WO2019179436A1 - 一种酰胺类化合物及其在治疗癌症中的用途 - Google Patents

一种酰胺类化合物及其在治疗癌症中的用途 Download PDF

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WO2019179436A1
WO2019179436A1 PCT/CN2019/078725 CN2019078725W WO2019179436A1 WO 2019179436 A1 WO2019179436 A1 WO 2019179436A1 CN 2019078725 W CN2019078725 W CN 2019078725W WO 2019179436 A1 WO2019179436 A1 WO 2019179436A1
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substituted
group
unsubstituted
cancer
chloro
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PCT/CN2019/078725
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English (en)
French (fr)
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杜武
温坤
任闻
艾朝武
李海波
陈江
李宇
李兴海
陈元伟
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成都海创药业有限公司
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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Definitions

  • the invention belongs to the field of medicine and relates to an amide compound and its use in the treatment of cancer, especially in the treatment of prostate cancer.
  • Prostate cancer is one of the common malignant tumors in older men.
  • the incidence of prostate cancer ranks second among all malignant tumors in men.
  • the incidence of prostate cancer ranks first among all male malignancies, with the second highest mortality rate.
  • China its incidence has also leapt to the third place in genitourinary malignancies in recent years.
  • the clinical symptoms of prostate cancer are few in the early stage, and most of the patients have reached the advanced stage when they are diagnosed, and they have lost the opportunity to cure the disease.
  • the treatment of castration-resistant prostate cancer is mainly based on the combination of docetaxel, mitoxantrone, prednisone and other drugs, with obvious side effects, and there is no optimal treatment.
  • New anti-tumor drugs are currently in the process of continuous development and research. Therefore, the search for an anti-tumor drug with high efficiency, safety and few side effects has broad market prospects.
  • the present invention provides an amide compound and its use in the treatment of cancer.
  • the present invention provides a compound of Formula I, or a crystalline form thereof, or a stereoisomer thereof, or a isotope thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof , or its prodrug, or its metabolite:
  • R 1 to R 9 are each independently selected from the group consisting of hydrogen, hydrazine, hydrazine, halogen, hydroxy, amino, amide, cyano, nitro, -CO 2 R a , substituted or unsubstituted C 1 -C 12 alkyl, Substituted or unsubstituted C 1 -C 12 alkoxy, cycloalkyl, aryl;
  • R a is selected from C 1 -C 12 alkyl; the substituent is anthracene, fluorene, halogen, C 1 -C 12 alkyl, aryl;
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl
  • R 11 is selected from the group consisting of OR, SR', and NR 12 R 13 ;
  • R, R', R 12 and R 13 are each independently selected from the group consisting of hydrogen, hydrazine, hydrazine,
  • R 14 is selected from substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 3-8-membered heterocyclic group, substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl, -OR 15 ,
  • the substituent is hydrazine, hydrazine, halogen, cyano, C 1 -C 12 alkyl, C 1 -C 12 alkoxy;
  • R 15 is selected from a substituted or unsubstituted C 1 -C 12 alkyl group, a substituted or unsubstituted 3-8 membered cycloalkyl group;
  • R 16 and R 17 are each independently selected from hydrogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted 3-8-membered cycloalkyl; or R 16 and R 17 are bonded to form a substituted or unsubstituted Replaced 3 to 8 yuan ring.
  • R 1 to R 9 are each independently selected from the group consisting of hydrogen, hydrazine, hydrazine, halogen, hydroxy, amino, amide, cyano, nitro, -CO 2 R a , substituted or unsubstituted C 1 -C 8 An alkyl group, a substituted or unsubstituted C 1 -C 8 alkoxy group, a cycloalkyl group, an aryl group;
  • R a is selected from the group consisting of C 1 -C 8 alkyl
  • the substituent is ruthenium, osmium, halogen, C 1 -C 8 alkyl, aryl;
  • R 10 is selected from hydrogen, C 1 ⁇ C 8 alkyl group.
  • R 1 to R 9 are each independently selected from hydrogen, hydrazine, hydrazine, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy;
  • the substituent is hydrazine, hydrazine, halogen, C 1 -C 4 alkyl;
  • R 10 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl.
  • R 1 to R 9 are each independently selected from hydrogen, hydrazine, hydrazine, halogen, substituted or unsubstituted C 1 -C 2 alkyl;
  • the substituent is ruthenium, osmium, halogen
  • R 10 is selected from hydrogen.
  • R 11 is selected from the group consisting of OR, SR', and NR 12 R 13 ;
  • R, R', R 12 and R 13 are each independently selected from the group consisting of hydrogen, hydrazine, hydrazine,
  • R 14 is selected from substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 3-8-membered heterocyclic group, substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl, -OR 15 ,
  • the substituent is ruthenium, rhodium, halogen, cyano, C 1 -C 8 alkyl, C 1 -C 8 alkoxy;
  • R 15 is selected from C 1 -C 8 alkyl
  • R 16, R 17 are each independently selected from hydrogen, C 1 ⁇ C 8 alkyl group; alternatively, R 16, R 17 is connected to form a 3- to 8-membered ring.
  • R 1 ⁇ R 9 are each independently selected from hydrogen, deuterium, tritium, F, Cl, Br, CF 3, CH 3;
  • R 12 and R 13 are each independently selected from the group consisting of hydrogen, hydrazine, hydrazine,
  • R 14 is selected from substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted 3-6-membered heterocyclic group, substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl, -OR 15 ,
  • the substituent is an anthracene, an anthracene, a halogen, a cyano group, a C 1 -C 2 alkyl group;
  • R 15 is selected from C 1 -C 4 alkyl
  • R 16, R 17 are each independently selected from hydrogen, C 1 ⁇ C 6 alkyl; or, R 16, R 17 are linked to form 3 to 6-membered ring.
  • R 1 , R 3 and R 6 are each independently selected from the group consisting of hydrogen, hydrazine and hydrazine.
  • R 14 ' is selected from substituted or unsubstituted C 1 ⁇ C 4 alkyl group; the substituent is deuterium, tritium, a halogen.
  • R 14 ' is selected from C 1 -C 3 alkyl, CF 3 .
  • the A ring is selected from a substituted or unsubstituted 3-6 membered cycloalkyl group, a substituted or unsubstituted 3-6 membered heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group;
  • the group is selected from the group consisting of ruthenium, osmium, halogen, cyano, and C 1 -C 2 alkyl.
  • R 2 , R 3 , R 5 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of F, Cl, Br, CF 3 , and CH 3 ;
  • Ring A is selected from a 3- to 6-membered cycloalkyl group, a substituted or unsubstituted 4-6-membered heterocyclic group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted heteroaryl group;
  • the substituent is selected from the group consisting of Cl, cyano, and methyl.
  • ring A is cyclopropane.
  • R 15 is selected from C 1 ⁇ C 4 alkyl group.
  • R 15 is selected from the group consisting of C 1 -C 4 alkyl groups.
  • R 16 and R 17 are each independently selected from hydrogen, C 1 -C 2 alkyl
  • R 16, R 17 attached to form a 4- to 6-membered ring.
  • R 16 and R 17 are each independently selected from hydrogen and methyl
  • R 16 and R 17 are bonded to form a 5- to 6-membered heterocyclic group.
  • R 14" is selected from the group consisting of C 1 -C 4 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, and aryl. Further, the compound IIIE is as shown in Formula IIIE-1:
  • R 14" is selected from the group consisting of C 1 -C 3 alkyl, 3- to 5-membered cycloalkyl, 5- to 6-membered heterocyclic, and phenyl.
  • the present invention also provides the aforementioned compound, or a crystalline form thereof, or a stereoisomer thereof, or a isotope thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or Use of a prodrug, or a metabolite thereof, for the manufacture of a medicament for the treatment and/or prevention of cancer.
  • the cancer is breast cancer, brain cancer, prostate cancer, lung cancer, ovarian cancer, bone cancer, neuro-cancer, liver cancer, blood cancer, esophageal cancer, glioblastoma, multiple myeloma, mantle cell lymphoma, acute Myeloid leukemia and concurrent cancer.
  • the cancer is prostate cancer, ovarian cancer, bone cancer or neuro-cancer.
  • the present invention also provides the aforementioned compound, or a crystalline form thereof, or a stereoisomer thereof, or a isotope thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or The use of a prodrug, or a metabolite thereof, for the manufacture of a medicament for reducing the expression of a full length androgen receptor, a variant androgen receptor.
  • the present invention also provides the aforementioned compound, or a crystalline form thereof, or a stereoisomer thereof, or a isotope thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or Use of a prodrug, or a metabolite thereof, for the manufacture of a medicament for inhibiting proliferation of cancer cells.
  • cancer cells are cancer cells of the following cancers: breast cancer, brain cancer, prostate cancer, lung cancer, ovarian cancer, bone cancer, neuro-cancer, liver cancer, blood cancer, esophageal cancer, glioblastoma, multiple bone marrow Tumor, mantle cell lymphoma, acute myeloid leukemia and concurrent cancer.
  • the cancer cell is a prostate cancer cell, an ovarian cancer cell, a bone cancer cell, or a neural cancer cell.
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • the structures of the compounds described in the present invention all refer to structures which are stably present.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • ⁇ refers to the isotope of hydrogen (H), also known as heavy hydrogen, and the elemental symbol is generally D or 2H.
  • ⁇ refers to the isotope of hydrogen (H), and the element symbol is generally T or 3H.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C a - C b ) alkyl group indicates any alkyl group having "a" to "b" carbon atoms.
  • C 1 -C 4 alkyl means an alkyl group containing from 1 to 4 carbon atoms.
