CN110357789A - N- substituted acrylamide derivative and its preparation and use as DHODH inhibitor - Google Patents

N- substituted acrylamide derivative and its preparation and use as DHODH inhibitor Download PDF

Info

Publication number
CN110357789A
CN110357789A CN201810321850.XA CN201810321850A CN110357789A CN 110357789 A CN110357789 A CN 110357789A CN 201810321850 A CN201810321850 A CN 201810321850A CN 110357789 A CN110357789 A CN 110357789A
Authority
CN
China
Prior art keywords
compound
group
substituted
base
unsubstituted
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.)
Granted
Application number
CN201810321850.XA
Other languages
Chinese (zh)
Other versions
CN110357789B (en
Inventor
徐晓勇
李洪林
李忠
李诗良
曾凡勋
王蕊
章乐天
朱丽丽
齐甜甜
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.)
East China University of Science and Technology
Original Assignee
East China University of Science and Technology
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 East China University of Science and Technology filed Critical East China University of Science and Technology
Priority to CN201810321850.XA priority Critical patent/CN110357789B/en
Priority to PCT/CN2019/081066 priority patent/WO2019196714A1/en
Publication of CN110357789A publication Critical patent/CN110357789A/en
Application granted granted Critical
Publication of CN110357789B publication Critical patent/CN110357789B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/40—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P17/06—Antipsoriatics
    • 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
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/55—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to the N- substituted acrylamide derivatives and its preparation and use as DHODH inhibitor.Specifically, the invention discloses general formula I compound represented and its preparation and uses.The compound of the present invention has excellent DHODH inhibitory activity, so as to the various diseases for treating or preventing DHODH mediation, including but not limited to cancer, the autoimmune diseases such as rheumatoid arthritis, lupus erythematosus and organ-graft refection, the diseases associated with inflammation such as colitis and rhinitis.

