CN113230240B - 1,3-diphenylprop-2-en-1-one derivative and application thereof - Google Patents

1,3-diphenylprop-2-en-1-one derivative and application thereof Download PDF

Info

Publication number
CN113230240B
CN113230240B CN202110317148.8A CN202110317148A CN113230240B CN 113230240 B CN113230240 B CN 113230240B CN 202110317148 A CN202110317148 A CN 202110317148A CN 113230240 B CN113230240 B CN 113230240B
Authority
CN
China
Prior art keywords
compound
dmso
group
preparation
yield
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202110317148.8A
Other languages
Chinese (zh)
Other versions
CN113230240A (en
Inventor
胡文辉
杨忠金
孙平
张�成
岳虎
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangzhou Medical University
Original Assignee
Guangzhou Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangzhou Medical University filed Critical Guangzhou Medical University
Priority to CN202110317148.8A priority Critical patent/CN113230240B/en
Publication of CN113230240A publication Critical patent/CN113230240A/en
Application granted granted Critical
Publication of CN113230240B publication Critical patent/CN113230240B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Abstract

The invention provides a 1,3-diphenylprop-2-en-1-one derivative shown in formula (I) or a pharmaceutically acceptable salt thereof, and an application of the derivative as an active ingredient in preparation of an NLRP3 inflammasome inhibitor. The compounds can selectively inhibit the activation of NLRP3 inflammasome, thereby treating or improving diseases related to NLRP3 inflammasome, such as: acute peritonitis and colitis, thus can be used for preparing the therapeutic drug of the disease related to NLRP3 inflammasome.
Figure DDA0002987353620000011

