WO2024061257A1 - Composé cétone n-hétérocyclique polycyclique et son utilisation - Google Patents

Composé cétone n-hétérocyclique polycyclique et son utilisation Download PDF

Info

Publication number
WO2024061257A1
WO2024061257A1 PCT/CN2023/119931 CN2023119931W WO2024061257A1 WO 2024061257 A1 WO2024061257 A1 WO 2024061257A1 CN 2023119931 W CN2023119931 W CN 2023119931W WO 2024061257 A1 WO2024061257 A1 WO 2024061257A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
add
pharmaceutically acceptable
acceptable salt
stereoisomer
Prior art date
Application number
PCT/CN2023/119931
Other languages
English (en)
Chinese (zh)
Inventor
冯嘉杰
李鹏
江凯璇
聂伟
曹亚明
贺海鹰
黎健
陈曙辉
Original Assignee
吉斯凯(苏州)制药有限公司
重庆药友制药有限责任公司
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 吉斯凯(苏州)制药有限公司, 重庆药友制药有限责任公司 filed Critical 吉斯凯(苏州)制药有限公司
Publication of WO2024061257A1 publication Critical patent/WO2024061257A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to a polycyclic nitrogen heterocyclic ketone compound and its application, specifically to the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • Therapeutic agents for AIDS are mainly selected from a group of reverse transcriptase inhibitors (such as AZT, 3TC) and protease inhibitors (such as indinavir), but they have been shown to be associated with side effects such as kidney disease and the emergence of drug-resistant viruses. Therefore, people are eager to develop anti-HIV drugs with other mechanisms of action.
  • HIV integrase inhibitors are anti-HIV drugs with such a new mechanism of action.
  • the inventors discovered polycyclic azaheterocyclic ketone derivatives with effective HIV integrase inhibitory activity.
  • the present invention provides a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • Each R 1 is independently selected from H, halogen, CN , OH, NH 2 , C 1-4 alkyl and C 1-4 alkoxy, each of which is Independently optionally substituted by 1, 2 or 3 R a ;
  • Each R a is independently selected from H, halogen, CN, OH, NH 2 and -COOH;
  • Each R 1a is independently selected from H, C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 H, halogen, CN, OH or NH 2 substituents;
  • Each R b is independently selected from H, halogen, CN, OH and NH 2 ;
  • Each R 3 is independently selected from H, halogen, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optional Choose to be replaced by 1, 2 or 3 R c ;
  • each R c is independently selected from H, halogen, CN, OH and NH 2 ;
  • L 1 is selected from -(C(R 1b ) 2 ) p - and C 3-5 cycloalkyl, the C 3-5 cycloalkyl is optionally substituted by 1, 2, 3 or 4 Rd;
  • each R 1b is selected from H, F, CI, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted with 1, 2 or 3 substituents selected from H, F, CI, Br, I, OH and NH 2 ;
  • Each Rd is independently selected from H, halogen, CN, OH and NH 2 ;
  • T1 is selected from CH, N, O and S;
  • T 2 is selected from CH and N;
  • n, q are independently selected from 0, 1, 2, 3 and 4;
  • p is selected from 1 and 2;
  • Ring A is selected from 3-10 membered heterocycloalkyl
  • Ring B is selected from 5-6 membered heteroaryl
  • the 3-10-membered heterocycloalkyl group and the 5-6-membered heteroaryl group each independently contain 1, 2 or 3 heteroatoms or heteroatom groups that are independently selected from N, O, S and NH.
  • each of the above R 1 is independently selected from H, C 1-4 alkyl and C 1-4 alkoxy, and the C 1-4 alkyl and C 1-4 alkoxy are each independently selected. is optionally replaced by 1, 2 or 3 Ra , and Ra and other variables are as defined in the present invention.
  • each of the above R 1 is independently selected from H and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by 1, 2 or 3 R a , R a and other variables As defined herein.
  • each of the above R 1 is independently selected from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 2 CH 3 , the -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 ) CH 2 CH 3 and -C(CH 3 ) 2 CH 3 are optionally substituted by 1, 2 or 3 Ra , and Ra and other variables are as defined in the present invention.
  • the above-mentioned L 1 is selected from -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(OCH 3 )-, -C(OCH 3 ) 2 - and Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from 3-8 membered heterocycloalkyl, and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • T 1 , R 1 , R 3 , m, q and ring B are as defined in the present invention.
  • the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt has a structure represented by formula (IA):
  • T 1 is selected from CH and N;
  • R 1 , R 2 , R 3 , L 1 , T 2 , m, n, q, ring A and ring B are as defined in the present invention.
  • the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, its compound has the formula (I-1), (I-2), (I-3) or (I-4 ) shows the structure:
  • R 1 , R 2 , R 3 , L 1 , q and n are as defined in the present invention.