Description

N- substituted acrylamide derivative and its preparation and use as DHODH inhibitor
Technical field
The invention belongs to pharmaceutical chemistry and pharmacotherapeutics field, and in particular to the N- as DHODH inhibitor replaces third Alkenylamide derivative and its preparation and use.
Background technique
Dihydroorate dehydrogenase (Dihydroorotate dehydrogenase, DHODH) is a kind of iron-containing flavine The cyclophorase of dependence is intracellular rate-limiting enzyme in the synthesis of nucleic acid pyrimidine, the 4th be catalyzed in from the beginning pyrimidine biosynthesis pathway Step reaction.Inhibit DHODH, de novo pyrimidine can be blocked to synthesize, cause DNA and RNA dyssynthesis.It is phonetic in most of organism Pyridine synthesis is there are two types of mode: remedial pathway and by small molecule de novo formation.Demand of the organism to pyrimidine depends on cell type With locating differential period, the cell in rest period and idiophase obtains pyrimidine by de novo synthesis and only accounts for fraction, And rely primarily on remedial pathway.In contrast, in order to meet organism to the needs of nucleotide precursor and other cell components, swash The human cell that T- lymphocyte, B- lymphocyte and tumour cell living etc. quickly break up needs to rely on the de novo formation of pyrimidine Needs are grown to meet it, this makes DHODH inhibitor can be used as cellular antiproliferative agent for tumour and certain immune suppressions Make the treatment of reaction.
The leflunomide (leflunomide, LEF) of listing in 1998 is a kind of novel isoxazole class immunomodulator, Clinically it is mainly used for treating the autoimmune diseases such as rheumatic arthritis, lupus erythematosus and the acute and chronic of anti-organ transplant repels The prevention and treatment of reaction and Xeno-rejection reaction.Discovery leflunomide was a prodrug, the cell through liver and intestinal wall after taking orally later Matter and microsome are quickly converted to active metabolite A771726 (MI).MI is good human body dihydroorate dehydrogenase Inhibitor can block the from the beginning biosynthesis of pyrimidine, and then influence the synthesis of DNA and RNA.Research shows that MI can apply to Prevent, treat or inhibit various autoimmune disease, the acute and chronic rejection of anti-organ transplant and Xeno-rejection reaction, ox The skin diseases such as psoriasis, diversity hardening etc..
The cloth quinoline studied initially as anticarcinogen is one of the most powerful DHODH inhibitor, but the clinic II phase Experiments have shown that its antitumor action is general, which continues to develop as immunosuppressor.4SC-101 is proved to erythema wolf Sore and enteritis have good inhibiting effect, are in clinical development.
Since the long-time service of leflunomide can develop drug resistance and the side effects such as liver enzyme exception, hypertension or fash, seek Looking for novel, efficient and Small side effects DHODH inhibitor is still the research hotspot in immune correlated disease and oncotherapy.
Summary of the invention
The object of the present invention is to provide the compounds and preparation method thereof that can be used as DHODH inhibitor of a kind of structure novel And purposes.
First aspect present invention provide compound shown in a kind of Formulas I or its stereoisomer, its cis-trans-isomer, its mutually Tautomeric, its prodrug or its pharmaceutically acceptable salt or solvate or crystal form:
In formula,
A is unsubstituted or substituted C3-7Naphthenic base, unsubstituted or substituted C5-7Cycloalkenyl, unsubstituted or substituted C6- C10Aryl or unsubstituted or substituted 5-10 circle heterocyclic ring base；Described substituted refers to replaced group selected from the group below: halogen Element, cyano, nitro, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-7Naphthenic base, C5-7Cycloalkenyl, C1-6Halogenated alkyl, C1-6Alcoxyl Base, C1-6Halogenated alkoxy, C6-C10Aryl, C6-C10Aryloxy group, C6-C10Aryl-NH-CO- ,-O- (CH2)m-O-、-(CH2)n-； Wherein, the integer that m or n is 1~4；
B is unsubstituted or substituted C3-7Naphthenic base, C5-7Cycloalkenyl, C6-C10Aryl, 5-10 circle heterocyclic ring base；The substitution Refer to replaced group selected from the group below: halogen, cyano (- CN), nitro, carboxyl (- COOH), amide groups (- CONH2)、 Sulfonic group, sulfonamide, C1-6Sulfonate group, hydroxyl, C1-6Alkyl carbonyl, C1-6Halogenated alkyl carbonyl, C1-6Aldehyde radical, C1-6Ester group, C1-6Acyl Diazanyl, guanidine radicals, C1-6Alkyl, C1-6Halogenated alkyl, C3-7Naphthenic base, C2-6Alkenyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C6-C10 Aryl, C6-C10Aryloxy group, C6-C10Aryl-NH-CO- ,-O-CH2-O-、-(CH2)n-；Wherein, the integer that n is 2~4；
R1It is selected from the group: hydrogen, C1-6Alkyl, C1-6Halogenated alkyl, C3-7Naphthenic base, C5-7Cycloalkenyl；
R2It is selected from the group: hydrogen, halogen, cyano, nitro, C1-6Alkyl, C1-6Halogenated alkyl, C3-7Naphthenic base, C5-7Cycloalkenyl.
In another preferred example, the compound is selected from Formula II compound represented:
In formula,
A and R2It is as defined above；
X represents nitrogen-atoms or group CY, and wherein Y is selected from the group: carboxyl, amide groups, sulfonic group, sulfoamido, C1-6Sulfonic acid Ester group, hydroxyl, C1-6Alkyl carbonyl, C1-6Halogenated alkyl carbonyl, C1-6Aldehyde radical, C1-6Ester group, C1-6Hydrazide group, cyano, nitro, guanidine radicals；
R3、R4、R5It is each independently selected from the following group: hydrogen, halogen, cyano, nitro, C1-6Alkyl, C1-6Halogenated alkyl, C3-7Ring Alkyl, C2-6Alkenyl, C1-6Alkoxy, hydroxyl, C1-6Halogenated alkoxy, C6-C10Aryl, C6-C10Aryloxy group, C6-C10Aryl-NH- CO-、-O-CH2-O-、-(CH2)n-；Wherein, the integer that n is 2~4.
In another preferred example, the Y is selected from the group: carboxyl, amide groups, cyano.
In another preferred example, A be unsubstituted or substituted phenyl, it is unsubstituted or substituted pyridyl group, unsubstituted or take The indyl in generation, unsubstituted or substituted naphthalene, unsubstituted or substituted thienyl, unsubstituted or substituted benzothienyl, Unsubstituted or substituted furyl, unsubstituted or substituted benzofuranyl, unsubstituted or substituted quinoline or unsubstituted or take The isoquinolyl in generation.
In another preferred example, A is selected from the group:
In another preferred example, R2It is selected from the group: hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl, cyclopropyl.
In another preferred example, R3、R4、R5It is each independently selected from hydrogen, halogen, cyano, nitro, C1-4Alkyl, C1-4It is halogenated Alkane, C3-7Naphthenic base, C1-4Alkoxy, hydroxyl.
In another preferred example, R3、R4、R5It is each independently hydrogen, fluorine, chlorine, cyano, trifluoromethyl, methyl, ethyl, first Oxygroup, cyclopropyl, hydroxyl.
In another preferred example, the compound is selected from formula III compound represented:
In formula,
B and R2It is as defined above；
R6、R7、R8、R9、R10It is each independently selected from hydrogen, halogen, cyano, nitro, C1-6Alkyl, C1-6Halogenated alkane, C2-6 Alkenyl, C2-6Alkynyl, C3-7Naphthenic base, C5-7Cycloalkenyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C6-C10Aryl, C6-C10Fragrant oxygen Base, 5- or 6-membered heterocycle, hydroxyl, C6-C10Aryl-NH-CO-；
Or R6、R7、R8、R9、R10In any two can connect to form-O- (CH2)m-O-、-(CH2) n- ,-CH= CH-；Wherein, the integer that m or n is 1~4.
In another preferred example, B be selected from unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heterocycle, Or unsubstituted or substituted C5-7Cycloalkenyl.
In another preferred example, the 5- or 6-membered heterocycle is selected from the group: pyridyl group, thienyl, furyl.
In another preferred example, B is selected from the group:
In another preferred example, R8And R9It can connect to form-O- (CH2)m-O-、-(CH2) n- ,-CH=CH-；Wherein, m Or the integer that n is 1~4.
Second aspect of the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition contains change described in first aspect Close object or its stereoisomer, cis-trans-isomer, its tautomer, its prodrug or its pharmaceutically acceptable salt or solvation Object or crystal form；With pharmaceutically acceptable carrier or excipient.
In another preferred example, the pharmaceutical composition be injection, wafer (such as hard and Perle), tablet, It is coated tablet, pill, powder, granule, sugar coated tablet, solution, syrup, emulsion, suspension liquor, aerosol, suppository, defeated Injecting, ointment, emulsifiable paste and tincture.
Third aspect present invention provide compound described in first aspect or its stereoisomer, its cis-trans-isomer, its Tautomer, its prodrug or its pharmaceutically acceptable salt or solvate or crystal form or second aspect described pharmaceutical composition Purposes, be used to prepare dhodh inhibitors；It is used to prepare pyrimidine biosynthesis inhibitor；And/or it is used for It prepares for preventing or treating by the inhibition of dihydroorate dehydrogenase and/or the inhibition of pyrimidine biosynthesis come improved disease Symptom or disease of science.
In another preferred example, the pathological condition or disease are selected from the group: cancer, rheumatoid arthritis, knot Enteritis, lupus erythematosus, renal glomerular disease, anti-organ transplant rejection, melanoma, psoriasis, arthritis, fibrosis, Rhinitis, psoriasis, multiple sclerosis, uveitis, asthma, leukaemia and malaria.
Fourth aspect present invention provide compound described in first aspect or its stereoisomer, its cis-trans-isomer, its The preparation method of tautomer, its prodrug or its pharmaceutically acceptable salt or solvate or crystal form,
The method is method 1, comprising steps of
(1) in atent solvent, compound 1 and compound 2 are reacted, to form compound 3；
(2) in atent solvent, reaction is hydrolyzed in compound 3, to form compound 4；
(3) in atent solvent, compound 4 is successively reacted with oxalyl chloride and compound 5, to form compound 6；
Or the method is method 2, comprising steps of
(1) in atent solvent, compound 7 and TsCl are reacted, to form compound 8；
(2) in atent solvent, compound 8 and compound 5 are reacted, to form compound 6；
Or the method is method 3, comprising steps of
(1) in atent solvent, compound 1 and compound 9 are reacted, to form compound 10；
(2) in atent solvent, compound 10 is successively reacted with oxalyl chloride and compound 5, to form compound 6；
Or the method is method 4, comprising steps of
(1) in atent solvent, compound 1 and compound 11 and NCS or NBS are reacted, to form compound 12；
(2) in atent solvent, reaction is hydrolyzed in compound 12, to form compound 13；
(3) in atent solvent, compound 13 is successively reacted with oxalyl chloride and compound 5, to form compound 6；
Or the method is method 5, comprising steps of
(1) in atent solvent, compound 15 and compound 16 are reacted, to form compound 17；
(2) in atent solvent, reaction is hydrolyzed in compound 17, to form compound 18；
(3) in atent solvent, compound 18 is successively reacted with oxalyl chloride and compound 5, to form compound 19；
Or the method is method 6, comprising steps of
(1) in atent solvent, compound 1 and compound 20 are reacted, to form compound 21；
(2) in atent solvent, compound 21 is successively reacted with oxalyl chloride and compound 5, to form compound 22；
Or the method is method 7, comprising steps of
(1) in atent solvent, compound 1 and compound 23 are reacted, to form compound 24；
(2) in atent solvent, reaction is hydrolyzed in compound 24, to form compound 25；
(3) in atent solvent, compound 25 is successively reacted with oxalyl chloride and compound 5, to form compound 26；
In the above formulas, in addition to providing the group of definition, other group definitions are the same.
The present invention provides a kind for the treatment of or prevention method, this method include applied to the object of needs it is of the invention described in Compound or its stereoisomer, its cis-trans-isomer, its tautomer, its prodrug or its pharmaceutically acceptable salt or molten Agent compound or crystal form or pharmaceutical composition of the invention.
In another preferred example, the compound is Formulas I, Formula II or formula III compound.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.
Specific embodiment
The present inventor is surprised to find that a kind of structure novel, is had excellent performance for the first time by extensive and in-depth research DHODH inhibitor.The present invention is completed on this basis.
Term
Terms used herein " C1-6Alkyl " refers to the linear or branched alkyl group with 1-6 carbon atom, such as methyl, second Base, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl or similar group.
Term " C2-6Alkenyl " refers to the alkenyl of the linear chain or branched chain with 2-6 carbon atom, such as vinyl, allyl, third Alkenyl, isopropenyl, 1- cyclobutenyl, 2- cyclobutenyl or similar group.
Term " C2-6Alkynyl " refers to the alkynyl of the linear chain or branched chain with 2-6 carbon atom, for example, acetenyl, propinyl, Or similar group.
Term " C3-7Naphthenic base " refers to the cyclic alkyl with 3-7 carbon atom, for example, cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl, suberyl or similar group.
Term " C5-7Cycloalkenyl " refers to cyclic alkenyl radicals with 5-7 carbon atom, with one or more double bonds, such as Cyclopentenyl, cyclohexenyl group, cycloheptenyl, 1,3- cyclohexadienyl, 1,4- cyclohexadienyl or similar group.
As used herein, term " C1-6Alkoxy " refers to the straight or branched alkoxyl with 1-6 carbon atom, such as first Oxygroup, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or similar group.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " C1-6Halogenated alkane ", which refers to, has 1-6 by what the identical or different above-mentioned halogen atom of one or more replaced The linear chain or branched chain alkane of carbon atom, such as trifluoromethyl, pentafluoroethyl group, hepta-fluoroiso-propyl or similar group.
Term " aryl " refers to the monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms, including phenyl, naphthalene, Phenanthryl, anthryl, indenyl, Fluorene base, tetrahydro naphthyl, indanyl etc..Herein, aryl is optionally by one or more sheets Substituent group described in text replaces.
Term " aryloxy group " refers to aryl-O-, such as phenoxy group (Curve mark be replace position, on similarly hereinafter).
Term " heterocycle " refers to single or condensed ring structure, can be aromatics and non-aromatic, and its in nature It preferably comprises 3-20 ring member nitrogen atoms, further preferably 5-14 or 5-10 annular atom, wherein at least 1 and preferably up to may be used It is the hetero atom selected from nitrogen, oxygen or sulphur to 4.Herein, the example of heterocycle includes furyl, thienyl, pyrrole radicals, pyrroles Alkyl, imidazole radicals, triazolyl, thiazolyl, tetrazole radical, oxazolyl, isoxazolyl, pyrazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, Pyridazinyl, triazine radical, quinolyl, isoquinolyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl, benzo Furyl, morpholinyl, carbazyl, dibenzothiophene, 1,2- methylenedioxyphenyl, indyl, indazolyl, benzimidazole Base, benzo [d] [1,2,3] thiadiazolyl group, imidazo [1,2-a] pyridyl group, cinnoline base, phthalazinyl, 1,8- naphthyridines base or benzo [d] [1,2,3] triazine -4 (3H) -3- base etc..Herein, heterocycle is optionally by one or more substituent groups as described herein Replace.
Term " 5- or 6-membered heterocycle " refers to containing one or more heteroatomic five yuan or hexa-atomic selected from nitrogen, oxygen or sulphur Ring, such as pyridyl group, thiazolyl, thienyl, furyl, pyrrole radicals, pyrazolyl, pyrimidine radicals, tetrahydrofuran base, oxazolyl, 1, 2,3- thiadiazolyl group, 1,3,4- thiadiazolyl group or 1,3,4- oxadiazoles base etc..
Terms used herein " C1-6Sulfonate group " refers to the sulfonate group (C with 1-6 carbon atom1-6Alkyl-S (= O)2O-)。
Terms used herein " C1-6Alkyl carbonyl " refers to C1-6Alkyl-C=O-.
Terms used herein " C1-6Ester group " refers to C1-5Alkyl-C (=O) O-).
Terms used herein " C1-6Hydrazide group " refers to-C1-6Alkyl-C=O-NHNH2Or C1-6Alkyl-C=O-NHNH-.
Terms used herein " C1-6Aldehyde radical " refers to-C1-5Alkyl-CHO.
Group of the present invention either illustrate " unsubstituted or optionally replace " or it is not specified be " not Replace or optionally replace " it can be by 0 to multiple (usual 0,1,2 or 3) replaced substituent group selected from the group below: halogen, Cyano, nitro, amino, carboxyl, sulfydryl, hydroxyl, methylol, C1-4Aldehyde radical, C1-6Alkyl, C1-6Halogenated alkyl (such as trifluoromethyl), Alkoxy (such as trifluoromethoxy), the C of halogen substitution2-6Alkenyl, C2-6Alkynyl, C3-7Naphthenic base, C5-7Cycloalkenyl, C1-6Alkoxy (such as methoxyl group), C1-6Alkylthio (such as five fluorine sulfidomethyls), C1-6Thio alkoxy (such as five fluorine sulphur methoxyl groups), alkyl halide Carbonyl (such as trifluoroacetyl group), C1-4Acyl group, morpholinyl, the aryl optionally replaced the heterocycle optionally replaced, optionally takes The aryloxy group (such as the phenoxy group optionally replaced) in generation, the benzyloxy optionally replaced, the fragrant formamido optionally replaced and optionally Substituted arylamine formoxyl.
Preparation method
The compound of the present invention can be used following methods and prepare:
Method 1:
Method 2:
Method 3:
Method 4:
Method 5:
Method 6:
Method 7:
Raw material aldehyde compound used can directly be bought from Reagent Company or is made by following methods:
1. being made by substitution formic acid:
2. being made by methylic raw material:
In above-mentioned preparation flow, A and B are as defined above described in text.Those skilled in the art can according to actually preparing needs, The various initial compounds for using this field routinely to obtain prepare the compound of the present invention for raw material.
In a preferred example, the compound of the present invention can be synthesized by the method included the following steps:
Raw material aldehyde compound can directly be bought from Reagent Company or synthesize using the following method.
1. being made by substitution formic acid:
