent" section below.
In one embodiment, the additional therapeutic or prophylactic agent is selected from at least one of an interferon, a pegylated interferon, or a nucleoside analog.
In one embodiment, the nucleoside analog is selected from entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide.
In one embodiment, the medicament is administered by a route selected from the group consisting of: oral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural. In one embodiment, the medicament is administered orally. In one embodiment, the medicament is administered by intravenous injection.
In one embodiment, the medicament is an oral formulation. In one embodiment, the medicament is in the form of a tablet or capsule.
In the medicament of the application, the compound of the general formula I, the general formula II or the general formula III or pharmaceutically acceptable salts, solvates, hydrates, crystal forms, stereoisomers and other therapeutic agents and/or preventive agents thereof can be prepared into one dosage form, and can also be prepared into independent dosage forms respectively and used as a combined product to be applied sequentially or simultaneously.
Hepatitis B
Hepatitis b is an infectious disease caused by hepatitis b virus and is mainly a liver lesion. Clinically, it is mainly manifested by anorexia, nausea, epigastric discomfort, pain in liver region and hypodynamia. Some patients may have jaundice fever and liver large with liver function impairment. Some patients may become chronicized, even develop cirrhosis, and a few may develop liver cancer.
The pathogen of viral hepatitis B is hepatitis B virus, abbreviated as HBV, and hepatitis B virus is DNA virus. The genome is double-stranded, circular, incompletely closed DNA. The outermost layer of the virus is the outer membrane or coating of the virus, the inner layer of which is the core, the nucleoprotein is the core antigen (HBcAg) and cannot be detected in serum. Serum from HBsAg positive subjects was visualized under electron microscopy for 3 particles: round and filiform particles of diameter 22nm, and also less spherical particles of diameter 42 angstroms, also known as Dane's particles, are intact HBV particles.
The markers for hepatitis b were detected as follows: (1) HBsAg and anti-HBs: HBsAg positive indicates that HBV is currently in the infectious stage, anti-HBs positive for immunoprotective antibodies indicates that immunity to HBV has developed. The diagnosis basis of the chronic HBsAg carrier is that the chronic HBsAg carrier has no clinical symptoms and signs and normal liver function, and the HBsAg is continuously positive for more than 6 months. (2) HBeAg with anti-HBe: HBeAg positive is an index of active replication and strong infectivity of HBV, and the change of the tested serum from HBeAg positive to anti-HBe positive indicates that the disease is relieved and the infectivity is weakened. (3) HBcAg with anti-HBc: HBcAg positive suggests that there is a direct reaction of intact HBV particles and that HBV active replication is rarely used clinically due to the complex detection method. anti-HBc is a marker of HBV infection, and positive IgM for anti-HBc suggests that there is viral replication in the body at the early stage of infection. Three positive HBsAg, HBeAg and anti-HBc in chronic mild hepatitis B and HBsAg carriers have high infectious index that is difficult to turn negative.
Additional therapeutic or prophylactic agents
In one embodiment, a medicament or pharmaceutical composition comprising a compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, according to the application may further comprise one or more additional therapeutic and/or prophylactic agents.
In one embodiment, the additional therapeutic or prophylactic agent may be selected from at least one of interferon, pegylated interferon, or a nucleoside analog.
In one embodiment, the additional therapeutic or prophylactic agent is selected from an interferon or a nucleoside analogue.
In one embodiment, the additional therapeutic or prophylactic agent is selected from nucleoside analogs.
In one embodiment, the nucleoside analog is selected from entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide.
In some embodiments, the additional therapeutic or prophylactic agent is selected from one or more of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide, for example, from one of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide, or from at least two of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide.
Entecavir (ETV) is known under the chemical name 2-amino-1, 9-dihydro-9- [ (1S, 3R, 4S) -4-hydroxy-3- (hydroxymethyl) -2-methylenecyclopentane ] -6H-purin-6-one, and has the following structural formula:
U.S. patent No. 5206244a discloses entecavir and its use for the treatment of hepatitis b virus; a novel entecavir synthesis method is disclosed in WO9809964 A1; WO0164421A1 discloses low dose entecavir solid formulations.
Entecavir is a highly potent antiviral agent, developed by the american schdule company in the 90 th century, with a potent anti-HBV effect. It can be phosphorylated to an active triphosphate, which has a half-life of 15h in the cell. Entecavir triphosphates inhibit all three activities of the viral polymerase (reverse transcriptase) by competing with deoxyguanosine triphosphate, the natural substrate of HBV polymerase: (1) initiation of HBV polymerase; (2) formation of negative strand of pregenomic mRNA reverse transcription; (3) Synthesis of HBV DNA plus strand.