Description

1,3-diphenylprop-2-en-1-one derivative and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to 1,3-diphenylprop-2-en-1-one derivatives and application thereof.
Background
The NLRP3 inflammasome is an NOD-like receptor, consists of an inflammasome sensor molecule (NLRP 3 protein), a linker protein ASC and an effector molecule caspase-1 precursor protein (pro-caspase-1), and is a multi-protein compound existing in cytoplasm. Upon activation of NLRP3 inflammasome, pro-caspase-1 self-cleaves to active caspase-1, further cleaving Pro-IL-1 β and Pro-IL-18 to active interleukin-1 β (IL-1 β) and interleukin-18 (IL-18), ultimately leading to an inflammatory response and apoptosis of cells. There is a large body of evidence that many human diseases, such as alzheimer's disease, gout, multiple sclerosis, type II diabetes, inflammatory bowel disease, etc., are closely associated with NLRP3 inflammasome. To date, several NLRP3 inflammasome inhibitors have been discovered, but none have been clinically useful. Therefore, the discovery of new inhibitors of NLRP3 inflammasome is of great significance for the treatment of NLRP 3-related diseases.
Disclosure of Invention
Based on the above, the invention discloses 1,3-diphenylprop-2-en-1-one derivatives, and the 1,3-diphenylprop-2-en-1-one derivatives can selectively inhibit the activation of NLRP3 inflammasome, so that diseases related to NLRP3 inflammasome can be treated or improved, for example: acute peritonitis and colitis.
The specific technical scheme is as follows:
the 1,3-diphenylprop-2-en-1-one derivative shown in the formula (I) or the pharmaceutically acceptable salt thereof is used as an active ingredient for preparing an NLRP3 inflammation corpuscle inhibitor;
Figure BDA0002987353600000011
wherein, the first and the second end of the pipe are connected with each other,
q is selected from: -COOH, -OR 4 ；
R 1 Selected from the group consisting of: c 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, amino, C 1 -C 6 Alkylamino, phenyl, R 7 Substituted phenyl, halogen, C 1 -C 6 Alkylsulfinyl radical, C 1 -C 6 Alkylsulfonyl, thiazolyl, R 7 Substituted thiazolyl, R 7 Substituted benzenesulfonamide group, C 1 -C 6 Alkylamino sulfonamide group, C 1 -C 6 Alkylsulfonamide group, acrylamide group, C 1 -C 6 Alkylamido, or-NHCONH-R 8 ；
R 2 、R 3 、R 5 、R 6 、R 7 Each independently selected from: hydrogen, hydroxy, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, carboxyl;
R 4 selected from: hydrogen, C 1 -C 6 Alkyl, carboxyl substituted C 1 -C 6 Alkyl, hydroxy substituted C 1 -C 6 Alkyl, 5-6 membered heterocyclyl substituted C 1 -C 6 Alkyl, -CONH-R 9 Carboxy-substituted allyl, or R 4 And R 3 Are connected to form a 5-6 membered heterocyclic structure;
R 8 selected from: hydrogen, C 1 -C 6 Alkyl radical, R 7 A substituted phenyl group;
R 9 selected from the group consisting of: hydrogen, C 1 -C 6 An alkyl group.
In some of these embodiments, R 1 Selected from the group consisting of: c 1 -C 3 Alkylthio, amino, C 1 -C 3 Alkylamino radical, halogen, C 1 -C 3 Alkylsulfinyl radical, C 1 -C 3 Alkylsulfonyl, halogen-substituted benzenesulfonamide group, C 1 -C 3 Alkylamino sulfonamide group, C 1 -C 3 Alkylsulfonamide group, acrylamide group, C 1 -C 3 Alkylamido, or-NHCONH-R 8 。
In some of these embodiments, R 1 Selected from the group consisting of: methylthio groupAmino, dimethylamino, phenyl, fluoro, chloro, iodo, bromo, methylsulfinyl, methylsulfonyl, thiazolyl, methyl-substituted thiazolyl, ethylsulfonamido, p-fluorobenzsulfonamido, isopropylaminosulfonamido, acrylamido, -NHCONH-R 8 Wherein R is 8 Selected from: isopropyl, propyl, fluorophenyl, tolyl.
In some of these embodiments, R 2 、R 3 、R 5 、R 6 、R 7 Each independently selected from: hydrogen, hydroxy, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halogen.
In some of these embodiments, R 2 、R 3 、R 5 、R 6 、R 7 Each independently selected from: hydrogen, hydroxy, methyl, methoxy, ethyl, halogen.
In some of these embodiments, R 2 Selected from: hydrogen, halogen, C 1 -C 3 An alkyl group.
In some of these embodiments, R 2 Selected from the group consisting of: hydrogen, fluorine, methyl.
In some of these embodiments, R 3 Selected from: hydrogen, halogen, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, hydroxyl.
In some of these embodiments, R 3 Selected from the group consisting of: hydrogen, methyl, methoxy, chlorine, fluorine, ethyl and hydroxyl.
In some of these embodiments, R 5 Selected from: hydrogen, C 1 -C 3 Alkyl radical, C 1 -C 3 An alkoxy group.
In some of these embodiments, R 5 Selected from: hydrogen, methyl, ethyl, methoxy.
In some of these embodiments, R 6 Selected from: hydrogen, C 1 -C 3 An alkyl group.
In some of these embodiments, R 6 Selected from the group consisting of: hydrogen, methyl.
In some of these embodiments, R 7 Selected from the group consisting of: hydrogen, halogen, C 1 -C 3 An alkyl group.
In some of these embodiments, R 7 Selected from: hydrogen, fluorine, methyl.
In some of these embodiments, R 4 Selected from: hydrogen, C 1 -C 3 Alkyl, carboxy substituted C 1 -C 6 Alkyl, hydroxy-substituted C 1 -C 3 Alkyl, 6-membered heterocyclyl substituted C 1 -C 3 Alkyl, -CONH-R 9 Carboxy-substituted allyl, or R 4 And R 3 Are connected to form a 5-membered heterocyclic structure; wherein R is 9 Selected from the group consisting of: hydrogen, C 1 -C 3 An alkyl group.
In some of these embodiments, R 4 Selected from the group consisting of: hydrogen, methyl, or the following structure:
Figure BDA0002987353600000031
or R 4 And R 3 Are linked to form a 5-membered heterocyclic structure.
In some of these embodiments, Q is selected from: -OH, COOH, hydroxy-substituted ethoxy, and, R 2 And R 6 Is not simultaneously C 1 -C 6 Alkyl radical, R 3 And R 5 Is not simultaneously C 1 -C 6 An alkoxy group.
In some of these embodiments, the 1,3-diphenylprop-2-en-1-one derivative has the structure of formula (II):
Figure BDA0002987353600000032
wherein Q is selected from: -OH, COOH, hydroxy-substituted ethoxy, and, R 2 And R 6 Is not simultaneously C 1 -C 6 Alkyl radical, R 3 And R 5 Is not simultaneously C 1 -C 6 An alkoxy group.
In some of these embodiments, the 1,3-diphenylprop-2-en-1-one derivative has the structure of formula (III):
Figure BDA0002987353600000033
R 1 selected from: c 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, amino, C 1 -C 6 Alkylamino radical, halogen, C 1 -C 6 Alkylsulfinyl radical, C 1 -C 6 Alkylsulfonyl radical, R 7 Substituted benzenesulfonamido, C 1 -C 6 Alkylamino sulfonamide group, C 1 -C 6 Alkylsulfonamide group, acrylamide group, C 1 -C 6 Alkylamido, or-NHCONH-R 8 。
In some of these embodiments, R 1 Selected from: c 1 -C 3 Alkylthio, amino, C 1 -C 3 Alkylamino radical, halogen, C 1 -C 3 Alkylsulfinyl radical, C 1 -C 3 Alkylsulfonyl, halogen-substituted benzenesulfonamide group, C 1 -C 3 Alkylamino sulfonamide group, C 1 -C 3 Alkylsulfonamide group, acrylamide group, C 1 -C 3 Alkylamido, or-NHCONH-R 8 。
In some of these embodiments, R 1 Selected from: c 1 -C 3 Alkylsulfinyl, halogen-substituted benzenesulfonamide, C 1 -C 3 Alkyl amino sulfonamide and acrylamide groups.
In some of these embodiments, R 1 Selected from the group consisting of: methylthio group, amino group, dimethylamino group, fluorine, chlorine, methylsulfinyl group, methylsulfonyl group, ethylsulfonamido group, p-fluorobenzenesulfonamido group, isopropylaminosulfonamido group, acrylamido group, -NHCONH-R 8 Wherein R is 8 Selected from: isopropyl, fluorophenyl.
In some of these embodiments, the 1,3-diphenylprop-2-en-1-one derivative has the structure of formula (IV):
Figure BDA0002987353600000041
wherein R is 4 Selected from: c 1 -C 3 Alkyl, hydroxy-substituted C 1 -C 3 Alkyl, 6-membered heterocyclyl substituted C 1 -C 3 Alkyl, -CONH-R 9 Carboxyl-substituted allyl, carboxyl-substituted C 4 -C 6 An alkyl group; wherein R is 9 Selected from: hydrogen, C 1 -C 3 An alkyl group.
In some of these embodiments, the 1,3-diphenylprop-2-en-1-one derivative has the structure of formula (V):
Figure BDA0002987353600000042
the 1,3-diphenylprop-2-en-1-one derivative or the pharmaceutically acceptable salt thereof is used as an active ingredient in the preparation of medicines for preventing and/or treating diseases related to NLRP3 inflammasome.
In some of these embodiments, the disease associated with NLRP3 inflammasome is peritonitis and colitis.
In some of these embodiments, the peritonitis is acute peritonitis.
The invention also provides a pharmaceutical composition for preventing and treating NLRP3 inflammasome-related diseases.
The specific technical scheme is as follows:
a pharmaceutical composition for preventing and treating NLRP3 inflammasome-related diseases is prepared from an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the 1,3-diphenylprop-2-en-1-one derivative or pharmaceutically acceptable salts thereof.
Compared with the prior art, the invention has the following beneficial effects:
the invention discovers 1,3-diphenylprop-2-en-1-one derivatives which can selectively inhibit the activation of NLRP3 inflammasome, thereby treating or improving diseases related to NLRP3 inflammasome, such as: acute peritonitis and colitis, thus can be used for preparing the therapeutic drug of the disease related to NLRP3 inflammasome.
Drawings
Figure 1 is a graph of the results of compound 40 specifically inhibiting activation of NLRP3 inflammasome and inhibiting apoptosis in vitro.
FIG. 2 is a graph showing the results of inhibition of LPS-induced acute peritonitis by Compound 40.
Figure 3 is a graph of the results of compound 40 in ameliorating Dextran Sodium Sulfate (DSS) -induced colitis.
Detailed Description
In the compounds of the invention, when any variable (e.g. R) 7 Etc.) occur more than one time in any constituent, then the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. The line drawn from a substituent into the ring system indicates that the indicated bond may be attached to any ring atom capable of substitution. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by those skilled in the art and by the methods set forth below from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon radicals having the specified number of carbon atoms. For example, "C 1 -C 6 Alkyl radical "middle" C 1 -C 6 The definition of "includes groups having 1, 2,3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. For example, "C 1 -C 6 Alkyl "specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl.
The term "alkoxy" as used herein refers to a group having the structure-O-alkyl, such as-OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 2 CH 3 、-O-CH 2 CH(CH 3 ) 2 、-OCH 2 CH 2 CH 2 CH 3 、-O-CH(CH 3 ) 2 And the like.