It weighs and aromatic acid (10mmol) is replaced to be dissolved in the anhydrous THF of 25mL, argon gas is protected, and is divided thereto under condition of ice bath It criticizes and is slowly added to LiAlH4(20mmol).React at room temperature 4h after ice bath reaction 10min, ice bath is cooling after reaction, successively to 0.76g ice water, 0.76g 15%NaOH aqueous solution and 2.28g water is wherein slowly added dropwise.20mL water, mistake is added in stirring in a moment Filter, is washed, filtrate decompression is spin-dried for being concentrated with a small amount of ethyl acetate.Suitable quantity of water is added into concentrate, ethyl acetate extraction merges Organic phase is dried, filtered with anhydrous sodium sulfate, and filtrate is spin-dried for up to substituted benzyl alcohol crude product, and yield 90-95% is directly used in down Single step reaction.
Substituted benzyl alcohol made from previous step is dissolved in 100mL DCM, 70mmol MnO is added under stirring condition2, room Temperature is lower to react 4h, filters, and filtrate is spin-dried for being concentrated, and aromatic formaldehyde, yield 85-95% must be replaced by crossing column purification.
2. being made by arylmethyl:
Substituted arylmethyl compound (5mmol) is dissolved in 10mL CCl4, 10mmol NBS, 0.1mmol BPO is added, returns Stream reaction 5h, is cooled to room temperature, filters, with appropriate petroleum ether filter cake, be spin-dried for being concentrated.Gained concentrate is dissolved in 10mL In dioxane, 10mL water, 20mmol CaCO is added3, flow back 10h, filtering, and ethyl acetate extraction merges organic phase, anhydrous sulphur Sour sodium is dry, is spin-dried for being concentrated, and crosses column purification and obtains substituted benzyl alcohol, yield about 80%.
Substituted benzyl alcohol made from previous step (4mmol) is dissolved in 40mL DCM, 28mmol is added under stirring condition MnO2, 4h is reacted at room temperature, is filtered, and filtrate is spin-dried for being concentrated, and aromatic formaldehyde, yield about 90% must be replaced by crossing column purification.
In the above formulas, A and B are as hereinbefore defined；
Aldehyde compound (5mmol) will be replaced to be dispersed in 15mL DCM, 9mmol ethoxycarbonyl ethylidene triphen is added Base phosphine reacts at room temperature 12h, and rotation removes partial solvent, crosses column purification and obtains 2- methyl -3- substitutional crylic acid ethyl ester intermediate, yield is about 95%.
2- methyl 3- substitutional crylic acid ethyl ester (4mmol) made from previous step is dissolved in 12mL THF and 12mL MeOH In, 16mL 2M NaOH aqueous solution is added.40 DEG C of reaction 5h.1M HCl acidification, there is white solid precipitation, filters, uses suitable quantity of water It washes, solid dries to obtain 2- methyl 3- substitutional crylic acid, yield about 95%.
2- methyl 3- substitutional crylic acid (1mmol) obtained is dispersed in the dry DCM of 3mL, oxalyl chloride is added dropwise in ice bath (3mmol) is added dropwise a drop DMF and makees catalyst, put on drying tube, react at room temperature 3h, decompression rotation is except solvent concentration is up in acyl chlorides Mesosome.
Amino-compound (1.2mmol) is dissolved in 2mL DCM, 1.5mmol TEA and 0.1mmol DMAP, ice is added Bath cooling.Acyl chlorides obtained is dissolved in 1mL DCM, is added dropwise in reaction solution, room temperature reaction to reaction terminates.With 1M HCl Acidification, there is solid precipitation, filters, and ethyl alcohol recrystallization obtains final product.Yield about 70%.
In another preferred example, the compound of the present invention can be synthesized by the method included the following steps:
In the above formulas, A and B are as hereinbefore defined；
The preparation method of raw material 2- methyl 3- substitutional crylic acid is similar with preference described above.To being cased with drying tube Addition 1mmol 2- methyl 3- substitutional crylic acid in 25mL reaction flask, 1.1mmol TsCl, 5mL DCE, 0.1mmol DMAP, 1.5mmol TEA, 35 DEG C of reaction 1h, are added 1mmol amino-compound, and 60 DEG C of reaction 10h are acidified with 1M HCl, filter solid Body is washed, dry, is crossed column purification and is obtained target product, yield about 50%.
In another preferred example, the compound of the present invention can be synthesized by the method included the following steps:
In the above formulas, A and B are as hereinbefore defined；
Aldehyde compound and 6mmol malonic acid is replaced to be dispersed in 1.2mL DMF 2mmol, addition 2mmol pyridine, 90 DEG C reaction 5h, be cooled to room temperature, be added 1.2mL water, 1M HCl be acidified to PH be 2, filter, washing twice, filtration cakes torrefaction to obtain the final product 3- substitutional crylic acid intermediate, yield about 80%.Subsequent the step of preparing target compound and above with 2- methyl -3- replace third Olefin(e) acid ethyl ester is similar for the method that raw material prepares final product.
In another preferred example, the compound of the present invention can be synthesized by the method included the following steps:
In the above formulas, A and B are as hereinbefore defined；
9mmol ethoxycarbonyl methylene triphenyl phosphine and 15mL DCM are added into reaction flask, argon gas is protected, and -20 DEG C Under 9mmol NCS or NBS is added portionwise, react 1h at -20 DEG C, 5mmol aldehyde compound and 12.5mmol be added at room temperature K2CO3, 10h is reacted at room temperature, reaction solution is washed with water, and organic phase is dry with anhydrous sodium sulfate, is spin-dried for being concentrated, and crosses column purification and obtains 2- halogen Generation -3- substitutional crylic acid ethyl ester.Subsequent the step of preparing target compound and it is with 2- methyl -3- substitutional crylic acid ethyl ester above The method that raw material prepares final product is similar.
In another preferred example, the compound of the present invention can be synthesized by the method included the following steps:
In the above formulas, A and B are as hereinbefore defined；
4.2mmol NaH is added in 50mL three-necked flask, argon gas protection is added the anhydrous THF of 24mL, 3.9mmol is added Three second lipoid substance of 2- phosphono, stirs 0.5h at room temperature, and the THF solution of 12mL carbonyls (3mmol) is added drop-wise to In reaction solution, 12h is reacted at room temperature, 2M HCl acidification spins off THF, and suitable quantity of water is added, and ethyl acetate extraction merges organic phase, satisfies It is washed with salt, anhydrous sodium sulfate dries, filters, and rotation removes solvent concentration, crosses column purification and obtains ethyl acrylate intermediate.Subsequent system The step of standby target compound, is similar with the method for preparing final product using 2- methyl -3- substitutional crylic acid ethyl ester as raw material above.
In another preferred example, the compound of the present invention can be synthesized by the method included the following steps:
Sequentially added in reaction flask 6mmol aldehyde compound, 4mmol 3,3,3- trifluoroacetic acid, 20mL THF and The TiCl of 8mL1M40.5h is stirred at room temperature in dichloromethane solution, and 16mmol triethylamine is added dropwise into reaction solution.React at room temperature 40h 30mL water is slowly added in backward reaction flask, methylene chloride extracts, organic phase saturated common salt water washing, and anhydrous sodium sulfate is dry Dry, filtering, filtrate is spin-dried for and uses silica gel column separating purification (methylene chloride: methanol=10:1), obtains in 2- trifluoromethyl acrylate Mesosome.Subsequent the step of preparing target compound and final product is prepared using 2- methyl -3- substitutional crylic acid ethyl ester as raw material above Method it is similar
In another preferred example, the compound of the present invention can be synthesized by the method included the following steps:
5mmol aldehyde compound is dispersed in 7.5mL methanol, 5mmol malonic methyl ester nitrile and 0.5mmol piperazine is added Pyridine, back flow reaction to fully reacting.It is cooled to room temperature, solid is precipitated, and filters, and filter cake is washed with proper amount of methanol, and filter cake drying is Obtain 2- cyano -3- substitutional crylic acid methyl ester intermediate.Subsequent the step of preparing target compound and above with 2- methyl -3- substitution Ethyl acrylate is similar for the method that raw material prepares final product.
Active constituent
The compounds of this invention be general formula I or II or III compound represented or its stereoisomer, its cis-trans-isomer, Its tautomer, its prodrug or its pharmaceutically acceptable salt or solvate or crystal form.
The example of pharmaceutically acceptable salt of the present invention includes but is not limited to inorganic and acylate, such as hydrochloric acid, The inorganic acids such as hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, rich horse Acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acids such as benzene sulfonic acid；With And the acidic amino acids such as aspartic acid, glutamic acid.Another kind of preferred salt is the salt that the compounds of this invention and alkali are formed, such as alkali Metal salt, especially sodium salt and sylvite.
Pharmaceutical composition
The compounds of this invention has excellent DHODH inhibitory activity, can be used for preparing the disease for treating or preventing DHODH mediation In the drug of disease.
Pharmaceutical composition of the invention contains the compounds of this invention and pharmaceutically acceptable carrier of therapeutically effective amount Or excipient.
Although the drug dose needed for everyone is different, those skilled in the art can determine every in pharmaceutical composition of the present invention The optimal dose of kind active constituent.Under normal circumstances, the compound of the present invention or its pharmaceutically acceptable salt, to mammal Oral administration daily, dose is according to 0.0025 to 50 mg kg of body weights, it is preferred that per kilogram oral administration about 0.01 to 10 Milligram.For example, unit oral doses may include about 0.01 to 50 milligrams, preferably about 0.1 to 10 milligrams of chemical combination of the present invention Object.Unit dose can be given one or many, be daily one or more pieces, and every contains about 0.1 to 50 milligrams, more preferably contain About 0.25 to 10 milligrams of the compounds of this invention or its solvate.
Pharmaceutical composition of the invention can be formulated into the dosage form for being suitble to various administration routes, including but not limited to quilt It is configured to parenteral, subcutaneous, vein, muscle, intraperitoneal, transdermal, oral cavity, intrathecal, encephalic, nasal cavity or the shape of topical route administration Formula, for treating tumour and other diseases.Dosage is the dose for effectively improving or eliminating one or more illnesss.For spy Determine the treatment of disease, effective quantity is the dose for being enough to improve or mitigate in some manner symptom related with disease.Such medicine Amount can be used as single dose application, or can be administered according to effective therapeutic scheme.Perhaps, dosage can cure disease, still It is administered typically to the symptom for improving disease.Repetitively administered is generally required to realize that required symptom improves.The dosage of medicine will According to the age of patient, health status and weight, the type of concurrent treatment, the frequency for the treatment of and required therapeutic effect are determined It is fixed.
Pharmaceutical preparation of the invention can give any mammal, as long as they can obtain the treatment of the compounds of this invention Effect.The most importantly mankind in these mammals.
Drug of the invention or its pharmaceutical composition can be used to treat or prevent the various diseases of DHODH mediation, including cancer Disease, rheumatoid arthritis, colitis, lupus erythematosus, renal glomerular disease, anti-organ transplant rejection, melanoma, silver bits Disease, arthritis, fibrosis, rhinitis, psoriasis, multiple sclerosis, uveitis, asthma, leukaemia, malaria etc..It is described Cancer includes but is not limited to breast cancer, prostate cancer, head and neck squamous cell carcinoma and multiple bone marrow cancer.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler or jello Matter, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as combines In object each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Medicine Acceptable carrier includes: filler, swelling agent, disintegrating agent, bonding agent, glidant, wetting agent, stabilizer, emulsification on Agent, preservative, sweetener, colorant, flavoring agent or fragrance, buffer substance etc., and the solvent for obtaining storage effect, increasing Solvent or reagent, and for changing the salt of osmotic pressure, it is coated with reagent or antioxidant etc..Specifically, pharmaceutically acceptable Carrier part example have cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate), Gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame oil, peanut oil, olive Olive oil etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as), wetting agent (such as dodecane Base sodium sulphate), apirogen water etc..
Solid dosage forms for oral administration includes: capsule (such as hard or soft gelatin capsule agent), tablet, pill, powder And granule.In these solid dosage forms, reactive compound is mixed at least one conventional inert excipients (or carrier), such as lemon Lemon acid sodium or Dicalcium Phosphate, or mixed with following compositions: (a) filler or solubilizer, for example, starch, lactose, sucrose, glucose, Mannitol and silicic acid；(b) adhesive, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, for example, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, Alginic acid, certain composition silicates and sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound； (g) wetting agent, such as cetanol and glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, Or mixtures thereof talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate,.Capsule, tablet and ball In agent, dosage form also may include buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture. In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, especially cottonseed Oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or the mixture of these substances etc..In addition to these inertia are dilute It releases outside agent, composition also may include auxiliary agent, such as wetting agent, emulsifier, suspending agent, sweetener, corrigent and fragrance.In addition to activity Outside compound, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and anhydrosorbitol Alcohol ester, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile water or anhydrous solution, dispersion liquid, hang Supernatant liquid or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.Suitable is aqueous and non- Water carrier, diluent, solvent or excipient, including water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, stock solution and inhalant. Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need Propellant be mixed together.
The compounds of this invention can be administered alone, or be administered in combination with other pharmaceutically acceptable compounds, such as With existing for treating the administered in combination of aforementioned diseases.The enhancing of curative effect can be observed in the later case.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are weight percent and weight Number.Experimental material used in following embodiment and reagent can obtain unless otherwise instructed from commercially available channel.
Embodiment 1 (E) -2- (2- methyl -3- phenylacryloyl amido) benzoic acid (compound 1)
Benzaldehyde (5mmol) is dispersed in 15mL DCM, 9mmol ethoxycarbonyl ethylidene triphenylphosphine, room is added Temperature reaction 4h, rotation remove partial solvent, cross column purification and obtain (E) -2- methyl 3- ethyl phenylacrylate, yield 95%.
(E) -2- methyl 3- ethyl phenylacrylate (4mmol) made from previous step is dissolved in 12mL THF and 12mL In MeOH, 16mL 2M NaOH aqueous solution is added.40 DEG C of reaction 5h.1M HCl acidification, there is white solid precipitation, filters, with suitable Amount washing, solid dry (E) -2- methyl 3- phenylacrylic acid, yield 95%.
(E) -2- methyl 3- phenylacrylic acid (1mmol) by made from is dispersed in the dry DCM of 3mL, and oxalyl is added dropwise in ice bath Chlorine (3mmol) is added dropwise a drop DMF and makees catalyst, put on drying tube, reacts at room temperature 3h, decompression rotation is except solvent concentration is up to acyl chlorides Intermediate.
Ortho-aminobenzoic acid (1.2mmol) is dissolved in 2mL DCM, 1.5mmol TEA and 0.1mmol DMAP is added, Ice bath is cooling.Acyl chlorides obtained is dissolved in 1mL DCM, is added dropwise in reaction solution, room temperature reaction to reaction terminates.Use 1M HCl acidification, there is solid precipitation, filters, and ethyl alcohol recrystallization obtains final product.Yield 70%.
Fusing point: 179.1-181.6 DEG C；1H NMR(400MHz,DMSO-d6):δ13.76(s,1H),11.84(s,1H), 8.70 (d, J=8.0Hz, 1H), 8.04 (dd, J=8.0,1.6Hz, 1H), 7.68-7.62 (m, 1H), 7.53 (d, J=0.8Hz, 1H), 7.50-7.43 (m, 4H), 7.40-7.35 (m, 1H), 7.22-7.16 (m, 1H), 2.19 (d, J=1.2Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ169.91,166.89,141.25,135.57,134.54,134.26,132.50,131.21, 129.43,128.51,128.20,122.68,119.73,116.22,13.87ppm；HRMS(EI)calc.for C17H15NO3 + 281.1052,found 281.1053。
Embodiment 2 (E) -2- (2- methyl -3- (4- trifluoromethyl) acrylamido) benzoic acid (compound 2)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 4- trifluoromethylated benzaldehyde as starting material.
Fusing point: 211.6-212.3 DEG C；1H NMR(400MHz,DMSO-d6):δ13.78(s,1H),11.88(s,1H), 8.69 (dd, J=8.4,0.8Hz, 1H), 8.05 (dd, J=8.0,1.6Hz, 1H), 7.81 (d, J=8.4Hz, 2H), 7.69 (d, J=8.4Hz, 2H), 7.67-7.63 (m, 1H), 7.57 (s, 1H), 7.23-7.18 (m, 1H), 2.20 (d, J=1.2Hz, 3H) ppm；19F NMR(376MHz,DMSO-d6):δ-61.05(s,3F)ppm；HRMS(EI)calc.for C18H14F3NO3 + 349.0926,found 349.0925。
Embodiment 3 (E) -2- (2- methyl -3- (6- trifluoromethyl pyridine -3- base) acrylamido) benzoic acid (compound 3)
Preparation method is similar with the method for embodiment 1, the difference lies in that being starting with 6- trifluoromethyl pyridine -3- formaldehyde Raw material.