The chemical name of tenofovir disoproxil fumarate (Tenofovir disoproxil fumarate, TDF) is (R) - [ [2- (6-amino-9H-purin-9-yl) -1-methylethoxy ] methyl ] phosphonic acid diisopropyl oxycarbonyl methyl ester fumarate, is an ester precursor of tenofovir, belongs to a novel nucleotide reverse transcriptase inhibitor, and has the effect of inhibiting HBV virus activity.
TDF is another novel ring-opened nucleoside phosphonate that was successfully developed by the us gilid company following adefovir dipivoxil, and was first marketed in the us 10 months in 2001, and has been marketed in countries such as europe, australia and canada.
TDF inhibits viral polymerase in vivo by competitively binding to natural deoxyribose substrates and terminates DNA strand synthesis by insertion into DNA. The main action mechanism is that the tenofovir is hydrolyzed into tenofovir after oral administration, the tenofovir is phosphorylated by cell kinase, and a metabolite tenofovir diphosphate with pharmacological activity is generated, the metabolite tenofovir diphosphate competes with 5 '-deoxyadenosine triphosphate to participate in the synthesis of virus DNA, and after entering the virus DNA, the DNA is prolonged and blocked due to the lack of 3' -OH groups, so that the replication of the virus is blocked. Clinical application shows that TDF has obvious anti-HBV virus curative effect and small toxic side effect, thus having great clinical application prospect.
Tenofovir alafenamide (Tenofovir Alafenamide), a prodrug of Tenofovir (Tenofovir), a novel Nucleoside Reverse Transcriptase Inhibitor (NRTI) developed by the american gilid science company. Compared with the previous generation of anti-hepatitis B similar drug tenofovir disoproxil TDF, the antiviral activity of tenofovir alafenamide is 10 times of that of tenofovir alafenamide, the stability in blood plasma is 200 times of that of tenofovir alafenamide, and the half life is 225 times higher than that of tenofovir alafenamide. Compared with TDF, tenofovir alafenamide only needs one tenth of TDF administration dose, and can achieve the same antiviral effect as TDF. Therefore, the tenofovir alafenamide is used for preventing or/and treating Hepatitis B Virus (HBV) infection, and has better curative effect, higher safety and lower drug resistance.
Route of administration
The medicament or pharmaceutical composition of the application may be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal and parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural. Those skilled in the art will appreciate that the particular route of administration may vary depending upon, for example, the pharmaceutical dosage form, the condition of the recipient.
In one embodiment, the medicament or pharmaceutical composition of the application may be administered by intravenous injection.
One advantage of the medicaments or pharmaceutical compositions of the present application is that they are orally bioavailable and can be administered orally. Thus, in one embodiment, the medicament or pharmaceutical composition of the application may be administered orally. In one embodiment, the medicament or pharmaceutical composition of the present application may be administered orally in the form of a tablet or capsule.
Pharmaceutical composition or formulation and formulation of a drug
In certain embodiments, the compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, is administered in a pharmaceutical composition. The pharmaceutical compositions of the present application may be formulated with conventional carriers and excipients which will be selected in accordance with common practice. The tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and are generally isotonic when used for delivery by non-oral administration. The pharmaceutical compositions or medicaments of the application or all formulations thereof will optionally contain excipients, for example as described in "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl celluloses, hydroxyalkyl methylcellulose, stearic acid and the like. The pH of the formulation ranges from about 3 to about 11, but is typically from about 7 to 10. In some embodiments, the pH of the formulation ranges from about 2 to about 5, but is typically from about 3 to 4.
Formulations include those suitable for the aforementioned routes of administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing co., easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which is composed of one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then shaping the product as necessary.
Formulations of the present application suitable for oral administration may exist as: discrete units, such as capsules or tablets, each containing a predetermined amount of the active ingredient; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
Tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by: the active ingredient in free-flowing form, such as a powder or granules, is pressed in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
The pharmaceutical compositions or medicaments of the present application may also be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous or oleaginous suspension. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol, or as a lyophilized powder. Acceptable carriers and solvents that can be used include water, ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Acceptable carriers and solvents that can be used include water, ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.
Definition of the definition
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.
In the present application, the singular is used to include the plural unless specifically stated otherwise. It should also be noted that the use of "or" means "and/or" unless otherwise indicated.
The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, according to the definition below, "optionally substituted alkyl" refers to "unsubstituted alkyl" (alkyl substituted with a substituent) or "substituted alkyl" (alkyl substituted with a substituent).
In the present application, the term "halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
In the present application, the term "alkyl" means a straight or branched chain group consisting of only carbon and hydrogen atoms, free of unsaturated bonds and linked to the rest of the molecule by a single bond. The term "C 1-4 Alkyl "refers to an alkyl group having 1 to 4 carbon atoms. C (C) 1-4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, and the like.