The term "alkylthio" as used herein refers to a group having the structure-S-alkyl, such as-SCH 3 、-SCH 2 CH 3 、-SCH 2 CH 2 CH 3 、-S-CH 2 CH(CH 3 ) 2 、-SCH 2 CH 2 CH 2 CH 3 、-S-CH(CH 3 ) 2 And the like.
The term "alkylamino" as used herein refers to a group in which one or two hydrogen atoms of an amino group are substituted with an alkyl group, such as dimethylamino, diethylamino, methylamino, ethylamino, and the like.
The term "heterocyclyl" as used herein, refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic ring substituent wherein one or more ring atoms is selected from the group consisting of N, O or S (O) m (where m is an integer of 0 to 2), the remaining ring atoms are carbon, and bicyclic or polycyclic rings including spiro, fused, and bridged rings. For example: morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, and the like, and N-oxides thereof. Attachment of the heterocyclic substituent may be through a carbon atom or through a heteroatom.
As understood by those skilled in the art, "halo" or "halo" as used herein means chloro, fluoro, bromo, and iodo.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The starting materials in the following examples are commercially available or prepared by methods known in the art or according to the methods described herein.
The synthetic route of the compounds of the invention is as follows:
Figure BDA0002987353600000061
wherein, the synthetic route of the intermediate 1h-1l is as follows:
Figure BDA0002987353600000062
example 1: (E) Preparation of (E) -3- (4-methoxy-3,5-dimethylphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 1)
Figure BDA0002987353600000071
4-Methylthioacetophenone (200mg, 1.20mmol) and 3,5-dimethyl-4-methoxybenzaldehyde (197mg, 1.20mmol) were dissolved in 5mL of methanol, followed by addition of sodium hydroxide (481mg, 12.03mmol), stirring at room temperature for 24 hours, solid precipitated and recrystallized from methanol to give 270mg of a white solid, a yield of 77%. 1 H NMR(400MHz,CDCl 3 )δ7.97–7.93(m,2H),7.72(d,J＝15.6Hz,1H),7.42(d,J＝15.6Hz,1H),7.33–7.27(m,2H),3.75(s,3H),2.53(s,3H),2.32(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ189.4,159.4,145.6,144.6,134.8,131.7,130.6,129.4,129.1,125.2,120.7,59.9,16.4,15.0；HRMS(ESI)calcd for C19H20O2S(M+H)+313.1257,found 313.1278.
Example 2: (E) Preparation of (E) -1- (4-aminophenyl) -3- (4-methoxy-3,5-dimethylphenyl) prop-2-en-1-one (Compound 2)
Figure BDA0002987353600000072
By reference to the procedure of example 1, to giveTo a yellow solid, yield 63%. 1 HNMR(400MHz,DMSO-d 6 )δ7.97–7.87(m,2H),7.75(d,J＝15.4Hz,1H),7.57–7.42(m,3H),6.69–6.56(m,2H),6.15(s,2H),3.68(s,3H),2.25(s,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ185.8,158.3,153.8,141.3,131.1,130.9,130.6,129.2,125.5,121.1,112.7,59.4,15.9；HRMS(ESI)calcd for C18H19NO2(M+H)+282.1489,282.1489.
Example 3: (E) Preparation of (E) -1- (4- (dimethylamino) phenyl) -3- (4-methoxy-3,5-dimethylphenyl) prop-2-en-1-one (Compound 3)
Figure BDA0002987353600000073
Referring to the procedure of example 1, a yellow solid was obtained in 75% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.14–8.00(m,2H),7.78(d,J＝15.5Hz,1H),7.59–7.51(m,3H),6.80–6.70(m,2H),3.68(s,3H),3.04(s,6H),2.26(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ186.1,158.4,153.3,141.5,130.9,130.7,130.6,129.2,125.3,121.1,110.8,59.4,39.6,15.8；HRMS(ESI)calcd for C 20 H 23 NO 2 (M+H) + 310.1802,found 310.1804.
Example 4: (E) Preparation of (E) -3- (2,3-dihydrobenzofuran-5-yl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 4)
Figure BDA0002987353600000081
Referring to the procedure of example 1, a yellow solid was obtained in 74% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.12–8.05(m,2H),7.85(d,J＝1.7Hz,1H),7.77(d,J＝15.4Hz,1H),7.69(d,J＝15.4Hz,1H),7.61(dd,J＝8.3,1.9Hz,1H),7.42–7.36(m,2H),6.84(d,J＝8.3Hz,1H),4.61(t,J＝8.7Hz,2H),3.23(t,J＝8.7Hz,2H),2.55(s,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.7,162.2,145.2,144.2,134.1,130.7,128.9,128.6,127.5,125.4,124.9,118.6,109.3,71.8,28.6,14.0；HRMS(ESI)calcd for C 18 H 16 O 2 S(M+H) + 297.0944,found297.0967.
Example 5: (E) Preparation of (E) -1-isopropyl-3- (4- (3- (4-methoxy-3,5-dimethylphenyl) acryloyl) phenyl) urea (Compound 5)
Figure BDA0002987353600000082
Compound 2 (50mg, 0.18mmol) and isopropyl isocyanate (18mg, 0.21mmol) were dissolved in 1.5mL of toluene. After the reaction solution was heated to 70 ℃ and stirred overnight, the formed precipitate was filtered and washed with toluene, and dried to obtain 48mg of a yellow solid in 74% yield. 1 H NMR(400MHz,DMSO-d 6 )δ8.78(s,1H),8.10–8.03(m,2H),7.80(d,J＝15.5Hz,1H),7.63–7.52(m,5H),6.19(d,J＝7.5Hz,1H),3.84–3.74(m,1H),3.69(s,3H),2.26(s,6H),1.11(d,J＝6.5Hz,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.1,158.7,154.0,145.3,142.7,131.0,130.4,130.3,130.1,129.5,120.8,116.6,59.4,41.1,22.9,15.9；HRMS(ESI)calcd for C 22 H 26 N 2 O 3 (M+H) + 367.2016,found 367.2013.
Example 6: (E) Preparation of (E) -1- (4- (3- (4-methoxy-3,5-dimethylphenyl) acryloyl) phenyl) -3-propylurea (Compound 6)
Figure BDA0002987353600000083
Referring to the procedure of example 5, a yellow solid was obtained in 74% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.91(s,1H),8.11–8.00(m,2H),7.80(d,J＝15.5Hz,1H),7.69–7.49(m,5H),6.33(t,J＝5.7Hz,1H),3.69(s,3H),3.11–3.02(m,2H),2.26(s,6H),1.54–1.39(m,2H),0.88(t,J＝7.4Hz,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.1,158.7,154.8,145.4,142.7,131.0,130.4,130.4,129.5,120.8,116.6,59.4,40.9,22.9,15.9,11.4；HRMS(ESI)calcd for C 22 H 26 N 2 O 3 (M+H) + 367.2016,found367.2019.
Example 7: (E) Preparation of (E) -1- (4-fluorophenyl) -3- (4- (3- (4-methoxy-3,5-dimethylphenyl) acryloyl) phenyl) urea (Compound 7)
Figure BDA0002987353600000091
Referring to the procedure of example 5, a yellow solid was obtained in 95% yield. 1 HNMR(400MHz,DMSO-d 6 )δ9.14(s,1H),8.85(s,1H),8.18–8.04(m,2H),7.82(d,J＝15.5Hz,1H),7.67–7.55(m,5H),7.53–7.44(m,2H),7.21–7.08(m,2H),3.69(s,3H),2.26(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.2,158.7,157.6(d,J＝237.0Hz),152.3,144.4,142.9,135.6(d,J＝2.6Hz),131.2,130.9,130.3,130.0,129.5,120.3(d,J＝7.9Hz),120.3,117.3,115.4(d,J＝22.3Hz)59.4,15.8；HRMS(ESI)calcd for C 25 H 23 FN 2 O 3 (M+H) + 419.1765,found419.1777.
Example 8: (E) Preparation of (E) -1- (4- (3- (4-methoxy-3,5-dimethylphenyl) acryloyl) phenyl) -3- (p-tolyl) urea (compound 8)
Figure BDA0002987353600000092
Referring to the procedure of example 5, a yellow solid was obtained in 90% yield. 1 HNMR(400MHz,DMSO-d 6 )δ9.10(s,1H),8.70(s,1H),8.18–8.01(m,2H),7.82(d,J＝15.4Hz,1H),7.67–7.50(m,5H),7.41–7.28(m,2H),7.16–7.02(m,2H),3.69(s,3H),2.27(s,6H),2.25(s,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.2,158.7,152.2,144.5,142.9,136.7,131.1,131.1,130.9,130.3,130.0,129.5,129.2,120.7,118.6,117.2,59.4,20.4,15.8；HRMS(ESI)calcd for C 26 H 26 N 2 O 3 (M+H) + 415.2016,found415.2021.
Example 9: (E) Preparation of (E) -3- (4-hydroxy-3,5-dimethylphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 9)
Figure BDA0002987353600000093
4-Methylthioacetophenone (2.33g, 14.00mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (2.10g, 14.00mmol) were added to 20mL of a hydrogen chloride methanol solution (4 mol/L), stirred at room temperature for 24h, and the precipitate formed was filtered and dried to give 3.20g of a yellow solid in 77% yield. 1 H NMR(400MHz,DMSO-d 6 )δ8.94(s,1H),8.14–8.02(m,2H),7.71(d,J＝15.4Hz,1H),7.60(d,J＝15.4Hz,1H),7.49(s,2H),7.43–7.34(m,2H),2.55(s,3H),2.20(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.8,156.3,145.2,144.6,134.2,129.7,129.0,125.8,125.0,124.7,118.2,16.7,14.0；HRMS(ESI)calcd for C 18 H 18 O 2 S(M+H) + 299.1100,found 299.1106.
Example 10: (E) Preparation of (E) -2- (2,6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenoxy) acetic acid (Compound 10)
Figure BDA0002987353600000101
Compound 9 (200mg, 0.67mmol) and ethyl bromoacetate (224mg, 1.34mmol) were dissolved in 2mL of anhydrous DMF solution, potassium carbonate (463mg, 3.35mmol) was added, stirred at 90 ℃ for 6h, then the reaction was diluted with water and extracted with ethyl acetate, the organic layers were combined, concentrated and purified by silica gel column to give the intermediate carboxylate as a yellow oil, 183mg, 71% yield. The above-mentioned carboxylate (300mg, 0.78mmol) was dissolved in THF/H 2 To O (8 mL/8 mL), lithium hydroxide (112mg, 4.68mmol) was added and stirred at 50 ℃ overnight, then the solution was adjusted to pH =2 with hydrochloric acid (1 mol/L) and extracted with ethyl acetate, and the organic layers were combined, concentrated and purified by silica gel column to give compound 10 as a yellow solid, 180mg, 65% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.14–8.03(m,2H),7.80(d,J＝15.5Hz,1H),7.61(d,J＝15.5Hz,1H),7.56(s,2H),7.43–7.29(m,2H),4.43(s,2H),2.55(s,3H),2.27(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.9,170.2,157.4,145.5,143.5,133.9,131.1,130.5,129.7,129.1,125.0,120.8,68.8,16.1,14.0；HRMS(ESI)calcd for C 20 H 20 O 4 S(M+H) + 357.1155,found 357.1159.
Example 11: (E) Preparation of (E) -3- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 11)
Figure BDA0002987353600000102
Compound 9 (100mg, 0.34mmol) and 2-bromoethanol (125mg, 1.00mmol) were dissolved in 2mL of anhydrous DMF solution, potassium carbonate (232mg, 1.68mmol) was added, stirring was carried out at 90 ℃ for 6h, then the reaction was diluted with water and extracted with ethyl acetate, the organic layers were combined, concentrated and purified by silica gel column to give 65mg of a yellow solid in 57% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.12–8.06(m,2H),7.80(d,J＝15.5Hz,1H),7.62(d,J＝15.5Hz,1H),7.56(s,2H),7.42–7.37(m,2H),4.91(t,J＝5.5Hz,1H),3.84–3.79(m,2H),3.74–3.68(m,2H),2.56(s,3H),2.28(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.8,157.9,145.4,143.6,133.9,131.2,130.0,129.7,129.0,125.0,120.5,74.0,60.5,16.0,14.0；HRMS(ESI)calcd for C 20 H 22 O 3 S(M+H) + 343.1362,found 343.1364.
Example 12: (E) Preparation of (E) -2- (2,6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenoxy) butanoic acid (Compound 12)
Figure BDA0002987353600000103
Compound 9 (200mg, 0.67mmol) and methyl 2-bromobutyrate (363mg, 2.01mmol) were dissolved in 2mL of anhydrous DMF solution, potassium carbonate (463mg, 3.35mmol) was added, stirring was carried out at 90 ℃ for 6h, then the reaction was diluted with water and extracted with ethyl acetate, the organic layers were combined, concentrated and purified by silica gel column to give the intermediate carboxylate as a yellow oil,210mg, yield 79%. The above-mentioned carboxylate (200mg, 0.50mmol) was dissolved in THF/H 2 To O (5 mL/5 mL), lithium hydroxide (72mg, 3.00mmol) was added and stirred at 50 ℃ overnight, then the solution was adjusted to pH =2 with hydrochloric acid (1 mol/L) and extracted with ethyl acetate, the organic layers were combined, concentrated and purified by silica gel column to give compound 12 as a yellow solid, 120mg, 62% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.14–8.04(m,2H),7.80(d,J＝15.6Hz,1H),7.61(d,J＝15.6Hz,1H),7.55(s,2H),7.44–7.35(m,2H),4.44(t,J＝5.9Hz,1H),2.55(s,3H),2.28(s,6H),1.97–1.81(m,2H),0.98(t,J＝7.4Hz,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.8,172.1,157.0,145.5,143.5,133.9,130.8,129.9,129.9,129.1,125.0,120.6,81.2,25.7,16.9,14.0,9.0；HRMS(ESI)calcd for C 22 H 24 O 4 S(M+H) + 385.1468,found 385.1473.
