WO2024001115A1 - 一种贝壳衫烷型四环二萜类衍生物、其制备方法及医药用途 - Google Patents

一种贝壳衫烷型四环二萜类衍生物、其制备方法及医药用途 Download PDF

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WO2024001115A1
WO2024001115A1 PCT/CN2022/141790 CN2022141790W WO2024001115A1 WO 2024001115 A1 WO2024001115 A1 WO 2024001115A1 CN 2022141790 W CN2022141790 W CN 2022141790W WO 2024001115 A1 WO2024001115 A1 WO 2024001115A1
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compound
cdcl
substituted
unsubstituted
hydrogen
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French (fr)
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徐进宜
姚鸿
徐盛涛
刘俊凯
吴宏玉
何晨
邵肖
薛松涛
李俊达
倪翔
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中国药科大学
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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    • 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
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

Definitions

  • the present invention relates to a novel derivative of a chilamane-type tetracyclic diterpenoid compound represented by the general formula (I and II) with anti-inflammatory activity and its C7 position structure modification, or its stereoisomer, solvate, Prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or co-crystals, their pharmaceutical compositions, preparation methods and uses in preparing drugs that inhibit NLRP3 inflammasome.
  • NLRP3 inflammasome inhibitor is an important drug developed in recent years to treat immune-related inflammation.
  • NLRP3 inflammasome is a multimeric protein complex mainly expressed in monocytes-macrophages, neutrophils and dendritic cells (DC).
  • the NLRP3 inflammasome is composed of three parts: NLRP3 sensor protein, adapter protein ASC and effector protein pro-caspase-1. Under normal physiological conditions, NLRP3 protein and pro-caspase-1 are located in the cytoplasm, while ASC is located in the nucleus.
  • NLRP3 can recruit the adapter protein ASC, and then combine with pro-caspase-1 through ASC to form an activated NLRP3 inflammasome.
  • the activated NLRP3 inflammasome can activate pro-caspase-1 to generate caspase-1, which further mediates the maturation and secretion of IL-1 ⁇ and IL-18.
  • caspase-1 can also cause cells to undergo pyroptosis by cleaving gasdermin D (GSDMD) (Nat. Rev. Drug. Discov. 2018, 17, 588-606).
  • NLRP3-related diseases include the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1 ⁇ antibody canakinumab, and the soluble IL-1 receptor trap rilonacept, all of which are biological products.
  • some small molecules with NLRP3 inflammasome inhibitory activity have been reported, such as: glyburide, MCC950, parthenolide, 3,4-methylenedioxy- ⁇ -nitrostyrene and Oridonin A, etc.
  • the above-mentioned small molecule inhibitors have or partially have shortcomings such as low specificity, average activity, and high toxicity (J. Med. Chem. 2021, 64, 101–122).
  • NLRP3 inhibitors In order to develop new small molecule NLRP3 inhibitors with high efficiency, low toxicity and high specificity, which can be used to treat autoimmune diseases caused by NLRP3 mutations, the present invention discovered a new type of NLRP3 inhibitor represented by general formula (I) Callesan-type tetracyclic diterpenoid derivative molecules provide new compound molecules that can better inhibit the activity of NLRP3 inflammasome and inhibit the release of interleukin.
  • the general formula (I) expands the potential of existing NLRP3 inflammasome inhibitors. Structural characteristics and scope, and methods for the preparation of these novel derivatives are provided. The present invention is achieved through the following technical solutions.
  • the present invention provides compounds represented by general formula (I), and optically active bodies or racemates thereof, diastereoisomer mixtures, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or Eutectic.
  • B is optionally selected from hydrogen, hydroxyl or OAc
  • U, Y and Z are carbon atoms; the U-Y bond and the Y-Z bond are each independently a carbon-carbon single bond or a carbon-carbon double bond;
  • M is selected from the following groups, substituted or unsubstituted:
  • n is the same or different, each independently 0, 1, 2, 3 or 4;
  • R 2a is the same or different, each independently selected from hydrogen, amino, carboxyl, aldehyde, hydroxyl, halogen, mercapto, cyano, nitro, or R 2a is selected from the following substituted or unsubstituted groups: C l- 6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl or 5-6 membered heteroaryl;
  • R 3a and R 4a are the same or different, each independently selected from the following groups: hydrogen or substituted or unsubstituted: C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 8-10 bridged ring or -(CH 2 ) m -R 5a ; where m is 0, 1 or 2, R 5a is selected from C 1-6 alkane Base, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl;
  • Ring E is a substituted or unsubstituted 5- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group;
  • X is -O-.
  • U, Y, and Z are carbon atoms; the U-Y bond is a carbon-carbon single bond or a carbon-carbon double bond; and the Y-Z bond is a carbon-carbon single bond.
  • the present invention also provides compounds having any of the following structures I-1 to I-9, as well as optically active bodies or racemates, diastereoisomer mixtures, solvates, prodrugs, metabolites, deuterated products, and pharmaceuticals thereof.
  • Acceptable salts or eutectics are:
  • M is selected from the following groups, substituted or unsubstituted:
  • n is the same or different, each independently 0, 1, 2, 3 or 4;
  • R 2a is the same or different, each independently selected from hydrogen, amino, carboxyl, aldehyde, hydroxyl, halogen, mercapto, cyano, nitro, or R 2a is selected from the following substituted or unsubstituted groups: C l- 6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl or 5-6 membered heteroaryl;
  • R 3a and R 4a are the same or different, each independently selected from the following groups: hydrogen or substituted or unsubstituted: C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 8-10 bridged ring or -(CH 2 ) m -R 5a ; where m is 0, 1 or 2, R 5a is selected from C 1-6 alkane Base, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl;
  • Ring E is a substituted or unsubstituted 5- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group;
  • R 6a is selected from hydrogen or the following groups substituted or unsubstituted: C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 Heteroaryl; the substituent is selected from amino, carboxyl, aldehyde, hydroxyl, halogen, thiol, cyano or nitro.
  • the present invention also provides the compound represented by the general formula (II) or its stereoisomer, hydrate, metabolite, deuterated product, solvate, pharmaceutically acceptable salt or co-crystal, and its structure is preferably from the following structure:
  • M is selected from substituted or unsubstituted groups:
  • n is the same or different, each independently 0, 1, 2, 3 or 4;
  • R 2a is the same or different, each independently selected from hydrogen, amino, carboxyl, aldehyde, hydroxyl, halogen, mercapto, cyano, nitro, or R 2a is selected from the following substituted or unsubstituted groups: C l- 6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl or 5-6 membered heteroaryl;
  • R 3a and R 4a are the same or different, each independently selected from the following groups: hydrogen or substituted or unsubstituted: C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 8-10 bridged ring or -(CH 2 ) m -R 5a ; where m is 0, 1 or 2, R 5a is selected from C 1-6 alkane Base, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl;
  • Ring E is a substituted or unsubstituted 5- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group;
  • the present invention also provides any of the following compounds, their optically active forms or racemates, diastereoisomer mixtures, solvates, prodrugs, metabolites, deuterated compounds, pharmaceutically acceptable salts or co- crystal:
  • the present invention also provides a composition, including the compound of the present invention, its optically active body or racemate, diastereoisomer mixture, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable Acceptable salts or co-crystals, and pharmaceutically acceptable carriers.
  • the present invention also provides the compounds of the present invention, and their optically active forms or racemates, diastereoisomer mixtures, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or co-crystals Application in the preparation of NLRP3 inhibitor drugs.
  • the present invention also provides the compounds of the present invention, and their optically active forms or racemates, diastereoisomer mixtures, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or co-crystals Application in the preparation of anti-inflammatory drugs; preferably, the inflammation is arthritis.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D , also called heavy hydrogen), tritium (T, also called superheavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • the isotopes of carbon include 12 C
  • Alkyl refers to a straight-chain or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (such as 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms.
  • the alkyl group is more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl And its various branched chain isomers; when the alkyl group is substituted, it can be optionally further substituted by one or more substituents.
  • Alkoxy refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-hexyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.
  • alkyl is the same as the definition of "alkyl" mentioned above.
  • Alkenyl refers to a straight group containing 1 to 10 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds and composed of 2 to 20 carbon atoms. Chain or branched unsaturated aliphatic hydrocarbon group, preferably an alkenyl group with 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 carbon atoms. An alkenyl group of 8 carbon atoms is further preferred, and an alkenyl group of 2 to 6 carbon atoms is further preferred.
  • Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-2-yl En-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decene-4-yl and undecen-yl -3-base.
  • the alkenyl group may be optionally further substituted by one or more substituents.
  • Alkynyl refers to a group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds and consisting of 2 to 20 carbon atoms.
  • Straight chain or branched unsaturated aliphatic hydrocarbon group preferably an alkynyl group with 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably 2 an alkynyl group having to 8 carbon atoms, more preferably an alkynyl group having 2 to 6 carbon atoms.
  • Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyn-2-yl, heptyn-1-yl, heptyn-2-yl, hexyn-1-yl, 1-heptynyl-1-yl, heptyn-3-yl, heptyn-4-yl Base, mid-block-3-base, non-block-3-base, decan-4-base, undecan-3-base, dodecene-4-base.
  • the alkynyl group may be optionally further substituted by one or more substituents.
  • Heteroaryl refers to a substituted or unsubstituted aromatic ring, which may be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring or 10 to 15-membered (such as 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1 to 6 (such as 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5 to 8-membered heteroaryl, 1 to 4 optionally substituted in the ring of the heteroaryl (for example, 1, 2 , 3, 4) N, S can be oxidized into various oxidation states.
  • N, S can be oxidized into various oxidation states.
  • the heteroaryl group can be connected to a heteroatom or a carbon atom, and the heteroaryl group can be a bridged ring or a spiro ring.
  • Non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, and pyrimidinyl.
  • Heteroaryl groups are optionally further substituted with one or more substituents.
  • Carbocyclyl or “carbocycle” refers to a saturated or unsaturated aromatic or non-aromatic ring. When it is an aromatic ring, its definition is the same as the definition of "aryl” above; when it is a non-aromatic ring, it can be 3 to 10 members (such as 3, 4, 5, 6, 7, 8, 9, 10 single ring of 4 to 12 members (such as 4, 5, 6, 7, 8, 9, 10, 11, 12 members) or double ring of 10 to 15 members (such as 10, 11, 12, 13, 14, 15 (membered) tricyclic system, which may be a bridged ring or a spiro ring.
  • Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2 -Alkenyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cyclohexyl Heptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, norbornenyl, decahydronaphthyl.
  • the "carbocyclic group” or “carbocyclic ring” is optionally further substituted by one or more substituents.
  • Heterocyclyl or “heterocycle” refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl” above; when When it is a non-aromatic heterocyclic ring, it can be a 3- to 10-membered (for example, 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4 to 12-membered (for example, 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring system or 10 to 15-membered (such as 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1 to 4 (such as 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably 3 to 8-membered heterocyclic groups.
  • heterocyclyl or “heterocycle”
  • N and S in the ring of “heterocyclyl” or “heterocycle” can be oxidized into various oxidation states;
  • heterocyclyl or “Heterocyclic ring” can be connected to a heteroatom or a carbon atom;
  • heterocyclyl or “heterocyclic ring” can be a bridged ring or a spiro ring.
  • heterocyclyl or “heterocycle” include oxyethyl, glycidyl, aziridyl, oxetanyl, azetidinyl, thietanyl , 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, azepanyl, oxahepyl, thiepanyl, oxygen Azazoyl, diazazoyl, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furyl, furyl, thienyl, N-alkylpyrrolyl, pyrimidinyl, pyrazine base, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydr
  • Cycloalkyl refers to a saturated cyclic hydrocarbon group, the ring of which can be a monocyclic ring with 3 to 10 members (such as 3, 4, 5, 6, 7, 8, 9, 10 members), or a 4 to 12 member (such as 4 , 5, 6, 7, 8, 9, 10, 11, 12 yuan) double ring or more than 10 to 20 yuan (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 yuan)
  • the ring carbon atoms are preferably 3 to 10 carbon atoms, and further preferably 3 to 8 carbon atoms.
  • Non-limiting examples of "cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptadienyl, etc. When the cycloalkyl group is substituted, it may be optionally further substituted with one or more substituents.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be a 3- to 8-membered (such as 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a 4- to 12-membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring system or 10 to 15-membered (e.g. 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1, 2 or 3 heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclic groups.
  • heterocycloalkyl can be oxidized into various oxidation states; “heterocycloalkyl” can be connected to heteroatoms or carbon atoms; “heterocycle” "Alkyl” can be a bridged ring or a spiro ring.
  • heterocycloalkyl include oxyethyl, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl Oxycyclyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxa Tricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.
  • “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, where "other chemical components” refers to pharmaceutically acceptable Acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of the compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders agents and disintegrants.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body.
  • the prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound of the present invention. The modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
  • Co-crystal refers to a crystal formed by combining an active pharmaceutical ingredient (API) and a co-crystal form (CCF) under the action of hydrogen bonds or other non-covalent bonds.
  • API active pharmaceutical ingredient
  • CCF co-crystal form
  • the pure states of API and CCF are both Solids, and there are fixed stoichiometric ratios between the components.
  • a eutectic is a multicomponent crystal that includes both a binary eutectic formed between two neutral solids and a multicomponent eutectic formed between a neutral solid and a salt or solvate.
  • Stepoisomers refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
  • heterocyclyl optionally substituted by alkyl means that the alkyl group may but need not be present, and this description includes the case where the heterocyclyl is substituted by an alkyl group, and the case where the heterocyclyl is not substituted by an alkyl group.
  • the present invention also provides a composition, including the compound of the present invention, its optically active body or racemate, diastereoisomer mixture, solvate, prodrug, metabolite, deuterated product, pharmaceutically acceptable Acceptable salts or co-crystals, and pharmaceutically acceptable carriers.
  • the compounds of the present invention and their optically active bodies or racemates, diastereoisomer mixtures, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or co-crystals are used in the preparation of Application of NLRP3 inhibitor drugs.
  • the compounds of the present invention and their optically active bodies or racemates, diastereoisomer mixtures, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or co-crystals are used in the preparation of Application in anti-inflammatory drugs; in some embodiments, the inflammation is arthritis.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10-6 (ppm). NMR was measured using (Bruker 400 and Bruker 300) nuclear magnetic instruments. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated acetone (acetone-d6), and the internal standard. is tetramethylsilane (TMS);
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm.
  • the specifications used for thin layer chromatography separation and purification products are 0.4mm. -0.5mm;
  • column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, Nanjing Chunqiu and other companies;
  • the reaction temperature is room temperature, and the most suitable reaction temperature at room temperature is 20°C-30°C;
  • Step 1 Dissolve 3-iodopropanol (b-1, 10.0g, 53.8mmol) and imidazole (5.5g, 80.6mmol) in 100mL of dry DCM, and add tert-butyldimethylchloride under ice bath Silane (8.9g, 59.1mmol) was then transferred to room temperature for reaction, and the reaction was completed in about 0.5h.
  • the reaction solution was washed with saturated ammonium chloride and extracted three times with DCM.
  • the organic phases were combined, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate.
  • the solvent was evaporated under reduced pressure, sand was made, and purified by silica gel column chromatography to collect the colorless oily product.
  • b-2 (15.5g, yield 96%).
  • Step 2 Dissolve intermediate 1 (3.1g, 9.0mmol) in 60mL anhydrous DMF and protect it with argon. Add NaH (0.4g, 10.8mmol) in batches under ice bath, and spontaneously raise the temperature to room temperature and stir for about 2 hours. The reaction solution becomes obviously turbid. Add b-2 (10.8mmol) and heat to 40°C for about 2 days. After the reaction is complete, wash with a large amount of water, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, make sand, and purify by silica gel column chromatography to collect product b-3. (3.2g, yield 68%).
  • Substrate compound 35 (2.3g, 5.7mmol) and sodium bicarbonate (2.4g, 28.7mmol) were added to 50 mL of dry DCM under argon protection.
  • DMP (3.2g, 7.5mmol) was added under ice bath, and then spontaneously Warm up to room temperature and react for about 2 hours. After the reaction is complete, add a large amount of water for washing, extract with DCM three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain the product compound 36 (1.9g, Yield 82%).
  • Dissolve compound 37 (50 mg, 0.11 mmol) in dry THF and protect it with argon. Add HATU (68.14 mg, 0.18 mmol) under ice bath and stir for about 5 min. Add methylamine (6.37 ⁇ L, 0.14 mmol) and keep in ice bath. Continue stirring for about 15 min, and then add DIPEA (30.88 mg, 0.24 mmol) in an ice bath. Spontaneously warm to room temperature for reaction. The reaction is complete in about 1 to 2 hours. Add water, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry, evaporate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain the corresponding compound 38 (29 mg, yield 58%).
  • Step 1 Dissolve 2-methyl-1,3-propanediol (1.0g, 11.1mmol) in tetrahydrofuran, add imidazole (755mg, 11.1mmol) and triphenylphosphine (3.26g, 11.1mmol) in sequence at room temperature. After reacting for 1 minute, elemental iodine (3.7g, 14.4mmol) was added and reacted for 30 minutes.
  • Step 2 Dissolve compound c-1 (1.13g, 5.65mmol) and imidazole (0.57g, 8.47mmol) in 100mL dry DCM, add tert-butyldimethylsilyl chloride (0.94g, 6.21 mmol), then transferred to room temperature for reaction, and the reaction was complete in about 0.5h.
  • the reaction solution was washed with saturated ammonium chloride and extracted three times with DCM.
  • the organic phases were combined, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate.
  • the solvent was evaporated under reduced pressure, sand was made, and purified by silica gel column chromatography to collect the colorless oily product.
  • c-2 (1.55g, yield 87%).
  • Step 3 Dissolve intermediate 1 (1.42g, 4.1mmol) in 60mL anhydrous DMF and protect it with argon. Add NaH (0.12g, 4.9mmol) in batches under ice bath, spontaneously raise the temperature to room temperature and stir for about 2 hours. The reaction solution becomes obviously turbid. Add c-1 (1.55g, 4.9mmol) and heat to 40°C for about 2 days. After the reaction is complete, wash with a large amount of water, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, make sand, and purify by silica gel column chromatography to collect product c-3 (1.45g, yield 68%).
  • Step 5 Add substrate compound c-4 (1.0g, 2.4mmol) and sodium bicarbonate (0.6g, 7.2mmol) to 50 mL of dry DCM, under argon protection, and add DMP (0.38g, under ice bath, 3.1 mmol), and then spontaneously heated to room temperature for about 2 h. After the reaction is complete, add a large amount of water for washing, extract with DCM three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and purify by silica gel column chromatography to collect the product compound c-5 (0.81 g, yield 82%).
  • Step 6 Slowly add an ice-water solution (10 mL) of sodium chlorite (0.4g, 4.1mmol) and sulfamic acid (0.5g, 5.4mmol) to compound c-5 (0.81g, 2.0mmol) in acetone. (10 mL) solution, stir at room temperature for about 2 hours and the reaction is complete. After the acetone was evaporated, a white solid precipitated, which was filtered with suction and washed with diethyl ether to obtain the product compound 54 (50 mg, yield 65%).
  • Step 1 Dissolve 2-iodoethanol (2.0g, 11.6mmol) and imidazole (1.2g, 17.5mmol) in 100mL dry DCM, add tert-butyldimethylsilyl chloride (1.9g, 12.7 mmol), then transferred to room temperature for reaction, and the reaction was complete in about 0.5h.
  • the reaction solution was washed with saturated ammonium chloride and extracted three times with DCM.
  • the organic phases were combined, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate.
  • the solvent was evaporated under reduced pressure, sand was made, and purified by silica gel column chromatography to collect the colorless oily product. d-1 (3.0g, yield 92%).
  • Step 2 Dissolve intermediate 1 (1.0g, 2.9mmol) in 60mL anhydrous DMF and protect it with argon. Add NaH (0.08g, 3.2mmol) in batches under ice bath, and spontaneously raise the temperature to room temperature and stir for about 2 hours. The reaction solution becomes obviously turbid. Add d-1 (1.24g, 4.3mmol), and heat to 40°C for about 2 days. After the reaction is complete, wash with a large amount of water, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, make sand, and purify by silica gel column chromatography to collect product d-2. (1.0g, yield 72%).
  • Step 4 Add substrate compound d-3 (0.6g, 1.5mmol) and sodium bicarbonate (0.4g, 4.6mmol) to 50 mL of dry DCM, under argon protection, add DMP (0.8g, under ice bath, 2mmol), and then spontaneously heated to room temperature to react for about 2h. After the reaction is complete, add a large amount of water for washing, extract with DCM three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and purify by silica gel column chromatography to collect the product compound d-4 (0.5 g, yield 82%).
  • Step 5 Slowly add an ice-water solution (20 mL) of sodium chlorite (0.2g, 2.7mmol) and sulfamic acid (0.3g, 3.6mmol) to compound d-4 (0.5g, 1.3mmol) in acetone. (10 mL) solution, stir at room temperature for about 2 hours and the reaction is complete. After the acetone was evaporated, a white solid precipitated, which was filtered with suction and washed with diethyl ether to obtain the product compound 55 (0.3 g, 61%).
  • Step 1 Dissolve 4-iodobutanol (2.0g, 10.0mmol) and imidazole (1.2g, 15.0mmol) in 100mL dry DCM, add tert-butyldimethylsilyl chloride (1.6g, 11.0 mmol), then transferred to room temperature for reaction, and the reaction was completed in about 0.5 h.
  • the reaction solution was washed with saturated ammonium chloride and extracted three times with DCM.
  • the organic phases were combined, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate.
  • the solvent was evaporated under reduced pressure, sand was made, and purified by silica gel column chromatography to collect the colorless oily product. e-1 (3.0g, yield 96%).
  • Step 2 Dissolve intermediate 1 (1.0g, 2.9mmol) in 60mL anhydrous DMF and protect it with argon. Add NaH (0.08g, 3.2mmol) in batches under ice bath, spontaneously raise the temperature to room temperature and stir for about 2 hours. The reaction solution becomes obviously turbid. Add e-1 (1.36g, 4.3mmol) and heat to 40°C for about 2 days. After the reaction is complete, wash with a large amount of water, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, make sand, and purify by silica gel column chromatography to collect the product e-2 (1.0g, yield 68%).
  • Step 4 Add substrate compound e-3 (0.6g, 1.4mmol) and sodium bicarbonate (0.4g, 1.8mmol) to 50 mL of dry DCM, under argon protection, add DMP (0.8g, under ice bath, 1.9mmol), and then spontaneously warmed to room temperature to react for about 2h. After the reaction is complete, add a large amount of water for washing, extract with DCM three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and purify by silica gel column chromatography to collect the product compound e-4 (0.5 g, yield 82%).
  • Step 5 Slowly add an ice-water solution (20 mL) of sodium chlorite (0.2g, 2.5mmol) and sulfamic acid (0.3g, 3.4mmol) to compound e-4 (0.5g, 1.2mmol) in acetone. (20 mL) solution, stir at room temperature for about 2 hours and the reaction is complete. After the acetone was evaporated, a white solid precipitated, which was filtered with suction and washed with diethyl ether to obtain the product compound 56 (0.3 g, 61%).
  • Step 1 Dissolve intermediate 2 (1g, 2.74mmol) and p-toluenesulfonic acid monohydrate (47mg, 0.27mmol) in 10mL anhydrous acetone, cool to 0°C in an ice bath, and then add 2,2-dimethyl Oxypropane (2.02 mL, 16.5 mmol), react at room temperature, stir and react at room temperature for about 1 hour. After the reaction is complete, wash with water, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, make sand, and purify by silica gel column chromatography to obtain f-1, white Solid (1.01g, yield 90%).
  • Step 2 Dissolve synthetic f-1 (2.5mmol) and SeO 2 (7.5mmol) in 1,4-dioxane (50mL), heat and stir at 100°C for 16h, filter after the reaction is completed, and dilute the filtrate with water Then extract with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, make sand, and purify by silica gel column chromatography to obtain f-2 (0.77g, yield 76 %).
  • Step 3 Dissolve f-2 (2mmol) in DCM, add pyridinium dichromate (PDC) (2.2mmol), and stir at room temperature for 4 hours. After the reaction is completed, suction filtrate, the filtrate is diluted with water and extracted with dichloromethane. The organic phases are combined, washed with NaHCO 3 and saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent is evaporated under reduced pressure, sand is made, and purified by silica gel column chromatography. f-3 (0.70g, yield 80%) can be obtained.
  • PDC pyridinium dichromate
  • the first step Dissolve oridonin g-1 (1g, 2.74mmol) and p-toluenesulfonic acid monohydrate (47mg, 0.27mmol) in 10mL anhydrous acetone, cool to 0°C in an ice bath, and then add 2 , 2-dimethoxypropane (2.02 mL, 16.5 mmol), react at room temperature, stir and react at room temperature for about 1 hour.