In the present application, the term "halogenated C 1-4 Alkyl "means C substituted by one or more halogen atoms 1-4 Alkyl, wherein C 1-4 Alkyl is as defined above. Halogenated C 1-4 Examples of alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-difluoroethyl, chloromethyl,2-chloroethyl, dichloromethyl, trichloromethyl, 1, 2-dichloroethyl, bromomethyl, 3-bromopropyl, iodomethyl, and the like.
In the present application, the term "5-10 membered heteroaryl" means a 5-, 6-, 7-, 8-, 9-or 10-membered ring system group having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur in the ring, and at least one aromatic ring. The 5-10 membered heteroaryl group may be a monocyclic or bicyclic ring system. The nitrogen, carbon or sulfur atoms in the 5-to 10-membered heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Examples of 5-10 membered heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, imidazopyridyl, thienopyridinyl, thienopyrimidinyl, thienopyrazinyl, thienopyridazinyl, thiazolopyridinyl, isothiazolopyridinyl, furopyrimidinyl, furopyridazinyl, triazolopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyridazinyl, indolinyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, pteridinyl, cinnolinyl, quinazolinyl, indolizinyl, and the like.
In the present application, the term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule. The compounds of the application contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomers as well as mixtures, including racemic mixtures, of the compounds of the application are part of the application. Diastereomeric mixtures can be separated into the individual diastereomers, based on their different physicochemical properties, by well known means, for example, resolution of an enantiomer can be converted into the diastereomer by reaction with an appropriate optically active material, which is separated and converted (e.g., hydrolyzed) into the corresponding individual isomer. Enantiomers may also be separated using chiral chromatography columns.
In the present application, the term "pharmaceutically acceptable" refers to a substance that does not affect the biological activity or properties of the compounds of the present application and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
In the present application, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acid and free base of the compounds of the present application and has no adverse effect on biology or other aspects.
In the present application, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a therapeutic agent is administered, and which is suitable for contacting the tissues of humans and/or other animals without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment.
In the present application, the term "hydrate" refers to a substance formed by associating a compound with water molecules.
In the present application, the term "solvate" refers to a substance formed by association of a compound with a solvent molecule.
In the present application, the term "therapeutically effective amount" or "effective amount" refers to an amount that is effective at that dose and for the period of time required to achieve the desired therapeutic result. The therapeutically effective amount will depend on factors such as the nature and severity of the hepatitis b or symptoms thereof, the particular therapeutic agent, the general condition of the recipient (e.g., height, weight, age, and physical condition), and the like, and can be determined by standard clinical techniques known to those skilled in the art.
In the present application, the term "treatment" may refer to, for example, alleviation of symptoms, prolongation of survival, improvement of quality of life, and the like. The treatment need not be a "cure". Treatment may also refer to functional cure and clearance of hepatitis b virus.
In the present application, the term "reducing Hepatitis B Virus (HBV) load" means reducing the amount of hepatitis b virus DNA in the blood of a patient that is detectable.
In the present application, the term "reducing the level of HBsAg and/or HBeAg" refers to reducing the amount of HBsAg and/or HBeAg of hepatitis B virus in the blood of a patient that is detectable. The amount of HBsAg and/or HBeAg is generally closely related to the functional cure of hepatitis B.
Examples
Example 1: preparation of Compound HTCP81-05
Step 1:
7-bromo-4-chloroquinoline (8 g,32.990mmol,1 equiv) was placed in a 250mL single-necked flask at room temperature, methylene chloride (80 mL) was added, and m-chloroperoxybenzoic acid (17 g,98.970mmol,3 equiv) was added to the flask. LCMS monitoring indicated the reaction was complete at room temperature for 7 hours. Then, a saturated sodium thiosulfate solution was added to the reaction system and stirred for 1 hour. The organic phases were combined by extraction with ethyl acetate three times, and the organic phase was backwashed three times with saturated brine, dried over anhydrous sodium sulfate and filtered to give 7-bromo-4-chloroquinoline 1-oxide as a pale yellow solid (weight: 8g, yield: 93.81%, purity: 87.39%). LCMS conditions, column model: kinetex EVO; the length is 30mm, and the inner diameter is 3.0mm; mobile phase A water/5 mM ammonium bicarbonate; mobile phase B, acetonitrile; the total time is 2.00min; the peak time was 0.756min.
ESI-MS m/z:259.95[M+H]+.