Example 13: (E) Preparation of (E) -2- (2,6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenoxy) -2-methylpropionic acid (Compound 13)
Figure BDA0002987353600000111
Compound 9 (150mg, 0.50mmol) and tert-butyl 2-bromo-2-methylpropionate (336 mg, 1.51mmol) were dissolved in 2mL of anhydrous DMF solution, potassium carbonate (347mg, 2.51mmol) was added, stirring was carried out at 90 ℃ for 6h, then the reaction solution was diluted with water and extracted with ethyl acetate, the organic layers were combined, concentrated and purified by silica gel column to give the intermediate carboxylate as a yellow oil, 180mg, 82% yield. The above carboxylate (180mg, 0.41mmol) was dissolved in dichloromethane, and trifluoroacetic acid (466mg, 4.08mmol) was added and stirred at normal temperature overnight, concentrated and purified by silica gel column to give compound 13 as a yellow solid, 110mg, yield 70%. 1 HNMR(400MHz,DMSO-d 6 )δ8.21–7.99(m,2H),7.80(d,J＝15.6Hz,1H),7.61(d,J＝15.6Hz,1H),7.55(s,2H),7.42–7.36(m,2H),2.56(s,3H),2.22(s,6H),1.39(s,6H)； 13 C NMR(101MHz,DMSO-d 6 )δ187.78,174.96,154.94,145.40,143.32,133.87,133.14,130.19,129.33,129.00,124.93,120.84,80.69,24.99,17.53,13.94；HRMS(ESI)calcd for C 22 H 24 O 4 S(M+H) + 385.1468,found 385.1468.
Example 14: (E) Preparation of (E) -2- ((2,6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenoxy) meth) acrylic acid (Compound 14)
Figure BDA0002987353600000112
Compound 9 (200mg, 0.67mmol) and methyl 2- (bromomethyl) acrylate (239mg, 1.34mmol) were dissolved in 2mL of anhydrous DMF and potassium carbonate (463mg, 3.35mmol) was added and stirred at 90 ℃ for 6h, after which the reaction was diluted with water and extracted with ethyl acetate, the organic layers were combined, concentrated and purified by silica gel column to give the intermediate carboxylate as a yellow oil, 185mg, 70% yield. The above-mentioned carboxylate (185mg, 0.47mmol) was dissolved in THF/H 2 To O (5 mL/5 mL), lithium hydroxide (67mg, 2.80mmol) was added and stirred at 50 ℃ overnight, then the solution was adjusted to pH =2 with hydrochloric acid (1 mol/L) and extracted with ethyl acetate, and the organic layers were combined, concentrated and purified by silica gel column to give compound 14 as a yellow solid, 55mg, 31% yield. 1 HNMR(400MHz,CDCl 3 )δ7.98–7.94(m,2H),7.73(d,J＝15.6Hz,1H),7.42(d,J＝15.6Hz,1H),7.35–7.28(m,4H),6.60–6.56(m,1H),6.29–6.25(m,1H),4.56–4.52(m,2H),2.54(s,3H),2.31(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.9,166.8,157.5,145.5,143.6,137.6,133.9,131.3,130.4,129.7,129.1,126.7,125.0,120.8,70.2,16.1,14.0；HRMS(ESI)calcd for C 22 H 22 O 4 S(M+H) + 383.1312,found 383.1315.
Example 15: (E) Preparation of (E) -5- (2,6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenoxy) pentanoic acid (Compound 15)
Figure BDA0002987353600000121
Compound 9 (200mg, 0.67mmol) and ethyl 5-bromovalerate (420mg, 2.01mmol) were dissolved in 2mL anhydrous DMF solution, potassium carbonate (463mg, 3.35mmol) was added, stirring was carried out at 90 ℃ for 6h, then the reaction was diluted with water and extracted with ethyl acetate, the organic layers were combined, concentrated and purified by silica gel column to give the intermediate carboxylate as a yellow oil, 240mg, 84% yield. The above-mentioned carboxylic acid ester (180mg, 0.42mmol) was dissolved in THF/H 2 To O (4 mL/4 mL), lithium hydroxide (50mg, 2.10 mmol) was added and stirred at 50 ℃ overnight, then the solution was adjusted to pH =2 with hydrochloric acid (1 mol/L) and extracted with ethyl acetate, and the organic layers were combined, concentrated and purified by silica gel column to give compound 15 as a yellow solid, 121mg, yield 72%. 1 HNMR(400MHz,DMSO-d 6 )δ8.12–8.06(m,2H),7.80(d,J＝15.5Hz,1H),7.62(d,J＝15.5Hz,1H),7.57(s,2H),7.43–7.36(m,2H),3.77(t,J＝5.8Hz,2H),2.56(s,3H),2.31(t,J＝6.9Hz,2H),2.25(s,6H),1.77–1.70(m,4H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.8,174.5,157.9,145.4,143.6,133.9,131.1,130.1,129.6,129.0,124.9,120.5,71.5,33.5,29.4,21.3,16.0,14.0；HRMS(ESI)calcd for C 23 H 26 O 4 S(M+H) + 399.1625,found 399.1629.
Example 16: (E) Preparation of (E) -2,6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenylpropylcarbamate (Compound 16)
Figure BDA0002987353600000122
Compound 9 (50mg, 0.17mmol) and triethylamine (3mg, 0.03mmol) were dissolved in anhydrous CH 2 Cl 2 To the reaction solution, propyl isocyanate was added and stirred at room temperature for 5 hours, and then the reaction solution was concentrated and purified by means of a silica gel column to obtain 46mg of a white solid in a yield of 72%. 1 HNMR(400MHz,CDCl 3 )δ7.99–7.90(m,2H),7.72(d,J＝15.6Hz,1H),7.42(d,J＝15.6Hz,1H),7.36–7.27(m,4H),5.21(t,J＝6.1Hz,1H),3.29–3.17(m,2H),2.53(s,3H),2.22(s,6H),1.66–1.53(m,2H),0.97(t,J＝7.4Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ189.3,153.8,150.1,145.6,144.3,134.6,132.3,132.0,129.1,128.8,125.2,121.3,43.1,23.3,16.4,14.9,11.3；HRMS(ESI)calcd for C 22 H 25 NO 3 S(M+H) + 384.1628,found 384.1631.
Example 17: (E) Preparation of (E) -3- (3,5-dimethyl-4- (3-morpholinopropoxy) phenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 17)
Figure BDA0002987353600000131
Compound 9 (100mg, 0.34mmol) and 4- (3-chloropropyl) morpholine (110mg, 0.67mmol) were dissolved in 2mL of anhydrous DMF solution, potassium carbonate (232mg, 1.68mmol) was added, stirring was carried out at 90 ℃ for 6h, then the reaction was diluted with water and extracted with ethyl acetate, the organic layers were combined, concentrated and purified by silica gel column to give 101mg of a white solid in 71% yield. 1 HNMR(400MHz,CDCl 3 )δ8.00–7.86(m,2H),7.71(d,J＝15.6Hz,1H),7.41(d,J＝15.6Hz,1H),7.34–7.27(m,4H),3.84(t,J＝6.3Hz,2H),3.73(t,J＝4.7Hz,4H),2.59(t,J＝7.3Hz,2H),2.53(s,3H),2.48(t,J＝4.7Hz,4H),2.30(s,6H),2.05–1.95(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ189.3,158.3,145.5,144.6,134.8,131.8,130.5,129.3,129.0,125.2,120.6,70.3,67.1,55.5,53.8,27.5,16.5,15.0；HRMS(ESI)calcd for C 25 H 31 NO 3 S(M+H) + 426.2097,found426.2101.
Example 18: (E) Preparation of (E) -4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) benzoic acid (Compound 18)
Figure BDA0002987353600000132
4-Methylthioacetophenone (366mg, 2.20mmol) and 4-formylbenzoic acid (300mg, 2.00mmol) were dissolved in 10mL of methanol, 4mL of a 40% sodium hydroxide solution was added, and stirring was performed at room temperature for 24 hours, and then, the solution was adjusted to pH =2, followed by filtration of the precipitate, washing with methanol and drying to obtain 415mg of a yellow solid, a yield of 70%. 1 H NMR(400MHz,DMSO-d 6 )δ8.14–8.10(m,2H),8.03(d,J＝15.6Hz,1H),8.00–7.97(m,4H),7.76(d,J＝15.6Hz,1H),7.47–7.35(m,2H),2.56(s,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.9,167.2,145.9,142.4,138.4,133.6,129.7,129.2,128.8,125.0,123.8,14.0；HRMS(ESI)calcd for C 17 H 14 O 3 S(M+H) + 299.0736,found 299.0740.
Example 19: (E) Preparation of (E) -3- (4-hydroxyphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 19)
Figure BDA0002987353600000133
Referring to the procedure of example 9, a yellow solid was obtained in 60% yield. 1 HNMR(400MHz,DMSO-d 6 )δ10.11(s,1H),8.10–8.03(m,2H),7.76–7.64(m,4H),7.43–7.32(m,2H),6.88–6.80(m,2H),2.55(s,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.8,160.1,145.1,144.2,134.1,131.0,128.9,125.9,124.9,118.3,115.9,14.0；HRMS(ESI)calcd for C 16 H 14 O 2 S(M+H) + 271.0787,found 271.0812.
Example 20: (E) Preparation of (E) -3- (4-hydroxy-3-methylphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 20)
Figure BDA0002987353600000141
Referring to the procedure of example 9, a yellow solid was obtained in 63% yield. 1 HNMR(400MHz,DMSO-d 6 )δ10.00(s,1H),8.12–7.99(m,2H),7.73–7.66(m,2H),7.63(d,J＝15.4Hz,1H),7.51(dd,J＝8.3,2.2Hz,1H),7.41–7.35(m,2H),6.85(d,J＝8.3Hz,1H),2.55(s,3H),2.17(s,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.7,158.4,145.0,144.4,134.2,131.3,128.9,125.7,124.9,124.7,118.0,114.9,15.9,14.0；HRMS(ESI)calcd for C 17 H 16 O 2 S(M+H) + 285.0944,found285.0968.
Example 21: (E) Preparation of (E) -3- (4-hydroxy-3-methoxyphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 21)
Figure BDA0002987353600000142
Referring to the procedure of example 9, a yellow solid was obtained in 51% yield. 1 HNMR(400MHz,DMSO-d 6 )δ9.68(s,1H),8.11–8.02(m,2H),7.75(d,J＝15.4Hz,1H),7.67(d,J＝15.4Hz,1H),7.51(d,J＝2.0Hz,1H),7.43–7.35(m,2H),7.28(dd,J＝8.3,1.9Hz,1H),6.84(d,J＝8.1Hz,1H),3.87(s,3H),2.55(s,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.8,149.7,148.0,145.1,144.6,134.2,128.9,126.3,124.9,124.1,118.5,115.6,111.7,55.8,14.0；HRMS(ESI)calcd for C 17 H 16 O 3 S(M+H) + 301.0893,found 301.0911.
Example 22: (E) Preparation of (E) -3- (3-fluoro-4-hydroxyphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 22)
Figure BDA0002987353600000143
Referring to the procedure of example 9, a yellow solid was obtained in 30% yield. 1 HNMR(400MHz,DMSO-d 6 )δ10.51(s,1H),8.12–8.03(m,2H),7.85(dd,J＝12.6,2.1Hz,1H),7.79(d,J＝15.5Hz,1H),7.64(d,J＝15.5Hz,1H),7.52–7.47(m,1H),7.41–7.36(m,2H),7.06–6.88(m,1H),2.55(s,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.7,151.2(d,J＝241.6Hz),147.5(d,J＝12.5Hz),145.3,143.0(d,J＝2.5Hz),133.9,129.0,126.9(d,J＝2.6Hz),126.7(d,J＝6.6Hz),124.9,120.0,117.8(d,J＝3.3Hz),115.8(d,J＝18.6Hz),14.0；HRMS(ESI)calcd for C 16 H 13 FO 2 S(M+H) + 289.0693,found289.0712.
Example 23: (E) Preparation of (E) -3- (2-fluoro-4-hydroxyphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 23)
Figure BDA0002987353600000151
Referring to the procedure of example 9, a yellow solid was obtained in 18% yield. 1 HNMR(400MHz,DMSO-d 6 )δ10.58(s,1H),8.09–8.01(m,2H),7.94(t,J＝8.8Hz,1H),7.81–7.70(m,2H),7.43–7.35(m,2H),6.72(dd,J＝8.6,2.3Hz,1H),6.66(dd,J＝12.6,2.3Hz,1H),2.55(s,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.7,162.2(d,J＝250.0Hz),,161.7(d,J＝12.6Hz),145.4,135.5(d,J＝3.7Hz),133.9,130.3(d,J＝4.5Hz),128.9,125.0,120.1(d,J＝4.3Hz),113.4(d,J＝11.5Hz),112.64(d,J＝2.3Hz),102.9(d,J＝24.1Hz),14.0；HRMS(ESI)calcd for C 16 H 13 FO 2 S(M+H) + 289.0693,found 289.0708.
Example 24: (E) Preparation of (E) -3- (3-chloro-4-hydroxyphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 24)
Figure BDA0002987353600000152
Referring to the procedure of example 9, a yellow solid was obtained in 23% yield. 1 HNMR(400MHz,DMSO-d 6 )δ10.81(s,1H),8.14–8.06(m,2H),8.02(d,J＝2.1Hz,1H),7.81(d,J＝15.5Hz,1H),7.67–7.60(m,2H),7.41–7.36(m,2H),7.02(d,J＝8.4Hz,1H),2.55(s,1H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.7,155.3,145.3,142.7,133.9,130.1,129.7,129.0,127.2,124.9,120.5,119.8,116.7,14.0；HRMS(ESI)calcd for C 16 H 13 ClO 2 S(M+H) + 305.0398,found 305.0411.
