WO2012130159A1 - Aminopyridine derivatives and uses thereof - Google Patents

Aminopyridine derivatives and uses thereof Download PDF

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Publication number
WO2012130159A1
WO2012130159A1 PCT/CN2012/073301 CN2012073301W WO2012130159A1 WO 2012130159 A1 WO2012130159 A1 WO 2012130159A1 CN 2012073301 W CN2012073301 W CN 2012073301W WO 2012130159 A1 WO2012130159 A1 WO 2012130159A1
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group
pyridyl
trifluoro
amino
indolyl
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PCT/CN2012/073301
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French (fr)
Chinese (zh)
Inventor
李松
郑志兵
樊士勇
***
钟武
刘洪英
肖军海
谢云德
周辛波
陈伟
李行舟
Original Assignee
中国人民解放军军事医学科学院毒物药物研究所
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Publication of WO2012130159A1 publication Critical patent/WO2012130159A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to an aminopyridine derivative, and in particular to a compound of the formula I or formula II, a process for the preparation thereof and use thereof for the preparation of a medicament for inhibiting excessive proliferation of cells.
  • Cancer is a disease that poses a serious threat to human health. Since the advent of the first anticancer drug, the nitrogen mustard, in the 1940s, scientists have isolated and extracted several natural products with potential cytotoxic activity from plants. Based on this, a variety of clear anti-tumor have been obtained through structural modification. Active compounds in which vinblastine, etoposide, paclitaxel, etc. are successively approved for clinical treatment of cancer. However, these natural product drugs have limited resources, their molecular structures are complex, chemical synthesis is difficult, and it is difficult to scale production. Therefore, there is a need to find small molecule antitumor drugs with structural cartridges. Summary of the invention
  • the present invention is directed to an aminopyridine derivative having an activity of inhibiting cell hyperproliferation.
  • a first aspect of the invention provides a compound of formula I, formula II, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof.
  • one represents an optional bond, provided that one and only one nitrogen atom in the ring is a double R 2 , R 3 , R 4 , R 5 , 11 7 or R 8 are each independently selected from hydrogen, hydroxy , halogen, Amino, nitro, nitrile, trifluoromethyl, -OR 9 , -C(0)R 9 , -C(0)OR 9 , -NR 10 C(O)OR 9 , -OC(0)R 9 -NR 10 SO 2 R 9 , -SO 2 NR 10 R 9 , -NR 10 C(O)R 9 , NR 10 R 9 , d-do alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 1Q cycloalkyl, C 3 -C 1Q cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocycloal
  • R 6 is independently selected from the group consisting of hydrogen, trifluoromethyl, d-do alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 1Q cycloalkyl, C 3 -C 1 ⁇ ring
  • W is independently selected from -OR 9 , -NR 10 OR 9 , -NR 10 SO 2 R 9 and -NR 10 R 9 ;
  • R 9 Each is independently selected from the group consisting of hydrogen, hydroxy, halogen, trifluoromethyl, d-do alkane > 3 ⁇ 4 ⁇ , C - C 10 f ⁇ , C2 - C 10 > C - C 10 ⁇ 3 ⁇ 4 C - C 10 ⁇ 3 ⁇ 4
  • Preferred compounds have the structure of ⁇ , IV
  • Preferred compounds have the structure of V, VI
  • Ri RR 3 , R 4 , R 5 , R 6 , R 7 , R 8 , W, R 9 and R 10 are as defined above.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are independently selected from the group consisting of hydrogen, halogen, nitro, nitrile, trifluoromethyl, dC 6 alkyl, C 3 - C 6 cycloalkyl, C 3 -C 6 Cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl;
  • W is independently selected from -OR 9 , -NR 10 OR 9 or -NR 10 R 9 .
  • the compound is selected from the group consisting of:
  • the invention relates to a method of synthesizing a compound of formula I, II or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, which comprises the synthesis of the following key intermediates:
  • the substituted benzoic acid containing the leaving group L is used as a starting material, and the carboxyl group is thiolated by reacting with a thiolation reagent; and the oxime ester is converted into an amide group by reacting with ammonia water; under the action of P0C1 3 A part of the water is removed to convert the amide bond to a cyano group; the substituted phenyl phthalocyanine containing the leaving group L is removed from the group by the action of a base such as a radical lithium. Carrying out a condensation reaction; hydrolyzing a cyano group to obtain a carboxyl group, and reacting a carboxyl group with a corresponding side chain to obtain a compound I;
  • L indicates the departure group, which can be a prime
  • the substituted benzoic acid containing the leaving group L is used as a starting material, and after the nitration reaction, a nitro group is introduced on the benzene ring; under the action of a base (for example, lithium), the group is removed and the substituted amino group is removed.
  • the pyridine compound undergoes a condensation reaction; under the action of ammonia water, an amino group is introduced into the benzene ring; after reacting with a thiolation reagent, a few groups are thiolated; after the nitro group is reduced to an amino group, a ring-forming reaction is carried out to obtain a deoximation ester.
  • a key intermediate containing a carboxyl group the carboxyl group is reacted with a corresponding side chain moiety to give a compound of formula II;
  • L represents the leaving group and can be halogen
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , W, R 9 and R 10 are as defined in the first aspect of the invention.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula i, a hydrazine compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, and a pharmaceutically acceptable carrier.
  • the -CH) alkyl group in the present invention means a straight or branched alkyl group having 1 to 10 carbon atoms, such as an anthracenyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group or a sec-butyl group.
  • Base tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-decylpentyl, heptyl, octyl and the like.
  • a preferred alkyl group is a d-alkyl group.
  • a more preferred alkyl group is dC 3 alkyl.
  • Alkenyl means an alkenyl group having 2 to 10 carbon atoms and at least one double bond, and includes ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hexyl- 5-alkenyl and the like. More preferred are lower alkenyl groups having 2 or 3-5 carbon atoms;
  • the C 2 -C 1Q alkynyl group means a hydrocarbon group having 2 to 10 carbon atoms and at least one hydrazone bond, and includes, for example, an ethyl group, a propynyl group, a butyl group, a pentyn-2-yl group and the like. More preferred are alkynyl groups having 3-5 carbon atoms; Halogen means fluorine, chlorine, bromine and iodine atoms;
  • An aryl group means a fused ring having a single ring (such as a phenyl group), a polycyclic ring (such as a biphenyl group), or at least one of which is aromatic (for example, 1, 2, 3, 4-tetrahydronaphthyl,
  • An anthranyl carbocyclyl group optionally substituted by, for example, a sulfonyl group, a lower alkyl group (for example, an alkyl group), a lower alkoxy group (for example, an alkoxy group), a trifluoromethyl group, or an aryl group.
  • Heteroaryl refers to one or more aromatic ring systems of a 5, 6 or 7 membered ring comprising a 5-10 atom fused ring system (wherein at least one ring is aromatic), said ring system containing At least one and up to four heteroatoms selected from nitrogen, oxygen or sulfur.
  • heteroaryl groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, iso Thiazolyl, pyrrole ring, quinoline ring, isoquinoline ring, anthracene ring, benzimidazole, benzofuran ring, benzothiophene ring, benzothiazole ring, pyridazine ring and the like.
  • a pharmaceutically acceptable group for example, a lower alkyl group (for example, a d-alkyl group), a lower alkoxy group (for example, an alkoxy group), a trifluoromethyl group, an aryl group, a heteroaryl group, and a hydroxy group.
  • a pharmaceutically acceptable group for example, a lower alkyl group (for example, a d-alkyl group), a lower alkoxy group (for example, an alkoxy group), a trifluoromethyl group, an aryl group, a heteroaryl group, and a hydroxy group.
  • a carbocyclic ring, a carbocyclic group, a cycloalkyl group, a C 3 -C 1Q cycloalkyl group means a saturated carbocyclic group having 3 to 10 carbon atoms.
  • the cycloalkyl group can be a monocyclic or polycyclic fused system and can be fused to the aromatic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the cycloalkyl groups herein may be unsubstituted or substituted by various groups at one or more substitutable positions, as described in detail.
  • these cycloalkyl groups may be optionally substituted by the following groups: Cr alkyl group, d-Ce alkoxy group, nitrile group, halogen, hydroxy group, amino group, nitro group, mono(d-Ce)alkylamino group, two ( d-Ce)alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, d-Ce halo pit, d-Ce halo pit;
  • Heterocyclic or heterocyclic group means one or more carbocyclic ring systems of a 5, 6 or 7 membered ring comprising a fused ring system of 4 to 10 atoms, said ring system containing at least one and up to four selected A hetero atom from nitrogen, oxygen or sulfur, provided that the ring of the group does not contain two adjacent O or S atoms.
  • the fused ring system may be a heterocyclic ring fused to an aromatic group.
  • Preferred heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophene, piperidinyl, morpholine, cyclohexyl, pyrazine ring, dioxolane (eg 1, 3- Dioxolane) and the like, which may be substituted by the following groups: d-Ce alkyl, d-Ce alkoxy, nitrile, halogen, hydroxy, amino, nitro, mono(-C6)alkylamino, two (d-)alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 haloalkyl, dC 6 haloalkoxy;
  • Arylalkyl means an alkyl group (as defined above) substituted by one or more (as defined above) aryl groups.
  • Heteroarylalkyl means an alkyl group (as defined above) substituted by a heteroaryl group (as defined above). More preferred heteroarylalkyl groups are 5- or 6-membered heteroaryl-d-alkyl groups. Examples include pyridylethyl and the like;
  • Heterocyclylalkyl means an alkyl group (as defined above) substituted by a heterocyclic group (as defined above).
  • a more preferred heterocyclylalkyl group is a 5- or 6-membered heterocyclyl-d-alkyl group. Examples include tetrahydropyranyl fluorenyl;
  • Cycloalkylalkyl refers to an alkyl group (as defined above) substituted by a cycloalkyl group (as defined above). More preferred heterocyclic groups are 5- or 6-membered cycloalkyl-d-alkyl groups. Examples include cyclopropyl fluorenyl;
  • the compounds of the invention may also be used in the form of their pharmaceutically acceptable salts or solvates.
  • Physiologically acceptable salts of the compound of formula I or formula II include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and quaternary ammonium acid addition salts.
  • Suitable acid salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, citric acid, lactic acid, maleic acid, Tartaric acid, citric acid, citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, sulfonic acid, naphthalene 2-sulfonate Salts of acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroquinone, malic acid, steroi citric acid, and the like.
  • acids such as oxalic
  • suitable base salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, N-decyl glucosamine and procaine salt.
  • Some of the compounds in the present invention may be crystallized or recrystallized with water or various organic solvents, in which case various solvates may be formed.
  • the present invention includes those stoichiometric solvates, such as hydrates, as well as compounds containing variable amounts of water formed upon preparation by low pressure sublimation drying.
  • the invention also includes prodrugs of the compounds of the invention which, once administered, pass The metabolic process undergoes chemical conversion and then becomes an active drug.
  • prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula I or formula II.
  • Conventional methods for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design Of Prodrugs", H Bund Saard, Elsevier, ed., 1985.
  • the invention also includes active metabolites of the compounds of the invention.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a racemate or an optical isomer of a compound of the invention and at least one pharmaceutically acceptable carrier which is useful for in vivo treatment and is biocompatible.
  • the pharmaceutical composition can be prepared in various forms depending on the route of administration.
  • the compounds mentioned in the present invention can also be prepared into various pharmaceutically acceptable salts.
  • compositions of the present invention comprise an effective amount of a compound of formula I or formula II of the present invention, or a pharmaceutically acceptable salt or hydrate thereof, and one or more suitable pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated plants.
  • composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Inside, intraventricular, intrasternal and intracranial injection or input or by means of an explant reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsule preparation generally comprises lactose and dried corn starch.
  • Aqueous suspension formulations are usually those in which the active ingredient is admix If desired, some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.
  • the hair When applied topically, especially in the treatment of facial or organs easily accessible by topical application, such as eye, skin or lower intestinal neuropathy, the hair may be according to different affected faces or organs.
  • the compounds are prepared in different topical formulations, as specified below:
  • the compounds of the invention When applied topically to the eye, the compounds of the invention may be formulated in the form of a micronized suspension or solution in which the carrier is isotonic at a certain pH. Sterile saline, with or without preservatives such as benzyl chloride alkoxide.
  • the compound can also be formulated in the form of a cream such as a Vaseline cream.
  • the compounds of the invention When applied topically to the skin, the compounds of the invention may be formulated in a suitable cartilage, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers which may be used in ointment preparations include, but are not limited to, mineral oil, liquid petroleum jelly, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents or creams which may be used include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile injectable aqueous or oily suspension or sterile injectable solutions.
  • a sterile injectable preparation including sterile injectable aqueous or oily suspension or sterile injectable solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament for inhibiting cell hyperproliferation.
  • the cell hyperproliferation includes diseases such as leukemia, glioblastoma, lymphoma, melanoma, cancer, neuropathic pain, inflammation, and the like.
  • the inhibiting cell hyperproliferation means inhibiting tumor cell proliferation.
  • the invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament for the treatment of tumors and/or cancer.
  • the invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament for the prevention and/or treatment of a cell hyperproliferative disorder.
  • the invention also relates to a method of preventing and/or treating a tumor and/or cancer comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate thereof, Optical isomer or N-oxide.
  • the invention also relates to a method of preventing and/or treating a cell hyperproliferative disorder comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate thereof, Optical isomer or N-oxide.
  • the cell hyperproliferative disease includes a tumor (benign or malignant) Tumors and/or diseases such as cancer, neuropathic pain, inflammation, etc.
  • the tumor and/or cancer described therein may be any tumor and/or cancer known in medicine.
  • the tumor and/or cancer includes but is not limited to:
  • Malignant tumors including but not limited to bladder cancer, breast cancer, colon cancer, kidney cancer, lung cancer (including small cell lung, non-small cell carcinoma), head and neck cancer, esophageal cancer, biliary cancer, stomach cancer, cervical cancer, Sickle adenocarcinoma, prostate cancer and skin cancer (including squamous cell carcinoma);
  • Hematopoietic tumors of the lymphatic system including but not limited to leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hair Cellular lymphoma, mantle cell lymphoma, myeloma, and Burketfs' lymphoma;
  • Hematopoietic tumors of the myeloid system including but not limited to acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia;
  • Tumors of interstitial origin including but not limited to fibrosarcoma and rhabdomyosarcoma;
  • Centrally occurring tumors including but not limited to fibrosarcoma and rhabdomyosarcoma;
  • Tumors of the central and peripheral nervous system including astrocytoma, fibrosarcoma, neuroglioma, and schwannomas;
  • tumors including but not limited to melanoma, seminoma, teratocarcinoma, osteosarcoma, femoral stromal tumor, xenoderoma pigmentosum, squamous cell carcinoma and Kapos sarcoma.
  • the compounds of the present invention are effective for inhibiting excessive proliferation of cells and are useful for treating hyperproliferative diseases in mammals such as various tumors, cancer, neuropathic pain, inflammation and the like. detailed description
  • 2,3,4,5-Tetrafluorobenzoic acid (48.5 g, 0.25 mol) was dissolved in 130 mL of anhydrous decyl alcohol, and trimethyl chlorosilane (63 mL, 0.50 mol) was slowly added dropwise. After the addition was completed, reflux was carried out for 12 h. The pump is distilled off under reduced pressure and the excess trimethyl chlorosilane is obtained as a pale yellow liquid.
  • Dichloromethane 200 mL is added and washed with a 10% aqueous sodium hydroxide solution, and the aqueous layer is combined with dichloromethane. The organic layer was dried over anhydrous sodium sulfate overnight.
  • 2,3,4,5-tetrafluorobenzamide (5 g, 0.026 mol) was added to 20 mL of anhydrous acetonitrile, phosphorus oxychloride (16. 6 g, 0.11 mol) was added, and the temperature was raised to 70 ° C. 1.5 h.
  • the reaction solution was slowly added dropwise to a 200 mL water-water mixture, which was strongly exothermic, and the temperature was controlled to be not higher than 30 by controlling the dropping rate. After the completion of the dropwise addition, the mixture was stirred at room temperature for 0.5 h, extracted with ethyl acetate, and the organic layer was dried overnight.
  • 2-J ⁇ -3-chloro-5-bromopyridine (10.30 g, 0.050 mol) and lithium amide (4.58 g, 0.20 mol) were added to 150 mL of diphenylbenzene under nitrogen atmosphere and heated to 100 °C. , stir the reaction for 2 h. Naturally, the temperature was lowered to room temperature, 2,3,4,5-tetrafluorobenzonitrile (7.33 g, 0.042 mol) was added, and the mixture was heated to 126 ° C for 3.5 h. The reaction solution was added to 100 mL of ethyl acetate and stirred for 10 min to yield a large white solid.
  • Example 22 N-[2-(Acridin-1-yl)ethyl b 3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino]phenyl hydrazide
  • the same procedure as in Example 4 gave a dark-yellow solid N-[2-(piperidin-1-yl)ethyl] -3,4,5-trifluoro ⁇ - ⁇ -chloro ⁇ -bromo ⁇ -pyr ⁇ ! ⁇ Benzanamide.
  • the fuming nitric acid (37 mL, 0.78 mol) was slowly added dropwise to concentrated sulfuric acid (200 mL) in a water bath.
  • 2,3,4-trifluorobenzoic acid (109.4 g, 0.62) was added. Mol) and 330 mL of concentrated sulfuric acid.
  • a concentrated sulfuric acid solution of fuming nitric acid was slowly added dropwise to the concentrated sulfuric acid solution of the reaction raw material under water bath conditions. The water bath was removed, and the temperature was naturally raised to room temperature, and the reaction was stirred for 5 hours.
  • reaction solution was slowly added dropwise to a 2000 mL aqueous solution under stirring, stirred at room temperature for 2 h, allowed to stand overnight, and filtered to give a white solid 5-nitro-2,3,4-trifluorobenzoic acid (123.7 g, 90.3%) , ESI-MS m/z: 222.0 [M+1] + step 2, 5-nitro-3,4-difluoro-2-[(5-iodo-3-indolyl-2-pyridyl 1 ⁇ )amino 2-Amino-3-indolyl-5-indole pyridine (10.61 g, 0.045 mol) was dissolved in 70 mL of anhydrous tetrahydrofuran (THF) under a nitrogen-protected solvent, and then cooled to -70.
  • THF anhydrous tetrahydrofuran
  • Step 6 5-[(5- ⁇ -3-indolyl 2-pyridyl 1 ⁇ 4-fluoro-1H-benzimidazole-6-decanoic acid 5--((5- broken-3- ⁇ ) 2-Pyryl 2-pyridyl)amino-4-fluoro-1H-benzimidazole-6-decanoate ( 1.35 g 3.17 mmol) was suspended in methanol (30 mL), 20% NaOH (8 mL), 16 After h, the reaction mixture was cooled to 0 ° C, and 1 NHC1 solution was added dropwise until pH 2-3.
  • a preliminary activity test was carried out on some of the compounds in Examples 1-25 to evaluate the activity of the compounds in inhibiting the proliferation of myeloid leukemia cells (K562) and human colorectal cancer cells (HT-29) tumor cells in vitro.
  • K562 myeloid leukemia cells
  • HT-29 human colorectal cancer cells
  • the adherent cells are digested with 0.25% trypsin for 2-5 min, and the suspension cells are centrifuged (1000 rpm/min), and the single cell suspension is prepared by using the corresponding culture medium to adjust the cell concentration to corresponding Density (lxlO 5 / mL), inoculated in 96-well culture plate, 100 ⁇ well, cultured at 37 ° C, 5 % C0 2 for 24 h, then added the whole medium of the corresponding cells of 80 ⁇ pupil, and then added different concentrations of the affected medium.
  • each treatment is set to 3 repetitions, continue to culture for 72h at 37°C and 5 % C02, then aspirate the supernatant ⁇ per well, then add 5mg/mL thiazolyl blue (MTT) solution ⁇ , 37°C Incubation was continued for 4 h, and finally 10% SDS was added to each well, and incubated at 37 ° C for 5 h under C 2 2 to completely dissolve the MTT crystal.
  • the absorbance per well was measured by an enzyme-linked immunosorbent assay at a wavelength of 570 nm. According to the formula:
  • Inhibition rate (%) (1—the OD value of the test well/the average OD value of the solvent control well) ⁇ 100% Calculate the inhibition rate, and take the logarithm of the concentration of the test compound as the abscissa, and the average value of the cell inhibition rate as the ordinate. Dose-response curve, and use the analysis software to find half of the cells Dosage value (IC 50 ).
  • the medium of K562 cells was 1640+10% FBS, and the medium of HT-29 was DMEM(Hg)+F12+5%FBS 0
  • the drug was dosed to the mother liquor concentration with DMSO (Sigma) before the test and diluted to the desired application concentration with whole medium without factor.
  • Table 1 Inhibitory activity of some compounds on ⁇ 562 and ⁇ -29

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Abstract

Disclosed are aminopyridine derivatives, specifically represented as compounds in formula I or formula II, the preparation method therefor, and the uses thereof in preparing medicines for inhibiting cell hyperproliferation. Also disclosed are pharmaceutical compositions comprising the present compounds. The present compounds are used for treating hyperproliferative diseases such as cancer.