Fusing point: 267.6-268.3 DEG C；1H NMR(400MHz,DMSO-d6):δ13.81(s,1H),11.90(s,1H), 8.87 (d, J=1.6Hz, 1H), 8.69 (d, J=7.6Hz, 1H), 8.19 (dd, J=8.0,1.6Hz, 1H), 8.06 (dd, J= 8.0,1.6Hz, 1H), 7.98 (d, J=8.4Hz, 1H), 7.70-7.63 (m, 1H), 7.60 (s, 1H), 7.24-7.18 (m, 1H), 2.23 (d, J=1.2Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ169.86,165.99,150.47,145.19(q ,2JCF=33.8Hz), 140.93,138.40,136.66,135.05,134.26,131.22,129.85,124.36 (q,1JCF= 264.8Hz),122.97,120.47(q,3JCF=2.7Hz), 119.86,116.49,13.90ppm；19F NMR(376MHz, DMSO-d6):δ-66.40(s,3F)ppm；HRMS(EI)calc.for C17H13F3N2O3 +350.0878,found 350.0879。
Embodiment 4 (E) -2- (3- (4- methoxyphenyl) -2- methacryl amido) benzoic acid (compound 4)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 4-methoxybenzaldehyde as starting material.
Fusing point: 191.4-192.3 DEG C；1H NMR(400MHz,DMSO-d6):δ13.73(s,1H),11.81(s,1H), 8.70 (d, J=8.4Hz, 1H), 8.04 (dd, J=8.0,1.6Hz, 1H), 7.67-7.60 (m, 1H), 7.49-7.42 (m, 3H), 7.20-7.14 (m, 1H), 7.02 (d, J=8.8Hz, 2H), 3.80 (s, 3H), 2.19 (d, J=1.2Hz, 3H) ppm；13C NMR (100MHz,DMSO-d6):δ169.93,167.14,159.21,141.39,134.37,134.24,131.18,130.26, 127.93,122.53,119.67,116.09,114.01,55.19,13.89ppm；HRMS(EI)calc.for C18H17NO4 + 311.1158,found 311.1159。
Embodiment 5 (E) -2- (3- (4- tert-butyl-phenyl) -2- methacryl amido) benzoic acid (compound 5)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 4- tert-butyl benzene formaldehyde as starting material.
Fusing point: 179.9-180.9 DEG C；1H NMR(400MHz,DMSO-d6):δ13.74(s,1H),11.84(s,1H), 8.71 (d, J=8.0Hz, 1H), 8.05 (dd, J=8.0,1.6Hz, 1H), 7.68-7.61 (m, 1H), 7.50 (s, 1H), 7.47 (d, J=8.4Hz, 2H), 7.42 (d, J=8.4Hz, 2H), 7.21-7.16 (m, 1H), 2.20 (d, J=1.2Hz, 3H), 1.31 (s,9H)ppm；13C NMR(100MHz,DMSO-d6):δ169.92,166.96,150.86,141.33,134.45,134.24, 132.74,131.71,131.20,129.32,125.28,122.59,119.69,116.12,34.39,30.96,13.90ppm； HRMS(EI)calc.for C21H23NO3 +337.1678,found 337.1680。
Embodiment 6 (E) -2- (3- (the chloro- 3- trifluoromethyl of 4-) -2- methacryl amido) benzoic acid (compound 6)
Preparation method is similar with the method for embodiment 1, the difference lies in that being starting with the chloro- 3- trifluoromethylated benzaldehyde of 4- Raw material.
Fusing point: 192.4-193.3 DEG C；1H NMR(400MHz,DMSO-d6):δ13.80(s,1H),11.87(s,1H), 8.69 (dd, J=8.0,0.6Hz, 1H), 8.05 (dd, J=8.0,1.6Hz, 1H), 7.91 (s, 1H), 7.81 (s, 2H), 7.69- 7.62 (m, 1H), 7.56 (s, 1H), 7.22-7.17 (m, 1H), 2.19 (d, J=1.2Hz, 3H) ppm；13C NMR(100MHz, DMSO-d6):δ169.86,166.37,141.03,135.32,134.99,134.57,134.26,131.92,131.78, 131.22,130.08(q,3JCF=1.5Hz), 128.64 (q,3JCF=5.2Hz), 126.75 (q,2JCF=30.6Hz), 124.04,122.68(q,1JCF=271.5Hz), 119.78,116.37,13.80ppm；19F NMR(376MHz,DMSO-d6): δ-61.33(s,3F)ppm；HRMS(EI)calc.for C18H13 35ClF3NO3 +383.0536,found 383.0542； calc.for C18H13 37ClF3NO3 +385.0507,found 385.0515。
Embodiment 7 (E) -2- (3- (the chloro- 4- aminomethyl phenyl of 3-) -2- methacryl amido) benzoic acid (compound 7)
Preparation method is similar with the method for embodiment 1, the difference lies in that using the chloro- 4- tolyl aldehyde of 3- as starting material.
Fusing point: 225.6-226.3 DEG C；1H NMR(400MHz,DMSO-d6):δ13.76(s,1H),11.84(s,1H), 8.69 (dd, J=8.0,0.4Hz, 1H), 8.04 (dd, J=8.0,1.6Hz, 1H), 7.68-7.61 (m, 1H), 7.51 (d, J= 1.6Hz, 1H), 7.46 (s, 1H), 7.43 (d, J=8.0Hz, 1H), 7.36 (dd, J=8.0,1.2Hz, 1H), 7.22-7.16 (m, 1H), 2.36 (s, 3H), 2.18 (d, J=1.2Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ169.89, 166.68,141.17,135.46,135.17,134.24,133.36,133.24,132.98,131.26,131.20,129.47, 128.06,122.72,119.72,116.26,19.39,13.86ppm；HRMS(EI)calc.for C18H16 35ClNO3 + 329.0819,found 329.0823；calc.for C18H16 37ClNO3 +331.0789,found 331.0791。
Embodiment 8 (E) -2- (3- (3,4- dichlorophenyl) -2- methacryl amido) benzoic acid (compound 8)
Preparation method is similar with the method for embodiment 1, the difference lies in that 4- dichlorobenzaldehyde is starting material with 3.
Fusing point: 211.8-212.5 DEG C；1H NMR(400MHz,DMSO-d6):δ13.78(s,1H),11.85(s,1H), 8.68 (d, J=8.4Hz, 1H), 8.04 (dd, J=7.8,1.4Hz, 1H), 7.74 (d, J=1.6Hz, 1H), 7.71 (d, J= 8.4Hz, 1H), 7.68-7.62 (m, 1H), 7.50-7.46 (m, 2H), 7.22-7.17 (m, 1H), 2.18 (d, J=1.2Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ169.87,166.42,141.06,136.37,134.55,134.26,132.07, 131.24,131.22,131.14,130.63,130.62,129.51,122.85,119.76,116.36,13.85ppm；HRMS (EI)calc.for C17H13 35Cl2NO3 +349.0272,found 349.0274；calc.for C17H13 35Cl37ClNO3 + 351.0243,found 351.0253；calc.for C17H13 37Cl2NO3 +353.0214,found 353.0196。
Embodiment 9 (E) -2- (3- (3,5- dichlorophenyl) -2- methacryl amido) benzoic acid (compound 9)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 35- dichlorobenzaldehyde as starting material.
Fusing point: 222.5-223.3 DEG C；1H NMR(400MHz,DMSO-d6):δ13.79(s,1H),11.85(s,1H), 8.67 (d, J=8.0Hz, 1H), 8.05 (dd, J=8.0,1.6Hz, 1H), 7.68-7.63 (m, 1H), 7.62 (t, J=2.0Hz, 1H), 7.53 (d, J=1.6Hz, 2H), 7.46 (s, 1H), 7.23-7.17 (m, 1H), 2.18 (d, J=1.2Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ169.84,166.27,140.99,139.25,135.34,134.27,134.16,131.80, 131.23,127.79,127.50,122.91,119.78,116.41,13.86ppm；HRMS(EI)calc.for C17H13 35Cl2NO3 +349.0272,found 349.0278；calc.for C17H13 35Cl37ClNO3 +351.0243,found 351.0251；calc.for C17H13 37Cl2NO3 +353.0214,found 353.0206。
Embodiment 10 (E) -2- (3- (3,4- 3,5-dimethylphenyl) -2- methacryl amido) benzoic acid (compound 10)
Preparation method is similar with the method for embodiment 1, the difference lies in that 4- dimethylbenzaldehyde is starting material with 3.
Fusing point: 221.4-222.3 DEG C；1H NMR(400MHz,DMSO-d6):δ13.75(s,1H),11.84(s,1H), 8.71 (d, J=8.0Hz, 1H), 8.05 (dd, J=8.0,1.6Hz, 1H), 7.67-7.61 (m, 1H), 7.46 (s, 1H), 7.25 (s, 1H), 7.21 (s, 2H), 7.20-7.15 (m, 1H), 2.26 (s, 3H), 2.25 (s, 3H), 2.19 (d, J=1.2Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ169.94,167.03,141.36,136.62,136.34,134.64,134.23, 133.08,131.45,131.20,130.61,129.58,126.91,122.54,119.66,116.08,19.33,19.18, 13.92ppm；HRMS(EI)calc.for C19H19NO3 +309.1365,found 309.1368。
Embodiment 11 (E) -2- (3- (3,4- Dimethoxyphenyl) -2- methacryl amido) benzoic acid (compound 11)
Preparation method is similar with the method for embodiment 1, the difference lies in that being that starting is former with Veratraldehyde Material.
Fusing point: 170.0-170.9 °C；1H NMR(400MHz,DMSO-d6):δ13.74(s,1H),11.81(s,1H), 8.71 (d, J=8.4Hz, 1H), 8.04 (dd, J=8.0,1.6Hz, 1H), 7.67-7.60 (m, 1H), 7.48 (s, 1H), 7.18 (t, J=7.4Hz, 1H), 7.09-7.02 (m, 3H), 3.80 (s, 3H), 3.80 (s, 3H), 2.22 (d, J=1.2Hz, 1H) ppm ；13C NMR(100MHz,DMSO-d6):δ169.91,167.16,148.94,148.46,141.40,134.74,134.23, 131.20,130.42,128.17,122.61,122.52,119.68,116.09,113.21,111.58,55.49, 13.96ppm；HRMS(EI)calc.for C19H19NO5 +341.1263,found 341.1262。
Embodiment 12 (E) -2- (3- (1,3- benzo two dislikes cyclopentadienyl -5- base) -2- methacryl amido) benzoic acid (compound 12)
Preparation method is similar with the method for embodiment 1, the difference lies in that 3- benzo two dislikes cyclopentadienyl -5- formaldehyde as starting with 1 Raw material.
HRMS(EI)calc.for C18H15NO5 +325.0950,found 325.0952。
Embodiment 13 (E) -2- (3- (2,3- dihydro -1H- indenes -5- base) -2- methacryl amido) benzoic acid (compound 13)
Preparation method is similar with the method for embodiment 1, the difference lies in that 3- dihydro -1H- indenes -5- formaldehyde is starting with 2 Raw material.
Fusing point: 185.4-186.3 DEG C；1H NMR(400MHz,DMSO-d6):δ13.75(s,1H),11.84(s,1H), 8.71 (d, J=7.6Hz, 1H), 8.04 (dd, J=8.0,1.6Hz, 1H), 7.67-7.59 (m, 1H), 7.50 (s, 1H), 7.33 (s, 1H), 7.30 (d, J=7.6Hz, 1H), 7.23 (d, J=7.6Hz, 1H), 7.20-7.15 (m, 1H), 2.89 (q, J= 6.8Hz, 4H), 2.19 (d, J=1.2Hz, 3H), 2.08-1.99 (m, 2H) ppm；13C NMR(100MHz,DMSO-d6):δ 169.94,167.05,144.17,144.09,141.36,135.07,134.24,133.51,131.37,131.20,127.69, 125.25,124.28,122.55,119.64,116.08,32.19,24.97,13.94ppm；HRMS(EI)calc.for C20H19NO3 +321.1365,found 321.1366。
Embodiment 14 (E) -2- (2- methyl -3- (5,6,7,8- naphthane -2- base) acrylamido) benzoic acid (compound 14)
5,6,7,8- naphthane -2- formic acid (10mmol) are dissolved in the anhydrous THF of 25mL, argon gas protection, condition of ice bath Under be slowly added to LiAlH in batches thereto4(20mmol).4h is reacted at room temperature after ice bath reaction 10min, ice bath is cold after reaction But, 0.76g ice water, 0.76g 15%NaOH aqueous solution and 2.28g water are successively slowly added dropwise thereto.Stirring is added in a moment 20mL water, filtering, is washed, filtrate decompression is spin-dried for being concentrated with a small amount of ethyl acetate.Suitable quantity of water, ethyl acetate are added into concentrate Extraction merges organic phase, is dried, filtered with anhydrous sodium sulfate, and filtrate is spin-dried for up to substituted benzyl alcohol crude product, yield 98%.
Substituted benzyl alcohol obtained is dissolved in 100mL DCM, 70mmol MnO is added under stirring condition2, at room temperature instead 4h is answered, is filtered, filtrate is spin-dried for being concentrated, and crosses column purification and obtains 5,6,7,8- naphthane -2- formaldehyde, yield 90%.Subsequent preparation target The step of compound, is similar to Example 1.Fusing point: 232.3-233.3 DEG C；1H NMR(400MHz,DMSO-d6):δ13.75(s, 1H), 11.84 (s, 1H), 8.70 (d, J=8.4Hz, 1H), 8.04 (dd, J=7.8,1.4Hz, 1H), 7.67-7.61 (m, 1H), 7.44 (s, 1H), 7.22-7.10 (m, 4H), 2.75 (d, J=3.6Hz, 4H), 2.18 (d, J=0.8Hz, 3H), 1.79-1.72 (m,4H)ppm；13C NMR(100MHz,DMSO-d6):δ169.94,167.05,141.35,141.09,137.11,136.77, 134.67,134.24,132.71,131.48,131.21,130.11,129.04,126.59,122.56,119.64,116.11, 28.71,28.62,22.58,13.93ppm；HRMS(EI)calc.for C21H21NO3 +335.1521,found 335.1522。
Embodiment 15 (E) -2- (3- (6- methoxynaphthalene -2- base) -2- methacryl amido) benzoic acid (compound 15)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 6- methoxy-2-naphthaldehyde as starting material.
Fusing point: 206.8-207.3 DEG C；1H NMR(400MHz,DMSO-d6):δ13.78(s,1H),11.90(s,1H), 8.74 (d, J=7.6Hz, 1H), 8.06 (dd, J=7.8,1.4Hz, 1H), 7.98 (s, 1H), 7.89 (t, J=8.8Hz, 2H), 7.69-7.63 (m, 2H), 7.58 (dd, J=8.4,1.6Hz, 1H), 7.36 (d, J=2.4Hz, 1H), 7.23-7.16 (m, 2H), 3.90 (s, 3H), 2.29 (d, J=1.2Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ169.96,167.03, 157.96,141.36,134.77,134.27,133.85,131.82,131.23,130.75,129.81,128.86,128.15, 127.63,126.82,122.61,119.70,119.09,116.15,105.83,55.25,14.07ppm；HRMS(EI) calc.for C22H19NO4 +361.1314,found 361.1312。
Embodiment 16 (E) -2- (3- (6- bromonaphthalene -2- base) -2- methacryl amido) benzoic acid (compound 16)
Preparation method is similar with the method for embodiment 1, the difference lies in that using the bromo- 2- naphthaldehyde of 6- as starting material.
Fusing point: 213.8-214.4 DEG C；1H NMR(400MHz,DMSO-d6):δ13.80(s,1H),11.93(s,1H), 8.74 (d, J=8.4Hz, 1H), 8.24 (s, 1H), 8.07 (s, 2H), 7.97 (dd, J=8.4,5.8Hz, 2H), 7.70-7.63 (m, 4H), 7.20 (t, J=7.6Hz, 1H), 2.28 (s, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ169.94, 166.76,141.24,134.25,134.19,133.76,133.44,133.28,131.25,131.22,130.38,129.46, 129.44,128.73,128.27,127.16,122.70,119.89,119.74,116.24,14.05ppm；HRMS(EI) calc.for C21H16 79BrNO3 +409.0314,found 409.0313；calc.for C21H16 81BrNO3 +411.0293, found 411.0291。
Embodiment 17 (E) -2- (3- (5- chloronaphthalene -2- base) -2- methacryl amido) benzoic acid (compound 17)
Preparation method is similar with the method for embodiment 1, the difference lies in that replacing benzaldehyde with the chloro- 2- naphthaldehyde of 5-.
Fusing point: 232.8-233.6 DEG C；1H NMR(400MHz,DMSO-d6):δ13.79(s,1H),11.92(s,1H), 8.72 (d, J=7.6Hz, 1H), 8.23 (d, J=8.8Hz, 1H), 8.15 (s, 1H), 8.06 (dd, J=8.0,1.6Hz, 1H), 8.02 (d, J=8.4Hz, 1H), 7.79 (dd, J=8.8,1.6Hz, 1H), 7.74 (dd, J=7.2,0.8Hz, 1H), 7.69 (s, 1H), 7.68-7.64 (m, 1H), 7.56 (t, J=8.0Hz, 1H), 7.23-7.18 (m, 1H), 2.29 (d, J=0.8Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ169.93,166.73,141.20,134.28,134.25,134.06,133.85, 133.77,131.23,130.44,129.24,129.18,128.73,127.97,126.93,126.82,123.82,122.78, 119.79,116.33,14.05ppm；HRMS(EI)calc.for C21H16 35ClNO3 +365.0819,found 365.0815； calc.for C21H16 37ClNO3 +367.0789,found 367.0783。
Wherein, the chloro- 2- naphthaldehyde of the 5- can be made by the following method of key step:
Bromo- 2 naphthoic acid (0.75g, 3mmol) of 5- is dispersed in 10mL methanol, ice bath is cooling, slowly drips into reaction solution Add the 1mL concentrated sulfuric acid, back flow reaction 2h is added 20mL water, is extracted with DCM.Organic phase successively uses saturated sodium bicarbonate solution and satisfies And brine It, anhydrous sodium sulfate dry, filter, filtrate is concentrated to give bromo- 2 2-methyl naphthoate of 5-, yield 97%.
By the bromo- 2- 2-methyl naphthoate of resulting 5-, CuCl (0.45g, 4.5mmol) and 12mL N,N-dimethylformamide (DMF) it is dispersed in 50mL eggplant-shape bottle, argon gas protection, back flow reaction is overnight.It is cooled to room temperature, 25mL water is added, filter, filter cake It is dry.Gained filter cake is dispersed in 10mL DCM, insoluble impurity is filtered to remove, is washed with appropriate DCM, filtrate is concentrated to give 5- Chloro- 2 2-methyl naphthoate, yield 97%.
Chloro- 2 2-methyl naphthoate (0.44g, 2mmol) of 5- is dissolved in the anhydrous THF of 10mL, argon gas protection, condition of ice bath Under be slowly added to LiAlH in batches thereto4(0.1g,2.6mmol).12h, ice are kept in room temperature state after ice bath reaction 10min Bath cooling, is successively slowly added dropwise the 15%NaOH aqueous solution and 0.3g water of 0.1g ice water, 0.1g thereto.Stirring is added in a moment 10mL water, filtering, is washed, filtrate decompression is spin-dried for being concentrated with a small amount of ethyl acetate.Suitable quantity of water, ethyl acetate are added into concentrate Extraction merges organic phase, is dried, filtered with anhydrous sodium sulfate, and filtrate is spin-dried for up to (5- chloronaphthalene -2- base) methanol crude product, yield 90%.
(5- chloronaphthalene -2- base) methanol obtained above is dissolved in the DCM of 20mL, is added 14mmol's under stirring condition MnO2, 4h is reacted at room temperature, is filtered, and filtrate is spin-dried for being concentrated, and crosses column purification and obtains the chloro- 2- naphthaldehyde of 5-, yield 90%.
Embodiment 18 (E) -2- (2- methyl -3- (4- Phenoxyphenyl) acrylamido) benzoic acid (compound 18)
By phenol (705mg, 7.5mmol), 4-Fluorobenzaldehyde (625mg, 5.0mmol) and K2CO3(1.38g, 10.0mmol) It is dispersed in 5mL DMSO, argon gas protection, 110 DEG C of reactions are overnight.It being cooled to room temperature, suitable water is added, ethyl acetate extracts, Merge organic phase, saturated common salt is washed three times, and anhydrous sodium sulfate is dry, is spin-dried for being concentrated, and is crossed column purification and is obtained 4- phenoxy benzaldehyde. The subsequent method for preparing final product is the same as embodiment 1.Fusing point: 184.4-185.2 DEG C；1H NMR(400MHz,DMSO-d6):δ 13.75 (s, 1H), 11.84 (s, 1H), 8.71 (d, J=8.4Hz, 1H), 8.05 (dd, J=7.6,1.2Hz, 1H), 7.67- 7.61 (m, 1H), 7.53 (s, 1H), 7.51 (s, 2H), 7.44 (t, J=8.0Hz, 2H), 7.19 (q, J=7.2Hz, 2H), 7.09 (d, J=8.0Hz, 2H), 7.06 (d, J=8.8Hz, 2H), 2.21 (s, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ 169.93,166.95,156.80,155.96,141.32,134.24,133.90,131.53,131.44,131.20,130.53, 130.13,123.94,122.60,119.69,119.17,118.10,116.14,13.88ppm；HRMS(EI)calc.for C23H19NO4 +373.1314,found 373.1316。
Embodiment 19 (E) -2- (2- methyl -3- (3- Phenoxyphenyl) acrylamido) benzoic acid (compound 19)
3-bromobenzaldehyde (5mmol) is dispersed in 15mL DCM, 9mmol ethoxycarbonyl ethylidene triphenyl is added Phosphine reacts at room temperature 4h, and rotation removes partial solvent, crosses column purification and obtains (E) -3- (3- bromophenyl)-ethyl 2-methacrylate, yield 94%.
In reaction flask be added phenol (6mmol), (E) -3- (3- bromophenyl)-ethyl 2-methacrylate (5mmol), K2CO3(10mmol), CuCl (0.25mmol), N- butyl imidazole (2.5mmol) and 5mL ortho-xylene, argon gas protection, 140 DEG C anti- Answer 16h.Filtering, filtrate successively use dilute hydrochloric acid and saturated common salt to wash, and anhydrous sodium sulfate is dry, is spin-dried for being concentrated, and cross column purification and obtain (E) -2- methyl -3- (3- Phenoxyphenyl) ethyl acrylate.The subsequent method for preparing final product is the same as embodiment 1.Fusing point: 158.6-159.3℃；1H NMR (400MHz, DMSO-d6): δ 13.75 (s, 1H), 11.82 (s, 1H), 8.68 (d, J= 8.0Hz, 1H), 8.04 (dd, J=8.0,1.6Hz, 1H), 7.66-7.61 (m, 1H), 7.50-7.45 (m, 2H), 7.45-7.39 (m, 2H), 7.25 (d, J=7.6Hz, 1H), 7.21-7.15 (m, 2H), 7.09-7.07 (m, 2H), 7.07-7.05 (m, 1H), 7.01 (dd, J=8.0,2.0Hz, 1H), 2.15 (d, J=1.2Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ 169.86,166.72,156.78,156.37,141.16,137.51,134.22,133.76,133.30,131.19,130.16, 130.09,124.49,123.66,122.71,119.75,119.20,118.80,118.22,116.29,13.89ppm；HRMS (EI)calc.for C23H19NO4 +373.1314,found 373.1313。
Embodiment 20 (E) -2- (2- methyl -3- (4- carbanilino phenyl) acrylamido) benzoic acid (compound 20)
4- aldehyde benzoic acid (10mmol), EDCI (11mmol) and HOBT (1.1mmol) are added in 30mL DCM, room temperature Under be stirred to react.(10mmol) aniline is added to 4- aldehyde benzoic acid fully reacting in TLC tracking reaction, continues at room temperature anti- It answers.After reaction, partial solvent is spun off, column purification is crossed and obtains 4- formoxyl-N- phenylbenzamaide.The subsequent final product of preparing Method is the same as embodiment 1.HRMS(EI)calc.for C24H20N2O4 +400.1423,found 400.1418。
Embodiment 21 (E) -2- (3- ([1,1'- biphenyl] -4- base) -2- methacryl amido) benzoic acid (compound 21)
Preparation method is similar with the method for embodiment 14, the difference lies in that being that starting is former with [1,1'- biphenyl] -4- formic acid Material.
Fusing point: 241.3-242.2 DEG C；1H NMR(400MHz,DMSO-d6):δ13.76(s,1H),11.87(s,1H), 8.71 (d, J=8.4Hz, 1H), 8.05 (dd, J=8.0,1.6Hz, 1H), 7.77 (d, J=8.0Hz, 2H), 7.73 (d, J= 6.8Hz, 2H), 7.68-7.63 (m, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.57 (s, 1H), 7.50 (t, J=7.6Hz, 2H), 7.40 (t, J=7.2Hz, 1H), 7.19 (t, J=7.6Hz, 1H), 2.25 (d, J=1.2Hz, 3H) ppm；13C NMR (100MHz,DMSO-d6):δ169.92,166.91,141.27,139.81,139.38,134.70,134.26,134.13, 132.56,131.22,130.17,129.00,127.73,126.71,126.63,122.68,119.74,116.26, 14.02ppm；HRMS(EI)calc.for C23H19NO3 +357.1365,found 357.1363。
Embodiment 22 (E) -2- (3- (1H- indoles -6- base) -2- methacryl amido) benzoic acid (compound 22)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 1H- indole -6-formaldehyde as starting material.
HRMS(EI)calc.for C19H16N2O3 +320.1161,found 320.1165。
Embodiment 23 (E) -2- (2- methyl -3- (1- Methyl-1H-indole -6- base) acrylamido) benzoic acid (compound 23)