Example 25: (E) Preparation of (E) -3- (4-hydroxy-2,5-dimethylphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (compound 25)
Figure BDA0002987353600000153
Referring to the procedure of example 9, a yellow solid was obtained in 71% yield. 1 HNMR(400MHz,DMSO-d 6 )δ9.87(s,1H),8.17–8.01(m,2H),7.92(d,J＝15.3Hz,1H),7.81(s,1H),7.64(d,J＝15.3Hz,1H),7.45–7.28(m,2H),6.67(s,1H),2.55(s,3H),2.33(s,3H),2.15(s,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.7,158.1,145.0,141.0,137.8,134.2,129.5,128.9,124.9,123.9,122.4,118.4,116.6,19.0,15.5,14.0；HRMS(ESI)calcd for C 18 H 18 O 2 S(M+H) + 299.1100,found 299.1114.
Example 26: (E) Preparation of (E) -3- (4-hydroxy-2,6-dimethylphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (compound 26)
Figure BDA0002987353600000161
Referring to the procedure of example 9, a yellow solid was obtained in 48% yield. 1 HNMR(400MHz,DMSO-d 6 ) 1 HNMR(400MHz,DMSO-d 6 )δ9.73(s,1H),δ8.02–7.95(m,2H),7.85(d,J＝15.8Hz,1H),7.40–7.35(m,2H),7.28(d,J＝15.8Hz,1H),6.56(s,2H),2.53(s,3H),2.34(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ188.1,158.0,145.4,141.6,139.8,134.1,129.0,125.1,124.6,124.4,115.8,21.6,14.0；HRMS(ESI)calcd for C 18 H 18 O 2 S(M+H) + 299.1100,found 299.1113.
Example 27: (E) Preparation of (E) -3- (4-hydroxy-3,5-dimethoxyphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 27)
Figure BDA0002987353600000162
Referring to the procedure of example 9, a yellow solid was obtained in 45% yield. 1 HNMR(400MHz,DMSO-d 6 )δ9.04(s,1H),8.13–8.06(m,2H),7.78(d,J＝15.4Hz,1H),7.67(d,J＝15.4Hz,1H),7.43–7.36(m,2H),7.20(s,2H),3.85(s,6H),2.56(s,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.8,148.1,145.1,145.0,138.7,134.1,129.0,125.1,124.9,118.9,106.9,56.2,14.0；HRMS(ESI)calcd for C 18 H 18 O 4 S(M+H) + 331.0999,found 331.1000.
Example 28: (E) Preparation of (E) -3- (3,5-diethyl-4-hydroxyphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 28)
Figure BDA0002987353600000163
Referring to the procedure of example 9, a yellow solid was obtained in 69% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.81(s,1H),8.19–7.99(m,2H),7.72(d,J＝15.4Hz,1H),7.64(d,J＝15.4Hz,1H),7.48(s,2H),7.42–7.34(m,2H),2.63(q,J＝7.5Hz,4H),2.55(s,3H),1.17(t,J＝7.5Hz,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.7,155.2,145.0,144.8,134.2,130.9,128.9,128.1,126.1,124.9,118.1,23.0,14.4,14.0；HRMS(ESI)calcd for C 20 H 22 O 2 S(M+H) + 327.1413,found 327.1429.
Example 29: (E) Preparation of (E) -3- (3,4-dihydroxyphenyl) -1- (4- (methylthio) phenyl) prop-2-en-1-one (Compound 29)
Figure BDA0002987353600000164
Referring to the procedure of example 9, a yellow solid was obtained in 46% yield. 1 HNMR(400MHz,DMSO-d 6 )δ9.61(s,1H),9.25(s,1H),8.14–7.93(m,2H),7.66–7.53(m,2H),7.43–7.34(m,2H),7.26(d,J＝2.1Hz,1H),7.18(dd,J＝8.2,2.1Hz,1H),6.81(d,J＝8.2Hz,1H),2.55(s,3H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.8,148.7,145.6,145.1,144.7,134.2,128.9,126.4,125.0,122.2,118.3,115.8,115.6,14.0；HRMS(ESI)calcd for C 16 H 14 O 3 S(M+H) + 287.0736,found 287.0740.
Example 30: (E) Preparation of (E) -1- (4-fluorophenyl) -3- (4-hydroxy-3,5-dimethylphenyl) prop-2-en-1-one (Compound 30)
Figure BDA0002987353600000171
Referring to the procedure of example 9, a yellow solid was obtained in 63% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.94(s,1H),8.29–8.09(m,2H),7.71(d,J＝15.4Hz,1H),7.62(d,J＝15.4Hz,1H),7.48(s,2H),7.41–7.31(m,2H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.4,164.9(d,J＝251.3Hz),156.4,145.1,134.7(d,J＝2.9Hz),131.3(d,J＝9.2Hz),129.7,125.7,124.7,118.0,115.7(d,J＝21.7Hz),16.6；HRMS(ESI)calcd for C 17 H 15 FO 2 (M+H) + 271.1129,found 271.1131.
Example 31: (E) Preparation of (E) -1- (4-chlorophenyl) -3- (4-hydroxy-3,5-dimethylphenyl) prop-2-en-1-one (Compound 31)
Figure BDA0002987353600000172
Referring to the procedure of example 9, a yellow solid was obtained in 67% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.18–8.10(m,2H),7.70(d,J＝15.4Hz,1H),7.65–7.58(m,3H),7.49(s,2H),2.21(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.7,156.5,145.4,137.7,136.7,130.3,129.8,128.8,125.6,124.7,117.9,16.5；HRMS(ESI)calcd for C 17 H 15 ClO 2 (M+H) + 287.0833,found 287.0832.
Example 32: (E) Preparation of (E) -3- (4-hydroxy-3,5-dimethylphenyl) -1- (4-iodophenyl) prop-2-en-1-one (Compound 32)
Figure BDA0002987353600000173
Referring to the procedure of example 9, a yellow solid was obtained in 44% yield. 1 HNMR(400MHz,DMSO-d 6 )δ7.96–7.92(m,2H),7.91–7.86(m,2H),7.67(d,J＝15.5Hz,1H),7.61(d,J＝15.5Hz,3H),7.49(s,2H),2.20(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ188.3,156.5,145.4,137.7,137.3,130.2,129.8,125.7,124.7,117.9,101.4,16.6；HRMS(ESI)calcd for C 17 H 15 IO 2 (M+H) + 379.0189,found379.0197.
Example 33: (E) Preparation of (E) -3- (4-hydroxy-3,5-dimethylphenyl) -1- (4- (methylsulfinyl) phenyl) prop-2-en-1-one (compound 33)
Figure BDA0002987353600000181
Compound 9 (500mg, 1.68mmol) was dissolved in 15mL of anhydrous CH with stirring at 0 deg.C 2 Cl 2 To the solution, 3-chloroperoxybenzoic acid (289mg, 1.68mmol) was then slowly added to the above solution and stirring was continued at room temperature for 5h, then the solution was filtered and the filter cake was purified by column chromatography to give 354mg of a yellow solid in 67% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.99(s,1H),8.31–8.25(m,2H),7.87–7.82(m,2H),7.73(d,J＝15.5Hz,1H),7.65(d,J＝15.5Hz,1H),7.50(s,2H),2.81(s,3H),2.21(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ188.4,156.6,151.0,145.7,139.8,129.9,129.1,125.6,124.7,123.9,118.2,43.1,16.6；HRMS(ESI)calcd for C 18 H 18 O 3 S(M+H) + 315.1049,found 315.1051.
Example 34: (E) Preparation of (E) -3- (4-hydroxy-3,5-dimethylphenyl) -1- (4- (methylsulfonyl) phenyl) prop-2-en-1-one (Compound 34)
Figure BDA0002987353600000182
Compound 9 (500mg, 1.68mmol) was dissolved in 15mL of anhydrous CH with stirring 2 Cl 2 To the solution, 3-chloroperbenzoic acid (754mg, 4.37mmol) was then slowly added to the above solution and the mixture was stirred at room temperature for 5h, then the solution was filtered and the filter cake was purified by column chromatography to give 338mg of yellow solid in 61% yield. 1 H NMR(400MHz,DMSO-d 6 )δ8.38–8.27(m,2H),8.15–8.02(m,2H),7.72(d,J＝15.6Hz,1H),7.66(d,J＝15.6Hz,1H),7.52(s,2H),3.31(s,3H),2.20(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ188.4,156.9,146.4,143.9,142.0,130.1,129.3,127.5,125.5,124.8,118.1,43.4,16.7；HRMS(ESI)calcd for C 18 H 18 O 4 S(M+H) + 331.0999,found 331.0996.
Example 35: (E) Preparation of (E) -1- ([ [1,1' -biphenyl ] -4-yl) -3- (4-hydroxy-3,5-dimethylphenyl) prop-2-en-1-one (Compound 35)
Figure BDA0002987353600000183
Referring to the procedure of example 9, a yellow solid was obtained in 47% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.27–8.18(m,2H),7.87–7.81(m,2H),7.80–7.71(m,3H),7.65(d,J＝15.5Hz,1H),7.55–7.47(m,4H),7.46–7.39(m,1H),2.21(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ188.5,156.5,145.0,144.3,139.1,136.9,129.9,129.3,128.5,127.1,127.0,125.8,124.8,118.4,16.7；HRMS(ESI)calcd for C 23 H 20 O 2 (M+H) + 329.1536,found 329.1537.
Example 36:
preparation of intermediate 1- (4- (thien-2-yl) phenyl) ethan-1-one (intermediate 1 h)
Figure BDA0002987353600000191
N 2 4-bromoacetophenone (200mg, 1.01mmol), thiophen 2-ylboronic acid (386mg, 3.02mmol), potassium carbonate (277mg, 2.01mmol), and tetrakis (triphenylphosphine) palladium (116mg, 0.10mmol) were dissolved in the 5mLDME solution under protection and stirred at 90 ℃ overnight, then the reaction solution was diluted with water and extracted with ethyl acetate, the organic layers were combined, concentrated and purified by silica gel column to give 145mg of white solid in 71% yield. 1 H NMR(400MHz,CDCl 3 )δ7.99–7.95(m,2H),7.73–7.67(m,2H),7.44(dd,J＝3.6,1.1Hz,1H),7.37(dd,J＝5.1,1.1Hz,1H),7.12(dd,J＝5.1,3.6Hz,1H),2.62(s,3H).
(E) Preparation of (E) -3- (4-hydroxy-3,5-dimethylphenyl) -1- (4- (thiophen-2-yl) phenyl) prop-2-en-1-one (Compound 36)
Figure BDA0002987353600000192
Referring to the procedure of example 9, a yellow solid was obtained in 38% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.96(s,1H),8.24–8.12(m,2H),7.88–7.79(m,2H),7.78–7.70(m,2H),7.69–7.60(m,2H),7.51(s,2H),7.20(dd,J＝5.1,3.7Hz,1H),2.22(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.9,156.4,144.9,142.2,137.7,136.7,129.8,129.4,128.9,127.5,125.7,125.5,125.4,124.7,118.2,16.6；HRMS(ESI)calcd for C 21 H 18 O 2 S(M+H) + 335.1100,found 35.1103.
Example 37:
preparation of intermediate 1- (4- (5-methylthiophen-2-yl) phenyl) ethan-1-one (intermediate 1 i)
Figure BDA0002987353600000193
N 2 4-bromoacetophenone (200mg, 1.01mmol), (5-methylthiophen-2-yl) boronic acid (285mg, 2.01mmol), potassium carbonate (277mg, 2.01mmol), and tetrakis (triphenylphosphine) palladium (116mg, 0.10mmol) were dissolved in 5mL of DME solution under protection and stirred at 90 ℃ overnight, then the reaction solution was diluted with water and extracted with ethyl acetate, and the organic layers were combined, concentrated and purified by silica gel column to give 148mg of white solid in 68% yield. 1 HNMR(400MHz,CDCl 3 )δ7.98–7.90(m,2H),7.69–7.57(m,2H),7.24(d,J＝3.6Hz,1H),6.77(m,1H),2.60(s,3H),2.53(d,J＝1.1Hz,3H).
(E) Preparation of (E) -3- (4-hydroxy-3,5-dimethylphenyl) -1- (4- (5-methylthiophen-2-yl) phenyl) prop-2-en-1-one (Compound 37)
Figure BDA0002987353600000201
Referring to the procedure of example 9, a yellow solid was obtained in 34% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.95(s,1H),8.18–8.08(m,2H),7.80–7.68(m,3H),7.62(d,J＝15.4Hz,1H),7.55–7.46(m,3H),6.94–6.81(m,1H),2.50–2.46(m,3H),2.21(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.8,156.3,144.7,141.2,139.7,138.0,136.3,129.7,129.4,127.4,125.8,125.5,124.8,124.7,118.2,16.6,15.2；HRMS(ESI)calcd for C 22 H 20 O 2 S(M+H) + 349.1257,found 349.1261.
Example 38:
preparation of intermediate N- (4-acetylphenyl) -4-fluorobenzenesulfonamide (intermediate 1 j)
Figure BDA0002987353600000202
P-aminoacetophenone (100mg, 0.74mmol) was dissolved in 1.5mL of anhydrous THF with stirring at 0 deg.C, pyridine (175mg, 2.22mmol) was added, p-fluorobenzenesulfonyl chloride (172mg, 0.89mmol) was added slowly, and stirring was continued at room temperature for 5h, then the solution was diluted with water, extracted with ethyl acetate, the organic layers were combined, concentrated and purified by silica gel column to give 205mg of white solid in 77% yield. 1 HNMR(400MHz,CDCl 3 )δ7.90–7.83(m,4H),7.39(s,1H),7.19–7.11(m,4H),2.54(s,3H)。
(E) Preparation of (E) -4-fluoro-N- (4- (3- (4-hydroxy-3,5-dimethylphenyl) acryloyl) phenyl) benzenesulfonamide (compound 38)
Figure BDA0002987353600000203