  • T 1 is selected from CH and N;
  • T 3 is selected from CH and N;
  • T 4 is selected from N and CH;
  • T5 is selected from CH2 , NH, O and S.
  • the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt has a structure represented by formula (IB):
  • T 1 is selected from O and S;
  • R 1 , R 2 , R 3 , L 1 , T 2 , m, n, q, ring A and ring B are as defined in the present invention.
  • the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt has a structure represented by formula (I-5):
  • R 1 , R 2 , R 3 , L 1 , q and n are as defined in the present invention
  • T 1 is selected from O and S;
  • T6 is selected from CH and N.
  • the above compounds, their stereoisomers or their pharmaceutically acceptable salts have the formulas (I-1A), (I-1B), (I-1C), (I-1D ), (I-2A), (I-3A), (I-4A) and (I-5A):
  • R 1 , R 2 , R 3 , L 1 , q and n are as defined in the present invention.
  • the present invention also provides the following compounds, their stereoisomers or their pharmaceutically acceptable salts:
  • the above-mentioned compounds, their stereoisomers or their pharmaceutically acceptable salts are selected from:
  • the present invention further provides a pharmaceutical composition, which contains an effective therapeutic dose of a compound of the present invention or a pharmaceutically acceptable salt thereof; which optionally further includes pharmaceutically acceptable excipients, auxiliaries or carriers.
  • this application also provides the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in the preparation of drugs for preventing and/or treating HIV infection.
  • the compound of the present invention has a significant inhibitory effect on HIV integrase activity, and at the same time inhibits HIV pseudovirus or mutant strain pseudovirus at the cellular level. It has shown positive effects in viral gene replication experiments and has good pharmacokinetic properties.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • 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, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
  • diastereomer refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
  • use wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
  • using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line
  • wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key and straight dotted keys
  • tautomer or “tautomeric form” means that at room temperature, isomers with different functional groups are in dynamic equilibrium and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers also called proton transfer tautomers
  • proton transfer tautomers include interconversions by proton migration, such as keto-enol isomerization and imine-enamine Isomerization.
  • Valence tautomers involve interconversion through the reorganization of some bonding electrons.
  • keto-enol tautomerization is pentane-2,4-dione and Interconversion between two tautomers of 4-hydroxypent-3-en-2-one.
  • the terms “enriched in an isomer,” “enantiomerically enriched,” “enriched in an enantiomer,” or “enantiomerically enriched” refer to one of the isomers or enantiomers.
  • 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 greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 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 enantiomeric excess (ee value) is 80%.
  • Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques.
  • one enantiomer of a compound of the present invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a basic functional group such as an amino group
  • an acidic functional group such as a carboxyl group
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered.
  • separation of enantiomers and diastereomers is often accomplished by the use of chromatography employing a chiral stationary phase, optionally coupled with chemical derivatization (eg, formation of carbamates from amines).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes such as tritium (3H), iodine-125 (125I) or C-14 (14C).
  • deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs.
  • the bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon.
  • deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All isotopic compositions of the compounds of the invention Transformations, whether radioactive or not, are included within the scope of the invention.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group.
  • the chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express.
  • the straight solid line bond in -OCH3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted bond in means that it is connected to other groups through both ends of the nitrogen atoms in the group;
  • the wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • C 1-4 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 2-3 and C 3-4 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent ( Such as methine).