Step 2:
7-bromo-4-chloroquinoline 1-oxide (4 g, 15.370 mmol,1 equiv) was placed in a 100mL single-necked flask, methylene chloride (40 mL) was added, and p-toluenesulfonyl chloride (3.2 g,17.021mmol,1.1 equiv), triethylamine (7.8, 77.370mmol,5 equiv) and ammonium chloride (4138.57 mg,77.370mmol,5 equiv) were added sequentially to the flask and reacted at room temperature for 7 hours, LCMS monitoring showed the reaction to be complete. Quenching with water, cooling the reaction system to room temperature, extracting with ethyl acetate three times, combining the organic phases, drying and filtering with anhydrous sodium sulfate, concentrating the filtrate under reduced pressure, purifying the crude product by silica gel column chromatography, wherein the ratio of petroleum ether as eluent to ethyl acetate is 5/1, to obtain 7-bromo-4-chloroquinolin-2-amine (weight: 3.3g, yield: 82.81%, purity: 96.92%) in the form of yellow solid.
LCMS conditions, column model: assentsExpress C18; the length is 50mm, and the inner diameter is 3.0mm; mobile phase A is water/0.05% trifluoroacetic acid; mobile phase B acetonitrile/0.05% trifluoroacetic acid; the total time is 2.00min; the peak time was 0.819min.
ESI-MS m/z:256.9[M+H]+.
Step 3:
7-bromo-4-chloroquinolin-2-amine (3 g,11.650mmol,1 equiv) was placed in a 50mL three-necked flask, N, N-dimethylformamide (30 mL) was added, then N- (t-butoxycarbonyl) -N-methylalanine (2.8 g, 13.480 mmol,1.2 equiv), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (6644.28 mg, 17.470 mmol,1.5 equiv), N, N-diisopropylethylamine (3011.26 mg,23.300mmol,2 equiv) was slowly added to the flask in sequence, and stirring at room temperature for 2h was monitored to show the end of the reaction. Water quenching, extraction three times with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the crude product by silica gel column chromatography, eluting with petroleum ether to ethyl acetate in a ratio of 5/1, to give tert-butyl (1- ((7-bromo-4-chloroquinolin-2-yl) amino) -1-oxopropan-2-yl) (methyl) carbamate (weight: 2g, yield: 38.78%, purity: 81.67%) as a yellow oil. LCMS conditions, namely, column type: HALO; the length is 30mm, and the inner diameter is 3.0mm; mobile phase A is water/0.05% trifluoroacetic acid; mobile phase B acetonitrile/0.05% trifluoroacetic acid; the total time is 2.00min; the peak time is 1.633min.
ESI-MS m/z:442.0[M+H]+.
Step 4:
tert-butyl (1- ((7-bromo-4-chloroquinolin-2-yl) amino) -1-oxopropan-2-yl) (methyl) carbamate (180 mg,4.066mmol,1 equiv) and diphenylmethane imine (1105.26 mg,6.099mmol,1.5 equiv) were dissolved in 1, 4-dioxane (20 mL) under nitrogen, and tris (dibenzylidene-BASE acetone) dipalladium (0) (372.30 mg,0.407mmol,0.1 equiv), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (506.32 mg,0.813mmol,0.2 equiv) and cesium carbonate (3973.94 mg, 12.39 mmol,3 equiv) were added sequentially to the reaction flask. The temperature was raised to 100℃and the reaction was carried out for 2 hours. After LCMS monitoring showed that the reaction was completed, the reaction was cooled to room temperature, quenched with water, extracted three times with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and filtered, the filtrate concentrated under reduced pressure, and the resulting crude product was purified by column chromatography on silica gel with a ratio of petroleum ether to ethyl acetate of 5/1 as eluent to give tert-butyl (1- ((4-chloro-7- ((diphenylmethylene) amino) quinolin-2-yl) amino) -1-oxo-2-yl) (methyl) carbamate (weight: 1.5g, yield: 67.94%, purity: 48.18%) as a yellow oil.
LCMS conditions, namely, column type: HALO; the length is 30mm, and the inner diameter is 3.0mm; mobile phase A is water/0.05% trifluoroacetic acid; mobile phase B acetonitrile/0.05% trifluoroacetic acid; the total time is 2.00min; the peak time was 1.698min.
ESI-MS m/z:543.25[M+H]+.
Step 5:
to tert-butyl (1- ((4-chloro-7- ((diphenylmethylene) amino) quinolin-2-yl) amino) -1-oxo-2-yl) (methyl) carbamate (1.5 g,2.767mmol,1 equiv) was added a solution of 1, 4-dioxane hydrochloride (15 mL), reacted at room temperature for 2h and tcl monitoring showed the reaction to end. The reaction system was then concentrated under reduced pressure, and the crude product obtained was used directly in the next step.