Referring to the procedure of example 9, a yellow solid was obtained in 49% yield. 1 HNMR(400MHz,DMSO-d 6 )δ8.93(s,1H),8.07–7.99(m,2H),7.95–7.86(m,2H),7.62(d,J＝15.4Hz,1H),7.55(d,J＝15.4Hz,1H),7.49–7.37(m,4H),7.32–7.20(m,2H),2.19(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.4,164.6(d,J＝252.3Hz),156.3,144.5,141.8,135.7(d,J＝2.9Hz),133.4,130.0,129.9(d,J＝9.7Hz),129.6,125.8,124.7,118.4,118.1,116.8(d,J＝23.0Hz),16.6；HRMS(ESI)calcd for C 23 H 20 FNO 4 S(M+H) + 426.1170,found426.1175.
Example 39:
preparation of intermediate N- (4-acetylphenyl) isopropylaminosulfonamide (intermediate 1 k)
Figure BDA0002987353600000211
P-aminoacetophenone (50mg, 0.37mmol) was dissolved in 2mL of anhydrous CH with stirring at 0 deg.C 2 Cl 2 To the solution was added triethylamine (74mg, 0.74mmol) followed by slow addition of isopropylaminosulfonyl chloride (70mg, 0.44mmol) and stirring continued at room temperature for 5h, then the solution was diluted with water, extracted with ethyl acetate, the organic layers combined, concentrated and purified by silica gel column to give 54mg of white solid in 57% yield. 1 HNMR(400MHz,CDCl 3 )δ7.98–7.86(m,2H),7.21–7.13(m,2H),7.07(s,1H),4.56(d,J＝7.7Hz,1H),3.64–3.50(m,1H),2.57(s,3H),1.13(d,J＝6.5Hz,6H).
(E) Preparation of (E) -3- (4-hydroxy-3,5-dimethylphenyl) -1- (4- { [ ((prop-2-yl) sulfamoyl ] amino } phenyl) prop-2-en-1-one (Compound 39)
Figure BDA0002987353600000212
Referring to the procedure of example 9, a yellow solid was obtained in 37% yield. 1 HNMR(400MHz,DMSO-d 6 )δ10.22(s,1H),8.90(s,1H),8.13–8.01(m,2H),7.77–7.64(m,2H),7.57(d,J＝15.4Hz,1H),7.47(s,2H),7.29–7.17(m,2H),3.34–3.29(m,1H),2.20(s,6H),0.99(d,J＝6.5Hz,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.4,156.2,144.1,143.6,131.5,129.9,129.6,125.9,124.7,118.3,116.5,45.2,23.1,16.6；HRMS(ESI)calcd for C 20 H 24 N 2 O 4 S(M+H) + 389.1560,found 389.1532.
Example 40:
preparation of intermediate N- (4-acetylphenyl) acrylamide (intermediate 1 l)
Figure BDA0002987353600000213
P-aminoacetophenone (405mg, 3.00mmol) was dissolved in 7mL of anhydrous THF solution with stirring at 0 ℃, triethylamine (413mg, 4.20mmol) was added, acryloyl chloride (299mg, 3.30mmol) was slowly added, stirring was continued at room temperature for 5h, then the solution was filtered, the filtrate was extracted with water and ethyl acetate, the organic layers were combined, concentrated and purified by silica gel column to give 428mg of white solid in 75% yield. 1 HNMR(400MHz,CDCl 3 )δ7.99–7.89(m,3H),7.74–7.67(m,2H),6.47(dd,J＝16.9,1.2Hz,1H),6.30(dd,J＝16.9,10.2Hz,1H),5.81(dd,J＝10.2,1.2Hz,1H),2.58(s,3H).
(E) Preparation of (E) -N- (4- (3- (4-hydroxy-3,5-dimethylphenyl) acryloyl) phenyl) acrylamide (compound 40)
Figure BDA0002987353600000221
Referring to the procedure of example 9, a yellow solid was obtained in 66% yield. 1 HNMR(400MHz,DMSO-d 6 )δ10.51(s,1H),8.94(s,1H),8.17–8.11(m,2H),7.87–7.81(m,2H),7.71(d,J＝15.4Hz,1H),7.60(d,J＝15.4Hz,1H),7.48(s,2H),6.48(dd,J＝17.0,10.0Hz,1H),6.32(dd,J＝17.0,2.0Hz,1H),5.82(dd,J＝10.0,2.0Hz,1H),2.20(s,6H)； 13 C NMR(100MHz,DMSO-d 6 )δ187.5,163.7,156.3,144.4,143.2,133.1,131.6,129.8,129.7,128.0,125.9,124.8,118.9,118.3,16.6；HRMS(ESI)calcd for C 20 H 19 NO 2 (M+H) + 322.1438,found 322.1437.
Example 41: in vitro study of inhibition effect of 1,3-diphenylprop-2-en-1-one derivative on NLRP3 inflammasome
J774A.1 cells were plated onto 96-well plates at 5X 10 wells per well 5 The cells were plated overnight, the supernatant was discarded, 100. Mu.L of DMEM medium containing 10% serum containing bacterial Lipopolysaccharide (LPS) (1. Mu.g/ml) was added to each well, and then treated with different concentrations of (1. Mu.M, 2. Mu.M, 5. Mu.M, 10. Mu.M, 20. Mu.M, 40. Mu.M) 1,3-diphenylprop-2-en-1-one derivative for 1 hour, followed by addition of Nigericin (10. Mu.M) for 1 hour, and after that, the cell supernatants were collected, and the IL-1. Beta. Content was measured using a Mouse IL-1. Beta. ELISA kit to calculate the inhibitory effect of the compounds of the present invention on NLRP3 inflammasome, and the results are shown in Table 1.
TABLE 1, 3-Diphenylprop-2-en-1-one derivatives inhibitory Activity on IL-1 beta Release mediated by activation of NLRP3 inflammasome in J774A.1 cells (IC) 50 ，μM)
Figure BDA0002987353600000222
Figure BDA0002987353600000231
Example 42 Compound 40 specifically inhibits activation of NLRP3 inflammasome and inhibits apoptosis of cells in vitro
1. NLRP3 inflammasome activation and IL-1 β detection: J774A.1 cells or mouse bone marrow-derived macrophages (BMDMs) were plated onto 96-well plates at 5X 10 wells per well 5 Cells were plated overnight, supernatants were discarded, and 100. Mu.L of 10% serum-containing DMEM medium containing bacterial Lipopolysaccharide (LPS) (1. Mu.g/ml) was added to each well, followed by treatment with different concentrations (1. Mu.M, 2. Mu.M, 5. Mu.M) of compound 40 for 1h, followed by treatment with Nigericin (10. Mu.M) for 1h, after which cell supernatants were collected and assayed for IL-1. Beta. Content using the Mouse IL-1. Beta. ELISA kit.
2. Detecting cell scorching: j774a.1 cells were treated as described before and LDH release in cell supernatants was assessed using an LDH detection kit.
3. Western blot analysis: the J774A.1 cell sample treated in step 1 was lysed in RIPA lysis buffer with protease inhibitor at 4 ℃ for 30min. Proteins in the lysate or supernatant were separated on a 12-percent SDS-polyacrylamide gel, transferred to PVDF membrane, and subjected to Western blotting with anti-mouse IL-1. Beta. Antibody, anti-ASC antibody, anti-caspase-1 antibody, anti-NLRP 3 antibody, anti-beta-actin antibody.
4. Activation of NLRC4 and AIM2 inflammasome and detection of IL-1. Beta. For NLRC4 or AIM2 inflammasome, J774A.1 cells were stimulated with 1. Mu.g/mLLPS for 5h, then treated with different concentrations of (1. Mu.M, 2. Mu.M, 5. Mu.M) compound 40 for 1h, and then cells were infected with bacterial flagellin (FLA-STUltrapure) (2.5. Mu.g/mL) for 4h, or transfected with poly (dA: dT) (0.25. Mu.g/mL) for 4h, after which cell supernatants were collected and assayed for IL-1. Beta. Content using the Mouse IL-1. Beta. ELISA kit.
Results as shown in figure 1, from the results of figure 1, it is seen that compound 40 can inhibit IL-1 β secretion concentration-dependently in NLRP3 inflammasome-activated j774a.1 and BMDMs cell models (a and B panels in figure 1). Western blot experiments showed that the effect of compound 40 in inhibiting caspase-1p20 maturation and IL-1 β secretion was dose-dependent, but did not affect pro-IL-1 β, pro-caspase-1, NLRP3 or ASC in the cell lysates (C panel in FIG. 1). Compound 40 also inhibited LPS/nigericin-induced apoptosis of cells (panels D and E in FIG. 1). At the same time, compound 40 had no inhibitory effect on the activation of AIM2 or NLRC4 inflammasome (panel F in fig. 1). The above results indicate that compound 40 can specifically inhibit NLRP3 inflammasome-dependent caspase-1 activation and IL-1 β secretion.
Example 43: compound 40 inhibits LPS-induced acute peritonitis
1. Female C57BL/6 mice at 6-8 weeks were divided into 4 groups of 6 mice each, and the specific groups were treated as follows:
a first group: perfusing a blank medium for three consecutive days;
second group: three consecutive days, intragastric administration of the blank vehicle, and the third day, intraperitoneal injection of LPS (20 mg/kg);
third group: intragastric compound 40 (25 mg/kg/day, intraperitoneal injection of LPS (20 mg/kg) on the third day) for three consecutive days;
and a fourth group: intragastric compound 40 (100 mg/kg/day) for three consecutive days, and intraperitoneal injection of LPS (20 mg/kg) for the third day;
2. after 6h of LPS intraperitoneal injection, blood was collected, and simultaneously 1ml of PBS was perfused into the abdominal cavity of each group of mice, and peritoneal lavage fluid was taken and centrifuged.
3. The blood supernatant and the peritoneal lavage fluid supernatant obtained in step 2 were subjected to IL-1. Beta. Assay by ELISA, and the results are shown in FIG. 2.
From the results in FIG. 2, it can be seen that the IL-1. Beta. Content in the blood and in the peritoneal fluid of mice was significantly increased after LPS injection, whereas the level of IL-1. Beta. Was dose-dependently decreased by the gavage compound 40, indicating that the compound 40 was effective in inhibiting LPS-induced acute peritonitis.
Example 44: compound 40 ameliorates Dextran Sodium Sulfate (DSS) -induced colitis
1. Female C57BL/6 mice at 6-8 weeks were divided into 4 groups of 5 mice each, and the specific groups were treated as follows:
a first group: administering distilled water to the diet on days 1-10, with daily gavage of vehicle;
second group: administering distilled water to the diet on days 1-3, beginning on days 4-10, administering 2% DSS of distilled water to the diet daily, with daily gavage of vehicle;
third group: gavage Compound 40 (25 mg/kg/day) for 10 consecutive days, with 2% DSS of distilled water being administered daily in the diet beginning on day four;
a fourth group of gavage Compound 40 (100 mg/kg/day) for 10 consecutive days, with 2% DSS of distilled water on a daily basis beginning on day four;
2. the degree of hematochezia and body weight of each group of mice were monitored daily from the beginning of the administration, and the colons of the mice were taken on day 11 for length measurement and determination of IL-1 β content in the colons.
As shown in FIG. 3, from the results of FIG. 3, it can be seen that after 2% DSS administration in the diet, the mice had increased fecal blood severity and the mice had shortened colon length and significantly increased IL-1 β in the colon, and that gavage compound 40 can dose-dependently improve the mice's fecal blood, improve the shortened colon length, and decrease the IL-1 β level in the colon.
The activity test result shows that the 1,3-diphenylprop-2-en-1-one compound of the invention has the activity of inhibiting NLRP3 inflammasome on tested cells J774A.1. Meanwhile, the representative compound 40 can selectively inhibit the activation of NLRP3 inflammasome and simultaneously improve LPS-induced acute peritonitis and DSS-induced colitis, and therefore, the 1,3-diphenylprop-2-en-1-one compound provided by the invention has the application for treating NLRP3 inflammasome-related diseases.
The technical features of the above-mentioned embodiments can be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the following embodiments are not described, however, as long as there is no contradiction between the combinations of the technical features, the combinations should be considered as the scope of the present description.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (4)