  • Step 2 Dissolve g-2 (1g, 2.47mmol) in 10mL pyridine, add TEA (1.71mL, 12.36mmol), cool to 0°C in an ice bath, and then use a constant pressure dropping funnel to add dropwise the solution in pyridine Acetic anhydride (1.16mL, 12.36mmol) solution, react at room temperature for 2h. After the reaction is complete, wash with water, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, make sand, and purify by silica gel column chromatography to obtain g-3.
  • Step 3 Dissolve g-3 (0.5g, 1.29mmol) in 10mLTHF, cool to 0°C in an ice bath, then add HCl (5.17mL, 1M, 5.17mmol), and react at room temperature for 1 hour. After the reaction is complete, wash with water, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, make sand, and purify by silica gel column chromatography to obtain compound 80 as a white solid. (0.31g, yield 82%).
  • Step 1 Dissolve compound 37 (100 mg, 0.24 mmol) in 5 mL dichloromethane, add BOC-alanine (54 mg, 0.29 mmol) with a catalytic amount of DMAP (6 mg), EDCI (52 mg, 0.29 mmol), and keep at room temperature Reaction 24h. Add a small amount of water to quench the reaction, extract with ethyl acetate three times, wash with saturated brine, dry, filter, concentrate in vacuum, and obtain h-1 as a white solid (102 mg, yield 72.4) by column chromatography.
  • Step 2 Dissolve h-1 (100 mg, 0.17 mmol) in DCM, slowly add 0.5 mL trifluoroacetic acid dropwise with stirring in an ice bath, complete the drop, and continue the reaction for 0.5-1 h.
  • the reaction solution was concentrated under reduced pressure, and the obtained oily liquid was dissolved in DCM, extracted and spun to dryness.
  • Compound 93 was obtained by column chromatography as a white solid (52 mg, yield 62.6%).
  • Bone marrow cells were collected from the femurs and tibias of 6-week-old C57BL/6 male mice. A brief description is as follows: a) In the animal room, kill the mice by cervical dislocation, soak them in 75% alcohol for 5-10 minutes, and fix them.
  • Mouse use scissors to remove the limbs of the mouse as soon as possible, remove excess skin and flesh, and temporarily place them in 0°C PBS buffer; b) Prepare sterile scissor tweezers, PBS buffer, 2ml syringe, and cell filter in a clean workbench and cell culture plate; c) Rinse the mouse leg bones twice with PBS and once with RPMI-1640 medium, place them in a clean medium, fill the 2ml syringe with the medium, and cut the two sides of the bones with scissors. end, use tweezers to pick up the bone, and then use a syringe to flush the bone marrow into a 50ml centrifuge tube.
  • the culture conditions are 37°C and 5% CO 2 ; f) On the third day of cell growth, replace the cells with fresh culture medium, which can be removed during the medium replacement process. For miscellaneous cells that cannot adhere to the wall, continue to culture the cells until day 6-7, and observe the cell morphology. A spindle shape indicates that the cells are in good condition and can be used for subsequent experiments.
  • the cells were seeded on culture plates and tested on days 6-7. Discard the culture medium, wash it once with PBS, and replace it with fresh RPMI-1640 culture medium.
  • the culture medium contains 10% FBS and 1 ⁇ g/ml LPS. Stimulate for 4 hours; discard the culture medium after 4 hours, wash it once with PBS, and replace it with incomplete.
  • Culture medium add compound, incubate for 0.5h; add ATP (2.5mM) after 0.5h to stimulate for 0.5h; collect the supernatant after 0.5h, centrifuge at 2000rpm for 5min, discard the cell debris, and use the supernatant for ELISA test (ABclonal, Mouse IL-1 ⁇ ELISA Kit, RK00006). Refer to the kit instructions for detailed steps. IC 50 was calculated using GraphPad Prism8.0 software. The results are shown in Table 1.
  • compound IC 50 compound IC 50 compound IC 50 compound IC 50 compound IC 50 compound IC 50 1 C 2 B 3 B 4 B 5 C 6 C 7 C 8 B 9 B 10 B 11 C 12 C 13 D 14 D 15 C 16 B 17 A 18 B 19 C 20 A twenty one A twenty two D twenty three C twenty four B 25 A 26 C 27 B 28 A 29 B 30 B 31 C 32 C 33 B 34 C 35 D 36 B 37 A 38 A 39 A 40 C 41 C 42 D 43 C 44 D 45 A 46 C 47 C 48 B 49 C 50 B 51 B 52 D
  • the results show that the compound of the present invention can effectively inhibit the release of inflammatory factor IL-1 ⁇ in bone marrow-derived macrophages BMDM after LPS and ATP induction modeling.
  • mice 4-week-old mice were taken, weighed, and then divided into groups of 5 mice each, and the width of the knee joints was measured.
  • the experimental group was administered oral or tail vein administration (DMSO was dissolved, and then Tween80 and physiological saline were added in sequence to dilute to the required concentration, so that the final ratio of DMSO: Tween80 physiological saline was 5:5:90).
  • MSU 0.5mg/20g; dissolved in PBS
  • the width of the left knee joint was measured at 1h, 6h, 12h, and 24h after modeling, and the degree of joint swelling was calculated.
  • mice in different groups 24 hours after compound administration, the degree of joint swelling of mice in different groups is shown in Table 2.
  • the animals were sacrificed 24 hours after modeling.
  • the left knee joints of the mice in the above groups were taken out and cultured in 200 ⁇ L opti-MEM for 1 hour.
  • the cultured supernatant was used to detect IL-1 ⁇ using ELISA.
  • the release amount is shown in Table 2.
  • the degree of joint swelling is the ratio of the width of the left knee joint of the subject mouse at 24 hours to the width at 0 hours.

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Abstract

本发明公开一种贝壳衫烷型四环二萜类衍生物、其制备方法及医药用途，具体涉及通式(I)或通式(II)所示贝壳衫烷型四环二萜类化合物的新型衍生物，或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其药物组合物以及制备方法和在制备抑制NLRP3炎症小体抑制药物中的用途。

Description

一种贝壳衫烷型四环二萜类衍生物、其制备方法及医药用途 技术领域
本发明涉及一种具有抗炎活性的如通式(Ⅰ和II)所示贝壳衫烷型四环二萜类化合物其C7位结构修饰的新型衍生物，或者其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶，其药物组合物以及制备方法和在制备抑制NLRP3炎症小体抑制药物中的用途。
背景技术
NLRP3炎症小体抑制剂是近年来研究开发的一种重要的治疗免疫相关炎症的药物。NLRP3炎症小体是一种多聚体蛋白复合体，主要表达于单核-巨噬细胞、中性粒细胞和树突状细胞(DC)。NLRP3炎症小体由三部分组成：NLRP3感受器蛋白，接头蛋白ASC以及效应蛋白pro-caspase-1。在正常生理情况下，NLRP3蛋白和pro-caspase-1定位于细胞质内，ASC则位于细胞核内。受到外源的病原相关分子模式(PAMPs)或机体内部的损伤相关分子模式(DAMPs)，NLRP3能够招募接头蛋白ASC，再通过ASC与pro-caspase-1结合，进而形成活化的NLRP3炎症小体。活化的NLRP3炎症小体能促使pro-caspase-1活化生成的caspase-1，caspase-1则进一步介导IL-1β和IL-18的成熟与分泌。同时，caspase-1也可以通过剪切gasdermin D(GSDMD)引起细胞发生焦亡(Nat.Rev.Drug.Discov.2018,17,588-606)。
当前治疗NLRP3相关疾病药物包括重组IL-1受体拮抗剂anakinra、中和IL-1β抗体canakinumab和可溶性IL-1受体诱捕剂rilonacept，以上均是生物制品。近年来报道了一些具有NLRP3炎症小体抑制活性的小分子，如：格列苯脲、MCC950、小白菊素(parthenolide)、3，4-亚甲基二氧基-β-硝基苯乙烯和冬凌草甲素等。然而，上述的小分子抑制剂存在或部分存在特异性不高、活性一般以及毒性较大等缺陷(J.Med.Chem.2021,64,101–122)。
发明内容
为了开发高效低毒的并具备较高特异性的新型小分子NLRP3抑制剂，可以用来治疗由NLRP3突变导致的自身免疫性疾病，本发明发现了一种如通式(I)所示的新型贝壳衫烷型四环二萜类衍生物分子，从而提供了具有更优抑制NLRP3炎症小体活性以及抑制白介素释放的新化合物分子，通式(I)拓展了现有NLRP3炎症小体抑制剂的结构特征和范围，并提供了这些新型衍生物的制备方法。本发明是通过以下技术方案实现的。
Figure PCTCN2022141790-appb-000001
本发明提供通式(Ⅰ)所示的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶。
其中：
A任选自氢、羟基、卤素、氰基、氨基、＝O、-OC(＝O)R 1a、或与相邻的Y和U一起形成取代或未取代的5～7元的芳杂环，取代基选自-NH-R 1，所述R 1a选自C 1-4烷基或C 1-4烯基；
B任选自氢、羟基或OAc；
L任选自氢、羟基、卤素、氰基、氨基或＝O；
U、Y和Z为碳原子；U-Y键和Y-Z键各自独立的为碳碳单键或碳碳双键；
M选自取代或未取代的以下基团：
Figure PCTCN2022141790-appb-000002
n相同或不同，各自独立的为0、1、2、3或4；
R 2a相同或不同，各自独立的选自氢、氨基、羧基、醛基、羟基、卤素、巯基、氰基、硝基，或R 2a选自取代的或未取代的以下基团：C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基或5～6元杂芳基；
R 3a、R 4a相同或不同，各自独立的选自氢或取代的或未取代的以下基团：C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基、5～6元杂芳基、C 8-10桥环或-(CH 2) m-R 5a；其中m为0、1或2，R 5a选自C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基、5～6元杂芳基；
E环为取代或未取代的5～6元杂环烷基或5～6元杂芳基；
取代基选自氢、氨基、羧基、＝O、醛基、羟基、卤素、巯基、氰基、硝基、C l-4烷基、C l-4烷氧基或C l-4卤代烷基；
K选自氢原子或取代或未取代的以下基团：-C(＝O)R 6a或-C(＝O)CH(R 5a)NH 2基；
R 6a选自氢或取代或未取代的以下基团：C l-4烷基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基；取代基选自氨基、羧基、醛基、羟基、卤素、巯基、氰基或硝基。
在一些实施例中，X为-O-。
在一些实施例中，U、Y和Z为碳原子；U-Y键为碳碳单键或碳碳双键；Y-Z键为碳碳单键。
本发明还提供具有以下I-1～I-9任一结构的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶：
Figure PCTCN2022141790-appb-000003
在一些实施例中，M选自取代或未取代的以下基团：
Figure PCTCN2022141790-appb-000004
n相同或不同，各自独立的为0、1、2、3或4；
R 2a相同或不同，各自独立的选自氢、氨基、羧基、醛基、羟基、卤素、巯基、氰基、硝基，或R 2a选自取代的或未取代的以下基团：C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基或5～6元杂芳基；
R 3a、R 4a相同或不同，各自独立的选自氢或取代的或未取代的以下基团：C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基、5～6元杂芳基、C 8-10桥环或-(CH 2) m-R 5a；其中m为0、1或2，R 5a选自C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基、5～6元杂芳基；
E环为取代或未取代的5～6元杂环烷基或5～6元杂芳基；
取代基选自氢、氨基、羧基、＝O、醛基、羟基、卤素、巯基、氰基、硝基、C l-4烷基、C l-4烷氧基或C l-4卤代烷基；
K选自氢原子或取代或未取代的以下基团：-C(＝O)R 6a或-C(＝O)CH(R 5a)NH 2基；
R 6a选自氢或取代或未取代的以下基团：C l-4烷基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基；取代基选自氨基、羧基、醛基、羟基、卤素、巯基、氰基或硝基。
本发明还提供通式(II)所示的化合物或其立体异构体、水合物、代谢产物、氘代物、溶剂化物、 药学上可接受的盐或共晶，其结构优选自以下结构：
Figure PCTCN2022141790-appb-000005
在一些实施例中，M选自取代或未取代的基团：
Figure PCTCN2022141790-appb-000006
n相同或不同，各自独立的为0、1、2、3或4；
R 2a相同或不同，各自独立的选自氢、氨基、羧基、醛基、羟基、卤素、巯基、氰基、硝基，或R 2a选自取代的或未取代的以下基团：C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基或5～6元杂芳基；
R 3a、R 4a相同或不同，各自独立的选自氢或取代的或未取代的以下基团：C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基、5～6元杂芳基、C 8-10桥环或-(CH 2) m-R 5a；其中m为0、1或2，R 5a选自C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基、5～6元杂芳基；
E环为取代或未取代的5～6元杂环烷基或5～6元杂芳基；
取代基选自氢、氨基、羧基、＝O、醛基、羟基、卤素、巯基、氰基、硝基、C l-4烷基、C l-4烷氧基或C l-4卤代烷基。
以下本发明还提供如下任一所示化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶：
Figure PCTCN2022141790-appb-000007
Figure PCTCN2022141790-appb-000008
Figure PCTCN2022141790-appb-000009
本发明还提供一种组合物，包括本发明所述的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶，以及药学上可接受的载体。
本发明还提供本发明所述的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶在用于制备NLRP3抑制剂药物中的应用。
本发明还提供本发明所述的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶在用于制备抗炎症药物中的应用；优选的，所述炎症为关节炎。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对映的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括 16O、 17O和 18O,硫的同位素包括 32S、 33S、 34S和 36S,氮的同位素包括 14N和 15N,氟的同位素包括 17F和 19F，氯的同位素包括 35Cl和 37Cl,溴的同位素包括 79Br和 81Br。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基，优选为1至8个(例如1、2、3、4、5、6、7、8个)碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戌基、异戌基、新戌基、正己基及其各种支链异构体；当烷基被取代基时，可以任选进一步被1个或者多个取代基所取代。
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戌氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。
“烯基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、10个)碳-碳双键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基，更优选2至8个碳原子的烯基，进一步优选2至6个碳原子的烯基。非限制性实施例包括乙烯基、丙烯2-基、丁烯-2-基、丁烯-2-基、戌烯-2-基、戌烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被1个或者多个取代基所取代。
“炔基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、或10个)碳-碳叁键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基，更优选2至8个碳原子的炔基，进一步优选2至6个碳原子的炔基。非限制性实施例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戌炔-1-基、戌炔-2-基、己炔-1-基、1-庚块-1-基、庚块-3-基、庚块-4-基、中块-3-基、壬块-3-基、癸块-4-基、十一块-3-基、十二炔-4-基。所述的炔基可以任选进一步被一至多个取代基所取代。
“芳基”是指是指取代的或未取代的芳香环，其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，其可以是桥环或者螺环，非限制性实施例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。
“杂芳基”是指取代的或未取代的芳香环，其可以是3至8元(例如3、4、5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至6个(例如1、2、3、4、5、6个)选自N、O或S的杂原子，优选5至8元杂芳基，杂芳基的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态。杂芳基可以连接在杂原子或者碳原子上，杂芳基可以是桥环或者螺环，非限制性实施例包括环吡咬基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基。杂芳基任选进一步被1个或多个取代基所取代。
“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当为芳香环时，其定义与上文“芳基”的定义相同；当为非芳香环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，可以是桥环或者螺环，非限制性实施例包括环丙基、环丁基、环戌基、1-环戌基-1-烯基、1-环戌基-2-烯基、1-环戌基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、金刚烷基、降冰片烯基、十氢萘基。所述的“碳环基”或“碳环”任选进一步被1个或者多个取代基所取代。
“杂环基”或“杂环”是指饱和或不饱和的芳香性杂环或者非芳香性杂环，当为芳香性杂环时，其定义与上文“杂芳基”定义相同；当为非芳香性杂环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子，优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态；“杂环基”或“杂环”可以连接在杂原子或者碳原子上；“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戌环基、1,4-二氧戌环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、呋喃基、噻吩基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戌环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戌基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的“杂环基”或“杂环”可以任选进一步被1个或者多个取代基所取代。
“环烷基”是指饱和的环烃基，其环可以为3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至20元(例如10、11、12、13、14、15、16、17、18、19、20元)多环体系，环碳原子优选3至10个碳原子，进一步优选3至8个碳原子。“环烷基”非限制性实施例包括环丙基、环丁基、环戌基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戌烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当环烷基被取代时，可以任选进一步被1个或者多个取代基所取代。
“杂环烷基”是指取代的或未取代的饱和非芳香环基，其可以是3至8元(例如3、4、5、6、7、 8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1、2或3个选自N、O或S的杂原子，优选3至8元杂环基。“杂环烷基”的环中选择性取代的1、2或3个N、S可被氧化成各种氧化态；“杂环烷基”可以连接在杂原子或者碳原子上；“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戌环基、1,4-二氧戌环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。
当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“碳环基”、“碳环”、“杂环基”、“杂环”、“环烷基”、“杂环烷基”或者“杂环基”被取代时，可以进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C 1-6烷基氨基、＝O、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-NR q4R q5,＝NR q6,-C(＝O)OC 1-6烷基、-OC(＝O)C 1-6烷基、-C(＝O)NR q4R q5、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C5-10杂芳基、-C(＝O)OC 6-10芳基、-OC(＝O)C 6-10芳基、-OC(＝O)C 5-10杂芳基、-C(＝O)OC 5-10杂芳基、-OC(＝O)C 3-8杂环烷基、-C(＝O)OC 3-8杂环烷基、-OC(＝O)C 3-8环烷基、-C(＝O)OC 3-8环烷基、-NHC(＝O)C 3-8杂环烷基、-NHC(＝O)C 6-10芳基、-NHC(＝O)C 5-10杂芳基、-NHC(＝O)C 3-8环烷基、-NHC(＝O)C 3-8杂环烷基、-NHC(＝O)C 2-6烯基或者-NHC(＝O)C 2-6炔基的取代基所取代，且其中所述的取代基C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基、-NHC(＝O)C 6-10芳基、-NHC(＝O)C 5-10杂芳基、-NHC(＝O)C 3-8杂环烷基或者-NHC(＝O)C 3-8环烷基任选进一步被1至3个选自羟基、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、-NR q4R q5或者＝O的取代基所取代；R q1选自C 1-6烷基、C 1-6烷氧基或者C6-10芳基；R q2、R q3选自H或者C 1-6烷基；其中，R q4、R q5选自H、C 1-6烷基、-NH(C＝NR q1)NR q2R q3、-S(＝O) 2NR q2R q3、-C(＝O)R q1或者-C(＝O)NR q2R q3，其中所述的C 1-6烷基任选进一步被1个或者多个选自羟基、F、C1、Br、I、C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 5-10杂芳基、C 3-8环烷基或者C 3-8杂环烷基的取代基所取代；或者R q4与R q5及N原子形成一个3至8元杂环，所述杂环可以含有1个或者多个选自N、O或者S的杂原子。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生， 该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“任选地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。
本发明还提供一种组合物，包括本发明所述的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶，以及药学上可接受的载体。
本发明所述的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶在用于制备NLRP3抑制剂药物中的应用。
本发明所述的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶在用于制备抗炎症药物中的应用；在一些实施例中，所述炎症为关节炎。
具体实施方式
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker 400和Bruker 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl 3),氘代丙酮(acetone-d6)，内标为四甲基硅烷(TMS)；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；柱层析一般使用烟台黄海硅胶200-300目硅胶为载体；
本发明的己知起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技、南京春秋等公司；
实施例中无特殊说明，溶液是指水溶液；
实施例中无特殊说明，反应的温度为室温，室温最适宜的反应温度，为20℃-30℃；
实施例
下述关键中间体均可通过之前报道的文献资料(J.Med.Chem.2020,63,8157-8178；Eur.J.Med.Chem.2022,231,114155；公开号：CN114437102A；J.Med.Chem.2013,56,8814-8825；公开号：CN102584760A；J.Med.Chem.2013,56,5048-5058；Bioorg.Med.Chem.Lett.2008,18,4741-4744.)由冬凌草甲素合成得到：
Figure PCTCN2022141790-appb-000010
实施例1
Figure PCTCN2022141790-appb-000011
将中间体1(0.20mmol)和TBAI(0.04mmol)溶于2mLDCM中，冰浴下加入1NNaOH(0.30mmol)搅拌约10min，随后加入溴化苄(0.25mmol)，置于室温下搅拌反应约5h。待反应完全后，用水洗涤，DCM萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化可得相应产物(55mg，收率76％)。 1H HMR(400MHz,CDCl 3)δ7.36–7.24(m,5H),6.28(s,1H),6.20(d,J＝1.2Hz,1H),5.78(dd,J＝10.2,2.0Hz,1H),5.58(d,J＝11.0Hz,1H),5.54(d,J＝1.1Hz,1H),5.17(dd,J＝10.2,2.9Hz,1H),4.80(s,1H),4.66(d,J＝11.3Hz,1H),4.57(d,J＝11.4Hz,1H),3.99(dd,J＝10.0,1.5Hz,1H),3.89-3.80(m,2H),3.29(d,J＝9.4Hz,1H),2.54–2.41(m,1H),1.98–1.92(m,1H),1.91–1.87(m,1H),1.87–1.83(m,1H),1.83–1.76(m,1H),1.75–1.64(m,1H),1.57(dd,J＝12.2,4.6Hz,1H),1.50(dd,J＝8.1,1.6Hz,1H),1.17(s,3H),1.04(s,3H). 13C NMR(101MHz,CDCl 3)δ205.09,149.79,136.00,130.76,128.69,128.35,127.84,124.25,121.01,97.29,81.60,72.63,71.25,65.34,62.06,58.81,52.67,41.15,38.42,38.36,32.37,30.84,30.18,21.84,17.48.HRMS(ESI,m/z)calculated for C 27H 32NaO 5[M+Na] +459.2142,found 459.2139.
实施例2
Figure PCTCN2022141790-appb-000012
化合物2的合成参照化合物1进行制备；化合物2，白色固体(67mg，收率81％)。 1H HMR(400MHz,CDCl 3)δ7.30–7.22(m,2H),7.02(t,J＝8.7Hz,2H),6.21(d,J＝1.8Hz,2H),5.79(dd,J＝10.3,2.0Hz,1H),5.59–5.49(m,2H),5.19(dd,J＝10.3,2.8Hz,1H),4.80(s,1H),4.64(d,J＝11.2Hz,1H),4.54(d,J＝11.1Hz,1H),4.00(dd,J＝10.0,1.5Hz,1H),3.86(dd,J＝11.0,8.1Hz,2H),3.30(d,J＝9.4Hz,1H),2.56–2.43(m,1H),1.99–1.89(m,2H),1.84(dd,J＝17.8,4.4Hz,2H),1.78–1.67(m,1H),1.59(dd,J＝11.9,4.5Hz,1H),1.51(dd,J＝8.1,1.5Hz,1H),1.18(s,3H),1.05(s,3H). 13C NMR(101MHz,CDCl 3)δ205.05,163.87,161.42,149.73,131.89,131.86,130.79,129.79,129.71,124.18,121.08,115.74,115.52,97.28,81.65,72.63,70.51,65.35,62.07,58.81,52.68,41.12,38.42,38.35,32.35,30.82,30.17,21.83,17.46.HRMS(ESI,m/z)calculated for C 27H 31FNaO 5[M+Na] +477.2048,found477.2042.
实施例3
Figure PCTCN2022141790-appb-000013
化合物3的合成参照化合物1进行制备；化合物3，白色固体(70mg，收率77％)。 1H HMR(300MHz,CDCl 3)δ7.29–7.19(m,2H),6.95–6.84(m,2H),6.35(s,1H),6.23(s,1H),5.82(dd,J＝10.3,2.1Hz,1H),5.64–5.51(m,2H),5.21(dd,J＝10.3,2.8Hz,1H),4.81(s,1H),4.64(d,J＝11.0Hz,1H),4.54(d,J＝10.9Hz,1H),4.03(dd,J＝9.9,1.4Hz,1H),3.93–3.84(m,2H),3.83(s,3H),3.32(d,J＝9.3Hz,1H),2.51(dd,J＝12.1,6.3Hz,1H),2.04–1.95(m,1H),1.93–1.87(m,2H),1.84–1.75(m,1H),1.72(dd,J＝6.2,3.4Hz,1H),1.65–1.58(m,1H),1.56–1.50(m,1H),1.21(s,3H),1.08(s,3H). 13C NMR(101MHz,CDCl 3)δ205.18,159.66,130.72,129.58,128.10,124.30,120.93,114.08,97.30,81.21,72.62,70.95,65.33,61.99,58.81,55.31,52.63,41.16,38.43,38.36,32.36,30.84,30.18,21.84,17.49.HRMS(ESI,m/z)calculated for C 28H 34NaO 6[M+Na] +489.2248,found 489.2244.