  • Examples of C 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-4 alkoxy means those alkyl groups containing 1 to 4 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-4 alkoxy group includes C 1-2 , C 2-3 , C 3-4 , C 4 , C 3 , C 2 alkoxy group, etc.
  • Examples of C 1-4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-3 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting 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 groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , and C 3 , C 2 alkoxy group, etc.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • the term "3-10 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include spirocyclic, paracyclic and bridged rings.
  • heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule.
  • the 3-10 membered heterocycloalkyl includes 3-8 membered, 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc.
  • 3-10 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl
  • C3-5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a single ring system, and the C3-5 cycloalkyl group includes C3-4 and C4-5 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 8 ring atoms, with 1, 2, 3 or 4 ring atoms. are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p,p is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro rings, parallel rings and bridged rings.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 3-8-membered heterocycloalkyl group includes 3-6-membered, 3-5-membered, 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups, etc.
  • 3-8 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidiny
  • 5-6 membered heteroaryl in the present invention can be used interchangeably.
  • the term “5-6 membered heteroaryl” refers to a single ring composed of 5 to 6 ring atoms and having a conjugated ⁇ electron system.
  • a ring group in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms.
  • the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • a 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 and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 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-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl,
  • 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, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, 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 involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • the solvent used in the present invention is commercially available.
  • the present invention adopts the following abbreviations: aq represents water; eq represents equivalent, equivalent amount; M represents mol/L; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N, N-dimethylformamide; DMSO Represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; r.t. represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; ACN stands for acetonitrile; mp stands for melting point.
  • the reagent 2,4-difluorobenzylamine (708.73 mg, 4.95 mmol, 3 eq) was added, and the reaction was carried out at 80°C for 16 hours.
  • Water (20 mL) was added to the reaction solution, and then ethyl acetate (20 mL ⁇ 3) was added for extraction.
  • the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Dissolve 6a (0.37g, 851.76 ⁇ mol) in acetic acid (4mL), add methanesulfonic acid (24.56mg, 255.53 ⁇ mol, 18.19 ⁇ L), and stir at 65°C for 48 hours.
  • the reaction solution was concentrated to obtain crude product 6b.
  • Dissolve 6b in 1,2-dichloroethane (4 mL) add L-aminopropanol (23.80 mg, 316.89 ⁇ mol, 24.66 ⁇ L), and heat the oil bath to 90°C and stir for 24 hours.
  • Dissolve 6d (40 mg, 89.32 ⁇ mol) in tetrahydrofuran (1 mL), add sodium hydroxide (17.86 mg, 446.61 ⁇ mol), and stir at 60°C for 12 hours. Take the Erlenmeyer flask, add 20 mL of water, pour the reaction solution, and then extract with 20 mL of methylene chloride. The organic phase is dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was slurried with methanol (1 mL) and filtered to obtain 6.
  • Dissolve 7a (1g, 6.33mmol) in acetonitrile (10mL), add anhydrous potassium carbonate (961.57mg, 6.96mmol) and dimethyl sulfate (877.56mg, 6.96mmol, 659.82 ⁇ L), and stir at 25°C for 12 hours.
  • anhydrous potassium carbonate 961.57mg, 6.96mmol
  • dimethyl sulfate 877.56mg, 6.96mmol, 659.82 ⁇ L
  • Dissolve 7e (0.2g, 430.65 ⁇ mol) in acetic acid (5mL), add methanesulfonic acid (12.42mg, 129.19 ⁇ mol, 9.20 ⁇ L), stir at 65°C for 12 hours, and concentrate the reaction solution to obtain crude 7f.
  • Dissolve 7f in 1,2-dichloroethane (2 mL) add L-aminopropanol (52.11 mg, 693.84 ⁇ mol, 54.00 ⁇ L), and heat the oil bath to 90°C and stir for 12 hours.
  • Dissolve 7g (0.1g, 225.53 ⁇ mol) in acetonitrile (2mL), add trichloroisocyanuric acid (25.16mg, 108.25 ⁇ mol) and 1,4-diazabicyclo[2,2,2]octane ( 1.26 mg, 11.28 ⁇ mol, 1.24 ⁇ L), heat the oil bath to 40°C and stir for 2 hours.
  • trichloroisocyanuric acid 25.16mg, 108.25 ⁇ mol