Step 6:
n- (7-amino-4-chloroquinolin-2-yl) -2- (methylamino) propionamide (800 mg, 2.87mmol, 1 equiv) was dissolved in methylene chloride (8 mL) at room temperature, and di-tert-butyl dicarbonate (689.03 mg,3.157mmol,1.1 equiv) was added to the reaction flask and reacted at room temperature for 20 hours. After the completion of the reaction, the reaction system was cooled to room temperature, quenched with water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography on silica gel with a ratio of petroleum ether as eluent to ethyl acetate of 2/1 to give tert-butyl (1- ((7-amino-4-chloroquinolin-2-yl) amino) -1-oxopropan-2-yl) (methyl) carbamate (400 mg by weight, 36.79% yield, purity: 77.06%) as a yellow solid. LCMS conditions, namely, column type: HALO; the length is 30mm, and the inner diameter is 3.0mm; mobile phase A is water/0.05% trifluoroacetic acid; mobile phase B acetonitrile/0.05% trifluoroacetic acid; the total time is 2.00min; the peak time was 1.026min.
ESI-MS m/z:379.35[M+H]+.
Step 7:
tert-butyl (1- ((7-amino-4-chloroquinolin-2-yl) amino) -1-oxopropan-2-yl) (methyl) carbamate (200 mg,0.528mmol,1 equiv) was dissolved in 1, 4-dioxane (2 mL) under nitrogen, and pinacol biborate (268.11 mg,1.056mmol,2 equiv), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (43.00 mg,0.053mmol,0.1 equiv) and potassium acetate (155.43 mg, 1.284 mmol,3 equiv) were added to a reaction flask and reacted at 100℃for 20 hours. After the reaction was completed, the reaction system was cooled to room temperature and the obtained system was directly used for the next reaction.
Step 8:
(7-amino-2- (2- ((tert-butoxycarbonyl) (methyl) amino) propanamido) quinolin-4-yl) boronic acid (200 mg,0.515mmol,1 equiv) and 7-chloro-1, 3, 5-trimethyl-1H-pyrazolo [4,3-d ] pyrimidine (101.30 mg,0.515mmol,1 equiv) were dissolved in 1, 4-dioxane (2 mL) under nitrogen, and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (41.97 mg,0.052mmol,0.1 equiv), potassium phosphate (328.05 mg,1.545mmol,3 equiv) and water (0.4 mL) were sequentially added to the reaction flask. The temperature was raised to 100℃and the reaction was carried out for 2 hours. After completion of LCMS monitoring showed that the reaction was cooled to room temperature, quenched with water, extracted three times with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and filtered, the filtrate concentrated under reduced pressure, and the resulting crude product purified by silica gel column chromatography with eluent petroleum ether to ethyl acetate in a ratio of 1/1 to give tert-butyl (1- ((7-amino-4- (1, 3, 5-trimethyl-1H-pyrazolo [4,3-d ] pyrimidin-7-yl) quinolin-2-yl) amino) -1-oxopropan-2-yl) (methyl) carbamate (70 mg by weight, 26.93% yield, 41.18%) as a yellow solid.
LCMS conditions, namely, column type: HALO; the length is 30mm, and the inner diameter is 3.0mm; mobile phase A is water/0.05% trifluoroacetic acid; mobile phase B acetonitrile/0.05% trifluoroacetic acid; the total time is 2.00min; the peak time is 0.999min.
ESI-MS m/z:505-55[M+H]+.
Step 9:
tert-butyl (1- ((7-amino-4- (1, 3, 5-trimethyl-1H-pyrazolo [4,3-d ] pyrimidin-7-yl) quinolin-2-yl) amino) -1-oxopropan-2-yl) (methyl) carbamate (60 mg,0.119mmol,1 equiv) and 5-chloro-3-fluoro-2-pyridinecarboxylic acid (20.87 mg,0.119mmol,1 equiv) were dissolved in dichloromethane (1 mL), then 4-dimethylaminopyridine (0.12 mg,0.001mmol,0.1 equiv), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.70 mg,0.030mmol,3 equiv) were slowly added to the flask in sequence, stirred at room temperature for 2H, and tlc monitoring showed the reaction to end. Quenched with water, extracted three times with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and filtered, the filtrate concentrated under reduced pressure, and the crude product obtained was purified by column chromatography on silica gel with a ratio of petroleum ether to ethyl acetate as eluent of 1/2 to give methyl tert-butyl (1- ((7- (5-chloro-3-fluoropyridinium-amido) -4- (1, 3, 5-trimethyl-1H-pyrazolo [4,3-d ] pyrimidin-7-yl) quinolin-2-yl) amino) -1-oxopropan-2-yl) (methyl) carbamate (weight: 70mg, yield: 88.91%) as a yellow solid. Step 10:
Tert-butyl (1- ((7- (5-chloro-3-fluoropyridinamide) -4- (1, 3, 5-trimethyl-1H-pyrazolo [4,3-d ] pyrimidin-7-yl) quinolin-2-yl) amino) -1-oxopropan-2-yl) (methyl) carbamate (40 mg,0.060mmol,1 equiv) was dissolved in a solution of 1, 4-dioxane (0.5 mL) of hydrochloric acid and stirred at room temperature for 2H, tlc monitoring showed the reaction to end. The reaction system was concentrated under reduced pressure, and the obtained crude product was purified by reverse phase column chromatography to give 5-chloro-3-fluoro-N- (2- (2- (methylamino) propanamido) -4- (1, 3, 5-trimethyl-1H-pyrazolo [4,3-d ] pyrimidin-7-yl) quinolin-7-yl) pyridinecarboxamide (weight: 6.2mg, yield: 18.02%, purity: 98.74%) as a white solid.