实施例4
Figure PCTCN2022141790-appb-000014
化合物4的合成参照化合物1进行制备；化合物4，白色固体(54mg，收率53％)。 1H HMR(400MHz,CDCl 3)δ8.56(d,J＝4.9Hz,2H),7.32–7.24(m,2H),6.23(s,1H),6.01(d,J＝11.8Hz,1H),5.82(dd,J＝10.1,2.0Hz,1H),5.61(s,1H),5.24(dd,J＝10.2,2.9Hz,1H),5.03(d,J＝11.6Hz,1H),4.92(d,J＝11.6Hz,1H),4.86(s,1H),4.58(s,1H),4.23(dd,J＝11.8,8.5Hz,1H),4.02(d,J＝9.9Hz,1H),3.86(dd,J＝9.9,1.5Hz,1H),3.02(d,J＝9.3Hz,1H),2.49(dd,J＝12.9,6.5Hz,1H),2.01–1.94(m,1H),1.88(d,J＝6.1Hz,1H),1.84(s,2H),1.74–1.66(m,1H),1.65–1.58(m,1H),1.57–1.53(m,1H),1.20(s,3H),1.08(s,3H). 13C NMR(101MHz,CDCl 3)δ205.62,151.25,149.99,146.23,130.83,124.48,122.28,121.51,102.19,71.83,69.35,65.60,63.28,62.85,57.51,52.43,42.45,41.01,38.60,32.41,30.79,30.19,29.73,21.80,17.79.HRMS(ESI,m/z)calculated for C 26H 31NNaO 5[M+Na] +460.2094,found 460.2088.
实施例5
Figure PCTCN2022141790-appb-000015
化合物5的合成参照化合物1进行制备；化合物5，白色固体(46mg，收率41％)。 1H HMR(300MHz,CDCl 3)δ8.57(d,J＝4.7Hz,1H),7.65(td,J＝7.6,1.8Hz,1H),7.32–7.24(m,1H),7.18(dd,J＝7.6,4.9Hz,1H),6.22(s,1H),5.99(d,J＝11.5Hz,2H),5.83(dd,J＝10.4,2.1Hz,1H),5.60(s,1H),5.27(dd,J＝10.3,2.9Hz,1H),5.22–5.02(m,2H),4.96(d,J＝1.4Hz,1H),4.23(dd,J＝11.6,8.5Hz,1H),4.03(d,J＝10.0Hz,1H),3.89(dd,J＝9.9,1.7Hz,1H),3.09(d,J＝9.3Hz,1H),2.53(dd,J＝15.2,3.9Hz,1H),1.97(d,J＝2.8Hz,1H),1.94–1.79(m,4H),1.72–1.63(m,1H),1.60–1.55(m,1H),1.24(s,3H),1.11(s,3H). 13C NMR(101MHz,CDCl 3)δ206.17,157.12,151.69,149.30,136.60,130.60,124.76,122.38,121.15,120.96,101.26,,71.62,69.79,65.56,64.04,63.04,57.76,52.44,42.77,41.06,38.70,32.40,30.84,29.88,21.84,17.78.HRMS(ESI,m/z)calculated for C 26H 31NNaO 5[M+Na] +460.2094,found 460.2099.
实施例6
Figure PCTCN2022141790-appb-000016
化合物6的合成参照化合物1进行制备；化合物6，白色固体(47mg，收率42％)。 1H HMR(300MHz,CDCl 3)δ8.70–8.50(m,2H),7.78(dt,J＝7.9,2.0Hz,1H),7.31–7.26(m,1H),6.27–6.21(m,1H),6.06(d,J＝11.8Hz,1H),5.85(dd,J＝10.2,2.1Hz,1H),5.60(d,J＝1.2Hz,1H),5.27(dd,J＝10.3,2.8Hz,1H),5.11–4.90(m,2H),4.85(d,J＝1.5Hz,1H),4.57(s,1H),4.29(dd,J＝11.8,8.6Hz,1H),4.09–4.02(m,1H),3.89(dd,J＝9.9,1.6Hz,1H),3.05–2.97(m,1H),2.50(dd,J＝14.9,3.8Hz,1H),2.01(dt,J＝17.5,2.6Hz,1H),1.93–1.89(m,1H),1.85(d,J＝6.2,2.8Hz,2H),1.75–1.66(m,1H),1.65–1.60 (m,1H),1.58(dd,J＝8.6,1.6Hz,1H),1.24(s,3H),1.12(s,3H). 13C NMR(101MHz,CDCl 3)δ205.64,151.34,149.61,149.55,136.17,130.78,124.56,123.66,121.35,102.06,71.77,69.36,65.56,62.82,62.27,57.52,52.41,42.44,41.03,38.61,32.42,30.81,29.72,21.82,17.78.HRMS(ESI,m/z)calculated for C 26H 31NNaO 5[M+Na] +460.2094,found 460.2091.
实施例7
Figure PCTCN2022141790-appb-000017
化合物7的合成参照化合物1进行制备；化合物7，白色固体(47mg，收率42％)。 1H HMR(300MHz,CDCl 3)δ8.70–8.50(m,2H),7.78(dt,J＝7.9,2.0Hz,1H),7.31–7.26(m,1H),6.27–6.21(m,1H),6.06(d,J＝11.8Hz,1H),5.85(dd,J＝10.2,2.1Hz,1H),5.60(d,J＝1.2Hz,1H),5.27(dd,J＝10.3,2.8Hz,1H),5.11–4.90(m,2H),4.85(d,J＝1.5Hz,1H),4.57(s,1H),4.29(dd,J＝11.8,8.6Hz,1H),4.09–4.02(m,1H),3.89(dd,J＝9.9,1.6Hz,1H),3.05–2.97(m,1H),2.50(dd,J＝14.9,3.8Hz,1H),2.01(dt,J＝17.5,2.6Hz,1H),1.93–1.89(m,1H),1.85(d,J＝6.2,2.8Hz,2H),1.75–1.66(m,1H),1.65–1.60(m,1H),1.58(dd,J＝8.6,1.6Hz,1H),1.24(s,3H),1.12(s,3H). 13C NMR(101MHz,CDCl 3)δ205.64,151.34,149.61,149.55,136.17,130.78,124.56,123.66,121.35,102.06,71.77,69.36,65.56,62.82,62.27,57.52,52.41,42.44,41.03,38.61,32.42,30.81,29.72,21.82,17.78.HRMS(ESI,m/z)calculated for C 26H 31NNaO 5[M+H] +439.2155,found 439.2156.
实施例8
Figure PCTCN2022141790-appb-000018
化合物8的合成参照化合物1进行制备；化合物8，白色固体(61mg，收率60％)。 1H HMR(400MHz,CDCl 3)δ6.74–6.65(m,1H),6.43–6.35(m,1H),6.19(d,J＝1.4Hz,1H),5.94(d,J＝11.8Hz,1H),5.80(dd,J＝10.2,2.0Hz,1H),5.56(d,J＝1.3Hz,1H),5.26–5.17(m,1H),4.95(d,J＝1.9Hz,2H),4.84(d,J＝1.4Hz,1H),4.47(s,1H),4.15(dd,J＝11.8,8.6Hz,1H),3.91(dd,J＝60.6,1.4Hz,2H),3.01(dd,J＝9.1,1.6Hz,1H),2.54–2.37(m,1H),2.00–1.91(m,1H),1.85(dd,J＝6.4,0.9Hz,1H),1.82–1.74(m,2H),1.61–1.54(m,1H),1.52(dd,J＝8.5,1.6Hz,1H),1.18(s,3H),1.06(s,3H).HRMS(ESI,m/z)calculated for C 26H 30NaO 6[M+Na] +501.1808,found 501.1802.
实施例9
Figure PCTCN2022141790-appb-000019
化合物9的合成参照化合物1进行制备；化合物9，白色固体(65mg，收率60％)。 1H HMR(400MHz,CDCl 3)δ6.74–6.65(m,1H),6.43–6.35(m,1H),6.19(d,J＝1.4Hz,1H),5.94(d,J＝11.8Hz,1H),5.80(dd,J＝10.2,2.0Hz,1H),5.56(d,J＝1.3Hz,1H),5.26–5.17(m,1H),4.95(d,J＝1.9Hz,2H),4.84(d,J＝1.4Hz,1H),4.47(s,1H),4.15(dd,J＝11.8,8.6Hz,1H),3.91(dd,J＝60.6,1.4Hz,2H),3.01(dd, J＝9.1,1.6Hz,1H),2.54–2.37(m,1H),2.00–1.91(m,1H),1.85(dd,J＝6.4,0.9Hz,1H),1.82–1.74(m,2H),1.61–1.54(m,1H),1.52(dd,J＝8.5,1.6Hz,1H),1.18(s,3H),1.06(s,3H).HRMS(ESI,m/z)calculated for C 26H 30SNaO 5[M+Na] +517.1708,found 517.1702.
实施例10
Figure PCTCN2022141790-appb-000020
化合物10的合成参照化合物1进行制备；化合物10，白色固体(65mg，收率60％)。 1H HMR(400MHz,CDCl 3)δ6.74–6.65(m,1H),6.43–6.35(m,1H),6.19(d,J＝1.4Hz,1H),5.94(d,J＝11.8Hz,1H),5.80(dd,J＝10.2,2.0Hz,1H),5.56(d,J＝1.3Hz,1H),5.26–5.17(m,1H),4.95(d,J＝1.9Hz,2H),4.84(d,J＝1.4Hz,1H),4.47(s,1H),4.15(dd,J＝11.8,8.6Hz,1H),3.91(dd,J＝60.6,1.4Hz,2H),3.01(dd,J＝9.1,1.6Hz,1H),2.54–2.37(m,1H),2.00–1.91(m,1H),1.85(dd,J＝6.4,0.9Hz,1H),1.82–1.74(m,2H),1.61–1.54(m,1H),1.52(dd,J＝8.5,1.6Hz,1H),1.18(s,3H),1.06(s,3H).HRMS(ESI,m/z)calculated for C 26H 30NNaO 5[M+Na] +500.1708,found 500.1702.
实施例11
Figure PCTCN2022141790-appb-000021
化合物11的合成参照化合物1进行制备；化合物11，白色固体(80mg，收率70％)。 1H HMR(300MHz,CDCl 3)δ7.89–7.81(m,3H),7.77(s,1H),7.52(dd,J＝6.3,3.2Hz,2H),7.42(dd,J＝8.5,1.7Hz,1H),6.38(s,1H),6.25(s,1H),5.81(dd,J＝10.3,2.1Hz,1H),5.64(d,J＝11.0Hz,1H),5.58(s,1H),5.20(dd,J＝10.3,2.8Hz,1H),4.92–4.74(m,3H),4.04(dd,J＝10.0,1.5Hz,1H),3.95–3.82(m,2H),3.36(d,J＝9.3Hz,1H),2.57–2.41(m,1H),2.00(dd,J＝13.8,3.8Hz,1H),1.91(dd,J＝12.2,7.3Hz,2H),1.86–1.79(m,1H),1.78–1.66(m,1H),1.64–1.57(m,1H),1.55(dd,J＝8.0,1.6Hz,1H),1.22(s,3H),1.09(s,3H). 13C NMR(75MHz,CDCl 3)δ205.26,149.84,133.55,133.15,130.75,128.66,128.00,127.77,126.77,126.38,125.45,124.27,121.14,97.35,81.72,72.68,71.40,65.37,62.13,58.85,52.70,41.15,38.46,38.36,32.38,30.86,30.16,21.88,17.47.HRMS(ESI,m/z)calculated for C 31H 34NaO 4[M+Na] +509.2298,found 509.2301.
实施例12
Figure PCTCN2022141790-appb-000022
化合物12的合成参照化合物1进行制备；化合物12，白色固体(69mg，收率80％)。 1H HMR(400MHz,CDCl 3)δ7.62(d,J＝8.3Hz,2H),7.39(d,J＝8.2Hz,2H),6.23(d,J＝1.2Hz,1H),5.99(s,1H),5.80(dd,J＝10.2,2.1Hz,1H),5.62–5.49(m,2H),5.18(dd,J＝10.3,2.9Hz,1H),4.83(s,1H),4.77–4.62(m,2H),4.00(dd,J＝10.0,1.5Hz,1H),3.90–3.82(m,2H),3.31(d,J＝9.4Hz,1H),2.51(dd,J＝13.6,7.2Hz,1H),2.00–1.91(m,2H),1.87(d,J＝5.7Hz,1H),1.84–1.79(m,1H),1.78–1.69(m,1H), 1.66–1.56(m,1H),1.51(dd,J＝8.1,1.6Hz,1H),1.17(s,3H),1.05(s,3H). 13C NMR(101MHz,CDCl 3)δ204.80,149.51,141.49,132.51,130.95,130.56,127.92,124.44,124.02,121.36,118.50,112.08,97.30,82.34,72.63,70.12,65.40,62.23,58.77,52.79,42.69,41.09,38.48,38.35,32.35,32.30,30.79,30.20,21.82,17.47.HRMS(ESI,m/z)calculated for C 28H 31NNaO 5[M+Na] +484.2094,found 484.2095.
实施例13
Figure PCTCN2022141790-appb-000023
化合物13的合成参照化合物1进行制备；化合物13，白色固体(87mg，收率79％)。 1H HMR(300MHz,CDCl 3)δ7.36–7.27(m,3H),7.22–7.15(m,3H),6.20(dd,J＝11.8,1.9Hz,2H),5.94(dd,J＝11.7,1.3Hz,1H),5.79(dd,J＝10.3,2.1Hz,1H),5.55(d,J＝1.2Hz,1H),5.20(d,J＝24.2Hz,4H),5.00(q,J＝10.9Hz,2H),4.86(d,J＝1.5Hz,1H),4.19(dd,J＝11.7,8.5Hz,1H),3.99(d,J＝9.9Hz,1H),3.83(dd,J＝10.0,1.7Hz,1H),3.00(dd,J＝9.2,1.6Hz,1H),2.45(dt,J＝9.2,6.0Hz,1H),1.93(t,J＝2.5Hz,1H),1.85–1.79(m,3H),1.65–1.49(m,3H),1.19(s,3H),1.06(s,3H). 13C NMR(101MHz,CDCl 3)δ205.83,151.67,148.91,136.41,130.57,130.14,128.76,127.97,127.84,124.83,120.93,104.91,101.46,71.69,69.51,65.42,62.84,58.49,57.59,55.92,52.41,42.58,41.08,38.66,32.39,30.87,29.85,21.84,17.77.HRMS(ESI,m/z)calculated for C 30H 35N 3NaO 5[M+Na] +540.2516,found 540.2519.
实施例14
Figure PCTCN2022141790-appb-000024
化合物14的合成参照化合物1进行制备；化合物14，白色固体(87mg，收率79％)。 1H HMR(300MHz,CDCl 3)δ7.36–7.27(m,3H),7.22–7.15(m,3H),6.20(dd,J＝11.8,1.9Hz,2H),5.94(dd,J＝11.7,1.3Hz,1H),5.79(dd,J＝10.3,2.1Hz,1H),5.55(d,J＝1.2Hz,1H),5.20(d,J＝24.2Hz,4H),5.00(q,J＝10.9Hz,2H),4.86(d,J＝1.5Hz,1H),4.19(dd,J＝11.7,8.5Hz,1H),3.99(d,J＝9.9Hz,1H),3.83(dd,J＝10.0,1.7Hz,1H),3.00(dd,J＝9.2,1.6Hz,1H),2.45(dt,J＝9.2,6.0Hz,1H),1.93(t,J＝2.5Hz,1H),1.85–1.79(m,3H),1.65–1.49(m,3H),1.19(s,3H),1.06(s,3H). 13C NMR(101MHz,CDCl 3)δ205.83,151.67,148.91,136.41,130.57,130.14,128.76,127.97,127.84,124.83,120.93,104.91,101.46,71.69,69.51,65.42,62.84,58.49,57.59,55.92,52.41,42.58,41.08,38.66,32.39,30.87,29.85,21.84,17.77.HRMS(ESI,m/z)calculated for C 29H 35N 4NaO 5[M+Na] +541.2516,found 541.2519.
实施例15
Figure PCTCN2022141790-appb-000025
化合物15的合成参照化合物1进行制备；化合物15，白色固体(53mg，收率50％)。 1H HMR(300MHz,CDCl 3)δ8.57(d,J＝1.5Hz,1H),8.51(dd,J＝2.6,1.5Hz,1H),8.46(d,J＝2.6Hz,1H),6.19(d,J ＝1.4Hz,1H),5.95(d,J＝11.7Hz,1H),5.80(ddd,J＝10.2,6.2,2.1Hz,1H),5.59–5.53(m,2H),5.25–5.12(m,3H),4.89(d,J＝1.5Hz,1H),4.19(dd,J＝11.7,8.5Hz,1H),3.99(dd,J＝10.0,0.9Hz,1H),3.85(dd,J＝10.0,1.6Hz,1H),3.04(dd,J＝9.2,1.6Hz,1H),2.49(tq,J＝9.3,3.3,2.5Hz,1H),1.93(d,J＝2.6Hz,1H),1.90–1.84(m,1H),1.82(d,J＝5.3Hz,2H),1.72(d,J＝6.8Hz,1H),1.65–1.60(m,1H),1.58–1.51(m,2H),1.20(s,3H),1.07(s,3H). 13C NMR(75MHz,CDCl 3)δ205.92,152.75,151.50,144.10,143.71,143.43,130.74,124.61,121.22,116.43,101.56,78.10,65.65,62.96,62.04,57.66,52.44,42.69,41.03,38.72,32.40,30.83,29.82,21.83,17.76.HRMS(ESI,m/z)calculated for C 25H 30N 2NaO 5[M+Na] +461.2047,found 461.2041.
实施例16
Figure PCTCN2022141790-appb-000026
化合物16的合成参照化合物1进行制备；化合物16，白色固体(50mg，收率46％)。 1H HMR(400MHz,CDCl 3)δ7.84(s,1H),7.63(d,J＝1.1Hz,1H),6.19(d,J＝1.6Hz,1H),5.95(d,J＝11.7Hz,1H),5.81(ddd,J＝10.2,6.2,2.0Hz,1H),5.57(d,J＝1.2Hz,1H),5.24(dd,J＝10.2,2.9Hz,1H),4.94(d,J＝4.6Hz,2H),4.91–4.84(m,2H),4.18(dd,J＝11.7,8.5Hz,1H),4.01(d,J＝9.9Hz,1H),3.88(dd,J＝10.0,1.6Hz,1H),3.02(d,J＝9.2Hz,1H),2.49(ddd,J＝12.8,9.4,6.7Hz,1H),2.01–1.94(m,1H),1.85(dd,J＝17.0,6.0Hz,3H),1.68–1.53(m,3H),1.20(s,3H),1.08(s,3H). 13C NMR(101MHz,CDCl 3)δ205.88,151.49,151.42,136.83,136.21,130.66,124.64,121.12,101.55,71.82,69.56,65.55,62.83,57.68,56.07,52.41,42.52,41.04,38.64,32.38,30.81,29.77,21.82,17.76.HRMS(ESI,m/z)calculated for C 24H 29NNaO 6[M+Na] +450.1887,found 450.1890.
实施例17
Figure PCTCN2022141790-appb-000027
化合物17的合成参照化合物1进行制备；化合物17，白色固体(50mg，收率56％)。 1H HMR(400MHz,CDCl 3)δ7.85(d,J＝2.6Hz,1H),7.10(d,J＝2.6Hz,1H),6.20(t,J＝2.0Hz,1H),5.96(dd,J＝11.7,2.7Hz,1H),5.87–5.75(m,1H),5.61–5.53(m,1H),5.23(dt,J＝10.3,2.8Hz,1H),5.02(d,J＝2.7Hz,2H),4.84(t,J＝2.1Hz,1H),4.48(d,J＝2.9Hz,1H),4.17(ddd,J＝11.5,8.5,2.7Hz,1H),4.01(dd,J＝9.9,2.6Hz,1H),3.86(dt,J＝10.0,2.1Hz,1H),3.00(t,J＝7.5,3.8Hz,1H),2.48(d,J＝13.2,2.3Hz,1H),2.01–1.92(m,1H),1.88–1.77(m,3H),1.70–1.62(m,1H),1.61–1.46(m,2H),1.20(d,J＝2.6Hz,3H),1.07(d,J＝2.6Hz,3H). 13C NMR(101MHz,CDCl 3)δ205.49,151.64,151.27,147.88,130.81,125.82,124.46,121.38,101.93,71.79,69.51,65.63,62.77,57.50,54.38,52.42,42.44,41.00,38.63,32.38,30.79,29.70,21.80,17.76.HRMS(ESI,m/z)calculated for C 24H 29NNaO 6[M+Na] +450.1887,found 450.1880.
实施例18
Figure PCTCN2022141790-appb-000028
化合物18的合成参照化合物1进行制备；化合物18，白色固体(50mg，收率55％)。 1H HMR(300MHz,CDCl 3)δ6.20(s,1H),6.00(s,1H),5.92(d,J＝11.8Hz,1H),5.80(dd,J＝10.3,2.1Hz,1H),5.57(s,1H),5.22(dd,J＝10.1,2.8Hz,1H),5.00(d,J＝2.9Hz,2H),4.83(d,J＝1.5Hz,1H),4.69(s,1H),4.17(dd,J＝11.9,8.5Hz,1H),3.98(d,J＝9.9Hz,1H),3.82(dd,J＝9.9,1.6Hz,1H),3.02(s,1H),2.52–2.41(m,1H),2.36(s,3H),1.96(d,J＝17.5Hz,1H),1.87–1.77(m,3H),1.63–1.49(m,3H),1.19(s,3H),1.06(s,3H). 13C NMR(101MHz,CDCl 3)δ205.63,169.95,161.01,151.43,130.74,124.58,121.25,101.90,100.55,77.37,77.05,76.73,71.71,69.33,65.52,62.83,57.50,56.64,52.43,42.52,41.02,38.64,32.38,30.81,29.77,21.80,17.77,12.26.HRMS(ESI,m/z)calculated for C 25H 31NNaO 6[M+Na] +464.2044,found 464.2046.
实施例19
Figure PCTCN2022141790-appb-000029
化合物19的合成参照化合物1进行制备；化合物19，白色固体(50mg，收率43％)。 1H HMR(300MHz,CDCl 3)δ7.96(s,1H),6.22(s,1H),6.06(s,1H),5.84(dd,J＝10.1,6.5Hz,1H),5.61(s,1H),5.25(dd,J＝10.2,2.7Hz,1H),5.10(s,2H),4.85(s,1H),4.19(s,1H),4.00(d,J＝5.3Hz,4H),3.87(d,J＝10.0Hz,1H),3.46(s,1H),3.04(d,J＝9.2Hz,1H),2.50(q,J＝8.5,5.1Hz,1H),1.97(s,1H),1.87(dd,J＝16.9,5.7Hz,3H),1.71–1.50(m,3H),1.21(s,3H),1.10(s,3H). 13C NMR(101MHz,CDCl 3)δ205.79,151.23,131.91,130.85,124.32,121.50,101.91,71.67,69.67,65.71,62.98,57.63,56.80,52.49,42.57,40.94,38.66,33.66,32.38,30.76,29.73,21.82,17.75.HRMS(ESI,m/z)calculated for C 25H 31N 3NaO 7[M+Na] +508.2054,found 508.2055.
实施例20
Figure PCTCN2022141790-appb-000030
化合物20的合成参照化合物1进行制备；化合物20，白色固体(50mg，收率62％)。 1H HMR(300MHz,CDCl 3)δ8.76(s,1H),7.82(d,J＝0.9Hz,1H),6.23–6.15(m,1H),5.98(d,J＝11.8Hz,1H),5.80(ddd,J＝10.2,6.2,2.1Hz,1H),5.56(d,J＝1.3Hz,1H),5.27–5.09(m,3H),4.85–4.78(m,1H),4.43(s,1H),4.20(dd,J＝11.6,8.5Hz,1H),4.00(dd,J＝9.9,1.1Hz,1H),3.84(dd,J＝9.9,1.6Hz,1H),2.97(dd,J＝9.1,1.6Hz,1H),2.56–2.37(m,1H),2.01–1.90(m,1H),1.86(dd,J＝6.2,1.0Hz,1H),1.80(td,J＝5.2,4.6,2.2Hz,2H),1.70–1.61(m,1H),1.61–1.50(m,2H),1.19(s,3H),1.06(s,3H). 13C NMR(101MHz,CDCl 3)δ205.45,154.39,151.28,142.75,134.34,130.80,124.51,121.40,102.10,71.73,69.52,65.57,62.76,57.41,56.76,52.42,42.44,41.00,38.63,32.39,30.81,29.71,21.80,17.77.HRMS(ESI,m/z)calculated for C 24H 29NNaO 5S[M+Na] +466.1659,found 466.1662.