  • the C 1 -C 4 alkyl group means a straight or branched hydrocarbon chain containing one to four carbon atoms.
  • alkyl group is a hydrocarbon group in which one hydrogen atom is lost in an alkane molecule, for example, methyl-CH 3 , ethyl-CH 3 CH 2 or the like.
  • alkylene group means a hydrocarbon group in which two hydrogen atoms are absent from an alkane molecule, such as methylene-CH 2 -, ethylene-CH 2 CH 2 - or the like.
  • C 1-4 alkylene refers to a hydrocarbon chain containing one to four carbon atoms, straight-chain or branched.
  • substituted or unsubstituted C 1-4 alkyl group means that the C 1-4 alkyl group may be substituted or unsubstituted.
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a conjugated ⁇ -electron system, such as phenyl and naphthyl.
  • the aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but may not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be in a conjugated pi-electron system.
  • the aryl group can be substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic group containing one to more heteroatoms. Containing at least one ring heteroatom selected from N, O or S, the remaining ring atoms are C, and additionally have a fully conjugated pi-electron system.
  • furyl pyrrolyl, quinolyl, thienyl, pyridyl, pyrazolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, thienopyridinyl and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring.
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • Cycloalkyl means a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic.
  • C 3-8 cycloalkyl means a cycloalkyl group having 3 to 8 carbon atoms.
  • Heterocyclyl means a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic and carries at least one cycloalkyl selected from O, S or substituted nitrogen atoms, the remainder The ring atom is carbon.
  • C 3-8 heterocyclic group means a heterocyclic group having 3 to 8 carbon atoms and a hetero atom number. The heterocyclic group may be unsubstituted or substituted with one or more substituents. Specifically, the "5-6-membered heterocyclic group" in the present invention may be Wait
  • the "compound of the present invention” means a compound represented by the formula (I).
  • the term also includes various crystalline forms, stereoisomers, isotopes, tautomers, stereochemical isomers, pharmaceutically acceptable salts, solvates, prodrugs, of the compounds of formula (I), metabolite.
  • Stepoisomer refers to isomers resulting from the arrangement of atoms in a molecule in a spatial arrangement, such as cis-trans isomers, enantiomers, conformational isomers, and the like.
  • “Pharmaceutically acceptable” refers to an additive or composition that is physiologically tolerable when administered to an animal, such as a mammal (eg, a human), and that typically does not produce an allergic or similar adverse reaction (eg, dizziness, etc.).
  • Pharmaceutical carriers and excipients may include, but are not limited to, diluents such as lactose, glucose, mannose and/or glycerin; lubricants; polyethylene glycols; binders such as magnesium aluminum silicate, starch, gelatin, methyl Cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; and, if necessary, a disintegrant such as starch, agar, alginic acid or a salt thereof such as sodium alginate; and/or an adsorbent, coloring Agents, preservatives, stabilizers, flavoring agents and sweeteners.
  • diluents such as lactose, glucose, mannose and/or glycerin
  • lubricants such as lactose, glucose, mannose and/or glycerin
  • polyethylene glycols such as magnesium aluminum silicate, starch, gelatin, methyl Cellulose, sodium carboxymethylcellulose and/or polyvinylpyrroli
  • Salt means the above-mentioned compound or a stereoisomer thereof, an acid form and/or a base salt formed with an inorganic and/or organic acid and a base, and also a zwitterionic salt (internal salt), and also includes a quaternary ammonium salt.
  • an alkyl ammonium salt can be obtained directly in the final isolation and purification of the compound. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount).
  • the salt in the present invention may be a hydrochloride, a hydrofluoride, a sulfate, a nitrate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate or a formic acid of the compound.
  • Salt acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, lactate, citrate, picrate, A Sulfonate, ethanesulfonate, tartrate, aspartate or trifluoroacetate.
  • Solvate of the compound of the formula (I) a solvent such as ethanol, water or the like, which may contain different amounts of water such as a monohydrate, a hemihydrate, a hemihydrate, a dihydrate or a trihydrate. Things.
  • a “prodrug” is a derivative of a compound of formula I which may be less active or even inactive, but which is converted to the activity of the invention under physiological conditions (for example by metabolism, solvolysis or otherwise) a compound that exerts its pharmacological action.
  • a compound containing a carboxyl group can form a physiologically hydrolyzable ester which is prepared by hydrolysis in vivo to give the compound of formula I itself.
  • the prodrug is preferably administered orally because hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration can be used when the ester itself is active or hydrolysis occurs in the blood.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Metal product refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • Cancer includes, but is not limited to, the following cancers: breast cancer, ovarian cancer, prostate cancer, cervical cancer, esophageal cancer, testicular cancer, stomach cancer, skin cancer, lung cancer, bone cancer, colon cancer, pancreatic cancer, thyroid cancer, biliary tract cancer, small intestine Cancer, colon-rectal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer, neuroblastoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, epidermoid carcinoma, seminoma, melanin Tumor, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorder, lymphatic disorder, Hodgkin's disease, hair cell carcinoma and leukemia.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the "room temperature" described in the present invention is 25 ⁇ 5 °C.
  • the "overnight” as described herein is 12 ⁇ 1 hour.
  • the present invention provides a novel structure of an amide compound and its use in the treatment of cancer.
  • the experimental results show that the compound of the present invention can inhibit the proliferation of prostate cancer cells, especially the drug-resistant prostate cancer cell line (22RV1).
  • the compounds of the invention are also capable of significantly inhibiting the proliferation of a variety of cancer cells.
  • the compounds of the invention have good pharmacokinetics. It has potential therapeutic effects on cancer, especially prostate cancer, and provides a new option for clinical screening and/or preparation of cancer drugs.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • the second step 2-amino-5-bromo-benzoic acid methyl ester (194 mg, 0.84 mmol) was dissolved in 2 ml of dichloromethane. After clarification, the system was transferred to an ice water bath, and then cooled, cooled and stirred, followed by the addition of pyridine ( 2 mL) and cyclopropylsulfonyl chloride (237 mg, 1.68 mmol), and the system was stirred and heated overnight in an oil bath. The next day, the mixture was cooled to room temperature, and 5 ml of 0.5 N HCl was added to the system and stirred vigorously. The mixture was separated and the aqueous phase was extracted with 10 ml of dichloromethane.
  • the fourth step 5-bromo-2-(cyclopropylsulfonamido)-benzoic acid (35 mg, 0.11 mmol) was dissolved in 3 ml of xylene, and 2-chloro-4-trifluoromethyl-phenylamine (22 mg, After 0.11 mmol), it was heated to 140 ° C, then phosphorus trichloride (9 mg, 0.07 mmol) was added, and the reaction was kept for 6 h.
  • 2-Amino-4-fluorobenzoic acid (620 mg, 4.0 mmol) was dissolved in 5 ml of DMF, NBS (712 mg, 4.0 mmol) was added, and the mixture was reacted at room temperature overnight, and the reaction was monitored by TLC until the starting material 2-amino-4-fluorobenzoic acid was reacted.
  • Completely (PE: EA 2:1), add 10 ml of EA, add 10 ml of water, and extract with stirring. The organic layer is washed with brine, dried over anhydrous sodium sulfate 4-fluorobenzoic acid (8-1) 400 mg, yield: 42.8%.
  • Methyl 2-amino-5-bromo-4-fluorobenzoate (141 mg, 0.57 mmol) was dissolved in 5 ml of toluene, pyridine (898 mg, 11.36 mmol) was added, and cyclopropylsulfonyl chloride (795 mg, 5.68 mmol) was added, 100 °C, the reaction was carried out overnight, the reaction was completed, and the reaction was completed. The mixture was cooled to room temperature. 5 ml of water was added, and the mixture was stirred, and the mixture was separated. The aqueous layer was extracted with 5 ml of EA.
  • the fourth step 5-chloro-4-fluoro-2-(cyclopropylsulfonylamino)-benzoic acid (8-4)
  • Step 5 5-Bromo-N-2-(2-chloro-4-trifluoromethyl-phenyl)-2-(cyclopropylsulfonylamino)-4-fluorobenzamide (8)
  • Example 9, 10 5-Chloro-N-2-(2-chloro-4-trifluoromethyl-phenyl)-2-(cyclopropylsulfonylamino)-4-fluorobenzamide (9) ,N-2-(2-chloro-4-trifluoromethyl-phenyl)-2-(cyclopropylsulfonylamino)-4-fluorobenzamide (10)
  • 2-chloro-4-trifluoromethyl- Aniline 39.95 mg, 0.20 mmol
  • phosphorus trichloride 9.82 mg, 0.07
  • 2-Amino-3,5-dichloro-benzoic acid methyl ester (440.1 mg, 2 mmol) was dissolved in 4 mL of dichloromethane. After clarification, the system was transferred to an ice water bath and then cooled, cooled and stirred, followed by the addition of pyridine (4 mL) And cyclopropylsulfonyl chloride (562.32 mg, 4 mmol), and the system was stirred and heated in an oil bath and stirred overnight. On the next day, the mixture was cooled to room temperature, and 10 mL of 0.5 N HCl was added to the system and stirred vigorously. The mixture was separated and the aqueous phase was extracted with 10 mL of dichloromethane.
  • the second step 2-amino-5-chloro-benzoic acid methyl ester (300 mg, 1.62 mmol) was dissolved in 2 mL of dichloromethane. After clarification, the system was transferred to an ice water bath, and then cooled, cooled and stirred, followed by the addition of pyridine ( 2 mL) and cyclopropylsulfonyl chloride (454 mg, 3.24 mmol), and the system was stirred and heated in an oil bath and stirred overnight. The next day, the mixture was cooled to room temperature, and 5 ml of 0.5 N HCl was added to the system and stirred vigorously. The mixture was separated and the aqueous phase was extracted with 10 ml of dichloromethane.