LCMS conditions column model Ascentis Express C; the length is 50mm, and the inner diameter is 3.0mm; mobile phase A is water/0.05% trifluoroacetic acid; mobile phase B acetonitrile/0.05% trifluoroacetic acid; the total time is 3.00min; the peak time was 1.709min.
ESI-MS m/z:562.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ1.25(d,J＝6.9Hz,3H),2.31(s,3H),2.59(s,3H),2.81(s,3H),2.97(s,2H),3.43(s,3H),7.44(d,J＝9.1Hz,1H),7.82–7.92(m,1H),8.30–8.41(m,2H),8.60(d,J＝2.1Hz,1H),8.69(d,J＝1.9Hz,1H),11.04(s,1H).
Example 2: evaluation of in vitro anti-HBV Activity of Compound HTCP81-05 Using HepG2.2.15 cells
Material
Compound HTCP81-05 was prepared by the method described in example 1;
entecavir is purchased from Shanghai Taitan technologies Co., ltd (lot number: P1214012;99.0% purity);
cell hepg2.2.15 was purchased from Shanghai Minkangde New drug development Co., ltd;
The cell subculture medium was DMEM medium (Gibco, cat No. 11960051) containing 10% fetal bovine serum (FBS, ex cell cat No. FSP 500), 500 μg/ml G418, 1% glutamine, 1% neaa (non-essential amino acids), 1mM sodium pyruvate, 1% penicillin-streptomycin, mainly for subculturing cells. Cell plating medium is DMEM medium (Gibco, cat No. 11960051) containing 2% fetal bovine serum (FBS, ex cell cat No. FSP 500), 500 μg/ml G418, 1% glutamine, 1% neaa (non-essential amino acids), 1mM sodium pyruvate, 1% penicillin-streptomycin, mainly for cell plating and drug addition and fluid change;
QIAamp 96 DNA Blood Kit is available from Qiagen (accession number 51162);
HBsAg ELISA kits were purchased from amblygraphic organisms (cat No. CL 0310);
HBeAg ELISA kit was purchased from amblygraphic organism (cat No. CL 0312);
CellTiter-Glo kit was purchased from Roche;
HBV virus was purchased from Shanghai Mingkang New drug development Co.
Cell spreading and compound treatment
On day 0, hepg2.2.15 in cell plating medium was plated into 96-well plates (6×10) 4 Individual cells/well).
On day 1, medium containing the compound was added. Test compound HTCP81-05 was diluted 2 single drug concentrations with DMSO, control compound ETV 9 total, 3-fold diluted, three-fold wells (table 1). DMSO controls containing DMSO alone without compound were also set. Cells at 5% CO 2 And cultured at 37℃for 3 days.
On day 4, the fresh cell plating medium containing the compound was changed once.
On day 7, the supernatant was collected, and the collected cell supernatant was assayed for HBeAg and HBsAg by ELISA, and HBV DNA levels by qPCR. Meanwhile, cellTiter-Glo detects cell viability and collects cells for cryopreservation (spare).
TABLE 1 test concentration of Compounds
Sample detection
qPCR method for detecting HBV DNA content in cell culture supernatant
DNA was extracted from the cell culture supernatant by reference to QIAamp 96DNA Blood Kit instructions. The HBV DNA content was detected by qPCR method. And (3) PCR reaction: 95 ℃ for 10min;95 ℃,15sec,60 ℃,1min,40 cycles.ELISA method for detection Measurement of HBeAg and HBsAg content in cell culture supernatant
The method is briefly described below with reference to the kit instructions: respectively adding 50 μl of standard substance, sample and reference substance into the detection plate, adding 50 μl of enzyme conjugate into each well, incubating at 37deg.C for 60 min, washing the plate with washing solution, blotting, adding 50 μl of premixed luminescent substrate, incubating at room temperature in dark for 10min, and measuring the luminescence value by enzyme-labeled instrument.
CellTiter-Glo cell viability assay
Cell viability was determined with reference to CellTiter-Glo kit instructions, briefly as follows: after collecting the cell culture supernatant, cellTiter-Glo (medium 1:1 dilution) was added to each well, incubated at room temperature for 10 minutes, and the luminescence value was measured by an enzyme-labeled instrument.