实施例21
Figure PCTCN2022141790-appb-000031
化合物21的合成参照化合物1进行制备；化合物21，白色固体(50mg，收率59％)。 1H HMR(300MHz,CDCl 3)δ7.73(d,J＝3.3Hz,1H),7.27(d,J＝3.2Hz,1H),6.21(s,1H),5.95(d,J＝11.8Hz,1H),5.86–5.74(m,1H),5.58(s,1H),5.27(d,J＝1.2Hz,2H),5.25–5.13(m,1H),4.95(s,1H),4.89(s,1H),4.18(dd,J＝11.8,8.6Hz,1H),4.00(d,J＝10.0Hz,1H),3.84(d,J＝9.9Hz,1H),3.03(d,J＝9.2Hz,1H),2.50(d,J＝14.3Hz,1H),1.96(d,J＝17.6Hz,1H),1.90–1.78(m,3H),1.65(s,1H),1.54(d,J＝8.7Hz,2H),1.19(s,3H),1.06(s,4H). 13C NMR(101MHz,CDCl 3)δ205.61,166.88,151.42,142.57,130.77,124.57,121.28,119.31,101.98,71.68,69.63,65.63,62.93,61.61,60.42,57.51,52.49,42.60,41.02,38.68,32.39,30.81,29.80,29.71,21.80,21.08,17.80,14.22.HRMS(ESI,m/z)calculated for C 24H 29NNaO 5S[M+Na] +466.1659,found 466.1663.
实施例22
Figure PCTCN2022141790-appb-000032
化合物22的合成参照化合物1进行制备；化合物22，白色固体(50mg，收率58％)。 1H HMR(400MHz,CDCl 3)δ6.41(s,1H),6.17(s,1H),5.99–5.74(m,2H),5.55(s,1H),5.35–5.04(m,2H),4.98–4.84(m,2H),4.76(d,J＝11.0Hz,1H),4.26–4.07(m,2H),3.98(d,J＝9.9Hz,1H),3.85(d,J＝10.0Hz,1H),3.77(q,J＝6.1,4.8Hz,4H),3.55–3.34(m,4H),3.01(d,J＝9.3Hz,1H),2.59–2.40(m,1H),2.05(d,J＝2.6Hz,1H),2.00–1.91(m,1H),1.88–1.78(m,3H),1.59–1.49(m,2H),1.26(q,J＝7.5,6.5Hz,3H),1.19(d,J＝6.1Hz,3H).HRMS(ESI,m/z)calculated for C 28H 36N 2NaO 6S[M+Na] +551.2186,found 551.2184.
实施例23
Figure PCTCN2022141790-appb-000033
化合物23的合成参照化合物1进行制备；化合物23，白色固体(50mg，收率46％)。 1H HMR(300MHz,CDCl 3)δ7.36–7.27(m,3H),7.22–7.15(m,3H),6.20(dd,J＝11.8,1.9Hz,2H),5.94(dd,J＝11.7,1.3Hz,1H),5.79(ddd,J＝10.3,6.2,2.1Hz,1H),5.55(d,J＝1.2Hz,1H),5.20(d,J＝24.2Hz,4H),5.00(q,J＝10.9Hz,2H),4.86(d,J＝1.5Hz,1H),4.19(dd,J＝11.7,8.5Hz,1H),3.99(d,J＝9.9Hz,1H),3.83(dd,J＝10.0,1.7Hz,1H),3.00(dd,J＝9.2,1.6Hz,1H),2.45(dt,J＝9.2,6.0Hz,1H),1.93(t,J＝2.5Hz,1H),1.85–1.79(m,3H),1.65–1.49(m,3H),1.19(s,3H),1.06(s,3H). 13C NMR(101MHz,CDCl 3)δ205.83,151.67,148.91,136.41,130.57,130.14,128.76,127.97,127.84,124.83,120.93,104.91,101.46,71.69,69.51,65.42,62.84,58.49,57.59,55.92,52.41,42.58,41.08,38.66,32.39,30.87,29.85,21.84,17.77.HRMS(ESI,m/z)calculated for C 31H 36N 2NaO 5[M+Na] +539.2516,found 539.2519.
实施例24
Figure PCTCN2022141790-appb-000034
化合物24的合成参照化合物1进行制备；化合物24，白色固体(51.2mg，收率56％)。 1H HMR(400MHz,DMSO-d6)δ5.96(dd,J＝8.2,1.7Hz,1H),5.85(dd,J＝3.3,2.0Hz,1H),5.64(dd,J＝3.3,2.0Hz,1H),5.47(m,1H),4.50(s,1H),4.40(d,J＝5.5Hz,1H),4.15(d,J＝4.9Hz,1H),4.09(d,J＝12.3Hz,1H),4.02(dd,J＝7.0,4.9Hz,1H),3.82(d,J＝12.4Hz,1H),3.61–3.46(m,2H),3.03–2.96(m,1H),2.63(t,J＝4.6Hz,1H),2.36(m,1H),1.85–1.46(m,14H),1.43–1.35(m,1H),1.35(m,1H),1.08(dd,J＝6.0,1.5Hz,6H)； 13C NMR(101MHz,CDCl 3)δ207.61,151.66,133.23,126.50,118.55,98.89,80.83,72.51,68.86,66.70,62.97,56.77,51.15,46.11,40.71,40.04,38.57,35.43,33.58,32.40,30.99,28.65,28.53,25.24,20.92；MS m/z＝443.3[M+H]。
实施例25
Figure PCTCN2022141790-appb-000035
将中间体1(，0.20mmol)溶于5mL无水DMF中，氩气保护。冰浴下分批加入NaH(5.3mg，0.22mmol)，自发升温至室温搅拌反应约2h，反应液明显变混浊，加入碘代底物(0.3mmol)，加热至40℃反应过夜。待反应完全后，大量水洗涤，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化，可得化合物25，白色固体(54.4mg，收率60％)。 1H HMR(300MHz,CDCl 3)δ6.19(d,J＝1.4Hz,1H),5.87(d,J＝11.6Hz,1H),5.77(ddd,J＝10.2,6.2,2.1Hz,1H),5.57(d,J＝1.3Hz,1H),5.30–5.15(m,2H),4.99(s,1H),4.97–4.93(m,1H),4.80(d,J＝1.5Hz,1H),4.10–4.05(m,1H),4.02–3.97(m,1H),3.97–3.87(m,6H),3.78(dd,J＝10.0,1.7Hz,1H),3.42–3.28(m,3H),3.06–2.98(m,1H),2.46(dq,J＝9.6,6.2,5.6Hz,1H),1.91(d,J＝2.7Hz,1H),1.83(d,J＝6.1Hz,1H),1.77(d,J＝5.2Hz,2H),1.68–1.58(m,5H),1.15(s,3H),1.13(s,1H),1.03(s,3H)； 13C NMR(101MHz,CDCl 3)δ205.82,151.43,130.62,124.67,121.21,101.59,71.93,69.22,67.96,67.92,65.33,62.62,59.57,57.61,52.26,42.45,41.04,38.47,36.55,32.92,32.78,32.36,31.86,30.82,29.77,21.81,17.75；MS m/z＝459.3[M+H]。
实施例26
Figure PCTCN2022141790-appb-000036
化合物26的合成参照化合物25进行制备；化合物26，白色固体(65.3mg，收率56％)。 1H HMR(300MHz,CDCl 3)δ6.19(s,1H),5.87(d,J＝11.7Hz,1H),5.78(ddd,J＝10.3,6.1,2.1Hz,1H),5.59(s,1H),5.19(dd,J＝10.2,2.8Hz,1H),4.83(s,2H),4.09(dd,J＝8.8,2.9Hz,1H),4.00(q,J＝7.0,5.3Hz,1H),3.95–3.87(m,2H),3.84–3.73(m,1H),3.12–2.85(m,6H),2.46(ddd,J＝12.3,9.4,4.4Hz,1H),2.21(d,J＝14.5Hz,1H),2.12(s,1H),1.91(s,1H),1.85–1.75(m,5H),1.63(ddd,J＝16.3,7.4,4.0Hz,7H),1.46(d,J＝8.4Hz,1H),1.14(s,3H),1.02(s,3H)； 13C NMR(75MHz,CDCl 3)δ207.61,151.66,133.23,126.50,118.55,98.89,80.83,72.51,68.87,66.70,62.97,56.77,51.89,51.15,46.11,40.71,40.04,35.09,33.59,30.99,30.92,28.76,28.65,28.53,20.92；MS m/z＝507.2[M+H]。
实施例27
Figure PCTCN2022141790-appb-000037
化合物27的合成参照化合物25进行制备；化合物27，白色固体(55.2mg，收率64％)。 1H HMR(300MHz,CDCl 3)δ5.96(dd,J＝8.1,1.7Hz,1H),5.85(dd,J＝3.3,2.0Hz,1H),5.64(dd,J＝3.3,2.0Hz,1H),5.47(m,1H),4.50(s,1H),4.40(d,J＝5.5Hz,1H),4.15(d,J＝4.9Hz,1H),4.09(d,J＝12.3Hz,1H),4.02(dd,J＝7.0,4.9Hz,1H),3.82(d,J＝12.5Hz,1H),3.77(m,2H),3.57(m,1H),3.50(m,1H),3.03–2.96(m,1H),2.63(t,J＝4.6Hz,1H),2.36(m,1H),1.90–1.76(m,2H),1.79–1.71(m,5H),1.75–1.67(m,1H),1.70–1.60(m,2H),1.63–1.56(m,1H),1.59–1.52(m,1H),1.49(m,2H),1.18(d,J＝5.3Hz,6H),1.08(dd,J＝6.0,1.5Hz,6H)； 13C NMR(75MHz,CDCl 3)δ207.61,151.66,133.23,126.50,118.55,98.89,80.83,72.51,70.33,68.93,66.70,62.97,56.77,51.15,46.11,40.71,40.04,39.06,36.26,33.58,31.68,30.99,28.65,28.53,20.99,20.92；MS m/z＝587.3[M+H]。
实施例28
Figure PCTCN2022141790-appb-000038
化合物28的合成参照化合物25进行制备；化合物28，白色固体(71mg，收率79％)。 1H HMR(300MHz,CDCl 3)δ6.17(d,J＝1.5Hz,1H),5.89(dd,J＝11.6,3.0Hz,1H),5.75(ddd,J＝10.3,6.2,2.1Hz,1H),5.55(d,J＝1.2Hz,1H),5.17(dd,J＝10.2,2.8Hz,1H),4.93(d,J＝2.9Hz,1H),4.78(d,J＝1.5Hz,1H),4.07(dd,J＝11.7,8.4Hz,1H),3.89(ddq,J＝9.8,7.5,3.8,2.7Hz,5H),3.81–3.65(m,3H),3.30(dt,J＝10.4,7.8Hz,1H),2.98(dd,J＝9.3,1.6Hz,1H),2.51–2.39(m,1H),2.22(td,J＝7.4,2.8Hz,1H),2.13–1.99(m,2H),1.96–1.87(m,1H),1.82–1.69(m,4H),1.56–1.43(m,3H),1.34(dd,J＝9.2,5.5Hz,1H),1.13(s,3H),1.01(s,3H)； 13C NMR(75MHz,CDCl 3)δ205.85,151.36,130.65,124.61,121.32,101.63,77.54,77.11,76.69,73.22,73.10,71.95,69.16,67.94,67.84,65.35,62.62,61.37,61.28,57.58,52.26,42.40,41.01,38.44,36.33,36.24,33.05,32.40,32.34,32.21,30.80,29.72,21.80,17.73；MS m/z＝445.3[M+H]。
实施例29
Figure PCTCN2022141790-appb-000039
化合物29的合成参照化合物25进行制备；化合物29，白色固体(66mg，收率70％)。 1H HMR(300MHz,CDCl 3)δ5.96(dd,J＝8.2,1.7Hz,1H),5.85(dd,J＝3.3,2.0Hz,1H),5.64(dd,J＝3.3,2.0Hz,1H),5.47(m,1H),4.50(s,1H),4.40(d,J＝5.5Hz,1H),4.15(d,J＝4.9Hz,1H),4.09(d,J＝12.3Hz,1H),4.02(dd,J＝7.0,4.9Hz,1H),3.82(d,J＝12.4Hz,1H),3.64–3.57(m,1H),3.57–3.49(m,1H),3.03–2.96(m,1H),2.99–2.86(m,2H),2.72–2.66(m,1H),2.63(t,J＝4.6Hz,1H),2.61–2.54(m,1H),2.36(m,1H),2.10–2.00(m,1H),1.94(m,1H),1.88–1.62(m,9H),1.56(m,1H),1.09(dd,J＝3.8,1.5Hz,6H)； 13C NMR(75MHz,CDCl 3)δ207.61,151.66,133.23,126.50,118.55,98.89,80.83,72.51,68.86,66.70,62.97,56.77,51.15,46.11,41.60,40.71,40.04,38.62,35.55,34.27,33.59,31.36,30.99,28.65, 28.53,20.92；MS m/z＝461.2[M+H]。
实施例30
Figure PCTCN2022141790-appb-000040
化合物30的合成参照化合物25进行制备；化合物30，白色固体(65.2mg，收率69％)。 1H HMR(300MHz,CDCl 3)δ8.50–8.46(m,2H),7.15–7.10(m,2H),5.96(dd,J＝8.1,1.7Hz,1H),5.85(dd,J＝3.3,2.0Hz,1H),5.64(dd,J＝3.3,2.0Hz,1H),5.47(m,1H),4.50(s,1H),4.39(d,J＝5.5Hz,1H),4.15(d,J＝4.9Hz,1H),4.09(d,J＝12.3Hz,1H),4.01(dd,J＝7.1,5.0Hz,1H),3.82(d,J＝12.4Hz,1H),3.60–3.47(m,2H),3.03–2.96(m,1H),2.74–2.66(m,1H),2.68–2.60(m,2H),2.36(m,1H),1.91–1.62(m,8H),1.56(m,1H),1.08(dd,J＝6.0,1.5Hz,6H)； 13C NMR(75MHz,CDCl 3)δ207.61,151.66,150.93,149.26,133.23,126.50,123.39,118.55,98.89,80.85,72.51,69.45,66.70,62.97,56.77,51.15,46.11,40.71,40.04,33.58,32.48,30.99,30.81,28.65,28.53,20.92；LCMS m/z＝466.3[M+H]。
实施例31
Figure PCTCN2022141790-appb-000041
化合物31的合成参照化合物25进行制备；化合物31，白色固体(66.6mg，收率68％)。 1H HMR(300MHz,CDCl 3)δ8.93(t,J＝1.6Hz,1H),8.58(dd,J＝4.4,1.6Hz,1H),7.00(dd,J＝4.4,1.6Hz,1H),5.96(dd,J＝8.1,1.7Hz,1H),5.85(dd,J＝3.3,2.0Hz,1H),5.64(dd,J＝3.3,2.0Hz,1H),5.47(m,1H),4.50(s,1H),4.39(d,J＝5.5Hz,1H),4.15(d,J＝4.9Hz,1H),4.09(d,J＝12.3Hz,1H),4.01(dd,J＝7.1,5.0Hz,1H),3.82(d,J＝12.4Hz,1H),3.64(m,1H),3.55(m,1H),3.03–2.96(m,1H),2.83–2.68(m,2H),2.63(t,J＝4.6Hz,1H),2.36(m,1H),1.98(m,2H),1.85–1.62(m,5H),1.56(m,1H),1.08(dd,J＝6.0,1.5Hz,6H)； 13C NMR(75MHz,CDCl 3)δ207.61,163.65,159.65,157.16,151.66,133.23,126.50,119.03,118.55,98.89,80.97,72.51,69.38,66.70,62.97,56.77,51.15,46.10,40.71,40.04,34.52,33.58,30.99,29.12,28.65,28.53,20.92；MS m/z＝467.3[M+H]。
实施例32
Figure PCTCN2022141790-appb-000042
化合物32的合成参照化合物25进行制备；化合物32，白色固体(79.5mg，收率82％)。 1H HMR(400MHz,CDCl 3)δ7.29–7.25(m,2H),7.19(d,J＝7.0Hz,3H),6.23(d,J＝1.4Hz,1H),5.80(ddd,J＝10.2,6.2,2.0Hz,1H),5.61(d,J＝1.2Hz,1H),5.23(dd,J＝10.2,2.9Hz,1H),5.08(s,1H),4.86(d,J＝1.5Hz,1H),4.12(dd,J＝11.7,8.5Hz,1H),4.07–3.98(m,1H),3.95(td,J＝7.4,6.4,1.8Hz,2H),3.82(dd,J＝10.0,1.6Hz,1H),3.05(dd,J＝9.1,1.6Hz,1H),2.74–2.64(m,2H),2.49(ddd,J＝13.0,9.2,6.8Hz,1H),2.00–1.90(m,3H),1.87–1.84(m,1H),1.79(d,J＝13.1Hz,1H),1.69–1.59(m,3H),1.51(dd,J＝8.5,1.6Hz,1H),1.19(s,3H),1.05(s,3H)； 13C NMR(101MHz,CDCl 3)δ205.85,151.52,141.64,130.62,128.47,128.35,125.82,124.73,121.18,101.73,71.95,69.22,65.34,62.68,61.98,57.62,52.33, 42.48,41.07,38.50,32.42,32.38,31.68,30.83,29.79,21.82,17.78；MS m/z＝465.3[M+H]。
实施例33
Figure PCTCN2022141790-appb-000043
化合物33的合成参照化合物25进行制备；化合物33，白色固体(63.0mg，收率72％)。 1H HMR(400MHz,CDCl 3)δ7.29(t,J＝1.6Hz,1H),6.18(dd,J＝4.8,1.6Hz,1H),6.03(dd,J＝4.9,1.6Hz,1H),5.96(dd,J＝8.1,1.7Hz,1H),5.75(dd,J＝3.3,2.0Hz,1H),5.66(dd,J＝3.3,2.0Hz,1H),5.47(m,1H),4.50(s,1H),4.39(d,J＝5.7Hz,1H),4.15(d,J＝4.9Hz,1H),4.09(d,J＝12.3Hz,1H),4.02(dd,J＝7.0,4.9Hz,1H),3.82(d,J＝12.4Hz,1H),3.62–3.47(m,2H),3.03–2.96(m,1H),2.86–2.70(m,2H),2.63(t,J＝4.6Hz,1H),2.36(m,1H),1.91(m,2H),1.85–1.77(m,1H),1.77(s,1H),1.77–1.62(m,2H),1.56(m,1H),1.08(dd,J＝6.0,1.5Hz,6H)； 13C NMR(75MHz,CDCl 3)δ207.61,155.60,151.66,141.57,133.23,126.50,118.55,110.07,107.40,98.89,81.15,72.51,69.27,66.70,62.97,56.77,51.15,46.10,40.71,40.04,33.58,30.99,28.65,28.53,27.68,26.54,20.92；MS m/z＝455.2[M+H]。
实施例34
Figure PCTCN2022141790-appb-000044
化合物34的合成参照化合物25进行制备；化合物34，白色固体(77.3mg，收率80％)。 1H HMR(300MHz,CDCl 3)δ8.88(dd,J＝4.1,2.3Hz,1H),8.63(dd,J＝7.9,2.4Hz,1H),7.89(dd,J＝7.6,1.4Hz,1H),7.48(dd,J＝7.7,4.2Hz,1H),7.42(dd,J＝8.2,7.6Hz,1H),7.30–7.24(m,1H),5.96(dd,J＝8.1,1.7Hz,1H),5.75(dd,J＝3.3,1.8Hz,1H),5.65(dd,J＝3.3,2.0Hz,1H),5.47(m,1H),4.50(s,1H),4.39(d,J＝5.7Hz,1H),4.15(d,J＝4.9Hz,1H),4.09(d,J＝12.3Hz,1H),4.01(dd,J＝7.1,5.0Hz,1H),3.82(d,J＝12.4Hz,1H),3.60(m,1H),3.53(m,1H),3.03–2.96(m,1H),2.87–2.70(m,2H),2.63(t,J＝4.6Hz,1H),2.36(m,1H),1.93–1.62(m,8H),1.56(m,1H),1.08(dd,J＝6.0,1.5Hz,6H)； 13C NMR(75MHz,CDCl 3)δ207.61,151.66,149.57,149.40,138.03,133.23,130.68,130.63,128.75,128.32,127.21,126.50,122.11,118.55,98.89,80.85,72.51,69.41,66.70,62.97,56.77,51.15,46.11,40.71,40.04,33.58,30.99,30.53,29.77,28.65,28.53,20.92；MS m/z＝516.3[M+H]。
实施例35
Figure PCTCN2022141790-appb-000045
第一步：将3-碘代丙醇(b-1，10.0g，53.8mmol)与咪唑(5.5g，80.6mmol)溶于100mL干燥的DCM中，冰浴下加入叔丁基二甲基氯硅烷(8.9g，59.1mmol)，随后转入室温下反应，约0.5h反应完全。反应液用饱和氯化铵洗涤，DCM萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂、制砂，硅胶柱层析纯化，收无色油状产物b-2(15.5g，收率96％)。
第二步：将中间体1(3.1g，9.0mmol)溶于60mL无水DMF中，氩气保护。冰浴下分批加入 NaH(0.4g，10.8mmol)，自发升温至室温搅拌反应约2h，反应液明显变混浊，加入b-2(10.8mmol)，加热至40℃反应约2d。待反应完全后，大量水洗涤，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化，收产物b-3(3.2g，收率68％)。
第三步：将上一步产物b-3(3.2g，6.2mmol)加入40mL AcOH：H 2O：THF＝13:7:3的混合溶液中，于室温下反应约4h。完全反应后用饱和碳酸氢钠水溶液中和反应液中的乙酸，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化。得固体产物35(2.3g，92％)。 1H HMR(400MHz,CDCl 3)δ6.21–6.19(m,1H),6.17(d,J＝11.7Hz,1H),5.78(ddd,J＝10.2,6.3,2.0Hz,1H),5.59(d,J＝1.2Hz,1H),5.19(dd,J＝10.2,2.9Hz,1H),5.00–4.84(m,1H),4.80(d,J＝1.5Hz,1H),4.23(dd,J＝11.8,8.6Hz,1H),4.12–4.04(m,1H),3.94(dd,J＝9.9,1.1Hz,1H),3.86(dt,J＝9.3,4.5Hz,1H),3.78(dd,J＝10.0,1.7Hz,1H),3.76–3.68(m,1H),3.61(dt,J＝11.6,4.7Hz,1H),3.00(dd,J＝9.1,1.7Hz,1H),2.46(ddd,J＝12.9,9.2,6.7Hz,1H),1.93(dt,J＝17.4,2.7Hz,1H),1.85–1.81(m,1H),1.81–1.74(m,3H),1.74–1.56(m,3H),1.54(q,J＝4.0,3.3Hz,1H),1.47(dd,J＝8.6,1.6Hz,1H),1.14(s,3H),1.02(s,3H). 13C NMR(101MHz,CDCl 3)δ205.98,151.33,130.76,124.51,121.52,101.74,71.81,68.48,65.40,62.69,58.29,57.85,57.16,52.33,42.46,40.96,38.40,32.38,31.71,30.78,29.74,29.72,21.75,17.76.MS m/z＝403.2121[M-1]。
实施例36
Figure PCTCN2022141790-appb-000046
将底物化合物35(2.3g，5.7mmol)与碳酸氢钠(2.4g，28.7mmol)加入到50mL干燥的DCM中，氩气保护，冰浴下加入DMP(3.2g，7.5mmol),随后自发升温至室温下反应约2h。反应完全后，加大量水洗涤，DCM萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，硅胶柱层析纯化，收产物化合物36(1.9g，收率82％)。 1H HMR(300MHz,CDCl 3)δ9.69(t,J＝6.2Hz,1H),5.98(ddd,J＝10.0,2.0,1.0Hz,2H),5.71(dt,J＝10.9,1.8Hz,1H),5.57(dt,J＝11.0,6.9Hz,1H),4.89(s,1H),4.45(dd,J＝7.0,3.7Hz,1H),4.29(d,J＝8.1Hz,1H),4.01–3.86(m,2H),3.79–3.63(m,3H),3.07(qt,J＝7.0,1.0Hz,1H),2.98–2.84(m,1H),2.51(ddt,J＝7.1,6.3,3.0Hz,2H),2.17(ddd,J＝7.0,2.5,1.8Hz,1H),2.10–1.97(m,1H),2.00(s,1H),2.02–1.85(m,2H),1.85–1.58(m,3H),1.06(s,3H),1.00(s,3H). 13C NMR(75MHz,CDCl 3)δ207.22,200.56,151.39,132.27,126.60,118.73,98.41,79.97,73.05,68.36,64.32,62.88,56.59,48.63,45.08,42.22,41.62,40.55,33.30,30.27,28.04,27.62,19.12.MS m/z＝403.2045[M+H]。
实施例37
Figure PCTCN2022141790-appb-000047
将亚氯酸钠(0.9g，9.9mmol)和氨基磺酸(1.3g，13.2mmol)的冰水溶液(20mL)缓慢滴加到化合物36(1.9g，4.7mmol)的丙酮(20mL)溶液，室温搅拌约2h反应完全。蒸出丙酮后有白色固体析出，抽滤，乙醚洗涤，即得产物化合物37(1.2g，61％)。 1H HMR(400MHz,DMSO-d 6)δ12.28(s,1H),6.03(s,1H),5.76(ddd,J＝10.2,6.3,1.9Hz,1H),5.63(s,1H),5.61(d,J＝11.4Hz,1H), 5.25(dd,J＝10.2,2.8Hz,1H),4.69(s,1H),4.45(s,1H),4.05(dd,J＝11.4,8.4Hz,1H),3.96(ddt,J＝15.0,9.7,5.2Hz,2H),3.81(q,J＝9.9Hz,2H),2.86(d,J＝9.1Hz,1H),2.49–2.31(m,3H),1.96–1.72(m,3H),1.64(dd,J＝13.7,4.7Hz,1H),1.58–1.40(m,2H),1.36(d,J＝8.3Hz,1H),1.07(s,3H),0.99(s,3H). 13C NMR(101MHz,DMSO-d 6)δ206.73,173.33,152.37,130.33,125.41,121.21,101.57,71.66,68.50,64.98,62.87,58.43,57.55,52.49,42.58,40.91,40.59,40.38,40.17,39.96,39.76,39.55,39.34,38.40,35.18,32.47,31.11,29.90,21.93,17.68.MS m/z＝417.1913[M+H].