1.1,3-diphenylprop-2-en-1-one derivative or pharmaceutically acceptable salt thereof as active ingredient in preparation of NLRP3 inflammation
The use in a symptomatic body inhibitor; the 1,3-diphenylprop-2-en-1-one derivative is selected from the following compounds:
Figure DEST_PATH_IMAGE001
。
2. use of 1,3-diphenylprop-2-en-1-one derivative as claimed in claim 1 or pharmaceutically acceptable salt thereof as an active ingredient in the preparation of a medicament for the prevention and/or treatment of NLRP3 inflammasome-related diseases.
3. The use according to claim 2, wherein the diseases associated with NLRP3 inflammasome are peritonitis and colitis.
4. The use according to claim 3, wherein the peritonitis is acute peritonitis.
CN202110317148.8A 2021-03-22 2021-03-22 1,3-diphenylprop-2-en-1-one derivative and application thereof Active CN113230240B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110317148.8A CN113230240B (en) 2021-03-22 2021-03-22 1,3-diphenylprop-2-en-1-one derivative and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110317148.8A CN113230240B (en) 2021-03-22 2021-03-22 1,3-diphenylprop-2-en-1-one derivative and application thereof

Publications (2)

Publication Number Publication Date
CN113230240A CN113230240A (en) 2021-08-10
CN113230240B true CN113230240B (en) 2022-12-27