Preparation method is similar with the method for embodiment 1, the difference lies in that being starting with 1- Methyl-1H-indole -6- formaldehyde Raw material.
HRMS(EI)calc.for C20H18N2O3 +334.1317,found 334.1312。
Embodiment 24 (E) -2- (2- methyl -3- (1- Methyl-1H-indole -2- base) acrylamido) benzoic acid (compound 24)
Raw material (E) -2- methyl -3- (1- Methyl-1H-indole -2- base) synthesis of conjugated carboxylic alkeneacid is different with embodiment 14 Point is, replaces 5,6,7,8- naphthane -2- formic acid with 1- Methyl-1H-indole -2- formic acid.
(E) -2- methyl -3- (1- Methyl-1H-indole -2- base) is sequentially added into the 25mL reaction flask for being cased with drying tube Acrylic acid (215mg, 1.0mmol), paratoluensulfonyl chloride (209mg, 1.1mmol), 1,2- dichloroethanes (5mL), 4- diformazan ammonia Yl pyridines (12mg, 0.1mmol) and triethylamine (152mg, 1.5mmol), 35 DEG C are reacted 1 hour, and ortho-aminobenzoic acid is added (137mg, 1.0mmol), 60 DEG C are reacted 10 hours, are acidified with the HCl of 1M, are filtered to obtain solid, washed, dry, ethyl alcohol recrystallization, Yield: 50%.Fusing point: 243.3-244.1 DEG C；1H NMR(400MHz,DMSO-d6):δ13.82(s,1H),11.98(s,1H), 8.73 (d, J=8.4Hz, 1H), 8.06 (dd, J=8.0,1.2Hz, 1H), 7.69-7.62 (m, 3H), 7.53 (d, J=8.4Hz, 1H), 7.25-7.17 (m, 2H), 7.08 (t, J=7.4Hz, 1H), 6.87 (s, 1H), 3.84 (s, 3H), 2.33 (s, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ170.03,166.61,141.50,141.35,137.40,134.47,134.30, 132.73,131.27,127.23,122.87,122.66,120.73,119.75,119.62,116.21,110.00,104.77, 29.74,14.68ppm；HRMS(EI)calc.for C20H18N2O3 +334.1317,found 334.1312。
Embodiment 25 (E) -2- (2- methyl -3- (quinoline -3- base) acrylamido) benzoic acid (compound 25)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 3- quinoline aldehyde as starting material.
HRMS(EI)calc.for C20H16N2O3 +332.1161,found 332.1159。
Embodiment 26 (E) -2- (3- (isoquinolin -3- base) -2- methacryl amido) benzoic acid (compound 26)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 3- Isoquindinealdehyde as starting material.
Fusing point: 252.6-253.2 DEG C；1H NMR(400MHz,DMSO-d6):δ13.86(s,1H),11.96(s,1H), 9.41 (s, 1H), 8.75 (d, J=8.4Hz, 1H), 8.16 (d, J=8.0Hz, 1H), 8.08-8.04 (m, 2H), 8.02 (d, J= 8.4Hz, 1H), 7.82 (t, J=7.6Hz, 1H), 7.73 (t, J=7.4Hz, 1H), 7.69-7.62 (m, 2H), 7.20 (t, J= 7.6Hz,1H),2.61(s,3H)ppm；13C NMR(100MHz,DMSO-d6):δ169.94,167.14,152.15,148.44, 141.26,135.43,134.45,134.23,133.35,131.22,130.99,128.19,127.61,127.13,126.95, 123.11,122.72,119.78,116.33,13.93ppm；HRMS(EI)calc.for C20H16N2O3 +332.1161,found 332.1160。
Embodiment 27 (E) -2- (2- methyl -3- (quinoline -7- base) acrylamido) benzoic acid (compound 27)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 7- quinoline aldehyde as starting material.
HRMS(EI)calc.for C20H16N2O3 +332.1161,found 332.1158。
Embodiment 28 (E) -2- (3- (isoquinolin -6- base) -2- methacryl amido) benzoic acid (compound 28)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 6- Isoquindinealdehyde as starting material.
HRMS(EI)calc.for C20H16N2O3 +332.1161,found 332.1163。
Embodiment 29 (E) -2- (3- (benzothiophene -2- base) -2- methacryl amido) benzoic acid (compound 29)
Preparation method is similar with the method for embodiment 1, the difference lies in that using benzothiophene -2- formaldehyde as starting material.
HRMS(EI)calc.for C19H15NO3S+337.0773,found 337.0771。
Embodiment 30 (E) -2- (3- (benzothiophene -6- base) -2- methacryl amido) benzoic acid (compound 30)
Preparation method is similar with the method for embodiment 1, the difference lies in that using benzothiophene -6- formaldehyde as starting material.
HRMS(EI)calc.for C19H15NO3S+337.0773,found 337.0774。
Embodiment 31 (E) -2- (3- (benzofuran -2- base) -2- methacryl amido) benzoic acid (compound 31)
Preparation method is similar with the method for embodiment 1, the difference lies in that using benzofuran -2- formaldehyde as starting material.
HRMS(EI)calc.for C19H15NO4 +321.1001,found 321.1003。
Embodiment 32 (E) -2- (3- (benzofuran -6- base) -2- methacryl amido) benzoic acid (compound 32)
Preparation method is similar with the method for embodiment 1, the difference lies in that using benzofuran -6- formaldehyde as starting material.
HRMS(EI)calc.for C19H15NO4 +321.1001,found 321.1006。
Embodiment 33 (E) -2- (3- (naphthalene -2- base) acrylamido) benzoic acid (compound 33)
2mmol 2- naphthaldehyde and 6mmol malonic acid are dispersed in 1.2mL DMF, 2mmol pyridine, 90 DEG C of reactions are added 5h is cooled to room temperature, and 1.2mL water is added, and 1M HCl acidification filters, and twice, filtration cakes torrefaction is up to (E) -3- (naphthalene -2- for washing Base) acrylic acid, yield 80%, the subsequent method for preparing final product is the same as embodiment 1.Fusing point: 241.9-242.7 DEG C；1H NMR (400MHz, DMSO-d6): δ 13.65 (s, 1H), 11.41 (s, 1H), 8.66 (d, J=8.4Hz, 1H), 8.23 (s, 1H), 8.04 (dd, J=8.0,1.6Hz, 1H), 7.99-7.92 (m, 4H), 7.80 (d, J=15.6Hz, 1H), 7.68-7.61 (m, 1H), 7.60-7.54 (m, 2H), 7.23-7.18 (m, 1H), 7.04 (d, J=15.6Hz, 1H) ppm；13C NMR(100MHz,DMSO- d6):δ169.44,163.79,141.34,140.85,134.00,133.60,132.94,132.01,131.13,129.48, 128.47,128.40,127.66,127.15,126.71,124.09,122.88,122.73,120.41,116.82ppm；HRMS (EI)calc.for C20H15NO3 +317.1052,found 317.1055。
Embodiment 34 (E) -2- (2- methyl -3- (naphthalene -2- base) acrylamido) benzoic acid (compound 34)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material.
Fusing point: 231.5-232.3 DEG C；1H NMR(400MHz,DMSO-d6):δ13.80(s,1H),11.92(s,1H), 8.74 (d, J=8.0Hz, 1H), 8.07 (dd, J=8.0,1.6Hz, 1H), 8.05 (s, 1H), 8.00-7.94 (m, 3H), 7.70- 7.64 (m, 2H), 7.62 (dd, J=8.8,1.6Hz, 1H), 7.60-7.54 (m, 2H), 2.30 (d, J=1.2Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ169.95,166.90,141.29,134.54,134.28,133.14,132.87,132.74, 132.37,131.23,128.81,128.19,127.92,127.52,127.09,126.71,126.50,122.69,119.74, 116.22,14.05ppm；HRMS(EI)calc.for C21H17NO3 +331.1208,found 331.1204。
Embodiment 35 (E) -2- (3- (naphthalene -2- base) -2- crotonoyl amido) benzoic acid (compound 35)
4.2mmol NaH is added in 50mL three-necked flask, argon gas protection is added the anhydrous THF of 24mL, 3.9mmol is added 2- phosphonoacetate, stirs 0.5h at room temperature, and the THF solution of 12mL 1- (naphthalene -2- base) -1- ethyl ketone (3mmol) is dripped It is added in reaction solution, reacts at room temperature 12h, 2M HCl acidification spins off THF, and suitable quantity of water is added, and ethyl acetate extraction merges organic Phase, saturated common salt washing, anhydrous sodium sulfate dry, filter, and rotation removes solvent concentration, cross column purification and obtain 2- (naphthalene -2- methylene) Butenoic acid ethyl, yield 50%.The subsequent method for preparing final product is the same as embodiment 1.HRMS(EI)calc.for C21H17NO3+ 331.1208,found 331.1206。
Embodiment 36 (E) -2- (2- methyl -3- (naphthalene -2- base) -2- crotonoyl amido) benzoic acid (compound 36)
Preparation method is similar with the method for embodiment 35, the difference lies in that replacing phosphoryl with 2- phosphono the third triethylenetetraminehexaacetic acid rouge Triethyl acetate.
HRMS(EI)calc.for C22H19NO3 +345.1365,found 345.1361。
Embodiment 37 (Z) -2- (the chloro- 3- of 2- (naphthalene -2- base) acrylamido) benzoic acid (compound 37)
9mmol ethoxycarbonyl methylene triphenyl phosphine and 15mL DCM are added into reaction flask, argon gas is protected, and -20 DEG C Under 9mmol NCS is added portionwise, 1h is reacted at -20 DEG C, 5mmol 2- naphthaldehyde and 12.5mmol K are added at room temperature2CO3, room temperature 10h is reacted, reaction solution is washed with water, and organic phase is dry with anhydrous sodium sulfate, is spin-dried for being concentrated, and crosses column purification and obtains the chloro- 3- of (Z) -2- (naphthalene -2- base) ethyl acrylate.The subsequent method for preparing final product is the same as embodiment 1.Fusing point: 236.1-237.0 DEG C；1H NMR (400MHz, DMSO-d6): δ 13.92 (s, 1H), 12.53 (s, 1H), 8.74 (d, J=8.0Hz, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 8.09 (dd, J=7.8,1.2Hz, 1H), 8.03 (s, 3H), 7.97 (d, J=7.2Hz, 1H), 7.70 (t, J= 7.4Hz, 1H), 7.66-7.56 (m, 2H), 7.27 (t, J=7.4Hz, 1H) ppm.13C NMR(100MHz,DMSO-d6):δ 169.61,160.22,140.24,134.39,134.29,133.26,132.53,131.29,130.97,130.23,128.66, 128.11,127.66,127.56,126.77,126.71,123.65,123.60,119.86,116.90ppm；HRMS(EI) calc.for C20H14 35ClNO3 +351.0662,found 351.0664；calc.for C20H14 37ClNO3 +353.0633, found 353.0643。
Embodiment 38 (Z) -2- (the bromo- 3- of 2- (naphthalene -2- base) acrylamido) benzoic acid (compound 38)
9mmol ethoxycarbonyl methylene triphenyl phosphine and 15mL DCM are added into reaction flask, argon gas is protected, and -20 DEG C Under 9mmol NBS is added portionwise, 1h is reacted at -20 DEG C, 5mmol 2- naphthaldehyde and 12.5mmol K are added at room temperature2CO3, room temperature 10h is reacted, reaction solution is washed with water, and organic phase is dry with anhydrous sodium sulfate, is spin-dried for being concentrated, and crosses column purification and obtains the bromo- 3- of (Z) -2- (naphthalene -2- base) ethyl acrylate.The subsequent method for preparing final product is the same as embodiment 1.Fusing point: 233.9-234.7 DEG C；1H NMR (400MHz, DMSO-d6): δ 13.89 (s, 1H), 12.36 (s, 1H), 8.69 (d, J=8.0Hz, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 8.08 (dd, J=8.0,1.6Hz, 1H), 8.04-7.99 (m, 3H), 7.97 (d, J=7.6Hz, 1H), 7.75-7.66 (m, 1H), 7.66-7.55 (m, 2H), 7.27 (t, J=7.6Hz, 1H) ppm；13C NMR(100MHz,DMSO-d6):δ169.49, 160.86,140.26,138.03,134.20,133.21,132.43,131.27,131.25,130.35,128.55,127.95, 127.61,127.56,126.77,126.39,123.62,119.97,117.08,115.82ppm；HRMS(EI)calc.for C20H14 79BrNO3 +395.0157,found 395.0158；calc.for C20H14 81BrNO3 +397.0137,found 397.0132。
Embodiment 39 (E) -2- (2- (naphthalene -2- methylene) crotonoyl amido) benzoic acid (compound 39)
Preparation method is similar with the method for embodiment 35, the difference lies in that replacing 1- (naphthalene -2- base) -1- with 2- naphthaldehyde Ethyl ketone replaces phosphonoacetate with 2- phosphono fourth triethylenetetraminehexaacetic acid rouge.
Fusing point: 184.6-185.2 DEG C；1H NMR(400MHz,DMSO-d6):δ13.78(s,1H),11.91(s,1H), 8.74 (d, J=8.4Hz, 1H), 8.06 (dd, J=7.8,1.4Hz, 1H), 8.02-7.93 (m, 4H), 7.70-7.63 (m, 1H), 7.62-7.55 (m, 4H), 7.21 (t, J=7.4Hz, 1H), 2.71 (q, J=7.2Hz, 2H), 1.23 (t, J=7.4Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ169.96,166.76,141.22,139.76,134.28,133.60,133.05, 132.79,132.40,131.23,128.24,128.21,128.11,127.51,126.70,126.56,126.55,122.72, 119.77,116.26,20.47,13.53ppm；HRMS(EI)calc.for C22H19NO3 +345.1365,found 345.1363。
Embodiment 40 (Z) -2- (3- (naphthalene -2- base) -2- trifluoromethyl acrylamido) benzoic acid (compound 40)
6mmol 2- naphthaldehyde, 4mmol 3,3,3- trifluoroacetic acid, 20mL THF and 8mL are sequentially added in reaction flask The TiCl of 1M40.5h is stirred at room temperature in dichloromethane solution, and 16mmol triethylamine is added dropwise into reaction solution.It is backward to react at room temperature 40h 30mL water is slowly added in reaction flask, methylene chloride extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, mistake Filter, filtrate are spin-dried for and use silica gel column separating purification (methylene chloride: methanol=10:1), obtain (Z) -3- (naphthalene -2- base) -2- (trifluoro Methyl) acrylic acid.The subsequent method for preparing final product is the same as embodiment 1.HRMS(EI)calc.for C21H14F3NO3 + 385.0926,found 385.0922。
Embodiment 41 (E) -2- (2- cyano -3- (naphthalene -2- base) acrylamido) benzoic acid (compound 41)
5mmol 2- naphthaldehyde is dispersed in 7.5mL methanol, 5mmol malonic methyl ester nitrile and 0.5mmol piperidines is added, Back flow reaction is to fully reacting.It is cooled to room temperature, solid is precipitated, and filters, and filter cake is washed with proper amount of methanol, and filter cake is obtained by drying (E) -2- cyano -3- (naphthalene -2- base) methyl acrylate intermediate.Yield 90%.The subsequent same embodiment of method for preparing final product 1。HRMS(EI)calc.for C21H14N2O3 +342.1004,found 342.1007。
The fluoro- 2- of embodiment 42 (E) -5- (2- methyl -3- (naphthalene -2- base) acrylamido) benzoic acid (compound 42)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with 2- amino-5-fluorobenzoic acid.
Fusing point: 237.4-238.2 DEG C；1H NMR(400MHz,DMSO-d6):δ14.11(s,1H),11.71(s,1H), 8.73 (dd, J=9.2,5.2Hz, 1H), 8.03 (s, 1H), 8.01-7.92 (m, 3H), 7.76 (dd, J=9.2,3.2Hz, 1H), 7.68 (s, 1H), 7.61 (dd, J=8.6,1.2Hz, 1H), 7.59-7.52 (m, 3H), 2.28 (s, 3H) ppm；13C NMR (100MHz,DMSO-d6):δ168.74,166.79,156.70(d,1JCF=239.4Hz), 137.71 (d,4JCF=2.3Hz), 134.61,133.10,132.69(d,3JCF=8.3Hz), 132.36,128.82,128.18,127.91,127.51,127.07, 126.71,126.50,121.99(d,3JCF=7.4Hz), 121.08 (d,2JCF=21.9Hz), 118.33,118.26,116.94 (d,2JCF=23.7Hz), 14.01ppm；19F NMR(376MHz,DMSO-d6):δ-118.88--118.96(m,1F)ppm； HRMS(EI)calc.for C21H16FNO3 +349.1114,found 349.1113。
The fluoro- 2- of embodiment 43 (E) -4- (2- methyl -3- (naphthalene -2- base) acrylamido) benzoic acid (compound 43)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with 2- amino -4- fluobenzoic acid.
Fusing point: 238.6-239.2 DEG C；1HNMR(400MHz,DMSO-d6):δ13.96(s,1H),12.17(s,1H), 8.58 (dd, J=12.4,2.4Hz, 1H), 8.13 (dd, J=8.6,7.0Hz, 1H), 8.04 (s, 1H), 8.00-7.93 (m, 3H), 7.70 (s, 1H), 7.61 (dd, J=8.6,1.0Hz, 1H), 7.59-7.55 (m, 2H), 7.03 (td, J=8.6,2.4Hz, 1H),2.29(s,3H)ppm；13C NMR(100MHz,DMSO-d6):δ169.27,167.18,165.00(d,1JCF= 247.8Hz),143.43(d,3JCF=13.0Hz), 135.11,133.96 (d,3JCF=11.2Hz), 132.98,132.72, 132.43,132.42,128.92,128.20,127.94,127.51,127.04,126.77,126.52,112.73(d,4JCF= 2.4Hz),109.65(d,2JCF=22.1Hz), 106.15 (d,2JCF=28.1Hz), 13.92ppm；19F NMR(376MHz, DMSO-d6):δ-102.67--102.97(m,1F)ppm；HRMS(EI)calc.for C21H16FNO3 +349.1114,found 349.1115。
The chloro- 2- of embodiment 44 (E) -5- (2- methyl -3- (naphthalene -2- base) acrylamido) benzoic acid (compound 44)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with 2- amino -5- chlorobenzoic acid.
Fusing point: 251.5-252.2 DEG C；1H NMR(400MHz,DMSO-d6):δ14.18(s,1H),11.83(s,1H), 8.74 (d, J=9.2Hz, 1H), 8.03 (s, 1H), 8.00-7.92 (m, 4H), 7.72 (dd, J=9.0,2.6Hz, 1H), 7.69 (s, 1H), 7.61 (dd, J=8.6,1.6Hz, 1H), 7.59-7.53 (m, 2H), 2.28 (d, J=1.2Hz, 3H) ppm；13C NMR (100MHz,DMSO-d6):δ168.69,166.90,140.05,134.86,133.83,133.04,132.72,132.56, 132.39,130.32,128.87,128.19,127.92,127.51,127.05,126.74,126.51,126.24,121.58, 118.12,13.99ppm；HRMS(EI)calc.for C21H16 35ClNO3 +365.0819,found 365.0816；calc.for C21H16 37ClNO3 +367.0789,found 367.0789。
The bromo- 2- of embodiment 45 (E) -5- (2- methyl -3- (naphthalene -2- base) acrylamido) benzoic acid (compound 45)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with 2- amino -5- bromobenzoic acid.
Fusing point: 256.9-257.6 DEG C；1H NMR(400MHz,DMSO-d6):δ14.18(s,1H),11.83(s,1H), 8.69 (d, J=8.8Hz, 1H), 8.11 (d, J=2.8Hz, 1H), 8.02 (s, 1H), 8.00-7.92 (m, 3H), 7.82 (dd, J =8.8,2.4Hz, 1H), 7.68 (s, 1H), 7.60 (dd, J=8.6,1.4Hz, 1H), 7.58-7.53 (m, 2H), 2.28 (d, J =0.8Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ168.62,166.88,140.44,136.67,134.88, 133.21,133.04,132.71,132.55,132.38,128.87,128.19,127.91,127.50,127.03,126.73, 126.49,121.81,118.34,114.01,13.98ppm；HRMS(EI)calc.for C21H16 79BrNO3 +409.0314, found 409.0312；calc.for C21H16 81BrNO3 +411.0293,found 411.0308。
Embodiment 46 (E) -2- (2- methyl -3- (naphthalene -2- base) acrylamido) -5- trifluoromethylbenzoic acid (compound 46)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with 2- amino -5- trifluoromethylbenzoic acid.
Fusing point: 228.7-229.4 DEG C；1H NMR (400MHz, DMSO-d6): δ 12.20 (s, 1H), 8.92 (d, J= 8.8Hz, 1H), 8.28 (d, J=2.0Hz, 1H), 8.04 (s, 1H), 8.02-7.93 (m, 4H), 7.72 (s, 1H), 7.62 (dd, J =8.6,1.4Hz, 1H), 7.59-7.54 (m, 2H), 2.30 (d, J=1.2Hz, 3H) ppm；13C NMR(100MHz,DMSO- d6):δ168.77,167.27,144.37,135.28,132.95,132.71,132.48,132.43,130.66(q,3JCF= 3.4Hz),128.96,128.21,127.94,127.91(q,3JCF=3.5Hz), 127.51,127.02,126.79,126.52, 123.83(q,1JCF=270Hz), 122.49 (q,2JCF=32.6Hz), 120.16,116.86,13.99ppm；19F NMR (376MHz,DMSO-d6):δ-60.79(s,3F)ppm；HRMS(EI)calc.for C22H16F3NO3 +399.1082,found 399.1088。
Embodiment 47 (E) -5- methyl -2- (2- methyl -3- (naphthalene -2- base) acrylamido) benzoic acid (compound 47)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with 2- amino -5- methyl benzoic acid.
Fusing point: 194.6-195.3 DEG C；1H NMR(400MHz,DMSO-d6):δ13.73(s,1H),11.81(s,1H), 8.63 (d, J=8.4Hz, 1H), 8.03 (s, 1H), 8.00-7.92 (m, 3H), 7.87 (s, 1H), 7.67 (s, 1H), 7.61 (d, J =8.4Hz, 1H), 7.58-7.53 (m, 2H), 7.47 (dd, J=8.4,1.2Hz, 1H), 2.33 (s, 3H), 2.28 (s, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ169.96,166.66,138.93,134.80,134.34,133.19,132.88, 132.74,132.34,131.76,131.23,128.77,128.17,127.89,127.51,127.09,126.68,126.48, 119.78,116.12,20.20,14.03ppm；HRMS(EI)calc.for C22H19NO3 +345.1365,found 345.1367。
Embodiment 48 (E) -5- methoxyl group -2- (2- methyl -3- (naphthalene -2- base) acrylamido) benzoic acid (compound 48)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with 2- amino -5- methoxy benzoic acid.
Fusing point: 218.6-219.3 DEG C；1H NMR(400MHz,DMSO-d6):δ13.70(s,1H),11.60(s,1H), 8.65 (d, J=9.2Hz, 1H), 8.02 (s, 1H), 7.99 (t, J=2.8Hz, 1H), 7.97-7.92 (m, 2H), 7.67 (s, 1H), 7.61 (dd, J=8.4,1.6Hz, 1H), 7.57 (d, J=3.2Hz, 1H), 7.55 (d, J=3.6Hz, 1H), 7.53 (d, J =2.8Hz, 1H), 7.28 (dd, J=9.2,3.2Hz, 1H), 3.81 (s, 3H), 2.28 (d, J=1.2Hz, 3H) ppm；13C NMR (100MHz,DMSO-d6):δ169.49,166.44,154.16,134.67,134.15,133.25,132.87,132.75, 132.32,128.72,128.15,127.88,127.49,127.08,126.64,126.46,121.63,120.23,117.74, 114.89,55.37,14.02ppm；HRMS(ES+)calcd for C22H19NO4Na(M+Na)+,384.1212；found, 384.1213。
Embodiment 49 (E) -2- (3- (1- fluoronaphthalene -2- base) -2- methacryl amido) benzoic acid (compound 49)
Preparation method is similar with the method for embodiment 1, the difference lies in that using the fluoro- 2- naphthaldehyde of 1- as raw material.
Fusing point: 247.3-248.2 DEG C；1H NMR(400MHz,DMSO-d6):δ13.83(s,1H),11.98(s,1H), 8.74 (d, J=8.0Hz, 1H), 8.14-8.09 (m, 1H), 8.07 (dd, J=8.0,1.4Hz, 1H), 8.05-8.01 (m, 1H), 7.85 (d, J=8.8Hz, 1H), 7.71-7.65 (m, 4H), 7.62 (t, J=8.0Hz, 1H), 7.24-7.18 (m, 1H), 2.19 (s,3H)ppm；13C NMR(100MHz,DMSO-d6):δ169.99,166.14,154.97(d,1JCF=252.1Hz), 141.14,135.12,134.30,134.08(d,3JCF=5.8Hz), 131.23,127.68,127.40 (d,3JCF=3.0Hz), 127.23(d,4JCF=1.4Hz), 126.71 (d,3JCF=3.2Hz), 123.71 (d,3JCF=4.1Hz), 122.83,122.58 (d,2JCF=16.6Hz), 120.23,120.17,119.77,117.85 (d,2JCF=12.7Hz), 116.30,14.25ppm；19F NMR (376MHz, DMSO-d6): δ -122.81 (d, J=7.2Hz, 1F) ppm；HRMS(EI)calc.for C21H16FNO3 + 349.1114,found 349.1120。