Description

氨基吡啶类衍生物及其用途 技术领域  Aminopyridine derivatives and uses thereof
本发明涉及氨基吡啶类衍生物，具体涉及如式 I或式 II所示的化合 物、 其制备方法以及其用于制备抑制细胞过度增殖的药物的用途。 背景技术  The present invention relates to an aminopyridine derivative, and in particular to a compound of the formula I or formula II, a process for the preparation thereof and use thereof for the preparation of a medicament for inhibiting excessive proliferation of cells. Background technique
癌症是严重威胁人类健康的疾病。 自上世纪 40年代第一个抗癌 药物一一氮芥问世以来， 科学家从植物中分离提取出若干具有潜在细 胞毒活性的天然产物， 在此基础上通过结构修饰获得了多种显示明确 抗肿瘤活性的化合物， 其中长春碱、 依托泊苷、 紫杉醇等相继被批准 用于临床治疗癌症。 然而， 这些天然产物药物的资源有限， 其分子结 构复杂， 化学合成困难， 不易规模化生产。 因此， 需要寻找结构筒单 的小分子抗肿瘤药物。 发明内容  Cancer is a disease that poses a serious threat to human health. Since the advent of the first anticancer drug, the nitrogen mustard, in the 1940s, scientists have isolated and extracted several natural products with potential cytotoxic activity from plants. Based on this, a variety of clear anti-tumor have been obtained through structural modification. Active compounds in which vinblastine, etoposide, paclitaxel, etc. are successively approved for clinical treatment of cancer. However, these natural product drugs have limited resources, their molecular structures are complex, chemical synthesis is difficult, and it is difficult to scale production. Therefore, there is a need to find small molecule antitumor drugs with structural cartridges. Summary of the invention
本发明旨在提供一种具有抑制细胞过度增殖活性的氨基吡啶类衍 生物。  The present invention is directed to an aminopyridine derivative having an activity of inhibiting cell hyperproliferation.
本发明的第一方面提供了式 I、 式 II所示的化合物， 或其可药用 的盐、 溶剂化物、 光学异构体或 N-氧化物。  A first aspect of the invention provides a compound of formula I, formula II, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof.
Figure imgf000003_0001
其中：
Figure imgf000003_0001
among them:
在式 Π中，一代表任选的键，条件为环中有且仅有一个氮原子是双 R2、 R3、 R4、 R5、 117或 R8各自独立地选自氢、 羟基、 卤素、 氨基、 硝基、 腈基、 三氟曱基、 -OR9、 -C(0)R9、 -C(0)OR9、 -NR10C(O)OR9 、 -OC(0)R9 、 -NR10SO2R9 、 -SO2NR10R9 、 -NR10C(O)R9、 NR10R9、 d-do 烷基、 C2-C 10烯基、 C2-C10炔基、 C3-C1Q环烷基、 C3-C 1Q环烷基烷基、 芳基、 芳基烷基、 杂芳基、 杂 芳基烷基、 杂环基和杂环基烷基； In the formula, one represents an optional bond, provided that one and only one nitrogen atom in the ring is a double R 2 , R 3 , R 4 , R 5 , 11 7 or R 8 are each independently selected from hydrogen, hydroxy , halogen, Amino, nitro, nitrile, trifluoromethyl, -OR 9 , -C(0)R 9 , -C(0)OR 9 , -NR 10 C(O)OR 9 , -OC(0)R 9 -NR 10 SO 2 R 9 , -SO 2 NR 10 R 9 , -NR 10 C(O)R 9 , NR 10 R 9 , d-do alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 1Q cycloalkyl, C 3 -C 1Q cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocycloalkane base;
R6独立地选自氢、三氟曱基、 d-do 烷基、 C2-C 10烯基、 C2-C10 炔基、 C3-C1Q环烷基、 C3-C 1β环烷基烷基、 芳基、 芳基烷基、 杂芳 基、 杂芳基烷基、 杂环基和杂环基烷基； R 6 is independently selected from the group consisting of hydrogen, trifluoromethyl, d-do alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 1Q cycloalkyl, C 3 -C 1β ring An alkylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group and a heterocyclic alkyl group;
W独立地选自 -OR9、 - NR10OR9、 - NR10SO2R9和 - NR10R9;W is independently selected from -OR 9 , -NR 10 OR 9 , -NR 10 SO 2 R 9 and -NR 10 R 9 ;
R9、 。各自独立选自氢、 羟基、 卤素、 三氟曱基、 d-do 烷 >¾^、 C - C 10 f^^^、 C2 - C 10 > C - C 10 ί^ ¾ C - C 10 ί^ ¾ R 9 , . Each is independently selected from the group consisting of hydrogen, hydroxy, halogen, trifluoromethyl, d-do alkane > 3⁄4^, C - C 10 f^^^, C2 - C 10 > C - C 10 ί^ 3⁄4 C - C 10 ί^ 3⁄4
芳基、 芳基烷基、 杂芳基、 杂芳基烷基、 杂环基、 杂环基烷基； 其中每个烷基、 烯基、 炔基、 环烷基、 芳基、 杂芳基和杂环基 部分任选地被 1-5 个（例如 1个、 2个、 3个、 4个、 5个）独立地 选自以下的基团取代： 羟基、 素、 氨基、 硝基和三氟曱基； Aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl And a heterocyclyl moiety is optionally substituted with from 1 to 5 (eg, 1, 2, 3, 4, 5) groups independently selected from the group consisting of: hydroxy, hydrazino, amino, nitro, and tri Fluorinated group;
优选的化合物具 式 ΙΠ、 IV的结构  Preferred compounds have the structure of ΙΠ, IV
Figure imgf000004_0001
Figure imgf000004_0001
III IV  III IV
其中， 各个取代基团如上所定义；  Wherein each substituent group is as defined above;
优选的化合物具 V、 VI的结构  Preferred compounds have the structure of V, VI
Figure imgf000004_0002
Figure imgf000004_0002
V VI  V VI
其中 Ri R R3、 R4、 R5、 R6、 R7、 R8、 W、 R9、 R10如上所定 义。 Wherein Ri RR 3 , R 4 , R 5 , R 6 , R 7 , R 8 , W, R 9 and R 10 are as defined above.
优选的， R2、 R3、 R4、 R5、 R6、 R7、 R8独立地选自氢、 卤 素、 硝基、 腈基、 三氟曱基、 d-C6 烷基、 C3-C 6环烷基、 C3-C 6 环烷基烷基、 芳基、 芳基烷基、 杂芳基、 杂芳基烷基、 杂环基、 杂 环基烷基； Preferably, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are independently selected from the group consisting of hydrogen, halogen, nitro, nitrile, trifluoromethyl, dC 6 alkyl, C 3 - C 6 cycloalkyl, C 3 -C 6 Cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl;
优选的， W独立地选自 -OR9、 - NR10OR9或 - NR10R9。 Preferably, W is independently selected from -OR 9 , -NR 10 OR 9 or -NR 10 R 9 .
在本发明的实施方案中， 所述化合物选自以下化合物：  In an embodiment of the invention, the compound is selected from the group consisting of:
3,4,5- =-氟 -2[(3-曱基 -5-碘 -2-吡啶基) J^】苯曱酸；  3,4,5- =-fluoro- 2[(3-indolyl-5-iodo-2-pyridyl) J^]benzoic acid;
N-{3_ [(叔丁基-二曱基)硅氧基】丙氧基 }-3，4，5_三氟 -2_[(3_曱基 _5-捵 -2-吡1^ )氨基】苯曱酰胺； N-{ 3 _ [(tert-butyl-diindenyl)silyloxy]propoxy}- 3 , 4 , 5 _trifluoro- 2 _[( 3曱 _ _ 5 - 捵-2-pyr 1 ^) amino] benzoquinone;
N-[(2，2-曱基 -1,3二氧戊环 -4基)曱氧基卜 3,4,5-三氟 -2-[(3-曱基 -5-破 -2-吡1^ )氨基】苯曱酰胺； N-[(2,2-Mercapto-1,3-dioxolan-4-yl)decyloxy 3,4,5-trifluoro-2-[(3-indolyl-5-break-2- Pyridin 1 ^ )amino]benzamide;
N-[2- (噻吩 -2-基）乙基卜 3，4，5-三氟-2-[(3-曱基-5-埃-2-吡啶基)氨基】 苯曱酰胺；  N-[2-(thiophen-2-yl)ethyl b 3,4,5-trifluoro-2-[(3-indolyl-5-e-2-pyridyl)amino]benzamide;
N- ( 2-吗啉乙基） -3,4,5-三氟 -2-[(3-曱基 -5-破 -2-吡啶基)氨基】苯曱 酰胺；  N-(2-morpholinylethyl)-3,4,5-trifluoro-2-[(3-indolyl-5-deactivate-2-pyridyl)amino]phenylhydrazine amide;
N-[2- (哌啶 -1-基）乙基卜 3，4，5-三氟 -2-[(3-曱基 -5-碘 -2-吡啶基)氨基】 苯曱酰胺；  N-[2-(piperidin-1-yl)ethyl b 3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino]benzamide;
N-苯曱氧基 -3，4，5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基)氨基】苯曱酰胺； N-苯曱氧基 -3，4，5-三氟 -2-[(3-曱基 -5-捵 -2-吡啶基) J^】苯曱酰胺； N- ( 3-苯丙基） -3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基) J ^苯曱酰胺； N-[(2,2-曱基 -1，3二氧戊环 -4基)曱氧基】 - 3，4，5-三氟 -2- [(3-氯 -5-溴 -2- 吡啶基) J ^苯曱酰胺；  N-benzoinoxy-3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridinyl)amino]benzamide; N-benzoquinone-3,4, 5-trifluoro-2-[(3-indolyl-5-fluoren-2-pyridyl) J^]benzamide; N-(3-phenylpropyl)-3,4,5-trifluoro-2 -[(3-chloro-5-bromo-2-pyridyl)J^benzamide; N-[(2,2-indolyl-1,3dioxolan-4-yl)decyloxy]-3 ,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)J^benzamide;
(R)-N-[(2，2-曱基 -1,3二氧戊环 -4基)曱氧基卜 3,4,5-三氟 -2-[(3-氯 -5- 溴 -2-吡啶基 ) J^】苯曱酰胺；  (R)-N-[(2,2-mercapto-1,3-dioxolan-4-yl)decyloxy 3,4,5-trifluoro-2-[(3-chloro-5-bromo) -2-pyridyl) J^]benzamide;
(R)-N-[(2，2-曱基 -1，3二氧戊环 -4基)曱氧基卜 3，4，5-三氟 -2-[(3-曱基 (R)-N-[(2,2-indolyl-1,3dioxolan-4-yl)decyloxy 3,4,5-trifluoro-2-[(3-indolyl)
-5-碘 -2-吡啶基 ) J^】苯曱酰胺； -5-iodo-2-pyridyl) J^]benzamide;
N- (环丙曱氧基) - 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基)氨基】苯曱酰 胺；  N-(cyclopropoxy)-3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino]benzoylamine;
N-(3-羟基丙氧基) - 3，4，5-三氟 -2-[(3-曱基 -5-捵 -2-吡啶基)氨基】苯曱 酰胺；  N-(3-hydroxypropoxy)-3,4,5-trifluoro-2-[(3-indolyl-5-indol-2-pyridyl)amino]phenylhydrazine amide;
N-(3-羟基丙氧基) - 3,4,5- =-氟 -2-[(3-氯 -5-溴 -2-吡啶基)氨基】苯曱酰 胺；  N-(3-hydroxypropoxy)-3,4,5- =-fluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino]benzoylamine;
(R)-N-(2，3-二羟基丙氧基) - 3,4,5- =-氟 -2- [(3-曱基 -5-碘 -2-吡1^ )氨 基】苯曱酰胺； (R)-N-(2，3-二羟基丙氧基) - 3,4,5- =.氟 -2- [(3-氯 -5-溴 -2-吡啶基)氨基】 苯曱酰胺； (R)-N-(2,3-dihydroxypropoxy)-3,4,5- =-fluoro-2-[(3-indolyl-5-iodo-2-pyridyl 1 ^ )amino]benzene Amide amide (R)-N-(2,3-dihydroxypropoxy)-3,4,5- =.fluoro-2-[(3-chloro-5-bromo-2-pyridinyl)amino]benzamide ;
N- (环己基曱基) - 3,4,5- =-氟 -2- [(3-曱基 -5-溴 -2-吡啶基)氨基】苯曱酰 胺；  N-(cyclohexyldecyl)-3,4,5- =-fluoro-2-[(3-indolyl-5-bromo-2-pyridyl)amino]benzoylamine;
N- ( 2-吗啉乙基） -3,4,5-三氟 -2-[(3-曱基 -5-溴 -2-吡啶基)氨基】苯曱 酰胺；  N-(2-morpholinylethyl)-3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridyl)amino]phenylhydrazine amide;
N-[2- (哌啶 -1-基）乙基】 - 3，4，5-三氟 -2-[(3-曱基 -5-溴 -2-吡啶基)氨基】 苯曱酰胺；  N-[2-(piperidin-1-yl)ethyl]-3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridyl)amino]benzamide;
N- ( 3-苯丙基） -3,4,5-三氟 -2-[(3-曱基 -5-碘 -2-吡啶基)氨基】苯曱 酰胺；  N-(3-phenylpropyl)-3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino]phenylhydrazine amide;
N-[2- (哌啶 -1-基）乙基】 - 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基)氨基】 苯曱酰胺；  N-[2-(piperidin-1-yl)ethyl]-3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino]benzamide;
5-[(5-碘 -3-曱基 2-吡啶基)氨基】 -4-氟 -1H-苯并咪唑 -6-曱酸；  5-[(5-iodo-3-indolyl 2-pyridyl)amino]-4-fluoro-1H-benzimidazole-6-decanoic acid;
N-[2_ (噻吩 _2_基）乙基】 _5_[(5_捵 _3_曱基 2_吡啶基）氨基】 _4-氟 -1H-苯并咪唑 -6-曱酰胺； N-[ 2 _ (thiophene- 2 -yl)ethyl] _ 5 _[( 5 _捵_ 3 _fluorenyl 2 _pyridyl)amino] _ 4 -fluoro-1H-benzimidazole-6-indoleamide ;
N-[2_ (哌啶 -1-基）乙基】 _5_[(5_捵 _3_曱基 2_吡啶基）氨基】 _4-氟 -1H-苯并咪唑 -6-曱酰胺。 N-[ 2 _ (piperidin-1-yl)ethyl] _ 5 _[( 5 _捵_ 3 _indolyl 2 _pyridyl)amino] _ 4 -fluoro-1H-benzimidazole-6-oxime Amide.
另一方面， 本发明还涉及式 I、 II化合物或其可药用的盐、 溶 剂化物、 光学异构体或 N-氧化物的合成方法， 其包括以下关键中间 体的合成：  In another aspect, the invention relates to a method of synthesizing a compound of formula I, II or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, which comprises the synthesis of the following key intermediates:
1 ) 四氟苯腈与取代 2-氨基吡啶类化合物在氨基锂存在条件下， 以二曱苯为反应溶剂， 在 125°C条件下反应得到中间体 3,4,5-三 -2- [(取代 -2-吡啶基 ) 】苯曱腈；  1) Tetrafluorobenzonitrile and substituted 2-aminopyridine compound are reacted in the presence of lithium amide in diphenylbenzene as a reaction solvent at 125 ° C to obtain intermediate 3,4,5-tri-2- [ (substituted-2-pyridyl) phenylphthalonitrile;
Figure imgf000006_0001
Figure imgf000006_0001
2 ) 2, 3, 4-三氟 -5-硝基苯曱酸与取代 2-氨基吡啶类化合物在 LDA 存在条件下，在 -70°C条件下，反应得到中间体 3，4，-二氟 -5-硝基 -2- [(取 代 -2-吡啶基) J ^苯曱酸；
Figure imgf000007_0001
2) 2, 3, 4-trifluoro-5-nitrobenzoic acid and substituted 2-aminopyridines are reacted in the presence of LDA at -70 ° C to obtain intermediates 3, 4, - 2 Fluoro-5-nitro-2-[(substituted-2-pyridyl)J^benzoic acid;
Figure imgf000007_0001
式 I化合物合成方案如下：  The synthesis scheme of the compound of formula I is as follows:
以取代的含离去集团 L的苯曱酸为起始原料，经过与曱基化试剂反 应，将羧基曱基化；再通过与氨水反应，将曱酯转化为酰胺基；在 P0C13 作用下脱去一份子的水， 将酰胺键转化为氰基； 取代的含离去集团 L的 苯曱氰在碱（例如森基锂）作用下， 离去集团离去与取代的氣基吡啶类 化合物进行缩合反应；在将氰基水解得到羧基，羧基与相应的侧链反应， 得到 I化合物；
Figure imgf000007_0002
Figure imgf000007_0003
The substituted benzoic acid containing the leaving group L is used as a starting material, and the carboxyl group is thiolated by reacting with a thiolation reagent; and the oxime ester is converted into an amide group by reacting with ammonia water; under the action of P0C1 3 A part of the water is removed to convert the amide bond to a cyano group; the substituted phenyl phthalocyanine containing the leaving group L is removed from the group by the action of a base such as a radical lithium. Carrying out a condensation reaction; hydrolyzing a cyano group to obtain a carboxyl group, and reacting a carboxyl group with a corresponding side chain to obtain a compound I;
Figure imgf000007_0002
Figure imgf000007_0003
L表示离去集团， 可以为 素； 和 /或 L indicates the departure group, which can be a prime; and / or
式 II化合物合成方案如下：  The synthesis scheme of the compound of formula II is as follows:
以取代的含离去集团 L的苯曱酸为起始原料， 经过硝基化反应， 在 苯环上引入硝基； 在碱（例如 ^锂）作用下， 离去集团离去与取代的 氨基吡啶类化合物进行缩合反应； 在氨水作用下， 苯环上引入氨基； 经 过与曱基化试剂反应， 将幾基曱基化； 将硝基还原为氨基以后， 进行成 环反应，脱曱酯得到含羧基的关键中间体，羧基与相应的侧链部分反应， 得到式 II化合物； The substituted benzoic acid containing the leaving group L is used as a starting material, and after the nitration reaction, a nitro group is introduced on the benzene ring; under the action of a base (for example, lithium), the group is removed and the substituted amino group is removed. The pyridine compound undergoes a condensation reaction; under the action of ammonia water, an amino group is introduced into the benzene ring; after reacting with a thiolation reagent, a few groups are thiolated; after the nitro group is reduced to an amino group, a ring-forming reaction is carried out to obtain a deoximation ester. a key intermediate containing a carboxyl group, the carboxyl group is reacted with a corresponding side chain moiety to give a compound of formula II;
Figure imgf000008_0001
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0002
15  15
L表示离去集团， 可以为卤素； L represents the leaving group and can be halogen;
其中 R2、 R3、 R4、 R5、 R6、 R7、 R8、 W、 R9、 R10如本发 明第一方面所定义。 Wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , W, R 9 and R 10 are as defined in the first aspect of the invention.
本发明还提供含有本发明的式 i、式 Π化合物或其可药用的盐、 溶剂化物、 光学异构体或 N-氧化物和可药用载体的药物组合物。  The invention further provides a pharmaceutical composition comprising a compound of formula i, a hydrazine compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, and a pharmaceutically acceptable carrier.
本发明中的 -CH) 烷基、 烷基是指具有 1-10 个碳原子的直链 或支链烷基， 例如曱基、 乙基、 丙基、 异丙基、 正丁基、 仲丁基、 叔丁基、 戊基、 2-戊基、 异戊基、新戊基、 己基、 2- 己基、 3- 己基、 3- 曱基戊基、 庚基、 辛基等。 优选的烷基是 d- 烷基。 更优选的 烷基是 d-C3 烷基。 The -CH) alkyl group in the present invention means a straight or branched alkyl group having 1 to 10 carbon atoms, such as an anthracenyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group or a sec-butyl group. Base, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-decylpentyl, heptyl, octyl and the like. A preferred alkyl group is a d-alkyl group. A more preferred alkyl group is dC 3 alkyl.
C2-C i。烯基是指具有 2-10个碳原子以及至少一个双键的烯基， 并 且包括乙烯基、 丙烯基、 1-丁 -3-烯基、 1-戊 -3-烯基、 1- 己 -5-烯基等。 更优选的是具有 2个或 3-5个碳原子的低级烯基； C 2 -C i. Alkenyl means an alkenyl group having 2 to 10 carbon atoms and at least one double bond, and includes ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hexyl- 5-alkenyl and the like. More preferred are lower alkenyl groups having 2 or 3-5 carbon atoms;
C2-C 1Q炔基是指具有 2-10个碳原子以及至少一个叁键的烃基，例 如包括乙块基、 丙炔基、 丁块基、 戊炔 -2-基等。 更优选的是具有 3-5 个碳原子的炔基； 卤素是指氟、 氯、 溴以及碘原子； The C 2 -C 1Q alkynyl group means a hydrocarbon group having 2 to 10 carbon atoms and at least one hydrazone bond, and includes, for example, an ethyl group, a propynyl group, a butyl group, a pentyn-2-yl group and the like. More preferred are alkynyl groups having 3-5 carbon atoms; Halogen means fluorine, chlorine, bromine and iodine atoms;
芳基是指具有单环 (如苯基)、 多环 (如联苯基)或其中至少一个环 是芳香性的多个稠合环 (如 1 , 2, 3, 4-四氢萘基、 萘基)的芳族碳环 基， 其任选被例如 素、 低级烷基（例如为 -^烷基） 、 低级烷氧 基（例如为 -^烷氧基） 、 三氟曱基、 芳基、 杂芳基和羟基单、 二 或三取代。  An aryl group means a fused ring having a single ring (such as a phenyl group), a polycyclic ring (such as a biphenyl group), or at least one of which is aromatic (for example, 1, 2, 3, 4-tetrahydronaphthyl, An anthranyl carbocyclyl group optionally substituted by, for example, a sulfonyl group, a lower alkyl group (for example, an alkyl group), a lower alkoxy group (for example, an alkoxy group), a trifluoromethyl group, or an aryl group. , heteroaryl and hydroxy, mono, di or trisubstituted.