  • 1,4-diazabicyclo[2,2,2]octane 1.26 mg, 11.28 ⁇ mol, 1.24 ⁇ L
  • reaction solution Cool the reaction solution to room temperature, then add 20 mL of water in a conical flask, pour the reaction solution into the reaction solution, add 20 mL of ethyl acetate for extraction, wash the organic phase with saturated brine and dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the residue. things.
  • Dissolve 8c (33 mg, 67.09 ⁇ mol) in anhydrous tetrahydrofuran (1 mL), add sodium hydroxide (13.42 mg, 335.47 ⁇ mol), and stir at 60°C for 12 hours. Cool the reaction solution, then add 20 mL of water to the conical flask, pour the reaction solution into the reaction solution, add 20 mL of ethyl acetate, and extract three times. The organic phase is washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • Dissolve 9a 80 mg, 167.42 ⁇ mol in anhydrous tetrahydrofuran (3 mL), add sodium hydroxide (33.48 mg, 837.09 ⁇ mol), and heat the oil bath to 60°C and stir for 12 hours. Cool the reaction solution, then add 20 mL of water to the conical flask, pour the reaction solution into the reaction solution, add 20 mL of ethyl acetate, and extract three times. The organic phase is washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • the crude product was purified by silica gel column chromatography to obtain compound 10f.
  • reaction solution take a conical flask, add 50 mL of water, pour the reaction solution, add 20 mL of ethyl acetate for extraction, dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product.
  • the crude product was purified by silica gel column to obtain 10 g of compound.
  • reaction solution was quenched by adding water (20 mL), extracted with ethyl acetate (20 mL ⁇ 2), and the organic phase was extracted with saturated sodium chloride solution (20 mL ⁇ 2), then dried over anhydrous sodium sulfate and filtered, and the filtrate was decompressed. Concentrate to obtain crude product.
  • the antiviral activity of the compounds against HIV pseudovirus was evaluated by determining the half effective concentration (EC 50 ) value of the compounds. HIV pseudovirus reporter gene experiments are widely used in early screening, replacing HIV virus experiments to evaluate the anti-HIV activity of compounds.
  • 293T cells were seeded into a 96-well test plate at a density of 55,000 cells per well and 100 ⁇ L per well, and cultured overnight in a 37°C incubator with 5% CO 2 .
  • the next day add the diluted compound (8 concentration points, double wells), 50 ⁇ L per well. Then the diluted virus was added to the cells at 100 TCID50 per well, 50 ⁇ L per well.
  • Set up cell control (cells, no compound treatment or virus infection), virus control (cells infected with virus, no compound treatment) and culture medium control (culture medium only).
  • the final volume of the experimental culture medium was 200 ⁇ L, and the final concentration of DMSO in the culture medium was 0.5%. Cells were cultured in a 5% CO 2 , 37°C incubator for 3 days.
  • the luciferase reporter gene detection reagent Britelite plus kit (PerkinElmer) was used to detect the luciferase activity in each well of the test plate, and the data was used for antiviral activity analysis of the samples.
  • Cell viability detection reagent CellTiter Glo was used, and a BioTek microplate reader was used to detect cell viability in each well, and the data were used for sample cytotoxicity analysis.
  • Antiviral activity (%) (EC 50 test well reading value - average value of virus control) / (average value of cell control - average value of virus control) ⁇ 100
  • the EC 50 value uses GraphPad Prism (version 5) software to conduct nonlinear fitting analysis of the antibody's inhibitory activity and cell viability.
  • the fitting method is "log(inhibitor) vs. response--Variable slope”.
  • the inhibitory activity of the compounds of the present invention against HIV pseudovirus is shown in Table 1.
  • the compounds of the present invention show positive effects in the test of inhibiting HIV pseudovirus gene replication at the cellular level.
  • the clear solution of the test compound was injected into SD rats (overnight fasting, 7-10 weeks old) through the tail vein, and the test compound was administered orally to SD rats (overnight fasting, 7-10 weeks old).
  • About 200 ⁇ L of blood was collected from the jugular vein or tail vein of the animals at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration and placed in anticoagulant tubes with EDTA-K2 added, 4°C, 3200g Centrifuge for 10 minutes to collect plasma.
  • the LC-MS/MS method was used to determine the blood drug concentration, and the PhoenixWinNonlin6.3 pharmacokinetic software was used to calculate the relevant pharmacokinetic parameters using the non-compartmental model open linear logarithmic trapezoidal method.
  • Table 2 The experimental results are shown in Table 2.

Abstract

L'invention concerne un composé cétone N-hétérocyclique polycyclique et son utilisation, et concerne plus particulièrement un composé représenté par la formule (I) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2023/119931 2022-09-20 2023-09-20 Composé cétone n-hétérocyclique polycyclique et son utilisation WO2024061257A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211146951.0 2022-09-20
CN202211146951 2022-09-20

Publications (1)

Publication Number Publication Date
WO2024061257A1 true WO2024061257A1 (fr) 2024-03-28

Family

ID=90453902

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/119931 WO2024061257A1 (fr) 2022-09-20 2023-09-20 Composé cétone n-hétérocyclique polycyclique et son utilisation

Country Status (1)

Country Link
WO (1) WO2024061257A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101346376A (zh) * 2005-10-27 2009-01-14 盐野义制药株式会社 具有hiv整合酶抑制活性的多环性氨基甲酰基吡啶酮衍生物
WO2014172188A2 (fr) * 2013-04-16 2014-10-23 Merck Sharp & Dohme Corp. Composés dérivés de 4-pyridone et leurs utilisations en tant qu'inhibiteurs de la vih intégrase
CN104995198A (zh) * 2012-12-21 2015-10-21 吉里德科学公司 多环-氨基甲酰基吡啶酮化合物及其药物用途
CN112513042A (zh) * 2018-05-31 2021-03-16 盐野义制药株式会社 多环氨基甲酰基吡啶酮衍生物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101346376A (zh) * 2005-10-27 2009-01-14 盐野义制药株式会社 具有hiv整合酶抑制活性的多环性氨基甲酰基吡啶酮衍生物
CN104995198A (zh) * 2012-12-21 2015-10-21 吉里德科学公司 多环-氨基甲酰基吡啶酮化合物及其药物用途
WO2014172188A2 (fr) * 2013-04-16 2014-10-23 Merck Sharp & Dohme Corp. Composés dérivés de 4-pyridone et leurs utilisations en tant qu'inhibiteurs de la vih intégrase
CN112513042A (zh) * 2018-05-31 2021-03-16 盐野义制药株式会社 多环氨基甲酰基吡啶酮衍生物

Similar Documents

Publication Publication Date Title
CN112955432B (zh) 稠合芳香环类衍生物、其制备方法及其在医药上的应用
KR20230136636A (ko) 피리미딘 방향족 환 화합물
WO2022161443A1 (fr) Composé pyrimidopyrane
WO2021104488A1 (fr) Composé tri-hétérocyclique en tant qu'inhibiteur de jak et son utilisation
WO2022063308A1 (fr) Classe de composés 1,7-naphtyridine et leur application
TW202227422A (zh) 組織蛋白酶ｃ小分子抑制劑及其醫藥用途
WO2022247757A1 (fr) Composé pyrimidopyridine substitué par du fluor et son utilisation
CN113825757A (zh) 取代的稠合双环类衍生物、其制备方法及其在医药上的应用
KR20230154953A (ko) 푸란 축합 고리로 치환된 글루타르이미드계 화합물
WO2021129817A1 (fr) Composé à base de pyrimidine ayant un effet inhibiteur de la cétohexokinase (chk)
WO2021027647A1 (fr) Composé de pyrimidine substitué par hétérocyclyle ponté, son procédé de préparation et son utilisation pharmaceutique
WO2024061257A1 (fr) Composé cétone n-hétérocyclique polycyclique et son utilisation
WO2022166721A1 (fr) Dérivés cycliques fusionnés contenant du 1,4-oxazépane
WO2023160572A1 (fr) Dérivé de pyrazole, composition pharmaceutique et utilisation
WO2023001069A1 (fr) Composés amides macrocycliques et leur application
WO2023109878A1 (fr) Antagoniste de lpar1 triazaspiro et son utilisation
WO2022262782A1 (fr) Composé cyclique condensé d'isoxazole substitué par glutarimide et son application
TW202322819A (zh) 含氮的四環化合物、其製備方法及其在醫藥上的應用
WO2021147953A1 (fr) Dérivé cyclique pyrimidino à cinq chaînons et application correspondante
WO2022199635A1 (fr) Dérivés de benzylaminoquinazoline
WO2021219088A1 (fr) Composé tricyclique à base de pyrimidine et son utilisation
WO2022037680A1 (fr) Composé d'acide boracique
CN113493453A (zh) 稠合芳香环类衍生物、其制备方法及其在医药上的应用
CN111971285A (zh) 咪唑并吡咯酮化合物及其应用
WO2023208127A1 (fr) Composé bicyclique substitué par hétéroaryle et son utilisation