实施例38
Figure PCTCN2022141790-appb-000048
将化合物37(50mg，0.11mmol)溶解于干燥的THF中，氩气保护，冰浴下加入HATU(68.14mg，0.18mmol)后搅拌约5min，加入甲胺(6.37μL，0.14mmol)，冰浴下继续搅拌约15min，随后在冰浴下加入DIPEA(30.88mg，0.24mmol)。自发升温至室温下反应。约1～2h反应完全。加水，EA萃取三次，合并有机相后饱和氯化钠洗涤，干燥，减压蒸去溶剂，硅胶柱层析纯化可得相应化合物38(29mg，收率58％)。 1H HMR(400MHz,CDCl 3)δ6.70(d,J＝5.6Hz,1H),6.54(d,J＝13.1Hz,1H),6.17(d,J＝1.5Hz,1H),5.97(d,J＝11.8Hz,1H),5.77(ddd,J＝10.2,6.2,2.1Hz,1H),5.57(d,J＝1.3Hz,1H),5.19(dd,J＝10.3,2.9Hz,1H),4.77(d,J＝1.5Hz,1H),4.63–4.48(m,1H),4.16–4.07(m,3H),3.93(d,J＝10.1Hz,1H),3.79(dd,J＝10.0,1.6Hz,1H),3.70(pd,J＝6.7,4.2Hz,2H),3.18(qd,J＝7.4,4.3Hz,2H),3.02–2.90(m,4H),2.74(d,J＝4.8Hz,3H),2.62–2.38(m,4H),1.92(dt,J＝17.2,2.4Hz,2H),1.84–1.73(m,3H),1.66–1.52(m,3H),1.14(s,4H),1.02(s,4H). 13C NMR(101MHz,CDCl 3)δ206.12,171.29,151.36,130.75,124.43,121.52,101.67,71.81,68.77,65.45,62.80,58.30,57.40,55.53,52.43,43.52,42.42,40.94,38.43,36.41,32.35,30.77,29.72,26.30,21.75,18.54,17.74,17.07,12.70.MS m/z＝432.2310[M+H]。
实施例39
Figure PCTCN2022141790-appb-000049
化合物39的合成参照化合物38进行制备；化合物39，白色固体(35mg，收率67％)。 1H HMR(300MHz,CDCl 3)δ6.12(s,1H),5.82(d,J＝11.5Hz,1H),5.73(ddt,J＝10.1,6.4,1.9Hz,1H),5.50(s,1H),5.22–5.10(m,1H),4.79(d,J＝2.0Hz,1H),4.22–4.09(m,2H),4.09–3.98(m,1H),3.96–3.68(m,2H),2.95(d,J＝9.3Hz,1H),2.89(dd,J＝13.6,1.7Hz,6H),2.74–2.34(m,4H),1.96–1.84(m,1H),1.82–1.76(m,1H),1.73(d,J＝5.9Hz,2H),1.66–1.53(m,1H),1.55–1.44(m,1H),1.42(d,J＝8.5Hz,1H),1.11(d,J＝1.9Hz,3H),0.99(d,J＝1.8Hz,3H). 13C NMR(101MHz,CDCl 3)δ206.19,170.66,151.72,130.49,124.81,120.83,101.36,77.40,71.73,68.58,65.29,62.84,58.28,57.62,52.39,42.54,41.06,38.41,37.16,35.30,33.26,32.38,30.77,30.19,29.84,29.69,21.76,17.75.MS m/z＝446.2470[M+H]。
实施例40
Figure PCTCN2022141790-appb-000050
化合物40的合成参照化合物38进行制备；化合物40，白色固体(39mg，收率71％)。 1H HMR(400MHz,CDCl 3)δ6.51(t,J＝5.9Hz,1H),6.16(d,J＝1.4Hz,1H),5.96(d,J＝11.8Hz,1H),5.78(ddd,J＝10.2,6.2,2.0Hz,1H),5.56(d,J＝1.2Hz,1H),5.19(dd,J＝10.2,2.8Hz,1H),4.78(d,J＝1.7Hz,1H),4.58(s,1H),4.13(dd,J＝8.1,3.9Hz,3H),3.94(dd,J＝10.0,1.1Hz,1H),3.78(dd,J＝10.0,1.6Hz,1H),3.09–2.96(m,3H),2.60–2.38(m,3H),1.93(dt,J＝17.4,2.6Hz,2H),1.86–1.82(m,1H),1.80–1.71(m,3H),1.65–1.52(m,2H),1.46(dd,J＝8.5,1.6Hz,1H),1.28–1.20(m,1H),1.14(s,3H),1.02(s,3H),0.86(dd,J＝6.7,5.1Hz,6H). 13C NMR(101MHz,CDCl 3)δ205.92,170.42,151.39,130.74,124.50,121.35,101.72,71.76,68.89,65.42,62.77,58.41,57.36,52.46,46.98,42.40,40.97,38.48,36.64,32.36,30.77,29.70,28.29,21.77,20.22,20.19,17.76.MS m/z＝458.2634[M-H]。
实施例41
Figure PCTCN2022141790-appb-000051
化合物41的合成参照化合物38进行制备；化合物41，白色固体(36mg，收率67％)。 1H HMR(300MHz,CDCl 3)δ6.78(s,1H),6.17(s,1H),5.94(d,J＝11.8Hz,1H),5.76(ddd,J＝10.2,6.1,2.1Hz,1H),5.56(s,1H),5.17(dd,J＝10.2,2.8Hz,1H),4.75(d,J＝1.5Hz,1H),4.49(s,1H),4.10–4.03(m,3H),3.91(d,J＝10.0Hz,1H),3.77(dd,J＝10.0,1.6Hz,1H),2.98(d,J＝9.2Hz,1H),2.69(dt,J＝7.2,3.6Hz,1H),2.47(q,J＝5.3Hz,3H),1.95–1.88(m,1H),1.82(d,J＝6.1Hz,1H),1.75(dd,J＝6.5,4.0Hz,2H),1.65–1.51(m,2H),1.44(d,J＝8.5Hz,1H),1.13(s,4H),1.00(s,4H),0.73–0.64(m,2H),0.53–0.41(m,2H). 13C NMR(101MHz,CDCl 3)δ205.99,171.78,151.34,130.75,124.43,121.45,101.69,71.76,68.85,65.42,62.75,58.27,57.41,52.43,42.40,40.96,38.46,36.47,32.35,30.75,29.69,22.63,21.75,17.74,6.19,6.00.MS m/z＝458.2428[M+H]。
实施例42
Figure PCTCN2022141790-appb-000052
化合物42的合成参照化合物38进行制备；化合物42，白色固体(38mg，收率64％)。 1H HMR(300MHz,CDCl 3)δ6.36(d,J＝8.1Hz,1H),6.19(d,J＝1.4Hz,1H),5.99(d,J＝11.8Hz,1H),5.80(ddd,J＝10.2,6.1,2.1Hz,1H),5.58(d,J＝1.3Hz,1H),5.22(dd,J＝10.2,2.8Hz,1H),4.80(d,J＝1.4Hz,1H),4.58(s,1H),4.22–4.07(m,4H),3.96(dd,J＝10.0,1.0Hz,1H),3.77(ddd,J＝23.4,8.6,2.6Hz,3H),3.02(dd,J＝9.1,1.6Hz,1H),2.58–2.40(m,4H),1.95(dt,J＝17.6,2.6Hz,2H),1.89–1.76(m,6H),1.74–1.53(m,7H),1.49(dd,J＝8.5,1.5Hz,1H),1.33(ddt,J＝11.6,6.1,3.2Hz,2H),1.17(s,3H),1.15–1.08(m,2H),1.04(s,4H). 13C NMR(101MHz,CDCl 3)δ205.92,169.36,151.44,130.74,124.51,121.31, 101.71,71.76,69.01,65.40,62.76,58.34,57.42,52.45,48.35,42.41,40.99,38.50,36.72,32.91,32.80,32.37,30.80,29.71,29.69,25.60,25.06,21.78,17.76.MS m/z＝500.2944[M+H]。
实施例43
Figure PCTCN2022141790-appb-000053
化合物43的合成参照化合物38进行制备；化合物43，白色固体(44mg，收率79％)。 1H HMR(300MHz,CDCl 3)δ6.12(s,1H),5.83(d,J＝11.5Hz,1H),5.78–5.67(m,1H),5.50(s,1H),5.16(dd,J＝10.4,2.8Hz,1H),4.78(s,1H),4.15(ddd,J＝10.8,6.4,2.7Hz,2H),4.06(ddd,J＝11.2,5.2,3.2Hz,2H),3.89(d,J＝10.0Hz,1H),3.76(d,J＝10.0Hz,1H),3.35(dt,J＝17.9,6.7Hz,4H),2.95(d,J＝9.2Hz,1H),2.65–2.53(m,1H),2.44(ddd,J＝22.0,11.7,6.2Hz,2H),1.93–1.72(m,9H),1.55(td,J＝13.0,11.7,8.1Hz,3H),1.44–1.23(m,4H),1.11(d,J＝1.6Hz,3H),0.99(s,3H). 13C NMR(101MHz,CDCl 3)δ206.24,169.28,151.77,130.48,124.80,120.77,101.35,71.72,68.59,65.28,62.85,58.21,57.63,52.39,46.66,45.63,42.53,41.05,38.40,34.67,32.37,30.76,29.83,25.97,24.32,21.75,17.74.MS m/z＝484.2630[M+H3]。
实施例44
Figure PCTCN2022141790-appb-000054
化合物44的合成参照化合物38进行制备；化合物44，白色固体(43mg，收率71％)。 1H HMR(300MHz,CDCl 3)δ6.46(d,J＝8.1Hz,1H),6.20(s,1H),6.00(d,J＝11.8Hz,1H),5.81(ddd,J＝10.3,6.1,2.1Hz,1H),5.60(s,1H),5.23(dd,J＝10.2,2.7Hz,1H),4.82(s,1H),4.60(s,1H),4.14(td,J＝8.2,4.5Hz,4H),4.01–3.87(m,2H),3.82(dd,J＝9.9,1.5Hz,1H),3.04(d,J＝9.1Hz,1H),2.51(t,J＝11.0,5.6Hz,4H),2.03–1.75(m,8H),1.73–1.34(m,18H),1.19(s,4H),1.06(s,4H). 13C NMR(101MHz,CDCl 3)δ205.90,169.03,151.47,130.71,124.51,121.22,101.71,71.75,69.02,65.39,62.76,58.38,57.44,52.47,50.47,42.42,41.00,38.50,36.74,34.89,34.78,32.35,30.78,29.69,28.18,28.15,24.12,24.08,21.77,17.75.MS m/z＝526.3097[M+H3]。
实施例45
Figure PCTCN2022141790-appb-000055
化合物45的合成参照化合物38进行制备；化合物45，白色固体(39mg，收率67％)。 1H HMR(300MHz,CDCl 3)δ6.18(s,1H),5.89(dd,J＝11.6,1.4Hz,1H),5.79(ddd,J＝10.3,6.1,2.0Hz,1H),5.57(s,1H),5.21(dd,J＝10.2,2.7Hz,1H),4.91–4.81(m,2H),4.27–4.05(m,3H),3.99–3.76(m,2H),3.67–3.58(m,6H),3.48–3.38(m,2H),3.05–2.95(m,1H),2.79–2.37(m,3H),1.95(d,J＝17.6Hz,1H),1.88–1.71(m,3H),1.67–1.52(m,2H),1.50–1.42(m,1H),1.16(d,J＝1.6Hz,3H),1.04(s,3H). 13C NMR(101MHz,CDCl 3)δ206.20,169.40,151.64,130.56,124.71,120.99,101.49,77.40,77.08, 76.76,71.76,68.61,66.78,66.48,65.33,62.83,58.25,57.61,52.38,45.89,42.52,41.87,41.03,38.41,33.00,32.38,30.76,29.79,21.76,17.74.MS m/z＝480.2576[M+H]。
实施例46
Figure PCTCN2022141790-appb-000056
化合物46的合成参照化合物38进行制备；化合物46，白色固体(27mg，收率47％)。 1H HMR(300MHz,CDCl 3)δ6.54(s,1H),6.16(s,1H),5.92(d,J＝11.7Hz,1H),5.77(ddd,J＝10.2,6.1,2.1Hz,1H),5.55(s,1H),5.19(dd,J＝10.3,2.7Hz,1H),4.80(t,J＝1.8Hz,1H),4.69(s,1H),4.12(ddt,J＝10.7,8.2,4.0Hz,4H),3.98–3.67(m,6H),3.51(td,J＝6.2,5.2,2.8Hz,1H),3.14(dddd,J＝16.3,13.5,7.2,4.8Hz,1H),2.99(d,J＝9.1Hz,1H),2.59–2.36(m,4H),2.03(s,1H),1.99–1.86(m,5H),1.81(ddd,J＝20.6,7.4,2.8Hz,5H),1.71–1.52(m,3H),1.52–1.38(m,3H),1.15(s,4H),1.02(s,4H). 13C NMR(101MHz,CDCl 3)δ205.82,170.71,151.56,130.66,124.63,121.11,101.66,71.68,68.92,68.00,65.37,62.77,60.41,58.45,57.36,52.45,43.19,42.48,41.02,38.50,36.61,32.36,30.78,29.79,28.68,25.74,21.76,17.76.MS m/z＝500.2730[M-1]。
实施例47
Figure PCTCN2022141790-appb-000057
化合物47的合成参照化合物38进行制备；化合物47，白色固体(35mg，收率57％)。 1H HMR(300MHz,CDCl 3)δ6.18(s,1H),5.95(d,J＝11.8Hz,1H),5.78(qd,J＝6.2,2.2Hz,2H),5.57(s,1H),5.20(dd,J＝10.2,2.8Hz,1H),4.80(d,J＝1.4Hz,1H),4.58(s,1H),4.10(tt,J＝8.8,4.6Hz,4H),3.94(d,J＝9.9Hz,1H),3.78(dd,J＝9.9,1.6Hz,1H),3.02(d,J＝9.2Hz,1H),2.55–2.33(m,3H),2.09–1.95(m,10H),1.87–1.72(m,5H),1.64(d,J＝3.2Hz,8H),1.60–1.52(m,2H),1.47(d,J＝8.5Hz,1H),1.43–1.32(m,2H),1.15(s,3H),1.03(s,3H). 13C NMR(101MHz,CDCl 3)δ205.91,169.48,151.56,130.68,124.60,121.13,101.71,71.79,69.11,65.34,62.78,58.69,57.51,52.48,52.03,42.45,41.28,41.03,38.53,37.84,36.39,32.37,30.81,29.72,29.47,21.79,17.77.MS m/z＝526.3095[M+H]。
实施例48
Figure PCTCN2022141790-appb-000058
化合物48的合成参照化合物38进行制备；化合物48，白色固体(25mg，收率42％)。 1H HMR(400MHz,CDCl 3)δ6.62(d,J＝7.5Hz,1H),6.19(d,J＝4.0Hz,1H),6.00(d,J＝11.7Hz,1H),5.80(ddd,J＝10.4,6.4,3.7Hz,1H),5.63–5.50(m,1H),5.20(dt,J＝9.8,3.3Hz,1H),4.78(d,J＝4.0Hz,1H),4.18–4.05(m,3H),3.94(tt,J＝8.6,4.1Hz,4H),3.88–3.77(m,1H),3.45(dddt,J＝12.4,9.6,6.4,3.5Hz,2H),3.00(d,J＝8.9Hz,1H),2.57–2.40(m,3H),1.95(d,J＝17.7Hz,1H),1.87–1.76(m,5H),1.65(d,J＝14.6Hz,1H),1.58–1.45(m,4H),1.19–1.12(m,3H),1.06–0.99(m,3H). 13C NMR(101MHz, CDCl 3)δ205.89,169.71,151.33,130.82,124.39,121.52,101.79,71.81,68.98,67.01,66.95,65.48,62.75,58.16,57.41,52.44,45.78,42.41,40.97,38.50,36.63,32.85,32.65,32.37,30.79,29.67,21.78,17.76.MS m/z＝502.2731[M+H]。
实施例49
Figure PCTCN2022141790-appb-000059
化合物49的合成参照化合物38进行制备；化合物49，白色固体(28mg，收率42％)。 1H HMR(400MHz,CDCl 3)δ7.09(t,J＝5.7Hz,1H),7.07–6.98(m,2H),6.92(td,J＝8.5,2.6Hz,1H),6.14(d,J＝1.4Hz,1H),5.92(d,J＝11.9Hz,1H),5.77(ddd,J＝10.2,6.2,2.1Hz,1H),5.56(s,1H),5.18(dd,J＝10.2,2.9Hz,1H),4.65(d,J＝1.5Hz,1H),4.53(s,1H),4.48–4.31(m,2H),4.18–4.06(m,3H),3.91(d,J＝10.0Hz,1H),3.71(dd,J＝10.0,1.6Hz,1H),2.97(d,J＝9.2Hz,1H),2.64–2.49(m,2H),2.42(ddt,J＝12.0,8.7,4.2Hz,1H),1.91(dt,J＝17.6,2.5Hz,2H),1.82(d,J＝6.2Hz,1H),1.72(d,J＝4.4Hz,2H),1.69–1.56(m,2H),1.56–1.48(m,1H),1.43(dd,J＝8.5,1.5Hz,1H),1.12(s,3H),1.01(s,3H). 13C NMR(101MHz,CDCl 3)δ205.81,170.44,164.16,161.71,151.27,140.91,140.84,130.76,130.01,129.93,124.42,123.67,123.64,121.49,115.02,114.80,114.17,113.96,101.79,77.38,77.26,77.06,76.74,71.69,68.89,65.40,62.73,58.29,57.29,52.41,43.10,43.08,42.38,40.95,38.62,38.47,36.49,32.33,30.72,29.68,21.75,17.70.MS m/z＝562.2333[M+H]。
实施例50
Figure PCTCN2022141790-appb-000060
化合物50的合成参照化合物38进行制备；化合物50，白色固体(35mg，收率59％)。 1H HMR(300MHz,CDCl 3)δ6.14(s,1H),5.81(d,J＝11.5Hz,1H),5.78–5.70(m,1H),5.52(d,J＝1.1Hz,1H),5.18(dd,J＝10.2,2.8Hz,1H),4.83(d,J＝20.6Hz,2H),4.21–4.02(m,3H),3.91(d,J＝9.9Hz,1H),3.77(dd,J＝9.9,1.6Hz,1H),3.59(q,J＝4.4Hz,2H),3.47–3.38(m,2H),2.98(d,J＝9.2Hz,1H),2.72–2.51(m,2H),2.48–2.41(m,1H),2.34(dt,J＝10.1,5.1Hz,5H),2.27(s,3H),1.96–1.86(m,1H),1.85–1.79(m,1H),1.75(d,J＝5.9Hz,2H),1.67–1.58(m,1H),1.54–1.47(m,1H),1.44(d,J＝8.4Hz,1H),1.13(s,3H),1.01(s,3H). 13C NMR(101MHz,CDCl 3)δ206.17,169.01,151.74,130.53,124.78,120.86,101.47,71.74,68.63,65.30,62.83,58.30,57.61,54.88,54.52,52.39,45.90,45.27,42.54,41.34,41.06,38.42,33.13,32.38,30.78,29.82,21.77,17.76.MS m/z＝501.2891[M+H]。
实施例51
Figure PCTCN2022141790-appb-000061
化合物51的合成参照化合物38进行制备；化合物51，白色固体(26mg，收率44％)。 1H HMR(300MHz,CDCl 3)δ7.34(d,J＝1.7Hz,1H),6.90(d,J＝5.8Hz,1H),6.30(dd,J＝3.2,1.9Hz,1H),6.22(d,J＝3.2Hz,1H),6.16(d,J＝1.4Hz,1H),5.88(d,J＝11.8Hz,1H),5.77(ddd,J＝10.2,6.1,2.1Hz,1H),5.56(d,J＝1.2Hz,1H),5.19(dd,J＝10.4,2.8Hz,1H),4.71(d,J＝1.5Hz,1H),4.55(s,1H),4.47(dd,J＝15.4,5.5Hz,1H),4.35(dd,J＝15.4,5.1Hz,1H),4.16–4.06(m,3H),3.92(d,J＝10.0Hz,1H),3.74(dd,J＝10.0,1.6Hz,1H),2.98(dd,J＝9.1,1.5Hz,1H),2.55(q,J＝5.6Hz,2H),2.44(ddd,J＝13.3,9.4,5.0Hz,1H),1.92(d,J＝17.8Hz,1H),1.83(d,J＝6.1Hz,1H),1.74(td,J＝5.6,2.4Hz,2H),1.64–1.51(m,2H),1.45(dd,J＝8.5,1.6Hz,1H),1.13(s,3H),1.02(s,3H). 13C NMR(101MHz,CDCl 3)δ205.66,170.15,151.40,151.37,142.04,130.74,124.51,121.30,110.37,107.50,101.79,71.65,68.89,65.43,62.73,58.24,57.25,52.44,42.42,40.98,38.50,36.51,36.45,32.34,30.76,29.73,21.75,17.75.MS m/z＝498.2418[M+H]。
实施例52
Figure PCTCN2022141790-appb-000062
化合物52的合成参照化合物38进行制备；化合物52，白色固体(28mg，收率49％)。 1H HMR(400MHz,CDCl 3)δ6.58(s,1H),6.18(d,J＝1.5Hz,1H),5.93(d,J＝11.8Hz,1H),5.78(ddd,J＝10.2,6.3,2.0Hz,1H),5.56(t,J＝0.9Hz,1H),5.20(dd,J＝10.2,2.9Hz,1H),4.83–4.75(m,1H),4.63(s,1H),4.18–4.06(m,3H),3.94(dd,J＝10.0,1.1Hz,1H),3.79(dd,J＝10.0,1.7Hz,1H),3.43(dq,J＝3.7,2.3,1.7Hz,4H),3.34(s,3H),2.99(dd,J＝9.0,1.5Hz,1H),2.55–2.39(m,3H),1.97–1.89(m,1H),1.85–1.81(m,1H),1.80–1.75(m,3H),1.64(d,J＝10.6Hz,1H),1.59–1.51(m,1H),1.47(dd,J＝8.6,1.5Hz,1H),1.16(s,3H),1.03(s,3H). 13C NMR(101MHz,CDCl 3)δ205.82,170.53,151.53,130.69,124.61,121.17,101.69,71.68,71.00,68.89,65.41,62.77,58.65,58.37,57.35,52.46,42.48,41.01,39.22,38.50,36.59,32.37,30.79,29.78,21.76,17.78.MS m/z＝476.2591[M+H]。
实施例53
Figure PCTCN2022141790-appb-000063
化合物53的合成参照化合物38进行制备；化合物53，白色固体(46mg，收率78％)。 1H HMR(400MHz,CDCl 3)δ6.15(d,J＝1.4Hz,1H),5.82(d,J＝11.5Hz,1H),5.75(ddd,J＝10.3,6.3,2.0Hz,1H),5.52(s,1H),5.18(dd,J＝10.2,2.8Hz,1H),4.80(d,J＝1.4Hz,1H),4.27–4.01(m,3H),3.91(d,J＝9.9Hz,1H),3.77(dd,J＝10.0,1.6Hz,1H),3.36–3.22(m,1H),3.20–3.06(m,3H),3.04–2.89(m,1H),2.60(qq,J＝11.0,6.4,5.6Hz,2H),2.43(ddd,J＝13.2,9.4,7.1Hz,1H),1.91(dt,J＝17.2,2.6Hz,1H),1.84–1.71(m,3H),1.60(dd,J＝13.6,10.8Hz,1H),1.55–1.40(m,6H),1.13(s,3H),1.01(s,3H),0.84(dt,J＝12.0,7.3Hz,6H). 13C NMR(101MHz,CDCl 3)δ206.14,170.06,151.72,130.50,124.83,120.84,101.39,77.40,71.73,68.66,65.27,62.81,58.58,57.58,52.39,49.61,47.58,42.52,41.06,38.42,33.12,32.38,30.79,29.83,29.70,22.12,21.76,20.88,17.76,11.42,11.23.MS m/z＝502.3091[M+H]。
实施例54
Figure PCTCN2022141790-appb-000064
第一步：将2-甲基-1,3-丙二醇(1.0g，11.1mmol)溶于四氢呋喃，室温下依次加入咪唑(755mg，11.1mmol)和三苯基膦(3.26g，11.1mmol)，反应1min后加入单质碘(3.7g，14.4mmol)反应30min。反应完成后加入饱和Na 2S 2O 3水溶液，再加入DCM萃取，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂、制砂，硅胶柱层析纯化得到产物c-1(1.13g，收率51％)。
第二步：将化合物c-1(1.13g，5.65mmol)与咪唑(0.57g，8.47mmol)溶于100mL干燥的DCM中，冰浴下加入叔丁基二甲基氯硅烷(0.94g，6.21mmol)，随后转入室温下反应，约0.5h反应完全。反应液用饱和氯化铵洗涤，DCM萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂、制砂，硅胶柱层析纯化，收无色油状产物c-2(1.55g，收率87％)。
第三步：将中间体1(1.42g，4.1mmol)溶于60mL无水DMF中，氩气保护。冰浴下分批加入NaH(0.12g，4.9mmol)，自发升温至室温搅拌反应约2h，反应液明显变混浊，加入c-1(1.55g，4.9mmol)，加热至40℃反应约2d。待反应完全后，大量水洗涤，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化，收产物c-3(1.45g，收率68％)。
第四步：将底物(1.45g，2.7mmol)加入40mL AcOH：H 2O：THF＝13:7:3的混合溶液中，于室温下反应约4h。完全反应后用饱和碳酸氢钠水溶液中和反应液中的乙酸，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化。得固体产物c-4(1.0g，收率89％)。
第五步：将底物化合物c-4(1.0g，2.4mmol)与碳酸氢钠(0.6g，7.2mmol)加入到50mL干燥的DCM中，氩气保护，冰浴下加入DMP(0.38g，3.1mmol),随后自发升温至室温下反应约2h。反应完全后，加大量水洗涤，DCM萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，硅胶柱层析纯化，收产物化合物c-5(0.81g，收率82％)。