杂芳基是指 5、 6或 7元环的一个或多个芳族环系，其包括 5-10 个 原子的稠合环系（其中至少一个环是芳香性的）， 所述环系含有至少 一个和最多四个选自氮、 氧或硫的杂原子。 杂芳基的实例为吡啶基、 咪唑基、 嘧啶基、 吡唑基、 ***基、 吡嗪基、 四唑基、 呋喃基、 噻 吩基、 异噁唑基、 噻唑基、 噁唑基、 异噻唑基、 吡咯环、 喹啉环、 异喹啉环、 吲哚环、 苯并咪唑、 苯并呋喃环、 苯并噻吩环、 苯并噻 唑环、哒嗪环等。其任选被例如 素、低级烷基（例如为 d- 烷基）、 低级烷氧基（例如为 -^烷氧基） 、 三氟曱基、 芳基、 杂芳基和羟 基单、 二或三取代。  Heteroaryl refers to one or more aromatic ring systems of a 5, 6 or 7 membered ring comprising a 5-10 atom fused ring system (wherein at least one ring is aromatic), said ring system containing At least one and up to four heteroatoms selected from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, iso Thiazolyl, pyrrole ring, quinoline ring, isoquinoline ring, anthracene ring, benzimidazole, benzofuran ring, benzothiophene ring, benzothiazole ring, pyridazine ring and the like. It is optionally, for example, a pharmaceutically acceptable group, a lower alkyl group (for example, a d-alkyl group), a lower alkoxy group (for example, an alkoxy group), a trifluoromethyl group, an aryl group, a heteroaryl group, and a hydroxy group. Three substitutions.
碳环、 碳环基、 环烷基、 C3-C1Q环烷基是指具有 3 -10 个碳原 子的饱和碳环基团。 该环烷基可以是单环或者多环稠合***， 而且 可以稠合在芳环上。 这些基团的实例包括环丙基、 环丁基、 环戊基 和环己基。 本文的环烷基可以是未取代的或者如详细说明， 在一个 或多个可取代的位置被各种基团取代。 例如， 这些环烷基可任选被 以下基团取代： Cr 烷基、 d-Ce 烷氧基、 腈基、 卤素、 羟基、 氨基、 硝基、 单 (d-Ce)烷基氨基、 二 (d-Ce)烷基氨基、 C2-C6 烯基、 C2-C6炔基、 d-Ce 卤代坑基、 d-Ce 卤代坑氧基； A carbocyclic ring, a carbocyclic group, a cycloalkyl group, a C 3 -C 1Q cycloalkyl group means a saturated carbocyclic group having 3 to 10 carbon atoms. The cycloalkyl group can be a monocyclic or polycyclic fused system and can be fused to the aromatic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl groups herein may be unsubstituted or substituted by various groups at one or more substitutable positions, as described in detail. For example, these cycloalkyl groups may be optionally substituted by the following groups: Cr alkyl group, d-Ce alkoxy group, nitrile group, halogen, hydroxy group, amino group, nitro group, mono(d-Ce)alkylamino group, two ( d-Ce)alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, d-Ce halo pit, d-Ce halo pit;
杂环或杂环基是指 5、 6或 7元环的一个或者多个碳环环系， 其包 括 4-10个原子的稠合环系， 所述环系含有至少一个和最多四个选自 氮、 氧或硫的杂原子， 条件是该基团的环不含两个相邻的 O 或 S 原 子。 稠合环系可以是稠合在芳组基团上的杂环。 优选的杂环包括但 不限于吡咯烷基、 四氢呋喃基、 二氢呋喃基、 四氢噻吩、 哌啶基、 吗啉环、 环己环、 派嗪环、 二氧戊环（例如 1, 3-二氧戊环）等， 它们 可以被以下基团取代： d-Ce 烷基、 d-Ce 烷氧基、 腈基、 卤素、 羟基、 氨基、 硝基、 单 ( -C6)烷基氨基、 二 (d- )烷基氨基、 C2-C6 烯基、 C2-C6炔基、 C}-C6 卤代烷基、 d-C6 卤代烷氧基； 芳基烷基是指被一个或多个 (如上定义的）芳基取代的 (如上定义 的)烷基。 更优选的芳基烷基是芳基 -d- 烷基。 实例包括苄基、 苯 基乙基等； Heterocyclic or heterocyclic group means one or more carbocyclic ring systems of a 5, 6 or 7 membered ring comprising a fused ring system of 4 to 10 atoms, said ring system containing at least one and up to four selected A hetero atom from nitrogen, oxygen or sulfur, provided that the ring of the group does not contain two adjacent O or S atoms. The fused ring system may be a heterocyclic ring fused to an aromatic group. Preferred heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophene, piperidinyl, morpholine, cyclohexyl, pyrazine ring, dioxolane (eg 1, 3- Dioxolane) and the like, which may be substituted by the following groups: d-Ce alkyl, d-Ce alkoxy, nitrile, halogen, hydroxy, amino, nitro, mono(-C6)alkylamino, two (d-)alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C } -C 6 haloalkyl, dC 6 haloalkoxy; Arylalkyl means an alkyl group (as defined above) substituted by one or more (as defined above) aryl groups. A more preferred arylalkyl group is an aryl-d-alkyl group. Examples include benzyl, phenylethyl, and the like;
杂芳基烷基是指被 (如上定义的）杂芳基取代的 (如上定义的)烷 基。 更优选的杂芳基烷基是 5-或 6-元杂芳基 -d- 烷基。 实例包括 吡啶基乙基等；  Heteroarylalkyl means an alkyl group (as defined above) substituted by a heteroaryl group (as defined above). More preferred heteroarylalkyl groups are 5- or 6-membered heteroaryl-d-alkyl groups. Examples include pyridylethyl and the like;
杂环基烷基是指被 (如上定义的）杂环基取代的 (如上定义的)烷 基。 更优选的杂环基烷基是 5-或 6-元杂环基 -d- 烷基。 实例包括 四氢吡喃基曱基；  Heterocyclylalkyl means an alkyl group (as defined above) substituted by a heterocyclic group (as defined above). A more preferred heterocyclylalkyl group is a 5- or 6-membered heterocyclyl-d-alkyl group. Examples include tetrahydropyranyl fluorenyl;
环烷基烷基是指被 (如上定义的)环烷基取代的 (如上定义的)烷 基。 更优选的杂环基是 5-或 6-元环烷基 -d- 烷基。 实例包括环丙 基曱基；  Cycloalkylalkyl refers to an alkyl group (as defined above) substituted by a cycloalkyl group (as defined above). More preferred heterocyclic groups are 5- or 6-membered cycloalkyl-d-alkyl groups. Examples include cyclopropyl fluorenyl;
本发明化合物也可以以其药学上可接受的盐或溶剂化物的形式 使用。 式 I或式 II化合物的生理学上可接收的盐包括由药学上可接受 的无机酸或有机酸或者无机碱或有机碱形成的常规的盐以及季铵的 酸加成盐。 合适的酸盐的更具体的例子包括盐酸、 氢溴酸、 硫酸、 磷酸、 硝酸、 高氯酸、 富马酸、 乙酸、 丙酸、 琥珀酸、 羟基乙酸、 曱酸、 乳酸、 马来酸、 酒石酸、 柠檬酸、 朴酸、 丙二酸、 羟基马来 酸、 苯乙酸、 谷氨酸、 苯曱酸、 水杨酸、 富马酸、 曱苯磺酸、 曱磺 酸、 萘 _2-磺酸、 苯磺酸、 羟基萘曱酸、 氢捵酸、 苹果酸、 steroi 鞣酸等的盐。 其它的酸， 如草酸， 虽然其本身并非药学上可接受的， 但可以用于制备用作中间体的盐， 以获得本发明化合物及其药学上 可接受的盐。 合适的碱盐的更具体的例子包括钠、 锂、 钾、 镁、 铝、 钙、 锌、 N，N，-二苄基乙二胺、 氯代普鲁卡因、 胆碱、 二乙醇胺、 乙 二胺、 N-曱基葡糖胺和普鲁卡因盐。  The compounds of the invention may also be used in the form of their pharmaceutically acceptable salts or solvates. Physiologically acceptable salts of the compound of formula I or formula II include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, citric acid, lactic acid, maleic acid, Tartaric acid, citric acid, citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, sulfonic acid, naphthalene 2-sulfonate Salts of acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroquinone, malic acid, steroi citric acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable base salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, N-decyl glucosamine and procaine salt.
本发明中的某些化合物可能用水或各种有机溶剂结晶或重结晶， 在这种情况下， 可能形成各种溶剂合物。 本发明包括那些化学计量的 溶剂合物， 例如水合物， 也包括在用低压升华干燥法制备时形成的包 含可变量水的化合物。  Some of the compounds in the present invention may be crystallized or recrystallized with water or various organic solvents, in which case various solvates may be formed. The present invention includes those stoichiometric solvates, such as hydrates, as well as compounds containing variable amounts of water formed upon preparation by low pressure sublimation drying.
因此当涉及到本发明的化合物时， 包括式 I或式 II化合物及其药 学上可接受的盐和溶剂化物。  Thus, when referring to a compound of the invention, a compound of formula I or formula II, and pharmaceutically acceptable salts and solvates thereof, are included.
本发明还包括本发明化合物的前药， 该前药一经给药， 即通过 代谢过程进行化学转化， 之后变成具有活性的药物。 通常， 这类前 药是本发明化合物的功能性衍生物， 其在体内. 容易转化成所需的 式 I或式 II化合物。 例如， 在" Design Of Prodrugs", H Bund Saard, Elsevier编辑， 1985中描述了选择和制备适宜前药衍生物的常规方 法。 The invention also includes prodrugs of the compounds of the invention which, once administered, pass The metabolic process undergoes chemical conversion and then becomes an active drug. Typically, such prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula I or formula II. Conventional methods for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design Of Prodrugs", H Bund Saard, Elsevier, ed., 1985.
本发明也包括本发明化合物的活性代谢物。  The invention also includes active metabolites of the compounds of the invention.
本发明的另一个方面涉及药物组合物， 其含有本发明化合物的 消旋体或旋光异构体和至少一种药学上可接受的载体， 其可用于体 内治疗并具有生物相容性。 所述药物组合物可以根据不同给药途径 而制备成各种形式。 本发明所提及的化合物也可以被制备成各种药 学可接受的盐。  Another aspect of the invention relates to a pharmaceutical composition comprising a racemate or an optical isomer of a compound of the invention and at least one pharmaceutically acceptable carrier which is useful for in vivo treatment and is biocompatible. The pharmaceutical composition can be prepared in various forms depending on the route of administration. The compounds mentioned in the present invention can also be prepared into various pharmaceutically acceptable salts.
本发明的药物组合物包括有效剂量的本发明式 I或式 II化合物 或其可药用盐或水合物和一种或多种适宜的可药用载体。 这里的药 用载体包括但不限于： 离子交换剂， 氧化铝， 硬脂酸铝， 卵磷脂， 血清蛋白如人血白蛋白， 緩沖物质如磷酸盐， 甘油， 山梨酸， 山梨 酸钾， 饱和植物脂肪酸的部分甘油酯混合物， 水， 盐或电解质， 如 硫酸鱼精蛋白， 磷酸氢二钠， 磷酸氢钾， 氯化钠， 锌盐， 胶态氧化 硅， 三硅酸镁， 聚乙烯吡咯烷酮， 纤维素物质， 聚乙二醇， 羧曱基 纤维素钠， 聚丙烯酸酯， 蜂蜡， 羊毛脂。  The pharmaceutical compositions of the present invention comprise an effective amount of a compound of formula I or formula II of the present invention, or a pharmaceutically acceptable salt or hydrate thereof, and one or more suitable pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated plants. Partial glyceride mixture of fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, fiber Substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.
本发明化合物的药物组合物可以以下面的任意方式施用： 口服， 喷雾吸入， 直肠用药， 鼻腔用药， 颊部用药， 局部用药， 非肠道用 药，如皮下，静脉，肌内，腹膜内，鞘内，心室内，胸骨内和颅内注射或输入 或借助一种外植储器用药。 其中优选口服、 腹膜内或静脉内给药方 式。  The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Inside, intraventricular, intrasternal and intracranial injection or input or by means of an explant reservoir. Among them, oral, intraperitoneal or intravenous administration is preferred.
当口服用药时，本发明化合物可制成任意口服可接受的制剂形 式，包括但不限于片剂、 胶嚢、 水溶液或水悬浮液。 其中，片剂使用的 栽体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。 胶 嚢制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。 水悬浮液制剂 则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。 如果需要， 以上口服制剂形式中还可加入一些甜味剂、 芳香剂或着色剂。  When administered orally, the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions. Among them, the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added. The diluent used in the capsule preparation generally comprises lactose and dried corn starch. Aqueous suspension formulations are usually those in which the active ingredient is admix If desired, some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.
当局部用药时，特别是治疗局部外敷容易达到的患面或器官，如 眼睛、 皮肤或下肠道神经性疾病时，可根据不同的患面或器官将本发 明化合物制成不同的局部用药制剂形式，具体说明如下： 当眼部局部施用时， 本发明化合物可配制成一种微粉化悬浮液 或溶液的制剂形式， 所使用栽体为等渗的一定 pH的无菌盐水，其中 可加入也可不加防腐剂如氯化苄基烷醇盐。 对于眼用，也可将化合物 制成膏剂形式如凡士林膏。 When applied topically, especially in the treatment of facial or organs easily accessible by topical application, such as eye, skin or lower intestinal neuropathy, the hair may be according to different affected faces or organs. The compounds are prepared in different topical formulations, as specified below: When applied topically to the eye, the compounds of the invention may be formulated in the form of a micronized suspension or solution in which the carrier is isotonic at a certain pH. Sterile saline, with or without preservatives such as benzyl chloride alkoxide. For ophthalmic use, the compound can also be formulated in the form of a cream such as a Vaseline cream.
当皮肤局部施用时， 本发明化合物可制成适当的软骨、 洗剂或 霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。 软 膏制剂可使用的载体包括但不限于： 矿物油，液体凡士林，白凡士林， 丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂或霜剂可使用的载 体包括但不限于:矿物油，脱水山梨糖醇单硬脂酸酯，吐温 60，十六烷酯 蜡，十六碳烯芳醇，2-辛基十二烷醇，苄醇和水。  When applied topically to the skin, the compounds of the invention may be formulated in a suitable cartilage, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers which may be used in ointment preparations include, but are not limited to, mineral oil, liquid petroleum jelly, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents or creams which may be used include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
本发明化合物还可以无菌注射制剂形式用药，包括无菌注射水 或油悬浮液或无菌注射溶液。 其中，可使用的载体和溶剂包括水、 林 格氏溶液和等渗氯化钠溶液。 另外，灭菌的非挥发油也可用作溶剂或 悬浮介质，如单甘油酯或二甘油酯。  The compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile injectable aqueous or oily suspension or sterile injectable solutions. Among them, carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution. Alternatively, sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
本发明还涉及本发明的化合物或其可药用的盐、 溶剂化物、 光 学异构体或 N-氧化物用于制备抑制细胞过度增殖的药物的用途。  The invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament for inhibiting cell hyperproliferation.
所述细胞过度增殖包括白血病、 成胶质细胞瘤、 淋巴瘤、 黑色素 瘤、 癌症、 神经性疼痛、 炎症等疾病。 在本发明的一个实施方案中， 所述抑制细胞过度增殖是指抑制肿瘤细胞增殖。  The cell hyperproliferation includes diseases such as leukemia, glioblastoma, lymphoma, melanoma, cancer, neuropathic pain, inflammation, and the like. In one embodiment of the invention, the inhibiting cell hyperproliferation means inhibiting tumor cell proliferation.
本发明还涉及本发明的化合物或其可药用的盐、 溶剂化物、 光 学异构体或 N-氧化物用于制备抗肿瘤和 /或癌症药物的用途。  The invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament for the treatment of tumors and/or cancer.
本发明还涉及本发明的化合物或其可药用的盐、 溶剂化物、 光 学异构体或 N-氧化物用于制备预防和 /或治疗细胞过度增殖性疾病 的药物的用途。  The invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament for the prevention and/or treatment of a cell hyperproliferative disorder.
本发明还涉及预防和 /或***和 /或癌症的方法，其包括给有 需要的受试者施用预防和 /或治疗有效量的本发明的化合物或其可 药用的盐、 溶剂化物、 光学异构体或 N-氧化物。  The invention also relates to a method of preventing and/or treating a tumor and/or cancer comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate thereof, Optical isomer or N-oxide.
本发明还涉及预防和 /或治疗细胞过度增殖性疾病的方法， 其包 括给有需要的受试者施用预防和 /或治疗有效量的本发明的化合物 或其可药用的盐、 溶剂化物、 光学异构体或 N-氧化物。  The invention also relates to a method of preventing and/or treating a cell hyperproliferative disorder comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate thereof, Optical isomer or N-oxide.
在本发明中， 所述细胞过度增殖性疾病包括肿瘤 （良性或恶性 肿瘤）和 /或癌症、 神经性疼痛、 炎症等疾病。 In the present invention, the cell hyperproliferative disease includes a tumor (benign or malignant) Tumors and/or diseases such as cancer, neuropathic pain, inflammation, etc.
在本发明中，其中所述的肿瘤和 /或癌症可以是医学上已知的任何肿 瘤和 /或癌症。 优选地， 所述的肿瘤和 /或癌症包括但不限于：  In the present invention, the tumor and/or cancer described therein may be any tumor and/or cancer known in medicine. Preferably, the tumor and/or cancer includes but is not limited to:
恶性肿瘤， 包括但不限于膀胱癌、 乳腺癌、 结肠癌、 肾癌肝癌、 肺 癌（包括小细胞肺、 非小细胞癌）、 头和颈癌、 食管癌、 胆嚢癌、 胃癌、 子***、 曱状腺癌、 ***癌和皮肤癌（包括鳞状细胞癌)；  Malignant tumors, including but not limited to bladder cancer, breast cancer, colon cancer, kidney cancer, lung cancer (including small cell lung, non-small cell carcinoma), head and neck cancer, esophageal cancer, biliary cancer, stomach cancer, cervical cancer, Sickle adenocarcinoma, prostate cancer and skin cancer (including squamous cell carcinoma);
淋巴***的造血肿瘤，包括但不限于白血病、急性淋巴细胞白血病、 急性成淋巴细胞白血病、 B-细胞淋巴瘤、 T-细胞淋巴瘤、霍奇金淋巴瘤、 非-霍奇金淋巴瘤、毛细胞淋巴瘤、外套细胞淋巴瘤、骨髓瘤和 Burketfs 氏淋巴瘤；  Hematopoietic tumors of the lymphatic system, including but not limited to leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hair Cellular lymphoma, mantle cell lymphoma, myeloma, and Burketfs' lymphoma;
骨髓***的造血肿瘤， 包括但不限于急性和慢性髓细胞性白血病、 骨髓增生异常综合征和前髓细胞性白血病；  Hematopoietic tumors of the myeloid system, including but not limited to acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia;
间质成因的肿瘤， 包括但不限于纤维肉瘤和横纹肌肉瘤；  Tumors of interstitial origin, including but not limited to fibrosarcoma and rhabdomyosarcoma;
中枢成因的肿瘤， 包括但不限于纤维肉瘤和横纹肉瘤；  Centrally occurring tumors, including but not limited to fibrosarcoma and rhabdomyosarcoma;
中枢和周围神经***的肿瘤， 包括星形细胞瘤、 成纤维神经瘤、 神 经胶质瘤和神经鞘瘤； 以及  Tumors of the central and peripheral nervous system, including astrocytoma, fibrosarcoma, neuroglioma, and schwannomas;
其他肿瘤， 包括但不限于黑素瘤、 ***瘤、 畸胎癌、 骨肉瘤、 成股质细胞瘤、外生性色紫颈瘤 (xenoderoma pigmentosum)、 曱状腺滤 嚢癌和卡波氏肉瘤。 发明的有益效果  Other tumors, including but not limited to melanoma, seminoma, teratocarcinoma, osteosarcoma, femoral stromal tumor, xenoderoma pigmentosum, squamous cell carcinoma and Kapos sarcoma. Advantageous effects of the invention
本发明的化合物能够有效抑制细胞的过度增殖， 可用于治疗哺乳 动物中过度增殖性疾病， 如各种肿瘤、 癌症、 神经性疼痛、 炎症等。 具体实施方式  The compounds of the present invention are effective for inhibiting excessive proliferation of cells and are useful for treating hyperproliferative diseases in mammals such as various tumors, cancer, neuropathic pain, inflammation and the like. detailed description
下面将结合实施例对本发明的实施方案进行详细描述， 但是本领 域技术人员将会理解， 下列实施例仅用于说明本发明， 而不应视为限 定本发明的范围。 实施例中未注明具体条件者， 按照常规条件或制造 商建议的条件进行。 所用试剂或仪器未注明生产厂商者， 均为可以通 过市购获得的常规产品。  The embodiments of the present invention are described in detail below with reference to the accompanying drawings. If no specific conditions are specified in the examples, they are carried out according to the general conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained commercially.
化合物熔点由 RY-1型熔点仪测定， 温度未经校正。 iH NMR光 谱由 Bruker ARX 400型核磁仪测定。 3,4,5- =-氟-2[(3-曱基-5-捵-2-吡^ ^】苯曱酸 The melting point of the compound was determined by a RY-1 type melting point apparatus, and the temperature was not corrected. The iH NMR spectrum was measured by a Bruker ARX 400 type nuclear magnetic instrument. 3,4,5- =-fluoro-2[(3-indolyl-5-indole-2-pyridinium]^benzoic acid
Figure imgf000014_0001
Figure imgf000014_0001
步骤 1、 2，3，4，5-四氟苯曱酸曱酯  Step 1, 2,3,4,5-tetrafluorobenzoate
将 2，3，4，5-四氟苯曱酸（48.5 g， 0.25 mol )溶于 130 mL无水曱醇中, 緩慢滴加三曱基氯硅烷（63 mL, 0.50 mol ) 。 滴加完毕， 回流 12 h。 水泵减压蒸除溶剂以及过量的三曱基氯硅烷， 得淡黄色液体， 加入二氯 曱烷 200 mL, 并用 10 %的氢氧化钠水溶液洗涤， 二氯曱烷反提水层， 合并有机层，有机层用无水硫酸钠干燥过夜。次日过滤，减压蒸除溶剂， 得无色液体 2，3，4，5-四氟苯曱酸曱酯 ( 30.52 g, 97.8 % )， ^-NMR (400 MHz, CDC13) δ ppm: 7.65-7.60 (m, 1H), 3.97 (s, 1H)。 步骤 2、 2，3，4，5-四氟苯曱酰胺 2,3,4,5-Tetrafluorobenzoic acid (48.5 g, 0.25 mol) was dissolved in 130 mL of anhydrous decyl alcohol, and trimethyl chlorosilane (63 mL, 0.50 mol) was slowly added dropwise. After the addition was completed, reflux was carried out for 12 h. The pump is distilled off under reduced pressure and the excess trimethyl chlorosilane is obtained as a pale yellow liquid. Dichloromethane (200 mL) is added and washed with a 10% aqueous sodium hydroxide solution, and the aqueous layer is combined with dichloromethane. The organic layer was dried over anhydrous sodium sulfate overnight. Filtration the next day, and the solvent was evaporated under reduced pressure to give EtOAc (3,3,4,5-tetrafluorobenzoic acid decyl ester (30.52 g, 97.8 %), ^-NMR (400 MHz, CDC1 3 ) δ ppm: 7.65-7.60 (m, 1H), 3.97 (s, 1H). Step 2, 2, 3, 4, 5-tetrafluorobenzamide
将 2，3，4，5-四氟苯曱酸曱酯 ( 29.5 g, 0.147 mol )和浓氨水 ( 244 mL, 3.24 mol )加入到茄形瓶中， 体系为两相体系， 随着反应进行， 有白色 不溶物出现，机械搅拌过夜，过滤得白色固体 2，3，4，5-四氟苯曱酰胺（ 21.2 g, 74.7 % )， ^-NMR (400 MHz, DMSO-D6) δ ppm: 7.93 (br s, 1H)， 7.91 (br s, 1H)， 7.63-7.61 (m, 1H)， ESI-MS m/z: 194.0 [M+l】+。 步骤 3、 2，3，4，5-四氟苯腈 Add 2,3,4,5-tetrafluorobenzoic acid decyl ester (29.5 g, 0.147 mol) and concentrated ammonia water (244 mL, 3.24 mol) to the eggplant-shaped flask. The system is a two-phase system. , white insolubles appeared, mechanically stirred overnight, filtered to give white solid 2,3,4,5-tetrafluorobenzamide (21.2 g, 74.7 %), ^-NMR (400 MHz, DMSO-D 6 ) δ ppm : 7.93 (br s, 1H), 7.91 (br s, 1H), 7.63-7.61 (m, 1H), ESI-MS m/z: 194.0 [M+l]+. Step 3, 2,3,4,5-tetrafluorobenzonitrile
将 2，3，4，5-四氟苯曱酰胺（5 g, 0.026 mol )加入到 20 mL无水乙腈 中， 加入三氯氧磷（ 16.6 g, 0.11 mol ) , 升温到 70 °C , 反应 1.5 h。 将 反应液緩慢滴加到 200 mL水水混合物中， 该过程强烈放热， 通过控制 滴加速度来控制温度不高于 30。C , 滴加完毕后室温搅袢 0.5 h, 乙酸乙 酯萃取， 有机层干燥过夜， 次日减压蒸除溶剂， 得无色液体 2，3，4，5-四 氟苯腈 ( 4.21 g, 92.5 % )。 iH-NMR (400 MHz, DMSO-D6) δ ppm: 10.01 (br s, 1H)， 7.35-7.28 (m, 1H)， 19F-NMR (400 MHz, CDC13) δ ppm: -130.04.〜- 130.06 (m,lH), -134.62—134.66 (m, 1H), -143.48—143.60 (m, 1H), -150.60—150.62 (m, 1H), ESI-MS m/z: 176.0[M+1]+。 步骤 4、 2- J.-3曱基 -5-捵吡啶 2,3,4,5-tetrafluorobenzamide (5 g, 0.026 mol) was added to 20 mL of anhydrous acetonitrile, phosphorus oxychloride (16. 6 g, 0.11 mol) was added, and the temperature was raised to 70 ° C. 1.5 h. The reaction solution was slowly added dropwise to a 200 mL water-water mixture, which was strongly exothermic, and the temperature was controlled to be not higher than 30 by controlling the dropping rate. After the completion of the dropwise addition, the mixture was stirred at room temperature for 0.5 h, extracted with ethyl acetate, and the organic layer was dried overnight. The solvent was evaporated under reduced pressure over the next day to obtain 2,3,4,5-tetrafluorobenzonitrile ( 4.21 g, 92.5 % ). iH-NMR (400 MHz, DMSO-D 6 ) δ ppm: 10.01 (br s, 1H), 7.35-7.28 (m, 1H), 19 F-NMR (400 MHz, CDC1 3 ) δ ppm: -130.04. - 130.06 (m,lH), -134.62-134.66 (m, 1H), -143.48-143.60 (m, 1H), -150.60-150.62 (m, 1H), ESI-MS m/z: 176.0[M+1 ] + . Step 4, 2-J.-3 mercapto-5-purine pyridine
将 2- J^-3曱基吡啶（ 5.5 g, 0.05 mol ) 、 破（ 5.1 g, 0.02 mol )、 高碘酸二水合物（ 2.28 g, 0.01 mol )加入到反应瓶中，依次加入醋酸（ 30 mL )、 水（60 mL )和 fefe酸（0.9 mL )， 体系放热， 体系内温度由室 温上升到 25。C , 得到深棕色溶液，加热到 80。C , 反应 4 h。体系自然冷 却到室温，向其中加入 10%的 Na2S204水溶液（ 150 mL )中，搅袢 30 min, 二氯曱烷提取水层，用 10%的氢氧化钠水溶液洗涤有机层，有机层用无 «<酸钠干燥过夜。 次日过滤， 减压蒸除溶剂， 得淡黄色固体 2-氨基 -3 曱基 -5-破吡啶（10.76 g, 92.0% ) , ^-NMR (400 MHz, CDC13) δ ppm:8.11(s, 1H), 7.53(s, 1H), 4.85-4.80 (br s, 2H), 2.01(s, 3H), ESI-MS m/z: 235.8 [M+l】+。 步骤 5、 3，4，5-三氟 -2-[(3-曱基 -5-碘 -2-吡啶基) J^】苯曱腈 2-J^-3 mercaptopyridine (5.5 g, 0.05 mol), broken (5.1 g, 0.02 mol), periodate dihydrate (2.88 g, 0.01 mol) was added to the reaction flask, followed by acetic acid ( 30 mL), water (60 mL) and fefe acid (0.9 mL), the system exothermed and the temperature in the system rose from room temperature to 25. C, a dark brown solution was obtained and heated to 80. C, reaction for 4 h. The system was naturally cooled to room temperature, and a 10% aqueous solution of Na 2 S 2 4 4 (150 mL) was added thereto, and the mixture was stirred for 30 min, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with 10% aqueous sodium hydroxide. The organic layer was dried overnight without sodium sulfate. Filtration the next day, and the solvent was evaporated under reduced pressure to give pale-yellow solid 2-amino-3 decyl-5-pyridylpyridine (10.76 g, 92.0%), ^-NMR (400 MHz, CDC1 3 ) δ ppm: 8.11 (s , 1H), 7.53 (s, 1H), 4.85-4.80 (br s, 2H), 2.01 (s, 3H), ESI-MS m/z: 235.8 [M+l]+. Step 5, 3,4,5-Trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl) J^]benzonitrile
氮气保护糾下， 将 2- J^-3曱基 -5-捵吡啶 ( 23.10 g, 0.0986 mol ) 和氨基锂 ( 7.89 g, 0.343 mol )加入到 170 mL二曱苯中，加热到 100 。C , 搅拌反应 2 h。 自然降温到室温， 加入 2，3，4，5-四氟苯腈（15 g, 0.0857 mol ) , 加热到 126。C , 反应 3.5 h。 将反应过程得到的黑色固体过滤， 黑色固体中包夹有产物， 用乙酸乙酯少量多次洗涤， 并用超声波超声 5 min。 用 IN盐酸水溶液洗涤得到的乙酸乙酯层和反应液， 合并有机层， 有机层用无水硫酸钠干燥过夜。 次日过滤， 减压蒸除溶剂， 柱层析得淡 黄色固体 3,4,5-三氟 -2-[(3-曱基 -5-捵 -2-吡啶基)氨基】苯曱腈（8.9 g, 27 % ) , ^-NMR (400 MHz, CDC13) δ ppm: 8.24-8.23 (m, 1H)， 7.76-7-75(br s, 1H)， 7.21-7.19 (m, 1H)， 5.99 (s, 1H)， 2.31(s,3H), 19F-NMR (400 MHz, CDC13) δ ppm: -122.29(s, 1H)， -133.63~-133.72(m, 1H)， -135.71—135.76 (m, 1H), ESI-MS m/z: 390.0 [M+l]+。 步骤 6、 3，4，5-三氟 -2-[(3-曱基 -5-碘 -2-吡啶基) J^】苯曱酸 After the nitrogen protection was corrected, 2-J^-3-mercapto-5-indole pyridine (23.10 g, 0.0986 mol) and lithium amide (7.99 g, 0.343 mol) were added to 170 mL of diphenylbenzene and heated to 100 Å. C, stir the reaction for 2 h. Naturally cooled to room temperature, 2,3,4,5-tetrafluorobenzonitrile (15 g, 0.0857 mol) was added and heated to 126. C, reaction 3.5 h. The black solid obtained in the reaction was filtered, and the product was sandwiched between black solids, washed several times with ethyl acetate, and ultrasonicated for 5 min. The obtained ethyl acetate layer and the reaction mixture were washed with aqueous EtOAc. Filtration the next day, the solvent was evaporated under reduced pressure, and then purified by column chromatography to give pale yellow solid (3,4,5-trifluoro-2-[(3-indolyl-5-indole-2-pyridyl)amino]benzonitrile ( 8.9 g, 27 % ) , ^-NMR (400 MHz, CDC1 3 ) δ ppm: 8.24-8.23 (m, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 5.99 (s, 1H), 2.31(s,3H), 19 F-NMR (400 MHz, CDC1 3 ) δ ppm: -122.29(s, 1H), -133.63~-133.72(m, 1H), -135.71— 135.76 (m, 1H), ESI-MS m/z: 390.0 [M+l] + . Step 6, 3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl) J^]benzoic acid
将 3,4,5-三氟 -2-[(3-曱基 -5-埃 -2-吡 氨基】苯曱腈（ 8.90 g， 0.023 mol )溶于无水乙醇： 蒸馏水： THF=150 mL: 75 mL: 22.5 mL的混合 溶剂中， 加入氢氧化钾（ 6.44 g， 0.115 mol ) , 加热回流， 反应 30 h。 减压蒸除溶剂， 得油状物， 用 10 %盐酸水溶液调节 pH值到 1, 乙酸乙酯 萃取， 有机层用无水硫酸钠干燥过夜。 次日过滤， 减压蒸除溶剂， 得淡
Figure imgf000016_0001
3,4,5-Trifluoro-2-[(3-indolyl-5-e-2-pyridyl)benzonitrile ( 8.90 g, 0.023 mol) was dissolved in absolute ethanol: distilled water: THF = 150 mL : 75 mL: 22.5 mL of a mixed solvent, adding potassium hydroxide (6.44 g, 0.115 mol), heating under reflux, and reacting for 30 h. Evaporate the solvent under reduced pressure to give an oil, and adjust pH to 1 with 10% aqueous hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate overnight.
Figure imgf000016_0001
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ιοεε薦 IOZXD/工：) d 6ST0CI/Z10Z OAV 将实施例 1中制得的 3,4,5-三氟 -2[(3-曱基 -5-碘 -2-吡啶基)氨基】苯曱 酸（ 0.43 g, 1.06 mmol ) , 溶于无水 THF20 mL中， 体系冷却到 -15 °C , 加入二苯膦酰氯 ( 0.27 mL, 1.38 mmol ) , -15 °C反应 30 min。 加入 N- 曱基吗淋 ( 0.12 mL, 1.06 mmol ) , -15 °C反应 30 min。 加入 0-[(2，2- 二曱基 -1，3-二酮 -4-基)曱基】羟胺（ 0.19 g, 1.27 mmol ), -15。(：反应 30 min。 加入 N-曱基吗啉（0.18 mL， 1.59 mmol ) ,恢复至室温， 室温搅拌过夜。 反应液中加入乙酸乙酯 60 mL, 依次用饱和碳酸氢钠水溶液液、饱和氯 化钠水溶液洗涤， 有机层用无水硫酸钠干燥过夜。 次日过滤， 减压蒸除 溶剂， 柱层析得淡黄色固体 N-[(2，2-曱基 -1,3二氧戊环 -4基)曱氧基卜 3，4，5-三氟 -2-[(3-曱基-5-破-2-吡》^)氨基】苯曱酰胺（ 0.21 g, 37.1 % )。 ιοεεRecommended IOZXD/Work:) d 6ST0CI/Z10Z OAV 3,4,5-trifluoro-2[(3-indolyl-5-iodo-2-pyridyl)amino]benzoic acid (0.43 g, 1.06 mmol) obtained in Example 1 was dissolved in none In 20 mL of water THF, the system was cooled to -15 °C, diphenylphosphonyl chloride (0.27 mL, 1.38 mmol) was added, and the reaction was carried out at -15 °C for 30 min. N-Mercaptoin (0.12 mL, 1.06 mmol) was added and the reaction was carried out at -15 °C for 30 min. Add 0-[(2,2-dimercapto-1,3-dione-4-yl)indolyl]hydroxylamine (0.19 g, 1.27 mmol), -15. (Reaction: 30 min. Add N-decylmorpholine (0.18 mL, 1.59 mmol), return to room temperature, and stir at room temperature overnight. Add 60 mL of ethyl acetate to the mixture, and then sat. The organic layer was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The next day was filtered, and the solvent was evaporated under vacuo to give a pale yellow solid N-[(2,2-indolyl-1,3 dioxolane) -4 benzyloxy 3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridyl)^amino]benzamide (0.21 g, 37.1%).
匪 R (400 MHz, CDC13) δ ppm: 9.70-9.68 (m, 1H)， 8.23 (s, 1H)， 7.75-7.74 (m, 1H)， 7.69-7.676(m, 1H)， 6.00 (br s, 1H)， 4.47-4.45 (m, 1H), 4.18-4.13 (m, 2H), 3.88-3.86 (m, 1H), 3.51-3.46 (m, 1H), 2.30 (s, 3H), 1.50 (s, 3H)， 1.39 (s, 3H)， ESI-MS m/z: 538.2 [M+l]+。 实施例 4 N- [2- (噻吩 -2-基）乙基卜 3,4,5-三氟 -2-[(3-曱基 -5-破 -2-吡 ¾^) J^】苯曱酰胺 匪R (400 MHz, CDC1 3 ) δ ppm: 9.70-9.68 (m, 1H), 8.23 (s, 1H), 7.75-7.74 (m, 1H), 7.69-7.676(m, 1H), 6.00 (br s , 1H), 4.47-4.45 (m, 1H), 4.18-4.13 (m, 2H), 3.88-3.86 (m, 1H), 3.51-3.46 (m, 1H), 2.30 (s, 3H), 1.50 (s , 3H), 1.39 (s, 3H), ESI-MS m/z: 538.2 [M+l] + . Example 4 N-[2-(Thien-2-yl)ethyl b 3,4,5-trifluoro-2-[(3-indolyl-5-dea-2-pyridyl) J^]benzene Amide
将实施例 1中制得的
Figure imgf000017_0001
5-碘 -2-吡啶基)氨基】苯曱 酸（0.23 g, 0.57 mol )、 2- (噻吩 -2-基） 乙胺（ 0.13 g, 1.03 mmol )、 DIEA( 0.12 mL, 0.68 mmol )溶于 20 mL二氯曱烷中，加入 PyBOP( 0.34 g, 0.65 mmol )室温搅拌过夜。 向反应体系中加入无水*** 40 mL, 分 别用水、饱和氯化钠水溶液洗 '涤有机相，有机层用无水硫酸钠干燥过夜。 次日过滤， 减压蒸除溶剂， 柱层析得淡黄色固体 N-[2- (噻吩 -2-基)乙基】 - 3，4，5-三氟 -2-[(3-曱基 -5-碘 -2-吡1^ )氨基】苯曱酰胺（0.21 g, 72.1 % )。 ^-NMR (400MHz, CDC13) δ ppm: 8.22 (m, 1H)， 7.72 (s, 1H)， 7.71-7.68 (m, 1H), 7.20-7.19 (m, 1H), 6.98-6.96 (m, 2H), 6.89-6.88 (m, 1H), 6.75-6.78 (m, 1H)， 5.84 (br s, 1H)， 3.78-3.75 (m, 2H)， 3.18-3.15 (t, 2H， J=6.7Hz), ESI-MS m/z: 518.2 [M+l】+。 实施例 5 N- ( 2-吗啉乙基） -3,4,5-三氟 -2-[(3-曱基 -5-碘 -2-吡^) J^】苯曱酰胺 Prepared in Example 1
Figure imgf000017_0001
5-iodo-2-pyridyl)amino]benzoic acid (0.23 g, 0.57 mol), 2-(thiophen-2-yl)ethylamine (0.13 g, 1.03 mmol), DIEA (0.12 mL, 0.68 mmol) PyBOP (0.34 g, 0.65 mmol) was added to 20 mL of dichloromethane to dry overnight. To the reaction system, 40 mL of anhydrous diethyl ether was added, and the organic phase was washed with water and a saturated aqueous solution of sodium chloride, and the organic layer was dried over anhydrous sodium sulfate. Filtration the next day, distilling off the solvent under reduced pressure and chromatography to give a pale yellow solid N-[2-(thiophen-2-yl)ethyl] -3,4,5-trifluoro-2-[(3-indoleyl) -5-iodo-2-pyridin 1 ^)amino]benzamide (0.21 g, 72.1%). ^-NMR (400MHz, CDC1 3 ) δ ppm: 8.22 (m, 1H), 7.72 (s, 1H), 7.71-7.68 (m, 1H), 7.20-7.19 (m, 1H), 6.98-6.96 (m, 2H), 6.89-6.88 (m, 1H), 6.75-6.78 (m, 1H), 5.84 (br s, 1H), 3.78-3.75 (m, 2H), 3.18-3.15 (t, 2H, J=6.7Hz ), ESI-MS m/z: 518.2 [M+l]+. Example 5 N-(2-morpholineethyl)-3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl) J^]benzamide
Figure imgf000018_0001
方法同实施例 4, 得白色固体 N- ( 2-吗啉乙基） -3,4,5-三氟 -2-[(3- 曱基 -5-捵 -2-吡啶基) J^】苯曱酰胺。 iH-NMR (400MHz, CDC13) δ ppm: 8.23 (m, 1H)， 7.72 (s, 1H)， 7.71-7.68 (m, 1H)， 7.67-7.64 (m, 1H)， 5.81(br s, 1H)， 3.78 (br s, 4H)， 3.61 (br s, 2H)， 2.62 (br s, 2H)， 2.54 (br s, 2H)， 2.30(s, 3H)， 1.59(br s, 2H)， ESI-MS m/z: 521.2 [M+l】+。 实施例 6 N- [2- (哌啶 -1-基）乙基】 - 3,4,5-三氟 -2-[(3-曱基 -5-破 -2-吡 ^) 】苯曱酰胺
Figure imgf000018_0002
Figure imgf000018_0001
The same procedure as in Example 4 gave N-(2-morpholinethyl)-3,4,5-trifluoro-2-[(3-indolyl-5-indole-2-pyridyl) J^ as a white solid. Benzoylamide. iH-NMR (400MHz, CDC1 3 ) δ ppm: 8.23 (m, 1H), 7.72 (s, 1H), 7.71-7.68 (m, 1H), 7.67-7.64 (m, 1H), 5.81 (br s, 1H ), 3.78 (br s, 4H), 3.61 (br s, 2H), 2.62 (br s, 2H), 2.54 (br s, 2H), 2.30(s, 3H), 1.59(br s, 2H), ESI -MS m/z: 521.2 [M+l]+. Example 6 N-[2-(piperidin-1-yl)ethyl]-3,4,5-trifluoro-2-[(3-indolyl-5-dea-2-pyridyl)]phenylhydrazine Amide
Figure imgf000018_0002
方法同实施例 4 , 得白色固体 Ν-[2- (哌啶 -1-基）乙基] - 3,4,5-三氟 -2- [(3-曱基 -5-碘 -2-吡啶基) J^】苯曱酰胺。 iH-NMR (400MHz， CDC13) δ ppm: 8.23 (m, 1H)， 7.72 (s, 1H)， 7.68-7.64 (m, 1H)， 7.59 (br s, 1H)， 5.80 (br s, 1H)， 3.61-3.59 (m, 2H)， 2.63(br s, 2H)， 2.53 (br s, 4H)， 2.30 (s, 3H)， 1.66 (br s, 4H)， 1.50 (br s, 2H)， ESI-MS m/z:519.2 [M+l】+。 实施例 7 N-苯曱氧基 -3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基)氨基】苯 曱酰胺 The same procedure as in Example 4 gave y-[2-(piperidin-1-yl)ethyl]-3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-) Pyridyl) J^]benzamide. iH-NMR (400MHz, CDC1 3 ) δ ppm: 8.23 (m, 1H), 7.72 (s, 1H), 7.68-7.64 (m, 1H), 7.59 (br s, 1H), 5.80 (br s, 1H) , 3.61-3.59 (m, 2H), 2.63 (br s, 2H), 2.53 (br s, 4H), 2.30 (s, 3H), 1.66 (br s, 4H), 1.50 (br s, 2H), ESI -MS m/z: 519.2 [M+l]+. Example 7 N-Phenyloxy-3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino]benzamide
Figure imgf000018_0003
步骤 1、 2- J^-3-氯 -5-溴吡啶
Figure imgf000018_0003
Step 1, 2-J^-3-chloro-5-bromopyridine
将 2-氨基 -5-溴吡啶（3.0 g, 17.34 mmol ) , 溶于 DMF ( 10 mL ) 中，得深黄色溶液。水浴冷却到 0°C ,加入 NCS ( 2.40 g, 18.03mmol ) , 0°C反应 l h。 向反应体系中加入 30 mL水， 用无水***萃取，有机层用 无水硫酸钠干燥过夜。 次日过滤， 减压蒸除溶剂， 得黑色固体（2.72 g, 75.6% ) ， ESI-MS m/z:207.9[M+l】+。 步骤 2、 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡^) J^】苯曱腈 2-Amino-5-bromopyridine (3.0 g, 17.34 mmol) in DMF (10 mL) In the middle, a dark yellow solution was obtained. The mixture was cooled to 0 ° C in a water bath, and NCS ( 2.40 g, 18.03 mmol) was added and reacted at 0 ° C for 1 h. 30 mL of water was added to the reaction mixture, and the mixture was extracted with anhydrous diethyl ether. Filtration the next day, the solvent was evaporated under reduced pressure to give a white solid (2.72 g, 75.6%), ESI-MS m/z: 207.9 [M+l]+. Step 2, 3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyrrole) J^]benzonitrile
氮气保护条件下， 将 2- J^-3-氯 -5-溴吡啶（ 10.30 g, 0.050 mol ) 和氨基锂 ( 4.58 g, 0.20 mol )加入到 150 mL二曱苯中， 加热到 100°C， 搅拌反应 2 h。 自然降温到室温， 加入 2，3，4，5-四氟苯腈（7.33 g, 0.042 mol ) , 加热到 126 °C， 反应 3.5 h。 将反应液加入到 100 mL乙酸乙酯 中， 搅拌 10 min， 产生大量的黑色固体， 过滤。 黑色固体中包夹有 产物， 用乙酸乙酯少量多次洗涤， 并用超声波超声 5 min。 用 1N 盐酸水溶液洗涤得到的乙酸乙酯层和反应液， 合并有机层， 有机层 干燥过夜， 次日减压蒸除溶剂， 柱层析得淡黄色固体 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基) J^】苯甲腈（4.5 g, 29.6 % ) ， ^ NMR (400MHz, CDC13) δ ppm: 8.16-8.13 (m, 1H)， 7.82-7.81 (m, 1H)， 7.24-7.23 (m, 1H)， 6.57 (br s, 1H)， ESI-MS m/z:363.9 [M+l】+。 步骤 3、 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基) J^】苯甲酸 2-J^-3-chloro-5-bromopyridine (10.30 g, 0.050 mol) and lithium amide (4.58 g, 0.20 mol) were added to 150 mL of diphenylbenzene under nitrogen atmosphere and heated to 100 °C. , stir the reaction for 2 h. Naturally, the temperature was lowered to room temperature, 2,3,4,5-tetrafluorobenzonitrile (7.33 g, 0.042 mol) was added, and the mixture was heated to 126 ° C for 3.5 h. The reaction solution was added to 100 mL of ethyl acetate and stirred for 10 min to yield a large white solid. The product was sandwiched between black solids, washed in small portions with ethyl acetate, and sonicated for 5 min. The obtained ethyl acetate layer and the reaction mixture were washed with 1N aqueous hydrochloric acid, and the organic layer was combined, and the organic layer was dried overnight, and the solvent was evaporated under reduced pressure to give a pale yellow solid 3,4,5-trifluoro-2- [(3-Chloro-5-bromo-2-pyridyl) J^]benzonitrile (4.5 g, 29.6 %), ^ NMR (400MHz, CDC1 3 ) δ ppm: 8.16-8.13 (m, 1H), 7.82 -7.81 (m, 1H), 7.24-7.23 (m, 1H), 6.57 (br s, 1H), ESI-MS m/z: 363.9 [M+l]+. Step 3, 3,4,5-Trifluoro-2-[(3-chloro-5-bromo-2-pyridinyl)J^]benzoic acid
将 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基) J^】苯甲腈 （4.50 g, 12.4 mmmol )溶于无水乙醇： 蒸馏水： THF=100 mL: 50 mL: 15 mL的混合溶剂中，加入氢氧化钾（ 3.48 g )，加热回流，反应 30 h。 减压蒸除溶剂， 得油状物， 用 10 %盐酸水溶液调节 pH值到 1， 乙 酸乙酯萃取， 有机层干燥过夜， 次日减压蒸除溶剂， 得淡黄色固体 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基) J^】苯甲酸（4.27 g， 90.2% ) 。 步骤 4、 N-苯甲氧基 -3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基)氨基】 苯甲酰胺  3,4,5-Trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)J^]benzonitrile (4.50 g, 12.4 mmmol) was dissolved in absolute ethanol: distilled water: THF = 100 mL: 50 mL: 15 mL of a mixed solvent, potassium hydroxide (3.48 g) was added, and the mixture was heated under reflux for 30 h. The solvent was evaporated under reduced pressure to give crystals crystals crystals crystalssssssssssssssssssssssssssssssssssssssssssssssssssssssssss Fluor-2-[(3-chloro-5-bromo-2-pyridyl)J^]benzoic acid (4.27 g, 90.2%). Step 4. N-Benzyloxy-3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino]benzamide
将 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基)^ &】苯甲酸（ 0.22 g, 0.57 mol ) 、 O-苯甲基羟胺 ( 0.13 g, 1.03 mmol ) 、 DIEA ( 0.12 mL, 0.68 mmol )溶于 20 mL二氯甲烷中， 加入 PyBOP ( 0.34 g, 0.65 mmol )，室温搅拌过夜。 向反应体系中加入无水*** 40 mL， 分别 用水、 饱和氯化钠水溶液洗涤有机相， 有机层用无水硫酸钠干燥过 夜。次日过滤，减压蒸除溶剂，柱层析得白色固体 N-苯甲氧基 -3,4,5- 三氟 -2-[(3-氯 -5-溴 -2-吡啶基)氨基】苯甲酰胺（0.16 g, 57.6 % ) 。 ^ NMR (400 MHz, CDC13) δ ppm: 8.98-8.96 (d, 1H， J=10.9 Hz), 8.10 (s, 1H)， 7.79 (s, 1H)， 7.70-7.68 (m, 1H)， 7.45-7.40 (m, 5H)， 6.50 (s, 1H)， 5.06 (s, 2H). ESI-MS m/z: 488.0 [M+l】+ 实施例 8、 N-苯甲氧基 -3,4,5-三氟 -2-[(3-甲基 -5-碘 -2-吡啶基) 氨基】苯甲酰胺
Figure imgf000020_0001
方法同实施例 4 ,得淡黄色固体 Ν-苯曱氧基 -3,4,5-三氟 -2- [(3-曱基 -5- 捵 -2-吡啶基）氨基】苯曱酰胺。 iH-NMR (400 MHz, CDC13) δ ppm: 9.01-8.98 (d, 1H， J=10.2 Hz), 8.22 (s, 1H)， 7.73 (s, 1H)， 7.67-7.66 (m, 1H)， 7.45-7.40 (m, 5H), 5.97 (s, 1H)， 5.06 (s, 2H)， 2.29 (s, 3H). ESI-MS m/z: 514.2 [M+l]+。 实施例 9、 N- ( 3-苯丙基 ) -3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基) J^】 苯曱醜胺 3,4,5-Trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)^ & benzoic acid (0.22 g, 0.57 mol), O-benzylhydroxylamine (0.13 g, 1.03 mmol ), DIEA (0.12 mL, 0.68 mmol) was dissolved in 20 mL of dichloromethane. PyBOP (0.34 g, 0.65 mmol). To the reaction system, 40 mL of anhydrous diethyl ether was added, and the organic layer was washed with water and aq. Filtration the next day, the solvent was evaporated under reduced pressure, and then purified to give white crystals of white crystals of N- benzyloxy-3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino Benzylamide (0.16 g, 57.6 %). ^ NMR (400 MHz, CDC1 3 ) δ ppm: 8.98-8.96 (d, 1H, J = 10.9 Hz), 8.10 (s, 1H), 7.79 (s, 1H), 7.70-7.68 (m, 1H), 7.45 -7.40 (m, 5H), 6.50 (s, 1H), 5.06 (s, 2H). ESI-MS m/z: 488.0 [M+l] + Example 8. N-Benzyloxy-3,4 ,5-trifluoro-2-[(3-methyl-5-iodo-2-pyridyl)amino]benzamide
Figure imgf000020_0001
The procedure was the same as in Example 4 to give a pale-yellow solid of y-phenyl- hydrazino-3,4,5-trifluoro-2-[(3-indolyl-5-indole-2-pyridinyl)amino]benzamide. iH-NMR (400 MHz, CDC1 3 ) δ ppm: 9.01-8.98 (d, 1H, J = 10.2 Hz), 8.22 (s, 1H), 7.73 (s, 1H), 7.67-7.66 (m, 1H), 7.45-7.40 (m, 5H), 5.97 (s, 1H), 5.06 (s, 2H), 2.29 (s, 3H). ESI-MS m/z: 514.2 [M+l] + . Example 9. N-(3-Phenylpropyl)-3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)J^] benzoquinone
Figure imgf000020_0002
Figure imgf000020_0002
方法同实施例 7, 得淡黄色固体 N- ( 3-苯丙基） -3,4,5-三氟 -2-[(3- 氯 -5-溴 -2-吡啶基)氨基】苯曱酰胺。 iH-NMR (400 MHz, CDC13) δ ppm: 8.12-8.11 (d, 1H)， 7.79 (s, 1H)， 7.71-7.67(m, 1H), 7.32-7.19 (m, 5H), 6.64-6.61(m,lH), 6.50(s, 1H)， 3.53-3.47(m, 2H)， 2.75-2.71(t, 2H， J=13.2 Hz), 2.00-1.96(m, 2H)， ESI-MS m/z: 498.1 [M-l】十 。 实施例 10、 N-[(2，2-曱基 -1,3二氧戊环 -4基)曱氧基卜 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基) ^苯曱酰胺 The same procedure as in Example 7 gave N-(3-phenylpropyl)-3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino]phenylhydrazine as a pale yellow solid. Amide. iH-NMR (400 MHz, CDC1 3 ) δ ppm: 8.12-8.11 (d, 1H), 7.79 (s, 1H), 7.71-7.67 (m, 1H), 7.32-7.19 (m, 5H), 6.64-6.61 (m,lH), 6.50(s, 1H), 3.53-3.47(m, 2H), 2.75-2.71(t, 2H, J=13.2 Hz), 2.00-1.96 (m, 2H), ESI-MS m/z: 498.1 [Ml]. Example 10 N-[(2,2-Mercapto-1,3-dioxolan-4-yl)decyloxy 3,4,5-trifluoro-2-[(3-chloro-5-bromo) -2-pyridyl) benzoquinone
Figure imgf000021_0001
Figure imgf000021_0001
将 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基)氨基】苯曱酸（0.40 g, 1.06 mmol ) , 溶于无水 THF 20 mL中， 体系冷却到 -15 °C , 加入二苯膦酰 氯（ 0.27 mL, 1.38 mmol ) , -15 °C反应 30 min。加入 N-曱基吗淋 ( 0.12 mL, 1.06 mmol )， -15°C反应 30 min。 加入 0-[(2，2-二曱基 -1,3-二酮 -4- 基)曱基】羟胺（0.19 g, 1.27 mmol ) , -15 °C反应 30 min。 加入 N-曱基 吗啉（0.18 mL, 1.59 mmol ) , 恢复至室温， 室温搅袢过夜。 反应液中 加入乙酸乙酯 60 mL, 依次用饱和碳酸氢钠水溶液液、饱和氯化钠水溶 液洗涤， 有机层用无水硫酸钠干燥过夜。 次日过滤， 减压蒸除溶剂， 柱 层析的白色固体（ 0.38 g, 71.1 % ) 。 iH-NMR (400 MHz, DMSO-D6) δ ppm: 11.90 (s, 1H)，8.84 (s, 1H),8.17-8.16 (m, 1H)， 8.12-8.11 (m, 1H)， 7.45-7.42 (m, 1H)， 4.36-4.33 (m, 1H)， 4.08-4.06 (m, 1H)， 3.95-3.94 (m, 2H)， 3.77-3.75 (m, lH),1.35(s, 3H)， 1.29(s, 3H). ESI-MS m/z: 512.2 [M+l】+ 。 实施例 11、 （11)- [(2，2-曱基-1，3二氧戊环-4基)曱氧基】- 3，4，5-三氟 -2-[(3-氯 -5-溴 -2-吡1^ ) J^】苯曱酰胺 3,4,5-Trifluoro-2-[(3-chloro-5-bromo-2-pyridinyl)amino]benzoic acid (0.40 g, 1.06 mmol), dissolved in anhydrous THF 20 mL, system Cool to -15 ° C, add diphenylphosphonochloride (0.27 mL, 1.38 mmol), and react at -15 °C for 30 min. N-decyl hydrazine (0.12 mL, 1.06 mmol) was added and the reaction was carried out at -15 ° C for 30 min. 0-[(2,2-Dimercapto-1,3-dione-4-yl)indolyl]hydroxylamine (0.19 g, 1.27 mmol) was added, and the reaction was carried out at -15 °C for 30 min. N-Mercaptomorpholine (0.18 mL, 1.59 mmol) was added, the mixture was taken to room temperature and stirred at room temperature overnight. 60 ml of ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium Filtration the next day, the solvent was evaporated under reduced pressure, and white crystals (0.38 g, 71.1%) iH-NMR (400 MHz, DMSO-D 6 ) δ ppm: 11.90 (s, 1H), 8.84 (s, 1H), 8.17-8.16 (m, 1H), 8.12-8.11 (m, 1H), 7.45-7.42 (m, 1H), 4.36-4.33 (m, 1H), 4.08-4.06 (m, 1H), 3.95-3.94 (m, 2H), 3.77-3.75 (m, lH), 1.35(s, 3H), 1.29 (s, 3H). ESI-MS m/z: 512.2 [M+l]+. Example 11, (11)-[(2,2-Mercapto-1,3-dioxolan-4-yl)nonyloxy]-3,4,5-trifluoro-2-[(3-chloro- 5-bromo-2-pyridyl 1 ^ ) J^]benzamide
氮气保护条件下，将 3，
Figure imgf000021_0002
-2-吡啶基 ) J^】苯曱酸 ( 0.40 g, 1.06 mmol )溶于无水 THF10 mL中， 加入 (R)0-{3 [(叔丁基- 二曱 ·Μ氧基】丙基 }羟胺（ 0.16 g, 1.06 mmol )、 N-曱基吗啉（ 0.30 mL、 2.65 mmol ) ， 将上述体系水浴冷却到 0 。C , 水浴条件下滴加二苯膦酰 氯（0.24 mL, 1.27 mmol ) , 滴加完毕， 恢复至室温， 室温搅拌过夜。 减压蒸除溶剂， 向剩余物中加入乙酸乙酯 20 mL、 水 20 mL， 依次用饱 和碳酸氢钠水溶液、饱和氯化钠水溶液洗涤有机相， ，有机层干燥过夜， 次日减压蒸除溶剂， 柱层析得淡黄色固体 (R)-N-[(2，2-曱基 -1,3二氧戊环 -4基)曱氧基】- 3，4，5-三氟-2-[(3-氯-5-溴-2-吡^ ^】苯曱酰胺（0.41 77.4% )。 匪 R (400 MHz, DMSO-D6) δ ppm: 11.90 (s, 1H)， 8.84 (s, 1H), 8.17-8.16 (m, 1H), 8.12-8.11 (m, 1H), 7.43-7.42 (m, 1H), 4.36-4.33 (m, 1H), 4.08-4.06 (m, 1H), 3.95-3.94 (m, 2H), 3.77-3.75 (m, 1H), 1.35(s, 3H)， 1.29(s, 3H)， ESI-MS m/z: 512.2 [M+l]+。 实施例 12、 （11)- [(2，2-曱基-1，3二氧戊环-4基)曱氧基】- 3，4，5-三氟 -2- [(3-曱基 -5-捵 -2-吡啶基) J^】苯曱酰胺 Under nitrogen protection conditions, will be 3,
Figure imgf000021_0002
-2-pyridyl) J^]benzoic acid (0.40 g, 1.06 mmol) was dissolved in anhydrous THF 10 mL, and (R) 0-{3 [(tert-butyl-difluorenyloxy)propyl group was added. } Hydroxylamine (0.16 g, 1.06 mmol), N-decylmorpholine (0.30 mL, 2.65 mmol), the above system water bath was cooled to 0 ° C, and diphenylphosphonyl was added dropwise under water bath. Chlorine (0.24 mL, 1.27 mmol), after completion of dropwise addition, was taken to room temperature and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and ethyl acetate (20 mL) and water (20 mL) were added to the residue. The organic phase was washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Solvent, column chromatography to give a pale yellow solid (R)-N-[(2,2-mercapto-1,3 dioxolan-4-yl) decyloxy]-3,4,5-trifluoro-2 -[(3-Chloro-5-bromo-2-pyridin^^)benzamide (0.41 77.4%). 匪R (400 MHz, DMSO-D 6 ) δ ppm: 11.90 (s, 1H), 8.84 (s , 1H), 8.17-8.16 (m, 1H), 8.12-8.11 (m, 1H), 7.43-7.42 (m, 1H), 4.36-4.33 (m, 1H), 4.08-4.06 (m, 1H), 3.95 -3.94 (m, 2H), 3.77-3.75 (m, 1H), 1.35 (s, 3H), 1.29 (s, 3H), ESI-MS m/z: 512.2 [M+l] + . (11)-[(2,2-Mercapto-1,3-dioxolan-4-yl)nonyloxy]- 3,4,5-trifluoro-2-[(3-indolyl-5-oxime) -2-pyridyl) J^]benzamide
Figure imgf000022_0001
Figure imgf000022_0001
氮气保护条件下，将 3，4，5-三氟 -2-[(3-曱基 -5-碘 -2-吡啶基) J ^苯曱 酸（ 0.43 g, 1.06 mmol )溶于无水 THF10 mL中， 加入 (R)0-{3 [(叔丁基 -二曱基硅)氧基】丙基 }羟胺（0.16 g, 1.06 mmol )、 N-曱基吗啉（0.30 mL、 2.65 mmol ) ， 将上述体系冰浴冷却到。。C， 水浴条件下滴加二苯膦酰 氯（0.24 mL, 1.27 mmol ) , 滴加完毕， 恢复至室温， 室温搅拌过夜。 减压蒸除溶剂， 向剩余物中加入乙酸乙酯 20 mL、 水 20 mL， 依次用饱 和碳酸氢钠水溶液、饱和氯化钠水溶液洗涤有机相， ，有机层干燥过夜， 次日减压蒸除溶剂， 柱层析得淡黄色固体 (R)-N-[(2，2-曱基 -1,3二氧戊环 -4基)曱氧基】 - 3，4，5-三氟 -2-[(3-曱基 -5-碘 -2-吡啶基) J^】苯曱酰胺（ 0.35 g, 61.8% )。 匪 R (400 MHz, DMSO-D6) δ ppm: 11.85 (s, 1H)， 8.28 (s, 1H)， 8.07-8.06 (m, 1H)， 7.82-7.81 (m, 1H)， 7.40-7.37 (m, 1H)， 4.36-4.33 (m, 1H), 4.08-4.06 (m, 1H), 3.95-3.94 (m, 2H), 3.78-3.75 (m, 1H), 2.26(s, 3H), 1.35(s, 3H), 1.29(s, 3H), ESI-MS m/z: 538.2 [M+l】+。 实施例 13、 N- (环丙曱氧基) - 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基)氨 基】苯曱酰胺
Figure imgf000023_0001
3,4,5-Trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)J^benzoic acid (0.43 g, 1.06 mmol) was dissolved in anhydrous THF 10 under nitrogen atmosphere. In the mL, add (R) 0-{3 [(tert-butyl-didecylsilyloxy) propyl}hydroxylamine (0.16 g, 1.06 mmol), N-decylmorpholine (0.30 mL, 2.65 mmol) , Cool the above system ice bath to. . C. Diphenylphosphonoyl chloride (0.24 mL, 1.27 mmol) was added dropwise under water bath. After the dropwise addition, the mixture was returned to room temperature and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and ethyl acetate (20 mL) and water (20 mL) were added to the residue. The organic phase was washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Solvent, column chromatography to give a pale yellow solid (R)-N-[(2,2-decyl-1,3 dioxolan-4-yl) decyloxy] - 3,4,5-trifluoro-2 -[(3-indolyl-5-iodo-2-pyridyl) J^]benzamide (0.35 g, 61.8%).匪R (400 MHz, DMSO-D 6 ) δ ppm: 11.85 (s, 1H), 8.28 (s, 1H), 8.07-8.06 (m, 1H), 7.82-7.81 (m, 1H), 7.40-7.37 ( m, 1H), 4.36-4.33 (m, 1H), 4.08-4.06 (m, 1H), 3.95-3.94 (m, 2H), 3.78-3.75 (m, 1H), 2.26(s, 3H), 1.35 ( s, 3H), 1.29 (s, 3H), ESI-MS m/z: 538.2 [M+l]+. Example 13. N-(Cyclopropoxycarbonyl)-3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino]benzamide
Figure imgf000023_0001
将 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡1^ ) J^】苯曱酸（0.22 g, 0.58 mmol )溶于无水 THF 15 mL中，加入 N-曱基吗1 ( 0.16 mL， 1.44 mmol ), 将该体系冷却到 -15 °C .同时将二苯基次膦酰氯（ 0.13 mL, 0.69 mmol ) 溶于无水 THF 3 mL的混合体系冷却到 -15 °C。 用蠕动泵将二苯基次膦 酰氯的无水 THF 溶液加入到反应体系中。加入完毕， -15。(：反应 0.5 h。 将冷却到 -15 °( 的22 ( 0.086g, 0.069mmol ) 的 THF: DMF=1: 1溶液 也加入到反应体系中。 加入完毕， -15 °C反应 1.5 h。 体系恢复到室温， 室温搅袢过夜。减压蒸除溶剂，得到深黄色油状物，加入乙酸乙酯溶解， 依次用 1M硫酸氢钠溶液、饱和碳酸氢钠溶液、饱和氯化钠水溶液洗涤， 有机层用无水硫酸钠干燥过夜。 次日过滤， 减压蒸除溶剂， 柱层析得淡 黄色固体 N- (环丙曱氧基) - 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡^) J ^苯曱 酰胺（ O.llg, 42.3% )。 iH-NMR (400 MHz, DMSO-D6) δ ppm: 11.71 (s, 1H), 9.87 (s, 1H), 8.83 (s, 1H), 8.16-8.08 (m, 1H), 7.42-7.39 (m, 1H), 3.74-3.73 (m, 2H)， 1.08-1.04 (m, 1H)， 0.60-0.58 (m, 2H)， 0.29-0.27 (m, 2H), ESI-MS m/z: 451.9 [M+l】+。 实施例 14 N-(3-羟基丙氧基) - 3,4,5-三氟 -2-[(3-曱基 -5-碘 -2-吡1^ ) J ^苯曱酰胺 3,4,5-Trifluoro-2-[(3-chloro-5-bromo-2-pyridin 1 ^)J^]benzoic acid (0.22 g, 0.58 mmol) was dissolved in anhydrous THF 15 mL. Add N-fluorenyl 1 (0.16 mL, 1.44 mmol), cool the system to -15 ° C. Also dissolve diphenylphosphinyl chloride (0.13 mL, 0.69 mmol) in anhydrous THF 3 mL. Cool to -15 °C. An anhydrous THF solution of diphenylphosphinyl chloride was added to the reaction system using a peristaltic pump. Joined, -15. (: Reaction 0.5 h. Cooling to -15 ° (22 (0.086 g, 0.069 mmol) of THF: DMF = 1: 1 solution was also added to the reaction system. After the addition, -15 ° C reaction for 1.5 h. After returning to room temperature, stir at room temperature overnight. Evaporate the solvent under reduced pressure to give a dark-yellow oil, which is dissolved in ethyl acetate, washed sequentially with 1M sodium hydrogen sulfate solution, saturated sodium hydrogen carbonate solution and saturated aqueous sodium chloride, organic layer Dry overnight with anhydrous sodium sulfate. Filter the next day, dilute the solvent under reduced pressure, and then elute to give a pale yellow solid N-(cyclopropyloxy)-3,4,5-trifluoro-2-[(3- bromo-2-chloro-5 ^) J ^ benzene Yue amide (O.llg, 42.3%) iH- NMR (400 MHz, DMSO-D 6) δ ppm:. 11.71 (s, 1H), 9.87 (s , 1H), 8.83 (s, 1H), 8.16-8.08 (m, 1H), 7.42-7.39 (m, 1H), 3.74-3.73 (m, 2H), 1.08-1.04 (m, 1H), 0.60-0.58 (m, 2H), 0.29-0.27 (m, 2H), ESI-MS m/z: 451.9 [M+l] +. Example 14 N-(3-hydroxypropoxy) - 3,4,5- Trifluoro-2-[(3-indolyl-5-iodo-2-pyridin 1 ^ ) J ^benzamide
将实施例 2 中制得的
Figure imgf000023_0002
硅氧基】丙氧基 }-3，4，5- 三氟 -2- [(3-曱基 -5-碘 -2-吡啶基) J^】苯曱酰胺（0.40 g, 0.67 mmol )溶 于 5 mL的无水曱醇中， 加入 5 M的硫酸的曱醇溶液 0.10 mL， 室温搅 拌 l h, 补加 5 M的硫酸的曱醇溶液 0.05 mL, 室温搅拌 2 h。 饱和碳酸 氢钠水溶液调 pH值到 7， 加入蒸馏水 10 mL, 乙酸乙酯萃取， 饱和氯 化钠水溶液洗涤有机层， 有机层用无水硫酸钠干燥过夜。 次日过滤， 减 压蒸除溶剂， 柱层析得淡黄色固体 N-(3-羟基丙氧基) - 3,4,5-三氟 -2-[(3- 曱基 -5-捵 -2-吡啶基) J^】苯曱酰胺（ 0.32 g, 71.2 % )。 Ή-NMR (400 MHz DMSO-D6) δ ppm: 11.77 (s, 1H)， 8.27 (s, 1H)， 8.06-8.05 (m, 1H)， 7.82-7.81 (m, 1H)， 7.39-7.35 (m, 1H)， 4.87-4.86 (d, 1H， J=4.8Hz), 4.64-4.61 (t, 1H， J=5.3 Hz), 3.99-3.96 (m, 1H)， 3.81-3.76 (m, 2H)， 3.41-3.39 (m, 2H), 2.25(s, 3H). ESI-MS m/z: 481.2 [M+l】+。 实施例 15 N-(3-羟基丙氧基) - 3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡啶基) J^】苯曱酰胺 Prepared in Example 2
Figure imgf000023_0002
Silyloxy]propoxy}-3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl) J^]benzamide (0.40 g, 0.67 mmol) To 5 mL of anhydrous decyl alcohol, 0.10 mL of a 5 M solution of sulphuric acid in sulphuric acid was added, and the mixture was stirred at room temperature for 1 hour, and a 0.05 M solution of 5 M sulfuric acid in methanol was added thereto, and the mixture was stirred at room temperature for 2 h. The aqueous sodium hydrogencarbonate solution was adjusted to pH 7 to dryness. EtOAc was evaporated. Filtration the next day, the solvent was evaporated under reduced pressure, and then purified by column chromatography to give a pale yellow solid N-(3-hydroxypropoxy) - 3,4,5-trifluoro-2-[(3- Mercapto-5-indole-2-pyridyl) J^]benzamide (0.32 g, 71.2%). Ή-NMR (400 MHz DMSO-D 6 ) δ ppm: 11.77 (s, 1H), 8.27 (s, 1H), 8.06-8.05 (m, 1H), 7.82-7.81 (m, 1H), 7.39-7.35 ( m, 1H), 4.87-4.86 (d, 1H, J=4.8Hz), 4.64-4.61 (t, 1H, J=5.3 Hz), 3.99-3.96 (m, 1H), 3.81-3.76 (m, 2H) , 3.41-3.39 (m, 2H), 2.25 (s, 3H). ESI-MS m/z: 481.2 [M+l]+. Example 15 N-(3-Hydroxypropoxy)-3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl) J^]benzamide
Figure imgf000024_0001
Figure imgf000024_0001
方法同实施例 14,得白色固体 N-(3-羟基丙氧基) - 3,4,5-三氟 -2-[(3- 曱基 -5-破 -2-吡啶基 ) J^】苯曱酰胺。 iH-NMR (400 MHz, DMSO-D6) δ ppm: 11.82 (s, 1H)， 8.84 (s, 1H)，8.17-8.12 (m, 2H)， 7.44-7.41 (m, 1H)， 3.81-3.76 (m, 2H), 3.41-3.39 (m, 4H)。 ESI-MS m/z: 454.6 [M+l】+。 实施例 16 (R)-N-(2，3-二羟基丙氧基) - 3,4,5-三氟 -2- [(3-曱基 -5-破 -2- -比啶基) J ^苯曱酰胺 The same procedure as in Example 14 gave N-(3-hydroxypropoxy)-3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridyl) Benzoylamide. iH-NMR (400 MHz, DMSO-D 6 ) δ ppm: 11.82 (s, 1H), 8.84 (s, 1H), 8.17-8.12 (m, 2H), 7.44-7.41 (m, 1H), 3.81-3.76 (m, 2H), 3.41-3.39 (m, 4H). ESI-MS m/z: 454.6 [M+l]+. Example 16 (R)-N-(2,3-Dihydroxypropoxy)-3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-indolyl) J benzoquinone
Figure imgf000024_0002
Figure imgf000024_0002
将实施例 3中制得的 N-[(2，2-曱基 -1,3二氧戊环 -4基)曱氧基卜 3,4,5- 三氟 -2- [(3-曱基 -5-破 -2-吡啶基) J ^苯曱酰胺（0.21 g, 0.39 mmol )加 入到曱醇（ 5 mL )和水（ 0.5 mL )的混合溶剂中， 加入对曱苯磺酸一水 合物（0.037 g, 0.196 mmol )， 室温搅袢 18 h。 浓缩反应液， 加入水 10 mL, 乙酸乙酯萃取， 依次用饱和碳酸氢钠溶液、 饱和氯化钠水溶液洗 涤， 有机层用无水硫酸钠干燥过夜。 次日过滤， 减压蒸除溶剂， 柱层析 得深黄色颗粒状固体 (R)-N-(2，3-二羟基丙氧基) - 3,4,5-三氟 -2- [(3-曱基 -5- 破 -2-吡啶基)氨基】苯曱酰胺（0.14 g, 72.2% ) 。 iH-NMR (400 MHz, DMSO-D6) δ ppm: 8.23 (s, 1H)， 7.73 (s, 1H)， 7.64-7.60 (m, 1H)， 7.49-7.48 -£Z-
Figure imgf000025_0001
N-[(2,2-Mercapto-1,3-dioxolan-4-yl)decyloxy 3,4,5-trifluoro-2-[(3-oxime) prepared in Example 3. Benzyl-5-bromo-2-pyridyl) J^benzamide (0.21 g, 0.39 mmol) was added to a mixed solvent of decyl alcohol (5 mL) and water (0.5 mL), and p-toluenesulfonic acid monohydrate was added. (0.037 g, 0.196 mmol), stirred at room temperature for 18 h. The reaction mixture was concentrated, EtOAc EtOAc EtOAc. Filtration the next day, the solvent was evaporated under reduced pressure, and then purified by column chromatography to give (D)-N-(2,3-dihydroxypropoxy)-3,4,5-trifluoro-2-[( 3-mercapto-5-bromo-2-pyridyl)amino]benzamide (0.14 g, 72.2%). iH-NMR (400 MHz, DMSO-D 6 ) δ ppm: 8.23 (s, 1H), 7.73 (s, 1H), 7.64-7.60 (m, 1H), 7.49-7.48 -£Z-
Figure imgf000025_0001
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ιοεε薦 IOZXD/工：) d 6ST0CI/Z10Z OAV 方法同实施例 4, 得淡黄色固体 N- ( 2-吗啉乙基） -3,4,5-三氟 -2-[(3- 曱基 -5-溴 -2-吡啶基) J ^苯曱酰胺。 iH-NMR (400 MHz, DMSO-D6) δ ppm: 8.42(m, IH), 8.27(s, IH), 7.96(m, IH), 7.72(m, IH), 7.35-7.32(m, 1H)， 3.59-3.57(m, 4H)， 3.40-3.37(m, 2H)， 2.49-2.42(m, 6H), 2.28(s, 3H)， ESI-MS m/z: 473.3 [M+l】+。 实施例 20 N-[2- (哌啶 -1-基）乙基】 - 3，4，5-三氟 -2-[(3-曱基 -5-溴 -2-吡 ) J ^苯曱酰胺
Figure imgf000026_0001
ιοεεRecommended IOZXD/Work:) d 6ST0CI/Z10Z OAV The same procedure as in Example 4 gave N-(2-morpholinethyl)-3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridyl) Benzoylamide. iH-NMR (400 MHz, DMSO-D 6 ) δ ppm: 8.42 (m, IH), 8.27 (s, IH), 7.96 (m, IH), 7.72 (m, IH), 7.35-7.32 (m, 1H) ), 3.59-3.57(m, 4H), 3.40-3.37(m, 2H), 2.49-2.42(m, 6H), 2.28(s, 3H), ESI-MS m/z: 473.3 [M+l]+ . Example 20 N-[2-(piperidin-1-yl)ethyl]-3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridyl)J^phenylhydrazine Amide
Figure imgf000026_0001
方法同实施例 4, 得淡黄色固体 N-[2- (哌啶 -1-基)乙基】 - 3，4，5-三氟 -2-[(3-曱基 -5-溴 _2_吡啶基）氨基】苯曱酰胺。 iH-NMR (400 MHz, DMSO-D6) δ ppm: 8.39(m, 1H)， 8.27(s, 1H)， 7.96 (m, 1H)， 7.72 (m, IH), 7.34-7.33 (m, 1H)， 3.37-3.34 (m, 2H)， 2.450-2.40(m, 6H), 2.28(s, 3H)， 1.51-1.50(m, 4H), 1.39-1.38 (m, 2H), ESI-MS m/z: 471.2 [M+l】+。 实施例 21 N- ( 3-苯丙基） -3,4,5-三氟 -2-[(3-曱基 -5-碘 -2-吡1^ ) J ^苯曱酰胺 The method was the same as in Example 4 to give a pale yellow solid N-[2-(piperidin-1-yl)ethyl] -3,4,5-trifluoro- 2 -[(3-indolyl-5-bromo- 2) _Pyridinyl)amino]benzamide. iH-NMR (400 MHz, DMSO -D 6) δ ppm: 8.39 (m, 1H), 8.27 (s, 1H), 7.96 (m, 1H), 7.72 (m, IH), 7.34-7.33 (m, 1H ), 3.37-3.34 (m, 2H), 2.450-2.40 (m, 6H), 2.28 (s, 3H), 1.51-1.50 (m, 4H), 1.39-1.38 (m, 2H), ESI-MS m/ z: 471.2 [M+l]+. Example 21 N-(3-Phenylpropyl)-3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridin 1 ^)J^benzamide
Figure imgf000026_0002
Figure imgf000026_0002
方法同实施例 4, 得深黄色固体 N- ( 3-苯丙基） -3,4,5-三氟 -2-[(3- 曱基 -5-捵 -2-吡啶基) J ^苯曱酰胺。 iH-NMR (400MHz, CDC13) δ ppm: 8.23 (s, 1H)， 7.76 (s, 1H)， 7.67-7.64 (m, 1H)， 7.28-7.20 (m, 5H), 6.66 (br s, 1H)， 6.17 (br s, 1H)， 3.52-3.49 (m, 2H)， 2.74-2.71 (t, 2H， J=7.6Hz), 2.29 (s, 3H), 1.99-1.96 (m, 2H)。 ESI-MS m/z: 526.3 [M+l】+。 The same procedure as in Example 4 gave a dark yellow solid N-(3-phenylpropyl)-3,4,5-trifluoro-2-[(3-indolyl-5-indole-2-pyridyl)J^benzene Amide amide. iH-NMR (400MHz, CDC1 3 ) δ ppm: 8.23 (s, 1H), 7.76 (s, 1H), 7.67-7.64 (m, 1H), 7.28-7.20 (m, 5H), 6.66 (br s, 1H ), 6.17 (br s, 1H), 3.52-3.49 (m, 2H), 2.74-2.71 (t, 2H, J = 7.6 Hz), 2.29 (s, 3H), 1.99-1.96 (m, 2H). ESI-MS m/z: 526.3 [M+l]+.