Family

ID=77130715

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110317148.8A Active CN113230240B (en) 2021-03-22 2021-03-22 1,3-diphenylprop-2-en-1-one derivative and application thereof

Country Status (1)

Country Link
CN (1) CN113230240B (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019094777A1 (en) * 2017-11-13 2019-05-16 Gilead Sciences, Inc. Compositions and methods for identifying and treating liver diseases and monitoring treatment outcomes
CN112424207A (en) * 2018-07-25 2021-02-26 诺华股份有限公司 NLRP3 inflammasome inhibitor

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2841900B1 (en) * 2002-07-08 2007-03-02 Genfit S A NOVEL SUBSTITUTED 1,3-DIPHENYLPROP-2-EN-1-ONE DERIVATIVES, PREPARATION AND USES
US20040181075A1 (en) * 2002-12-19 2004-09-16 Weingarten M. David Process of making chalcone derivatives
FR2857361B1 (en) * 2003-07-08 2005-09-09 Genfit S A PREPARATION OF 1,3-DIPHENYPROP-2-¼n-1-one DERIVATIVES
CN111848461A (en) * 2019-04-29 2020-10-30 苏州大学 NLRP3 inflammasome inhibitor and preparation method and application thereof
US20220259144A1 (en) * 2019-07-16 2022-08-18 Virginia Commonwealth University Compounds as nlrp3 inflammasome inhibitors and compositions and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019094777A1 (en) * 2017-11-13 2019-05-16 Gilead Sciences, Inc. Compositions and methods for identifying and treating liver diseases and monitoring treatment outcomes
CN112424207A (en) * 2018-07-25 2021-02-26 诺华股份有限公司 NLRP3 inflammasome inhibitor

Also Published As

Publication number Publication date
CN113230240A (en) 2021-08-10

Similar Documents

Publication Publication Date Title
EP1783116B1 (en) 2-phenylpyridine derivative
CN105358550A (en) Novel histone deacetylase inhibitors
JP4880678B2 (en) Sulfonamide derivatives useful as liver carnitine palmitoyltransferase (L-CPT1) inhibitors
CN110101700A (en) The pharmaceutical applications of polysubstituted aromatic compounds as serpin
JP5898230B2 (en) Novel substituted bicyclic aromatic compounds as S-nitrosoglutathione reductase inhibitors
JP2003507372A (en) Benzoic acid derivatives for treating diabetes
AU2006212761A1 (en) Combination therapy
JP7344959B2 (en) Matrix metalloproteinase (MMP) inhibitors and methods of use thereof
PT1258484E (en) Novel isoxazole and thiazole compounds and use thereof as drugs
JP2001503037A (en) Preparation and use of ortho-sulfonamidoheteroarylhydroxamic acids as inhibitors of matrix metalloproteinases and tace
KR100710958B1 (en) Dehydroamino acids
AU2005202553A1 (en) Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use
JP2004511456A (en) Diabetes medicine
JP2021519312A (en) Calpain modulator and its therapeutic use
KR20110051286A (en) Novel prostaglandin i2 derivative
JP2021529193A (en) How to treat liver fibrosis with calpain inhibitors
HU193348B (en) Process for producing piroxicam salts of antiflogistic activity
KR20210097100A (en) 2-(1-acyloxy-n-pentyl)benzoic acid and a salt formed by a basic amino acid or aminoguanidine, preparation method and use thereof
JPH072666A (en) Analgesic or antiphlogistic
KR900006118B1 (en) Process for preparing 4-quinolone derivatives
CN113230240B (en) 1,3-diphenylprop-2-en-1-one derivative and application thereof
KR20040027927A (en) Prime Ring Substituted Thyroid Receptor Antagonists for the Treatment of Cardiac and Metabolic Disorders
JP2002053557A (en) Apolipoprotein a-i-producing facilitator
WO2016026372A1 (en) Thienocycloalkyl or thienoheterocyclic derivatives, preparation method thereof and use thereof in medicine
KR20200037363A (en) New amide compounds, and Pin1 inhibitors using the same, therapeutic agents for inflammatory diseases and therapeutic agents for cancer

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant