WO2012171488A1 - Coumarin derivative, pharmaceutical composition and use thereof - Google Patents

Coumarin derivative, pharmaceutical composition and use thereof Download PDF

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Publication number
WO2012171488A1
WO2012171488A1 PCT/CN2012/077019 CN2012077019W WO2012171488A1 WO 2012171488 A1 WO2012171488 A1 WO 2012171488A1 CN 2012077019 W CN2012077019 W CN 2012077019W WO 2012171488 A1 WO2012171488 A1 WO 2012171488A1
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Prior art keywords
methyl
oxo
benzopyran
ester
chloro
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PCT/CN2012/077019
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French (fr)
Inventor
Long Ma
Bo Zhang
Min Li
Baoyu Xue
Bi Zhang
Wei Zhang
Hongjuan QIU
Sunghwan Moon
Maengsup KIM
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Beijing Hanmi Pharmaceutical Co., Ltd.
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Publication of WO2012171488A1 publication Critical patent/WO2012171488A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • 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
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a coumarin derivative, or a pharmaceutically acceptable salt or solvate thereof, and to pharmaceutical composition comprising the same, and use thereof.
  • the present invention relates to a coumarin derivative having anti-tumor activity and anti-inflammatory activity, a pharmaceutically acceptable salt or solvate thereof, and to pharmaceutical composition comprising the same, and use thereof.
  • Coumarin and derivatives thereof are a group of lactone compounds widely occurred in the nature, and normally classified as simple coumarins, furanyl coumarins, pyranyl coumarins and other coumarins, based on the differences in the substituent on the benzo-a-pyrone ring.
  • Coumarin compounds have various biological activities, such as anti-tumor, anti-HIV, anti-oxidation, anti-bacterial, anti-arrhythmia, anti-osteoporosis, analgesia, antiasthmatic, anticoagulant (non-patent documents 1 , 2).
  • the anti-tumor effects of coumarins have long been a focus of investigation.
  • Simple coumarins have substituents only at C-6, C-7 or C-8 position on the phenyl side of the coumarin, and the substituent at C-7 position is always an oxygen-containing group.
  • Cnidicin has been reported (non-patent documents 3, 4) to shown obvious inhibiting activities on lung adenocarcinoma cells MK-1 , A549, passage cells of human cervical carcinoma B 16F10, hepatoma cell Bel-7402. Esculetin has been reported (non-patent documents 5, 6) to inhibit the proliferation of leukemia cell HL-60 by inducing Gl phase cell cycle arrest.
  • Furanyl coumarins are coumarin derivatives wherein 7-OH forms a furan ring with 6- or 8-isopentenyl, accompanied with degradation to lose 3 carbon atoms.
  • Psoralen has been reported (non-patent document 7) to show good dose-dependent inhibition to breast cancer cell MCF-7; and peucedanin, columbianadin and the like have been reported (non-patent documents 8-10) to show different levels of inhibitions to human gastric cancer cell line BGC cells, human leukemia cell line HL-60 cells, human epidermoid carcinoma cell line A-432 cell strains etc.
  • pyranyl coumarins are coumarin derivatives wherein
  • Pra-C praeruptorin C
  • coumarin compounds such as those having substituents on the a-pyrone ring, dimer and trimer of coumarin, etc., also show good anti -tumor activity.
  • capillarin has been reported to inhibit the proliferation of lung cancer cells by inhibiting DNA synthesis (non-patent document 13).
  • non-patent document 15 compounds having aralkyl at 4-position and substituents at both 3- and 7- positions on the coumarin skeleton (patent document 1); compounds having phenyl at 4-position and phenoxy at 3-position on the coumarin skeleton (patent document 2); compounds having alkoxy at 5-, 6- and 7-positions on the coumarin skeleton (non-patent document 16); compounds having alkoxy at 4-, 5-, 6-, 7- and 8-positions on the coumarin skeleton (non-patent document 17).
  • Patent document 1 WO 2000/039120.
  • Patent document 2 WO 2004/069820.
  • Non-patent document 1 Hao Guang, Wang Zhenguo, Fu Wenyan, Yang Ying. China Journal of Chinese Materia Medica, 2008, 33(18): 2016.
  • Non-patent document 2 Wu longhuo, Xu ruian. Herald of Medicine, 2010, 29(4): 498.
  • Non-patent document 3 Fijioka T, Furumi K, Fujii H, et al. Chem Pharm Bull, 1999, 47(1): 96.
  • Non-patent document 4 Zhou jun, Shen xiu, Wu xiaoxia, et al. Carcinogenesis, Teratogenesis & Mutagenesis, 2002, 14(4): 231.
  • Non-patent document 5 Chu C Y, Tsai Y Y, Wang C J, et al. Euro J Pharmacol, 2001 , 416(1): 25.
  • Non-patent document 6 Wang C J, Chu C Y, et al. Cancer Lett, 2002, 183(2): 163.
  • Non-patent document 7 Zhao Y Y, Cai Y. China Journal of Traditional Chinese Medicine and Pharmacy, 2006, 21 (6): 370.
  • Non-patent document 8 Yang xiuwei, Xu bo, Wu jun, et al. Modern Chinese Medicine, 2006, 8(10): 8.
  • Non-patent document 9 Yang xiuwei, Xu bo, Ran fuxiang, et al. Modern Chinese
  • Non-patent document 10 Yang xiuwei, Xu bo, Ran fuxiang, et al. Modern Chinese Medicine, 2006, 8(12): 9.
  • Non-patent document 11 Fong W F, Zhang J X, Wu J Y, et al. Plant Med, 2004, 70(6): 489.
  • Non-patent document 12 Wu J Y, Fong W F, Zhang J X, et al. Eur J Pharmacol, 2003, 473(1): 9.
  • Non-patent document 13 Jiang youfan, Bai bing, Shen qingguo. China Pharmaceuticals, 2002, 11 (8): 30.
  • Non-patent document 14 Baba M, Jin Y, Mizuno A, Suzuki H, Okada Y, Takasuka N,
  • Non-patent document 15 Mazzei M, Miele M, Nieddu E, Barbieri F, Bruzzo C, Alama A. Eur J Med Chem. 2001 , 36, 915.
  • Non-patent document 16 Riveiro M E, Shaya C, Monczor F, Fernandez N, Baldi A, De Kimpe N, Rossi J, Debenedetti S, Davio C. Cancer Letters. 2004, 210, 179.
  • Non-patent document 17 Kimura S, Ito C, Jyoko N, Segawa H, Kuroda J, Okada M, Adachi S, Nakahata T, Yuasa T, Filho V C, Furukawa H, Maekawa T. Int J Cancer 2005, 113, 158. Summary
  • the present invention is aimed to provide a coumarin derivative having anti-tumor activity and anti-inflammatory activity, or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition comprising said derivative, and use thereof.
  • the present invention provides a compound of formula (I):
  • X is selected from heteroaryl optionally substituted with Ci_ 6 alkyl or halogen, and R 5 R 6 NCO-;
  • Ri is selected from H, halogen, Ci_ 6 alkyl
  • R 2 is selected from Ci_ 6 alkyl optionally substituted with hydroxyl
  • R3 and R 4 are each independently selected from H, OH, NH 2 , Ci_ 6 alkyl, C3-8 cycloalkyl, C 6 -io aryl, heterocyclyl, -COR 8 , -NHCOR 8 , -CONR9R10, wherein said heterocyclyl is optionally substituted with OH or Ci_ 6 alkyl, said Ci_ 6 alkyl is optionally substituted with a substituent selected from: halogen, OH, COOH, NH 2 , Ci_ 6 alkoxy, heterocyclyl, heteroaryl, -COOR 8 , -NR9R10 and -CONR9R10; or
  • R 3 and R 4 together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_6 alkyl; or
  • R 5 and R 6 are each independently selected from H, Ci_ 6 alkyl, C3- 8 cycloalkyl, C 6 -io aryl; or R5 and R 6 , together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom;
  • R 7 is selected from H, OH, halogen, Ci_ 6 alkyl
  • each R 8 is independently selected from Ci_ 6 alkyl and heterocyclyl
  • each R 9 and Rio is independently selected from H and Ci_ 6 alkyl, or R 9 and Rio, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_ 6 alkyl,
  • the present invention relates to a compound of formula (I), wherein:
  • X is pyrimidin-2-yl optionally substituted with Ci_ 6 alkyl or halogen
  • R 2 is selected from Ci_ 6 alkyl
  • R 3 and R 4 are each independently selected from H, Ci_ 6 alkyl, -CONR9R10;
  • R 7 is selected from H, halogen
  • R and Rio are independently selected from H and Ci_ 6 alkyl, or R and Rio, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_ 6 alkyl,
  • the present invention relates to a compound of formula (I), wherein:
  • X is R 5 R 6 NCO-, wherein R 5 and R 6 are both Ci_ 6 alkyl;
  • Ri is selected from H, halogen, Ci_ 6 alkyl
  • R 2 is selected from Ci_ 6 alkyl optionally substituted with hydroxyl
  • R3 and R 4 are each independently selected from H, OH, NH 2 , Ci_ 6 alkyl, C3-8 eye lo alkyl, heterocyclyl, -COR 8 , -NHCORg, -CONR 9 R 10 , wherein said heterocyclyl is optionally substituted with OH or Ci_ 6 alkyl, said Ci_ 6 alkyl is optionally substituted with a substituent selected from: halogen, OH, COOH, NH 2 , Ci_ 6 alkoxy, heterocyclyl, heteroaryl, -COOR 8 , -NR9R10 and -CONR9R10; or
  • R3 and R 4 together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_6 alkyl;
  • R 7 is selected from H, OH, halogen
  • each R 8 is independently selected from Ci_ 6 alkyl and heterocyclyl
  • each R 9 and Rio is independently selected from H and Ci_ 6 alkyl, or R 9 and Rio, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_ 6 alkyl,
  • the compound of formula (I) is selected from:
  • the present invention provides a pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use of treating proliferative disease or inflammatory disease.
  • the present invention provides use of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating proliferative disease or inflammatory disease.
  • proliferative disease may be that commonly referred to in the art, and may be tumor, especially cancer.
  • the cancer includes, but is not limited to, liver cancer, gastric cancer, esophageal cancer, leukemia, lung cancer, laryngeal cancer, uterus cancer, intestinal cancer, breast cancer, pancreatic cancer, brain cancer, neural cancer, renal cancer, lymphoma (including lymphocytoma), penis cancer, ovarian cancer, anal canal cancer, prostate cancer, colon cancer, skin cancer
  • the cancer is melanoma, breast cancer, colon cancer, pancreatic cancer or lung cancer.
  • Alkyl as a group or part of another group, for example halogen-substituted alkyl, hydroxyl-substituted alkyl or alkoxy, may be linear or branched.
  • Ci_ 6 alkyl refers to alkyl with 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.
  • Alkoxy includes but is not limited to methoxy, ethoxy, iso-propoxy, cyclopropoxy, etc.
  • Aryl refers to single or fused aromatic ring containing six to ten carbon atoms. Examples of aryl include phenyl and naphthyl, preferably phenyl.
  • Heteroaryl refers to any fused or non-fused aromatic ring system, wherein at least one of the rings is 5- to 8-membered ring containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur; preferably, at least one heteroatom is nitrogen.
  • heteroaryl include but are not limited to thiophenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, diazinyl, benzimidazolyl, benzopyrazolyl, indolyl, etc.
  • Cycloalkyl refers saturated or partly unsaturated single, fused or bridged ring system containing specified number of carbon atoms.
  • C 3 _ 8 cycloalkyl refers to cycloalkyl containing three to eight carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • Heterocyclyl refers to the cycloalkyl as defined herein, wherein one or more of the ring carbon atoms is replaced by oxygen, nitrogen, -NR-, sulfur, carbonyl, -S(O)- or -S(0) 2 , etc.
  • the heterocycyclyl may be a 3- to 8-membered ring system comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclyl include but are not limited to azetidinyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, etc.
  • “Pharmaceutically acceptable carrier” refers to inert carrier, auxiliary, excipient, or diluent which is commonly used in pharmaceuticals, including but not limited to starch, lactose, sucrose, glucose, magnesium stearate, mannitol, cellulose, water, alcohol/water mixture, phosphate buffer (0.01-0.1M, preferably 0.05M) and 0.9% saline, propylene glycol, polyethylene glycol, plant oil, albumin, gelatin, detergent (e.g. Tween 20, Tween 80, etc.), solubilizer (e.g.
  • glycerine polyethylene glycol, etc.
  • antioxidant preservative
  • fatty acid wax
  • filler or tensile modifier polymer for covalent bonding or complex with metal ion
  • polylactose polyglycolic acid
  • hydrogel liposome
  • microemulsion multilaminar vesicle, or spherical bulking agent.
  • Solidvate refers crystals obtained by changing the lattice by introducing solvent molecule during the crystallization of a drug, including but not limited to: hydrate, alcoholate and etherate.
  • the solvate of the compound of formula (I) of the present invention is preferably a pharmaceutically acceptable solvate, including but not limited to solvates formed with ethanol and water.
  • “Pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt of the compound of formula (I) of the present invention.
  • the salt examples include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as formic acid, acetic acid, methanesulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, propionic acid, citric acid, succine acid, tartaric acid, fumaric acid, butanoic acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, etc., as well as salts formed with inorganic bases such as sodium, potassium, etc., and organic bases such as 2-aminoethanol, arginine, lysine, trihy droxym ethyl aminomethane, etc.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid
  • the compound of the present invention is normally administered in a form of a suitable dosage form prepared with one or more pharmaceutically acceptable carriers.
  • dosage forms are suitable for oral, rectal, topical and other parenteral (such as subcutaneous, intramuscular, intravenous, etc.) administrations.
  • dosage forms suitable for oral administration include capsule, tablet, granule, syrup, etc.
  • the compound of the present invention in these dosage forms may be in a form of solid powder or granule; solution or suspension in an aqueous or non-aqueous liquid; emulsion of wate-in-oil or oil-in-water type; or the like.
  • the above dosage forms may be prepared from active compounds and one or more carriers or auxiliaries by conventional pharmaceutical methods.
  • the above carriers shall be compatible with active compounds or other auxiliaries.
  • non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, saccharose, etc.
  • Carriers used for liquid dosage forms include water, physiological saline, aqueous solution of glucose, ethylene glycol, polyethylene glycol, etc. Active compounds may form solutions or suspensions with the above carriers.
  • composition of the present invention is formulated, quantified and administered in a way which complys the regulations of medical practice.
  • the "effective amount" of the compound to be applied may be determined based on the factors such as specific diseases to be treated, the subject receiving treatment, etiology of the disease, target of the drug, and administration methods. Generally, the dosage for parenteral administration would be 1 - 200 mg/kg. Dosage forms for oral administration may contain 1 - 1000 mg/kg of the compounds of the present invention.
  • the compound of the present invention represented by formula (I) may be prepared by the following procedure, or similar procedure, or other procedure or similar procedure described in documents.
  • the compounds of formula (I) may be prepared according to the schemes and Examples below.
  • m-toluene sulfonyl chloride is reacted with methylamine, using triethyl amine as the base, tetrahydrofuran as the solvent, under stirring at room temperature for 3 hours to give the corresponding product.
  • the sulfonamide benzoic acid intermediate 2b is reduced to the corresponding alcohol 2c under the action of a reducing agent, wherein the reducing agent may be sodium borohydride (NaBH 4 )/ boron trifluoride, sodium borohydride (NaBH 4 )/iodine (I 2 ), diborane (B 2 H 6 ), etc., the solvent for the reaction may be tetrahydrofuran, and the reaction temperature may be 0 °C to room temperature. 3.
  • the reducing agent may be sodium borohydride (NaBH 4 )/ boron trifluoride, sodium borohydride (NaBH 4 )/iodine (I 2 ), diborane (B 2 H 6 ), etc.
  • the solvent for the reaction may be tetrahydrofuran
  • the reaction temperature may be 0 °C to room temperature. 3.
  • the alcohol intermediate 2c is reacted with a brominating agent to give the corresponding brominated intermediate 2d, wherein the solvent may be tetrahydrofuran, the brominating agent may be phosphorus tribromide (PC1 3 ), sulfuric acid/hydrogen bromide (H ⁇ SCVHBr), the reaction temperature may be 0 °C to room temperature, and the reaction time may be 2-5 hours.
  • the solvent may be tetrahydrofuran
  • the brominating agent may be phosphorus tribromide (PC1 3 )
  • sulfuric acid/hydrogen bromide H ⁇ SCVHBr
  • the reaction temperature may be 0 °C to room temperature
  • the reaction time may be 2-5 hours.
  • the intermediate 2e is reacted with substituted or unsubstituted resorcinol at the presence of a strong acid to be dehydrated to give the coumarin intermediate 2f, wherein the reaction temperature may be -10 °C to room temperature, concentrated sulfuric acid is preferably used, and the reaction time may be 4-15 hours.
  • the intermediate 2f is reacted with ⁇ , ⁇ -dimethyl formyl chloride or other acyl chlorides under basic conditions to give the intermediate 2g, wherein the base may be potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, etc., the solvent may be ⁇ , ⁇ -dimethylformamide (DMF), tetrahydrofuran, dichloromethane, carbon tetrachloride, etc., the reaction temperature may be -10 °C to room temperature, and the reaction time may be 1 -5 hours.
  • the base may be potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, etc.
  • the solvent may be ⁇ , ⁇ -dimethylformamide (DMF), tetrahydrofuran, dichloromethane, carbon tetrachloride, etc.
  • the reaction temperature may be -10 °C to room temperature
  • the reaction time may be 1 -5 hours.
  • the intermediate 2g is reacted with a halogenated hydrocarbon under basic conditions to give the final product 2h, wherein the base may be potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, etc., the solvent may be ⁇ , ⁇ -dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DCM), acetonitrile, etc., the reaction temperature may be -10 - 100 °C to room temperature, and the reaction time may be 1 -5 hours.
  • the base may be potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, etc.
  • the solvent may be ⁇ , ⁇ -dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DCM), acetonitrile, etc.
  • the reaction temperature may be -10 - 100 °C to room temperature
  • the reaction time may be 1 -5 hours.
  • the starting material l a is reduced to give the intermediate lb with a tetrahydrofuran solution of sodium borohydride and boron trifluoride dimethyl ether, wherein the reaction temperature may be 0 °C to room temperature, the solvent for the reaction may be tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • the intermediate lb is reacted with a brominating agent, phosphorus tribromide, to give the corresponding brominated intermediate l c, wherein the solvent may be dichloromethane, and the reaction temperature may be 0 °C to room temperature.
  • a brominating agent phosphorus tribromide
  • the intermediate I d is reacted with resorcinol substituted with A or unsubstituted at the presence of a strong acid to be dehydrated to give the coumarin intermediate l e, wherein the reaction temperature may be -10 °C to room temperature, concentrated sulfuric acid is preferably used, and the reaction time may be 4-15 hours.
  • the intermediate le is reacted with a chloride or other chlorides under basic conditions to give the intermediate I f, wherein the base may be potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, etc., the solvent may be ⁇ , ⁇ -dimethylformamide (DMF), tetrahydrofuran, dichloromethane, carbon tetrachloride, etc., the reaction temperature may be -10 °C to room temperature, and the reaction time may be 1-15 hours.
  • the base may be potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, etc.
  • the solvent may be ⁇ , ⁇ -dimethylformamide (DMF), tetrahydrofuran, dichloromethane, carbon tetrachloride, etc.
  • the reaction temperature may be -10 °C to room temperature
  • the reaction time may be 1-15 hours.
  • the intermediate If is reacted at the presence of ammonium chloride and zinc powder to give the intermediate lg, wherein the solvent may be N,N-dimethylformamide (DMF), tetrahydrofuran, methanol, ethanol, water, etc., the reaction temperature may be 70 - 80 °C, and the reaction time may be 2-15 hours.
  • the solvent may be N,N-dimethylformamide (DMF), tetrahydrofuran, methanol, ethanol, water, etc.
  • the reaction temperature may be 70 - 80 °C
  • the reaction time may be 2-15 hours.
  • the intermediate lg is subjected to diazotization at the presence of sodium nitrite and an acid, and then reacted with a acetic acid solution of cuprous chloride saturated with sulfur dioxide to give the intermediate lh, wherein the solvent may be hydrochloric acid (HC1), acetic acid (HAc), water, etc., the reaction temperature may be -10 °C to room temperature, and the reaction time may be 2-5 hours.
  • the solvent may be hydrochloric acid (HC1), acetic acid (HAc), water, etc.
  • the reaction temperature may be -10 °C to room temperature
  • the reaction time may be 2-5 hours.
  • the intermediate lh is reacted with an amine compound under basic conditions to give the final product li, wherein the base may be potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, etc., the solvent may be ⁇ , ⁇ -dimethylformamide (DMF), tetrahydrofuran, dichloromethane, etc., the reaction temperature may be 0 °C to room temperature, and the reaction time may be 1 -15 hours.
  • the base may be potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, etc.
  • the solvent may be ⁇ , ⁇ -dimethylformamide (DMF), tetrahydrofuran, dichloromethane, etc.
  • the reaction temperature may be 0 °C to room temperature
  • the reaction time may be 1 -15 hours.
  • the unit of the temperature is degree Celsius, and room temperature is defined as 18 - 25 °C;
  • reaction process is monitored by TLC or LC-MS;
  • Example 1 Synthesis of Dimethylcarbamic acid 2-oxo-2H-3-(3-N,N-dimethylaminoethyl aminosulfonylbenzyl)-4-methyl-6-chloro-l-benzofuran-7-yl ester (subject compound 2.8)
  • the subject compound 2.8 is synthesized following the procedure described in Scheme
  • Sodium borohydride (0.19 g, 4.97 mmol) is dissolved in tetrahydrofuran (5 ml). To this solution is added dropwise a tetrahydrofuran solution (5 mL) of 3-(N-cylcopropylamino sulfonyl)benzoic acid (0.6 g, 2.49 mmol, subject compound 2.2) at 0°C, and the resulted mixture is stirred for 0.5 h at 0°C. To the solution is then added dropwise a solution of boron trifluoride-dimethyl ether (0.57 g, 4.97 mmol) at 0°C. After adding, the mixture is heated up to room temperature, and stirred overnight at room temperature.
  • Dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-aminobenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester (20 g, 54.0 mmol, subject compound 10) is dissolved in 100 mL of hydrochloric acid and 50 mL of acetic acid in a flask 1 , and cooled to -10°C with an ice-salt bath. To this solution is added dropwise an aqueous solution of sodium nitrite (3.72 g, 54.0 mmol). After adding, the mixture is stirred at -10°C for 1 h.
  • cuprous chloride (1.34 g, 13.5 mmol) is dissolved in 100 mL of acetic acid, into which sulfur dioxide gas is charged to saturation at room temperature.
  • the reaction is cooled to 0°C, and the solution from cooled flask 1 is added dropwise into flask 2. After adding, the reaction is continued at room temperature for another 2 h. After the reaction is completed as indicated by TLC, the reaction mixture is poured into ice water, when a yellowish solid is precipitated which is filtered to give crude product, which is further purified with silica gel column chromatography (dichloromethane) to give a white solid (subject compound 11, 5 g, 20.7%).
  • the materials used in the tumor cell growth inhibition experiment of the present invention are shown in Table 2 below, wherein the cells are all obtained from CAS (Cell Bank of the Chinese Academy of Sciences (Shanghai, China)), and the cell growth is tested with CCK-3 test agent (DojinDo, CK04-20).
  • Inoculation of cells cells of logarithmic growth phase are digested with 0.25% pancreatin, formulated into single cell suspension with RPMI1640 media comprising 10% FBS. Cells are counted on Invitrogen Countess. Cells shown in the above table are inoculated on a 96-well plate according to the cell inoculation number shown in the above table at 100 ⁇ /well. 100 of the culture media is added for the blank control group. The plate is placed in an incubator and incubated overnight at 37 °C, 5% C0 2 .
  • test compound is 5 -fold diluted in 6 concentrations from 10 ⁇ , and each concentration is tested in duplicate.
  • the test sample is gradiently diluted with culture media to 2 folds of the final concentration.
  • the culture plate is taken out, and the media containing the test compound in 2 folds of the final concentration is added at 100 ⁇ /well.
  • the 96-well plate is returned to the incubator and incubated at 37 °C, 5% C0 2 for 72 hours.
  • culture media containing no drug is added.
  • the test compound of the present invention is dissolve in actonitrile or acetonitrile-water (1/1 , V/V) to prepare a 1 mM stock solution. 2 ⁇ of the stock solution is added into a centrifuge tube, followed by adding 148 ⁇ of phosphate buffer (50 mM, pH 7.4) and 10 ⁇ of liver microsome (protein concentration: 20 mg/ml) suspension, mixed up, and pre-incubated in a 37 °C water bath for 3 min.
  • actonitrile or acetonitrile-water (1/1 , V/V)
  • a NADPH generation system (containing NADP + : 6.5 mM, glucose-6-phosphate: 16.5 mM, MgCl 2 : 16.5 mM, glucose-6-phosphate dehydrase: 2 U/ml) is added to initiate the reaction. After incubation in a 37 °C water bath for 0.5 h, 400 ⁇ of acetonitrile is added to terminate the reaction. The mixture is vortex shaked for 3 min, and centrifuged (13000 rpm) for 5 min. The supernatant is tested with HPLC for the residue drug concentration C r .
  • Drug residue (%) C r ⁇ C 0 x 100 %
  • mice Male SD rats are purchased and adaptive feeding in this laboratory for 7 days. 8 SD rats were randomly divided into 2 groups, with 4 in each group, one for intragastric administration, the other for tail intravenous administration. The rats in the intragastric administration group should be fasted overnight before administration.
  • blood samples are collected from orbital venous plexus at the following time points: 0 min (before administration), 5 min, 15min, 30min, 1 h, 2 h, 3 h, 5 h, 7.5 h, 24 h. The amount of collected sample at each time point is about 300 ⁇ .
  • the collected blood samples are centrifuged at 12000rpm for 5 min at 4°C. The upper layer of plasma samples are taken and stored in a freezer at -20 °C for the test.
  • Table 7 The summary of the experimental procedure is shown in Table 7.
  • the concentrations of the compounds in the plasma are tested by LC-MS/MS.
  • the pharmacokinetical parameters are calculated with WinNonlin software.
  • Monolayer cultured cells are digested and detached, and diluted to cell suspensions with certain concentrations, which are subcutaneously transplanted to right side body of the nude mice with a 1 ml syringe.
  • the tumor grows to a volume of 500-600 mm , it is taken out, and opened.
  • Well grown without degeneration and necrosis, light red, and fish-flesh-like tumor tissues are selected and cut into small pieces (about 5 x 5 x 5 mm).
  • Nude mouse are incised at outer side of the back, and the tumor pieces are placed subcutaneously in the incision with a 12G inoculation needle.
  • the tumor piece After the tumor piece is passged 2-3 generations, it can be used for evaluating the efficacy of the anti-tumor drug.
  • the tumor in the mice grows to a volume of 100-150 mm , the animals with well-grown tumors are randomly grouped, and administered, with the administration protocol shown in Table 8.
  • the frequency for testing the diameter of the tumor after grouping is determined depending on the growth conditions of the transplanted tumor, and is normally 2-3 times per week.
  • the weight of the mice should be measured along with each testing.
  • the experiment is normally terminated 24 to 48 hours after the last administration.
  • Compound 053 in Table 1 is tested for its tumor growth inhibition.
  • the TGIs determined according to the method shown in Table 8 are: 77% for A375; 65.6% for MDA-MB-231 ; and 75% for Bx-PC-3. No significant decrease in body weight of the animals is observed, indicating that this compound has good in vivo anti-tumor efficacy, as well as good safety.
  • RAW264.7 (rat macrophage; ATCC No. TIB-71) purchase from Peking Union Medical College
  • DMEM Gibco #11995
  • FBS fetal bovine serum
  • RAW264.7 cells are inoculated in a 96-well plate at a density of 3 x 10 5 ⁇ / ⁇ / ⁇ 96, and cultured at 37 °C for about 6 hours.
  • LPS stimulation LPS with a final concentration of 30 ng/ml is added to stimulate the cell for about 16 hours.
  • TNF-a level is tested with mouse: TNF-a ELISA kit.
  • the number of strips is determined depending on the number of the experimental wells (blank and standards). The samples (including standards) and the blank are tested in duplicate.
  • Adding sample Diluted TNF-a standards are added to standard wells at 100 ⁇ /well; the samples are added in the sample wells at 100 ⁇ /well; and blank wells are set.
  • test antibody Diluted Biotinylated antibody is added at 50 ⁇ /well. After mixing uniformly, the plate is covered, and incubated at 37 °C for 90 min.
  • washing plate The liquid in the wells is discarded, and l x washing buffer is added at 300 ⁇ /well. After maintaining for 1 min, the liquid in the wells are discarded. The procedure is repeated for 4 times, then the plate is dried over a filter paper.
  • Diluted Streptavidin-HRP is added at 100 ⁇ /well. The plate is covered, and incubated at 37 °C for 30 min.
  • washing plate The liquid in the wells is discarded, and l x washing buffer is added at 300 ⁇ /well. After maintaining for 1 min, the liquid in the wells are discarded. The procedure is repeated for 4 times, then the plate is dried over a filter paper.
  • TMB is added at 100 ⁇ /well. The plate is incubated at 37 °C for 20 min. Terminating liquid is added, and the absorbance at 450 nm is determined within 10 min.
  • Compound 053 in Table 1 is tested for its in vitro anti-inflammatory activity.
  • the EC50 is 86 nM, indicating this compound has very good in vitro anti-inflammatory activity.

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Abstract

The present invention relates to a coumarin derivative of formula (I): wherein X, Y1, Y2, Y3, R1, R2, R3 and R4 are as defined herein, or a pharmaceutically acceptable salt or solvate thereof. The present invention also relates to a pharmaceutical composition comprising the compound of the present invention, and use of the compound of the present invention in treating tumor and/or inflammation.

Description

Coumarin Derivative, Pharmaceutical Composition and Use Thereof
Technical Field
The present invention relates to a coumarin derivative, or a pharmaceutically acceptable salt or solvate thereof, and to pharmaceutical composition comprising the same, and use thereof. Particularly, the present invention relates to a coumarin derivative having anti-tumor activity and anti-inflammatory activity, a pharmaceutically acceptable salt or solvate thereof, and to pharmaceutical composition comprising the same, and use thereof. Background Art
Coumarin and derivatives thereof are a group of lactone compounds widely occurred in the nature, and normally classified as simple coumarins, furanyl coumarins, pyranyl coumarins and other coumarins, based on the differences in the substituent on the benzo-a-pyrone ring. Coumarin compounds have various biological activities, such as anti-tumor, anti-HIV, anti-oxidation, anti-bacterial, anti-arrhythmia, anti-osteoporosis, analgesia, antiasthmatic, anticoagulant (non-patent documents 1 , 2). The anti-tumor effects of coumarins have long been a focus of investigation. In recent years, the anti-tumor effects of coumarins from different origins have been studied on molecular level with various cell models, which indicated that coumarins inhibit the proliferation of tumor cells by affecting cell cycles, inducing cell apoptosis and various signal channels, etc. (non-patent document 2)·
Simple coumarins have substituents only at C-6, C-7 or C-8 position on the phenyl side of the coumarin, and the substituent at C-7 position is always an oxygen-containing group. Cnidicin has been reported (non-patent documents 3, 4) to shown obvious inhibiting activities on lung adenocarcinoma cells MK-1 , A549, passage cells of human cervical carcinoma B 16F10, hepatoma cell Bel-7402. Esculetin has been reported (non-patent documents 5, 6) to inhibit the proliferation of leukemia cell HL-60 by inducing Gl phase cell cycle arrest.
Furanyl coumarins are coumarin derivatives wherein 7-OH forms a furan ring with 6- or 8-isopentenyl, accompanied with degradation to lose 3 carbon atoms. Psoralen has been reported (non-patent document 7) to show good dose-dependent inhibition to breast cancer cell MCF-7; and peucedanin, columbianadin and the like have been reported (non-patent documents 8-10) to show different levels of inhibitions to human gastric cancer cell line BGC cells, human leukemia cell line HL-60 cells, human epidermoid carcinoma cell line A-432 cell strains etc. Similar to furanyl coumarins, pyranyl coumarins are coumarin derivatives wherein
7- OH at the phenyl side forms a pyran ring with 6- or 8-isopentenyl. Among them, praeruptorin C (Pra-C) has been reoported to accelerate the apoptosis of leukemia HL-60 cancer cells (non-patent documents 11 , 12).
Other coumarin compounds, such as those having substituents on the a-pyrone ring, dimer and trimer of coumarin, etc., also show good anti -tumor activity. For example, capillarin has been reported to inhibit the proliferation of lung cancer cells by inhibiting DNA synthesis (non-patent document 13).
Besides the above naturally-occurring coumarin compounds described above, chemically synthesized new compounds were also widely reported. For example, the following compounds have been reported: compounds having alkoxy at only 7-position on the coumarin skeleton (non-patent document 14); compounds having substituents at 7- and
8- positions and methyl at 4-position on the coumarin skeleton (non-patent document 15); compounds having aralkyl at 4-position and substituents at both 3- and 7- positions on the coumarin skeleton (patent document 1); compounds having phenyl at 4-position and phenoxy at 3-position on the coumarin skeleton (patent document 2); compounds having alkoxy at 5-, 6- and 7-positions on the coumarin skeleton (non-patent document 16); compounds having alkoxy at 4-, 5-, 6-, 7- and 8-positions on the coumarin skeleton (non-patent document 17).
Although various coumarin compounds having anti-tumor activities have been discussed above, no coumarin anti-tumor compounds having clinical applicability have been developed. Accordingly, research and development of applicable coumarin anti-tumor compounds with high activities are important.
Patent document 1 : WO 2000/039120.
Patent document 2: WO 2004/069820.
Non-patent document 1 : Hao Guang, Wang Zhenguo, Fu Wenyan, Yang Ying. China Journal of Chinese Materia Medica, 2008, 33(18): 2016.
Non-patent document 2: Wu longhuo, Xu ruian. Herald of Medicine, 2010, 29(4): 498.
Non-patent document 3 : Fijioka T, Furumi K, Fujii H, et al. Chem Pharm Bull, 1999, 47(1): 96.
Non-patent document 4: Zhou jun, Shen xiu, Wu xiaoxia, et al. Carcinogenesis, Teratogenesis & Mutagenesis, 2002, 14(4): 231.
Non-patent document 5 : Chu C Y, Tsai Y Y, Wang C J, et al. Euro J Pharmacol, 2001 , 416(1): 25.
Non-patent document 6: Wang C J, Chu C Y, et al. Cancer Lett, 2002, 183(2): 163. Non-patent document 7: Zhao Y Y, Cai Y. China Journal of Traditional Chinese Medicine and Pharmacy, 2006, 21 (6): 370.
Non-patent document 8: Yang xiuwei, Xu bo, Wu jun, et al. Modern Chinese Medicine, 2006, 8(10): 8.
Non-patent document 9: Yang xiuwei, Xu bo, Ran fuxiang, et al. Modern Chinese
Medicine, 2006, 8(11): 7.
Non-patent document 10: Yang xiuwei, Xu bo, Ran fuxiang, et al. Modern Chinese Medicine, 2006, 8(12): 9.
Non-patent document 11 : Fong W F, Zhang J X, Wu J Y, et al. Plant Med, 2004, 70(6): 489.
Non-patent document 12: Wu J Y, Fong W F, Zhang J X, et al. Eur J Pharmacol, 2003, 473(1): 9.
Non-patent document 13 : Jiang youfan, Bai bing, Shen qingguo. China Pharmaceuticals, 2002, 11 (8): 30.
Non-patent document 14: Baba M, Jin Y, Mizuno A, Suzuki H, Okada Y, Takasuka N,
Tokuda H, Nishino H, Okuyama T. Biol Pharm Bull. 2002, 25, 244.
Non-patent document 15 : Mazzei M, Miele M, Nieddu E, Barbieri F, Bruzzo C, Alama A. Eur J Med Chem. 2001 , 36, 915.
Non-patent document 16: Riveiro M E, Shaya C, Monczor F, Fernandez N, Baldi A, De Kimpe N, Rossi J, Debenedetti S, Davio C. Cancer Letters. 2004, 210, 179.
Non-patent document 17: Kimura S, Ito C, Jyoko N, Segawa H, Kuroda J, Okada M, Adachi S, Nakahata T, Yuasa T, Filho V C, Furukawa H, Maekawa T. Int J Cancer 2005, 113, 158. Summary
The present invention is aimed to provide a coumarin derivative having anti-tumor activity and anti-inflammatory activity, or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition comprising said derivative, and use thereof.
In one aspect, the present invention provides a compound of formula (I):
Figure imgf000005_0001
(I)
wherein:
X is selected from heteroaryl optionally substituted with Ci_6 alkyl or halogen, and R5R6NCO-;
Yi, Y2 and Y3 are each independently selected from -N= and -CR7=;
Ri is selected from H, halogen, Ci_6 alkyl;
R2 is selected from Ci_6 alkyl optionally substituted with hydroxyl;
R3 and R4 are each independently selected from H, OH, NH2, Ci_6 alkyl, C3-8 cycloalkyl, C6-io aryl, heterocyclyl, -COR8, -NHCOR8, -CONR9R10, wherein said heterocyclyl is optionally substituted with OH or Ci_6 alkyl, said Ci_6 alkyl is optionally substituted with a substituent selected from: halogen, OH, COOH, NH2, Ci_6 alkoxy, heterocyclyl, heteroaryl, -COOR8, -NR9R10 and -CONR9R10; or
R3 and R4, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_6 alkyl; or
-NR3R4, as a whole, forms alkyl ene amino substituted with di(Ci_6 alkyl)amino;
R5 and R6 are each independently selected from H, Ci_6 alkyl, C3-8 cycloalkyl, C6-io aryl; or R5 and R6, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom;
R7 is selected from H, OH, halogen, Ci_6 alkyl;
each R8 is independently selected from Ci_6 alkyl and heterocyclyl;
each R9 and Rio is independently selected from H and Ci_6 alkyl, or R9 and Rio, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_6 alkyl,
or a pharmaceutically acceptable salt or solvate thereof.
According to one embodiment, the present invention relates to a compound of formula (I), wherein:
X is pyrimidin-2-yl optionally substituted with Ci_6 alkyl or halogen;
Yi, Y2 and Y3 are each independently -CR7=; Ri is selected from H, halogen, Ci_6 alkyl;
R2 is selected from Ci_6 alkyl;
R3 and R4 are each independently selected from H, Ci_6 alkyl, -CONR9R10;
R7 is selected from H, halogen;
R and Rio are independently selected from H and Ci_6 alkyl, or R and Rio, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_6 alkyl,
or a pharmaceutically acceptable salt or solvate thereof.
According to one embodiment, the present invention relates to a compound of formula (I), wherein:
X is R5R6NCO-, wherein R5 and R6 are both Ci_6 alkyl;
Yi, Y2 and Y3 are each independently -CR7=;
Ri is selected from H, halogen, Ci_6 alkyl;
R2 is selected from Ci_6 alkyl optionally substituted with hydroxyl;
R3 and R4 are each independently selected from H, OH, NH2, Ci_6 alkyl, C3-8 eye lo alkyl, heterocyclyl, -COR8, -NHCORg, -CONR9R10, wherein said heterocyclyl is optionally substituted with OH or Ci_6 alkyl, said Ci_6 alkyl is optionally substituted with a substituent selected from: halogen, OH, COOH, NH2, Ci_6 alkoxy, heterocyclyl, heteroaryl, -COOR8, -NR9R10 and -CONR9R10; or
R3 and R4, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_6 alkyl;
R7 is selected from H, OH, halogen;
each R8 is independently selected from Ci_6 alkyl and heterocyclyl;
each R9 and Rio is independently selected from H and Ci_6 alkyl, or R9 and Rio, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_6 alkyl,
or a pharmaceutically acceptable salt or solvate thereof.
According to another embodiment, the compound of formula (I) is selected from:
dimethylcarbamic acid 2-oxo-2H-3-(3-methylaminosulfonylbenzyl)-4-methyl-6- chloro- l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -(N,N-dimethylaminocarbonyl)(methyl)amino sulfonyl) benzyl-4-methyl-6-chloro-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-iso-propylaminosulfonylbenzyl)-4-methyl-6- chloro- l -benzopyran-7-yl ester; dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(iso-propylaminosulfonyl)benzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-methylaminosulfonylbenzyl)-4-methyl-l- benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-methylaminosulfonylbenzyl)-4-methyl-6- methyl-l -benzopyran-7-yl ester;
pyrimidin-2-yl 2-oxo-2H-3-(3-methylaminosulfonylbenzyl)-4-methyl-6-chloro-l- benzopyran-7-yl ether;
dimethylcarbamic acid 2-oxo-2H-3-(3-methylaminosulfonylbenzyl)-4-methyl-6- f uoro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(carboxylmethyl)(methyl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(hydroxypropyl)(methyl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(methylaminocarbonylmethyl)(methyl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(ethoxycarbonylethyl)(methyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(hydroxyethyl)(methyl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(dimethylaminocarbonylmethyl)(methyl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(2,2,2-trif uoroethyl)aminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(aminocarbonylmethyl)(methyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(carboxyethyl)(methyl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-aminosulfonylbenzyl)-4-methyl-6-chloro-l - benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(2,2,2-trif uoroethyl)aminosulfonylbenzyl)-4- methyl-6-f uoro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoropropyl)aminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(2,2,2-trif uoroethyl)aminosulfonylbenzyl)-4- methyl- l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(2,2,2-trif uoroethyl)aminosulfonylbenzyl)-4- methyl-6-methyl- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(6-f uoro-3-cyclopropylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoropropyl)aminosulfonylbenzyl)-4- methyl-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(6-f uoro-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-aminosulfonylbenzyl)-4-methyl-6-chloro-l - benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-aminosulfonylbenzyl)-4-methyl-6-methyl-l - benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -cyclopropylaminosulfonylbenzyl)-4-methyl- 1 - benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoropropyl)aminosulfonylbenzyl)-4- methyl-6-fiuoro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -cyclopropylaminosulfonylbenzyl)-4-methyl-6- methyl-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(6-f uoro-3-(2,2,2-trifluoroethyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(6-f uoro-3-(dimethylaminoethylaminosulfonyl) benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(N-dimethylaminoethylaminosulfonyl)benzyl)- 4-methyl-6-methyl- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(N,N-bis(dimethylaminoethyl)aminosulfonyl) benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -cyclopropylaminosulfonylbenzyl)-4-methyl-6- f uoro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-aminosulfonylbenzyl)-4-methyl-6-f uoro-l- benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-aminosulfonylbenzyl)-4-methyl-l-benzopyran- 7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoropropylaminosulfonyl)benzyl)-4- methyl-6-methyl- 1 -benzopyran-7-yl ester; dimethylcarbamic acid 2-oxo-2H-3-(3-(dimethylaminoethylaminosulfonyl)benzyl)-4- methyl-6chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2,6-dif uoro-3-cyclopropylaminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(N,N-bis(methylaminocarbonylmethyl)amino sulfonyl)benzyl)-4-methyl-6-methyl- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(dimethylaminocarbonylmethylaminosulfonyl) benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -(N,N-bis(aminocarbonylmethyl)aminosulfonyl) methylaminosulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2,6-dif uoro-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(dimethylaminoalkyleneaminosulfonyl)benzyl)- 4-methyl-6-f uoro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(dimethylaminopropylaminosulfonyl)benzyl)- 4-methyl- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(aminocarbonylmethylaminosulfonyl)benzyl)- 4-methyl-6-methyl- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(dimethylaminoethylaminosulfonyl)benzyl)-4- methyl-6-f uoro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -(N,N-bis(aminocarbonylmethyl)aminosulfonyl) benzyl)-4-methyl- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-dimethylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-f uoro-3-cyclopropylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(N,N-bis(methylaminocarbonylmethyl)amino sulfonyl)benzyl)-4-methyl-6-fluoro-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(N,N-bis(methylaminocarbonylmethyl)amino sulfonyl)benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-f uoro-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(aminocarbonylmethylaminosulfonyl)benzyl)- 4-methyl-6-fluoro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -(N,N-bis(aminocarbonylmethyl)aminosulfonyl) benzyl)-4-methyl-6-fluoro-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2,6-dif uoro-3-dimethylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-methylpiperidinylsulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-phenylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-morpholinylsulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-methylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-f uoro-3-methylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-f uoro-3-methylpiperidinylsulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-cyclopropylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-tert-butylcarbonyl hydrazinylsulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-propionylhydrazinylsulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-chloro-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester;
N-methyl-N-ethyl-carbamic acid 2-oxo-2H-3-(4-fluoro-3-aminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
Morpholine carboxylic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl- 6-chloro- 1 -benzopyran-7-yl ester;
Piperidine carboxylic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl- 6-chloro-l -benzopyran-7-yl ester;
N-methyl-N-pehnyl-carbamic acid 2-oxo-2H-3-(4-fluoro-3-aminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
Diiso-propylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester; dimethylcarbamic acid 2-oxo-2H-3-(4-chloro-6-f uoro-3-aminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-6-chloro-7-(p-methylpyrimidin-2-yl oxy)-2-oxo-2H- 1 -benzopyrane;
3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-l- benzopyrane;
3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-6-chloro-7-(p-ethylpyrimidin-2-yloxy)- 2-oxo-2H-l -benzopyrane;
3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-7-(p-methylpyrimidin-2-yloxy)-2-oxo- 2H- 1 -benzopyrane;
3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-7-(p-ethylpyrimidin-2-yloxy)-2-oxo- 2H- 1 -benzopyrane;
dimethylcarbamic acid 2-oxo-2H-3-(2,4-difluoro-3-methylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-l- benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-hydrazinylsulfonylbenzyl)-4-methyl- 6-chloro-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-6- f uoro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-hydroxy-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-hydroxyethylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-dimethylaminoethylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-tert-butylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-hydroxyaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-dimethylaminocarbonylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-fluoro-3-piperidinylcarbonylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-fluoro-3-morpholinylcarbonylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
3-(4-fluoro-3-aminosulfonylbenzyl)-4-methyl-6-chloro-7-(p-chloropyrimidin-2-yl oxy)-2-oxo-2H- 1 -benzopyrane;
3-(4-fluoro-3-aminosulfonylbenzyl)-4-methyl-6-chloro-7-(pyrimidin-2-yloxy)-2-oxo- 2H- 1 -benzopyrane;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-acetamidosulfonylbenzyl)-4-methyl- 6-chloro-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-f uoro-3-acetamidosulfonylbenzyl)-4-methyl- 6-chloro-l -benzopyran-7-yl ester;
3-(4-f uoro-3-piperidinylcarbonylaminosulfonylbenzyl)-4-methyl-6-chloro-7- (pyrimidin-2-yloxy)-2-oxo-2H- 1 -benzopyrane;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-piperidinylcarbonylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-morpholinylcarbonylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
3-(4-f uoro-3-morpholinylcarbonylaminosulfonylbenzyl)-4-methyl-6-chloro-7- (pyrimidin-2-yloxy)-2-oxo-2H- 1 -benzopyrane;
dimethylcarbamic acid 2-oxo-2H-3-(2-fluoro-3-methylpiperazinylcarbonylamino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
3-(4-f uoro-3-morpholinylcarbonylaminosulfonylbenzyl)-4-methyl-7-(pyrimidin-2-yl oxy)-2-oxo-2H- 1 -benzopyrane;
3-(4-f uoro-3-piperidinylcarbonylaminosulfonylbenzyl)-4-methyl-7-(pyrimidin-2-yl oxy)-2-oxo-2H- 1 -benzopyrane;
3-(4-f uoro-3-N-methylaminocarbonylaminosulfonylbenzyl)-4-methyl-6-chloro-7- (pyrimidin-2-yloxy)-2-oxo-2H- 1 -benzopyrane;
3-(4-f uoro-3-N-methylaminocarbonylaminosulfonylbenzyl)-4-methyl-7-(pyrimidin-2- yloxy)-2-oxo-2H-l -benzopyrane;
dimethylcarbamic acid 2-oxo-2H-3-(2-fluoro-3-N-methylaminocarbonylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-hydroxyethyl- 6-chloro-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-hydroxypropylaminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(methoxyethyl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester; dimethylcarbamic acid 2-oxo-2H-3 -(4-f uoro-3 -(methoxypropyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(morpholinylethyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(methylpiperazinylethyl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(piperidinylethyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-carboxylmethylaminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-carboxyethylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(aminocarbonylmethyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(methylaminocarbonylmethyl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(N,N-dimethylaminocarbonylmethyl) aminosulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(N-methylpiperidin-4-yl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(pyridin-4-ylethyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(aminopropyl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(aminoethyl)aminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(azetidin-3-yl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(pyrrolidin-3-yl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(piperidin-4-ylethyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-fluoro-3-(hydroxyethylamino)sulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(methyl)(pyrrolidin-3-yl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(4-hydroxycylcohexyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(methyl)(hydroxyethyl)aminosulfonyl benzyl)-4-methyl-6-chloro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(2,3-dihydroxypropyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(hydroxymethyl)(hydroxyethyl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(l -aminocarbonyl-2-hydroxyethyl aminosulfonyl)benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester,
or a pharmaceutically acceptable salt or solvate thereof.
According to another aspect, the present invention provides a pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. According to another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use of treating proliferative disease or inflammatory disease.
According to another aspect, the present invention provides use of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating proliferative disease or inflammatory disease.
In the present invention, proliferative disease may be that commonly referred to in the art, and may be tumor, especially cancer. The cancer includes, but is not limited to, liver cancer, gastric cancer, esophageal cancer, leukemia, lung cancer, laryngeal cancer, uterus cancer, intestinal cancer, breast cancer, pancreatic cancer, brain cancer, neural cancer, renal cancer, lymphoma (including lymphocytoma), penis cancer, ovarian cancer, anal canal cancer, prostate cancer, colon cancer, skin cancer
and melanoma.
In some embodiments of the present invention, the cancer is melanoma, breast cancer, colon cancer, pancreatic cancer or lung cancer.
Definitions of Terms:
"Alkyl", as a group or part of another group, for example halogen-substituted alkyl, hydroxyl-substituted alkyl or alkoxy, may be linear or branched. Ci_6 alkyl refers to alkyl with 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl. Alkoxy includes but is not limited to methoxy, ethoxy, iso-propoxy, cyclopropoxy, etc.
"Aryl" refers to single or fused aromatic ring containing six to ten carbon atoms. Examples of aryl include phenyl and naphthyl, preferably phenyl.
"Heteroaryl" refers to any fused or non-fused aromatic ring system, wherein at least one of the rings is 5- to 8-membered ring containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur; preferably, at least one heteroatom is nitrogen. Examples of heteroaryl include but are not limited to thiophenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, diazinyl, benzimidazolyl, benzopyrazolyl, indolyl, etc.
"Cycloalkyl" refers saturated or partly unsaturated single, fused or bridged ring system containing specified number of carbon atoms. For example, C3_8 cycloalkyl refers to cycloalkyl containing three to eight carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
"Heterocyclyl" refers to the cycloalkyl as defined herein, wherein one or more of the ring carbon atoms is replaced by oxygen, nitrogen, -NR-, sulfur, carbonyl, -S(O)- or -S(0)2, etc. For Example, the heterocycyclyl may be a 3- to 8-membered ring system comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl include but are not limited to azetidinyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, etc.
"Alkylene amino" refers to a group containing the structure of -N=C-R, wherein R is alkyl as defined above.
"Pharmaceutically acceptable carrier" refers to inert carrier, auxiliary, excipient, or diluent which is commonly used in pharmaceuticals, including but not limited to starch, lactose, sucrose, glucose, magnesium stearate, mannitol, cellulose, water, alcohol/water mixture, phosphate buffer (0.01-0.1M, preferably 0.05M) and 0.9% saline, propylene glycol, polyethylene glycol, plant oil, albumin, gelatin, detergent (e.g. Tween 20, Tween 80, etc.), solubilizer (e.g. glycerine, polyethylene glycol, etc.), antioxidant, preservative, fatty acid, wax, filler or tensile modifier, polymer for covalent bonding or complex with metal ion, polylactose, polyglycolic acid, hydrogel, liposome, microemulsion, multilaminar vesicle, or spherical bulking agent.
"Solvate" refers crystals obtained by changing the lattice by introducing solvent molecule during the crystallization of a drug, including but not limited to: hydrate, alcoholate and etherate. The solvate of the compound of formula (I) of the present invention is preferably a pharmaceutically acceptable solvate, including but not limited to solvates formed with ethanol and water. "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of the compound of formula (I) of the present invention. Examples of the salt include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as formic acid, acetic acid, methanesulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, propionic acid, citric acid, succine acid, tartaric acid, fumaric acid, butanoic acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, etc., as well as salts formed with inorganic bases such as sodium, potassium, etc., and organic bases such as 2-aminoethanol, arginine, lysine, trihy droxym ethyl aminomethane, etc.
Application and Pharmaceutical Composition
The compound of the present invention is normally administered in a form of a suitable dosage form prepared with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral, rectal, topical and other parenteral (such as subcutaneous, intramuscular, intravenous, etc.) administrations. For example, dosage forms suitable for oral administration include capsule, tablet, granule, syrup, etc. The compound of the present invention in these dosage forms may be in a form of solid powder or granule; solution or suspension in an aqueous or non-aqueous liquid; emulsion of wate-in-oil or oil-in-water type; or the like. The above dosage forms may be prepared from active compounds and one or more carriers or auxiliaries by conventional pharmaceutical methods. The above carriers shall be compatible with active compounds or other auxiliaries. For solid dosage forms, commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, saccharose, etc. Carriers used for liquid dosage forms include water, physiological saline, aqueous solution of glucose, ethylene glycol, polyethylene glycol, etc. Active compounds may form solutions or suspensions with the above carriers.
Specific administration methods and dosage forms would depend on the physical-chemical properties of the compound itself and the severity of the disease to be treated, etc.
The composition of the present invention is formulated, quantified and administered in a way which complys the regulations of medical practice. The "effective amount" of the compound to be applied may be determined based on the factors such as specific diseases to be treated, the subject receiving treatment, etiology of the disease, target of the drug, and administration methods. Generally, the dosage for parenteral administration would be 1 - 200 mg/kg. Dosage forms for oral administration may contain 1 - 1000 mg/kg of the compounds of the present invention.
The compound of the present invention represented by formula (I) may be prepared by the following procedure, or similar procedure, or other procedure or similar procedure described in documents.
Preparation of the Compounds of the Present Invention
Synthesis Procedure
The compounds of formula (I) may be prepared according to the schemes and Examples below.
Scheme 1
Figure imgf000017_0001
Compound 2h in Scheme 1 and general procedure of synthesis thereof are described in details in Scheme 1.
1. Mono- or di-fluoro substituted or un-substituted 3-(chlorosulfonyl)benzoic acid starting material 2a is reacted with cyclopropyl amine to give the sulfonamide intermediate 2b, wherein the base used may be triethyl amine, diiso-propylethyl amine (DIPEA), etc., the reaction temperature may be 0-70 °C, the solvent for the reaction may be tetrahydrofuran (THF), dichloromethane (DCM), etc. For example, m-toluene sulfonyl chloride is reacted with methylamine, using triethyl amine as the base, tetrahydrofuran as the solvent, under stirring at room temperature for 3 hours to give the corresponding product.
2. The sulfonamide benzoic acid intermediate 2b is reduced to the corresponding alcohol 2c under the action of a reducing agent, wherein the reducing agent may be sodium borohydride (NaBH4)/ boron trifluoride, sodium borohydride (NaBH4)/iodine (I2), diborane (B2H6), etc., the solvent for the reaction may be tetrahydrofuran, and the reaction temperature may be 0 °C to room temperature. 3. The alcohol intermediate 2c is reacted with a brominating agent to give the corresponding brominated intermediate 2d, wherein the solvent may be tetrahydrofuran, the brominating agent may be phosphorus tribromide (PC13), sulfuric acid/hydrogen bromide (H^SCVHBr), the reaction temperature may be 0 °C to room temperature, and the reaction time may be 2-5 hours.
4. Ethyl acetoacetate is deprotonated with sodium hydride at -10 - 0 °C, and then reacted with the brominated intermediate 2d under a low temperature to give the intermediate 2e, wherein the solvent may be tetrahydrofuran.
5. The intermediate 2e is reacted with substituted or unsubstituted resorcinol at the presence of a strong acid to be dehydrated to give the coumarin intermediate 2f, wherein the reaction temperature may be -10 °C to room temperature, concentrated sulfuric acid is preferably used, and the reaction time may be 4-15 hours.
6. The intermediate 2f is reacted with Ν,Ν-dimethyl formyl chloride or other acyl chlorides under basic conditions to give the intermediate 2g, wherein the base may be potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, etc., the solvent may be Ν,Ν-dimethylformamide (DMF), tetrahydrofuran, dichloromethane, carbon tetrachloride, etc., the reaction temperature may be -10 °C to room temperature, and the reaction time may be 1 -5 hours.
7. The intermediate 2g is reacted with a halogenated hydrocarbon under basic conditions to give the final product 2h, wherein the base may be potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, etc., the solvent may be Ν,Ν-dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DCM), acetonitrile, etc., the reaction temperature may be -10 - 100 °C to room temperature, and the reaction time may be 1 -5 hours.
Scheme 2
Figure imgf000019_0001
Compound li in Scheme 2 and general procedure of synthesis thereof are described in details in Scheme 2.
1. The starting material l a is reduced to give the intermediate lb with a tetrahydrofuran solution of sodium borohydride and boron trifluoride dimethyl ether, wherein the reaction temperature may be 0 °C to room temperature, the solvent for the reaction may be tetrahydrofuran (THF). The reaction is stirred at room temperature for 3 hours to give the corresponding product.
2. The intermediate lb is reacted with a brominating agent, phosphorus tribromide, to give the corresponding brominated intermediate l c, wherein the solvent may be dichloromethane, and the reaction temperature may be 0 °C to room temperature.
3. Ethyl acetoacetate is deprotonated with sodium hydride at -10 - 0 °C, and then reacted with the brominated intermediate lc to give the intermediate Id, wherein the solvent may be tetrahydrofuran.
4. The intermediate I d is reacted with resorcinol substituted with A or unsubstituted at the presence of a strong acid to be dehydrated to give the coumarin intermediate l e, wherein the reaction temperature may be -10 °C to room temperature, concentrated sulfuric acid is preferably used, and the reaction time may be 4-15 hours.
5. The intermediate le is reacted with a chloride or other chlorides under basic conditions to give the intermediate I f, wherein the base may be potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, etc., the solvent may be Ν,Ν-dimethylformamide (DMF), tetrahydrofuran, dichloromethane, carbon tetrachloride, etc., the reaction temperature may be -10 °C to room temperature, and the reaction time may be 1-15 hours.
6. The intermediate If is reacted at the presence of ammonium chloride and zinc powder to give the intermediate lg, wherein the solvent may be N,N-dimethylformamide (DMF), tetrahydrofuran, methanol, ethanol, water, etc., the reaction temperature may be 70 - 80 °C, and the reaction time may be 2-15 hours.
7. The intermediate lg is subjected to diazotization at the presence of sodium nitrite and an acid, and then reacted with a acetic acid solution of cuprous chloride saturated with sulfur dioxide to give the intermediate lh, wherein the solvent may be hydrochloric acid (HC1), acetic acid (HAc), water, etc., the reaction temperature may be -10 °C to room temperature, and the reaction time may be 2-5 hours.
8. The intermediate lh is reacted with an amine compound under basic conditions to give the final product li, wherein the base may be potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, etc., the solvent may be Ν,Ν-dimethylformamide (DMF), tetrahydrofuran, dichloromethane, etc., the reaction temperature may be 0 °C to room temperature, and the reaction time may be 1 -15 hours.
Specific Embodiments
Preparation Examples
The experiments, synthesis and intermediates involved therein described below are illustration of the present invention, rather than a limitation of the scope thereof.
The starting materials used in the experiments of the present invention are either purchased from provides or synthesized from known raw materials. Unless otherwise indicated, the following conditions are employed in the Examples herein:
1) The unit of the temperature is degree Celsius, and room temperature is defined as 18 - 25 °C;
2) Organic solvents are dried over anhydrous magnesium sulfate or anhydrous sodium sulfate. Evaporation is conducted with a rotary evaporator under reduced pressure and elevated temperature (e.g., 15 mmHg, 30 °C);
3) Silica gel is used for column chromatographic separation, and TLC refers to silica gel thin layer chromatography;
4) Generally, the reaction process is monitored by TLC or LC-MS;
5) Characterization of the final products is conducted on NMR (Bruker AVANCE 300, 300 MHz) and LC-MS (Bruker esquine 6000, Agilent 1200 series). Example 1 : Synthesis of Dimethylcarbamic acid 2-oxo-2H-3-(3-N,N-dimethylaminoethyl aminosulfonylbenzyl)-4-methyl-6-chloro-l-benzofuran-7-yl ester (subject compound 2.8) The subject compound 2.8 is synthesized following the procedure described in Scheme
1
Figure imgf000021_0001
3-(N-cylcopropylaminosulfonyl)benzoic acid (2.2):
Cyclopropyl amine (0.26 g, 4.53 mmol) and triethyl amine (1.38 g, 13.6 mmol) are dissolved in tetrahydrofuran (15 ml). To this solution is added dropwise a tetrahydrofuran solution (5 mL) of 3-(chlorosulfonyl)benzoic acid (1 g, 4.53 mmol, subject compound 2.1) at 0°C. After adding, the mixture is heated up to room temperature, and stirred at room temperature for 3 h. After the reaction is completed as indicated by TLC, the reaction mixture is poured into 30 mL of saturated saline, and treated with 1 N hydrochloric acid to pH = 3. The mixture is extracted with ethyl acetate (20 mL x 2), and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to obtain a light white solid (subject compound 2.2, 0.6 g, 55%).
3-(Hydroxymethyl)-N-cyclopropylbenzenesulfonamide (2.3):
Sodium borohydride (0.19 g, 4.97 mmol) is dissolved in tetrahydrofuran (5 ml). To this solution is added dropwise a tetrahydrofuran solution (5 mL) of 3-(N-cylcopropylamino sulfonyl)benzoic acid (0.6 g, 2.49 mmol, subject compound 2.2) at 0°C, and the resulted mixture is stirred for 0.5 h at 0°C. To the solution is then added dropwise a solution of boron trifluoride-dimethyl ether (0.57 g, 4.97 mmol) at 0°C. After adding, the mixture is heated up to room temperature, and stirred overnight at room temperature. After the reaction is completed as indicated by TLC and MS, the reaction is quenched with 1 N hydrochloric acid (3 ml). The mixture is extracted with ethyl acetate (10 mL x 2). The organic phase is washed with saturated saline, dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to obtain a colorless oil (subject compound 2.3, 0.4 g, 71 %). 3-(Bromomethyl)-N-cvclopropylbenzenesulfonamide (2.4):
3-(Hydroxymethyl)-N-cyclopropylbenzenesulfonamide (0.75 g, 2.49 mmol, subject compound 2.3) is dissolved in tetrahydrofuran (20 ml). To this solution is added dropwise phosphorus tribromide (0.89 g, 3.3 mmol) at 0°C. After adding, the mixture is heated up to room temperature, and stirred at room temperature for 3 h. After the reaction is completed as indicated by TLC and MS, the reaction mixture is extracted with ethyl acetate (20 mL x 2). The organic phase is washed sequentially with saturated solution of sodium bicarbonate and saturated saline, and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to obtain a yellowish oil (subject compound 2.4, 0.87 g, 91 %).
2-(3-Cyclopropylaminosulfonylbenzyl)-3-ketobutyric acid ethyl ester (2.5):
Sodium hydride (NaH, 0.45 g, 60% wt, 11 .4 mmol) is dissolved in 30 ml of tetrahydrofuran, and cooled to 0°C with an ice-salt bath. To this solution is added dropwise ethyl acetoacetate (1.18 g, 9.10 mmol) at 0°C, and the mixture is stirred for 1 h at 0°C. To this solution is then added dropwise a tetrahydrofuran solution (20 ml) of 3-(bromo methyl)-N-cyclopropylbenzene sulfonamide (2.2 g, 7.58 mmol, subject compound 2.4) at 0°C. After adding, the mixture is heated up to room temperature, and stirred overnight. After the reaction is completed as indicated by TLC and MS, the reaction mixture is quenched with saturated solution of ammonium chloride (10 ml), and extracted with ethyl acetate (30 mL x 2). The organic phase is washed with saturated saturated saline, dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the residue is purified with column chromatography (n-hexane: ethyl acetate = 10: 1 ~ 3 : 1) to obtain a colorless oil (subject compound 2.5, 1.3 g, 5 1 %). 3-(3-Aminosulfonylbenzyl)-7-hvdroxy-4-methyl-6-chloro-2-oxa-2H- l - benzopyran (2.6):
2-(3-Cyclopropylaminosulfonylbenzyl)-3-ketobutyric acid ethyl ester (0.5 g, 1 .47 mmol, subject compound 2.5) and 4-chlororesorcinol (0.21 g, 1.47 mmol) are dissolved in carbon tetrachloride (1 ml). Concentrated sulfuric acid (0.43 g, 4.4 mmol) is added dropwise at 0°C. After adding, the mixture is stirred overnight at room temperature. After the reaction is completed as indicated by TLC, the reaction mixture is poured into ice water. A white solid is precipitated, which is filtered, washed with ethyl acetate, and dried to give a white solid (subject compound 2.6, 0.5623 g, 41 %).
1H NMR (300 Hz, DMSO) δ (ppm): 11 .326(s, 1H), 7.832 (s, 1H), 7.637 (s, 2H), 7.481 -7.459 (m, 2H), 7.327 (s, 2H), 6.909 (s, 1H), 4.01 (s, 2H), 2.51 -2.42 (m, 3H).
MS (ESI, m/z): [M+H]+: 380. Dimethylcarbamic acid 2-oxo-2H-3-(3-aminosulfonylbenzyl)-4-methyl-6- chloro- 1 - benzopyran-7-yl ester (2.7):
3-(3-Aminosulfonylbenzyl)-7-hydroxy-4-methyl-6-chloro-2-oxo-2H-l -benzopyran (200 mg, 0.53 mmol, subject compound 2.6) and potassium carbonate (364 mg, 2.6mmol) are dissolved in tetrahydrofuran (10 ml). To this solution is added dropwise N,N-dimethylformamide (57 mg, 0.583 mmol) while cooling with ice bath. After adding, the solution is stirred under reflux overnight. After the reaction is completed as indicated by TLC, the reaction mixture is poured into water (20 ml), extracted with ethyl acetate, dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to obtain crude product, which is recrystallized to give a white solid (subject compound 2.7, 0.14 g, 58%).
1H NMR (300MHz, CDC13) δ (ppm): 7.79 (s, 1H), 7.766 (s, 1H), 7.684 (s, 1 H), 7.27 (m, 1H), 4.744 (s, 2H), 4.116 (s, 2H), 3.178 (s, 3H), 3.052 (s, 3H), 2.465 (s, 3H).
MS (ESI, m/z): [M+H]+: 451
Dimethylcarbamic acid 2-oxo-2H-3-(3-N,N-dimethylaminoethylaminosulfonylbenzyl)-4- methyl-6-chloro- l -benzopyran-7-yl ester(2.8):
Dimethylcarbamic acid 2-oxo-2H-3-(3-aminosulfonylbenzyl)-4-methyl-6-chloro-l - benzopyran-7-yl ester (50 mg, 0.12 mmol, subject compound 2.7), N,N-dimethyl-2-chloroethyl amine (17.3 mg, 0.12 mmol) and potassium carbonate (50 mg, 0.36 mmol) are dissolved in acetonitrile (3 ml), and the resulted mixture is stirred overnight at room temperature. After the reaction is completed as indicated by TLC, the reaction mixture is filtered and purified with P-HPLC to give a white solid (subject compound 2.8, 15 mg, 23%).
1H-NMR (300 MHz, MeOH-d4) δ: 7.98 (s, 1 H), 7.81 -7.74 (m, 2H), 7.61 -7.52 (m, 2H), 7.36 (s, 1H), 4.17 (s, 2H), 3.32 (s, 3H), 3.13 (s, 3H), 3.18-3.10 (m, 2H), 3.04 (s, 3H), 2.91 (s, 6H), 2.58-2.56 (m, 2H).
MS (ESI, m/z): [M+H]+: 522.2
Example 2: Synthesis of dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(piperidinylethyl) aminosulfonylbenzyl)-4-methyl-6-chloro- l -benzopyran-7-yl ester (subject compound 13)
Subject compound 13 is synthesized following the procedure described in Scheme 2.
Figure imgf000024_0001
Figure imgf000024_0002
4-Fluoro-3-nitrobenzyl alcohol (2):
Sodium borohydride (22.6 g, 590 mmol) is dissolved in 700ml of tetrahydrofuran, and is cooled to 0°C with an ice-salt bath. To this solution is added portion-wise 4-fluoro-3-nitrobenzoic acid (100 g, 540 mmol, subject compound 1) at 0°C, and the resulted solution is stirred at 0°C for 1 h. To the solution is then added dropwise a tetrahydrofuran solution of boron trifluoride-dimethyl ether (54.2 mL, 590 mmol) at 0°C. After adding, the reaction is continued at room temperature for 3 h. After the reaction is completed as indicated by TLC, the reaction is quenched with ice water, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent is removed to give a white solid (subject compound 2, 90 g, 97.4%).
4-(Bromomethyl)-l-fluoro-2 -nitrobenzene (3):
4-Fluoro-3-nitrobenzyl alcohol (50g, 290 mmol, subject compound 2) is dissolved in
500 ml of dichloromethane, and is cooled to 0°C with an ice-salt bath. To this solution is added drop-wise phosphorus tribromide (27.5 mL, 290 mmol) at 0°C, and the reaction is continued at room temperature for 2 h. After the reaction is completed as indicated by TLC, the reaction is quenched with ice water, extracted with dichloromethane, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent is removed to give a yellowish solid, which is recrystallized (n-hexane: ethyl acetate = 1 : 1) to give a white solid (subject compound 3, 54 g, 79.9%).
2-(3-Nitro-4-fluorobenzyl)-3-ketobutyric acid ethyl ester (5):
Sodium hydride (NaH, 13.8 g, 345 mmol) is dissolved in 400ml of tetrahydrofuran, and cooled to 0°C with an ice-salt bath. To this solution is added dropwise ethyl acetoacetate (32.0 mL, 250 mmol, subject compound 4) at 0°C, and the mixture is stirred for 1 h at 0°C. To this solution is then added dropwise 100 ml tetrahydrofuran solution of 4-(bromomethyl)-l -fluoro-2-nitro benzene (54g, 230 mmol, subject compound 3) at 0°C. After adding, the mixture is stirred overnight at room temperature. After the reaction is completed as indicated by TLC, the reaction mixture is quenched with ice water, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent is removed to give crude product, which is purified with silica gel column chromatography (n-hexane: ethyl acetate = 10: 1-5 : 1) to give a yellowish oil (subject compound 5, 36 g, 55.4%).
3-(4-Fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-6-chloro-2-oxo-2H-2- benzopyran (7):
2- (3-Nitro-4-fluorobenzyl)-3-ketobutyric acid ethyl ester (36 g, 127 mmol, subject compound 5) and 4-chlororesorcinol (18.4 g, 127 mmol, subject compound 6) are placed in an ice-salt bath. Concentrated sulfuric acid (20.3 ml) is added dropwise at 0°C. After adding, the mixture is stirred overnight at room temperature. After the reaction is completed as indicated by TLC, the reaction mixture is poured into ice water. A white solid is precipitated, which is filtered and dried to give a white solid (subject compound 7, 29 g, 65.9%). Dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-nitrobenzyl)-4-methyl-6-chloro-l - benzopyran-7-yl ester (9):
3- (4-Fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-6-chloro-2-oxo-2H-2- benzopyran (29 g, 83.7 mmol, subject compound 7) is dissolved in 200 ml of tetrahydrofuran and 50 ml of water, and cooled to -10°C with an ice-salt bath. To this solution is added portion- wise potassium carbonate (57.8 g, 418.5 mmol). After adding, the mixture is stirred overnight at room temperature. After the reaction is completed as indicated by TLC, the reaction mixture is poured into ice water. A white solid is precipitated. The mixture is filtered, and dried to give crude product, which is recrystallized (ethanol) to give a white solid (subject compound 9, 30g, 82.6%).
Dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-aminobenzyl)-4-methyl-6-chloro-l - benzopyran-7-yl ester (10):
Dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-nitrobenzyl)-4-methyl-6-chloro-l- benzopyran-7-yl ester (30 g, 78.3 mmol, subject compound 9) is dissolved in Ν,Ν-dimethylformamide (DMF, 200 ml), and cooled to -10°C with an ice-salt bath. To this solution is added ammonium chloride (21.7 g, 391.5 mmol) and zinc powder (10.2 g, 156.6 mmol) separately. After adding, the mixture is heated to reflux overnight. After the reaction is completed as indicated by TLC, the reaction mixture is filtered to remove the white solid. The filtrate is poured into ice water. A white solid is precipitated, which is filtered, and dried to give a white solid (subject compound 10, 40 g, >100%).
Dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-chloroaulfonylbenzyl)-4-methyl-6-chloro- l -benzopyran-7-yl ester (11):
Dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-aminobenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester (20 g, 54.0 mmol, subject compound 10) is dissolved in 100 mL of hydrochloric acid and 50 mL of acetic acid in a flask 1 , and cooled to -10°C with an ice-salt bath. To this solution is added dropwise an aqueous solution of sodium nitrite (3.72 g, 54.0 mmol). After adding, the mixture is stirred at -10°C for 1 h. In a three-necked flask 2, cuprous chloride (1.34 g, 13.5 mmol) is dissolved in 100 mL of acetic acid, into which sulfur dioxide gas is charged to saturation at room temperature. The reaction is cooled to 0°C, and the solution from cooled flask 1 is added dropwise into flask 2. After adding, the reaction is continued at room temperature for another 2 h. After the reaction is completed as indicated by TLC, the reaction mixture is poured into ice water, when a yellowish solid is precipitated which is filtered to give crude product, which is further purified with silica gel column chromatography (dichloromethane) to give a white solid (subject compound 11, 5 g, 20.7%).
Dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(piperidinylethyl)aminosulfonylbenzyl)-4- methyl-6-chloro-l-benzopyran-7-yl ester(13):
Dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-chlorosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester (400 mg, 0.84 mmol, subject compound 11) is dissolved in 10 ml of tetrahydrofuran. To this solution is added potassium carbonate (347.8 g, 2.52 mmol), which is cooled to 0°C with an ice-salt bath. 1-Piperidinyl ethyl amine (126 mg, 1.68 mmol, subject compound 12) is added dropwise. After adding, the mixture is stirred overnight at room temperature. After the reaction is completed as indicated by TLC, the reaction mixture is poured into ice water, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent is removed to give crude product which is purified with silica gel column chromatography (dichloromethane: methanol = 1 :0-10: 1) to give a white solid (subject compound 13, 100 mg, 20.6%).
1H NMR (300 MHz, CDC13) δ (ppm): 7.75-7.78 (m, 1H), 7.69 (s, 1H), 7.45-7.51 (m, 1 H), 7.26-7.27 (m, 1 H), 7.09-7.15 (t, 1H, J = 8.7 Hz), 4.07-4.15 (m, 2H), 3.19 (s, 3H), 3.06 (s, 3H), 2.98-3.02 (m, 2H), 2.47 (s, 3H), 2.37-2.40 (m, 2H), 2.25 (s, 4H), 1.50-1 .57 (m, 4H), 1 .41 -1 .42 (m, 2H).
ESIMS m/z: 580.3 (M+H).
Example 3 : Synthesis of dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-aminosulfonyl benzyl)-4-(2-hvdoxyethyl)-6-chloro- 1 -benzopyran-7-yl ester:
Figure imgf000027_0001
Dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-aminosulfonlylbenzyl)-4-methyl-6- chloro- l -benzopyran-7-yl ester (468 mg, 1 mmol) is dissolved in tetrahydrofuran (THF, 120 ml), and cooled -78°C under nitrogen. To this solution is added dropwise tetramethyldisilylamino lithium (1 mol/L, 3.2 ml, 3.2mmol). After adding, the mixture is kept below -78°C for 1 hour under stirring. To the cooled reaction mixture is added a solution of paraformaldehyde (30 mg, 1 mmol) in tetrahydrofuran (THF, 3 ml). After adding, the mixture is warmed up gradually to room temperature and stirred overnight. After the reaction is completed as indicated by TLC, 20 mL of H20 is added into the reaction mixture, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product obtained by removal of solvent is subjected to silica gel column chromatography to give a white solid (56 mg, 11 .2%).
1H NMR (300 MHz, DMSO-^) δ: 8.08 (1H, s), 7.64 (3H, s), 7.51 (2H), 7.32 (1H, t, J =
8.4 Hz), 5.76 (1 H, s), 4.92 (1H, t, J = 6.0 Hz), 4.05 (2H, s), 3.62 (2H, q, J = Hz), 3.10 (5H, m), 2.95(3H, s).
MS (ESI, m/z): [M+H]+: 499.1 Compounds Prepared Herein
The compounds listed in Table 1 below are prepared with similar methods from similar starting materials.
Figure imgf000028_0001
1H-NMR (300 MHz, CDC13) δ: 7.95 (s, IH), 7.74 (brs, IH), 7.66-7.50 (m, 3H), 7.30 (s, IH), 4.16 (s, 2H), 3.62 (s, 2H), 3.18 (s, 3H), 3.03 (s, 3H), 2.77 (s, 3H), 2.54 (S, 3H) 1H-NMR (300 MHz, CDCI3) δ: 7.700 (IH, s), 7.690 (IH, s), 7.636 (IH, m), 7.455 (IH, s), 7.439 (IH, d, J = 0.24 Hz), 7.264 (IH, d, J =
3.0 Hz), 4.113 (2H, s), 3.704 (2H, t, J=5.7 Hz), 3.177 (3H, s), 3.109 (2H, t, J = 6.6 Hz), 3.050 (3H, s), 2.743 (3H, s), 2.483 (3H, s),
1.701 (2H, m)
1H-NMR (300 MHz, CDCI3) δ: 8.015 (IH, s), 7.918 (IH, d, J = 4.5 Hz), 7.728 (IH, s), 7.625 (IH, m), 7.497-7.538 (3H, m), 4.104 (2H, s), 3.584 (2H, s), 3.103 (3H, s), 2.948 (3H, s), 2.696 (3H, s), 2.552 (3H, d, J = 4.5
Hz), 2.496 (3H, s)
1H-NMR (300 MHz, CDCI3) δ: 7.713 (s, IH), 7.682 (s, IH), 7.648-7.626 (s, IH, J = 6.6 Hz), 7.461 -7.437 (m, 2H), 7.262 (S, IH), 4.150-4.103 (m, 4H), 3.332-3.284 (t, 2H, J = 7.2 Hz), 3.177 (s, 3H), 3.051 (s, 3H), 2.772 (s, 3H), 2.630-2.582 (t, 2H, J = 7.2 Hz), 2.466 (s, 3H), 1.285-1.238 (t, 3H, J = 6.9 Hz) 1H-NMR (300 MHz, DMSO-^) δ: 8.02 (s, IH), 7.69 (s, IH), 7.59-7.57 (m, IH), 7.53-7.50 (m, 3H), 4.80 (t, IH, J = 5.7 Hz), 4.10 (s, 2H), 3.49 (d, 2H, J = 6.0 Hz), 3.10 (s, 3H), 2.96 (t, 2H, J = 6.0 Hz), 2.94 (s, 3H),
2.69 (s, 3H), 2.50 (s, 3H)
1H-NMR (300 MHz, MeOH-d4) δ: 7.92 (s, IH), 7.75 (s, IH), 7.66-7.68 (d, IH, J = 7.5 Hz), 7.56-7.59 (d, IH, J = 7.8 Hz), 7.48-7.53 (m, IH), 7.31 (s, IH), 4.14 (s, 2H), 3.94 (s, 2H), 3.35 (s, IH), 3.18 (s, 3H), 3.03 (s, 3H),
3.01 (s, 3H), 2.87 (s, 3H), 2.74 (s, 3H), 2.53
(s, 3H)
1H-NMR (300 MHz, CDCI3) δ: 7.43-7.68 (m, 3H), 7.48 (d, IH, J = 4.2 Hz), 7.45 (s, IH), 7.27 (s, IH), 4.86 (m, IH), 4.12 (s, 2H), 3.66 (m, 2H), 3.18 (s, 3H), 3.05 (s, 3H), 2.45 (s, 3H) 1H-NMR (300 MHz, MeOH-d4) δ: 7.97 (s, I H), 7.80 (s, IH), 7.72-7.67 (d, IH), 7.62-7.53 (m, 2H), 7.36 (s, I H), 4.19 (s, 2H),
1 0 3.70 (s, 2H), 3.21 (s, 3H), 3.06(s, 3H), 2.81
(s, 3H), 2.57 (s, 3H), 1.95 (s, 2H)
1H-NMR (300 MHz, MeOH-d4) δ: 7.94 (s, I H), 7.73-7.49 (m, 4H), 7.33 (s, IH), 4.16 (s, 2H), 3.26 (t, J = 7.5 Hz, 2H), 3.18 (s, 3 H),
1 0 1 3.03 (S, 3H), 2.73 (s, 3H), 2.54 (s, 3H), 2.51
(t, J = 7.5 Hz, 2H)
1H-NMR (300 MHz, CDC13) δ: 7.79 (s, I H), iXXX 7.766 (s, IH), 7.684 (s, I H), 7.27 (m, I H),
\ Xk o"i NH2 4.744 (s, 2H), 4.116 (s, 2H), 3.178 (s, 3H),
3.052 (s, 3H), 2.465 (s, 3H)
1H-NMR (300 MHz, CDC13) δ: 7.45-7.00 (m, 2H), 7.52-7.38 (m, 3H), 7.23 (d, IH, J = 6.6 Hz), 4.83 (m, IH), 4.12 (s, 2H), 3.66 (m, 2H),
Figure imgf000030_0001
3.15 (s, 3H), 3.05 (s, 3H), 2.43 (s, 3H)
1H-NMR (300 MHz, MeOH-d4) δ: 7.98 (s, I H), 7.77-7.72 (m, 2H), 7.60-7.58 (d, I H), 7.56-7.51 (d, I H), 7.37 (s, I H), 4.19 (s, 2H),
1 θ' H 3.21 (s, 3H), 3.09-3.06 (t, 2H), 3.05 (s, 3H),
2.56 (s, 3H), 2.37-2.34 (m, 2H)
1H-NMR (300 MHz, CDCI3) δ: 7.75 (s, I H), 7.70 (d, IH, J = 7.8 Hz), 7.63 (d, IH, J=9.6 Hz), 7.51 (m, 1H),7.44 (m, IH), 4.86 (m, I H), 4.12 (s, 2H), 3.65 (m, 2H), 3.13 (s, 3H), 3.04 (s, 3H), 2.46 (s, 3H)
1H-NMR (300 MHz, CDCI3) δ: 7.74 (s, 1H),7.69 (d, I H, J = 7.5 Hz), 7.46 (m, 3H), 7.11 (s, I H), 4.91 (m, IH), 4.11 (s, 2H), 3.64
T d' (m, 2H), 3.16 (s, 3H), 3.04 (s, 3H), 2.44 (s,
3H), 2.29 (s, 3H)
1H-NMR (300 MHz, MeOH-d4) δ: 7.94 (s, F I H), 7.74-7.79 (m, IH), 7.68-7.71 (m, I H),
7.26-7.33 (m, 2H), 4.12 (s, 2H), 3.18 (s, 3H),
1 O H 3.03 (s, 3H), 2.51 (s, 3H), 1 .67 (s, I H),
0.87-0.98 (m, 2H), 0.41 -0.48 (m, 2H)
1H-NMR (300 MHz, MeOH-d4) δ: 7.81 -7.78 (d, I H), 7.75 (s, I H), 7.71 -7.69 (d, I H), 7.57-7.54 (d, I H), 7.52-7.49 (d, I H), 7.16 (s,
1 O H IH), 7.13-7.12 (d, I H), 4.13 (s, 2H), 3.14 (s,
3H), 3.08-3.05 (t, 2H), 3.03 (s, 3H), 2.51 (s, 3H), 2.38-2.31 (m, 2H) 1H-NMR (300 MHz, MeOH- ¼) δ: 7.97 (s,
1 F
iXXX 1H), 7.78-7.83 (m, 1H), 7.62-7.75 (m, 1H),
] Xki ~NH2 7.35 (s, 1H), 7.25-7.31 (m, 1H), 4.13 (s, 2H),
3.19 (s, 3H), 2.87 (s, 3H), 2.52 (s, 3H)
1H-NMR (300 MHz, MeOH- ¼) δ: 7.95 (s,
1 1H), 7.73-7.71 (d, 2H), 7.58-7.50 (m, 2H),
7.34 (s, 1H), 4.16 (s, 2H), 3.18 (s, 3H), 3.03
1 (s, 3H), 2.52 (s, 3H), 2.13-2.02 (m, 1H),
0.49-0.44 (m, 4H)
1H-NMR (300 MHz, CDC13) δ: 7.78 (s, 1H),
1
7.75 (s, 1H), 7.50-7.40 (m, 3H), 7.11 (s, 1H),
T 4.11 (s, 2H), 3.16 (s, 3H), 3.04 (s, 3H), 2.46
(s, 3H), 2.29 (s, 3H)
1H-NMR (300 MHz, CDC13) δ: 7.83 (s, 1H), 7.76-7.73 (dd, 1H, J = 7.5, 1.2 Hz), 7.64-7.61
1 (d, 1H, J = 9.6 Hz), 7.51-7.41 (m, 2H), 7.137
(s, 1H), 7.13-7.10 ( dd, 1H, J = 4.8, 2.1 Hz), O H 4.846 (s, 1H), 4.124 (s, 2H), 3.132 (s, 3H),
3.037 (s, 3H), 2.47 (s, 3H), 2.224-2.201 (m, 1H), 0.615-0.579 (m, 4H)
1H-NMR (300 MHz, MeOR-d4) δ: 7.74-7.67 (m, 3H), 7.58-7.48 (m, 2H), 7.33-7.31 (d, 2H), 4.16 (s, 2H), 3.32 (s, 3H), 3.07-3.04 (t,
Figure imgf000031_0001
2H), 3.03 (s, 3H), 2.51 (s, 3H), 2.38-2.31 (m,
2H)
1H-NMR (300 MHz, CDCI3) δ: 7.77-7.73 (m, 2H), 7.50-7.41 (m, 3H), 7.12 (s, 1H), 4.76 (s, lH), 4.12 (s, 2H), 3.16 (s, 3H), 3.04 (s,
1 θ' H 3H), 2.45 (s, 3H), 2.29 (s, 3H), 2.23-2.18 (m,
1H), 0.62-0.58 (m, 4H)
1H-NMR (300 MHz, MeOR-d4) δ: 7.98 (s, 1H), 7.70-7.80 (m, 2H), 7.36 (s, 1H), 7.27-7.34 (m, 1H), 4.14 (s, 2H), 3.57-3.60 (m,
Figure imgf000031_0002
2H), 3.20 (s, 3H), 3.04 (s, 3H), 2.53 (s, 3H)
1H-NMR (300 MHz, MeOR-d4) δ: 8.00 (s, F 1H), 7.80-7.84 (m, 2H), 7.32-7.38 (m, 2H),
4.15 (s, 2H), 3.23-3.27 (m, 2H), 3.20 (s, 3H), O H 3.13-3.17 (m, 2H), 3.04 (s, 3H), 2.92 (s, 6H),
2.57 (s, 3H)
1H-NMR (300 MHz, CDCI3) δ: 7.76-7.73 (m, 2H), 7.50-7.43 (m, 3H), 7.10 (s, 1H), 4.10 (s, 1H), 3.35 (s, 2H), 3.16 (s, 5H), 3.04 (s, 3H), 2.80 (s, 6H), 2.52 (s, 3H), 2.11 (s, 3H)
Figure imgf000032_0001
1H-NMR (300 MHz, MeOH-d4) δ: 7.96 (s,
A A L P 1H), 7.82 (s, 1H), 7.74-7.72 (d, 1H),
7.60-7.49 (m, 2H), 7.34 (s, 1H), 4.17 (s, 2H), V 3.89 (s, 4H), 3.18 (s, 3H), 3.03 (s, 3H), 2.55
(s, 3H)
1 1H-NMR (300 MHz, CDC13) δ: 7.75-7.84 (m,
1H), 7.70 (s, 1H), 7.23 (s, 1H), 6.94-6.98 (m, 1H), 7.08-7.14 (m, 1H), 4.07 (s, 2H), 3.17 (s, 3H), 3.04 (s, 3H), 2.52 (s, 3H)
1H-NMR (300 MHz, CDCI3) δ: 8.10 (s, 1H),
1 7.71-7.76 (m, 2H), 7.37-7.41 (m, 3H), 7.22
(d, 1H, J = 6.6 Hz), 4.13-4.08 (m, 2H), 3.15 (s, 3H), 3.13 (s, 3H), 3.05 (s, 3H), 3.01 (s, 3H), 2.42 (s, 3H)
1H-NMR (300 MHz, MeOH-d4) δ: 7.875-7.843 (dd, 1H, J = 7.5, 2.1Hz), 7.785
1 (s, 1H), 7.745-7.720 (d, 1H, J = 7.5 Hz),
7.605-7.579 (d, 1H, J = 7.8 Hz), 7.558-7.507
1 (t, 1H, J = 7.8 Hz), 7.189-7.165 (m, 2H),
4.160 (s, 2H), 3.253-3.216 (t, 2H, J = 5.4 Hz), 3.161-3.126 (t, 2H, J = 5.2 Hz), 3.141 (s, 3H), 3.018 (s, 3H), 2.912 (s, 6H), 2.569 (s, 3H)
1H-NMR (300 MHz, CDCI3) δ: 7.71 (s, 2H), 7.51-7.42 (m, 3H), 7.10 (s, 1H), 5.95 (s, 1H), 5.34 (s, 1H), 5.18 (s, lH), 4.10 (s, 2H), 3.59
Figure imgf000033_0001
(d, 2H, J =5.4 Hz), 3.16 (s, 3H), 3.04 (s, 3H),
2.50 (s, 3H), 2.29 (s, 3H)
1 1H-NMR (300 MHz, CDCI3) δ: 11.54 (s, 1H),
7.02-7.76 (m, 2H), 7.40-7.46 (m, 3H), 7.20 (s, 1H), 4.09(s, 2H), 3.22-3.32 (m, 4H), 3.15 (s, 3H), 3.04 (s, 3H), 2.88 (s, 6H), 2.48 (s, 3H)
1H-NMR (300 MHz, DMSO-^) δ: 8.067 (s, 1H), 7.867-7.838 (d, 1H, J = 6.6 Hz), 7.783
A I I I L I (s, 1H), 7.669-7.649 (m, 1H), 7.518-7.502 (d,
2H, J = 4.8 Hz), 7.263-7.256 (d, 2H, J =
V 2.1Hz), 7.207-7.170 (dd, 1H, J = 8.7, 2.4 Hz),
4.098 (s, 2H), 3.782 (s, 4H), 3.065 (s, 3H), 2.931 (s, 3H)
1H-NMR (300 MHz, CDCI3) δ: 8.03 (s,
1
1H),7.71 (dd, 1H, J =2.1 Hz, J =3 Hz), 7.60-7.56 (m, 1H),7.51 (s, 1H), 7.42-7.36 (m, 1H), 4.07 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H), 2.70-2.69 (m, 6H), 2.51 (s, 3H)
Figure imgf000034_0001
1H-NMR (300 MHz, CDC13) δ: 7.71 (IH, dt, J = 6.3 Hz, J = 1.8 Hz), 7.68 (IH, s), 7.43-7.52 (IH, m), 7.27 (IH, s), 7.14 (IH, t, J = 9.0 Hz), 4.06 (2H, s), 3.73-3.76 (4H, m), 3.18 (7H, m), 3.05 (3H, s), 2.46 (3H, s)
1H-NMR (300 MHz, CDCI3) δ: 7.75 (IH, dt, J
1 = 6.9 Hz, J = 2.4 Hz), 7.68 (IH, s), 7.46-7.52
XXXXXXf (IH, m), 7.27 (IH, s), 7.13 (IH, t, J = 8.7 Hz),
4.56 (IH, d, J = 8.4 Hz), 4.06 (2H, s), 3.18 (3H, s), 3.05 (6H, s), 2.70 (3H, d, J = 5.4 Hz), 2.47 (3H, s)
1H NMR (300 MHz, CDCI3) δ (ppm):
1
7.74-7.78 (m, IH), 7.69-7.72 (m, IH), 7.47-7.54 (m, 2H), 7.16-7.21 (m, 2H), 4.09 (s, 2H), 3.17 (s, 3H),3.05 (s, 3H), 2.69-2.71 (s, 3H), 2.46 (s, 3H)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.68-7.72 (m, 2H), 7.46-7.50 (m, IH), 7.26 (s, IH), 7.17-7.22 (m, IH), 4.08 (s, 2H), 3.57-3.60 (m, 2H), 3.31-3.40 (m, 2H), 3.17 (s, 3H), 3.05 (s, 3H), 2.93-3.02 (m, 2H), 2.89 (s, 3H), 2.50 (s, 3H)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.78-7.81 (m, IH), 7.68 (s, IH), 7.47-7.52 (m, IH), 7.26-7.27 (m, IH), 7.10-7.16 (m, IH), oclAAfJL Yo
4.07 (s, 2H), 3.17 (s, 3H), 3.05 (s, 3H), 2.46 ° Α (s, 3H), 2.23-2.25 (m, IH), 0.83-0.94 (m, 2H),
0.58-0.68 (m, 2H)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.69-7.72 (m, IH), 7.69 (s, IH), 7.56-7.63 (m, 2H), 7.48-7.53 (m, IH), 7.27 (s, IH),
1 O H π 7.10-7.16 (m, IH), 4.03 (s, 2H), 3.17 (s, 3H),
3.05 (s, 3H), 2.45 (s, 3H), 0.96 (s, 9H)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.67-7.71 (m, 2H), 7.47-7.52 (m, 2H), 7.37-7.39 (m, IH), 7.26 (s, IH), 7.11 -7.17 (m, IH), 4.04 (s, 2H), 3.17 (s, 3H), 3.05 (s, 3H),
Figure imgf000035_0001
2.45 (s, 3H), 2.05-2.07 (m, 2H), 0.91-0.96 (m, 3H)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.96 (s, IH), 7.68 (s, IH), 7.43 (s, 2H), 7.25-7.26 (m,
\ g NH2 IH), 4.06 (s, 2H), 3.17 (s, 3H), 3.07 (s, 3H),
2.46 (s, 3H) 1H NMR (300 MHz, CDC13) δ (ppm):
7.68-7.76 (m, 2H), 7.48-7.52 (m, 1H),
1
7.26-7.31 (m, 1H), 7.12-7.18 (t, 1H, J = 9.0
1 " Hj Hz), 5.03 (s, 2H), 4.05 (s, 2H), 3.42-3.55 (m,
2H), 3.03-3.14 (m, 3H), 2.45 (s, 3H), 1.20-1.33 (m, 3H)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.70-7.76 (m, 2H), 7.48-7.52 (m, 1H), 7.26-7.28 (m, 1H), 7.12-7.18 (t, 1H, J = 9.0
Figure imgf000036_0001
Hz), 5.02 (s, 2H), 4.06 (s, 2H), 3.67-3.70 (m,
3H), 3.60 (s, 3H), 3.26-3.29 (m, 2H), 2.48 (s, 3H)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.74-7.77 (m, 1H), 7.68 (s, 1H), 7.47-7.52 (m, 1H), 7.25-7.26 (m, 1H), 7.11-7.17 (t, 1H, J = 1 0 n 9.0 Hz), 5.07 (s, 2H), 4.05 (s, 2H), 3.67 (s,
2H), 3.53 (s, 2H), 2.47 (s, 3H), 1.50-1.79 (m, 6H)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.74-7.77 (m, 1H), 7.67 (s, 1H), 7.47-7.49 (m,
Figure imgf000036_0002
oci y^AroH2 1H), 7.38-7.42 (m, 4H), 7.42-7.38 (m, 1H),
7.11-7.17 (t, 1H, J = 9.0 Hz), 5.03 (s, 2H), 4.04 (s, 2H), 3.43 (s, 3H), 2.47 (s, 3H)
1H-NMR (300 MHz, CDCI3) δ: 7.75 (1H, dt, J = 6.9 Hz, J = 2.4 Hz), 7.68 (1H, s), 7.46-7.51 (1H, m), 7.23 (1H, s), 7.14 (1H, t, J = 9.3 Hz),
Figure imgf000036_0003
5.08 (2H, s), 4.05 (2H, s), 3.97-3.99 (2H, m),
2.47 (3H, s), 1.25-1.37 (12H, m)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.97-8.00 (d, 1H, J = 8.7 Hz), 7.70 (s, 1H), 7.27-7.29 (m, 1H), 7.23-7.25 (m, 1H), 5.13 (s,
Figure imgf000036_0004
2H), 4.04 (s, 2H), 3.18-3.20 (m, 3H),
3.05-3.07 (m, 3H), 2.48 (s, 3H)
1H NMR (300 MHz, CDCI3) δ (ppm): 8.40 (s, 2H), 7.74-7.77 (m, 2H), 7.47-7.53 (m, 1H), -γθγ ΟγΟ ^yF
7.28-7.29 (m, 1H), 7.12-7.18 (t, 1H, J = 9.0
Figure imgf000036_0005
Hz), 5.07 (s, 2H), 4.07 (s, 2H), 2.50 (s, 3H),
2.26-2.30 (m, 3H)
1H-NMR (300 MHz, CDCI3) δ: 8.59 (2H, d, J = 4.8 Hz), 7.76 (1H, dt, J = 6.9 Hz, J = 2.1
Γ ν°τΎ°τ° rrF Hz), 7.72 (1H, d, J = 8.7 Hz), 7.49-7.54 (1H,
T § H2 m), 7.10-7.25 (4H, m), 4.99 (2H, s), 4.08 (2H, s), 2.51 (3H, s)
Figure imgf000037_0001
1H-NMR (300 MHz, DMSO-^) δ: 8.02 (IH, s), 7.77 (IH), 7.64 (IH, dt, J = 6.9 Hz, J = 2.1 Hz), 7.51-7.56 (IH, m), 7.49 (IH, s), 7.32 (IH, t, J = 9.3 Hz), 4.04 (2H, s), 3.10 (3H, s), 2.95 (3H, s), 2.92 (2H, t, J = 6.9 Hz), 2.49 (3H, s), 2.19 (2H, t, J = 6.9 Hz), 1.98 (6H, s)
1H-NMR (300 MHz, DMSO-^) δ: 8.02 (IH,
1
s), 7.74 (IH), 7.65 (IH, dt, J = 6.9 Hz, J = 2.1 Hz), 7.52-7.54 (IH, m), 7.50 (IH, s), 7.30 O H
(IH, t, J = 9.3 Hz), 4.04 (2H, s), 3.10 (3H, s), 2.94 (3H, s), 2.48 (3H, s), 1.07 (9H, s)
1H NMR (300 MHz, CDC13) δ (ppm): 7.79-7.82 (m, IH), 7.68 (s, IH), 7.56-7.61 (m, IH), 7.27-7.29 (m, IH), 7.12-7.19 (t, IH, J =
Figure imgf000038_0001
9.0 Hz), 7.04 (s, IH), 4.06-4.08 (m, 2H), 3.18 (s, 3H), 3.05 (s, 3H), 2.47 (s, 3H)
1H-NMR (300 MHz, DMSO-^) δ: 8.02 (IH,
1 s), 7.75 (IH), 7.64 (IH, dt, J = 6.9 Hz, J = 2.1
T ΤΎ T T o o Hz), 7.52-7.54 (IH, m), 7.50 (IH, s), 7.30
1 0 H 1 (IH, t, J = 9.3 Hz), 4.04 (2H, s), 3.10 (3H, s),
3.04 (3H, s), 2.94 (3H, s), 2.90 (3H, s), 2.48 (3H, s)
1H-NMR (300 MHz, CDC13) δ: 7.95 (IH, dt, J = 8.1 Hz, J = 1.5 Hz), 7.68 (IH, s), 7.48 (IH,
X Τ Ύ T Γ 1 o o t, J = 6.6 Hz), 7.27 (IH, s), 7.21 (IH, t, J =
T ΐ d' B Q 7.8 Hz), 4.09 (2H, s), 3.36-3.38 (4H, m), 3.18
(3H, s), 3.05 (3H, s), 2.43 (3H, s), 1.50-1.62 (6H, m)
1H-NMR (300 MHz, CDCI3) δ: 7.92 (IH, t, J = 7.2 Hz), 7.69 (IH, s), 7.48 (IH, t, J = 7.2
T Τ Ύ Τ Γ 1 ο ο Hz), 7.28 (IH, s), 7.21 (IH, t, J = 7.8 Hz),
1 ' Ν Ν 4.10 (2H, s), 3.64-3.70 (4H, m), 3.41-3.47
(4H, m), 3.18 (3H, s), 3.05 (3H, s), 2.46 (3H,
8)
1H NMR (300 MHz, CDCI3) δ (ppm): 8.62 (s, 2H), 7.90-7.92 (m, IH), 7.74-7.76 (m, IH),
Τ d' 7.48 (s, IH), 7.04-7.14 (m, 2H), 4.06-4.09 (m,
2H), 2.50 (s, 3H)
1H NMR (300 MHz, CDCI3) δ (ppm): 8.57-8.59 (d, 2H, J = 4.8 Hz), 7.90-7.92 (m, IH), 7.74-7.76 (m, IH), 7.48 (s, IH),
Figure imgf000038_0002
7.04-7.14 (m, 2H), 4.06-4.09 (m, 2H), 2.50 (s, 3H) 1H NMR (300 MHz, CDC13) δ (ppm):
7.79-7.82 (m, 1 H), 7.68 (s, 1H), 7.56-7.61 (m, 1H), 7.27-7.29 (m, 1H), 7.12-7.19 (t, 1H, J =
Figure imgf000039_0001
9.0 Hz), 7.04 (s, 1 H), 4.08 (s, 2H), 3.18 (s, 3H), 3.05 (s, 3H), 2.46 (s, 3H), 2.09 (s, 3H)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.91 (s, 1 H), 7.69 (s, 1 H), 7.53 (s, 1H), 7.21 -7.27 (m,
Figure imgf000039_0002
2H), 4.08 (s, 2H), 3.18 (s, 3H), 3.05 (s, 3H),
2.44 (s, 3H), 2.07 (s, 3H)
1H NMR (300 MHz, CDCI3) δ (ppm): 8.55-8.57 (d, 2H, J = 4.5 Hz), 7.80-7.82 (m, 1 H), 7.69 (s, 1 H), 7.19 (s, 1H), 7.05-7.13 (m,
0 η Ο 2H), 6.78-6.84 (m, 1 H), 3.89 (s, 2H), 2.41 (s,
3H), 1.94-2.05 (m, 4H), 1.24- 1.43 (m, 6H)
1H-NMR (300MHz, DMSO) δ: 8.03 (1H, s),
1
7.65-7.68 (1H, d, J = 6.9 Hz), 7.51 -7.56 (1 H, m), 7.50 (1H, s), 7.30 (1H, t, J = 9.0 Hz), 4.04 (2H, s), 3.26 (4H, m), 3.10 (3H, s), 2.95 (3H, s), 2.47 (3H, s), 1.50 (2H, m). 1.37 (4H, m)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.74-7.77 (m, 1 H), 7.46 (s, 1H), 7.02-7.12 (m, 2H), 4.06-4.09 (m, 2H), 3.5 1 -3.69 (m, 4H),
Figure imgf000039_0003
3.40-3.47 (m, 4H), 3.23 (3H, s), 3.18 (3H, s);
2.50 (s, 3H)
1H NMR (300 MHz, CDCI3) δ (ppm): 8.57-8.59 (d, 2H, J = 4.8 Hz), 7.90-7.92 (m, 1 H), 7.74-7.76 (m, 1H), 7.48 (s, 1 H), 7.04-7.14 (m, 2H), 4.06-4.09 (m, 2H), 3.49-3.69 (m, 4H), 3.40-3.49 (m, 4H), 2.50 (s, 3H)
1H NMR (300 MHz, CDCI3) δ: 7.83 (1 H, dt, J = 7.2 Hz, J = 1.5 Hz), 7.69 (1 H, s), 7.40 (1H, t, J = 6.6 Hz), 7.23 (1H, s), 7.11 (1 H, t, J = 7.8 Hz), 4.08 (2H, s), 3.53-3.60 (6H, m),
Figure imgf000039_0004
3.39-3.43 (2H, m), 3.17 (3H, s), 3.04 (6H, s), 2.49 (3H, s)
1H NMR (300 MHz, CDCI3) δ (ppm): 8.58-8.59 (d, 2H, J = 4.8 Hz), 7.90-7.92 (m, 1 H), 7.68-7.72 (m, 1H), 7.42 (s, 1 H),
Figure imgf000039_0005
7.15-7.20 (m, 2H), 7.10-7.13 (t, 1 H, J = 4.8
Hz), 7.00-7.06 (m, 1 H), 4.03 (s, 2H), 3.56 (s, 4H), 3.39 (s, 4H), 2.50 (s, 3H)
Figure imgf000040_0001
1H NMR (300 MHz, CDC13) δ (ppm): 7.72-7.75 (m, 1H), 7.68 (s, 1H), 7.44-7.50 (m, 1H), 7.26-7.27 (m, 1H),7.09-7.15 (t, 1H, J = 8.7 Hz), 5.43-5.47 (m, 1H), 4.06 (s, 2H), 3.41-3.45 (m, 2H), 3.30 (s, 3H), 3.18 (s, 3H), 3.05-3.11 (m, 5H), 2.46 (s, 3H), 1.71-1.79 (m,
2H)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.74-7.77 (m, 1H), 7.69 (s, 1H), 7.45-7.50 (m, 1H), 7.26-7.27 (m, 1H), 7.08-7.14 (t, 1H, J = 8.7 Hz), 5.63 (s, 1H), 4.06 (s, 2H), 3.67-3.70 (m, 4H), 3.18 (s, 3H), 3.05-3.10 (m, 5H),
2.48-2.50 (m, 5H), 2.38 (s, 4H)
1H NMR (300 MHz, CDCI3) δ (ppm):
7.74- 7.77 (m, 1H), 7.69 (s, 1H), 7.45-7.50 (m, 1H), 7.26-7.27 (m, 1H), 7.08-7.14 (t, 1H, J = 8.7 Hz), 5.51 (s, 1H), 4.06 (s, 2H), 3.18 (s, 3H), 3.02-3.05 (m, 5H), 2.05-2.66 (m, 16H) 1H NMR (300 MHz, CDCI3) δ (ppm):
7.75- 7.78 (m, 1H), 7.69 (s, 1H), 7.45-7.51 (m, 1H), 7.26-7.27 (m, 1H), 7.09-7.15 (t, 1H, J = 8.7 Hz), 4.07-4.15 (m, 2H), 3.19 (s, 3H), 3.06 (s, 3H), 2.98-3.02 (m, 2H), 2.47 (s, 3H), 2.37-2.40 (m, 2H), 2.25 (s, 4H), 1.50-1.57 (m,
4H), 1.41-1.42 (m, 2H)
1H NMR (300 MHz, CDC13) δ (ppm): 11.11 (s, 1H), 7.78-7.81 (m, 1H), 7.65 (s, 1H), 7.22-7.26 (m, 2H), 6.96-7.02 (t, 1H, J = 8.7 Hz), 4.02 (s, 2H), 3.09-3.18 (m, 5H), 3.05 (s,
3H), 2.42 (s, 3H)
1H NMR (300 MHz, CDCI3) δ (ppm): 10.02 (s, 1H), 7.77-7.78 (m, 1H), 7.56 (s, 1H), 7.17-7.26 (m, 2H), 6.87-6.90 (m, 1H), 3.88 (s, 2H), 3.11-3.20 (m, 7H), 3.02 (s, 3H), 2.42 (s,
3H)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.69-7.73 (m, 2H), 7.48-7.52 (m, 1H), 7.25-7.26 (m, 1H), 7.11 -7.17 (t, 1H, J = 9.0 Hz), 6.09 (s, 1H), 5.61-5.65 (m, 1H), 5.51 (s, 1H), 4.08 (s, 2H), 3.66-3.68 (m, 2H), 3.18 (s, 3H), 3.05 (s, 3H), 2.48 (s, 3H) 1H NMR (300 MHz, CDC13) δ: 7.68-7.74 (2H, m), 7.46-7.52 (1H, m), 7.13 (1H, t, J = 8.7 Hz), 6.29 (1H, s), 5.70 (1H, t, J = 6.0 Hz),
" 0 4.05 (2H, s), 3.60 (2H, d, J = 6.0 Hz), 3.18
(3H, s), 3.05 (3H, s), 2.76 (3H, d, J = 4.8 Hz), 2.48 (3H, s)
1H NMR (300 MHz, CDCI3) δ: 7.69-7.74 (2H, m), 7.40-7.46 (1H, m), 7.28 (1H, s), 7.11 (1H, t, J = 8.7 Hz), 5.91 (1H, s), 4.05 (2H, s), 3.84
0 (2H, s), 3.18 (3H, s), 3.05 (3H, s), 2.91 (3H, s), 2.89 (3H, s), 2.46 (3H, s)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.73-7.76 (m, 1H), 7.69 (s, 1H), 7.43-7.48 (m, 1H), 7.26-7.27 (m, 1H), 7.09-7.15 (t, 1H, J =
1 0 H 8.7 Hz), 4.06 (s, 2H), 3.37-3.49 (m, 4H), 3.18
(s, 3H), 3.05 (s, 3H), 2.91-3.02 (m, 1H), 2.47 (s, 6H), 1.84-1.97 (m, 4H)
1H NMR (300 MHz, CDCI3) δ (ppm): 8.39-8.53 (m, 2H), 7.71-7.74 (m, 1H), 7.68 (s, 1H), 7.43-7.48 (m, 1H), 7.26-7.27 (m, 1H),
1 θ' H 7.05-7.11 (m, 3H), 5.19 (s, 1H), 4.05 (s, 2H),
3.29-3.31 (m, 2H), 3.18 (s, 3H), 3.05 (s, 3H), 2.80-2.85 (m, 2H), 2.46 (s, 3H)
1H NMR (300 MHz, MeOD) δ (ppm): 7.96 (s, 1H), 7.74-7.77 (m, 1H), 7.54-7.59 (m, 1H), 7.34 (s, 1H), 7.21-7.28 (m, 1H), 4.10 (s, 2H),
Figure imgf000042_0001
3.19 (s, 3H), 2.96-3.05 (m, 7H), 2.55 (s, 3H), 1.78-1.88 (m, 2H)
1H NMR (300 MHz, CDCI3) δ (ppm): 7.77-7.80 (m, 1H), 7.64 (s, 1H), 7.40-7.44 (m, 1H), 7.21 (s, 1H), 7.01 -7.07 (t, 1H, J = 9.0
Figure imgf000042_0002
Hz), 4.01 (s, 2H), 3.37 (s, 2H), 3.25 (s, 2H), 3.15 (s, 3H), 3.02 (s, 3H),2.43 (s, 3H)
1H NMR (300 MHz, MeOH-d4) δ (ppm): 7.91 (s, 1H), 7.74-7.77 (m, 1H), 7.54-7.59 (m, 1H), 7.29 (s, 1H), 7.21-7.27 (m, 1H), 4.41-4.51 (m, 1H), 4.10-4.17 (m, 2H), 4.07 (s, 2H), 3.96-4.03 (m, 2H), 3.18 (s, 3H), 3.03 (s, 3H), 2.51 (s, 3H)
1H NMR (300 MHz, CDCI3) δ: 7.68-7.70 (2H, m), 7.45 (1H, m), 7.23 (1H, s), 7.03-7.13 (2H, m), 4.14 (1H), 4.02 (2H, s), 3.46 (1H, s), 3.32
1 0 H
(3H), 3.17 (3H, s), 3.04 (3H, s), 2.47 (3H, s), 2.04-2.16 (2H, m)
Figure imgf000043_0001
1H NMR (300 MHz, MeOH-d4 & CDCI3) δ
(ppm): 7.84 (s, 1H), 7.75-7.78 (m, 1H), 7.61 (s, 1H), 7.49-7.54 (m, 1H), 7.15-7.21 (t, 1H, J = 8.7 Hz), 4.09 (s, 1H), 3.85-3.88 (m, 1H), 3.76-3.81 (m, 1H), 3.60-3.65 (m, 1H), 3.21 (s, 3H), 3.06 (s, 3H), 2.53 (s, 3H)
In the above Table 1 , compounds 018, 025, 027, 036, 037, 039, 044, 045, 053 are prepared according to Scheme 1 ; compound 112 is prepared according to Scheme 2 and Eample 3; and other compounds are prepared according to Scheme 2. Effects Example: Test experiments of the compounds of the present invention
1. Tumor cell growth inhibition experiment
Materials and Methods
The materials used in the tumor cell growth inhibition experiment of the present invention are shown in Table 2 below, wherein the cells are all obtained from CAS (Cell Bank of the Chinese Academy of Sciences (Shanghai, China)), and the cell growth is tested with CCK-3 test agent (DojinDo, CK04-20).
Table 2
Figure imgf000044_0001
Inoculation of cells: cells of logarithmic growth phase are digested with 0.25% pancreatin, formulated into single cell suspension with RPMI1640 media comprising 10% FBS. Cells are counted on Invitrogen Countess. Cells shown in the above table are inoculated on a 96-well plate according to the cell inoculation number shown in the above table at 100 μΐ/well. 100 of the culture media is added for the blank control group. The plate is placed in an incubator and incubated overnight at 37 °C, 5% C02.
Treatment with drugs: Each test compound is 5 -fold diluted in 6 concentrations from 10 μΜ, and each concentration is tested in duplicate. The test sample is gradiently diluted with culture media to 2 folds of the final concentration. The culture plate is taken out, and the media containing the test compound in 2 folds of the final concentration is added at 100 μΐ/well. The 96-well plate is returned to the incubator and incubated at 37 °C, 5% C02 for 72 hours. For the control group, culture media containing no drug is added.
Development and Calculation of IC50 : After incubation for 72 hours, the 96-well plate is taken out from the incubator. The culture media in the wells are discarded, and fresh media containing 10% CCK-8 are added at 100 μΐ/well. After adding, the 96-well plate is returned to the incubator and incubated for another 1-4 h until it obviously turns to orange red. The light absorbance at 450 nm is measured to make the absorbance between 1 and 1.8. Cell growth = (OD value of the treatment group - OD value of the control group)/(OD value of the control group - OD value of the blank control group) * 100%. The data are logistically fitted with origin8 to calculate the IC50 value of the corresponding sample. The lower the IC50 indicates the more significant of the inhibition of the drug on the cell growth.
The inhibition activities of some compounds in Table 1 on melanoma cell A375 are shown in Table 3A.
Table 3 A. Activity IC o
Compounds Activities Compounds Activities Compounds Activities Compounds Activities
001 002 ** 003 004
005 ** 006 007 * 008 **
009 * 010 011 012 *
013 014 015 ** 016 # # # #
017 * 018 ** 019 ** 020 *
021 * 022 ** 023 * 024 **
025 * 026 027 ** 028 **
029 ** 030 ** 031 * 032 *
033 034 035 ** 036 **
037 ** 038 ** 039 040 * 041 ** 042 ** 043 ** 044 *
045 ** 046 ** 047 ** 048 **
049 * 054 * 051 052
053 058 * 055 ** 056
057 ** 062 ** 059 * 060
061 ** 066 063 064 **
065 070 ** 071 ** 068 **
069 ** 074 * 075 * 072 *
073 * 078 * 079 * 076 *
077 * 082 083 ** 080 *
081 * 090 091 084 *
085 ** 112 ** 099 ** 092
093 ** 106 ** 099 ** 104 **
indicates: IC5o> 1 μΜ
indicates: IC50=0.1 μΜ~ 1 μΜ
indicates: IC50=0.01 μΜ~0.1 μΜ
****indicates: IC50< 0.01 μΜ
The above in vitro test results indicate that the compound of formula (I) of the present invention have the activities for inhibiting the growth of A375 tumor cells, wherein some of the compounds show strong activities.
The inhibition activities of some compounds in Table 1 on rectal cancer cell Colo-205 are shown in Table 3B.
Table 3B. Activity IC^n
Figure imgf000046_0001
indicates: IC5o> 1 μΜ
indicates: IC50=0.1 μΜ~ 1 μΜ The above in vitro test results indicate that the compound of formula (I) of the present invention have the activities for inhibiting the growth of Colo-205 tumor cells.
Some of the compounds in Table 1 are tested for their inhibition activities on various tumor cells (see Table 4).
Table 4: Activity IC^n (nM)
Figure imgf000047_0001
indicates: ICso> 1 μΜ
indicates: IC50=0.1 μΜ~ 1 μΜ
indicates: IC50=0.01 μΜ~0.1 μΜ
The above in vitro test results indicate that the representative compounds of the present invention have inhibition activities on the growth of various tumor cells.
Some of the compounds in Table 1 are tested for their inhibition activities on normal cells (see Table 5).
Table 5
Figure imgf000047_0002
The above in vitro test results indicate that the representative compounds of the present invention have no obvious inhibition activities on normal cell Hs27, suggesting good safety.
2. Research on the stabilities of the compound of the present invention in liver microsome (method for testing the in vitro metabolic stabilities of the compound of the present invention)
The test compound of the present invention is dissolve in actonitrile or acetonitrile-water (1/1 , V/V) to prepare a 1 mM stock solution. 2 μΐ of the stock solution is added into a centrifuge tube, followed by adding 148 μΐ of phosphate buffer (50 mM, pH 7.4) and 10 μΐ of liver microsome (protein concentration: 20 mg/ml) suspension, mixed up, and pre-incubated in a 37 °C water bath for 3 min. Then 40 μΐ of a NADPH generation system (containing NADP+: 6.5 mM, glucose-6-phosphate: 16.5 mM, MgCl2: 16.5 mM, glucose-6-phosphate dehydrase: 2 U/ml) is added to initiate the reaction. After incubation in a 37 °C water bath for 0.5 h, 400 μΐ of acetonitrile is added to terminate the reaction. The mixture is vortex shaked for 3 min, and centrifuged (13000 rpm) for 5 min. The supernatant is tested with HPLC for the residue drug concentration Cr.
Parallel prepared 0-min sample: After pre-incubting the mixed system at 37 °C for 3 min, 400 μΐ of actonitrile is added, followed by addition of 40 μΐ of the NADPH generation system. The mixture is vortex shaked for 3 min, and centrifuged for 5 min. The supernatant is tested with HPLC for the drug concentration Co.
The residue percentage of the drug in the incubated system is calculated according to the following equation:
Drug residue (%) = Cr ÷ C0 x 100 %
Some of the compounds listed in Table 1 are tested for their stabilities in liver microsome (see Table 6). Table 6
Figure imgf000048_0001
The test results in Table 6 indicate that the representative compounds of formula (I) of the present invention are stable in liver microsome environment. 3. The research on the pharmacokinetics of the compounds in rats
Male SD rats are purchased and adaptive feeding in this laboratory for 7 days. 8 SD rats were randomly divided into 2 groups, with 4 in each group, one for intragastric administration, the other for tail intravenous administration. The rats in the intragastric administration group should be fasted overnight before administration. After administration, blood samples are collected from orbital venous plexus at the following time points: 0 min (before administration), 5 min, 15min, 30min, 1 h, 2 h, 3 h, 5 h, 7.5 h, 24 h. The amount of collected sample at each time point is about 300 μΐ. The collected blood samples are centrifuged at 12000rpm for 5 min at 4°C. The upper layer of plasma samples are taken and stored in a freezer at -20 °C for the test. The summary of the experimental procedure is shown in Table 7.
Table 7
Intragastric administration
Items Intravenous administration group
group
Concentration of 1.25 mg/ml
administered
preparations
Adminisration
DMSO/PEG-400/physio logical saline (10/70/20)
media
Test animals 3 SD rats in each group
Dosage 2.5 mg/kg 5 mg/kg
Time points for 0 min (before administration), 5 min, 15min, 30min, 1 h, 2 h, 3 h, 5 h, blood sampling 7.5 h, 24 h
The concentrations of the compounds in the plasma are tested by LC-MS/MS. The pharmacokinetical parameters are calculated with WinNonlin software.
Compound 053 in Table 1 is test as decribed above to determine that its bioavailability is 98%, indicating a very good bioavailability for this compound.
4. Tumor growth inhibition experiments in animals
Monolayer cultured cells (see Table 2 for their sources) are digested and detached, and diluted to cell suspensions with certain concentrations, which are subcutaneously transplanted to right side body of the nude mice with a 1 ml syringe. When the tumor grows to a volume of 500-600 mm , it is taken out, and opened. Well grown without degeneration and necrosis, light red, and fish-flesh-like tumor tissues are selected and cut into small pieces (about 5 x 5 x 5 mm). Nude mouse are incised at outer side of the back, and the tumor pieces are placed subcutaneously in the incision with a 12G inoculation needle. After the tumor piece is passged 2-3 generations, it can be used for evaluating the efficacy of the anti-tumor drug. After the tumor in the mice grows to a volume of 100-150 mm , the animals with well-grown tumors are randomly grouped, and administered, with the administration protocol shown in Table 8. The frequency for testing the diameter of the tumor after grouping is determined depending on the growth conditions of the transplanted tumor, and is normally 2-3 times per week. The weight of the mice should be measured along with each testing. The equation for calculating the volume of the tumor: TV (mm ) = long diameter (a) x short diameter (b) /2. The experiment is normally terminated 24 to 48 hours after the last administration. The tumor growth inhibition rate is calculated according to the equation: TGI = (TVctri - TVtre) / TVctri x 100%.
Table 8
Figure imgf000050_0001
Compound 053 in Table 1 is tested for its tumor growth inhibition. The TGIs determined according to the method shown in Table 8 are: 77% for A375; 65.6% for MDA-MB-231 ; and 75% for Bx-PC-3. No significant decrease in body weight of the animals is observed, indicating that this compound has good in vivo anti-tumor efficacy, as well as good safety.
5. In vitro anti-inflammatory activities
1. Examperimental materials
1.1. Cell lines
RAW264.7 (rat macrophage; ATCC No. TIB-71) purchase from Peking Union Medical College
1.2. Culture medium
DMEM (Gibco #11995) supplemented with 10% fetal bovine serum (FBS, Gibco #)
1.3. Reagents
LPS (Sigma, # L6529-1MG); rat TNF-a ELISA kit (DKW12-2720-096)
1.4. Instruments
Cytometer (invitrogen, C I 0227); enzyme-labeling instrument (Tecan IF200)
2. Experimental method
2.1. Cell inoculation
RAW264.7 cells are inoculated in a 96-well plate at a density of 3 x 105 οεΐΐβ/ΐθθμΐ/ννεΐΐ 96, and cultured at 37 °C for about 6 hours.
2.2. Drug pretreatment: Each test compound is 5-fold gradiently diluted in 6 concentrations from 50 μΜ, and each concentration is tested in duplicate. Pretreatment lasts for 2 hours.
2.3. LPS stimulation: LPS with a final concentration of 30 ng/ml is added to stimulate the cell for about 16 hours.
2.4. TNF-a test
16 Hours after the LPS stimulation, the sample is centrifuged at 3,000 rpm for 10 min. The supernatant is collected and diluted about 100-folds. The TNF-a level is tested with mouse: TNF-a ELISA kit.
2.5. Analysis of the results
Excel 2007, OriginPro 8.0.
3. Use of ELISA
3.1. Before use, all the reagents are uniformly mixed, avoiding foam formation.
3.2. The number of strips is determined depending on the number of the experimental wells (blank and standards). The samples (including standards) and the blank are tested in duplicate.
3.3. Adding sample: Diluted TNF-a standards are added to standard wells at 100 μΐ/well; the samples are added in the sample wells at 100 μΐ/well; and blank wells are set.
3.4. Adding test antibody: Diluted Biotinylated antibody is added at 50 μΐ/well. After mixing uniformly, the plate is covered, and incubated at 37 °C for 90 min.
3.5. Washing plate: The liquid in the wells is discarded, and l x washing buffer is added at 300 μΐ/well. After maintaining for 1 min, the liquid in the wells are discarded. The procedure is repeated for 4 times, then the plate is dried over a filter paper.
3.6. Adding enzyme: Diluted Streptavidin-HRP is added at 100 μΐ/well. The plate is covered, and incubated at 37 °C for 30 min.
3.7. Washing plate: The liquid in the wells is discarded, and l x washing buffer is added at 300 μΐ/well. After maintaining for 1 min, the liquid in the wells are discarded. The procedure is repeated for 4 times, then the plate is dried over a filter paper.
3.8. Development: TMB is added at 100 μΐ/well. The plate is incubated at 37 °C for 20 min. Terminating liquid is added, and the absorbance at 450 nm is determined within 10 min.
4. References
Funakoshi, T., et al. (2012) A novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates inflammatory colonic injury in mice, J Crohns Colitis, 6, 215-225.
Sae-Wong, C, et al. (2011) Suppressive effects of methoxyflavonoids isolated from Kaempferia parviflora on inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells, J Ethnopharmacol, 136, 488-495.
Sun, B.W., et al. (2010) [Inhibitive effect of exogenous carbon monoxide-releasing molecules 2 on the activation of Janus kinase/signal transducer and activator of transcription pathway in sepsis], Zhonghua Shao Shang Za Zhi, 26, 100-103.
Yu, T., et al. (2012) The ability of an ethanol extract of Cinnamomum cassia to inhibit Src and spleen tyrosine kinase activity contributes to its anti-inflammatory action, J Ethnopharmacol, 139, 566-573.
Compound 053 in Table 1 is tested for its in vitro anti-inflammatory activity. The EC50 is 86 nM, indicating this compound has very good in vitro anti-inflammatory activity.
A person skilled in the art would understand that any change or modification made without departing from the scope and spirit of the present invention as defined in the appending Claims are all within the scope of protection of the Claims of the present invention.

Claims

We claim:
1. A compound of formula (I)
Figure imgf000053_0001
(I)
wherein:
X is selected from heteroaryl optionally substituted with Ci_6 alkyl or halogen, and R5R6NCO-;
Yi, Y2 and Y3 are each independently selected from -N= and -CR7=;
Ri is selected from H, halogen, Ci_6 alkyl;
R2 is selected from Ci_6 alkyl optionally substituted with hydroxyl;
R and R4 are each independently selected from H, OH, NH2, Ci_6 alkyl, C3_8 cycloalkyl, C6-io aryl, heterocyclyl, -COR8, -NHCOR8, -CONR9R10, wherein said heterocyclyl is optionally substituted with OH or Ci_6 alkyl, said Ci_6 alkyl is optionally substituted with a substituent selected from: halogen, OH, COOH, NH2, Ci_6 alkoxy, heterocyclyl, heteroaryl, -COOR8, -NR9R10 and -CONR9R10; or
R3 and R4, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_6 alkyl; or
-NR3R4, as a whole, forms alkyl ene amino substituted with di(Ci_6 alkyl)amino;
R5 and R6 are each independently selected from H, Ci_6 alkyl, C3_8 cycloalkyl, C6-io aryl; or R5 and R6, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom;
R7 is selected from H, OH, halogen, Ci_6 alkyl;
each R8 is independently selected from Ci_6 alkyl and heterocyclyl;
each R and Rio is independently selected from H and Ci_6 alkyl, or R9 and Rio, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_6 alkyl,
or a pharmaceutically acceptable salt or solvate thereof.
2. The compound of Claim 1 , wherein:
X is pyrimidin-2-yl optionally substituted with Ci_6 alkyl or halogen; Yi, Y2 and Y3 are each independently -CR7=;
Ri is selected from H, halogen, Ci_6 alkyl;
R2 is selected from Ci_6 alkyl;
R3 and R4 are each independently selected from H, Ci_6 alkyl, -CONR9R10;
R7 is selected from H, halogen;
R and Rio are independently selected from H and Ci_6 alkyl, or R and Rio, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_6 alkyl,
or a pharmaceutically acceptable salt or solvate thereof.
3. The compound of Claim 1 , wherein:
X is R5R6NCO-, wherein R5 and R6 are both Ci_6 alkyl;
Yi, Y2 and Y3 are each independently -CR7=;
Ri is selected from H, halogen, Ci_6 alkyl;
R2 is selected from Ci_6 alkyl optionally substituted with hydroxyl;
R3 and R4 are each independently selected from H, OH, NH2, Ci_6 alkyl, C3_8 cycloalkyl, heterocyclyl, -COR8, -NHCOR8, -CONR9R10, wherein said heterocyclyl is optionally substituted with OH or Ci_6 alkyl, said Ci_6 alkyl is optionally substituted with a substituent selected from: halogen, OH, COOH, NH2, Ci_6 alkoxy, heterocyclyl, heteroaryl, -COOR8, -NR9R10 and -CONR9R10; or
R3 and R4, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_6 alkyl;
R7 is selected from H, OH, halogen;
each R8 is independently selected from Ci_6 alkyl and heterocyclyl;
each R9 and Rio is independently selected from H and Ci_6 alkyl, or R9 and Rio, together with the nitrogen atom to which they attach, form 4- to 6-membered heterocyclyl having at least one nitrogen atom and optionally substituted with Ci_6 alkyl,
or a pharmaceutically acceptable salt or solvate thereof.
4. The compound of Claim 1 , wherein the compound is selected from:
dimethylcarbamic acid 2-oxo-2H-3-(3-methylaminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -(N,N-dimethylaminocarbonyl)(methyl)amino sulfonyl) benzyl-4-methyl-6-chloro-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-iso-propylaminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester; dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(iso-propylaminosulfonyl)benzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-methylaminosulfonylbenzyl)-4-methyl-l- benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-methylaminosulfonylbenzyl)-4-methyl-6- methyl-l -benzopyran-7-yl ester;
pyrimidin-2-yl 2-oxo-2H-3-(3-methylaminosulfonylbenzyl)-4-methyl-6-chloro-l- benzopyran-7-yl ether;
dimethylcarbamic acid 2-oxo-2H-3-(3-methylaminosulfonylbenzyl)-4-methyl-6- f uoro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(carboxylmethyl)(methyl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(hydroxypropyl)(methyl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(methylaminocarbonylmethyl)(methyl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(ethoxycarbonylethyl)(methyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(hydroxyethyl)(methyl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(dimethylaminocarbonylmethyl)(methyl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(2,2,2-trif uoroethyl)aminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(aminocarbonylmethyl)(methyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(carboxyethyl)(methyl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-aminosulfonylbenzyl)-4-methyl-6-chloro-l - benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(2,2,2-trif uoroethyl)aminosulfonylbenzyl)-4- methyl-6-f uoro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoropropyl)aminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(2,2,2-trif uoroethyl)aminosulfonylbenzyl)-4- methyl- l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(2,2,2-trif uoroethyl)aminosulfonylbenzyl)-4- methyl-6-methyl- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(6-f uoro-3-cyclopropylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoropropyl)aminosulfonylbenzyl)-4- methyl-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(6-f uoro-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-aminosulfonylbenzyl)-4-methyl-6-chloro-l - benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-aminosulfonylbenzyl)-4-methyl-6-methyl-l - benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -cyclopropylaminosulfonylbenzyl)-4-methyl- 1 - benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoropropyl)aminosulfonylbenzyl)-4- methyl-6-fiuoro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -cyclopropylaminosulfonylbenzyl)-4-methyl-6- methyl-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(6-f uoro-3-(2,2,2-trifluoroethyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(6-f uoro-3-(dimethylaminoethylaminosulfonyl) benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(N-dimethylaminoethylaminosulfonyl)benzyl)- 4-methyl-6-methyl- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(N,N-bis(dimethylaminoethyl)aminosulfonyl) benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -cyclopropylaminosulfonylbenzyl)-4-methyl-6- f uoro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-aminosulfonylbenzyl)-4-methyl-6-f uoro-l- benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-aminosulfonylbenzyl)-4-methyl-l-benzopyran- 7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoropropylaminosulfonyl)benzyl)-4- methyl-6-methyl- 1 -benzopyran-7-yl ester; dimethylcarbamic acid 2-oxo-2H-3-(3-(dimethylaminoethylaminosulfonyl)benzyl)-4- methyl-6chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2,6-dif uoro-3-cyclopropylaminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(N,N-bis(methylaminocarbonylmethyl)amino sulfonyl)benzyl)-4-methyl-6-methyl- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(dimethylaminocarbonylmethylaminosulfonyl) benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -(N,N-bis(aminocarbonylmethyl)aminosulfonyl) methylaminosulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2,6-dif uoro-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(dimethylaminoalkyleneaminosulfonyl)benzyl)- 4-methyl-6-f uoro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(dimethylaminopropylaminosulfonyl)benzyl)- 4-methyl- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(aminocarbonylmethylaminosulfonyl)benzyl)- 4-methyl-6-methyl- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(dimethylaminoethylaminosulfonyl)benzyl)-4- methyl-6-f uoro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -(N,N-bis(aminocarbonylmethyl)aminosulfonyl) benzyl)-4-methyl- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-dimethylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-f uoro-3-cyclopropylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(N,N-bis(methylaminocarbonylmethyl)amino sulfonyl)benzyl)-4-methyl-6-fluoro-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(N,N-bis(methylaminocarbonylmethyl)amino sulfonyl)benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-f uoro-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(3-(aminocarbonylmethylaminosulfonyl)benzyl)- 4-methyl-6-fluoro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3 -(3 -(N,N-bis(aminocarbonylmethyl)aminosulfonyl) benzyl)-4-methyl-6-fluoro-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2,6-dif uoro-3-dimethylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-methylpiperidinylsulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-phenylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-morpholinylsulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-methylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-f uoro-3-methylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-f uoro-3-methylpiperidinylsulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-cyclopropylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-tert-butylcarbonyl hydrazinylsulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-propionylhydrazinylsulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-chloro-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester;
N-methyl-N-ethyl-carbamic acid 2-oxo-2H-3-(4-fluoro-3-aminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
Morpholine carboxylic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl- 6-chloro- 1 -benzopyran-7-yl ester;
Piperidine carboxylic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl- 6-chloro-l -benzopyran-7-yl ester;
N-methyl-N-pehnyl-carbamic acid 2-oxo-2H-3-(4-fluoro-3-aminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
Diiso-propylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester; dimethylcarbamic acid 2-oxo-2H-3-(4-chloro-6-f uoro-3-aminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-6-chloro-7-(p-methylpyrimidin-2-yl oxy)-2-oxo-2H- 1 -benzopyrane;
3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-l- benzopyrane;
3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-6-chloro-7-(p-ethylpyrimidin-2-yloxy)- 2-oxo-2H-l -benzopyrane;
3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-7-(p-methylpyrimidin-2-yloxy)-2-oxo- 2H- 1 -benzopyrane;
3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-7-(p-ethylpyrimidin-2-yloxy)-2-oxo- 2H- 1 -benzopyrane;
dimethylcarbamic acid 2-oxo-2H-3-(2,4-difluoro-3-methylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-l- benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-hydrazinylsulfonylbenzyl)-4-methyl- 6-chloro-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-methyl-6- f uoro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-hydroxy-3-aminosulfonylbenzyl)-4-methyl-6- chloro-l-benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-hydroxyethylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-dimethylaminoethylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-tert-butylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-hydroxyaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-dimethylaminocarbonylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-fluoro-3-piperidinylcarbonylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-fluoro-3-morpholinylcarbonylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
3-(4-fluoro-3-aminosulfonylbenzyl)-4-methyl-6-chloro-7-(p-chloropyrimidin-2-yl oxy)-2-oxo-2H- 1 -benzopyrane;
3-(4-fluoro-3-aminosulfonylbenzyl)-4-methyl-6-chloro-7-(pyrimidin-2-yloxy)-2-oxo- 2H- 1 -benzopyrane;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-acetamidosulfonylbenzyl)-4-methyl- 6-chloro-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-f uoro-3-acetamidosulfonylbenzyl)-4-methyl- 6-chloro-l -benzopyran-7-yl ester;
3-(4-f uoro-3-piperidinylcarbonylaminosulfonylbenzyl)-4-methyl-6-chloro-7- (pyrimidin-2-yloxy)-2-oxo-2H- 1 -benzopyrane;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-piperidinylcarbonylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-morpholinylcarbonylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
3-(4-f uoro-3-morpholinylcarbonylaminosulfonylbenzyl)-4-methyl-6-chloro-7- (pyrimidin-2-yloxy)-2-oxo-2H- 1 -benzopyrane;
dimethylcarbamic acid 2-oxo-2H-3-(2-fluoro-3-methylpiperazinylcarbonylamino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
3-(4-f uoro-3-morpholinylcarbonylaminosulfonylbenzyl)-4-methyl-7-(pyrimidin-2-yl oxy)-2-oxo-2H- 1 -benzopyrane;
3-(4-f uoro-3-piperidinylcarbonylaminosulfonylbenzyl)-4-methyl-7-(pyrimidin-2-yl oxy)-2-oxo-2H- 1 -benzopyrane;
3-(4-f uoro-3-N-methylaminocarbonylaminosulfonylbenzyl)-4-methyl-6-chloro-7- (pyrimidin-2-yloxy)-2-oxo-2H- 1 -benzopyrane;
3-(4-f uoro-3-N-methylaminocarbonylaminosulfonylbenzyl)-4-methyl-7-(pyrimidin-2- yloxy)-2-oxo-2H-l -benzopyrane;
dimethylcarbamic acid 2-oxo-2H-3-(2-fluoro-3-N-methylaminocarbonylaminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-aminosulfonylbenzyl)-4-hydroxyethyl- 6-chloro-l -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-hydroxypropylaminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(methoxyethyl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester; dimethylcarbamic acid 2-oxo-2H-3 -(4-f uoro-3 -(methoxypropyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(morpholinylethyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(methylpiperazinylethyl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(piperidinylethyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-carboxylmethylaminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-carboxyethylaminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(aminocarbonylmethyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(methylaminocarbonylmethyl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(N,N-dimethylaminocarbonylmethyl) aminosulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(N-methylpiperidin-4-yl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(pyridin-4-ylethyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(aminopropyl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(aminoethyl)aminosulfonylbenzyl)-4- methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(azetidin-3-yl)aminosulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(pyrrolidin-3-yl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(piperidin-4-ylethyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(2-fluoro-3-(hydroxyethylamino)sulfonylbenzyl)- 4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-f uoro-3-(methyl)(pyrrolidin-3-yl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(4-hydroxycylcohexyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(methyl)(hydroxyethyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(2,3-dihydroxypropyl)aminosulfonyl benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(hydroxymethyl)(hydroxyethyl)amino sulfonylbenzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester;
dimethylcarbamic acid 2-oxo-2H-3-(4-fluoro-3-(l -aminocarbonyl-2-hydroxyethyl aminosulfonyl)benzyl)-4-methyl-6-chloro- 1 -benzopyran-7-yl ester,
or a pharmaceutically acceptable salt or solvate thereof.
5. A pharmaceutical composition, comprising the compound of any one of Claims 1 -4, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
6. Use of the compound of any one of Claims 1-4, or a pharmaceutically acceptable salt or solvate thereof in the preparation of a pharmaceutical composition for treating proliferative disease or inflammatory disease.
7. The use of Claim 6, wherein the proliferative disease is cancer.
8. The use of Claim 7, wherein the cancer is selected from melanoma, breast cancer, colon cancer, pancreatic cancer and lung cancer.
PCT/CN2012/077019 2011-06-17 2012-06-15 Coumarin derivative, pharmaceutical composition and use thereof WO2012171488A1 (en)

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CN107823200A (en) * 2017-11-14 2018-03-23 三峡大学 Inhibitor application on pharmacy of the coumarin derivative as KLK7
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