第六步：将亚氯酸钠(0.4g，4.1mmol)和氨基磺酸(0.5g，5.4mmol)的冰水溶液(10mL)缓慢滴加到化合物c-5(0.81g，2.0mmol)的丙酮(10mL)溶液，室温搅拌约2h反应完全。蒸出丙酮后有白色固体析出，抽滤，乙醚洗涤，即得产物化合物54(50mg，收率65％)。 1H HMR(300MHz,CDCl 3)δ5.80(dd,J＝2.0,1.0Hz,1H),5.71(dd,J＝10.9,1.8Hz,1H),5.66(dd,J＝2.0,1.0Hz,1H),5.57(dt,J＝11.0,6.9Hz,1H),4.70(s,1H),4.43(d,J＝7.0Hz,1H),4.29(d,J＝8.0Hz,1H),3.98(dd,J＝8.1,7.0Hz,1H),3.96–3.84(m,2H),3.84–3.67(m,2H),3.31–3.18(m,1H),3.13–2.99(m,1H),2.81(h,J＝6.9Hz,1H),2.68(ddq,J＝7.1,3.1,1.6Hz,1H),2.17–1.98(m,1H),1.95(d,J＝6.9Hz,2H),1.81–1.65(m,1H),1.71–1.54(m,2H),1.29(d,J＝6.8Hz,3H),1.02(dd,J＝5.4,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.93,178.16,151.46,131.57,127.26,118.83,98.63,78.79,73.05,69.79,68.93,61.82,55.98,51.42,46.34,42.03,40.67,40.10,34.44,28.58,27.88,19.58,13.66.MS m/z＝433.2156[M+H]。
实施例55
Figure PCTCN2022141790-appb-000065
第一步：将2-碘乙醇(2.0g，11.6mmol)与咪唑(1.2g，17.5mmol)溶于100mL干燥的DCM中，冰浴下加入叔丁基二甲基氯硅烷(1.9g，12.7mmol)，随后转入室温下反应，约0.5h反应完全。反应液用饱和氯化铵洗涤，DCM萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂、制砂，硅胶柱层析纯化，收无色油状产物d-1(3.0g，收率92％)。
第二步：将中间体1(1.0g，2.9mmol)溶于60mL无水DMF中，氩气保护。冰浴下分批加入NaH(0.08g，3.2mmol)，自发升温至室温搅拌反应约2h，反应液明显变混浊，加入d-1(1.24g，4.3mmol)，加热至40℃反应约2d。待反应完全后，大量水洗涤，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化，收产物d-2(1.0g，收率72％)。
第三步：将底物(1.0g，1.9mmol)加入20mL AcOH：H 2O：THF＝13:7:3的混合溶液中，于室温下反应约4h。完全反应后用饱和碳酸氢钠水溶液中和反应液中的乙酸，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化。得固体产物d-3(0.7g，收率89％)。
第四步：将底物化合物d-3(0.6g，1.5mmol)与碳酸氢钠(0.4g，4.6mmol)加入到50mL干燥的DCM中，氩气保护，冰浴下加入DMP(0.8g，2mmol),随后自发升温至室温下反应约2h。反应完全后，加大量水洗涤，DCM萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，硅胶柱层析纯化，收产物化合物d-4(0.5g，收率82％)。
第五步：将亚氯酸钠(0.2g，2.7mmol)和氨基磺酸(0.3g，3.6mmol)的冰水溶液(20mL)缓慢滴加到化合物d-4(0.5g，1.3mmol)的丙酮(10mL)溶液，室温搅拌约2h反应完全。蒸出丙酮后有白色固体析出，抽滤，乙醚洗涤，即得产物化合物55(0.3g，61％)。 1H HMR(300MHz,CDCl 3)δ5.83(dd,J＝2.0,1.0Hz,1H),5.71(dd,J＝10.9,1.8Hz,1H),5.65(dd,J＝2.0,1.0Hz,1H),5.57(dt,J＝11.0,6.9Hz,1H),4.58(s,1H),4.37(d,J＝7.0Hz,1H),4.29(d,J＝8.0Hz,1H),4.19(s,2H),3.98(dd,J＝8.1,7.0Hz,1H),3.89(d,J＝12.4Hz,1H),3.72(d,J＝12.4Hz,1H),3.32–3.21(m,1H),3.08(qt,J＝6.9,1.0Hz,1H),2.68(ddq,J＝7.0,3.1,1.6Hz,1H),2.10–1.92(m,1H),1.96(s,1H),1.94(s,1H),1.79–1.53(m,3H),1.02(dd,J＝6.0,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.82,173.39,151.03,132.17,126.60,118.73,98.68,79.18,73.08,68.56,66.15,61.97,55.23,51.49,46.22,40.55,40.49,34.02,29.94,27.77,27.67,20.62.MS m/z＝405.1846[M+H]。
实施例56
Figure PCTCN2022141790-appb-000066
第一步：将4-碘丁醇(2.0g，10.0mmol)与咪唑(1.2g，15.0mmol)溶于100mL干燥的DCM中，冰浴下加入叔丁基二甲基氯硅烷(1.6g，11.0mmol)，随后转入室温下反应，约0.5h反应完全。反应液用饱和氯化铵洗涤，DCM萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂、制砂，硅胶柱层析纯化，收无色油状产物e-1(3.0g，收率96％)。
第二步：将中间体1(1.0g，2.9mmol)溶于60mL无水DMF中，氩气保护。冰浴下分批加入NaH(0.08g，3.2mmol)，自发升温至室温搅拌反应约2h，反应液明显变混浊，加入e-1(1.36g，4.3mmol)，加热至40℃反应约2d。待反应完全后，大量水洗涤，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化，收产物e-2(1.0g，收率68％)。
第三步：将底物(1.0g，1.8mmol)加入20mL AcOH：H 2O：THF＝13:7:3的混合溶液中，于室温下反应约4h。完全反应后用饱和碳酸氢钠水溶液中和反应液中的乙酸，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化。得固体产物e3(0.63g，收率80％)。
第四步：将底物化合物e-3(0.6g，1.4mmol)与碳酸氢钠(0.4g，1.8mmol)加入到50mL干燥的DCM中，氩气保护，冰浴下加入DMP(0.8g，1.9mmol),随后自发升温至室温下反应约2h。反应完全后，加大量水洗涤，DCM萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，硅胶柱层析纯化，收产物化合物e-4(0.5g，收率82％)。
第五步：将亚氯酸钠(0.2g，2.5mmol)和氨基磺酸(0.3g，3.4mmol)的冰水溶液(20mL)缓慢滴加到化合物e-4(0.5g，1.2mmol)的丙酮(20mL)溶液，室温搅拌约2h反应完全。蒸出丙酮后有白色固体析出，抽滤，乙醚洗涤，即得产物化合物56(0.3g，61％)。 1H HMR(300MHz,CDCl 3)δ5.80(dd,J＝2.0,1.0Hz,1H),5.71(dd,J＝10.9,1.8Hz,1H),5.63(dd,J＝2.0,1.0Hz,1H),5.57(dt,J＝11.0,6.9Hz,1H),4.70(s,1H),4.36(d,J＝7.0Hz,1H),4.29(d,J＝8.0Hz,1H),3.98(dd,J＝8.1,7.0Hz,1H),3.89(d,J＝12.4Hz,1H),3.72(d,J＝12.4Hz,1H),3.65(t,J＝7.1Hz,2H),3.26–3.16(m,1H),3.11–2.98(m,1H),2.68(ddq,J＝7.0,3.1,1.5Hz,1H),2.46–2.35(m,2H),2.15–1.98(m,1H),2.03–1.86(m,4H),1.80–1.55(m,3H),1.02(dd,J＝5.4,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.93,177.76,151.46,131.57,127.26,118.83,98.63,78.94,73.05,69.17,68.93,61.82,55.98,51.42,46.34,40.67,40.10,34.44,33.26,28.45,27.88,27.44,19.58.MS m/z＝433.2136[M+H]。
实施例57
Figure PCTCN2022141790-appb-000067
将中间体2(0.20mmol)和TBAI(0.04mmol)溶于2mL DCM中，冰浴下加入1N NaOH(0.30mmol)搅拌约10min，随后加入5-溴甲基噻唑(0.25mmol)，置于室温下搅拌反应约5h。待反应完全后，用水洗涤，DCM萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化可得相应产物57(34mg，收率73％)。 1H HMR(300MHz,CDCl 3)δ8.77 (s,1H),7.61(d,J＝0.4Hz,1H),5.98(ddd,J＝12.7,2.0,1.0Hz,2H),5.72(dd,J＝10.9,1.8Hz,1H),5.58(dt,J＝10.9,6.8Hz,1H),4.89(s,1H),4.82(s,2H),4.45(d,J＝7.0Hz,1H),3.85(d,J＝12.4Hz,1H),3.69(d,J＝12.4Hz,1H),3.19–3.01(m,2H),2.31–2.17(m,2H),2.16–1.96(m,2H),1.91(d,J＝6.9Hz,2H),1.78–1.55(m,3H),0.96(dd,J＝4.4,1.3Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.60,152.88,151.44,136.29,135.39,132.91,126.47,118.91,100.18,78.90,69.08,65.66,61.44,51.91,46.60,46.12,41.15,37.77,34.36,33.01,29.90,26.32,26.25,20.86.MS m/z＝428.1728[M+H]。
实施例58
Figure PCTCN2022141790-appb-000068
将中间体2(0.20mmol)溶于5mL无水DMF中，氩气保护。冰浴下分批加入NaH(0.22mmol)，自发升温至室温搅拌反应约2h，反应液明显变混浊，加入碘代底物(0.3mmol)，加热至40℃反应过夜。待反应完全后，大量水洗涤，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化，得白色固体58(27mg，收率50％)。 1H HMR(300MHz,CDCl 3)δ5.98(dd,J＝10.5,1.0Hz,2H),5.72(dd,J＝10.9,1.8Hz,1H),5.58(dt,J＝10.9,6.9Hz,1H),5.02(s,1H),4.45(d,J＝7.0Hz,1H),3.85(d,J＝12.4Hz,1H),3.76(d,J＝0.6Hz,1H),3.77–3.63(m,4H),3.53(td,J＝6.9,2.1Hz,2H),3.18–2.98(m,2H),2.33–2.16(m,2H),2.13–1.95(m,2H),1.91(d,J＝6.9Hz,2H),1.86–1.74(m,1H),1.78–1.70(m,1H),1.71(d,J＝1.6Hz,1H),1.73–1.65(m,3H),1.69–1.54(m,4H),0.96(dd,J＝4.4,1.4Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.47,151.43,132.34,127.97,118.83,102.12,77.82,69.54,69.39,66.91,61.52,51.29,46.34,44.46,41.38,35.11,34.69,34.39,34.25,33.09,32.57,28.58,26.45,20.04.MS m/z＝443.2728[M+H]。
实施例59
Figure PCTCN2022141790-appb-000069
化合物59的合成参照化合物37进行制备；化合物29，白色固体(28mg，收率50％)。 1H HMR(300MHz,CDCl 3)δ5.98(dd,J＝10.0,1.0Hz,2H),5.72(dd,J＝10.9,1.8Hz,1H),5.57(dt,J＝10.9,6.9Hz,1H),4.98(s,1H),4.36(d,J＝7.0Hz,1H),3.92–3.78(m,3H),3.68(d,J＝12.4Hz,1H),3.25–3.15(m,1H),3.05(dddd,J＝7.8,6.8,5.9,1.0Hz,1H),2.65(t,J＝7.1Hz,2H),2.31–2.16(m,2H),2.16–1.96(m,2H),1.91(d,J＝6.9Hz,2H),1.74–1.55(m,3H),0.96(dd,J＝3.9,1.3Hz,6H). 13C NMR(75MHz,CDCl 3)δ205.98,175.38,151.02,133.62,126.47,118.73,99.89,79.00,69.06,64.97,60.71,52.27,46.65,46.25,41.15,37.96,35.41,34.35,33.01,29.90,26.33,26.23,20.57.MS m/z＝402.2028[M+H]。
实施例60
Figure PCTCN2022141790-appb-000070
将中间体3(0.20mmol)和TBAI(0.04mmol)溶于2mL DCM中，冰浴下加入1N NaOH(0.30mmol)搅拌约10min，随后加入5-溴甲基噻唑(0.25mmol)，置于室温下搅拌反应约5h。待反应 完全后，用水洗涤，DCM萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化可得相应产物(36mg，收率72％)。 1H HMR(300MHz,CDCl 3)δ8.77(s,1H),7.64–7.58(m,1H),5.98(dd,J＝10.5,1.0Hz,2H),4.94(s,1H),4.82(s,2H),4.43(d,J＝7.0Hz,1H),4.00(d,J＝12.4Hz,1H),3.95–3.82(m,2H),3.81(d,J＝12.4Hz,1H),3.26–3.14(m,1H),3.07(qt,J＝6.9,1.0Hz,1H),2.30–2.15(m,1H),2.15–2.01(m,1H),2.06–1.93(m,2H),1.99–1.82(m,1H),1.77–1.57(m,4H),1.55–1.33(m,2H),0.96(dd,J＝8.2,1.3Hz,5H). 13C NMR(75MHz,CDCl 3)δ206.62,152.83,151.35,136.12,135.39,118.74,100.27,79.05,72.78,65.83,65.46,60.17,52.14,46.28,46.12,39.71,38.75,34.33,31.67,30.18,28.15,26.78,20.68.MS m/z＝446.1928[M+H]。
实施例61
Figure PCTCN2022141790-appb-000071
将中间体3(0.20mmol)溶于5mL无水DMF中，氩气保护。冰浴下分批加入NaH(0.22mmol)，自发升温至室温搅拌反应约2h，反应液明显变混浊，加入碘代底物(0.3mmol)，加热至40℃反应过夜。待反应完全后，大量水洗涤，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化，白色固体(26mg，收率51％)。 1H HMR(300MHz,CDCl 3)δ5.98(dd,J＝7.7,1.0Hz,2H),4.94(s,1H),4.45(d,J＝6.9Hz,1H),3.99(d,J＝12.4Hz,1H),3.94–3.84(m,2H),3.80(d,J＝12.4Hz,1H),3.73(d,J＝7.1Hz,3H),3.70(s,1H),3.62–3.42(m,2H),3.24–3.14(m,1H),3.11–2.98(m,1H),2.22(dd,J＝12.2,6.8Hz,1H),2.14–1.92(m,3H),1.97–1.85(m,1H),1.91–1.73(m,1H),1.78–1.64(m,8H),1.70–1.56(m,3H),1.55–1.33(m,2H),0.97(dd,J＝8.0,1.4Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.47,151.43,118.39,102.12,77.82,72.59,69.30,66.96,66.92,60.04,53.49,46.49,46.34,38.75,37.27,34.40,34.34,34.16,33.60,32.79,29.53,29.08,26.67,20.35.MS m/z＝461.2828[M+H]。
实施例62
Figure PCTCN2022141790-appb-000072
化合物62的合成参照化合物37进行制备；化合物62，白色固体(28mg，收率50％)。 1H HMR(300MHz,CDCl 3)δ5.98(dd,J＝10.2,1.0Hz,2H),4.91(s,1H),4.41(d,J＝7.0Hz,1H),4.05–3.89(m,1H),3.93–3.76(m,5H),3.26–3.15(m,1H),3.12–2.98(m,1H),2.66(t,J＝7.1Hz,2H),2.34–2.19(m,1H),2.16–1.92(m,3H),1.78–1.55(m,5H),1.45(td,J＝7.1,0.7Hz,2H),0.97(dd,J＝7.8,1.3Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.62,175.38,151.44,118.73,100.15,79.09,72.68,66.18,64.97,59.99,52.36,46.28,46.11,39.87,38.81,35.41,34.33,31.68,30.01,28.13,26.64,20.56.MS m/z＝421.2128[M+H]。
实施例63
Figure PCTCN2022141790-appb-000073
将中间体4(0.20mmol)和TBAI(0.04mmol)溶于2mL DCM中，冰浴下加入1N NaOH(0.30mmol)搅拌约10min，随后加入5-溴甲基噻唑(0.25mmol)，置于室温下搅拌反应约5h。待反应完全后，用水洗涤，DCM萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化可得相应产物(37mg，收率71％)。 1H HMR(300MHz,CDCl 3)δ8.77(s,1H),7.64–7.58(m,1H),5.80(dd,J＝2.0,1.0Hz,1H),5.66(dd,J＝2.0,1.0Hz,1H),4.89(s,1H),4.82(s,2H),4.44(d,J＝6.9Hz,1H),3.95(d,J＝12.4Hz,1H),3.76(d,J＝12.4Hz,1H),3.15–3.01(m,1H),3.07–2.93(m,1H),2.20(dd,J＝12.3,7.0Hz,1H),2.15–1.96(m,2H),1.88(dd,J＝7.0,1.4Hz,1H),1.73–1.46(m,7H),1.51–1.37(m,1H),1.37–1.24(m,1H),0.92(dd,J＝2.6,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.61,152.88,151.44,136.29,135.39,118.75,100.19,78.77,69.13,65.66,60.97,53.73,47.58,46.12,41.12,37.58,34.76,33.87,33.37,29.95,27.08,20.42,18.68.MS m/z＝429.1928[M+H]。
实施例64
Figure PCTCN2022141790-appb-000074
将中间体4(0.20mmol)溶于5mL无水DMF中，氩气保护。冰浴下分批加入NaH(5.3mg，0.22mmol)，自发升温至室温搅拌反应约2h，反应液明显变混浊，加入碘代底物(0.3mmol)，加热至40℃反应过夜。待反应完全后，大量水洗涤，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化，可得化合物64，白色固体(28mg，收率50％)。 1H HMR(300MHz,CDCl 3)δ5.98(ddd,J＝10.5,2.0,1.0Hz,2H),5.02(s,1H),4.45(d,J＝7.0Hz,1H),3.95(d,J＝12.4Hz,1H),3.84–3.67(m,5H),3.53(td,J＝7.0,2.2Hz,2H),3.11–2.93(m,2H),2.20(dd,J＝12.4,7.0Hz,1H),2.15–1.96(m,2H),1.89(ddt,J＝7.0,4.0,1.4Hz,1H),1.89–1.68(m,3H),1.73–1.64(m,6H),1.68–1.57(m,2H),1.61–1.53(m,1H),1.57–1.43(m,3H),1.49–1.34(m,1H),1.37–1.22(m,1H),0.92(dd,J＝2.5,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.47,151.43,118.39,102.12,77.82,69.47,69.26,66.91,60.53,55.46,47.07,46.34,41.67,36.54,35.32,35.15,34.39,34.25,33.62,32.79,28.45,27.20,19.94,19.20.MS m/z＝444.2868[M+H]。
实施例65
Figure PCTCN2022141790-appb-000075
化合物65的合成参照化合物37进行制备；化合物65，白色固体(28mg，收率50％)。 1H HMR(300MHz,CDCl 3)δ5.98(dd,J＝10.0,1.0Hz,2H),4.86(s,1H),4.36(d,J＝6.9Hz,1H),3.95(d,J＝12.4Hz,1H),3.92–3.79(m,2H),3.76(d,J＝12.4Hz,1H),3.12–2.98(m,2H),2.65(t,J＝7.1Hz,2H),2.20(dd,J＝12.3,7.0Hz,1H),2.15–1.95(m,2H),1.88(dt,J＝7.0,3.0,1.4Hz,1H),1.76–1.58(m,3H),1.63–1.54(m,1H),1.58–1.47(m,3H),1.51–1.37(m,1H),1.37–1.24(m,1H),0.92(dd,J＝2.4,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.00,175.38,151.02,118.62,100.07,78.85,69.05,64.97,60.65,53.63,47.46,46.25,41.10,38.14,35.41,34.80,33.87,33.34,29.95,27.23,20.31,18.70.MS m/z＝405.2168[M+H]。
实施例66
Figure PCTCN2022141790-appb-000076
化合物66的合成参照化合物20进行制备；化合物66，白色固体(29mg，收率54％)。 1H HMR(300MHz,CDCl 3)δ8.77(s,1H),7.65–7.59(m,1H),6.66(dd,J＝10.9,1.7Hz,1H),5.98(dd,J＝10.5,1.0Hz,2H),5.90(d,J＝10.9Hz,1H),4.84–4.78(m,2H),4.70(s,1H),4.39(d,J＝6.9Hz,1H),4.20(d,J＝8.1Hz,1H),4.06(dd,J＝8.1,6.9Hz,1H),3.90(d,J＝12.4Hz,1H),3.74(d,J＝12.4Hz,1H),3.22–3.12(m,1H),3.16–3.00(m,2H),2.12–1.95(m,1H),1.79–1.56(m,3H),1.18(dd,J＝2.7,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.86,204.70,152.83,151.43,151.36,136.12,135.39,125.98,118.74,98.82,80.45,73.66,68.74,65.46,61.16,54.50,50.37,46.39,46.14,39.79,30.12,24.97,20.84.MS m/z＝458.1568[M+H]。
实施例67
Figure PCTCN2022141790-appb-000077
化合物67的合成参照化合物64进行制备；化合物67，白色固体(25mg，收率48％)。 1H HMR(300MHz,CDCl 3)δ6.66(dd,J＝10.9,1.7Hz,1H),5.90(d,J＝11.0Hz,1H),5.83(dd,J＝2.0,1.0Hz,1H),5.67(dd,J＝2.0,1.0Hz,1H),4.70(s,1H),4.37(d,J＝6.9Hz,1H),4.20(d,J＝8.1Hz,1H),4.06(dd,J＝8.0,6.9Hz,1H),3.90(d,J＝12.4Hz,1H),3.81–3.61(m,5H),3.61–3.41(m,2H),3.29–3.19(m,1H),3.14–2.98(m,2H),2.12–1.93(m,1H),1.86–1.67(m,3H),1.73–1.61(m,7H),1.66–1.55(m,1H),1.20(dd,J＝3.2,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.96,204.49,151.01,150.24,125.96,119.01,98.63,80.64,73.04,69.33,68.65,66.92,63.70,54.18,51.43,46.34,44.94,39.94,34.44,34.32,32.89,28.58,25.00,20.04.MS m/z＝473.2468[M+H]。
实施例68
Figure PCTCN2022141790-appb-000078
化合物68的合成参照化合物37进行制备；化合物68，白色固体(26mg，收率47％)。 1H HMR(300MHz,CDCl 3)δ6.66(dd,J＝10.9,1.7Hz,1H),5.98(dd,J＝12.7,1.0Hz,2H),5.90(d,J＝10.9Hz,1H),4.70(s,1H),4.44(d,J＝6.9Hz,1H),4.20(d,J＝8.1Hz,1H),4.06(dd,J＝8.1,6.9Hz,1H),3.90(d,J＝12.4Hz,1H),3.89–3.78(m,2H),3.74(d,J＝12.4Hz,1H),3.21–3.11(m,1H),3.15–2.98(m,2H),2.66(t,J＝7.1Hz,2H),2.13–1.96(m,1H),1.78–1.55(m,3H),1.17(dd,J＝2.9,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ207.09,204.70,175.38,151.45,151.32,125.96,118.74,98.82,79.63,73.27,68.38,64.97,61.09,54.37,50.37,46.38,46.12,39.98,35.41,29.94,25.04,20.70.MS m/z＝433.1768[M+H]。
实施例69
Figure PCTCN2022141790-appb-000079
第一步：将中间体2(1g，2.74mmol)和对甲苯磺酸一水合物(47mg，0.27mmol)用10mL无水丙酮溶解，冰浴冷却至0℃，随后加入2，2-二甲氧基丙烷(2.02mL，16.5mmol)，室温下反应，于室温下搅拌反应约1h。待反应完全后，用水洗涤，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化可得f-1，白色固体(1.01g，收率90％)。
第二步：将合成f-1(2.5mmol)与SeO 2(7.5mmol)溶于1,4-二氧六环(50mL)中，100℃加热搅拌16h，反应结束后抽滤，滤液用水稀释后用二氯甲烷萃取，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化可得f-2(0.77g，收率76％)。
第三步：将f-2(2mmol)溶于DCM中，加入重铬酸吡啶盐(PDC)(2.2mmol)，室温搅拌反应4h。反应结束后抽滤，滤液用水稀释后用二氯甲烷萃取，合并有机相后用NaHCO 3、饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化可得f-3(0.70g，收率80％)。