  • Methyl 5-chloro-2-(cyclopropanesulfonyl)benzoate (100.0 mg, 0.35 mmol) and a selective fluoro reagent (1.2 g, 3.50 mmol) were added to 4 mL of acetic acid under nitrogen. Heat at 95 ° C and stir overnight. After cooling to room temperature, ethyl acetate and water were added, and the organic layer was evaporated. A white solid, methyl 5-chloro-2-(cyclopropanesulfonamido)-3-fluorobenzoate (40.0 mg, 0.11 mmol) was obtained. Yield: 37.6%. MS (ESI) m / e 308.0 (M + H) + .
  • the third step 5-chloro-2-(cyclopropylsulfonamide)-3-fluorobenzoic acid
  • Methyl 5-chloro-2-(cyclopropanesulfonamido)benzoate (100.0 mg, 0.35 mmol) (1.2 g, 3.50 mmol) was dissolved in 2 mL methanol, and 2 mL of 2N lithium hydroxide was added. Stir at room temperature overnight. Ice water was added, and the pH was adjusted to 5 to 6 with 2N diluted hydrochloric acid to precipitate a white solid.
  • the third step 2-amino-5-chloro-4-fluorobenzoic acid methyl ester (91 mg, 0.45 mmol) was dissolved in 1 ml of dichloromethane, pyridine (1 ml) was added, and cyclopropylsulfonyl chloride (126 mg, 0.9 mmol) was added. The reaction was carried out at room temperature overnight, washed with 5 ml of 0.5N EtOAc, EtOAc (EtOAc m. 1) The product 5-chloro-4-fluoro-2-(cyclopropylsulfonylamino)-benzoic acid methyl ester 45 mg was obtained in a yield: 32.7%.
  • 2-Amino-5-chloro-3-methyl-benzoic acid methyl ester (399.28 mg, 2 mmol) was dissolved in 4 mL of dichloromethane. After clarification, the system was transferred to an ice water bath and then cooled, cooled and stirred, followed by the addition of pyridine. (4 mL) and cyclopropylsulfonyl chloride (562.32 mg, 4 mmol), and the mixture was stirred and stirred overnight in an oil bath. On the next day, the mixture was cooled to room temperature, and 10 mL of 0.5 N HCl was added to the system and stirred vigorously. The mixture was separated and the aqueous phase was extracted with 10 mL of dichloromethane.
  • the first step the synthesis of cyclohexylsulfonyl chloride
  • NCS (4.6 g, 34.4 mmol) was added to 50 mL of acetonitrile, and 6.5 mL of 2N diluted hydrochloric acid was added, and the mixture was stirred for 2 minutes, and cyclohexyl mercaptan (1.0 g, 8.6 mmol) was added to the reaction mixture, and stirred at room temperature for 2 h. It was extracted with ethyl acetate and water, and the organic layer was washed twice with brine, dried and dried. A colorless liquid cyclohexylsulfonyl chloride (1.1 g, 6.0 mmol) was obtained. Yield: 70.0%.
  • Fetal bovine serum (FBS) (Gibco Cat#10099-141)
  • Cell culture medium RIPM1640 medium, 10% FBS, 1% Pen Strep.
  • 22RV1 cells were subcultured with cell culture medium, and then seeded in a 96-well plate at 80 ⁇ l per well, and the number of cells per well was 20,000. The cells were cultured overnight at 37 ° C in a 5% CO 2 incubator.
  • the drug was formulated with dimethyl sulfoxide (DMSO) as a 30 mM stock solution. Dilute 3 times with DMSO before use, then dilute by 3 times to obtain 9 concentration gradients, and then dilute the compound at each concentration 200 times with the culture solution (to ensure the DMSO concentration in the culture system is 0.1%). The concentration is made to repeat 2 holes. Add 20 ⁇ l of the diluted compound to the cell culture well and mix gently by shaking. In addition, three cell-only negative control wells and three blank control wells (only 20 ⁇ l of the culture solution diluted with 200 ⁇ l of DMSO) were added, and chlorhexidine was used as a reference compound.
  • DMSO dimethyl sulfoxide
  • the absorbance (OD value) was measured at 450 nm using a multi-function microplate reader.
  • Example 22RV1 cell inhibitory activity (IC 50 , M)
  • Example 22RV1 cell inhibitory activity (IC 50 , M) 1 >10 27 0.61 2 3.7 28 1.2 3 1.1 29 2.9 4 1.1 32 4.5 5 1.2 33 8.5 6 1 34 >10 7 1 35 >10 8 >10 36 2.8 9 2.6 37 5.9 10 1.2 38 >10 12 7.3 39 >10 13 1.1 40 >10 14 3.9 41 >10 15 1.8 42 >10 16 1.1 43 >10 20 5.8 44 >10 twenty one 9.7 45 >10 twenty two 1.9 46 >10 twenty three 2.3 47 >10 twenty four 4.3 48 >10 25 >10 49 >10 26 2.3 50 >10
  • the compounds of the invention also have significant proliferative activity against other cancer cell lines, including the ovarian cancer cell line SKOV-3:
  • the above experimental results show that the compound of the present invention can significantly inhibit a plurality of cancer cell lines, and in particular, can significantly inhibit the proliferation of prostate cancer cells 22RV1, breast cancer cells, ovarian cancer cells, and liver cancer cells.
  • the compounds of the invention have potential for use in the treatment of a variety of cancers, particularly prostate, breast, ovarian and liver cancer.
  • Test Example 2 Mouse pharmacokinetics of the compounds of the present invention
  • mice Chengdu Dashuo Experimental Animal Co., Ltd.
  • the compound 6 was accurately weighed and added to the corresponding solvent to a final volume of 10 ml, and vortexed and mixed.
  • a solution having a concentration of 0.5 mg/ml was prepared.
  • 0.2 ml of the final solution was prepared and stored at -20 ° C for concentration determination.
  • the concentration of the test compound in the plasma was then determined by LC/MS/MS.
  • Oral bioavailability was calculated from the amount of drug exposure measured by PO administration and the amount of drug exposure measured by IV administration.
  • Compound 6 was subjected to a mouse PK experiment.
  • the compounds of the present invention have been shown to achieve higher exposures (AUC), with a significant increase in pharmacokinetics over longer half-lives and better oral bioavailability than similar reference compounds of the invention.
  • the present invention provides a novel structure of an amide compound and its use in the treatment of cancer.
  • the experimental results show that the compound of the present invention can inhibit the proliferation of prostate cancer cells, especially the drug-resistant prostate cancer cell line (22RV1).
  • the compounds of the invention are also capable of significantly inhibiting the proliferation of a variety of cancer cells.
  • the compounds of the invention have good pharmacokinetics. It has potential therapeutic effects on cancer, especially prostate cancer, and provides a new option for clinical screening and/or preparation of cancer drugs.