Wherein, the fluoro- 2- naphthaldehyde of the 1- can be prepared as follows:
2- methyl-1-naphthylamines (1.57g, 10mmol) is added in 100mL eggplant-shape bottle, fluoboric acid is added dropwise into reaction flask (15mL), ice bath is cooling, and 10mL NaNO is slowly added dropwise into reaction solution2Solution (2.76g, 40mmol), ice bath react 0.5h, It filters, filtration cakes torrefaction obtains diazonium salt.Gained diazonium salt is added in 50mL toluene, 90 DEG C of reactions 1h, back flow reaction 2h.Successively With saturation NaHCO3Solution and saturated salt solution washing reaction liquid, concentration of reaction solution dry with anhydrous sodium sulfate are crossed column purification and are obtained The fluoro- 2- methyl naphthalene of 1-, yield 67%.
The fluoro- 2- methyl naphthalene (5mmol) of 1- obtained is dissolved in 10mL CCl4, 10mmol NBS, 0.1mmol peroxide is added Change dibenzoyl (BPO), back flow reaction 5h is cooled to room temperature, and is filtered, with appropriate petroleum ether filter cake, concentration.Gained is dense Contracting liquid is dissolved in 10mL dioxane, and 10mL water, 20mmol CaCO is added3, flow back 10h, filtering, and ethyl acetate extraction is closed And organic phase, anhydrous sodium sulfate is dry, is spin-dried for being concentrated, and crosses column purification and obtains (1- fluoronaphthalene -2- base) methanol, yield 80%.
(1- fluoronaphthalene -2- base) methanol (4mmol) by made from is dissolved in the DCM of 40mL, is added under stirring condition The MnO of 28mmol2, 4h is reacted at room temperature, is filtered, and filtrate is spin-dried for being concentrated, and crosses column purification and obtains the fluoro- 2- naphthaldehyde of 1- (starting original Material), yield 90%.
Embodiment 50 (Z) -2- (the chloro- 3- of 2- (1- fluoronaphthalene -2- base) acrylamido) -5- fluobenzoic acid (compound 50)
Preparation method is similar with the method for embodiment 37, the difference lies in that using the fluoro- 2- naphthaldehyde of 1- as raw material, by adjacent ammonia Yl benzoic acid replaces with 2- amino-5-fluorobenzoic acid.
1H NMR(400MHz,DMSO-d6): δ 14.21 (s, 1H), 12.53 (s, 1H), 8.73 (dd, J=9.2,5.2Hz, 1H), 8.06 (dd, J=8.0,1.4Hz, 1H), 8.05-8.01 (m, 1H), 7.81 (d, J=8.8Hz, 1H), 7.71-7.63 (m, 4H), 7.62 (t, J=8.0Hz, 1H), 7.25-7.20 (m, 1H), ppm；HRMS(EI)calc.for C20H12ClF2NO3 + 387.0474,found 387.0471；HRMS(EI)calc.for C20H12 37ClF2NO3 +389.0445,found 389.0447.
The fluoro- 2- of embodiment 51 (E) -5- (3- (1- fluoronaphthalene -2- base) -2- methacryl amido) benzoic acid (compound 51)
Preparation method is similar with the method for embodiment 1, the difference lies in that using the fluoro- 2- naphthaldehyde of 1- as raw material, by adjacent amino Benzoic acid replaces with 2- amino-5-fluorobenzoic acid.
Fusing point: 250.8-251.7 DEG C；1H NMR(400MHz,DMSO-d6):δ14.13(s,1H),11.76(s,1H), 8.72 (dd, J=9.2,5.2Hz, 1H), 8.14-8.09 (m, 1H), 8.06-8.01 (m, 1H), 7.85 (d, J=8.4Hz, 1H), 7.77 (dd, J=9.2,3.2Hz, 1H), 7.70-7.64 (m, 3H), 7.61 (d, J=8.0Hz, 1H), 7.59-7.53 (m, 1H), 2.17(s,3H)ppm；13C NMR(100MHz,DMSO-d6):δ168.76,166.07,156.80(d,1JCF=239.8Hz), 154.97(d,1JCF=252.3Hz), 137.54 (d,4JCF=2.3Hz), 134.94,134.08 (d,3JCF=5.0Hz), 127.69,127.67,127.47(d,4JCF=3.2Hz), 127.23 (d,4JCF=1.3Hz), 126.69 (d,3JCF=3.4Hz), 123.71(d,3JCF=4.2Hz), 122.59 (d,2JCF=16.5Hz), 122.07 (d,3JCF=7.4Hz), 121.09 (d,2JCF =22.1Hz), 120.20 (d,3JCF=5.6Hz), 118.46 (d,3JCF=6.7Hz), 117.82 (d,2JCF=12.6Hz), 116.97(d,2JCF=23.5Hz), 14.22ppm；19F NMR(376MHz,DMSO-d6):δ-118.53--119.11(m, 1F), -122.80 (d, J=6.6Hz, 1F) ppm；HRMS(EI)calc.for C21H15F2NO3 +367.1020,found 367.1018。
Embodiment 52 (E) -2- (3- (1- chloronaphthalene -2- base) -2- methacryl amido) benzoic acid (compound 52)
Preparation method is similar with the method for embodiment 1, the difference lies in that using the chloro- 2- naphthaldehyde of 1- as starting material.
Fusing point: 240.3-241.2 DEG C；1H NMR(400MHz,DMSO-d6):δ13.82(s,1H),11.99(s,1H), 8.75 (d, J=8.0Hz, 1H), 8.28 (d, J=8.4Hz, 1H), 8.08-8.05 (m, 2H), 8.02 (d, J=8.4Hz, 1H), 7.78 (s, 1H), 7.77-7.71 (m, 1H), 7.71-7.65 (m, 2H), 7.62 (d, J=8.4Hz, 1H), 7.22 (t, J= 7.2Hz, 1H), 2.13 (d, J=0.8Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ169.96,166.11, 141.11,134.80,134.31,133.50,132.21,131.74,131.26,130.17,130.07,128.40,128.04, 127.38,127.22,127.07,123.76,122.87,119.78,116.29,14.02ppm；HRMS(EI)calc.for C21H16 35ClNO3 +365.0819,found 365.0824；calc.for C21H16 37ClNO3 +367.0789,found 367.0827。
Embodiment 53 (E) -2- (3- (1- chloronaphthalene -2- base) -2- methacryl amido) -5- fluobenzoic acid (compound 53)
Preparation method is similar with the method for embodiment 1, the difference lies in that using the chloro- 2- naphthaldehyde of 1- as starting material, it will be adjacent Aminobenzoic acid replaces with 2- amino-5-fluorobenzoic acid.
Fusing point: 255.8-256.7 DEG C；1H NMR(400MHz,DMSO-d6):δ14.15(s,1H),11.79(s,1H), 8.75 (dd, J=9.2,5.2Hz, 1H), 8.27 (d, J=5.6Hz, 1H), 8.08-7.98 (m, 2H), 7.80-7.65 (m, 4H), 7.63-7.52(m,2H),2.12(s,3H)ppm；13C NMR(100MHz,DMSO-d6):δ168.76,165.99,156.79(d ,1JCF=239.6Hz), 137.52 (d,4JCF=2.4Hz), 134.60,133.49,132.28,131.69,130.18, 130.06,128.38,128.02,127.36,127.18,127.05,123.75,122.00(d,3JCF=6.6Hz), 121.11 (d,2JCF=22.3Hz), 118.35 (d,3JCF=5.4Hz), 116.99 (d,2JCF=24.0Hz), 13.98ppm；19F NMR (376MHz,DMSO-d6):δ-118.64--118.74(m,1F)ppm；HRMS(EI)calc.for C21H15 35ClFNO3 + 383.0724,found 383.0724。
Embodiment 54 (Z) -2- (the chloro- 3- of 2- (1- chloronaphthalene -2- base) acrylamido) -5- fluobenzoic acid (compound 54)
Preparation method is similar with the method for embodiment 37, the difference lies in that using the chloro- 2- naphthaldehyde of 1- as starting material, it will Ortho-aminobenzoic acid replaces with 2- amino-5-fluorobenzoic acid.
1H NMR(400MHz,DMSO-d6): δ 14.23 (s, 1H), 12.32 (s, 1H), 8.72 (dd, J=9.2,5.2Hz, 1H), 8.05-7.96 (m, 3H), 7.71 (dd, J=9.2,3.2Hz, 1H), 7.63 (s, 1H), 7.61 (dd, J=8.6,1.2Hz, 1H),7.58-7.49(m,3H)ppm；HRMS(EI)calc.for C20H12 35Cl2FNO3 +403.0178,found 403.0176。
Embodiment 55 (E) -2- (3- (1- bromonaphthalene -2- base) -2- methacryl amido) benzoic acid (compound 55)
Preparation method is similar with the method for embodiment 1, the difference lies in that using the bromo- 2- naphthaldehyde of 1- as starting material.
Fusing point: 235.6-236.2 DEG C；1H NMR(400MHz,DMSO-d6):δ13.83(s,1H),11.99(s,1H), 8.76 (d, J=8.4Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 8.09-8.01 (m, 3H), 7.76-7.71 (m, 2H), 7.70- 7.63 (m, 2H), 7.61-7.55 (m, 1H), 7.22 (t, J=7.6Hz, 1H), 2.10 (s, 3H) ppm；13C NMR(100MHz, DMSO-d6):δ169.95,166.04,141.11,134.85,134.32,134.28,134.22,133.45,131.41, 131.27,128.45,128.27,127.80,127.46,127.33,126.40,123.41,122.86,119.77,116.25, 13.92ppm；HRMS(EI)calc.for C21H16 79BrNO3 +409.0314,found 409.0316；calc.for C21H16 81BrNO3 +411.0293,found 411.0302。
Embodiment 56 (Z) -2- (3- (1- bromonaphthalene -2- base) -2- chloroacrylamide base) -5- fluobenzoic acid (compound 56)
Preparation method is similar with the method for embodiment 37, the difference lies in that using the bromo- 2- naphthaldehyde of 1- as starting material, it will Ortho-aminobenzoic acid replaces with 2- amino-5-fluorobenzoic acid.
1H NMR(400MHz,DMSO-d6): δ 14.24 (s, 1H), 12.22 (s, 1H), 8.71 (dd, J=9.2,5.2Hz, 1H), 8.01-7.93 (m, 3H), 7.74 (dd, J=9.2,3.2Hz, 1H), 7.63 (s, 1H), 7.61 (dd, J=8.6,1.2Hz, 1H),7.59-7.49(m,3H)ppm；HRMS(EI)calc.for C20H12 79Br35ClFNO3 +446.9673,found 446.9678。
Embodiment 57 (E) -2- (3- (1- bromonaphthalene -2- base) -2- methacryl amido) -5- fluobenzoic acid (compound 57)
Preparation method is similar with the method for embodiment 1, the difference lies in that using the bromo- 2- naphthaldehyde of 1- as starting material, it will be adjacent Aminobenzoic acid replaces with 2- amino-5-fluorobenzoic acid.
Fusing point: 261.9-262.7 DEG C；1H NMR(400MHz,DMSO-d6):δ14.17(s,1H),11.79(s,1H), 8.76 (dd, J=9.2,5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 8.07-8.03 (m, 2H), 7.77 (dd, J=9.2, 3.2Hz, 1H), 7.75-7.71 (m, 2H), 7.69-7.65 (m, 1H), 7.60-7.54 (m, 2H), 2.09 (d, J=1.6Hz, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ168.72,165.94,156.79(d,1JCF=239.9Hz), 137.55 (d,4JCF =2.2Hz), 134.91,134.24,134.04,133.45,131.41,128.44,128.26,127.79,127.42, 127.32,126.40,123.40,122.00(d,3JCF=7.2Hz), 121.12 (d,2JCF=21.6Hz), 118.31 (d,3JCF =6.8Hz), 116.99 (d,2JCF=23.6Hz), 13.88ppm；19F NMR(376MHz,DMSO-d6):δ-118.64-- 118.72(m,1F)ppm；HRMS(EI)calc.for C21H15 79BrFNO3 +427.0219,found 427.0216；calc.for C21H15 81BrFNO3 +429.0199,found 429.0189。
Embodiment 58 (E) -2- (3- (the fluoro- 6- methoxynaphthalene -2- base of 1-) -2- methacryl amido) benzoic acid (chemical combination Object 58)
Preparation method is similar with the method for embodiment 1, the difference lies in that being starting with the fluoro- 6- methoxy-2-naphthaldehyde of 1- Raw material.
HRMS(EI)calc.for C22H18FNO4 +379.1220,found 379.1226。
Embodiment 59 (E) -2- (3- (the bromo- 1- fluoronaphthalene -2- base of 6-) -2- methacryl amido) benzoic acid (compound 59)
Preparation method is similar with the method for embodiment 1, the difference lies in that being that starting is former with the fluoro- 2- naphthaldehyde of the bromo- 1- of 6- Material.
HRMS(EI)calc.for C21H15 79BrFNO3 +427.0219,found 427.0217；calc.for C21H15 81BrFNO3 +429.0199,found 429.0192。
Embodiment 60 (E) -2- (3- (1,6- dichloronaphtalene -2- base) -2- methacryl amido) benzoic acid (compound 60)
Preparation method is similar with the method for embodiment 1, the difference lies in that the chloro- 2- naphthaldehyde of 6- bis- is starting material with 1.
HRMS(EI)calc.for C21H15 35Cl2NO3 +399.0429,found 399.0427；calc.for C21H15 35Cl37ClNO3 +401.0399,found 401.0392；calc.for C21H15 37Cl2NO3 +403.0396,found 403.0394。
Embodiment 61 (E) -2- (3- (1,6- dichloronaphtalene -2- base) -2- methacryl amido) -5- fluobenzoic acid (chemical combination Object 61)
Preparation method is similar with the method for embodiment 1, the difference lies in that the chloro- 2- naphthaldehyde of 6- bis- is starting material with 1, Ortho-aminobenzoic acid is replaced with into 2- amino-5-fluorobenzoic acid.
HRMS(EI)calc.for C21H15 35Cl2FNO3 +417.0335,found 417.0336；calc.for C21H15 35Cl37ClFNO3 +419.0305,found 419.0302；calc.for C21H15 37Cl2FNO3 +421.0275,found 421.0277。
Embodiment 62 (E) -2- (3- (the chloro- 1- fluoronaphthalene -2- base of 5-) -2- methacryl amido) benzoic acid (compound 62)
Preparation method is similar with the method for embodiment 1, the difference lies in that being that starting is former with the fluoro- 2- naphthaldehyde of the chloro- 1- of 5- Material.
HRMS(EI)calc.for C21H15 35ClFNO3 +383.0724,found 383.0722；calc.for C21H15 37ClFNO3 +385.0694,found 385.0692。
Embodiment 63 (E) -2- (2- methyl -3- (naphthalene -2- base) acrylamido) thiophene -3- formic acid (compound 63)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with 2- amino-thenoic acid.
Fusing point: 219.0-219.9 DEG C；1H NMR(400MHz,DMSO-d6):δ13.36(s,1H),11.93(s,1H), 8.07 (s, 1H), 8.04-7.93 (m, 3H), 7.76 (s, 1H), 7.64 (d, J=8.4Hz, 1H), 7.57 (s, 2H), 7.23 (d, J =5.6Hz, 1H), 7.04 (d, J=5.6Hz, 1H), 2.31 (s, 3H) ppm；13C NMR(100MHz,DMSO-d6):δ166.75, 164.77,147.92,136.27,132.76,132.70,132.51,130.01,129.14,128.26,127.98,127.54, 127.06,126.89,126.56,124.30,116.68,114.14,13.69ppm；HRMS(ES+)calcd for C19H15NO3SNa(M+Na)+,360.0670；found,360.0672.
2- amino-the thenoic acid can be made by the following method of key step:
2- amino -3- thiophene methyl esters (314mg, 2.0mmol) is dispersed in 10mL water and 10mL methanol mixed solvent, is added Enter sodium hydroxide (1.6g, 40.0mmol), argon gas protection is back flow reaction 2 hours, cooling, and rotation removes methanol, 1M HCl acidification, second Acetoacetic ester extraction, saturated salt solution wash twice, and anhydrous sodium sulfate dries, filters, filtrate concentration, silica gel column separating purification (two Chloromethanes: methanol=10:1), obtain 2- amino-thenoic acid, yield 46%.
Embodiment 64 (E) -4- methyl -2- (2- methyl -3- (naphthalene -2- base) acrylamido) thiophene -3- formic acid (compound 64)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with 2- amino -4- methylthiophene -3- formic acid.
HRMS(EI)calc.for C20H17NO3S+351.0929,found 351.0926。
Embodiment 65 (E) -4,5- dimethyl -2- (2- methyl -3- (naphthalene -2- base) acrylamido) thiophene -3- formic acid (is changed Close object 65)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with 2- amino -4,5- thioxene -3- formic acid.
HRMS(EI)calc.for C21H19NO3S+365.1086,found 365.1081。
Embodiment 66 (E) -4- (2- methyl -3- (naphthalene -2- base) acrylamido) niacin (compound 66)
(E) -2- methyl -3- benzene in raw material (E) -2- methyl -3- (naphthalene -2- base) method for producing acrylic acid and embodiment 1 Base synthesis of conjugated carboxylic alkeneacid is similar, the difference lies in that using 2- naphthaldehyde as starting material.
(E) -2- methyl -3- (naphthalene -2- base) acrylic acid (212mg, 1.0mmol) is dispersed in dry methylene chloride In (3mL), ice bath is cooling, and oxalyl chloride (381mg, 3.0mmol) is added dropwise thereto, and a drop dimethylformamide is added dropwise, puts on dry Dry pipe, reacts at room temperature 3h, and decompression rotation is dissolved in 1mL pyridine except solvent is to get acid chloride intermediate.
4- amino-nicotinic acid (138mg, 1.0mmol) is dispersed in 2mL pyridine, ice bath is cooling, and above-mentioned acyl is added dropwise thereto Chloropyridine solution, room temperature reaction is overnight.5mL water is added dropwise into reaction solution, filters, the appropriate water washing of filter cake, drying, silicagel column (methylene chloride: methanol=3:1) is isolated and purified, compound 66, yield 30% are obtained.Fusing point: 303.3-304.2 DEG C；1H NMR (400MHz, DMSO-d6): δ 14.55 (s, 1H), 9.11 (s, 1H), 8.51 (d, J=5.6Hz, 1H), 8.46 (d, J=5.6Hz, 1H), 8.02 (s, 1H), 7.97 (d, J=8.4Hz, 2H), 7.94 (d, J=5.2Hz, 1H), 7.69 (s, 1H), 7.61 (d, J= 8.4Hz,1H),7.58-7.52(m,2H),2.27(s,3H)ppm.13C NMR(100MHz,DMSO-d6):δ169.28, 167.65,152.54,151.23,147.21,134.69,133.23,133.02,132.73,132.35,128.82,128.17, 127.88,127.51,127.08,126.70,126.49,118.00,112.44,14.09ppm.HRMS(ES+)calcd for C20H17N2O3(M+H)+,333.1239；found,333.1241.
Embodiment 67 (E)-N- (2- cyano-phenyl) -2- methyl -3- (naphthalene -2- base) acrylamide (compound 67)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with adjacent cyanobenzoic acid.
HRMS(EI)calc.for C21H16N2O+312.1263,found 312.1266。
Embodiment 68 (E) -2- (2- methyl -3- (naphthalene -2- base) acrylamido) benzamide (compound 68)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with 2- aminobenzamide.
Fusing point: 169.8-170.6 DEG C；1H NMR (400MHz, DMSO-d6): δ 12.57 (s, 1H), 8.69 (d, J= 8.0Hz, 1H), 8.39 (s, 1H), 8.03 (s, 1H), 8.00-7.93 (m, 3H), 7.89 (dd, J=7.6,1.2Hz, 1H), 7.83 (s, 1H), 7.64 (s, 1H), 7.61 (dd, J=8.4,1.2Hz, 1H), 7.59-7.54 (m, 3H), 7.20-7.14 (m, 1H), 2.27 (d, J=0.8Hz, 1H) ppm；13C NMR(100MHz,DMSO-d6):δ171.07,166.67,140.14,134.17, 133.24,133.05,132.75,132.42,132.33,128.73,128.66,128.17,127.89,127.51,127.09, 126.66,126.48,122.42,120.06,119.25,14.05ppm；HRMS(EI)calc.for C21H18N2O2 + 330.1368,found 330.1371。
Embodiment 69 (E) -2- (2- methyl -3- (naphthalene -2- base) acrylamido) methyl benzoate (compound 69)
Compound 34 (1.0mmol) and 5mL methylene chloride are added sequentially to be cased in the reaction flask of drying tube, ice bath is cold But, 3mmol oxalyl chloride, a drop DMF and 1.5mmol methanol are added dropwise into reaction solution.12h is reacted at room temperature, and reaction solution is spin-dried for Concentration, silica gel column separating purification (petroleum ether: ethyl acetate=3:1) obtain compound 64, yield 40%.Fusing point: 113.4- 114.2℃；1H NMR(400MHz,CDCl3): δ 11.71 (s, 1H), 8.90 (d, J=8.4Hz, 1H), 8.08 (dd, J=8.0, 1.6Hz, 1H), 7.89-7.83 (m, 4H), 7.78 (s, 1H), 7.63-7.58 (m, 1H), 7.54 (dd, J=8.6,1.4Hz, 1H), 7.52-7.48 (m, 2H), 7.14-7.09 (m, 1H), 3.95 (s, 3H), 2.37 (d, J=1.2Hz, 3H) ppm；13C NMR (100MHz,CDCl3):δ168.93,167.99,141.92,135.71,134.76,133.76,133.16,132.99, 132.81,130.94,128.99,128.23,127.92,127.68,127.19,126.52,126.39,122.52,120.62, 115.24,52.42,14.31ppm；HRMS(EI)calc.for C22H19NO3 +345.1365,found 345.1366。
Embodiment 70 (E) -2- methyl -3- (naphthalene -2- base)-N- (pyridine -2- base) acrylamide (compound 70)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with 2-aminopyridine.
HRMS(EI)calc.for C19H16N2O+288.1263,found 288.1261。
Embodiment 71 (E)-N- (2- cyano -1- cyclopentene -1- base) -2- methyl -3- (naphthalene -2- base) acrylamide (chemical combination Object 71)
Preparation method is similar with the method for embodiment 1, the difference lies in that using 2- naphthaldehyde as starting material, by adjacent amino Benzoic acid replaces with 1- amino -2- cyano -1- cyclopentene.
HRMS(EI)calc.for C20H18N2O+302.1419,found 302.1415。
The DHODH inhibitory activity of 72 the compounds of this invention of embodiment is tested
DHODH can be catalyzed its natural substrate DHO (dihydrooratic acid) under certain condition and be oxidized to Orotate.In DHODH Catalysis under, first by two H of substrate DHO+And e-It is transferred on coenzyme F MN, the FMNH of subsequent reduction-state2By electron transmission To free ubiquinone.Electron transmission is finally given chromogenic substrate DCIP, DCIP to be reduced by free ubiquinone.DCIP has at 600nm Maximum light absorption, and the DCIP of reduction-state no light absorption at 600nm.It can determine whether substrate according to the Weaken degree of absorbance The degree that DHO is oxidized.It is enzymatic reaction initial velocity that substrate DHO, which is oxidized degree, in unit time, after inhibitor is added, enzyme Promoting initial velocity of reaction reduces.96 orifice plates are used when measurement, and 600nm light absorption value is read by BioTek microplate reader.Every hole is added 199 μ L survey buffer living (50mM HEPES (pH8.0), 0.15M KCl, 0.1%Triton X-100,100 μM of ubiquinones, 100 μM DCIP).0.4 μ L compound is added, is incubated at room temperature 5min, then every hole is added 1 μ L substrate DHO (final concentration of 500 μM) and mixes It is even, then a data are read every 30s, are read 6min altogether with light absorption value at microplate reader measurement 600nm at once.Each experiment is extremely 3 are set less in parallel.The inhibiting rate for finally calculating various concentration compound, calculates half by Origin8.0 and effectively inhibits dense Spend IC50Value.Particular reference Sci.Rep., 2015.5:14836.
The active list of 1 representative compound 1-71 of table
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (10)