第四步：将第二步的产物f-3溶于MeOH:CH 2Cl 2:HCl(5％)＝4:1:1的混合溶液中，室温搅拌4h，反应结束后抽滤，滤液用水稀释后用二氯甲烷萃取，合并有机相后用NaHCO 3、饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化可得化合物69(0.65g，收率85％)。 1H NMR(300MHz,CDCl 3)δ6.47(m,1H),6.06(d,J＝7.9Hz,1H),5.75(t,J＝1.8Hz,1H),5.67(t,J＝1.9Hz,1H),5.37(s,1H),4.62(m,1H),4.14(d,J＝4.8Hz,1H),4.10(d,J＝12.3Hz,1H),3.82(d,J＝12.3Hz,1H),3.05–2.98(m,1H),2.46(m,1H),2.33(dd,J＝12.5,5.1Hz,1H),2.21(m,1H),1.92–1.83(m,1H),1.86–1.80(m,1H),1.83–1.72(m,2H),1.75–1.62(m,1H),1.23(s,2H),1.14(s,2H). 13C NMR(75MHz,CDCl 3)δ204.98,204.89,154.69,152.78,125.64,117.38,99.85,74.01,66.47,60.35,52.77,45.92,44.98,44.94,37.32,34.92,31.52,25.13,23.23,18.78.MS m/z＝367.1514[M+Na]。
实施例70
Figure PCTCN2022141790-appb-000080
化合物70的合成参照化合物20进行制备；化合物70，白色固体(31mg，收率55％)。 1H HMR(300MHz,CDCl 3)δ8.77(s,1H),7.64–7.58(m,1H),6.67(dd,J＝10.9,1.8Hz,1H),6.04(d,J＝10.9Hz,1H),5.82(dd,J＝2.1,1.0Hz,1H),5.68(dd,J＝2.0,1.0Hz,1H),4.98(s,1H),4.82(s,2H),4.45(d,J＝7.0Hz,1H),3.87(d,J＝12.4Hz,1H),3.70(d,J＝12.3Hz,1H),3.21–3.10(m,1H),3.06(dd,J＝8.0,1.0Hz,1H),2.86(dd,J＝7.0,1.6Hz,1H),2.32(dd,J＝12.3,7.0Hz,1H),2.15–1.96(m,2H),1.79–1.52(m,3H),1.11(dd,J＝2.5,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.56,204.70,154.23,152.83,151.35,136.29,135.39,126.43,118.74,100.34,79.00,69.04,65.46,61.44,50.70,46.60,46.12,44.66,35.68,34.59,29.90,24.03,20.69.MS m/z＝442.1768[M+H]。
实施例71
Figure PCTCN2022141790-appb-000081
化合物71的合成参照化合物64进行制备；化合物71，白色固体(27mg，收率48％)。 1H HMR(300MHz,CDCl 3)δ6.67(dd,J＝10.9,1.8Hz,1H),6.09–5.96(m,2H),5.97(dd,J＝2.0,1.1Hz,1H),4.98(s,1H),4.45(d,J＝7.0Hz,1H),3.87(d,J＝12.4Hz,1H),3.79–3.63(m,5H),3.62–3.42(m,2H),3.20–3.10(m,1H),3.10–2.97(m,1H),2.85(dd,J＝7.1,1.6Hz,1H),2.32(dd,J＝12.3,7.0Hz,1H),2.16–1.96(m,2H),1.86–1.56(m,10H),1.11(dd,J＝2.4,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.47,204.71,151.43,149.63,126.62,118.83,102.02,77.82,69.46,69.28,66.91,60.90,50.79,46.34,45.96,43.47,34.84,34.34,34.16,32.96,32.79,28.45,24.43,19.98.MS m/z＝456.2568[M+H]。
实施例72
Figure PCTCN2022141790-appb-000082
化合物72的合成参照化合物37进行制备；化合物72，白色固体(31mg，收率51％)。 1H HMR(300MHz,CDCl 3)δ6.67(dd,J＝10.9,1.8Hz,1H),6.09–5.96(m,2H),5.96(dd,J＝2.0,1.1Hz,1H),4.94(s,1H),4.41(d,J＝7.0Hz,1H),3.92–3.79(m,3H),3.70(d,J＝12.4Hz,1H),3.26–3.16(m,1H),3.05(dd,J＝7.0,1.1Hz,1H),2.82(dd,J＝7.0,1.5Hz,1H),2.66(t,J＝7.1Hz,2H),2.34(dd,J＝12.4,6.9Hz,1H),2.15–1.95(m,2H),1.72–1.54(m,3H),1.11(dd,J＝2.4,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.57,204.64,175.38,154.23,151.44,126.16,118.84,100.21,79.10,68.59,64.97,60.81,51.25,46.59,46.25,44.72,35.80,35.41,34.55,29.90,23.93,20.61.MS m/z＝416.1868[M+H]。
实施例73
Figure PCTCN2022141790-appb-000083
将中间体3与琼斯试剂溶于丙酮，加热回流2h。反应完成后，反应液由乙酸乙酯萃取三次，饱和食盐水洗涤，干燥后过滤，真空浓缩，柱层析得化合物73，白色固体0.92g(收率82％)。 1H HMR(300MHz,CDCl 3)δ5.98(dd,J＝9.9,1.0Hz,2H),5.10(s,1H),4.50(d,J＝5.9Hz,1H),4.32(dd,J＝7.0,5.9Hz,1H),4.05(d,J＝12.4Hz,1H),3.91(d,J＝12.3Hz,1H),3.50(t,J＝6.9Hz,1H),3.05–2.92(m,1H),2.46(dd,J＝6.8,1.5Hz,1H),2.41–2.26(m,3H),2.16–1.97(m,2H),1.79–1.55(m,5H),0.96(dd,J＝5.0,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ210.24,206.20,151.74,117.38,100.75,73.57,63.66,61.51,50.91,49.38,46.04,45.44,38.75,35.20,34.45,32.93,31.18,28.05,20.86.MS m/z＝347.1868[M+H]。
实施例74
Figure PCTCN2022141790-appb-000084
化合物74的合成参照化合物20进行制备；化合物74，白色固体(34mg，收率56％)。 1H HMR(300MHz,CDCl 3)δ8.77(s,1H),7.61(d,J＝0.4Hz,1H),5.98(dd,J＝10.5,1.0Hz,2H),4.98(s,1H),4.82(s,2H),4.44(d,J＝7.0Hz,1H),4.05(d,J＝12.4Hz,1H),3.92(d,J＝12.4Hz,1H),3.26–3.15(m,1H),3.07(qt,J＝6.9,1.0Hz,1H),2.51(dd,J＝7.1,1.5Hz,1H),2.38–2.25(m,3H),2.16–1.99(m,2H),1.99–1.82(m,1H),1.74–1.56(m,4H),0.95(dd,J＝4.8,1.5Hz,6H). 13C NMR(75MHz,CDCl 3) δ206.47,151.43,118.39,102.12,77.82,69.47,69.26,66.91,60.53,55.46,47.07,46.34,41.67,36.54,35.32,35.15,34.39,34.25,33.62,32.79,28.45,27.20,19.94,19.20.MS m/z＝443.1768[M+H]。
实施例75
Figure PCTCN2022141790-appb-000085
化合物75的合成参照化合物64进行制备；化合物75，白色固体(27mg，收率48％)。 1H HMR(300MHz,CDCl 3)δ5.98(dd,J＝7.7,1.0Hz,2H),4.98(s,1H),4.46(d,J＝6.9Hz,1H),4.05(d,J＝12.4Hz,1H),3.92(d,J＝12.4Hz,1H),3.72(t,J＝7.0Hz,4H),3.62–3.42(m,2H),3.26–3.15(m,1H),3.05(dtd,J＝6.9,6.0,1.0Hz,1H),2.51(dd,J＝7.0,1.5Hz,1H),2.39–2.24(m,3H),2.14–2.03(m,1H),2.09–1.96(m,1H),2.02–1.86(m,1H),1.91–1.72(m,1H),1.77–1.57(m,11H),0.96(dd,J＝4.6,1.4Hz,6H). 13C NMR(75MHz,CDCl 3)δ211.74,206.47,151.43,118.83,102.02,77.82,69.28,67.55,66.91,60.47,50.21,49.82,46.34,45.05,39.66,36.04,34.75,34.34,34.16,33.62,32.79,29.57,27.18,20.21.MS m/z＝458.2648[M+H]。
实施例76
Figure PCTCN2022141790-appb-000086
化合物76的合成参照化合物37进行制备；化合物76，白色固体(32mg，收率55％)。 1H HMR(300MHz,CDCl 3)δ5.98(dd,J＝10.2,1.0Hz,2H),4.94(s,1H),4.42(d,J＝7.0Hz,1H),4.02(d,J＝12.4Hz,1H),3.91(d,J＝12.4Hz,1H),3.84(t,J＝7.1Hz,2H),3.32(dd,J＝6.9,1.6Hz,1H),3.05(dt,J＝7.9,6.1,0.7Hz,1H),2.66(t,J＝7.1Hz,2H),2.44(dd,J＝7.0,1.5Hz,1H),2.43–2.24(m,3H),2.17–1.97(m,2H),1.76–1.56(m,5H),0.96(dd,J＝4.5,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ210.62,206.72,175.38,151.44,118.84,100.22,79.20,64.97,63.75,60.46,50.12,49.87,46.11,45.52,39.17,35.41,35.36,34.42,32.95,30.08,27.03,20.99.MS m/z＝419.1948[M+H]。
实施例77
Figure PCTCN2022141790-appb-000087
化合物77的合成参照化合物20进行制备；化合物77，白色固体(34mg，收率56％)。 1H HMR(300MHz,CDCl 3)δ8.77(s,1H),7.62(d,J＝0.4Hz,1H),5.99(dd,J＝13.2,1.0Hz,2H),4.81(d,J＝0.4Hz,2H),4.70(s,1H),4.47(d,J＝6.9Hz,1H),4.19(d,J＝8.6Hz,1H),4.11(d,J＝12.3Hz,1H),4.04(dd,J＝8.6,7.0Hz,1H),3.95(d,J＝12.3Hz,1H),3.54–3.44(m,1H),3.08(dtd,J＝7.6,5.8,0.9Hz,1H),2.92(d,J＝7.0,1.5Hz,1H),2.33(t,J＝7.1Hz,2H),2.17–1.97(m,1H),1.84–1.57(m,5H),0.98(dd,J＝4.4,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ211.18,207.01,152.83,151.43,136.12,135.34,118.74,98.82,80.45,73.51,65.46,62.80,60.69,52.88,51.92,50.14,46.14,39.51,36.16,33.96,30.29,27.93,27.81,21.12.MS m/z＝459.1748[M+H]。
实施例78
Figure PCTCN2022141790-appb-000088
化合物78的合成参照化合物64进行制备；化合物78，白色固体(31mg，收率52％)。 1H HMR(300MHz,CDCl 3)δ5.98(dd,J＝7.7,1.0Hz,2H),4.70(s,1H),4.48(d,J＝6.9Hz,1H),4.19(d,J＝8.6Hz,1H),4.15–4.01(m,2H),3.95(d,J＝12.4Hz,1H),3.71(td,J＝7.0,2.7Hz,4H),3.67–3.41(m,3H),3.05(dd,J＝7.9,1.0Hz,1H),2.92(d,J＝6.9,1.5Hz,1H),2.33(t,J＝7.1Hz,2H),2.13–1.96(m,1H),1.86–1.71(m,2H),1.76–1.56(m,11H),0.98(dd,J＝4.7,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ211.68,206.99,151.01,119.01,98.63,79.31,73.32,69.33,68.46,66.92,62.74,52.68,52.14,52.11,46.34,40.22,36.33,34.44,34.32,34.03,32.89,29.57,28.00,20.31.MS m/z＝475.1548[M+H]。
实施例79
Figure PCTCN2022141790-appb-000089
化合物79的合成参照化合物37进行制备；化合物79，白色固体(32mg，收率55％)。 1H HMR(300MHz,CDCl 3)δ5.80(dd,J＝2.0,1.0Hz,1H),5.63(dd,J＝2.0,1.0Hz,1H),4.70(s,1H),4.46(d,J＝6.9Hz,1H),4.19(d,J＝8.7Hz,1H),4.11(d,J＝12.3Hz,1H),4.04(dd,J＝8.6,6.9Hz,1H),3.95(d,J＝12.3Hz,1H),3.90–3.77(m,2H),3.39–3.28(m,1H),3.05(dtd,J＝8.0,5.9,1.0Hz,1H),2.92(ddq,J＝7.5,3.0,1.5Hz,1H),2.66(t,J＝7.1Hz,2H),2.33(t,J＝7.1Hz,2H),2.13–1.94(m,1H),1.84–1.57(m,5H),0.98(dd,J＝4.3,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ211.01,207.02,175.38,151.45,118.37,98.82,79.64,73.46,64.97,62.80,60.31,52.88,51.95,50.15,46.12,39.48,35.96,35.41,33.96,30.29,27.68,27.62,21.00.MS m/z＝435.1948[M+H]。
实施例80
Figure PCTCN2022141790-appb-000090
第一步：将冬凌草甲素g-1(1g，2.74mmol)和对甲苯磺酸一水合物(47mg，0.27mmol)用10mL无水丙酮溶解，冰浴冷却至0℃，随后加入2，2-二甲氧基丙烷(2.02mL，16.5mmol)，室温下反应，于室温下搅拌反应约1h。待反应完全后，用水洗涤，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化可得g-2，白色固体(0.92g，产率85％)。
第二步：将g-2(1g，2.47mmol)溶于10mL吡啶中，加入TEA(1.71mL，12.36mmol)，冰浴冷却至0℃，随后用恒压滴液漏斗滴加溶于吡啶的乙酸酐(1.16mL，12.36mmol)溶液，室温反应2h。待反应完全后，用水洗涤，EA萃取三次，合并有机相后用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化可得g-3。
第三步：将第g-3(0.5g，1.29mmol)溶于10mLTHF中，冰浴冷却至0℃，随后加入HCl(5.17mL，1M，5.17mmol)，室温下反应1h。待反应完全后，用水洗涤，EA萃取三次，合并有机相后 用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，制砂，硅胶柱层析纯化可得化合物80，白色固体(0.31g，收率82％)。
实施例81
Figure PCTCN2022141790-appb-000091
化合物81的合成参照化合物20以中间体81为原料进行制备；化合物78，白色固体(34mg，收率56％)。 1H HMR(300MHz,CDCl 3)δ8.76(s,1H),7.60(d,J＝0.4Hz,1H),5.99(dd,J＝8.6,1.0Hz,2H),4.96(d,J＝6.9Hz,1H),4.89(s,1H),4.82–4.70(m,3H),4.46(d,J＝6.9Hz,1H),4.03(d,J＝12.4Hz,1H),3.85(d,J＝12.4Hz,1H),3.16–3.02(m,2H),2.97(d,J＝7.0,1.5Hz,1H),2.05(d,J＝13.6Hz,7H),1.96–1.75(m,2H),1.75–1.56(m,3H),1.51–1.40(m,2H),0.97(dd,J＝13.1,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.43,170.53,170.04,150.92,150.76,139.75,129.69,118.97,97.64,80.13,77.03,74.01,69.55,65.99,63.63,51.34,51.16,46.48,44.59,38.38,33.97,29.06,28.00,25.11,21.10,20.98,20.19.MS m/z＝546.1948[M+H]。
实施例82
Figure PCTCN2022141790-appb-000092
化合物82的合成参照化合物64以化合物80为原料进行制备；化合物82，白色固体(32mg，收率53％)。 1H HMR(300MHz,CDCl 3)δ5.99(d,J＝2.0,1.0Hz,2H),4.98(d,J＝7.0Hz,1H),4.89(s,1H),4.74(t,J＝7.0Hz,1H),4.48(d,J＝7.0Hz,1H),4.03(d,J＝12.4Hz,1H),3.85(d,J＝12.4Hz,1H),3.79–3.55(m,4H),3.50(t,J＝7.0Hz,2H),3.16–2.99(m,2H),2.94(d,J＝7.0,1.5Hz,1H),2.04(d,J＝6.8Hz,8H),1.95–1.56(m,12H),1.51–1.40(m,2H),0.97(dd,J＝13.1,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.35,170.57,170.01,150.52,118.65,97.64,80.10,77.77,74.10,70.32,69.69,67.28,63.63,51.34,51.16,46.44,44.59,38.38,34.69,34.28,33.97,32.56,29.08,28.00,25.25,21.11,21.00,20.33.MS m/z＝561.2948[M+H]。
实施例83
Figure PCTCN2022141790-appb-000093
化合物83的合成参照化合物37以化合物80为原料进行制备；化合物83，白色固体(29mg，收率51％)。 1H HMR(300MHz,CDCl 3)δ5.81(dd,J＝2.0,1.0Hz,1H),5.68(dd,J＝2.0,1.0Hz,1H),4.89(s,1H),4.84–4.70(m,2H),4.45(d,J＝6.9Hz,1H),4.03(d,J＝12.4Hz,1H),3.92–3.72(m,3H),3.17–2.99(m,2H),2.94(d,J＝7.1,1.5Hz,1H),2.65(t,J＝7.1Hz,2H),2.11–1.96(m,7H),2.01–1.86(m,1H),1.91–1.82(m,1H),1.86–1.74(m,1H),1.74–1.55(m,2H),1.51–1.40(m,2H),0.97(dd,J＝13.3,1.6Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.35,175.39,170.67,170.07,150.41,119.02,97.66,79.79,77.87,74.00,69.52,65.56,63.63,51.31,51.16,46.36,44.33,38.35,35.53,33.97,29.60,28.00,25.11,21.13,20.89,20.21.MS m/z＝521.2348[M+H]。
实施例84
Figure PCTCN2022141790-appb-000094
化合物84的合成参照化合物20以中间体7为原料进行制备；化合物84，白色固体(32mg，收率53％)。 1H HMR(300MHz,CDCl 3)δ8.77(s,1H),7.59(d,J＝0.4Hz,1H),5.81(dd,J＝2.0,1.0Hz,1H),5.64(dd,J＝2.0,1.0Hz,1H),4.88–4.73(m,3H),4.65(s,1H),4.46(d,J＝6.9Hz,1H),4.07–3.94(m,3H),3.82(d,J＝12.4Hz,1H),3.18–3.01(m,2H),2.73(dh,J＝6.2,1.5Hz,1H),2.15–2.00(m,1H),2.02(s,3H),2.00–1.86(m,1H),1.91–1.82(m,1H),1.82(dd,J＝7.0,2.0Hz,1H),1.75–1.55(m,2H),1.52–1.41(m,2H),0.97(dd,J＝13.0,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.49,170.56,150.75,150.41,139.75,129.80,118.72,98.63,80.33,77.53,73.31,69.52,66.20,62.92,56.54,51.31,46.16,43.00,38.16,34.18,29.60,28.03,25.09,21.14,20.21.MS m/z＝504.1958[M+H]。
实施例85
Figure PCTCN2022141790-appb-000095
化合物85的合成参照化合物64以中间体7为原料进行制备；化合物85，白色固体(31mg，收率51％)。 1H HMR(300MHz,CDCl 3)δ5.81(dd,J＝2.0,1.0Hz,1H),5.71(dd,J＝2.0,1.0Hz,1H),4.84(t,J＝7.0Hz,1H),4.69(s,1H),4.48(d,J＝7.0Hz,1H),4.08–3.95(m,3H),3.83(d,J＝12.4Hz,1H),3.78–3.46(m,6H),3.15–2.99(m,2H),2.73(dh,J＝5.9,1.5Hz,1H),2.14–1.95(m,1H),2.03(s,3H),1.93–1.55(m,12H),1.52–1.41(m,2H),0.97(dd,J＝12.7,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.43,170.61,150.41,119.02,98.63,79.79,77.12,73.31,69.52,69.33,67.14,63.26,56.64,51.31,46.36,42.82,38.26,34.44,34.32,34.18,32.79,29.60,28.20,25.25,20.90,20.21.MS m/z＝519.2858[M+H]。
实施例86
Figure PCTCN2022141790-appb-000096
化合物86的合成参照化合物37以中间体7为原料进行制备；化合物86，白色固体(31mg，收率52％)。 1H HMR(300MHz,CDCl 3)δ5.83(dd,J＝2.0,1.0Hz,1H),5.67(dd,J＝2.0,1.0Hz,1H),4.84(t,J＝7.0Hz,1H),4.66(s,1H),4.45(d,J＝6.9Hz,1H),4.07–3.94(m,3H),3.89–3.77(m,3H),3.27–3.16(m,1H),3.12–2.98(m,1H),2.73(d,J＝5.3,1.5Hz,1H),2.74–2.59(m,2H),2.15–1.96(m,1H),2.02(s,3H),1.95–1.73(m,2H),1.78–1.57(m,3H),1.53–1.42(m,2H),0.97(dd,J＝12.4,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.87,175.39,170.55,151.21,119.02,98.64,79.20,77.53,73.29,69.16,65.65,61.87,56.63,51.44,46.34,43.02,38.37,35.54,34.12,29.60,28.16,25.11,21.10,20.36.MS m/z＝479.2308[M+H]。
实施例87
Figure PCTCN2022141790-appb-000097
化合物87的合成参照化合物20以中间体8为原料进行制备；化合物87，白色固体(30mg，收率51％)。 1H HMR(300MHz,CDCl 3)δ8.76(s,1H),7.60(d,J＝0.4Hz,1H),7.00(t,J＝3.4Hz,1H),5.99(dd,J＝2.0,1.0Hz,1H),6.01–5.95(m,1H),6.00–5.84(m,1H),5.23–5.11(m,2H),4.79(d,J＝1.3Hz,2H),4.71(s,1H),4.57(dd,J＝7.0,3.7Hz,1H),4.53–4.40(m,2H),4.24(d,J＝12.3Hz,1H),4.17(dd,J＝6.1,0.9Hz,2H),3.85(dd,J＝8.5,7.0Hz,1H),3.21–2.99(m,2H),2.67(d,J＝12.4Hz,1H),2.63–2.50(m,2H),2.10–1.94(m,1H),1.87–1.77(m,1H),1.83–1.66(m,2H),1.14(s,3H),1.07(s,3H). 13C NMR(75MHz,CDCl 3)δ208.18,164.91,150.76,150.41,146.31,139.75,135.38,129.69,118.65,115.51,104.94,100.05,79.87,72.83,68.17,65.99,62.50,49.45,48.54,46.17,45.10,43.17,37.07,35.20,30.14,29.16,25.57,21.07.MS m/z＝556.1908[M+H]。
实施例88
Figure PCTCN2022141790-appb-000098
化合物88的合成参照化合物64以中间体8为原料进行制备；化合物88，白色固体(31mg，收率51％)。 1H HMR(300MHz,CDCl 3)δ7.00(t,J＝3.4Hz,1H),5.99(dd,J＝2.0,1.0Hz,1H),6.01–5.95(m,1H),6.00–5.84(m,1H),5.23–5.11(m,2H),4.77(s,1H),4.58–4.40(m,3H),4.24(d,J＝12.3Hz,1H),4.17(dd,J＝6.0,0.9Hz,2H),3.88(dd,J＝8.5,7.0Hz,1H),3.79–3.54(m,4H),3.52(t,J＝6.9Hz,2H),3.18–2.99(m,2H),2.67(d,J＝12.4Hz,1H),2.63–2.50(m,2H),2.12–1.95(m,1H),1.86–1.61(m,10H),1.14(s,3H),1.07(s,3H). 13C NMR(75MHz,CDCl 3)δ208.22,164.91,150.50,146.31,135.38,118.65,115.53,104.94,100.05,80.73,72.83,69.69,68.17,67.34,62.50,49.45,48.54,45.96,45.12,43.17,37.07,35.20,34.69,34.40,31.56,29.67,29.16,25.57,21.07.MS m/z＝583.2708[M+Na]。
实施例89
Figure PCTCN2022141790-appb-000099