实施例 22 N- [2- ( 啶 -1-基）乙基卜 3,4,5-三氟 -2- [(3-氯 -5-溴 -2-吡啶 基)氨基】苯曱酰胺
Figure imgf000026_0003
方法同实施例 4, 得深黄色固体 N-[2- (哌啶 -1-基）乙基】 - 3，4，5-三氟 ^-^-氯^-溴^-吡^^！^^^苯曱酰胺。 iH-NMR (400 MHz, DMSO-D6) δ ppm: 8.81 (s, 1H), 8.15-8.11 (s, 2H), 7.39-7.36 (m, 1H), 3.36-3.34 (m, 2H), 2.43-2.38 (m, 6H), 1.51-1.49 (m, 6H)。 ESI-MS m/z: 493.1 [M+l】+。 实施例 23、 5-[(5-礁 -3-曱基 2-吡啶基)氨基卜4-氟 -1H-苯并咪唑 -6-曱 酸 Example 22 N-[2-(Acridin-1-yl)ethyl b 3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino]phenyl hydrazide
Figure imgf000026_0003
The same procedure as in Example 4 gave a dark-yellow solid N-[2-(piperidin-1-yl)ethyl] -3,4,5-trifluoro^-^-chloro^-bromo^-pyr^^! ^^^Benzanamide. iH-NMR (400 MHz, DMSO-D 6 ) δ ppm: 8.81 (s, 1H), 8.15-8.11 (s, 2H), 7.39-7.36 (m, 1H), 3.36-3.34 (m, 2H), 2.43 -2.38 (m, 6H), 1.51-1.49 (m, 6H). ESI-MS m/z: 493.1 [M+l]+. Example 23, 5-[(5-Resal-3-indolyl 2-pyridyl)amino-4-fluoro-1H-benzimidazole-6-decanoic acid
Figure imgf000027_0001
Figure imgf000027_0001
步骤 1、 5-硝基 -2,3,4-三氟苯曱酸  Step 1. 5-Nitro-2,3,4-trifluorobenzoic acid
将发烟硝酸（ 37 mL, 0.78 mol )水浴条件下緩慢滴加到浓硫酸（ 200 mL )中，在另外一个反应体系中，加入 2,3,4-三氟苯曱酸（109.4 g, 0.62 mol ) 以及浓硫酸 330mL。 水浴条件下将发烟硝酸的浓硫酸溶液緩慢滴 加到反应原料的浓硫酸溶液中。 撤掉水浴， 自然升温至室温， 搅拌反应 5h。 搅拌条件下将反应溶液緩慢滴加到 2000mL的水水溶液中， 室温搅 拌 2h,静置过夜，过滤得到白色固体 5-硝基 -2,3,4-三氟苯曱酸（ 123.7 g, 90.3% ) , ESI-MS m/z: 222.0[M+1]+ 步骤 2、 5-硝基 -3，4-二氟 -2-[(5-碘 -3-曱基 2-吡1^ )氨基卜苯曱酸 氮气保护条件下，将 2-氨基 -3-曱基 -5-捵吡啶（10.61g, 0.045mol ) , 溶于 70mL无水四氢呋喃（ THF )中， 降温到 -70° (：。将 2M的二异丙基 ^锂 ( LDA )的 THF溶液滴（ 34mL， 0.068mol )加到反应体系中， -70°C条件下反应 lh。 向反应体系中滴加 5-硝基 -2,3,4-三氟苯曱酸 ( 5.01g, 0.023mol )的 THF溶液， 滴加完毕， -70°C反应 lh。 自然升温 到室温， 室温搅拌过夜。 依次饱和氯化铵水溶液、 饱和氯化钠水溶液洗 涤， 乙酸乙酯提取水层， 有机层干燥过夜， 柱层析得到黄色固体 5-硝基 -3,4-二氟 -2-[(5-碘 -3-曱基 2-吡啶基)氨基卜苯曱酸（4.78g, 47.8% ) , 匪 R (400 MHz, CDC13) δ ppm: 8.26-8.25 (m, 1H), 7.76-7-75(br s, 1H)， 7.21-7.19 (m, 1H)， 5.99 (s, 1H)， 2.31(s,3H), ESI-MS m/z: 436.0 [M+l】+。 步骤 3、 5-硝基 -4-氨基 -3-氟 -2-[(5-碘 -3-曱基 2-吡啶基 ) J^】-苯曱酸 将 5-硝基 -3,4-二氟 -2-[(5-碘 -3-曱基 2-吡啶基) J^】-苯曱酸（ 2.30g, 5.29mmol )加入到 lOOmL蒸馏水中， 降温到 0°C。 向反应体系中逐滴 加入浓氨水（ 2.21mL, 29.6mmol ) , 0°C反应 lh。 自然恢复至室温， 反 应 4h, 过滤得黄色固体 5-硝基 -4- J^-3-氟 -2-[(5-捵 -3-曱基 2-吡^)氨 基卜苯曱酸（1.82g, 79.5% ) , ^-NMR (400 MHz, CDC13) δ ppm: 8.26-8.25 (m, 1H)， 7.76-7-75(br s, 1H)， 7.21-7.19 (m, 1H)， 6.27 (s, 2H)， 5.99 (s, 1H)， 2.31(s，3H)， ESI-MS m/z: 433.1 [M+l]+。 步骤 4、 5-硝基 -4-氨基 -3-氟 -2-[(5-碘 -3-曱基 2-吡啶基 ) J^】-苯曱酸 曱酯 The fuming nitric acid (37 mL, 0.78 mol) was slowly added dropwise to concentrated sulfuric acid (200 mL) in a water bath. In another reaction system, 2,3,4-trifluorobenzoic acid (109.4 g, 0.62) was added. Mol) and 330 mL of concentrated sulfuric acid. A concentrated sulfuric acid solution of fuming nitric acid was slowly added dropwise to the concentrated sulfuric acid solution of the reaction raw material under water bath conditions. The water bath was removed, and the temperature was naturally raised to room temperature, and the reaction was stirred for 5 hours. The reaction solution was slowly added dropwise to a 2000 mL aqueous solution under stirring, stirred at room temperature for 2 h, allowed to stand overnight, and filtered to give a white solid 5-nitro-2,3,4-trifluorobenzoic acid (123.7 g, 90.3%) , ESI-MS m/z: 222.0 [M+1] + step 2, 5-nitro-3,4-difluoro-2-[(5-iodo-3-indolyl-2-pyridyl 1 ^ )amino 2-Amino-3-indolyl-5-indole pyridine (10.61 g, 0.045 mol) was dissolved in 70 mL of anhydrous tetrahydrofuran (THF) under a nitrogen-protected solvent, and then cooled to -70. 2M of diisopropyl lithium (LDA) in THF solution (34 mL, 0.068 mol) was added to the reaction system, and reacted at -70 ° C for 1 h. To the reaction system, 5-nitro-2 was added dropwise. 3,4-Trifluorobenzoic acid (5.01 g, 0.023 mol) in THF, after completion of dropwise addition, reaction at -70 ° C for 1 h. Naturally warm to room temperature, stir at room temperature overnight. Saturated aqueous ammonium chloride solution, saturated chlorination The sodium aqueous solution was washed, the aqueous layer was extracted with ethyl acetate, and the organic layer was dried overnight, and then purified to give a yellow solid 5- nitro-3,4-difluoro-2-[(5-iodo-3-indolyl 2-pyridyl) ) aminobenzic acid (4.78g, 47.8%), 匪R (400 MHz, CDC1 3 ) δ ppm: 8.26-8.25 (m, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 5.99 (s, 1H), 2.31 (s, 3H), ESI-MS m/z: 436.0 [M+l 】+. Step 3. 5-Nitro-4-amino-3-fluoro-2-[(5-iodo-3-indolyl 2-pyridyl)J^]-benzoic acid 5-nitro-3,4- Difluoro-2-[(5-iodo-3-indolyl 2-pyridyl)J^]-benzoic acid ( 2.30 g, 5.29 mmol) was added to 100 mL of distilled water and cooled to 0 °C. Concentrated aqueous ammonia ( 2.21 mL, 29.6 mmol) was added dropwise to the reaction system, and reacted at 0 ° C for 1 h. Naturally returned to room temperature, reacted for 4 h, and filtered to give a yellow solid, 5-nitro-4-J^-3-fluoro-2-[(5-indole-3-indolyl-2-pyridyl)aminobenzoic acid (1.82) g, 79.5%), ^-NMR (400 MHz, CDC1 3 ) δ ppm: 8.26-8.25 (m, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.27 (s, 2H), 5.99 (s, 1H), 2.31 (s, 3H), ESI-MS m/z: 433.1 [M+l] + . Step 4. 5-Nitro-4-amino-3-fluoro-2-[(5-iodo-3-indolyl 2-pyridyl) J^]-benzoic acid decyl ester
将 5-硝基 -4-氨基 -3-氟 -2- [(5-碘 -3-曱基 2-吡啶基)氨基卜苯曱酸（ 1.82 g, 4.21mmol )溶于 20 mL无水曱醇中，緩慢滴加三曱基氯硅烷（ 1.06 mL, 8.42mmol )。 滴加完毕， 回流 12 h。 水泵减压蒸除溶剂以及过量的三曱 基氯硅烷， 得淡黄色液体， 加入二氯曱烷 20 mL, 并用 10 %的氢氧化 钠水溶液洗涤， 二氯曱烷反提水层， 合并有机层， 有机层用无水硫酸钠 干燥过夜。 次日过滤， 减压蒸除溶剂， 得黄色固体 5-硝基 -4-氨基 -3-氟 -2-[(5-碘 -3-曱基 2-吡啶基) J^】-苯曱酸曱酯（ 1.84 g, 97.9 % )， ^-NMR (400 MHz, CDC13) δ ppm: 8.26-8.25 (m, 1H), 7.76-7-75(br s, 1H)， 7.21-7.19 (m, 1H)， 6.27 (s, 2H)， 5.99 (s, 1H)， 3.97 (s, 3H), 2.31(s，3H)， ESI-MS m/z: 447.1 [M+l]+。 步骤 5、 5-[(5-破 -3-曱基 2-吡啶基)氨基】 -4-氟 -1H-苯并咪唑 -6-曱酸曱 酯 5-Nitro-4-amino-3-fluoro-2-[(5-iodo-3-indolyl 2-pyridyl)aminopropionic acid (1.82 g, 4.21 mmol) was dissolved in 20 mL of anhydrous hydrazine. Tridecylchlorosilane (1.06 mL, 8.42 mmol) was slowly added dropwise to the alcohol. After the addition was completed, reflux was carried out for 12 h. The pump is distilled off under reduced pressure and the excess trimethyl chlorosilane is obtained as a pale yellow liquid. 20 mL of dichloromethane is added and washed with a 10% aqueous sodium hydroxide solution, and the aqueous layer is combined with dichloromethane. The organic layer was dried over anhydrous sodium sulfate overnight. Filtration the next day, and the solvent was evaporated under reduced pressure to give a white solid, 5-nitro-4-amino-3-fluoro-2-[(5-iodo-3-indolyl-2-pyridyl)J^]-benzoic acid Oxime ester ( 1.84 g, 97.9 % ), ^-NMR (400 MHz, CDC1 3 ) δ ppm: 8.26-8.25 (m, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.27 (s, 2H), 5.99 (s, 1H), 3.97 (s, 3H), 2.31 (s, 3H), ESI-MS m/z: 447.1 [M+l] + . Step 5, 5-[(5-But-3-indolyl 2-pyridyl)amino]-4-fluoro-1H-benzimidazole-6-decanoate
将 5-硝基 -4- J^-3-氟 -2-[(5-捵 -3-曱基 2-吡啶基 ) J^】-苯曱酸曱酯 ( 1.84g , 4.12mmol ) 、 曱酸 (25 mL)以及 20% Pd(OH)/C (1.57 g, 2.95mrnol)在 25 mL乙醇 中加热至 95°C 。 16 小时后， 将反应混合物 冷却至室温， 并添加 0.5 g 20% Pd(OH)2/C和 10mL 曱酸。 将反应混 合物加热至 95 V 。 16 小时后， 将反应混合物冷却至室温， 并通过硅 藻土过滤， 用乙醇洗涤。 减压浓缩滤液， 有固体析出， 过滤得到深黄色 固体 5-[(5-礁 -3-曱基 2-吡啶基)氨基】 -4-氟 -1H-苯并咪唑 -6-曱酸曱酯 ( 1.35g, 76.7% )， Ή-NMR (400 MHz, CDC13) δ ppm: 8.41-8.39 ( m, 1H )， 8.19 ( ( s, 1H )， 7.76-7-75(br s, 1H)， 7.21-7.19 (m, 1H)， 6.21 (s, 1H)， 5.99 (s, 1H)， 3.97 (s, 3H), 2.31(s，3H)， ESI-MS m/z: 427.1 [M+l】+。 步骤 6、 5-[(5-捵 -3-曱基 2-吡1^ ^卜4-氟 -1H-苯并咪唑 -6-曱酸 将 5-[(5-破 -3-曱基 2-吡啶基)氨基卜4-氟 -1H-苯并咪唑 -6-曱酸曱酯 ( 1.35g 3.17mmol )悬浮在曱醇中 (30 mL) 中，加入 20% NaOH (8mL), 16 h后，将反应混合物冷却至 0°C ，并滴加 1 NHC1溶液，直至 pH为 2-3 。 将反应混合物用乙酸乙酯和水稀释， 并分离各层。 用饱和氯化钠 水溶液洗漆有机层， 有机层用无水硫酸钠干燥过夜。 次日过滤， 减压蒸 除溶剂， 柱层析得深黄色固体 5-[(5-碘 -3-曱基 2-吡啶基)氨基卜4-氟 -1H- 苯并咪唑 -6-曱酸（ 0.68g， 52.3% ) , ^-NMR (400 MHz, CDC13) δ ppm: 8.41-8.39 ( m, 1H ) , 8.19 ( ( s, 1H ) , 7.76-7-75(br s, 1H), 7.21-7.19 (m， 1H)， 6.21 (s, 1H)， 5.99 (s, 1H)， 2.31(s，3H)， ESI-MS m/z: 413.1 [M+l】+。 实施例 24、N-[2- (噻吩 -2-基）乙基】 -5-[(5-碘 -3-曱基 2-吡1^ ) J^】-4- 氟 -1H-苯并咪唑 -6-曱酰胺 5-Nitro-4-J^-3-fluoro-2-[(5-indole-3-indenyl 2-pyridyl) J^]-benzoic acid decyl ester ( 1.84 g, 4.12 mmol), hydrazine The acid (25 mL) and 20% Pd(OH)/C (1.57 g, 2.95 mrnol) were heated to 95 ° C in 25 mL ethanol. After 16 hours, the reaction mixture was cooled to room temperature, and 0.5 g of 20% Pd(OH) 2 / C and 10 mL of decanoic acid were added. The reaction mixture was heated to 95 V. After 16 hours, the reaction mixture was cooled to rt and filtered over EtOAc EtOAc. The filtrate was concentrated under reduced pressure, and a solid was precipitated, which was filtered to give a dark-yellow solid 5-[(5- </RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI> 2-pyridyl 2-pyridyl)amino]-4-fluoro-1H-benzimidazole-6-decanoate ( 1.35g, 76.7% ), Ή-NMR (400 MHz, CDC1 3 ) δ ppm: 8.41-8.39 ( m, 1H ), 8.19 ( ( s, 1H ), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 3.97 (s, 3H), 2.31 (s, 3H), ESI-MS m/z: 427.1 [M+l] +. Step 6, 5-[(5-捵-3-indolyl 2-pyridyl 1 ^^ 4-fluoro-1H-benzimidazole-6-decanoic acid 5--((5- broken-3-曱) 2-Pyryl 2-pyridyl)amino-4-fluoro-1H-benzimidazole-6-decanoate ( 1.35 g 3.17 mmol) was suspended in methanol (30 mL), 20% NaOH (8 mL), 16 After h, the reaction mixture was cooled to 0 ° C, and 1 NHC1 solution was added dropwise until pH 2-3. The reaction mixture was diluted with ethyl acetate and water, and the layers were separated and washed with saturated aqueous sodium chloride The organic layer was dried over anhydrous sodium sulfate overnight. filtered over Celt. -Fluoro-1H-benzimidazole-6-decanoic acid (0.68g, 52.3%), ^-NMR (400 MHz, CDC1 3 ) δ ppm: 8.41-8.39 ( m, 1H ) , 8.19 ( ( s, 1H ) , 7.76-7-75(br s, 1H), 7.21-7.19 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 2.31 (s, 3H), ESI-MS m/z: 413.1 [M+l] +. Example 24, N-[2-(thiophen-2-yl)ethyl] -5-[(5 -iodo-3-indolyl 2-pyridyl 1 ^ ) J^]-4-fluoro-1H-benzimidazole-6-indoleamide
Figure imgf000029_0001
将实施例 23中制得的 35-[(5-碘 -3-曱基 2-吡啶基)氨基卜4-氟 -1H-苯 并咪唑 -6-曱酸 ( 0.23 g, 0.57 mol ) 、 2- (噻吩 -2-基） 乙胺 ( 0.13 g, 1.03 mmol )、 DIEA ( 0.12 mL, 0.68 mmol )溶于 20 mL二氯曱烷中， 加入 PyBOP ( 0.34 g, 0.65 mmol )室温搅拌过夜。 向反应体系中加入无 水*** 40 mL, 分别用水、 饱和氯化钠水溶液洗、涤有机相， 有机层用无 水硫酸钠干燥过夜。 次日过滤， 减压蒸除溶剂， 柱层析得淡黄色固体 N-[2- (噻吩 -2-基）乙基】 -5-[(5-捵 -3-曱基 2-吡啶基)氨基】 -4-氟 -1H-苯并咪 唑 -6-曱酰胺 （ 0.17 g , 56.7% ) , ^-NMR (400 MHz, CDC13) δ ppm:8.41-8.39 ( m, 1H ) , 8.19 ( ( s, 1H ) , 7.76-7-75(br s, 1H), 7.21-7.19 (m， 1H)， 6.98-6.96 (m, 2H)， 6.89-6.88 (m, 1H)， 6.21 (s, 1H)， 5.99 (s, 1H)， 6.75-6.78 (m, 1H), 3.78-3.75 (m, 2H), 3.18-3.15 (t, 2H, J=6.7Hz), 2.31(s,3H), ESI-MS m/z: 522.0 [M+l]+。 实施例 25、N- [2- (哌啶 -1-基）乙基】 -5- [(5-捵 -3-曱基 2-吡1 ¾J J^】-4- 氟 -1H-苯并咪唑 -6-曱酰胺
Figure imgf000029_0001
35-[(5-iodo-3-indolyl 2-pyridyl)amino-4-fluoro-1H-benzimidazole-6-decanoic acid (0.23 g, 0.57 mol), 2 obtained in Example 23. -(Thien-2-yl)ethylamine (0.13 g, 1.03 mmol), DIEA (0.12 mL, 0.68 mmol). To the reaction system, 40 mL of anhydrous diethyl ether was added, and the organic phase was washed with water and a saturated aqueous solution of sodium chloride, and the organic layer was dried over anhydrous sodium sulfate. Filtration the next day, distilling off the solvent under reduced pressure and chromatography to give a pale yellow solid N-[2-(thiophen-2-yl)ethyl] -5-[(5-indole-3-indolyl 2-pyridyl) Amino] 4-fluoro-1H-benzimidazole-6-indoleamide (0.17 g, 56.7%), ^-NMR (400 MHz, CDC1 3 ) δ ppm: 8.41-8.39 (m, 1H), 8.19 ( s, 1H), 7.76-7-75(br s, 1H), 7.21-7.19 (m, 1H), 6.98-6.96 (m, 2H), 6.89-6.88 (m, 1H), 6.21 (s, 1H) , 5.99 (s, 1H), 6.75-6.78 (m, 1H), 3.78-3.75 (m, 2H), 3.18-3.15 (t, 2H, J=6.7Hz), 2.31(s,3H), ESI-MS m/z: 522.0 [M+ l] + . Example 25, N-[2-(piperidin-1-yl)ethyl]-5-[(5-捵-3-indolyl-2-pyridyl 1 3⁄4J J^]-4-fluoro-1H-benzo Imidazole-6-indoleamide
Figure imgf000030_0001
Figure imgf000030_0001
方法同实施例 24， 得得黄色固体 N-[2- (哌啶 -1-基)乙基】 -5-[(5-破 -3- 曱基 2-吡1 ¾^) J^】-4-氟 -1H-苯并咪唑 -6-曱酰胺， ^-NMR (400 MHz, DMSO-D6) δ ppm:8.41-8.39 ( m, 1H ) , 8.19 ( ( s, 1H )， 7.76-7-75(br s, 1H)， 6.89-6.88 (m, 1H)， 6.21 (s, 1H)， 5.99 (s, 1H)， 6.75-6.78 (m, 1H)， 3.36-3.34 (m, 2H)， 2.43-2.38 (m, 6H), 2.31(s，3H)， 1.51-1.49 (m, 6H), ESI-MS m/z: 523.1 [M+l]+。 实施例 26、 活性测试 The same procedure as in Example 24 gave a yellow solid N-[2-(piperidin-1-yl)ethyl] -5-[(5-bromo-3-indolyl-2-pyridyl 1 3⁄4^) J^]- 4-fluoro-1H-benzimidazole-6-indoleamide, ^-NMR (400 MHz, DMSO-D 6 ) δ ppm: 8.41-8.39 ( m, 1H ) , 8.19 ( ( s, 1H ), 7.76-7 -75(br s, 1H), 6.89-6.88 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 6.75-6.78 (m, 1H), 3.36-3.34 (m, 2H), 2.43-2.38 (m, 6H), 2.31 (s, 3H), 1.51-1.49 (m, 6H), ESI-MS m/z: 523.1 [M+l] + . Example 26, Activity Test
对实施例 1-25 中的部分化合物进行了初步活性测试， 评价了化合 物在体外抑制骨髓性白血病细胞 ( K562 )和人大肠癌细胞 ( HT-29 )肿 瘤细胞增殖的活性。  A preliminary activity test was carried out on some of the compounds in Examples 1-25 to evaluate the activity of the compounds in inhibiting the proliferation of myeloid leukemia cells (K562) and human colorectal cancer cells (HT-29) tumor cells in vitro.
培养的肿瘤细胞生长至一定密度后，贴壁细胞用 0.25 %胰蛋白酶消 化 2-5 min, 悬浮细胞离心（ 1000 rpm/min ) ， 用细胞相应培养液制备 单细胞悬液， 调整细胞浓度至相应密度（lxlO5个 /mL ) , 接种于 96孔 培养板， 100 μΐ孔， 37°C、 5 % C02下培养 24 h后先加入 80μΙ孔相 应细胞的全培养基， 再加入不同浓度的受试化合物 20μΐ孔， 每种处理 设 3个重复， 37°C 、 5 % C02下继续培养 72h后，每孔吸出上清 ΙΟΟμ , 再加入 5mg/mL的噻唑蓝（ MTT )溶液 ΙΟμ , 37°C继续孵育 4h, 最后 每孔加入 ΙΟΟμΙ^ 10%的 SDS， 37°C 5 % C02下孵育 24 h,使 MTT结晶 完全溶解。 酶联免疫检测仪 570nm波长测定每孔吸光度。 按公式： After the cultured tumor cells grow to a certain density, the adherent cells are digested with 0.25% trypsin for 2-5 min, and the suspension cells are centrifuged (1000 rpm/min), and the single cell suspension is prepared by using the corresponding culture medium to adjust the cell concentration to corresponding Density (lxlO 5 / mL), inoculated in 96-well culture plate, 100 μΐ well, cultured at 37 ° C, 5 % C0 2 for 24 h, then added the whole medium of the corresponding cells of 80 μ pupil, and then added different concentrations of the affected medium. Try compound 20μΐ, each treatment is set to 3 repetitions, continue to culture for 72h at 37°C and 5 % C02, then aspirate the supernatant 每μ per well, then add 5mg/mL thiazolyl blue (MTT) solution ΙΟμ, 37°C Incubation was continued for 4 h, and finally 10% SDS was added to each well, and incubated at 37 ° C for 5 h under C 2 2 to completely dissolve the MTT crystal. The absorbance per well was measured by an enzyme-linked immunosorbent assay at a wavelength of 570 nm. According to the formula:
抑制率（％ ) = ( 1—受试孔 OD值 /溶剂对照孔平均 OD值） χ100% 计算抑制率， 并以受试化合物浓度的对数为横坐标， 细胞抑制率平 均值为纵坐标绘制剂量效应曲线， 并用 Origin分析软件求半数细胞抑 制剂量值 ( IC50 ) 。 Inhibition rate (%) = (1—the OD value of the test well/the average OD value of the solvent control well) χ100% Calculate the inhibition rate, and take the logarithm of the concentration of the test compound as the abscissa, and the average value of the cell inhibition rate as the ordinate. Dose-response curve, and use the analysis software to find half of the cells Dosage value (IC 50 ).