1. compound shown in a kind of Formulas I or its stereoisomer, its cis-trans-isomer, its tautomer, its prodrug or its medicine Acceptable salt or solvate or crystal form on:
In formula,
A is unsubstituted or substituted C3-7Naphthenic base, unsubstituted or substituted C5-7Cycloalkenyl, unsubstituted or substituted C6-C10Virtue Base or unsubstituted or substituted 5-10 circle heterocyclic ring base；Described substituted refers to replaced group selected from the group below: halogen, cyanogen Base, nitro, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-7Naphthenic base, C5-7Cycloalkenyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6 Halogenated alkoxy, C6-C10Aryl, C6-C10Aryloxy group, C6-C10Aryl-NH-CO- ,-O- (CH2)m-O-、-(CH2)n-；Wherein, m Or the integer that n is 1~4；
B is unsubstituted or substituted C3-7Naphthenic base, C5-7Cycloalkenyl, C6-C10Aryl, 5-10 circle heterocyclic ring base；It is described substituted to be Refer to replaced group selected from the group below: halogen, cyano (- CN), nitro, carboxyl (- COOH), amide groups (- CONH2), sulfonic acid Base, sulfonamide, C1-6Sulfonate group, hydroxyl, C1-6Alkyl carbonyl, C1-6Halogenated alkyl carbonyl, C1-6Aldehyde radical, C1-6Ester group, C1-6Hydrazide group, Guanidine radicals, C1-6Alkyl, C1-6Halogenated alkyl, C3-7Naphthenic base, C2-6Alkenyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C6-C10Aryl, C6-C10Aryloxy group, C6-C10Aryl-NH-CO- ,-O-CH2-O-、-(CH2)n-；Wherein, the integer that n is 2~4；
R1It is selected from the group: hydrogen, C1-6Alkyl, C1-6Halogenated alkyl, C3-7Naphthenic base, C5-7Cycloalkenyl；
R2It is selected from the group: hydrogen, halogen, cyano, nitro, C1-6Alkyl, C1-6Halogenated alkyl, C3-7Naphthenic base, C5-7Cycloalkenyl.
2. compound as described in claim 1 or its stereoisomer, its cis-trans-isomer, its tautomer, its prodrug Or its pharmaceutically acceptable salt or solvate or crystal form, which is characterized in that the compound is selected from chemical combination shown in Formula II Object:
In formula,
A and R2It is as defined above；
X represents nitrogen-atoms or group CY, and wherein Y is selected from the group: carboxyl, amide groups, sulfonic group, sulfoamido, C1-6Sulphonic acid ester Base, hydroxyl, C1-6Alkyl carbonyl, C1-6Halogenated alkyl carbonyl, C1-6Aldehyde radical, C1-6Ester group, C1-6Hydrazide group, cyano, nitro, guanidine radicals；
R3、R4、R5It is each independently selected from the following group: hydrogen, halogen, cyano, nitro, C1-6Alkyl, C1-6Halogenated alkyl, C3-7Cycloalkanes Base, C2-6Alkenyl, C1-6Alkoxy, hydroxyl, C1-6Halogenated alkoxy, C6-C10Aryl, C6-C10Aryloxy group, C6-C10Aryl-NH- CO-、-O-CH2-O-、-(CH2)n-；Wherein, the integer that n is 2~4.
3. compound as claimed in claim 1 or 2 or its stereoisomer, its cis-trans-isomer, its tautomer, before it Medicine or its pharmaceutically acceptable salt or solvate or crystal form, which is characterized in that A is unsubstituted or substituted phenyl, does not take Generation or the pyridyl group replaced, unsubstituted or substituted indyl, unsubstituted or substituted naphthalene, unsubstituted or substituted thiophene Base, unsubstituted or substituted benzothienyl, unsubstituted or substituted furyl, unsubstituted or substituted benzofuranyl, not The quinoline or unsubstituted or substituted isoquinolyl for replacing or replacing.
4. compound as claimed in claim 1 or 2 or its stereoisomer, its cis-trans-isomer, its tautomer, before it Medicine or its pharmaceutically acceptable salt or solvate or crystal form, which is characterized in that R2It is selected from the group: hydrogen, fluorine, chlorine, bromine, trifluoro Methyl, methyl, ethyl, propyl, cyclopropyl.
5. compound as described in claim 1 or its stereoisomer, its cis-trans-isomer, its tautomer, its prodrug Or its pharmaceutically acceptable salt or solvate or crystal form, which is characterized in that the compound is selected from chemical combination shown in formula III Object:
In formula,
B and R2It is as defined above；
R6、R7、R8、R9、R10It is each independently selected from hydrogen, halogen, cyano, nitro, C1-6Alkyl, C1-6Halogenated alkane, C2-6Alkenyl, C2-6Alkynyl, C3-7Naphthenic base, C5-7Cycloalkenyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C6-C10Aryl, C6-C10Aryloxy group, 5 yuan Or 6 circle heterocyclic ring bases, hydroxyl, C6-C10Aryl-NH-CO-；
Or R6、R7、R8、R9、R10In any two can connect to form-O- (CH2)m-O-、-(CH2) n- ,-CH=CH-；Its In, integer that m or n are 1~4.
6. compound as claimed in claim 1 or 5 or its stereoisomer, its cis-trans-isomer, its tautomer, before it Medicine or its pharmaceutically acceptable salt or solvate or crystal form, which is characterized in that B is selected from unsubstituted or substituted phenyl, not The 5- or 6-membered heterocycle or unsubstituted or substituted C for replacing or replacing5-7Cycloalkenyl.
7. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition contains of any of claims 1-6ization Close object or its stereoisomer, cis-trans-isomer, its tautomer, its prodrug or its pharmaceutically acceptable salt or solvation Object or crystal form；With pharmaceutically acceptable carrier or excipient.
8. compound or its stereoisomer, its cis-trans-isomer, its tautomerism as described in any one of claim 1-6 The purposes of body, its prodrug or its pharmaceutically acceptable salt or solvate or crystal form or claim 7 described pharmaceutical composition, It is characterized in that,
It is used to prepare dhodh inhibitors；
It is used to prepare pyrimidine biosynthesis inhibitor；And/or
Be used to prepare for prevent or treat by dihydroorate dehydrogenase inhibition and/or pyrimidine biosynthesis inhibition Lai Improved pathological condition or disease.
9. purposes described in as claimed in claim 8, which is characterized in that the pathological condition or disease is selected from the group: cancer Disease, rheumatoid arthritis, colitis, lupus erythematosus, renal glomerular disease, anti-organ transplant rejection, melanoma, silver bits Disease, arthritis, fibrosis, rhinitis, psoriasis, multiple sclerosis, uveitis, asthma, leukaemia and malaria.
10. compound or its stereoisomer, its cis-trans-isomer, its tautomerism as described in any one of claim 1-6 The preparation method of body, its prodrug or its pharmaceutically acceptable salt or solvate or crystal form, which is characterized in that
The method is method 1, comprising steps of
(1) in atent solvent, compound 1 and compound 2 are reacted, to form compound 3；
(2) in atent solvent, reaction is hydrolyzed in compound 3, to form compound 4；
(3) in atent solvent, compound 4 is successively reacted with oxalyl chloride and compound 5, to form compound 6；
Or the method is method 2, comprising steps of
(1) in atent solvent, compound 7 and TsCl are reacted, to form compound 8；
(2) in atent solvent, compound 8 and compound 5 are reacted, to form compound 6；
Or the method is method 3, comprising steps of
(1) in atent solvent, compound 1 and compound 9 are reacted, to form compound 10；
(2) in atent solvent, compound 10 is successively reacted with oxalyl chloride and compound 5, to form compound 6；
Or the method is method 4, comprising steps of
(1) in atent solvent, compound 1 and compound 11 and NCS or NBS are reacted, to form compound 12；
(2) in atent solvent, reaction is hydrolyzed in compound 12, to form compound 13；
(3) in atent solvent, compound 13 is successively reacted with oxalyl chloride and compound 5, to form compound 6；
Or the method is method 5, comprising steps of
(1) in atent solvent, compound 15 and compound 16 are reacted, to form compound 17；
(2) in atent solvent, reaction is hydrolyzed in compound 17, to form compound 18；
(3) in atent solvent, compound 18 is successively reacted with oxalyl chloride and compound 5, to form compound 19；
Or the method is method 6, comprising steps of
(1) in atent solvent, compound 1 and compound 20 are reacted, to form compound 21；
(2) in atent solvent, compound 21 is successively reacted with oxalyl chloride and compound 5, to form compound 22；
Or the method is method 7, comprising steps of
(1) in atent solvent, compound 1 and compound 23 are reacted, to form compound 24；
(2) in atent solvent, reaction is hydrolyzed in compound 24, to form compound 25；
(3) in atent solvent, compound 25 is successively reacted with oxalyl chloride and compound 5, to form compound 26；
In the above formulas, in addition to providing the group of definition, other group definitions are the same.
CN201810321850.XA 2018-04-11 2018-04-11 N-substituted acrylamide derivative as DHODH inhibitor and preparation and application thereof Active CN110357789B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201810321850.XA CN110357789B (en) 2018-04-11 2018-04-11 N-substituted acrylamide derivative as DHODH inhibitor and preparation and application thereof
PCT/CN2019/081066 WO2019196714A1 (en) 2018-04-11 2019-04-02 N-substituted acrylamide derivative as dhodh inhibitor, and preparation and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810321850.XA CN110357789B (en) 2018-04-11 2018-04-11 N-substituted acrylamide derivative as DHODH inhibitor and preparation and application thereof

Publications (2)

Publication Number Publication Date
CN110357789A true CN110357789A (en) 2019-10-22
CN110357789B CN110357789B (en) 2022-09-30

Family

ID=68162813

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810321850.XA Active CN110357789B (en) 2018-04-11 2018-04-11 N-substituted acrylamide derivative as DHODH inhibitor and preparation and application thereof

Country Status (2)

Country Link
CN (1) CN110357789B (en)
WO (1) WO2019196714A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111991380A (en) * 2020-09-28 2020-11-27 郑州大学第一附属医院 Application of derivative of natural product of traditional Chinese medicine in inhibiting growth and metastasis of esophageal cancer
CN112876754A (en) * 2021-01-21 2021-06-01 湖南工业大学 Bio-based antioxidant modified rubber and preparation method thereof
CN113018281A (en) * 2021-02-23 2021-06-25 中国人民解放军海军军医大学 Pellino1 natural small-molecule inhibitor and application thereof
CN115010622A (en) * 2022-06-20 2022-09-06 山东百启生物医药有限公司 Preparation method of 2-bromo-5-cyanobenzaldehyde

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB202202921D0 (en) * 2022-03-02 2022-04-13 Nrg Therapeutics Ltd Novel compounds

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50135047A (en) * 1974-04-16 1975-10-25
US3940422A (en) * 1973-01-18 1976-02-24 Kissei Yakuhin Kogyo Kabushiki Kaisha Aromatic carboxylic amide derivatives
JPS5283429A (en) * 1975-12-31 1977-07-12 Kissei Pharmaceut Co Ltd Preparation of aromatic unsaturated carboxylic acid amide derivatives
JPS5738759A (en) * 1981-01-23 1982-03-03 Kissei Pharmaceut Co Ltd Preparation of novel aromatic carboxylic acid derivative
JPS59122449A (en) * 1982-12-28 1984-07-14 Kissei Pharmaceut Co Ltd Preparation of aromatic carboxylic acid amide derivative
JPS6019754A (en) * 1983-07-14 1985-01-31 Kissei Pharmaceut Co Ltd Production of aromatic carboxylic acid amide derivative
JPS6097946A (en) * 1983-11-01 1985-05-31 Ono Pharmaceut Co Ltd Carboxamide derivative, its production and remedy containing said derivative
US6046239A (en) * 1997-08-05 2000-04-04 American Home Products Corporation Anthranilic acid analogs
CN1273579A (en) * 1997-08-05 2000-11-15 美国家用产品公司 Anthranilic acid analogs
WO2001007020A2 (en) * 1999-07-27 2001-02-01 Boehringer Ingelheim Pharma Kg Carboxylic acid amides, medicaments containing these compounds and the use and production thereof
EP1798224A1 (en) * 2004-10-05 2007-06-20 Shionogi Co., Ltd. Biaryl derivative
CN101094829A (en) * 2004-12-07 2007-12-26 富山化学工业株式会社 Novel anthranilic acid derivative or salt thereof
CN101257897A (en) * 2005-07-07 2008-09-03 西特里斯药业公司 Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders
CN102164887A (en) * 2007-12-21 2011-08-24 法博太科制药有限公司 Halogenated analogues of anti-fibrotic agents
CN103228275A (en) * 2010-11-24 2013-07-31 法博太科制药有限公司 Methods of treating eye diseases associated with inflammation and vascular proliferation
WO2017188357A1 (en) * 2016-04-28 2017-11-02 宇部興産株式会社 Substituted dihydropyrrolopyrazole compound, and pharmaceutical composition for dosing in combination with other psoriasis treatment drug

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3940422A (en) * 1973-01-18 1976-02-24 Kissei Yakuhin Kogyo Kabushiki Kaisha Aromatic carboxylic amide derivatives
JPS50135047A (en) * 1974-04-16 1975-10-25
JPS5283429A (en) * 1975-12-31 1977-07-12 Kissei Pharmaceut Co Ltd Preparation of aromatic unsaturated carboxylic acid amide derivatives
JPS5738759A (en) * 1981-01-23 1982-03-03 Kissei Pharmaceut Co Ltd Preparation of novel aromatic carboxylic acid derivative
JPS59122449A (en) * 1982-12-28 1984-07-14 Kissei Pharmaceut Co Ltd Preparation of aromatic carboxylic acid amide derivative
JPS6019754A (en) * 1983-07-14 1985-01-31 Kissei Pharmaceut Co Ltd Production of aromatic carboxylic acid amide derivative
JPS6097946A (en) * 1983-11-01 1985-05-31 Ono Pharmaceut Co Ltd Carboxamide derivative, its production and remedy containing said derivative
CN1273579A (en) * 1997-08-05 2000-11-15 美国家用产品公司 Anthranilic acid analogs
US6046239A (en) * 1997-08-05 2000-04-04 American Home Products Corporation Anthranilic acid analogs
WO2001007020A2 (en) * 1999-07-27 2001-02-01 Boehringer Ingelheim Pharma Kg Carboxylic acid amides, medicaments containing these compounds and the use and production thereof
CN1414849A (en) * 1999-07-27 2003-04-30 贝林格尔英格海姆法玛公司 Carboxylic acid amides, medicaments containing these compounds and the use and preparation thereof
EP1798224A1 (en) * 2004-10-05 2007-06-20 Shionogi Co., Ltd. Biaryl derivative
CN101094829A (en) * 2004-12-07 2007-12-26 富山化学工业株式会社 Novel anthranilic acid derivative or salt thereof
CN101257897A (en) * 2005-07-07 2008-09-03 西特里斯药业公司 Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders
CN102164887A (en) * 2007-12-21 2011-08-24 法博太科制药有限公司 Halogenated analogues of anti-fibrotic agents
CN103228275A (en) * 2010-11-24 2013-07-31 法博太科制药有限公司 Methods of treating eye diseases associated with inflammation and vascular proliferation
WO2017188357A1 (en) * 2016-04-28 2017-11-02 宇部興産株式会社 Substituted dihydropyrrolopyrazole compound, and pharmaceutical composition for dosing in combination with other psoriasis treatment drug

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACT RN: "RN：1178530-73-8等", 《STN ON THE WEB REGISTRY数据库》 *
DIANE JOSEPH-MCCARTHY 等: "Use of Structure-Based Drug Design Approaches to Obtain Novel Anthranilic Acid Acyl Carrier Protein Synthase Inhibitors", 《J. MED. CHEM. 》 *
KERMANY,E.T 等: "Synthesis of 2-alkenyl-4H-3，1-benzoxazin-4-one under acid and basic media", 《HETEROLETTERS》 *
SPENCER J. WILLIAMS 等: "3’,4’-Bis-difluoromethoxycinnamoylanthranilate (FT061): An Orally-active antifibrotic agent that reduces albuminuria in a rat model of progressive diabetic nephropathy", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 》 *
YANYAN DIAO ETAL: "Discovery of Diverse Human Dihydroorotate Dehydrogenase Inhibitors as Immunosuppressive Agents by Structure-Based Virtual Screening", 《J. MED. CHEM.》 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111991380A (en) * 2020-09-28 2020-11-27 郑州大学第一附属医院 Application of derivative of natural product of traditional Chinese medicine in inhibiting growth and metastasis of esophageal cancer
CN111991380B (en) * 2020-09-28 2021-06-25 郑州大学第一附属医院 Application of derivative of natural product of traditional Chinese medicine in inhibiting growth and metastasis of esophageal cancer
CN112876754A (en) * 2021-01-21 2021-06-01 湖南工业大学 Bio-based antioxidant modified rubber and preparation method thereof
CN113018281A (en) * 2021-02-23 2021-06-25 中国人民解放军海军军医大学 Pellino1 natural small-molecule inhibitor and application thereof
CN113018281B (en) * 2021-02-23 2023-02-03 中国人民解放军海军军医大学 Pellino1 natural small-molecule inhibitor and application thereof
CN115010622A (en) * 2022-06-20 2022-09-06 山东百启生物医药有限公司 Preparation method of 2-bromo-5-cyanobenzaldehyde
CN115010622B (en) * 2022-06-20 2024-01-09 山东百启生物医药有限公司 Preparation method of 2-bromo-5-cyanobenzaldehyde

Also Published As

Publication number Publication date
CN110357789B (en) 2022-09-30
WO2019196714A1 (en) 2019-10-17

Similar Documents

Publication Publication Date Title
CN110357789A (en) N- substituted acrylamide derivative and its preparation and use as DHODH inhibitor
JP2664538B2 (en) Benzamide
TWI337607B (en) Piperidyl- and piperazinyl-alkylcarbamate derivatives, preparation and therapeutic application thereof
JP4422477B2 (en) Anthranilic acid amides having a heteroarylsulfonyl side chain, process for their preparation, their use as pharmaceuticals or diagnostic aids, and pharmaceutical formulations containing this compound
CN102883607B (en) Compounds for treatment of cancer
TWI339121B (en) 1-piperazine- and 1-homopiperazine-carboxylate derivatives, preparation and therapeutic application thereof
JP7046968B2 (en) 2- (Substituted Phenyl Hetero) Aromatic Carboxylic Acid FTO Inhibitor, Its Production Method and Its Use
BRPI0414130B1 (en) PHENYLAMIDE OR PYRIDYLAMIDE COMPOUNDS, THEIR USE AND PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM
JP2005533024A (en) Pyridazin-3 (2H) -one derivatives as PDE4 inhibitors
JP2010523579A (en) CFTR inhibitor compounds and their use
CA2200981A1 (en) Urea derivatives and their use as acat-inhibitors
WO2001032621A1 (en) Novel indole derivatives and drugs containing the same as the active ingredient
JP7030791B2 (en) Thiazole derivatives and their applications
CN100506788C (en) Arylalkylcarbamate derivatives production and use thereof in therapy
WO2005085201A1 (en) Novel cyclic compound having 4-pyridylalkylthio group having (un)substituted amino introduced therein
JP2007015928A (en) New olefin derivative
BR112013032306B1 (en) indanone derivatives, method of preparation thereof, pharmaceutical compositions and use thereof for prevention or treatment of viral diseases
JP2002529463A (en) Compound
JP2004075614A (en) Pharmaceutical containing chromene derivative
KR20030013360A (en) Production method of 1-substituted-1,2,3-triazole derivatives
JP3012338B2 (en) Aryl and heteroarylalkoxynaphthalene derivatives
TW200533637A (en) Aryl- and heteroarylalkylcarbamate derivatives, their preparation and their application in therapeutics
JP2004043458A (en) 4-aryl-5-hydroxyisoquinoline derivative and method for producing the same
CN110105286B (en) Substituted heterocyclic compound containing urea skeleton and preparation method and application thereof
JP6069485B2 (en) (L, 2,3-triazolyl) sulfonyl derivative

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