Data computation
HBV DNA inhibition (%) = (HBV copy number of 1-compound group sample/HBV copy number of DMSO control group) ×100%
HBsAg inhibition (%) = (HBsAg value of 1-sample/HBsAg value of DMSO control) ×100%
HBeAg inhibition (%) = (HBeAg value of 1-sample/HBeAg value of DMSO control group) ×100%
Cell viability (%) = ((sample value-medium control group mean)/(DMSO group mean-medium control group mean) ×100%)
Calculation of EC using GraphPad Prism software (four parameter logistic equations) 50 Values.
Data analysis
The results of the control compound ETV are shown in table 2 below:
TABLE 2
The results of the control compound ETV indicate that the test method is effective. Furthermore, it can be seen from table 2 that ETV has a significant inhibitory effect on HBV DNA, but not on HBeAg and HBsAg.
The results of the test compounds are shown in table 3 below:
TABLE 3 Table 3
As shown in Table 3, the compound HTCP81-05 has better inhibition effect on HBsAg and HBeAg at the concentration of 20 mu M, and can effectively reduce the levels of HBsAg and HBeAg, thereby being expected to remove hepatitis B virus, achieve functional cure and avoid long-term or lifelong administration.
Example 3: the inhibition of IAP (apoptosis inhibitor) by compound HTCP81-05 was evaluated by fluorescence luminescence method, and the test results are shown in Table 4 below:
TABLE 4 Table 4
As shown in Table 4 and FIG. 1, the IC50 for the compound HTCP81-05 against IAP was 199.32nM, indicating that this compound is a good IAP inhibitor.
Example 4: the in vitro antitumor activity of compound HTCP81-05 was evaluated using MDA-MB-231 cells (human breast cancer cells) and the test results are shown in Table 5 below:
TABLE 5
As shown in Table 5 and FIG. 2, the compound HTCP81-05 showed good in vitro antitumor activity with an EC50 of 3470nM against MDA-MB-231 cells.
Example 5: using ME-180 (human cervical epidermoid carcinoma cells), hela (cervical carcinoma cells), UPCI-SCC-152 (human tongue squamous carcinoma cells), 3 cell lines to evaluate compound HTCP81-02 for in vitro antitumor activity; the ME-180 (human cervical epidermoid carcinoma cell) cell line was used to evaluate the in vitro antitumor activity of compound HTCP 81-05.
Experimental methods cells of the cell lines were plated into 384 well plates, HTCP81-02 and HTCP81-05 at corresponding concentrations, respectively, were added the next day, the concentrations were shown in Table 6, and cell viability was measured by adding CellTiter-Glo after 3 days of incubation.
TABLE 6
The test results are shown in tables 7 and 8 below:
TABLE 7
TABLE 8
As shown in Table 7, table 8, FIG. 3 and FIG. 4, the compounds HTCP81-02 and HTCP81-05 showed good in vitro antitumor activity.
Although the present application has been described with reference to particular embodiments, those skilled in the art will recognize that changes and modifications may be made to the embodiments without departing from the spirit and scope of the application, which is defined by the appended claims.

Claims (10)

1. A compound having a structure according to formula I:
wherein:
R 1 a 5-10 membered heteroaryl group selected from optionally substituted with one or more substituents selected from halogen, C1-4 alkyl, halo C1-4 alkyl, said heteroaryl group comprising 1 to 5 heteroatoms selected from N, O and S;
a is selected from-C (=O) NR 8 -、-NR 8 C(＝O)-、-S(＝O) 2 NR 8 -、-NR 8 S(＝O) 2 -、-C(＝O)O-、-OC(＝O)-、-S(＝O) 2 O-and-OS (=O) 2 -, wherein R is 8 Selected from C1-4 alkyl, H and halogenated C1-4 alkyl;
R 2 、R 3 and R is 4 Each independently selected from H, C1-4 alkyl and halogenated C1-4 alkyl;
R 5 、R 6 and R is 7 Each independently selected from C1-4 alkyl, H and halogenated C1-4 alkyl; and is also provided with
X and Y are each independently selected from C and N.
2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, wherein R 1 Selected from:
wherein R is a And R is b Each independently selected from halogen and H; and is also provided with
Preferably, R 1 Is that
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, crystal form, stereoisomer thereof, wherein a is selected from-C (=o) NR 8 -、-NR 8 C(＝O)-、-S(＝O) 2 NR 8 -and-NR 8 S(＝O) 2 -, wherein R is 8 Selected from C1-4 alkyl and H;
preferably, a is selected from-C (=o) NH-, -NHC (=o) -, -S (=o) 2 NH-and-NHS (=O) 2 -; and is also provided with
More preferably, a is-C (=o) NH-, wherein the carbonyl end is bonded to R 1 And (5) connection.