其中 K562 细胞的培养基为 1640+10%FBS， HT-29 的培养基为 DMEM(Hg)+F12+5%FBS0 The medium of K562 cells was 1640+10% FBS, and the medium of HT-29 was DMEM(Hg)+F12+5%FBS 0
测试前用 DMSO ( Sigma )将药物配至母液浓度， 用不含因子的 全培养基稀释至所需应用浓度。初步评价化合物对于肿瘤细胞的生长抑 制作用时， 选用化合物浓度为 3、 30、 300μΜ三个剂量组、 空白对照组 (不加肿瘤细胞和受试化合物， 只加培养液）、 溶剂对照组（只加溶剂 不加受试化合物） ； 进一步求其半数细胞抑制剂量值（IC5Q ) 时， 根据 初筛结果选用化合物浓度为 1、 3、 10、 30、 100、 200、 300μΜ的六个 剂量组、 空白对照组（同前）、 溶剂对照组（同前）。 具体结果见表 1。 表 1 部分化合物对 Κ562和 ΗΤ-29的抑制活性 The drug was dosed to the mother liquor concentration with DMSO (Sigma) before the test and diluted to the desired application concentration with whole medium without factor. When initially evaluating the growth inhibition effect of the compound on tumor cells, three dose groups of compound concentration of 3, 30, 300 μΜ, blank control group (no tumor cells and test compound, only culture medium), solvent control group (only The solvent was added without the test compound); when the half cytostatic amount (IC 5Q ) was further determined, six dose groups with compound concentrations of 1, 3, 10, 30, 100, 200, 300 μΜ were selected according to the preliminary screening results. Blank control group (same as before), solvent control group (same as before). The specific results are shown in Table 1. Table 1 Inhibitory activity of some compounds on Κ562 and ΗΤ-29
IC5o平均值 (μΜ) IC5o平均值 (μΜ) 编号 Κ562 HT-29 编号 Κ562 HT-29 实施例 1 139.35 -300 实施例 13 35.91 27.31 实施例 2 89.73 63.48 实施例 16 181.69 253.83 实施例 3 114.49 122.68 实施例 17 206.73 >300 实施例 4 28.66 13.74 实施例 18 41.76 23.70 实施例 5 50.53 75.44 实施例 19 70.52 97.93 实施例 6 11.31 10.05 实施例 20 11.68 14.54 实施例 7 43.37 23.64 实施例 21 75.79 57.25 实施例 8 49.06 26.02 实施例 22 10.35 9.24 实施例 10 129.11 123.66 实施例 24 112.36 137.59 实施例 11 103.63 97.71 实施例 25 14.47 12.65 实施例 12 131.14 129.09 Pdl98306 9.62 1.53 其中 Pdl98306为阳性对照， 其结构式如下: IC 5 o average (μΜ) IC 5 o average (μΜ) No. Κ562 HT-29 No. 562 HT-29 Example 1 139.35 -300 Example 13 35.91 27.31 Example 2 89.73 63.48 Example 16 181.69 253.83 Example 3 114.49 122.68 Example 17 206.73 >300 Example 4 28.66 13.74 Example 18 41.76 23.70 Example 5 50.53 75.44 Example 19 70.52 97.93 Example 6 11.31 10.05 Example 20 11.68 14.54 Example 7 43.37 23.64 Example 21 75.79 57.25 Example 8 49.06 26.02 Example 22 10.35 9.24 Example 10 129.11 123.66 Example 24 112.36 137.59 Example 11 103.63 97.71 Example 25 14.47 12.65 Example 12 131.14 129.09 Pdl98306 9.62 1.53 wherein Pdl98306 is a positive control and its structural formula is as follows:
Figure imgf000031_0001
实验结果表明， 本发明的化合物对肿瘤细胞具有显著的抑制效果。 尽管本发明的具体实施方式已经得到详细的描述， 本领域技术人 员将会理解。 根据已经公开的所有教导， 可以对那些细节进行各种修 改和替换， 这些改变均在本发明的保护范围之内。 本发明的全部范围 由所附权利要求及其任何等同物给出。
Figure imgf000031_0001
The experimental results show that the compound of the present invention has a remarkable inhibitory effect on tumor cells. Although specific embodiments of the invention have been described in detail, those skilled in the art will understand. Various modifications and substitutions may be made to those details in light of the teachings of the invention, which are within the scope of the invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims

权 利 要 求 Rights request
1、式 I或式 II所示的化合物，或其药学可接受的盐、溶剂化物 光学异构体或 N-氧化物， A compound of formula I or formula II, or a pharmaceutically acceptable salt, solvate optical isomer or N-oxide thereof,
Figure imgf000033_0001
Figure imgf000033_0001
II 其中： II where:
在式 II中，一代表任选的键，条件为环中有且仅有一个氮原子是双 鍵；  In Formula II, one represents an optional bond, provided that one and only one nitrogen atom in the ring is a double bond;
Ri. R2, R3、 R4、 R5、 R7或 R8各自独立地 羟基、 卤素、 氨基、 硝基、 腈基、 三氟曱基、 -OR9、 -C(0)R9、 -C(0)OR9、 -NR10C(O)OR9 、 -OC(0)R9 、 -NR10SO2R9 、 -SO2NR10R9 、 -NR10C(O)R9、 NR10R9、 d-do 烷基、 C2-C 10烯基、 C2-C10炔基、 C3-C1Q环烷基、 C3-C 1Q环烷基烷基、 芳基、 芳基烷基、 杂芳基、 杂 芳基烷基、 杂环基和杂环基烷基； Ri. R 2 , R 3 , R 4 , R 5 , R 7 or R 8 are each independently hydroxy, halogen, amino, nitro, nitrile, trifluoromethyl, -OR 9 , -C(0)R 9 , -C(0)OR 9 , -NR 10 C(O)OR 9 , -OC(0)R 9 , -NR 10 SO 2 R 9 , -SO 2 NR 10 R 9 , -NR 10 C(O) R 9 , NR 10 R 9 , d-do alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 1Q cycloalkyl, C 3 -C 1Q cycloalkylalkyl, An aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group and a heterocyclic alkyl group;
R6选自氢、三氟曱基、 d-do 烷基、 C2-C 10烯基、 C2-C10块基、 C3-C1Q环烷基、 C3-C 1Q环烷基烷基、 芳基、 芳基烷基、 杂芳基、 杂 芳基烷基、 杂环基和杂环基烷基； R 6 is selected from the group consisting of hydrogen, trifluoromethyl, d-do alkyl, C 2 -C 10 alkenyl, C 2 -C 10 block, C 3 -C 1Q cycloalkyl, C 3 -C 1Q cycloalkyl An alkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group and a heterocyclic alkyl group;
W选自 -OR9、 - NR10OR9、 - NR10SO2R9和 - NR10R9; W is selected from the group consisting of -OR 9 , - NR 10 OR 9 , - NR 10 SO 2 R 9 and - NR 10 R 9 ;
R9、 。各自独立地选自氢、 羟基、 卤素、 三氟曱基、 d-do 烷 基、 C2-C 10婦基、 C2-C 10块基、 C3-C 10环坑基、 C3-C 10环坑基坑基、 芳基、 芳基烷基、 杂芳基、 杂芳基烷基、 杂环基和杂环基烷基； 其中每个烷基、 烯基、 炔基、 环烷基、 芳基、 杂芳基和杂环基 任选地被 1-5 个独立地选自以下的基团取代： 羟基、 面素、 氨基、 硝基和三氟曱基。 R 9 , . Each is independently selected from the group consisting of hydrogen, hydroxy, halogen, trifluoromethyl, d-do alkyl, C 2 -C 10 cation, C 2 -C 10 block, C 3 -C 10 ring pit, C 3 - a C 10 ring pit base group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group and a heterocyclic alkyl group; wherein each alkyl group, alkenyl group, alkynyl group, naphthenic group The aryl, aryl, heteroaryl and heterocyclyl are optionally substituted with from 1 to 5 groups independently selected from the group consisting of hydroxy, flavonoid, amino, nitro and trifluoromethyl.
2、根据权利要求 1所述的化合物， 其为式 III或式 IV所示化合物，
Figure imgf000034_0001
2. A compound according to claim 1 which is a compound of formula III or formula IV,
Figure imgf000034_0001
III IV  III IV
其中， 各个取代基团的定义同权利要求 1。  Wherein each substituent group is as defined in claim 1.
3、根据权 2所述的化合物， 其为式 V或式 VI所示化合物: 3. A compound according to claim 2 which is a compound of formula V or formula VI:
Figure imgf000034_0002
Figure imgf000034_0002
V VI  V VI
其中， 各个取代基团的定义同权利要求 1。  Wherein each substituent group is as defined in claim 1.
4、 根据权利要求 1-3任一项所述的化合物， 其中 R3、 R4、 R5、 R6、 R7或 R8各自独立地为氢、 卤素、 硝基、 腈基、 三氟 曱基、 烷基、 C3-C 6环烷基、 C3-C 6环烷基烷基、 芳基、 芳基 烷基、 杂芳基、 杂芳基烷基、 杂环基或杂环基烷基。 4. A compound according to any one of claims 1 to 3, wherein R 3 , R 4 , R 5 , R 6 , R 7 or R 8 are each independently hydrogen, halogen, nitro, nitrile, trifluoro Mercapto, alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic or heterocyclic Alkyl group.
5、 根据权利要求 1-3任一项所述的化合物， 其中 W为 -OR9、 - NR10OR9或 - NR10R9, R9、 。的定义同权利要求 1。 The compound according to any one of claims 1 to 3, wherein W is -OR 9 , -NR 10 OR 9 or -NR 10 R 9 , R 9 , . The definition is the same as claim 1.
6、 根据权利要求 1 所述的化合物， 其选自： 6. A compound according to claim 1 selected from the group consisting of:
3,4,5- =-氟 -2[(3-曱基 -5-碘 -2-吡啶基) J^】苯曱酸；  3,4,5- =-fluoro- 2[(3-indolyl-5-iodo-2-pyridyl) J^]benzoic acid;
N-{3- [(叔丁基-二曱基)硅氧基】丙氧基 }-3，4，5-三氟 -2-[(3-曱基 -5-埃 -2-吡^)氨基】苯曱酰胺；  N-{3-[(tert-butyl-diindenyl)silyloxy]propoxy}-3,4,5-trifluoro-2-[(3-indolyl-5-e-2-pyrene) Amino]benzamide;
N-[(2，2-曱基 -1,3二氧戊环 -4基)曱氧基卜 3,4,5-三氟 -2-[(3-曱基 -5-破 -2-吡^)氨基】苯曱酰胺；  N-[(2,2-Mercapto-1,3-dioxolan-4-yl)decyloxy 3,4,5-trifluoro-2-[(3-indolyl-5-break-2- Pyridyl)aminobenzamide;
N-[2- (噻吩 -2-基）乙基卜 3，4，5-三氟 -2-[(3-曱基 -5-捵 -2-吡啶基)氨基】 苯曱酰胺；  N-[2-(thiophen-2-yl)ethyl b 3,4,5-trifluoro-2-[(3-indolyl-5-indol-2-pyridyl)amino]benzamide;
N- ( 2-吗啉乙基） -3,4,5-三氟 -2-[(3-曱基 -5-破 -2-吡啶基) J^】苯曱酰 胺； N-(2-morpholinylethyl)-3,4,5-trifluoro-2-[(3-indolyl-5-dea-2-pyridyl) J^]benzoyl Amine
N-[2- (哌啶 -1-基）乙基卜 3,4,5-三氟 -2-[(3-曱基 -5-碘 -2-吡啶基)氨基】 苯曱酰胺；  N-[2-(piperidin-1-yl)ethyl b 3,4,5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino]benzamide;
N-苯曱氧基 -3，4，5-三氟 -2-[(3-氯 -5-溴 -2-吡^)氨基】苯曱酰胺； N-苯曱氧基 -3，4，5-三氟 -2- [(3-曱基 -5-碘 -2-吡啶基) J^】苯曱酰胺； N- ( 3-苯丙基） -3,4,5-三氟 -2-[(3-氯 -5-溴 -2-吡 氨基】苯曱酰胺； N-[(2，2-曱基 -1，3二氧戊环 -4基)曱氧基】- 3，4，5-三氟 -2-[(3-氯 -5-溴 -2- 吡啶基) J ^苯曱酰胺；  N-benzofluorenyl-3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino]benzamide; N-benzoquinone-3,4, 5-trifluoro-2-[(3-indolyl-5-iodo-2-pyridyl) J^]benzamide; N-(3-phenylpropyl)-3,4,5-trifluoro-2 -[(3-chloro-5-bromo-2-pyridylamino)benzamide; N-[(2,2-indolyl-1,3dioxolan-4-yl)decyloxy]-3,4 , 5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)J^benzamide;
(R)-N-[(2，2-曱基 -1,3二氧戊环 -4基)曱氧基卜 3,4,5-三氟 -2-[(3-氯 -5- 溴 -2-吡啶基 ) J^】苯曱酰胺；  (R)-N-[(2,2-mercapto-1,3-dioxolan-4-yl)decyloxy 3,4,5-trifluoro-2-[(3-chloro-5-bromo) -2-pyridyl) J^]benzamide;
(R)-N-[(2，2-曱基 -1,3二氧戊环 -4基)曱氧基】 - 3,4,5-三氟 -2-[(3-曱基 (R)-N-[(2,2-indolyl-1,3dioxolan-4-yl)nonyloxy]-3,4,5-trifluoro-2-[(3-fluorenyl)
-5-碘 -2-吡^) J ^苯曱酰胺； -5-iodo-2-pyridyl))J^benzamide;
N- (环丙曱氧基) - 3，4，5-三氟 -2-[(3-氯 -5-溴 -2-吡1^ ) J^】苯曱酰胺； N-(3-羟基丙氧基) 3,4,5- =-氟 -2-[(3-曱基 -5-捵 -2-吡啶基)氨基】苯曱 酰胺； N-(cyclopropoxy)- 3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridin 1 ^) J^]benzamide; N-(3-hydroxyl Propoxy) 3,4,5- =-fluoro-2-[(3-indolyl-5-indol-2-pyridyl)amino]benzamide;
N-(3-羟基丙氧基) - 3,4,5- =-氟 -2-[(3-氯 -5-溴 -2-吡啶基)氨基】苯曱酰 胺；  N-(3-hydroxypropoxy)-3,4,5- =-fluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino]benzoylamine;
(R)-N-(2，3-二羟基丙氧基) - 3,4,5- =-氟 -2- [(3-曱基 -5-碘 -2-吡啶基)氨 基】苯曱酰胺；  (R)-N-(2,3-dihydroxypropoxy)-3,4,5-=-fluoro-2-[(3-indolyl-5-iodo-2-pyridyl)amino]phenylhydrazine Amide
(R)-N-(2，3-二羟基丙氧基) - 3，4，5-三氟 -2-[(3-氯-5-溴-2-吡¾^) ^】 苯曱酰胺；  (R)-N-(2,3-dihydroxypropoxy)-3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridinium)]]benzamide ;
N- (环己基曱基) - 3,4,5- =-氟 -2- [(3-曱基 -5-溴 -2-吡啶基 ) J^】苯曱酰 胺；  N-(cyclohexyldecyl)-3,4,5- =-fluoro-2-[(3-indolyl-5-bromo-2-pyridyl)J^]benzoylamine;
N- ( 2-吗啉乙基） -3,4,5-三氟 -2-[(3-曱基 -5-溴 -2-吡啶基 ) J^】苯曱酰 胺；  N-(2-morpholinoethyl)-3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridyl)J^]benzoylamine;
N-[2- (哌啶 -1-基）乙基卜 3,4,5-三氟 -2-[(3-曱基 -5-溴 -2-吡啶基)氨基】 苯曱酰胺；  N-[2-(piperidin-1-yl)ethyl b 3,4,5-trifluoro-2-[(3-indolyl-5-bromo-2-pyridyl)amino]benzamide;
N- ( 3-苯丙基） -3,4,5-三氟 -2-[(3-曱基 -5-捵 -2-吡啶基)氨基】苯曱 酰胺；  N-(3-phenylpropyl)-3,4,5-trifluoro-2-[(3-indolyl-5-indol-2-pyridyl)amino]phenylhydrazine amide;
N-[2_ (哌啶 -1-基）乙基】 - 3，4，5_三氟 -2_[(3_氯 _5_溴 _2_吡啶基)氨基】 苯曱酰胺； N-[_ 2 (piperidin-1-yl) ethyl] - 3 and 4, 5-trifluoromethyl _ - 2 _ [(3-chloro-_ _ _ 2 _ 5 _ bromo-pyridinyl) amino] phenyl Yue amide;
5-[(5-捵 -3-曱基 2-吡啶基)氨基】 -4-氟 -1H-苯并咪唑 -6-曱酸； N- [2_ (噻吩 _2_基）乙基】 _5_ [(5-^-3-曱基 2_吡啶基)氨基】 _4_氟 -1H- 苯并咪唑 -6-曱酰胺； 5-[(5-indole-3-indenyl 2-pyridyl)amino]-4-fluoro-1H-benzimidazole-6-decanoic acid; N-[ 2 _(thiophene- 2 -yl)ethyl] _ 5 _ [(5-^-3-decyl 2 _pyridyl)amino] _ 4 _fluoro-1H-benzimidazole-6-indoleamide ;
N-[2- (哌啶 -1-基）乙基】 -5-[(5-捵 -3-曱基 2-吡啶基)氨基】 _4_氟 -1H- 苯并咪唑 -6-曱酰胺。 N-[ 2 -(piperidin-1-yl)ethyl] -5-[(5-indole-3-indenyl- 2 -pyridyl)amino] _ 4 _fluoro-1H-benzimidazole-6-oxime Amide.
7、 制备权利要求 1所述化合物的方法， 其包括以下关键中间体 的合成： 7. A process for the preparation of a compound of claim 1 which comprises the synthesis of the following key intermediates:
1 ) 四氟苯腈与取代 2-氨基吡啶类化合物在氨基锂存在条件下， 以二曱苯为反应溶剂， 在 125。C条件下反应得到中间体 3,4,5-三氟 -2- [(取代 -2-吡啶基 】苯曱腈；  1) Tetrafluorobenzonitrile and a substituted 2-aminopyridine compound are in the presence of lithium amide, and diphenylbenzene is used as a reaction solvent at 125. The reaction under C conditions gives the intermediate 3,4,5-trifluoro-2-[(substituted-2-pyridyl)benzonitrile;
Figure imgf000036_0001
Figure imgf000036_0001
2 ) 2, 3, 4-三氟 -5-硝基苯曱酸与取代 2-氨基吡啶类化合物在 LDA 存在条件下，在 -70°C条件下，反应得到中间体 3，4，-二氟 -5-硝基 -2- [(取 代 -2-吡啶基 ) J^】苯曱酸；  2) 2, 3, 4-trifluoro-5-nitrobenzoic acid and substituted 2-aminopyridines are reacted in the presence of LDA at -70 ° C to obtain intermediates 3, 4, - 2 Fluoro-5-nitro-2-[(substituted-2-pyridyl)J^]benzoic acid;
Figure imgf000036_0002
Figure imgf000036_0002
式 I化合物合成方案如下：  The synthesis scheme of the compound of formula I is as follows:
以取代的含离去集团 L的苯曱酸为起始原料，经过与曱基化试剂反 应，将羧基曱基化；再通过与氨水反应，将曱酯转化为酰胺基；在 P0C13 作用下脱去一份子的水， 将酰胺键转化为氰基； 取代的含离去集团 L的 苯曱氰在碱（例如 基锂）作用下， 离去集团离去与取代的氣基吡啶类 化合物进行缩合反应；在将氰基水解得到羧基，羧基与相应的侧链反应， 得到式 I化合物； The substituted benzoic acid containing the leaving group L is used as a starting material, and the carboxyl group is thiolated by reacting with a thiolation reagent; and the oxime ester is converted into an amide group by reacting with ammonia water; under the action of P0C1 3 Part of the water is removed to convert the amide bond to a cyano group; the substituted benzoquinone containing the leaving group L is subjected to a base (for example, a lithium group) to remove the group-derived and substituted gas-based pyridine compound. a condensation reaction; the cyano group is hydrolyzed to obtain a carboxyl group, and the carboxyl group is reacted with the corresponding side chain to obtain a compound of the formula I;
Figure imgf000037_0001
Figure imgf000037_0001
Figure imgf000037_0002
Figure imgf000037_0002
L表示离去集团， 可以为 素； 和 /或 L indicates the departure group, which can be a prime; and / or
式 II化合物合成方案如下：  The synthesis scheme of the compound of formula II is as follows:
以取代的含离去集团 L的苯曱酸为起始原料， 经过硝基化反应， 在 苯环上引入硝基； 在碱（例如 ^锂）作用下， 离去集团离去与取代的 氨基吡啶类化合物进行缩合反应； 在氨水作用下， 苯环上引入氨基； 经 过与曱基化试剂反应， 将羧基曱基化； 将硝基还原为氨基以后， 进行成 环反应，脱曱酯得到含羧基的关键中间体，羧基与相应的侧链部分反应， 得到式 II化合物； The substituted benzoic acid containing the leaving group L is used as a starting material, and after the nitration reaction, a nitro group is introduced on the benzene ring; under the action of a base (for example, lithium), the group is removed and the substituted amino group is removed. The pyridine compound undergoes a condensation reaction; under the action of ammonia water, an amino group is introduced into the benzene ring; after reacting with a thiolation reagent, the carboxyl group is thiolated; after the nitro group is reduced to an amino group, a ring-forming reaction is carried out, and the decarboxylated ester is obtained. a key intermediate of a carboxyl group, the carboxyl group is reacted with a corresponding side chain moiety to provide a compound of formula II;
Figure imgf000038_0001
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000038_0002
15  15
L表示离去集团， 可以为卤素；  L represents the leaving group and can be halogen;
其中 R2、 R3、 R4、 R5、 R6、 R7、 R8、 W、 R9、 R10的定义同 权利要求 1。 Wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , W, R 9 and R 10 are as defined in claim 1.
8、 一种药物组合物， 其包含权利要求 1-6任一项的化合物或其 药学可接受的盐、 溶剂化物、 光学异构体或 N-氧化物， 以及可药用 载体。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, and a pharmaceutically acceptable carrier.
9、 权利要求 1-6任一项的化合物或其可药用的盐、 溶剂化物、 光学异构体或 N-氧化物用于制备预防和 /或治疗细胞过度增殖性疾 病的药物的用途。 Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof for the preparation of a medicament for preventing and/or treating a cell hyperproliferative disorder.
10、 权利要求 1-6任一项的化合物或其可药用的盐、 溶剂化物、 光学异构体或 N-氧化物用于制备抗肿瘤和 /或癌症药物的用途。 10. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament for antitumor and/or cancer.
11、一种预防和 /或***和 /或癌症的方法，其包括给有需要 的受试者施用预防和 /或治疗有效量的本发明的化合物或其可药用 的盐、 溶剂化物、 光学异构体或 N-氧化物。 11. A method of preventing and/or treating a tumor and/or cancer, comprising The subject is administered a prophylactically and/or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof.
12、 一种预防和 /或治疗细胞过度增殖性疾病的方法， 其包括给 有需要的受试者施用预防和 /或治疗有效量的本发明的化合物或其 可药用的盐、 溶剂化物、 光学异构体或 N-氧化物。 12. A method of preventing and/or treating a cell hyperproliferative disorder, comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate thereof, Optical isomer or N-oxide.
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