化合物89的合成参照化合物37以中间体8为原料进行制备；化合物89，白色固体(34mg，收率56％)。 1H HMR(300MHz,CDCl 3)δ7.00(t,J＝3.4Hz,1H),6.03–5.95(m,2H),6.00–5.84(m,1H),5.23–5.11(m,2H),4.71(s,1H),4.51(d,J＝4.0Hz,1H),4.52–4.39(m,2H),4.22(d,J＝12.4Hz,1H),4.17(dd,J＝6.2,0.8Hz,2H),3.92–3.79(m,2H),3.84–3.72(m,1H),3.18–2.99(m,2H),2.75– 2.61(m,3H),2.59(d,J＝12.4Hz,1H),2.54(dd,J＝7.0,2.5Hz,1H),2.12–1.95(m,1H),1.87–1.68(m,3H),1.14(s,3H),1.07(s,3H). 13C NMR(75MHz,CDCl 3)δ208.32,175.41,165.36,150.81,146.29,134.48,118.89,115.62,111.03,99.02,81.82,73.08,67.75,64.97,62.17,49.35,46.89,44.99,44.50,43.15,36.81,36.77,35.40,30.43,29.35,25.60,19.19.MS m/z＝531.2008[M+Na]。
实施例90
Figure PCTCN2022141790-appb-000100
化合物90的合成参照化合物20以中间体9为原料进行制备；化合物90，白色固体(30mg，收率51％)。 1H HMR(300MHz,CDCl 3)δ8.77(s,1H),7.64–7.58(m,1H),5.83(dd,J＝2.0,1.0Hz,1H),5.67(dd,J＝2.1,1.0Hz,1H),4.82(s,2H),4.69(s,1H),4.39(d,J＝7.0Hz,1H),4.30(d,J＝8.7Hz,1H),4.04–3.92(m,2H),3.79(d,J＝12.4Hz,1H),3.14–2.94(m,2H),2.53(d,J＝7.0,1.5Hz,1H),2.12–1.95(m,1H),1.79–1.59(m,3H),1.65–1.50(m,4H),1.56–1.26(m,2H),0.96(dd,J＝2.9,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.86,152.83,151.36,136.12,135.39,118.74,98.67,80.33,73.33,68.82,65.46,60.82,55.98,53.10,46.14,41.43,39.66,34.32,34.07,30.16,27.83,27.73,20.47,19.01.MS m/z＝446.1908[M+Na]。
实施例91
Figure PCTCN2022141790-appb-000101
化合物91的合成参照化合物64以中间体9为原料进行制备；化合物91，白色固体(31mg，收率51％)。 1H HMR(300MHz,CDCl 3)δ5.83(dd,J＝2.0,1.0Hz,1H),5.67(dd,J＝2.0,1.0Hz,1H),4.70(s,1H),4.46(d,J＝7.0Hz,1H),4.30(d,J＝8.7Hz,1H),4.04–3.92(m,2H),3.84–3.65(m,5H),3.59–3.50(m,1H),3.54–3.42(m,1H),3.11–2.94(m,2H),2.53(d,J＝7.0,1.5Hz,1H),2.14–1.96(m,1H),1.86–1.25(m,16H),0.96(dd,J＝2.9,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ206.96,151.43,118.83,98.55,80.08,73.41,69.30,69.20,66.92,60.84,56.44,54.82,46.34,42.21,40.31,34.47,34.34,34.32,34.29,32.79,28.58,27.53,19.95,19.28.MS m/z＝461.2808[M+Na]。
实施例92
Figure PCTCN2022141790-appb-000102
化合物92的合成参照化合物37以中间体9为原料进行制备；化合物92，白色固体(34mg，收率56％)。 1H HMR(300MHz,CDCl 3)δ5.98(dd,J＝14.3,2.0,1.0Hz,2H),4.67(s,1H),4.43(d,J＝7.0Hz,1H),4.28(d,J＝8.6Hz,1H),4.04–3.92(m,2H),3.90–3.78(m,2H),3.79(d,J＝12.4Hz,1H),3.17–2.99(m,2H),2.66(t,J＝7.1Hz,2H),2.53(d,J＝7.0,1.5Hz,1H),2.14–1.96(m,1H),1.77–1.46(m,7H),1.52–1.40(m,1H),1.40–1.26(m,1H),0.96(dd,J＝2.8,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ207.14,175.38,151.45,118.84,98.67,79.38,73.33,68.86,64.97,60.81,56.81,53.04,46.12,41.43,39.90,35.41,34.30,34.12,29.94,27.98,27.93,20.30,19.01.MS m/z＝421.2108[M+Na]。
实施例93
Figure PCTCN2022141790-appb-000103
第一步：将化合物37(100mg，0.24mmol)溶于5mL二氯甲烷中，BOC-丙氨酸(54mg，0.29mmol)加入催化量的DMAP(6mg)，EDCI(52mg，0.29mmol)，室温反应24h。加少量水淬灭反应，由乙酸乙酯萃取三次，饱和食盐水洗涤，干燥后过滤，真空浓缩，柱层析得h-1，白色固体(102mg，收率72.4)。
第二步：将h-1(100mg,0.17mmol)溶于DCM中，冰浴搅拌下缓慢滴加0.5mL三氟乙酸，滴毕，继续反应0.5-1h。减压浓缩反应液，所得油状液体溶于DCM，萃取旋干，柱层析得化合物93，白色固体(52mg,收率62.6％)。 1H NMR(300MHz,CDCl 3)δ5.94(dd,J＝8.2,1.8Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.47(m,1H),5.14(d,J＝5.9Hz,1H),4.05(d,J＝5.5Hz,1H),4.01(d,J＝12.4Hz,1H),3.90(dd,J＝6.8,5.3Hz,1H),3.87–3.72(m,4H),3.38(dd,J＝7.2,6.3Hz,1H),3.21–3.13(m,2H),2.75(t,J＝4.7Hz,1H),2.61(m,2H),2.36(m,1H),1.86–1.73(m,4H),1.73–1.56(m,2H),1.42(d,J＝5.9Hz,3H),1.08(dd,J＝6.0,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ207.08,175.47,173.65,151.18,134.49,126.50,118.57,107.15,76.97,71.57,68.10,61.87,61.64,55.95,49.67,49.17,45.59,40.71,40.03,35.70,33.58,30.91,28.63,28.51,20.77,16.42.MS m/z＝490.2433[M+H]。
实施例94
Figure PCTCN2022141790-appb-000104
化合物94的合成参照化合物93进行制备；化合物94，白色固体(40mg，收率48.4％)。 1H NMR(300MHz,CDCl 3)δ5.94(dd,J＝8.2,1.8Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.47(M,1H),5.10(d,J＝6.2Hz,1H),4.05(d,J＝5.5Hz,1H),4.01(d,J＝12.4Hz,1H),3.90(dd,J＝6.8,5.3Hz,1H),3.87–3.69(m,6H),3.22(m,1H),3.16(m,1H),2.75(t,J＝4.7Hz,1H),2.61(m,2H),2.36(m,1H),1.86–1.56(m,7H),1.08(dd,J＝6.0,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ207.10,175.47,168.70,151.13,134.49,126.50,118.57,107.15,76.28,71.57,68.10,61.85,61.64,55.95,49.25,45.59,42.69,40.71,40.03,35.70,33.58,30.91,28.63,28.51,20.77.MS m/z＝476.2280[M+H]。
实施例95
Figure PCTCN2022141790-appb-000105
化合物95的合成参照化合物93进行制备；化合物95，白色固体(32mg，收率37.5％)。 1H NMR(300MHz,CDCl 3)δ7.06(m,2H),6.75–6.69(m,2H),6.14(s,1H),5.94(dd,J＝8.2,1.8Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.47(m,1H),5.13(d,J＝5.9Hz,1H),4.05(d,J＝5.5Hz,1H),4.03–3.93(m,2H),3.90(dd,J＝6.8,5.3Hz,1H),3.83(m,1H),3.81–3.72(m,2H),3.20–3.13(m,1H),3.10(m,1H),2.95(m,1H),2.78(dd,J＝7.4,6.7Hz,1H),2.75(t,J＝4.7Hz,1H),2.65– 2.57(m,3H),2.36(m,1H),1.86–1.73(m,4H),1.73–1.56(m,2H),1.08(dd,J＝6.0,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ207.07,175.47,171.16,156.84,151.16,134.49,130.17,129.82,126.50,118.57,115.18,107.14,77.06,71.57,68.10,61.87,61.64,55.95,53.39,49.16,45.59,40.71,40.03,38.02,35.70,33.58,30.91,28.63,28.51,20.77.MS m/z＝604.2522[M+Na]。
实施例96
Figure PCTCN2022141790-appb-000106
化合物96的合成参照化合物93进行制备；化合物96，白色固体(55mg，收率64.3％)。 1H NMR(300MHz,CDCl 3)δ8.79(d,J＝7.3Hz,1H),7.80(dd,J＝7.4,1.6Hz,1H),7.57(d,J＝7.3Hz,1H),7.39–7.33(m,1H),7.18–7.08(m,2H),5.94(dd,J＝8.2,1.8Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.47(m,1H),5.21(t,J＝6.4Hz,1H),5.09(d,J＝5.9Hz,1H),4.18(dd,J＝7.4,6.5Hz,1H),4.10(dd,J＝7.5,6.4Hz,1H),4.05(d,J＝5.5Hz,1H),4.01(d,J＝12.4Hz,1H),3.90(dd,J＝6.8,5.3Hz,1H),3.83(m,1H),3.81–3.72(m,2H),3.19–3.12(m,1H),2.75(t,J＝4.7Hz,1H),2.61(m,2H),2.36(m,1H),1.86–1.56(m,7H),1.08(dd,J＝6.0,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ207.08,175.47,170.86,151.15,138.26,134.49,127.53,126.50,125.55,122.02,120.62,119.77,118.57,113.47,112.40,107.15,76.98,71.57,68.10,61.90,61.64,55.95,55.50,49.01,45.60,40.71,40.03,35.70,33.58,30.91,28.63,28.51,20.77.MS m/z＝591.2769[M+H]。
实施例97
Figure PCTCN2022141790-appb-000107
将化合物37(50mg，0.12mmol)溶于5mL二氯甲烷中，加入苯甲酸(18mg，0.14mmol)加入催化量的DMAP(5mg)，EDCI(26mg，0.14mmol)，室温反应24h。加少量水淬灭反应，由乙酸乙酯萃取三次，饱和食盐水洗涤，干燥后过滤，真空浓缩，柱层析得化合物97，白色固体(25mg，收率40.0％)。 1H NMR(300MHz,CDCl 3)δ8.03–7.97(m,2H),7.58–7.51(m,1H),7.49–7.42(m,2H),5.94(dd,J＝8.2,1.8Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.47(m,1H),5.17(d,J＝5.9Hz,1H),4.05(d,J＝5.4Hz,1H),4.01(d,J＝12.4Hz,1H),3.92(dd,J＝6.6,5.3Hz,1H),3.83(m,1H),3.81–3.72(m,2H),3.18(m,1H),2.69(t,J＝4.7Hz,1H),2.61(m,2H),2.36(m,1H),1.86–1.57(m,6H),1.08(dd,J＝6.0,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ207.13,175.47,166.01,151.27,134.49,133.40,130.46,129.69,129.02,126.50,118.57,107.35,77.53,71.57,68.10,62.02,61.64,55.95,49.07,45.58,40.71,40.03,35.70,33.58,30.92,28.63,28.51,20.77.MS m/z＝523.2322[M+H]。
实施例98
Figure PCTCN2022141790-appb-000108
将化合物37(50mg,0.12mmol)溶于5mL无水的二氯甲烷中，加入催化量的DMAP(5mg)， 0.03mL醋酸酐，0.1mL三乙胺，室温搅拌3h。加少量水淬灭反应，由乙酸乙酯萃取三次，饱和食盐水洗涤，干燥后过滤，真空浓缩，柱层析得化合物98(44mg,收率80.0％)。 1H NMR(300MHz,CDCl 3)δ5.94(dd,J＝8.2,1.8Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.47(m,1H),5.19(d,J＝5.9Hz,1H),4.05(d,J＝5.5Hz,1H),4.01(d,J＝12.5Hz,1H),3.90(dd,J＝6.8,5.3Hz,1H),3.83(m,1H),3.81–3.72(m,2H),3.19–3.12(m,1H),2.75(t,J＝4.7Hz,1H),2.61(m,2H),2.36(m,1H),1.86–1.69(m,4H),1.72–1.56(m,2H),1.08(dd,J＝6.0,1.5Hz,6H). 13C NMR(75MHz,CDCl 3)δ207.03,175.47,170.21,151.15,134.49,126.50,118.57,107.05,75.07,71.57,68.10,61.71,61.64,55.95,49.40,45.63,40.71,40.03,35.70,33.58,30.91,28.63,28.51,21.08,20.77.MS m/z＝483.1979[M+Na]。
生物测试例
1.BMDM细胞培养
骨髓细胞取自6周龄C57BL/6雄性小鼠的股骨和胫骨，其简要描述如下：a)在动物房中，用脱颈法处死小鼠，在75％酒精中浸泡5-10min，固定小鼠，尽快用剪刀将小鼠四肢取下，剔除多余皮肉，暂放于0℃PBS缓冲液中；b)超净工作台中，准备好无菌剪刀镊子、PBS缓冲液、2ml注射器、细胞过滤器以及细胞培养板；c)将小鼠腿骨用PBS冲洗两次，用RPMI-1640培养基冲洗一次，置于干净的培养基中，将2ml注射器内吸满培养基，用剪刀剪开骨头两端，用镊子夹取骨头，然后用注射器将骨髓冲至50ml离心管中，反复数次，直至骨头由红色变为白色，证明骨髓全部冲出；d)用移液枪小心地将冲出的骨髓打散，用细胞过滤器除去多余的脂肪组织，滤液1000rpm，离心5min；e)弃上清，用含有M-SCF的新鲜培养基重悬，细胞计数仪计数，调整细胞密度至5×10 6后，按照实验目的将细胞种于相应的细胞培养板中，培养条件为37℃，5％CO 2；f)在细胞生长第三天，为细胞更换新鲜培养基，换液过程中可以除去不能贴壁的杂细胞，继续将细胞培养至第6-7天，观察细胞形态，为梭形说明细胞状态良好，可用于后续实验。
2.BMDM IL-1β释放抑制试验
将细胞接种于培养板，于第6-7天进行试验。弃培养基，用PBS清洗一次，更换新鲜RPMI-1640培养基，培养基中含有10％FBS以及1μg/ml的LPS，刺激4h；4h后弃去培养基，用PBS清洗一次，更换为不完全培养基，加入化合物，孵育0.5h；0.5h后加入ATP(2.5mM)刺激0.5h；0.5h后收集上清，2000rpm离心5min，弃去细胞碎片，取上清用于ELISA试验(ABclonal,Mouse IL-1βELISA Kit,RK00006)。详细步骤参考试剂盒说明书进行，利用GraphPad Prism8.0软件计算IC 50，结果如表1所示。
表1
化合物 IC 50 化合物 IC 50 化合物 IC 50 化合物 IC 50
1 C 2 B 3 B 4 B
5 C 6 C 7 C 8 B
9 B 10 B 11 C 12 C
13 D 14 D 15 C 16 B
17 A 18 B 19 C 20 A
21 A 22 D 23 C 24 B
25 A 26 C 27 B 28 A
29 B 30 B 31 C 32 C
33 B 34 C 35 D 36 B
37 A 38 A 39 A 40 C
41 C 42 D 43 C 44 D
45 A 46 C 47 C 48 B
49 C 50 B 51 B 52 D
53 D 54 B 55 B 56 A
57 B 58 B 59 B 60 C
61 C 62 C 63 C 64 C
65 C 66 B 67 B 68 B
69 D 70 C 71 C 72 B
73 D 74 C 75 C 76 C
77 C 78 B 79 B 80 D
81 C 82 B 83 C 84 C
85 B 86 B 87 B 88 B
89 C 90 C 91 C 92 C
93 B 94 B 95 C 96 D
97 C 98 B        
注：50≤A≤100nM；100＜B≤200nM；200＜C≤500nM；D＞500nM
结果表明：本发明化合物能有效抑制骨髓源巨噬细胞BMDM经LPS和ATP诱导建模后炎症因子IL-1β的释放。
3.化合物在小鼠膝关节炎模型中的试验
取4周大小鼠，进行称重，然后进行分组，每组5只，并测量膝关节的宽度。实验组口服或尾静脉给药(DMSO溶解，再依次加入Tween80和生理盐水稀释至所需浓度，使其最终比例DMSO：Tween80生理盐水为5：5：90)。0.5h后左膝关节注射MSU(0.5mg/20g；PBS溶解)；对照组注射等体积无菌PBS，于造模后1h，6h，12h，24h测量左膝关节宽度，计算关节肿胀度，部分化合物给药24h后，不同组别小鼠关节肿胀度如表2所示。造模24h后处死动物，将上述组别小鼠的左膝关节取出，放置于含有200μL opti-MEM培养1h，将培养的上清用ELISA方法检测IL-1β，释放量如表2所示。
表2
Figure PCTCN2022141790-appb-000109
Figure PCTCN2022141790-appb-000110
注：关节肿胀度为受试小鼠左膝关节24h时的宽度与0h时宽度的比值。
结果表明：本发明的化合物能够有效缓解MSU所导致的小鼠关节的肿胀程度。
表3
Figure PCTCN2022141790-appb-000111
结果表明：本发明的化合物能够有效缓解MSU所导致的小鼠关节中炎症因子IL-1β的释放。

Claims (10)

  1. 通式(Ⅰ)所示的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶：
    Figure PCTCN2022141790-appb-100001
    其中：
    A任选自氢、羟基、卤素、氰基、氨基、＝O、-OC(＝O)R 1a、或与相邻的Y和U一起形成取代或未取代的5～7元的芳杂环，取代基选自-NH-R 1，所述R 1a选自C 1-4烷基或C 1-4烯基；
    B任选自氢、羟基或OAc；
    L任选自氢、羟基、卤素、氰基、氨基或＝O；
    U、Y和Z为碳原子；U-Y键和Y-Z键各自独立的为碳碳单键或碳碳双键；
    M选自取代或未取代的以下基团：
    Figure PCTCN2022141790-appb-100002
    n相同或不同，各自独立的为0、1、2、3或4；
    R 2a相同或不同，各自独立的选自氢、氨基、羧基、醛基、羟基、卤素、巯基、氰基、硝基，或R 2a选自取代的或未取代的以下基团：C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基或5～6元杂芳基；
    R 3a、R 4a相同或不同，各自独立的选自氢或取代的或未取代的以下基团：C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基、5～6元杂芳基、C 8-10桥环或-(CH 2) m-R 5a；其中m为0、1或2，R 5a选自C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基、5～6元杂芳基；
    E环为取代或未取代的5～6元杂环烷基或5～6元杂芳基；
    M的取代基选自氢、氨基、羧基、＝O、醛基、羟基、卤素、巯基、氰基、硝基、C l-4烷基、C l-4烷氧基或C l-4卤代烷基；
    K选自氢原子或取代或未取代的以下基团：-C(＝O)R 6a或-C(＝O)CH(R 5a)NH 2基；
    R 6a选自氢或取代或未取代的以下基团：C l-4烷基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基；取代基选自氨基、羧基、醛基、羟基、卤素、巯基、氰基或硝基。
  2. 根据权利要求1所述的通式(Ⅰ)所示的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶，其特征在于，U、Y和Z为碳原子；U-Y键为碳碳单键或碳碳双键；Y-Z键为碳碳单键。
  3. 式I-1～I-9任一结构的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶：
    Figure PCTCN2022141790-appb-100003
    其中，M选自取代或未取代的以下基团：
    Figure PCTCN2022141790-appb-100004
    n相同或不同，各自独立的为0、1、2、3或4；
    R 2a相同或不同，各自独立的选自氢、氨基、羧基、醛基、羟基、卤素、巯基、氰基、硝基，或R 2a选自取代的或未取代的以下基团：C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基或5～6元杂芳基；
    R 3a、R 4a相同或不同，各自独立的选自氢或取代的或未取代的以下基团：C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基、5～6元杂芳基、C 8-10桥环或-(CH 2) m-R 5a；其中m为0、1或2，R 5a选自C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基、5～6元杂芳基；
    E环为取代或未取代的5～6元杂环烷基或5～6元杂芳基；
    M的取代基选自氢、氨基、羧基、＝O、醛基、羟基、卤素、巯基、氰基、硝基、C l-4烷基、C l-4烷氧基或C l-4卤代烷基；
    K选自氢原子或取代或未取代的以下基团：-C(＝O)R 6a或-C(＝O)CH(R 5a)NH 2基；
    R 6a选自氢或取代或未取代的以下基团：C l-4烷基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基；取代基选自氨基、羧基、醛基、羟基、卤素、巯基、氰基或硝基。
  4. 式(II)所示的化合物或其立体异构体、水合物、代谢产物、氘代物、溶剂化物、药学上可接受的盐或共晶：
    Figure PCTCN2022141790-appb-100005
    其中：M选自取代或未取代的基团：
    Figure PCTCN2022141790-appb-100006
    n相同或不同，各自独立的为0、1、2、3或4；
    R 2a相同或不同，各自独立的选自氢、氨基、羧基、醛基、羟基、卤素、巯基、氰基、硝基，或R 2a选自取代的或未取代的以下基团：C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基或5～6元杂芳基；
    R 3a、R 4a相同或不同，各自独立的选自氢或取代的或未取代的以下基团：C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基、5～6元杂芳基、C 8-10桥环或-(CH 2) m-R 5a；其中m为0、1或2，R 5a选自C l-6烷基、C 3-8环烷基、5～6元杂环烷基、C 6-10芳基、5～6元杂芳基；
    E环为取代或未取代的5～6元杂环烷基或5～6元杂芳基；
    M的取代基选自氢、氨基、羧基、＝O、醛基、羟基、卤素、巯基、氰基、硝基、C l-4烷基、C l-4烷氧基或C l-4卤代烷基。
  5. 如下任一所示化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶：
    Figure PCTCN2022141790-appb-100007
    Figure PCTCN2022141790-appb-100008
    Figure PCTCN2022141790-appb-100009
  6. 权利要求1～5任一项所述的化合物的制备方法。
  7. 一种组合物，包括权利要求1～5任一项所述的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶，以及药学上可接受的载体。
  8. 权利要求1～5任一项所述的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶，或权利要求7所述的组合物在用于制备NLRP3抑制剂药物中的应用。
  9. 权利要求1～5任一项所述的化合物，及其光学活性体或消旋体、非对映异构体混合物，溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶，或权利要求7所述的组合物在用于制备抗炎症药物中的应用。
  10. 根据权利要求8所述的应用，其特征在于，所述炎症为由NLRP3炎症小体激活所引起的关节炎或皮肤病。
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102321096A (zh) * 2011-06-14 2012-01-18 华南理工大学 一种抗癌化合物
CN105473566A (zh) * 2013-04-05 2016-04-06 德克萨斯大学系统董事会 冬凌草素类似物、组合物及与其相关的方法
CN110151749A (zh) * 2018-02-13 2019-08-23 中国科学技术大学 冬凌草甲素在制备预防或治疗nlrp3炎症小体相关疾病的药物中的应用
WO2021185912A1 (en) * 2020-03-19 2021-09-23 Softhale Nv Method for the treatment nlrp3-associated diseases
CN114874172A (zh) * 2022-06-29 2022-08-09 南充市中心医院 一种冬凌草甲素衍生物及其制备方法和医用用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102321096A (zh) * 2011-06-14 2012-01-18 华南理工大学 一种抗癌化合物
CN105473566A (zh) * 2013-04-05 2016-04-06 德克萨斯大学系统董事会 冬凌草素类似物、组合物及与其相关的方法
CN110151749A (zh) * 2018-02-13 2019-08-23 中国科学技术大学 冬凌草甲素在制备预防或治疗nlrp3炎症小体相关疾病的药物中的应用
WO2021185912A1 (en) * 2020-03-19 2021-09-23 Softhale Nv Method for the treatment nlrp3-associated diseases
CN114874172A (zh) * 2022-06-29 2022-08-09 南充市中心医院 一种冬凌草甲素衍生物及其制备方法和医用用途

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