4. A compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, wherein R 2 、R 3 And R is 4 Each independently selected from C1-4 alkyl; and is also provided with
Preferably, R 2 、R 3 And R is 4 Is methyl.
5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, wherein R 5 Is H, and R 6 And R is 7 Each independently selected from C1-4 alkyl; and is also provided with
Preferably, R 5 Is H, and R 6 And R is 7 Is methyl.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, wherein
X is N, and Y is C; or alternatively
X is C, and Y is N.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, wherein the compound has a structure represented by formula II or formula III:
wherein each group is as defined in any one of claims 1 to 6; and, in addition, the processing unit,
Preferably, the compound is selected from:
8. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, and optionally one or more additional therapeutic and/or prophylactic agents, and optionally one or more pharmaceutically acceptable carriers, and,
preferably, wherein the additional therapeutic and/or prophylactic agent is selected from interferon, pegylated interferon or a nucleoside analogue, and preferably wherein the nucleoside analogue is selected from entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide.
9. The use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, stereoisomer thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of hepatitis B or tumour and,
preferably, the tumor is selected from lung cancer, stomach cancer, breast cancer, cervical cancer, tongue squamous carcinoma, oral squamous carcinoma, head and neck cancer, esophageal cancer, liver cancer, pancreatic cancer, kidney cancer, bladder cancer, soft tissue tumor of extremities, melanoma, skin cancer, lymphoma, wherein the compound is selected from:
10. A method for preparing a compound shown in a general formula I or pharmaceutically acceptable salt, solvate, hydrate, crystal form and stereoisomer thereof, which comprises the steps of deprotecting a compound shown in a formula I-1 to obtain the compound shown in the formula I,
wherein PG is an amino protecting group, preferably t-butoxycarbonyl (Boc) or p-methoxytrityl (MMT), the remaining groups being as defined in any of claims 1 to 7.
CN202210557316.5A 2022-05-20 2022-05-20 Benzopyridine compound and preparation method and application thereof Pending CN117126161A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210557316.5A CN117126161A (en) 2022-05-20 2022-05-20 Benzopyridine compound and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210557316.5A CN117126161A (en) 2022-05-20 2022-05-20 Benzopyridine compound and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN117126161A true CN117126161A (en) 2023-11-28

Family

ID=88861535

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210557316.5A Pending CN117126161A (en) 2022-05-20 2022-05-20 Benzopyridine compound and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN117126161A (en)

Similar Documents

Publication Publication Date Title
JP5763126B2 (en) Antiviral compounds
CA2876690C (en) Dihydropyrimidine compounds and their application in pharmaceuticals
US9777009B2 (en) Deuterated ibrutinib
CA3136745A1 (en) Dosage forms and regimens for amino acid compounds
AU2021268889A1 (en) Treatment of respiratory diseases with amino acid compounds
CN105518012B (en) A kind of substituted amino acid sulfur ester, its composition and application
CN113166115A (en) Monomeric and multimeric anti-HBV agents
EP3670500A1 (en) Chemical compound, pharmaceutical composition thereof, and use and application thereof
JP7250015B2 (en) Anti-HBV tetrahydroisoxazolo[4,3-c]pyridine class compounds
US20230108906A1 (en) Substituted bicyclic and tricyclic ureas and amides, analogues thereof, and methods using same
JP2024517765A (en) Expanded dosing regimens of integrin inhibitors
CN117126161A (en) Benzopyridine compound and preparation method and application thereof
CN117126163A (en) Benzo heterocyclic compound, and preparation method and application thereof
US20110288106A1 (en) Adenine receptor ligands
CN117126162A (en) Polysubstituted heterocyclic compound, preparation method and application thereof
CN117069715A (en) Polysubstituted pyridine compound and preparation method and application thereof
JP2021531331A (en) Its use as a thiadiazole derivative and a GLS1 inhibitor
WO2015127848A1 (en) Substituted phosphoramidate derivative, preparation method therefor, and uses thereof
TWI616453B (en) Substituted amino acid thioester compounds, materials and uses thereof
CN116178367A (en) Application of benzoheterocycle compounds in treatment or prevention of hepatitis B
CN109280028B (en) Quinoline compound and application thereof in DPP-4 enzyme inhibitor
WO2023067517A1 (en) Novel crystalline forms
TWI692476B (en) Cyclobutyl-imidazolidinone compounds
CN109232538B (en) 1,2, 4-triazole compound
CN116135210A (en) Application of 1H-pyrazolo [3,4-b ] pyridine-4-carboxamide compound in treatment or prevention of hepatitis B

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication