WO2021213445A1 - Dérivés de sultame et leur application - Google Patents

Dérivés de sultame et leur application Download PDF

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Publication number
WO2021213445A1
WO2021213445A1 PCT/CN2021/088736 CN2021088736W WO2021213445A1 WO 2021213445 A1 WO2021213445 A1 WO 2021213445A1 CN 2021088736 W CN2021088736 W CN 2021088736W WO 2021213445 A1 WO2021213445 A1 WO 2021213445A1
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Prior art keywords
compound
added
reaction solution
ring
stirred
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PCT/CN2021/088736
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English (en)
Chinese (zh)
Inventor
夏建华
贺海鹰
江志赶
张晓�
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202180043987.3A priority Critical patent/CN115702152A/zh
Publication of WO2021213445A1 publication Critical patent/WO2021213445A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention relates to a class of lactam derivatives and their application in the preparation of medicines for treating related diseases. Specifically, it relates to a compound represented by formula (III) or a pharmaceutically acceptable salt thereof.
  • Hepatitis B is an infectious disease caused by the invasion of hepatitis B virus, which is mainly caused by liver inflammatory lesions and can cause damage to multiple organs. It can easily develop into liver fibrosis, liver cirrhosis and liver cancer. The direct cause of primary liver cancer. It is widespread in countries all over the world. According to reports, about 257 million people worldwide are infected with hepatitis B virus, and about 887,000 people die from hepatitis B virus infection-related diseases each year. There were 1 million cases and 330,000 deaths.
  • Hepatitis B is a worldwide medical problem. At present, there are no specific drugs for treating hepatitis B worldwide.
  • the current first-line drugs for hepatitis B are mainly nucleoside and interferon drugs, but these drugs cannot be completely cured and require long-term medication.
  • the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • Each R 1 is independently selected from halogen, OH, CN, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Substituted by 1, 2 or 3 halogens;
  • n 0, 1, 2 and 3;
  • T is selected from NCH 3 and CH;
  • T is selected from CH
  • n is independently selected from 1, 2, 3, 4, 5, and 6;
  • Ring A is selected from phenyl and pyridyl
  • Ring B does not exist, that is, L 1 is directly connected to ring C;
  • Or ring B is selected from cyclohexyl, piperidinyl, piperazinyl, phenyl and 5-6 membered heteroaryl, the cyclohexyl, piperidinyl, piperazinyl, phenyl and 5-6 membered heteroaryl optionally substituted with one, two, or three R a;
  • Ring C is selected from 5-6 membered heteroaryl groups, which are optionally substituted with 1 or 2 R b ;
  • Each R a, R b are each independently selected from halogen, OH, CN, NH 2, C 1-3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl and a C 1-3 alkoxy oxygen The group is optionally substituted with 1, 2 or 3 halogens;
  • the 5-6 membered heteroaryl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, S, N and NH.
  • each of R 1 each independently selected from F, Cl, Br, C 1-3 alkyl group and a C 1-3 alkoxy group, a C 1- 3 alkyl and C 1-
  • the 3 alkoxy group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • each of the aforementioned R 1 is independently selected from F, Cl, Br, CH 3 , CF 3 , OCH 3 and OCF 3 , and other variables are as defined in the present invention.
  • each of the foregoing Ra and R b is independently selected from F, Cl, Br, CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally selected from 1, 2, or 3. Replace with F, and other variables are as defined in the present invention.
  • each of the foregoing Ra and R b is independently selected from F and Cl, and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from non-existent, cyclohexyl, piperidinyl, piperazinyl, phenyl, imidazolyl and pyridyl, the cyclohexyl, piperidinyl, piperazinyl, benzene group, imidazolyl and pyridinyl optionally substituted with one, two, or three R a, the other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from non-existent, phenyl, imidazolyl and pyridyl, and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from absent, Other variables are as defined in the present invention.
  • the above-mentioned ring C is selected from thienyl, thiazolyl, imidazolyl and pyridyl, and the ring C is selected from thienyl, thiazolyl, imidazolyl and pyridyl.
  • R b is substituted, and other variables are as defined in the present invention.
  • the above-mentioned ring C is selected from thienyl, thiazolyl, imidazolyl and pyridyl, and other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
  • R 1 , R 2 , L 1 , m, ring A, ring B, and ring C are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
  • R 1 , R 2 , L 1 , m and ring B are as defined in the present invention.
  • T 1 is selected from CH and N;
  • T 2 and T 3 are independently selected from CH and N, and T 2 and T 3 are not N at the same time.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • Each R 1 is independently selected from halogen, OH, CN, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Substituted by 1, 2 or 3 halogens;
  • n 0, 1, 2 and 3;
  • n is independently selected from 1, 2, 3, 4, 5, and 6;
  • Ring A is selected from phenyl and pyridyl
  • Ring B does not exist, that is, L 1 is directly connected to ring C;
  • ring B is selected from phenyl or 5-6 membered heteroaryl, said phenyl and 5-6 membered heteroaryl optionally substituted with one, two, or three R a;
  • Ring C is selected from 5-6 membered heteroaryl groups, which are optionally substituted by 1, 2 or R b ;
  • Each R a, R b are each independently selected from halogen, OH, CN, NH 2, C 1-3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl and a C 1-3 alkoxy oxygen The group is optionally substituted with 1, 2 or 3 halogens;
  • the 5-6 membered heteroaryl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, S and N.
  • each of R 1 each independently selected from F, Cl, Br, C 1-3 alkyl group and a C 1-3 alkoxy group, a C 1- 3 alkyl and C 1-
  • the 3 alkoxy group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • each of the aforementioned R 1 is independently selected from F, Cl, B r , CH 3 , CF 3 , OCH 3 and OCF 3 , and other variables are as defined in the present invention.
  • each of the above-mentioned Ra and R b are independently selected from F, Cl, Br, CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally selected by 1, 2 or 3 Replace with F, and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from non-existent, phenyl, imidazolyl and pyridyl, and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from absent, Other variables are as defined in the present invention.
  • the above-mentioned ring C is selected from thienyl, imidazolyl and pyridyl, and the ring C is selected from thienyl, imidazolyl and pyridyl, optionally substituted by 1 or 2 R b , and other variables As defined in the present invention.
  • the above-mentioned ring C is selected from thienyl, imidazolyl and pyridyl, and other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
  • R 1 , L 1 , m and ring B are as defined in any one of the present invention.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • Each R 1 is independently selected from halogen, OH, CN, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Substituted by 1, 2 or 3 halogens;
  • n 0, 1, 2 and 3;
  • n is independently selected from 1, 2, 3, 4, 5, and 6;
  • Ring A is selected from phenyl and pyridyl
  • Ring B does not exist, that is, L 1 is directly connected to ring C;
  • Or ring B is selected from cyclohexyl, piperidinyl, phenyl and 5-6 membered heteroaryl, the cyclohexyl, piperidinyl, phenyl and 5-6 membered heteroaryl are optionally selected by 1, 2 Or 3 R a substitutions;
  • Ring C is selected from 5-6 membered heteroaryl groups, which are optionally substituted by 1, 2 or R b ;
  • Each R a, R b are each independently selected from halogen, OH, CN, NH 2, C 1-3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl and a C 1-3 alkoxy oxygen The group is optionally substituted with 1, 2 or 3 halogens;
  • the 5-6 membered heteroaryl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, S and N.
  • each of R 1 each independently selected from F, Cl, Br, C 1-3 alkyl group and a C 1-3 alkoxy group, a C 1- 3 alkyl and C 1-
  • the 3 alkoxy group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • each of the aforementioned R 1 is independently selected from F, Cl, Br, CH 3 , CF 3 , OCH 3 and OCF 3 , and other variables are as defined in the present invention.
  • each of the above-mentioned Ra and R b are independently selected from F, Cl, Br, CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally selected by 1, 2 or 3 Replace with F, and other variables are as defined in the present invention.
  • each of the foregoing Ra and R b are independently selected from F and Cl, and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from non-existent, cyclohexyl, piperidinyl, phenyl, imidazolyl and pyridyl, and the cyclohexyl, piperidinyl, phenyl, imidazolyl and pyridyl are any is selected from 1, 2 or 3 substituents R a, the other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from non-existent, phenyl, imidazolyl and pyridyl, and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from absent, Other variables are as defined in the present invention.
  • the above-mentioned ring C is selected from thienyl, thiazolyl, imidazolyl and pyridyl, and the ring C is selected from thienyl, thiazolyl, imidazolyl and pyridyl.
  • R b is substituted, and other variables are as defined in the present invention.
  • the above-mentioned ring C is selected from thienyl, thiazolyl, imidazolyl and pyridyl, and other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
  • R 1 , L 1 , m and ring B are as defined in any one of the present invention.
  • T 1 is selected from CH and N;
  • T 2 and T 3 are independently selected from CH and N, and T 2 and T 3 are not N at the same time.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • Each R 1 is independently selected from halogen, OH, CN, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy optionally Substituted by 1, 2 or 3 halogens;
  • n 0, 1, 2 and 3;
  • R 2 is selected from H and -COOH
  • L 1 is selected from -(CH 2 ) n -, said -(CH 2 ) n -is optionally substituted with 1, 2 or 3 halogens;
  • n is independently selected from 0, 1, 2, 3, 4, 5, and 6;
  • Ring A is selected from phenyl and pyridyl
  • Ring B does not exist, that is, L 1 is directly connected to ring C;
  • Or ring B is selected from C 3-6 cycloalkyl, phenyl and 5-6 membered heteroaryl, the C 3-6 cycloalkyl, phenyl and 5-6 membered heteroaryl are optionally selected from 1, 2 or 3 Ra substitutions;
  • Ring C is selected from 5-6 membered heteroaryl groups, which are optionally substituted with 1, 2 or 3 R b ;
  • Each R a and R b is independently selected from halogen, OH, CN, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy The group is optionally substituted with 1, 2 or 3 halogens;
  • the 5-6 membered heteroaryl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, S and N.
  • each of R 1 each independently selected from F, Cl, Br, C 1-3 alkyl group and a C 1-3 alkoxy group, a C 1- 3 alkyl and C 1-
  • the 3 alkoxy group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • each of the aforementioned R 1 is independently selected from F, Cl, Br, CH 3 , CF 3 , OCH 3 and OCF 3 , and other variables are as defined in the present invention.
  • the above-mentioned L 1 is selected from absent, -CH 2 -, -(CH 2 ) 2 -and -(CH 2 ) 3 -, and other variables are as defined in the present invention.
  • each of the above-mentioned Ra and R b are independently selected from F, Cl, Br, CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally selected by 1, 2 or 3 Replace with F, and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from non-existent, cyclohexyl, phenyl, imidazolyl and pyridyl, and the cyclohexyl, phenyl, imidazolyl and pyridyl are optionally selected by 1, 2 or 3 Ra substitutions, other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from absent, Other variables are as defined in the present invention.
  • the above-mentioned ring C is selected from thienyl, imidazolyl and pyridyl, and the thienyl, imidazolyl and pyridyl are optionally substituted by 1 or 2 R b , and other variables are as defined in the present invention. definition.
  • the above-mentioned ring C is selected from Other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
  • R 1 , R 2 , L 1 , m and ring B are as defined in any one of the present invention.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof, which are selected from:
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof, which are selected from:
  • the present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of core protein modulator-related diseases.
  • the compound of the present invention has a significant inhibitory effect on HBV, has ideal in vitro pharmacokinetic test results and better liver-to-blood ratio distribution.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from the compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include amino acids (such as arginine, etc.) Salts, and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups,
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate the double bond or the single bond of the ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror-image relationship.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the compound of the present invention may be specific.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformations.
  • keto-enol tautomerization is the tautomerization between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterium can be substituted for hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • 5-6 membered heteroaryl ring and “5-6 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-6 membered heteroaryl group” means a ring consisting of 5 to 6 ring atoms. It is composed of a monocyclic group with a conjugated ⁇ -electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,
  • halogen or halogen by itself or as part of another substituent represents a fluorine, chlorine, bromine or iodine atom.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent.
  • the substituent may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the compound after substitution Is stable.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • a substituent When a substituent is vacant, it means that the substituent is absent.
  • X in AX when X in AX is vacant, it means that the structure is actually A.
  • the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
  • Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • the single crystal X-ray diffraction method uses the Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultured single crystal.
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: aq stands for water; eq stands for equivalent or equivalent; M stands for mol/L; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; DMSO Represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, which is an amine protecting group; Boc represents tert-butoxycarbonyl, which is an amine protecting group; rt Stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc 2 O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl 2 stands for thionyl chloride; mp Stands for
  • compound 1-a (100g, 487.63mmol, 1eq) was dissolved in MeOH (1L), and sodium methoxide methanol solution (5M, 195.05mL, 2eq) and dimethyl oxalate (86.38g, 731.45mmol, 1.5eq), the reaction was stirred at 70°C for 16 hours.
  • the reaction solution was filtered directly after cooling, 1L of water was added to the filter cake, and the mixture was homogenized and stirred for 1 hour, and then filtered.
  • the obtained filter cake was added with 1 L of methyl tert-butyl ether, stirred for 1 hour and filtered, and the filter cake was dried under reduced pressure to obtain compound 1-b, which was used directly in the next step without further treatment.
  • compound 1-e (9.57 g, 65.71 mmol, 3 eq) and dichloromethane (80 mL) were added to a three-necked flask. At 0°C, a toluene solution of trimethylaluminum (2M, 32.86 mL, 3eq) was added dropwise. After the addition was completed, the mixture was stirred at 0°C for 30 minutes, and then a solution of compound 1-d (8 g, 21.90 mmol, 1 eq) in dichloromethane (100 mL) was added dropwise. The mixture was stirred at 25°C for 1 hour.
  • the aqueous phase of the filtrate was extracted with ethyl acetate (15 mL ⁇ 2).
  • the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • compound 4-c 150mg, 283.10 ⁇ mol, 1.0eq
  • 4-b 95.95mg, 311.41 ⁇ mol, 1.1eq
  • potassium carbonate 117.38mg, 849.31 ⁇ mol, 3eq
  • Pd(dppf) Cl 2 .CH 2 Cl 2 46.24 mg, 56.62 ⁇ mol, 0.2 eq
  • 1,4-dioxane 8 mL
  • H 2 O 2 mL
  • cuprous chloride 35.33mg, 356.83 ⁇ mol, 8.53 ⁇ L, 0.03eq
  • sodium tert-butoxide 114.31mg, 1.19mmol, 0.1eq
  • Xantphos 206.47mg, 356.83 ⁇ mol, 0.03eq
  • tetrahydrofuran 30mL
  • double pinacol borate 3.32g, 13.08mmol, 1.1eq
  • reaction solution was directly concentrated under reduced pressure, diluted with ethyl acetate (30 mL), washed with a saturated aqueous sodium chloride solution (30 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • compound 13-h (70.0mg, 157.07 ⁇ mol, 1eq), 13-i (27.24mg, 159.11 ⁇ mol, 1eq), potassium carbonate (65.96mg, 477.34 ⁇ mol, 3eq), cuprous iodide (60.60 mg, 318.23 ⁇ mol, 2eq) and L-proline (36.63mg, 318.23 ⁇ mol, 2eq) were added to dimethyl sulfoxide (2mL). The reaction solution was stirred at 110°C for 1 hour.
  • compound 14-a (300g, 2.36mol, 243.90mL, 1eq), ethylene glycol (292.85g, 4.72mol, 263.83mL, 2eq) and toluene (1.5L) were added to a round bottom flask, and then added P-toluenesulfonic acid (40.63g, 235.92mmol, 0.1eq) was refluxed at 120°C for 12 hours while separating water with a water separator. The reaction solution was washed with water (300 mL ⁇ 2). The aqueous phase was extracted with ethyl acetate (100 mL).
  • Step 10 Chiral resolution to obtain compound 14-k:
  • reaction solution was added to saturated sodium chloride solution (20 mL), and extracted with ethyl acetate (20 mL ⁇ 2). The combined organic phase was concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate, gradient: 0-40%, flow rate: 20 mL/min) to obtain compound 16-b. MS m/z(ESI): 496.8[M+1] + .
  • compound 17-b (34.37g, 306.68mmol, 1eq) was added to dichloromethane (1000mL), and then aluminum trichloride (81.79g, 613.36mmol, 33.52mL, 2eq) was added at 20°C, The reaction mixture was stirred at 20°C for 30 min, and then a mixture of 17-a (50 g, 306.68 mmol, 29.76 mL, 1 eq) and dichloromethane (200 mL) was slowly added. After the addition was completed, the reaction mixture was stirred at 20°C for 1.5 hours.
  • reaction solution was poured into 1 mole of potassium hydrogen sulfate aqueous solution (2000 mL), and stirred for 5 min. During this period, a large amount of solid was generated, which was filtered.
  • the filter cake was added to ethyl acetate (1.5L), stirred for 20min and filtered, the filtrate was washed with saturated aqueous sodium chloride (1L ⁇ 1), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 17-c.
  • compound 1-e (1.48g, 10.16mmol, 3eq) was dissolved in dichloromethane (10mL), and trimethylaluminum (2M, 5.08mL, 3eq) was added dropwise at 0°C. The mixture Stir at 0°C for 15 min, and then add a solution of 17-j (1.2 g, 3.39 mmol, 1 eq) in dichloromethane (10 mL). The reaction solution was stirred at 20°C for 1 hour.
  • reaction solution was poured into 2M potassium hydrogen sulfate aqueous solution (50 mL), a large amount of viscous solid was generated, filtered, the filter cake was washed with dichloromethane (100 mL), the filtrate was concentrated under reduced pressure, and the residue was dichloromethane (10 mL) at room temperature The slurry was beaten, filtered, and the filter cake was dried under reduced pressure to obtain compound 17-1.
  • compound 17-1 (100 mg, 213.78 ⁇ mol, 1 eq) was added to 1,4-dioxane (3 mL) and water (1 mL), and then 1-h (74.44 mg, 256.54 ⁇ mol, 1.2 eq) and sodium carbonate (33.99mg, 320.68 ⁇ mol, 1.5eq). Replace with nitrogen 3 times, then add palladium tetrakistriphenylphosphine (2.47 mg, 2.14 ⁇ mol, 0.01 eq), replace with nitrogen 3 times, raise the temperature to 90° C. and stir for 12 hours.
  • reaction solution was diluted with 2-methyltetrahydrofuran (10 mL), washed with a saturated aqueous sodium chloride solution (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was diluted with 2-methyltetrahydrofuran (10 mL), washed with water (10 mL ⁇ 1) and saturated sodium chloride aqueous solution (10 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was diluted with 2-methyltetrahydrofuran (10 mL), washed with water (10 mL ⁇ 1) and saturated sodium chloride aqueous solution (10 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • compound 24-b (3g, 12.14mmol, 1eq), double pinacol borate (3.70g, 14.57mmol, 1.2eq), Pd(dppf)C12 (1.78g, 2.43mmol, 0.2 eq) and potassium acetate (3.57g, 36.42mmol, 3eq) were added to 1,4-dioxane (50mL), and the reaction solution was stirred at 90°C for 2 hours.
  • the real-time-qPCR test was used to detect the HBV DNA content in HepG2.2.15 cells, and the compound's EC50 value was used as an indicator to evaluate the compound's inhibitory effect on HBV.
  • HepG2.2.15 cell culture medium (DMEM/F12, Invitrogen-11330057; 10% serum, Invitrogen-10099141; 100units/ml penicillin and 10 ⁇ g/ml streptomycin, Invitrogen-15140122; 1% non-essential amino acids, Invitrogen-11140076; 2mM L-glutamine, Invitrogen-25030081; 300 ⁇ g/ml geneticin, Invitrogen-10131027
  • HepG2.2.15 cells 4 ⁇ 10 4 cells/well were transferred to a 96-well plate and cultured overnight at 37° C., 5% CO 2.
  • the compound was diluted to a total of 8 concentrations, with a 3-fold gradient dilution. Add different concentrations of compounds to the culture wells, double-repeat the wells. The final concentration of DMSO in the culture broth is 1%. 1 ⁇ M GLS4 was used as a 100% inhibition control; 1% DMSO was used as a 0% inhibition control.
  • Upstream primer sequence GTGTCTGCGGCGTTTTATCA
  • the PCR reaction conditions are: heating at 95°C for 10 minutes; then denaturation at 95°C for 15 seconds, and extension at 60°C for 1 minute, a total of 40 cycles.
  • %Inh. [1-(number of DNA copies in the sample-1 ⁇ Mnumber of DNA copies in GLS4)/(number of DNA copies in the DMSO control-1 ⁇ Mnumber of DNA copies in GLS4)]x100.
  • the compound of the present invention has a significant inhibitory effect on HBV.
  • test compound 3 The inhibitory effect of test compound 3 on the activity of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) was determined.
  • the test compound 3 (10mM) is gradient, and the working solution (100 ⁇ final concentration) is prepared.
  • the working solution concentration is: 5, 1.5, 0.5, 0.15, 0.05, 0.015, 0.005mM, and the P450 isoenzyme ( CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) the working solution of each positive inhibitor and its specific substrate mixture; thaw the human liver microsomes frozen at -80°C on ice, and wait until the human liver microsomes are completely dissolved.
  • the P450 isoenzyme CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4
  • mice The purpose of this study is to determine the pharmacokinetic parameters of the compound and calculate its oral bioavailability in female Balb/c mice.
  • This project uses four female Balb/c mice, two mice are administered intravenously at a dose of 3mg/kg, collected 0h (before administration) and 0.0833, 0.25, 0.5, 1, 2 after administration , 4, 7, 24 hours of plasma samples, the other two rats were orally administered by gavage at a dose of 1 mg/kg, collected 0 hours (before administration) and 0.5, 1, 2, 3, 4 after administration, 6 and 24h plasma samples, and then perform LC/MS/MS analysis on the collected samples and collect data, and use Phoenix WinNonlin 6.2.1 software to calculate the relevant pharmacokinetic parameters for the collected analysis data.
  • the compound of the present invention has ideal in vitro pharmacokinetic test results.
  • Compound 3 was prepared as a clear solution and administered to female Balb/c mice for a single oral administration (PO, 3mpk).
  • the oral vehicle is 10% solutol. Collect whole blood for 0.5, 2.0, and 8.0 hours, prepare plasma, collect tissue at corresponding time, prepare tissue homogenate, analyze drug concentration by LC-MS/MS method, and use Phoenix WinNonlin software to calculate pharmacokinetic parameters.
  • the compound of the present invention has a better liver-to-blood ratio distribution in mice.

Abstract

La présente invention concerne des dérivés de sultame, et une application de ceux-ci dans la préparation de médicaments pour le traitement de maladies associées. L'invention concerne plus précisément un composé représenté par la formule (III) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2021/088736 2020-04-22 2021-04-21 Dérivés de sultame et leur application WO2021213445A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040138448A1 (en) * 2002-10-12 2004-07-15 The Scripps Research Institute Synthesis of non-symmetrical sulfamides using burgess-type reagents
WO2018153285A1 (fr) * 2017-02-23 2018-08-30 福建广生堂药业股份有限公司 Composé à trois cycles et ses applications
WO2019206072A1 (fr) * 2018-04-24 2019-10-31 浙江海正药业股份有限公司 Dérivé de formamide aryl sulfamide, procédé de préparation associé et utilisations correspondantes
CN110621672A (zh) * 2017-03-02 2019-12-27 组装生物科学股份有限公司 环状磺酰胺化合物及其使用方法
WO2020051320A1 (fr) * 2018-09-05 2020-03-12 Assembly Biosciences, Inc. Composés sulfamide cycliques pour le traitement du vhb
WO2020051319A1 (fr) * 2018-09-05 2020-03-12 Assembly Biosciences, Inc. Composés sulfamide cyclique pour le traitement du vhb

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040138448A1 (en) * 2002-10-12 2004-07-15 The Scripps Research Institute Synthesis of non-symmetrical sulfamides using burgess-type reagents
WO2018153285A1 (fr) * 2017-02-23 2018-08-30 福建广生堂药业股份有限公司 Composé à trois cycles et ses applications
CN110621672A (zh) * 2017-03-02 2019-12-27 组装生物科学股份有限公司 环状磺酰胺化合物及其使用方法
WO2019206072A1 (fr) * 2018-04-24 2019-10-31 浙江海正药业股份有限公司 Dérivé de formamide aryl sulfamide, procédé de préparation associé et utilisations correspondantes
WO2020051320A1 (fr) * 2018-09-05 2020-03-12 Assembly Biosciences, Inc. Composés sulfamide cycliques pour le traitement du vhb
WO2020051319A1 (fr) * 2018-09-05 2020-03-12 Assembly Biosciences, Inc. Composés sulfamide cyclique pour le traitement du vhb

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