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Abstract

本发明公开了一种酰胺类化合物及其在治疗癌症中的用途，属于药物化学领域，本发明公开了式( I )所示的酰胺类化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在治疗癌症中的用途。实验结果表明，本发明化合物能够抑制前列腺癌细胞的增殖，尤其是对耐药性前列腺癌细胞系(22RV1)有明显抑制作用。同时，本发明化合物还能够显著抑制多种癌细胞的增殖。此外，本发明化合物具有良好的药代动力学。对癌症，尤其是前列腺癌具有潜在的治疗作用，为临床上筛选和/或制备癌症药物提供了一种新的选择。

Description

一种酰胺类化合物及其在治疗癌症中的用途 技术领域
本发明属于医药领域，涉及一种酰胺类化合物及其在治疗癌症中的用途，尤其是在治疗前列腺癌中的用途。
背景技术
癌症是人类面临的最危险的疾病之一。在多数情况下癌症最终会导致病人的死亡。尽管现代医学为治疗癌症做了很大的努力，但癌症目前仍然是一个有待解决的问题。前列腺癌是老年男性常见的恶性肿瘤之一。在世界范围内，前列腺癌发病率在男性所有恶性肿瘤中位居第二。在美国，前列腺癌发病率在所有男性恶性肿瘤中居第一位，死亡率居第二位。在我国，近年来其发病率亦已跃居泌尿生殖系恶性肿瘤的第三位。前列腺癌的发病临床早期症状少，大部分患者确诊时已到晚期，失去手术根治时机。行前列腺癌根治术的患者，有27％～53％在术后10年内局部复发或远处转移。内分泌治疗是目前晚期前列腺癌的主要治疗方法，但经过中位时间14～30个月后，几乎所有前列腺癌患者最终均转为雄激素非依赖前列腺癌(androgen-independent prostate cancer,AIPC)，进而发展为激素难治性前列腺癌(hormone-refractory prostate cancer,HRPC)。此类前列腺癌统称为去势抵抗性前列腺癌(castrate-resistant prostate cancer,CRPC)。去势抵抗性前列腺癌患者生存质量差，中位生存期12～20个月。随着前列腺癌发病率、死亡率的上升，如何有效治疗去势抵抗性前列腺癌患已成为现代医学研究的热点。
目前去势抵抗性前列腺癌的治疗手段主要是以多西紫杉醇、米托蒽醌、泼尼松等药物联合化学治疗，副作用明显，且尚无最佳治疗方案。新型抗肿瘤药物目前处于不断开发研究阶段。因此，寻找一种高效、安全、副作用少的抗肿瘤药物的研究具有广阔市场前景。
发明内容
为了解决上述问题，本发明提供了一种酰胺类化合物及其在治疗癌症中的用途。
本发明提供了式Ⅰ所示的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物：
Figure PCTCN2019078725-appb-000001
式中，
R 1～R 9各自独立地选自氢、氘、氚、卤素、羟基、氨基、酰胺基、氰基、硝基、-CO 2R a、取代或未取代的C 1～C 12烷基、取代或未取代的C 1～C 12烷氧基、环烷基、芳基；
其中，R a选自C 1～C 12烷基；所述取代基为氘、氚、卤素、C 1～C 12烷基、芳基；
R 10选自氢、C 1～C 12烷基；
R 11选自OR、SR’、NR 12R 13；
R、R’、R 12、R 13各自独立地选自氢、氘、氚、
Figure PCTCN2019078725-appb-000002
其中，R 14选自取代或未取代的C 1～C 12烷基、取代或未取代的3～8元环烷基、取代或未取代的3～8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-O-R 15、
Figure PCTCN2019078725-appb-000003
所述取代基为氘、氚、卤素、氰基、C 1～C 12烷基、C 1～C 12烷氧基；
R 15选自取代或未取代的C 1～C 12烷基，取代或未取代的3～8元环烷基；
R 16、R 17各自独立地选自氢、取代或未取代的C 1～C 12烷基、取代或未取代的3～8元环烷基；或者，R 16、R 17相连形成取代或未取代的3～8元环。
进一步地，R 1～R 9各自独立地选自氢、氘、氚、卤素、羟基、氨基、酰胺基、氰基、硝基、-CO 2R a、取代或未取代的C 1～C 8烷基、取代或未取代的C 1～C 8烷氧基、环烷基、芳基；
其中，R a选自C 1～C 8烷基；
所述取代基为氘、氚、卤素、C 1～C 8烷基、芳基；
R 10选自氢、C 1～C 8烷基。
进一步地，R 1～R 9各自独立地选自氢、氘、氚、卤素、取代或未取代的C 1～C 4烷基、取代或未取代的C 1～C 4烷氧基；
所述取代基为氘、氚、卤素、C 1～C 4烷基；
R 10选自氢、C 1～C 4烷基。
进一步地，R 1～R 9各自独立地选自氢、氘、氚、卤素、取代或未取代的C 1～C 2烷基；
所述取代基为氘、氚、卤素；
R 10选自氢。
进一步地，R 11选自OR、SR’、NR 12R 13；
R、R’、R 12、R 13各自独立地选自氢、氘、氚、
Figure PCTCN2019078725-appb-000004
其中，R 14选自取代或未取代的C 1～C 8烷基、取代或未取代的3～8元环烷基、取代或未取代的3～8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-O-R 15、
Figure PCTCN2019078725-appb-000005
所述取代基为氘、氚、卤素、氰基、C 1～C 8烷基、C 1～C 8烷氧基；
R 15选自C 1～C 8烷基；
R 16、R 17各自独立地选自氢、C 1～C 8烷基；或者，R 16、R 17相连形成3～8元环。
进一步地，所述化合物Ⅰ如式Ⅱ所示：
Figure PCTCN2019078725-appb-000006
其中，
R 1～R 9各自独立地选自氢、氘、氚、F、Cl、Br、CF 3、CH 3；
R 12、R 13各自独立地选自氢、氘、氚、
Figure PCTCN2019078725-appb-000007
其中，R 14选自取代或未取代的C 1～C 4烷基、取代或未取代的3～6元环烷基、取代或未取代的3～6元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-O-R 15、
Figure PCTCN2019078725-appb-000008
所述取代基为氘、氚、卤素、氰基、C 1～C 2烷基；
R 15选自C 1～C 4烷基；
R 16、R 17各自独立地选自氢、C 1～C 6烷基；或者，R 16、R 17相连形成3～6元环。
进一步地，
R 1、R 3、R 6各自独立地选自氢、氘、氚。
进一步地，所述化合物Ⅱ如式ⅢA所示：
Figure PCTCN2019078725-appb-000009
式中，
R 14’选自取代或未取代的C 1～C 4烷基；所述取代基为氘、氚、卤素。
进一步地，所述化合物ⅢA如式ⅢA-1所示：
Figure PCTCN2019078725-appb-000010
式中，
R 14’选自C 1～C 3烷基、CF 3。
进一步地，所述化合物ⅢA-1为下述结构式之一：
Figure PCTCN2019078725-appb-000011
进一步地，所述化合物Ⅱ如式ⅢB所示：
Figure PCTCN2019078725-appb-000012
式中，
A环选自取代或未取代的3～6元环烷基、取代或未取代的3～6元杂环基、取代或未取代的芳基、取代或未取代的杂芳基；所述取代基选自氘、氚、卤素、氰基、C 1～C 2烷基。
进一步地，所述化合物ⅢB如式ⅢB-1所示：
Figure PCTCN2019078725-appb-000013
Figure PCTCN2019078725-appb-000014
式中，
R 2、R 3、R 5、R 7、R 8、R 9各自独立地选自F、Cl、Br、CF 3、CH 3；
A环选自3～6元环烷基、取代或未取代的4～6元杂环基、取代或未取代的苯基、取代或未取代的杂芳基；
所述取代基选自Cl、氰基、甲基。
进一步地，A环为环丙烷。
进一步地，所述化合物ⅢB-1为下述结构式之一：
Figure PCTCN2019078725-appb-000015
Figure PCTCN2019078725-appb-000016
进一步地，所述化合物Ⅱ如式ⅢC所示：
Figure PCTCN2019078725-appb-000017
式中，
R 15选自C 1～C 4烷基。
进一步地，所述化合物ⅢC如式ⅢC-1所示：
Figure PCTCN2019078725-appb-000018
式中，
R 15选自C 1～C 4烷基。
进一步地，所述化合物ⅢC-1为下述结构式之一：
Figure PCTCN2019078725-appb-000019
进一步地，所述化合物Ⅱ如式ⅢD所示：
Figure PCTCN2019078725-appb-000020
式中，
R 16、R 17各自独立地选自氢、C 1～C 2烷基；
或者，R 16、R 17相连形成4～6元环。
进一步地，所述化合物ⅢD如式ⅢD-1所示：
Figure PCTCN2019078725-appb-000021
式中，
R 16、R 17各自独立地选自氢、甲基；
或者，R 16、R 17相连形成5～6元杂环基。
进一步地，所述化合物ⅢD-1为下述结构式之一：
Figure PCTCN2019078725-appb-000022
Figure PCTCN2019078725-appb-000023
进一步地，所述化合物Ⅱ如式ⅢE所示：
Figure PCTCN2019078725-appb-000024
式中，
R 14”选自C 1～C 4烷基、3～6元环烷基、3～6元杂环基、芳基。进一步地，所述化合物ⅢE如式ⅢE-1所示：
Figure PCTCN2019078725-appb-000025
式中，
R 14”选自C 1～C 3烷基、3～5元环烷基、5～6元杂环基、苯基。
进一步地，所述化合物ⅢE-1为下述结构式之一：
Figure PCTCN2019078725-appb-000026
本发明还提供了前述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗和/或预防癌症的药物中的用途。
进一步地，所述癌症为乳腺癌、脑癌、前列腺癌，肺癌、卵巢癌、骨癌、神经癌、肝癌、血癌、食道癌、恶性胶质瘤、多发性骨髓瘤、套细胞淋巴瘤、急性骨髓性白血病及并发的癌症。
进一步地，所述癌症为前列腺癌、卵巢癌、骨癌或神经癌。
本发明还提供了前述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异 构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备减少全长雄激素受体、变异雄激素受体表达的药物中的用途。
本发明还提供了前述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备抑制癌细胞增殖的药物中的用途。
进一步地，所述癌细胞是下述癌症的癌细胞：乳腺癌、脑癌、前列腺癌，肺癌、卵巢癌、骨癌、神经癌、肝癌、血癌、食道癌、恶性胶质瘤、多发性骨髓瘤、套细胞淋巴瘤、急性骨髓性白血病及并发的癌症。
进一步地，所述癌细胞为前列腺癌细胞、卵巢癌细胞、骨癌细胞或神经癌细胞。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
本发明中所述化合物的结构均是指能够稳定存在的结构。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
“氘”是指氢(H)的同位素，也被称为重氢，元素符号一般为D或2H。
“氚”是指氢(H)的同位素，元素符号一般为T或3H。
“卤素”为氟、氯、溴或碘。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀(C a～C b)烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，C 1～C 4烷基是指包含1～4个碳原子的烷基。C 1～C 4烷基是指含有一个至四个碳原子的直链或支链的烃链。
“烷基”是烷烃分子中少掉一个氢原子而成的烃基，例如，甲基-CH 3,乙基-CH 3CH 2等。
“亚烷基”是指烷烃分子中少掉两个氢原子而成的烃基，例如亚甲基-CH 2-,亚乙基-CH 2CH 2-等。“C 1-4亚烷基”是指含有一个至四个碳原子的直链或支链的烃链。
“取代或未取代的C 1-4烷基”是指C 1-4烷基可以是被取代的，也可以没有取代基的。
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环)，但不能含有杂原子如氮，氧，或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。
“杂芳基”指包含一个到多个杂原子的杂芳族基团。含有至少一个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子系统。例如呋喃基、吡咯基、喹啉 基、噻吩基、吡啶基、吡唑基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基、噻吩并吡啶基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
本发明所述“取代或未取代的杂芳基”可以是
Figure PCTCN2019078725-appb-000027
“环烷基”指饱和或不饱和的环状烃取代基；环状烃可以是单环也可以是多环。例如，“C 3-8环烷基”指碳原子数为3～8的环烷基。
“杂环基”指饱和或不饱和的环状烃取代基；环状烃可以是单环也可以是多环，且携带至少一个选自O、S或取代的氮原子的环烷基，其余环原子为碳，例如，“C 3-8杂环基”指碳原子数和杂原子数共为3～8的杂环基。杂环基可以是非取代的，也可以被一个或多个取代基取代。具体的，本发明中“5～6元杂环基”可以是
Figure PCTCN2019078725-appb-000028
等
“本发明化合物”指式(I)所示的化合物。该术语还包括式(I)化合物的各种晶型、立体异构体、同位素体、互变异构体、立体化学异构体、药学上可接受的盐、溶剂合物、前体药物、代谢产物。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，例如：顺反异构体、对映异构体、构象异构体等。
“药学上可接受的”是指当给药至动物例如哺乳动物(例如人类)时生理学上可耐受且通常不会产生过敏或类似的不良反应(例如头晕等)的添加剂或组合物。药物载体和赋形剂可以包括但不限于稀释剂，例如乳糖、葡萄糖、甘露糖和/或甘油；润滑剂；聚乙二醇；粘合剂，例如硅酸铝镁、淀粉、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮；并且，如果需要的话，还包括崩解剂，例如淀粉、琼脂、海藻酸或其盐如海藻酸钠；和/或吸附剂、着色剂、防腐剂、稳定剂、矫味剂和甜味剂。
“盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分 离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、氢氟酸盐、硫酸盐、硝酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、柠檬酸盐、苦味酸盐、甲磺酸盐、乙磺酸盐、酒石酸盐、天冬氨酸盐或三氟乙酸盐。
“式(I)所示的化合物的溶剂合物”，溶剂如乙醇、水等，其中，可含有不同量的水，如一水合物、半水合物、一个半水合物、二水合物或者三水合物。
“前体药物”是通式Ⅰ化合物的衍生物，其在可能具有较弱的活性或甚至没有活性，但在生理条件下(例如通过代谢、溶剂分解或另外的方式)转化为本发明的活性成分，从而发挥其药理作用的化合物。例如，含有羧基的化合物可形成生理上可水解的酯，其通过在体内水解以得到式I所示化合物本身而充当前药。所述前药优选口服给药，这是因为水解在许多情况下主要在消化酶的影响下发生。当酯本身具有活性或水解发生在血液中时，可使用肠胃外给药。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
癌症包括但不限于下列癌症：乳腺癌、卵巢癌、前列腺癌、子宫颈癌、食道癌、睾丸癌、胃癌、皮肤癌、肺癌、骨癌、结肠癌、胰腺癌、甲状腺癌、胆道癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、脑与中枢神经系统的癌症、神经母细胞瘤、大细胞癌、腺癌、腺瘤、滤泡癌、表皮样癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓障碍、淋巴障碍、何杰金氏病、毛发细胞癌和白血病。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
本发明所述“室温”为25±5℃。
本发明所述“过夜”为12±1小时。
通用合成方法：
通用合成方法A：
Figure PCTCN2019078725-appb-000029
通用合成方法B：
Figure PCTCN2019078725-appb-000030
本发明提供了一种结构新颖的酰胺类化合物及其在治疗癌症中的用途。实验结果表明，本发明化合物能够抑制前列腺癌细胞的增殖，尤其是对耐药性前列腺癌细胞系(22RV1)有明显抑制作用。同时，本发明化合物还能够显著抑制多种癌细胞的增殖。此外，本发明化合物具有良好的药代动力学。对癌症，尤其是前列腺癌具有潜在的治疗作用，为临床上筛选和/或制备癌症药物提供了一种新的选择。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1：5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(1)
Figure PCTCN2019078725-appb-000031
第一步：5-氯-N-(2-氯-4-三氟甲基苯基)-2-硝基苯甲酰胺(1-1)
氮气保护下，将5-氯-2-硝基苯甲酸(5.0g,24.8mmol),三乙胺(5.0g,24.8mmol)和3-氯-4-氨基三氟甲苯(4.6g,23.6mmol)加入到50mL二甲苯中，加热到110℃，缓慢滴加三氯化磷(3.4g,24.8mmol)。110℃下，搅拌2h。冷却至室温，真空旋干。加入100mL水，固体抽滤，滤饼用水洗涤，再用少量乙酸乙酯打浆，固体再抽滤，干燥，得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-硝基苯甲酰胺(8.2g,21.6mmol)。收率：87.2％。MS(ESI)m/e396.0(M+18) +。 1H NMR(400MHz,CDCl 3)δ8.63(d,J＝8.5Hz,1H),8.16(d,J＝8.4Hz,1H),7.99(s,1H),7.71(s,1H),7.69-7.57(m,3H)。
第二步：5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(1)
将5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-硝基苯甲酰胺(5.0g,13.2mmol)溶于50mL醋酸，铁粉(3.7g,65.9mmol)。加热到80℃，搅拌1h。冷却至室温。反应液倒入冰水中，大量固体析出。固体抽滤，滤饼用水洗涤，干燥，得到白色固体2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(4.1g,11.7mmol)。收率：89.0％。MS(ESI)m/e 349.0(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.60(d,J＝8.7Hz,1H),8.39(s,1H),7.70(s,1H),7.58(d,J＝8.7Hz,1H),7.48(d,J＝2.0Hz,1H),7.25(d,J＝1.8Hz,1H),6.70(d,J＝8.8Hz,1H),5.59(s,2H)。
实施例2：5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(甲磺酰胺基)苯甲酰胺(2)
将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)和3mL吡啶，缓慢滴加甲基磺酰氯(65.6mg,0.57mmol)。加热到40℃，搅拌过夜。加入二氯甲烷和水萃取，有机层用1N稀盐酸洗涤，再用饱和食盐水洗涤，干燥，旋干，硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(甲基磺酰胺基)苯甲酰胺(60.0mg,0.14mmol)。收率：49.0％。MS(ESI)m/e427.0(M+H) +。
实施例3：5-氯-N-(2-氯-4-三氟甲基苯基)-2-丙酰胺基苯甲酰胺(3)
25ml圆底烧瓶中，放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.2mmol,70mg),丙酰氯(1.2eq,23mg),二氯甲烷1ml和TEA(2eq,40mg),室温搅拌过夜，反应液稀盐酸洗，饱和食盐水洗，干燥，旋干，用冰二氯甲烷打浆，过滤，得白色固体10mg,产率13％
MS m/z(ESI):210.2。
实施例4：5-氯-N-(2-氯-4-三氟甲基苯基)-2-丙磺酰胺基苯甲酰胺(4)
25ml圆底烧瓶中，放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),丙磺酰氯(1.2eq,43mg),二氯甲烷2ml和TEA(2eq,50mg),室温搅拌过夜，反应液稀盐酸洗，饱和食盐水洗，干燥，浓缩，pre-TLC纯化，得类白色固体7mg,产率6％。
MS m/z(ESI):455.0(M+H) +。 1H NMR(400MHz,CDCl 3)δ10.03(s,1H),8.58(d,J＝8.7Hz,1H),8.48(s,1H),7.81(d,J＝9.0Hz,1H),7.74(d,J＝1.5Hz,1H),7.66(d,J＝2.3Hz,1H),7.63(dd,J＝8.7,1.2Hz,1H),7.54(dd,J＝9.0,2.3Hz,1H),3.17–3.10(m,2H),1.93–1.81(m,2H),1.02(t,J＝ 7.5Hz,3H).
实施例5：5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(异丙磺酰胺基)苯甲酰胺(5)
将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶，滴加异丙磺酰氯(147.3mg,1.15mmol)。室温搅拌过夜。加入二氯甲烷和水萃取，有机层用1N稀盐酸洗涤，再用饱和食盐水洗涤，干燥，旋干，硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(4-甲基苯磺酰胺基)苯甲酰胺(5.0mg,0.01mmol)。收率：3.8％。MS(ESI)m/e455.0(M+H) +。
实施例6：5-氯-N-(2-氯-4-三氟甲基苯基)-2-环丙磺酰胺基苯甲酰胺(6)
方法一：25ml圆底烧瓶中，放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.5mmol,174mg),环丙磺酰氯(1.2eq,85mg),二氯甲烷3ml和TEA(2eq,100mg),室温搅拌过夜，反应液稀盐酸洗，饱和食盐水洗，干燥，浓缩，pre-TLC纯化，得类白色固体23mg,产率10％MS m/z(ESI):453.0(M+H) +
1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),10.19(s,1H),8.17–7.87(m,3H),7.82(d,J＝8.4Hz,1H),7.70(dd,J＝8.8,2.4Hz,1H),7.61(d,J＝8.8Hz,1H),2.82–2.68(m,1H),0.94(ddd,J＝16.2,9.7,7.0Hz,4H).
方法二：氮气保护下，将5-氯-2-环丙基磺酰胺基苯甲酸(500.0mg,1.81mmol)和3-氯-4-氨基三氟甲苯(461.0mg,2.36mmol)加入到10mL二甲苯中，加热到140℃，缓慢滴加三氯化磷(124.0mg,0.91mmol)。140℃下，搅拌2h。冷却至室温，有白色固体析出。固体抽滤，滤饼少量甲醇打浆。固体再抽滤，干燥，得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(环丙磺酰胺基)苯甲酰胺(450.0mg,0.99mmol)。收率：54.7％。MS(ESI)m/e453.0(M+H) +。 1H NMR(400MHz,CDCl 3)δ9.89(s,1H),8.59(d,J＝8.6Hz,1H),8.48(s,1H),7.83(d,J＝8.9Hz,1H),7.74(d,J＝1.6Hz,1H),7.66(d,J＝2.4Hz,1H),7.63(dd,J＝8.7,1.7Hz,1H),7.54(dd,J＝8.9,2.4Hz,1H),2.52(tt,J＝8.0,4.8Hz,1H),1.28–1.20(m,2H),1.01–0.92(m,2H)。
实施例7：5-溴-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺(7)
Figure PCTCN2019078725-appb-000032
第一步：将2-氨基-5-溴-苯甲酸(1g，4.63mmol)溶于15ml甲醇，加入H 2SO 4(2ml)，体系在油浴中回流反应过夜。减压浓缩，柱层析分离纯化(PE/EA＝1:1)，得产品2-氨基-5-溴-苯甲酸甲酯873mg，收率：81.9％。
第二步：将2-氨基-5-溴-苯甲酸甲酯(194mg，0.84mmol)溶于2ml二氯甲烷，待澄清后将体系移置于冰水浴中继续降温冷却搅拌，随后加入吡啶(2mL)以及环丙基磺酰氯(237mg，1.68mmol)，完毕体系在油浴中升温加热搅拌反应过夜。翌日，冷却至室温，向体系中加入5ml 0.5N HCl剧烈搅拌，静置分层，水相用10ml二氯甲烷萃取，合并有机相，分别用纯净水以及饱和食盐水洗涤，无水硫酸钠干燥，旋蒸除去溶剂，薄层层析分离纯化(PE/EA＝5:1)，得产品5-溴-2-(环丙基磺酰胺基)-苯甲酸甲酯95mg，收率：33.7％。
第三步：将5-溴-2-(环丙基磺酰胺基)-苯甲酸甲酯(50mg，0.15mmol)溶于3ml甲醇，并加入1ml饱和LiOH溶液，室温搅拌反应过夜，TLC监测反应(PE/EA＝5:1)，至原料消失。旋蒸除去大部分溶剂，用1N HCl调节体系的pH值约2-3左右，加入乙酸乙酯剧烈搅拌，后静置分层，有机相分别用纯净水以及饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，得5-溴-2-(环丙基磺酰胺基)-苯甲酸35mg，收率：73.1％。
第四步：将5-溴-2-(环丙基磺酰胺基)-苯甲酸(35mg，0.11mmol)溶于3ml二甲苯，加入2-氯-4-三氟甲基-苯胺(22mg，0.11mmol)后，加热至140℃，随即加入三氯化磷(9mg，0.07mmol)，保温反应6h。旋蒸除去溶剂，薄层层析分离纯化(PE/EA＝1:1)，得目标产品5-氯-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺(7)17mg，收率：31.3％。MS(M+2)：499.0。 1HNMR(400Hz,DMSO-d 6):δ10.653(1H,s),10.205(1H,s),8.116(1H,d,J＝2.4Hz),8.036-8.009(2H,m),7.822-7.802(2H,m),7.552(1H,d,J＝8.8Hz),2.781-2.718(1H,m),0.993-0.893(4H,m).
实施例8：5-溴-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(8)
Figure PCTCN2019078725-appb-000033
第一步：2-氨基-5-溴-4-氟苯甲酸(8-1)
将2-氨基-4-氟苯甲酸(620mg，4.0mmol)溶于5ml DMF中，加入NBS(712mg，4.0mmol)，室温反应过夜，TLC监控反应直至原料2-氨基-4-氟苯甲酸反应完全(PE:EA＝2:1)，加入10ml EA，加入10ml水，搅拌萃取，有机层用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，得到产品2-氨基-5-溴-4-氟苯甲酸(8-1)400mg，收率：42.8％。
第二步：2-氨基-5-溴-4-氟苯甲酸甲酯(8-2)
将上一步产品2-氨基-5-溴-4-氟苯甲酸(400mg，1.71mmol)溶于15ml甲醇，加入H 2SO 4(1ml)，反应70℃回流过夜，减压浓缩，薄层层析纯化(PE:EA＝2:1)，得到产品2-氨基-5-溴-4-氟苯甲酸甲酯(8-2)141mg，收率：33.3％。
第三步：5-溴-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯(8-3)
将2-氨基-5-溴-4-氟苯甲酸甲酯(141mg，0.57mmol)溶于5ml甲苯，加入吡啶(898mg，11.36mmol)，加入环丙基磺酰氯(795mg，5.68mmol)，100℃反应过夜，TLC监控反应进程，反应完成，冷却至室温，加入水5ml，搅拌，静置分液，水层用5ml EA萃取，合并有机层，饱和食盐水洗涤，干燥，减压浓缩，薄层层析纯化(PE:EA＝2:1)，得到产品5-溴-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯(8-3)100mg，收率：49.1％。
第四步：5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸(8-4)
将5-溴-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯(100mg，0.28mmol)溶于5ml甲醇/5ml水中，加入LiOH(140mg，5.83mmol)固体，加热搅拌升温至70℃反应0.5h，TLC监控反应(PE:EA＝5:1)，直至原料5-溴-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯反应完全，用浓盐酸调节反应体系pH＝3～4，有固体析出，过滤，得到产品5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸(8-4)125mg(湿品)，收率：132.1％。
第五步：5-溴-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(8)
将5-溴-4-氟-2-(环丙基磺酰胺基)-苯甲酸(125mg，0.37mmol)溶于5ml二甲苯中，加入2-氯-4-三氟甲基-苯胺(86mg，0.44mmol)，加热搅拌升温至120℃，加入三氯化磷(19mg，0.14mmol)，反应过夜，TLC监控反应进程，反应完全，65℃减压浓缩至干，薄层层析纯化(PE:EA＝2:1)，得到目标产品5-溴-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(8)32mg，收率：16.8％。 1H NMR(400MHz,DMSO-d6)δ14.28(s,1H),8.75(d,J＝4Hz,1H),8.20(d,J＝12Hz,1H),7.84(s,1H),7.68(d,J＝8Hz,1H),7.58(d,J＝12Hz,1H),1.23(s,1H),0.83(m,2H),0.73(dd,2H)。
实施例9、10：5-氯-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(9)，N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(10)
Figure PCTCN2019078725-appb-000034
第一步：将2-氨基-4-氟苯甲酸(310mg，2.0mmol)溶于5mlDMF，加入NCS(266mg，2.0mmol)，50℃加热反应8h，TLC监控反应直至原料反应完全(PE/EA＝1：1)，加入10mlEa，加入10ml水，搅拌萃取，有机层用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，得到产品2-氨基-5-氯-4-氟苯甲酸350mg，收率：92.4％。
第二步：将上一步产品2-氨基-5-氯-4-氟苯甲酸(350mg，1.85mmol)溶于5ml甲醇，加入H 2SO 4(1ml)，反应70℃回流过夜，减压浓缩，薄层柱层析纯化(PE/Ea＝1:1)，得到产品2-氨基-5-氯-4-氟苯甲酸甲酯135mg，收率：35.9％。
第三步：将2-氨基-5-氯-4-氟苯甲酸甲酯(135mg，0.66mmol)溶于5ml甲苯，加入吡啶(1.05g，13.2mmol)，加入环丙基磺酰氯(930.4mg，6.6mmol)，120℃反应过夜，冷却至室温，加入5ml0.5N HCl洗涤，分层，水层用5ml EA萃取，合并有机层，饱和食盐水洗涤，干燥，减压浓缩，薄层柱层析纯化(PE/Ea＝5:1)，得到产品5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯65mg，收率：31.9％。
第四步：将5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯(65mg，0.21mmol)溶于3ml 四氢呋喃，加入1ml LiOH饱和水溶液，室温反应2h，TLC监控反应(PE/Ea＝5:1)，直至原料反应完全，用1N HCl调节Ph＝5.0，加入Ea萃取，有机层用饱和水溶液洗涤，无水硫酸钠干燥，减压浓缩，得到产品5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸60mg，收率：96.7％。
第五步：将5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸(60mg，0.20mmol)溶于3ml二甲苯，加入2-氯-4-三氟甲基-苯胺(39.95mg，0.20mmol)，加热至140℃，加入三氯化磷(9.82mg，0.07mmol)，保温反应4h，65℃减压浓缩干，薄层柱层析纯化(PE/Ea＝2:1)，得到目标产品5-氯-N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(9)12mg，收率：12.5％。MS(M+1)：471。 1H NMR(400MHz,DMSO)δ10.53(s,2H),8.19(d,J＝7.5Hz,1H),7.99(s,2H),7.79(d,J＝8.0Hz,1H),7.58(d,J＝11.5Hz,1H),2.87(s,1H),0.95(s,4H).
同时得到副产品N-2-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(10)11mg，MS(M+1)：437， 1H NMR(400MHz,DMSO)δ10.65(s,2H),8.07(dd,J＝23.2,16.6Hz,3H),7.80(d,J＝8.2Hz,1H),7.40(dd,J＝11.0,2.3Hz,1H),7.20(s,1H),2.88(s,1H),0.97(s,4H).
实施例11：3，5-二氯-N-(2-氯-5-氟-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)苯胺(11)
将3，5-氯-2-(环丙基磺酰胺基)-苯甲酸(124.06mg，0.4mmol)溶于5mL二甲苯，加入2-氯-4-三氟甲基-苯胺(78.23mg，0.4mmol)，体系加热至140℃，加入三氯化磷(19.23mg，0.14mmol)，保温反应6h，旋蒸除去溶剂，薄层层析纯化(PE/EA＝1:1)，得到目标产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺119mg，收率：61％。MS(M+1)：487。
1HNMR(400Hz,DMSO-d 6):δ10.20(1H,s),9.79(1H,s),8.20-8.18(1H,d,J＝8.8Hz),7.97-7.96(2H,m),7.81-7.78(1H,m),7.71-7.70(1H,d,J＝2.4Hz),2.67-2.65(1H,m)，0.92-0.90(2H,m)，0.84-0.82(1H,m)。
实施例12：3，5-二氯-N-(2-氯-5-氟-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)苯胺(12)
Figure PCTCN2019078725-appb-000035
第一步：化合物12-1的合成：
将2-氨基-3，5-二氯-苯甲酸(1g，4.85mmol)溶于15mL甲醇，加入H 2SO 4(2mL)，体系在油浴中回流反应过夜。减压浓缩，柱层析分离纯化(PE/EA＝1:1)，得产品2-氨基-3，5-二氯-苯甲酸甲酯845mg，收率：78.97％。
第二步：化合物12-2的合成：
将2-氨基-3，5-二氯-苯甲酸甲酯(440.1mg，2mmol)溶于4mL二氯甲烷，待澄清后将 体系移置于冰水浴中继续降温冷却搅拌，随后加入吡啶(4mL)以及环丙基磺酰氯(562.32mg，4mmol)，完毕体系在油浴中升温加热搅拌反应过夜。翌日，冷却至室温，向体系中加入10mL0.5N HCl剧烈搅拌，静置分层，水相用10mL二氯甲烷萃取，合并有机相，分别用纯净水以及饱和食盐水洗涤，无水硫酸钠干燥，旋蒸除去溶剂，薄层层析分离纯化(PE/EA＝4:1)，得产品3，5-氯-2-(环丙基磺酰胺基)-苯甲酸甲酯246.38mg，收率：38％。
第三步：化合物12-3的合成：
将3，5-氯-2-(环丙基磺酰胺基)-苯甲酸甲酯(194.51mg，0.6mmol)溶于3mL甲醇，并加入5mL饱和2N LiOH溶液，室温搅拌反应过夜，TLC监测反应(PE/EA＝4:1)，至原料消失。旋蒸除去大部分溶剂，用1N HCl调节体系的pH值约2-3左右，加入乙酸乙酯剧烈搅拌，后静置分层，有机相分别用纯净水以及饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，得3，5-氯-2-(环丙基磺酰胺基)-苯甲酸135.85mg，收率：73％。
第四步：化合物12的合成：
将3，5-氯-2-(环丙基磺酰胺基)-苯甲酸(124.06mg，0.4mmol)溶于5mL二甲苯，加入2-氯-5-氟-4-三氟甲基-苯胺(85.42mg，0.4mmol)，体系加热至140℃，加入三氯化磷(19.23mg，0.14mmol)，保温反应6h，旋蒸除去溶剂，薄层层析纯化(PE/EA＝1:1)，得到目标产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺116.92mg，收率：58％。MS(M+1)：505。 1HNMR(400Hz,DMSO-d 6):δ10.29(1H,s),9.87(1H,s),8.20-8.17(1H,d,J＝12Hz),8.02-7.98(1H,m),7.72-7.71(1H,d,J＝2.4Hz),2.67-2.64(1H,m),0.92-0.84(1H,m)，0.83-0.81(1H,m)。
实施例13：5-氯-N-2-(2-溴-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺(13)
Figure PCTCN2019078725-appb-000036
第一步：将2-氨基-5-氯-苯甲酸(1g，5.83mmol)溶于15ml甲醇，加入H 2SO 4(2ml)，体系在油浴中回流反应过夜。减压浓缩，柱层析分离纯化(PE/EA＝1:1)，得产品2-氨基-5-氯-苯甲酸甲酯780mg，收率：72.1％。
第二步：将2-氨基-5-氯-苯甲酸甲酯(300mg，1.62mmol)溶于2mL二氯甲烷，待澄清后将体系移置于冰水浴中继续降温冷却搅拌，随后加入吡啶(2mL)以及环丙基磺酰氯(454mg， 3.24mmol)，完毕体系在油浴中升温加热搅拌反应过夜。翌日，冷却至室温，向体系中加入5ml 0.5N HCl剧烈搅拌，静置分层，水相用10ml二氯甲烷萃取，合并有机相，分别用纯净水以及饱和食盐水洗涤，无水硫酸钠干燥，旋蒸除去溶剂，薄层层析分离纯化(PE/EA＝5:1)，得产品5-氯-2-(环丙基磺酰胺基)-苯甲酸甲酯250mg，收率：53.4％。
第三步：将5-氯-2-(环丙基磺酰胺基)-苯甲酸甲酯(100mg，0.35mmol)溶于6ml甲醇，并加入2ml饱和LiOH溶液，室温搅拌反应过夜，TLC监测反应(PE/EA＝5:1)，至原料消失。旋蒸除去大部分溶剂，用1N HCl调节体系的pH值约2-3左右，加入乙酸乙酯剧烈搅拌，后静置分层，有机相分别用纯净水以及饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，得5-氯-2-(环丙基磺酰胺基)-苯甲酸83mg，收率：87.2％。
第四步：将5-氯-2-(环丙基磺酰胺基)-苯甲酸(50mg，0.18mmol)溶于5ml二甲苯，加入2-溴-4-三氟甲基-苯胺(44mg，0.18mmol)，体系加热至140℃，加入三氯化磷(15mg，0.11mmol)，保温反应6h，旋蒸除去溶剂，薄层层析纯化(PE/EA＝1:1)，得到目标产品5-氯-N-2-(2-溴-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺41mg，收率：45.4％。MS(M+2)：499.0
1HNMR(400Hz,DMSO-d 6):δ10.637(1H,s),10.236(1H,s),8.137(1H,s),8.015(1H,d,J＝2.4Hz),7.953(1H,d,J＝8.0Hz),7.869-7.844(1H,dd,J 1＝8.6Hz,J 2＝1.4Hz),7.719-7.691(1H,dd,J 1＝8.8Hz,J 2＝2.4Hz)，7.624(1H,d,J＝8.8Hz)，2.789-2.726(1H,m),0.998-0.895(4H,m).
实施例14:5-氯-N-(2-氯-5-氟-4-三氟甲基)-2-(环丙磺酰胺基)-3-氟苯甲酰胺(14)
Figure PCTCN2019078725-appb-000037
第一步：5-氯-2-(环丙磺酰胺基)苯甲酸甲酯
氮气保护下，将5-氯-2-氨基苯甲酸甲脂(600.0mg,3.23mmol)加入到14mL甲苯和7mL吡啶中，缓慢滴加环丙磺酰氯(2.27g,16.13mmol)。加热110℃，搅拌过夜。冷却至室温，加入乙酸乙酯和水萃取，有机层用1N稀盐酸洗涤，再用饱和食盐水洗涤，干燥，旋干，硅胶柱层析纯化。得到白色固体5-氯-2-(环丙磺酰胺基)苯甲酸甲酯(600.0mg,2.1mmol)。收率： 76.9％。MS(ESI)m/e290.2(M+H) +。
第二步：.5-氯-2-(环丙磺酰胺基)-3-氟苯甲酸甲酯
氮气保护下，将5-氯-2-(环丙磺酰胺基)苯甲酸甲酯(100.0mg,0.35mmol)和选择性氟试剂(1.2g,3.50mmol)加入4mL乙酸中。加热95℃，搅拌过夜。冷却至室温，加入乙酸乙酯和水萃取，有机层用饱和碳酸氢钠洗涤，再用饱和食盐水洗涤，干燥，旋干，硅胶柱层析纯化。得到白色固体5-氯-2-(环丙磺酰胺基)-3-氟苯甲酸甲酯(40.0mg,0.11mmol)。收率：37.6％。MS(ESI)m/e308.0(M+H) +。
第三步：5-氯-2-(环丙基磺酰胺)-3-氟苯甲酸
将5-氯-2-(环丙磺酰胺基)苯甲酸甲酯(100.0mg,0.35mmol)(1.2g,3.50mmol)溶于2mL甲醇中，加入2mL2N氢氧化锂。室温搅拌过夜。加入冰水，用2N稀盐酸调节pH至5～6，有白色固体析出。固体抽滤，滤饼干燥，得到白色固体5-氯-2-(环丙磺酰胺基)-3-氟苯甲酸(30.0mg,0.05mmol)。收率：78.6％。
第四步：5-氯-2-(环丙磺酰胺基)-3-氟苯甲酸
氮气保护下，将5-氯-2-(环丙磺酰胺基)-3-氟苯甲酸(100.0mg,0.10mmol)和2-氯-5-氟-4-(三氟甲基)苯胺(26.2mg,0.12mmol)加入到2mL二甲苯中，加热到140℃，缓慢滴加三氯化磷(18.0mg,0.13mmol)。140℃下，搅拌2h。冷却至室温，有白色固体析出。固体抽滤，滤饼少量甲醇打浆。固体再抽滤，干燥，得到白色固体5-氯-N-(2-氯-4-氰基-5-氟苯基)-2-(环丙磺酰胺基)-3-氟苯甲酰胺(15.0mg,0.03mmol)。收率：30.0％。MS(ESI)m/e489.0(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ10.59–10.30(m,1H),9.93(s,1H),8.23(d,J＝12.8Hz,1H),8.03(d,J＝7.3Hz,1H),7.84(dd,J＝9.4,2.3Hz,1H),7.65(d,J＝1.4Hz,1H),2.64(ddd,J＝12.5,7.8,4.7Hz,1H),0.94–0.87(m,2H),0.85–0.76(m,2H)。
实施例15：5-氯-N-2-(2-溴-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(15)
Figure PCTCN2019078725-appb-000038
第一步：将2-氨基-4-氟苯甲酸(466mg，3.0mmol)溶于5mlDMF，加入NCS(399mg，3.0mmol)，60℃加热反应6h，TLC监控反应直至原料反应完全(PE/Ea＝1：1)，加入10mlEa，加入10ml水，搅拌萃取，有机层用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，得到产品 2-氨基-5-氯-4-氟苯甲酸500mg，收率：87.8％。
第二步：将上一步产品2-氨基-5-氯-4-氟苯甲酸(500mg，mmol)溶于5ml甲醇，加入H 2SO 4(1ml)，反应70℃回流过夜，减压浓缩，薄层柱层析纯化(PE/Ea＝1:1)，得到产品2-氨基-5-氯-4-氟苯甲酸甲酯405mg，收率：75.4％。
第三步：将2-氨基-5-氯-4-氟苯甲酸甲酯(91mg，0.45mmol)溶于1ml二氯甲烷，加入吡啶(1ml)，加入环丙基磺酰氯(126mg，0.9mmol)，室温反应过夜，加入5ml0.5N HCl洗涤，分层，水层用5mlEa萃取，合并有机层，饱和食盐水洗涤，干燥，减压浓缩，薄层柱层析纯化(PE/Ea＝5:1)，得到产品5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯45mg，收率：32.7％。
第四步：将5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸甲酯(45mg，0.15mmol)溶于3ml四氢呋喃，加入1ml LiOH饱和水溶液，室温反应2h，TLC监控反应(PE/Ea＝5:1)，直至原料反应完全，用1N HCl调节Ph＝5.0，加入Ea萃取，有机层用饱和水溶液洗涤，无水硫酸钠干燥，减压浓缩，得到产品5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸40mg，收率：93.1％。
第五步：将5-氯-4-氟-2-(环丙基磺酰胺基)-苯甲酸(40mg，0.14mmol)溶于3ml二甲苯，加入2-溴-4-三氟甲基-苯胺(33mg，0.14mmol)，加热至140℃，加入三氯化磷(7mg，0.05mmol)，保温反应4h，65℃减压浓缩干，薄层柱层析纯化(PE/Ea＝2:1)，得到目标产品5-氯-N-2-(2-溴-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-4-氟苯甲酰胺(15)10mg，收率：14.2％。MS(M+1)：514.9. 1H NMR(400MHz,DMSO)δ10.61(s,2H),8.22(d,J＝7.4Hz,1H),8.13(s,1H),7.85(d,J＝7.9Hz,2H),7.58(d,J＝11.3Hz,1H),2.90(s,1H),0.93(dd,J＝18.3,10.9Hz,4H).
实施例16：5-氯-N-(2-氯-4-三氟甲基-5-氟苯基)-2-环丙磺酰胺基苯甲酰胺(16)
25ml圆底烧瓶中，放入5-氯-2-环丙磺酰胺基苯甲酸(0.4mmol,110mg),2-氯-4-三氟甲基-5氟苯胺(1.2eq,102mg)和2ml二甲苯，室温搅拌下滴加三氯化磷(0.3eq,16mg),滴加完毕后升温至140℃搅拌过夜。搅拌下冷却至室温，pre-TLC纯化，得类白色固体20mg，产率10％
MS m/z(ESI):471.0(M+H) +。 1H NMR(400MHz,CDCl 3)δ9.81(s,1H),8.56(s,1H),8.49(d,J＝12.1Hz,1H),7.82(d,J＝8.9Hz,1H),7.70(d,J＝6.8Hz,1H),7.65(d,J＝2.2Hz,1H),7.55(dd,J＝8.9,2.2Hz,1H),2.59–2.48(m,1H),1.30–1.22(m,2H),1.04–0.97(m,2H).
实施例17：5-氯-2-(环丙基磺酰胺基)-N-(2-氟-4-(三氟甲基)苯基)苯甲酰胺(17)
用类似于实施例15的方法制备得到。MS m/z(ESI):437(M+H) +.
实施例18：5-氯-N-(4-氯-2-氟苯基)-2-(环丙基磺酰胺基)苯甲酰胺(18)
用类似于实施例15的方法制备得到。MS m/z(ESI):403(M+H) +.
实施例19：5-氯-2-(环丙基磺酰胺基)-N-(2,5-二氟-4-(三氟甲基)苯基)苯甲酰胺(19)
用类似于实施例15的方法制备得到。MS m/z(ESI):455(M+H) +.
实施例20：5-氯-N-(2-氯-5-氟-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-3-甲基-苯胺(20)
Figure PCTCN2019078725-appb-000039
第一步：化合物20-2的合成：
将2-氨基-5-氯-3-甲基-苯甲酸(1g，5.39mmol)溶于15mL甲醇，加入H 2SO 4(2mL)，体系在油浴中回流反应过夜。减压浓缩，柱层析分离纯化(PE/EA＝1:1)，得产品2-氨基-5-氯-3-甲基-苯甲酸甲酯852mg(20-2)。
第二步：化合物20-3的合成：
将2-氨基-5-氯-3-甲基-苯甲酸甲酯(399.28mg，2mmol)溶于4mL二氯甲烷，待澄清后将体系移置于冰水浴中继续降温冷却搅拌，随后加入吡啶(4mL)以及环丙基磺酰氯(562.32mg，4mmol)，完毕体系在油浴中升温加热搅拌反应过夜。翌日，冷却至室温，向体系中加入10mL 0.5N HCl剧烈搅拌，静置分层，水相用10mL二氯甲烷萃取，合并有机相，分别用纯净水以及饱和食盐水洗涤，无水硫酸钠干燥，旋蒸除去溶剂，薄层层析分离纯化(PE/EA＝4:1)，得产品5-氯-2-(环丙基磺酰胺基)-3-甲基-苯甲酸甲酯212.63mg(20-4)，收率：35％。
第三步：化合物20-4的合成：
将5-氯-2-(环丙基磺酰胺基)-3-甲基苯甲酸甲酯(182.26mg，0.6mmol)溶于3mL甲醇，并加入5mL饱和2N LiOH溶液，室温搅拌反应过夜，TLC监测反应(PE/EA＝4:1)，至原料消失。旋蒸除去大部分溶剂，用1N HCl调节体系的pH值约2-3左右，加入乙酸乙酯剧烈搅拌，后静置分层，有机相分别用纯净水以及饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，得5-氯-2-(环丙基磺酰胺基)-3-甲基-苯甲酸130.38mg，收率：75％。
第四步：化合物20-5的合成：
将5-氯-2-(环丙基磺酰胺基)-3-甲基-苯甲酸(115.90mg，0.4mmol)溶于5mL二甲苯，加入2-氯-5-氟-4-三氟甲基-苯胺(85.42mg，0.4mmol)，体系加热至140℃，加入三氯化磷(19.23mg，0.14mmol)，保温反应6h，旋蒸除去溶剂，薄层层析纯化(PE/EA＝1:1)，得到目标产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(环丙基磺酰胺基)-苯胺120.35mg，收率：62％。MS(M+1)：485.0。 1HNMR(400Hz,DMSO-d 6):δ10.25(1H,s),9.51(1H,s),8.20-8.17(1H,d,J＝12Hz),8.01-7.97(1H,m),7.50-7.54(2H,m),2.62-2.60(1H,m),2.49(3H,s),0.90-0.88(2H,m)，0.82-0.79(2H,m)。
实施例21：5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(氧杂环丁烷-3-磺酰氨基)苯胺(21)
将2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)苯胺(104.74mg，0.3mmol)溶于5mL二甲苯，待澄清后将体系移置于冰水浴中继续降温冷却搅拌，随后加入吡啶(4mL)以及加入氧 杂环丁烷-3-磺酰氯(62.64mg，0.4mmol)，完毕体系在油浴中升温加热搅拌反应过夜。翌日，冷却至室温，向体系中加入10mL 0.5N HCl剧烈搅拌，静置分层，水相用10mL二氯甲烷萃取，合并有机相，分别用纯净水以及饱和食盐水洗涤，无水硫酸钠干燥，旋蒸除去溶剂，薄层层析分离纯化(PE/EA＝4:1)，得产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(氧杂环丁烷-3-磺酰氨基)苯胺59.13mg，收率：42％。MS m/z(ESI):469(M+H) +。 1HNMR(400Hz,DMSO-d 6):δ14.47–14.08(m,1H),8.91–8.64(m,1H),8.53–8.22(m,1H),7.93(d,J＝17.7Hz,2H),7.67(d,J＝38.6Hz,2H),7.50–7.13(m,1H),4.68(s,4H),4.52–4.29(m,1H)。
实施例22:5-氯-N-(2-氯-4-三氟甲基)苯基)-2-(环戊磺酰胺基)苯甲酰胺(22)
用类似于实施例23的方法得到。MS m/z(ESI):481(M+H) +.
实施例23:5-氯-N-(2-氯-4-三氟甲基)苯基)-2-(环己磺酰胺基)苯甲酰胺(23)
Figure PCTCN2019078725-appb-000040
第一步：环己基磺酰氯的合成
NCS(4.6g,34.4mmol)加入到50mL乙腈中，冰水浴下，加入6.5mL2N稀盐酸，搅拌2分钟，将环己硫醇(1.0g,8.6mmol)加入到反应液中，室温搅拌2h。加入乙酸乙酯和水萃取，有机层用饱和食盐水洗涤2次，干燥，旋干。得到无色液体环己基磺酰氯(1.1g,6.0mmol)。收率：70.0％。
第二步：5-氯-N-(2-氯-4-三氟甲基)苯基)-2-(环己基磺酰胺)苯甲酰胺的合成
氮气保护下，将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶，滴加二甲胺基磺酰氯(261.0mg,1.43mmol)。室温搅拌过夜。加入二氯甲烷和水萃取，有机层用1N稀盐酸洗涤，再用饱和食盐水洗涤，干燥，旋干，硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-三氟甲基)苯基)-2-(环己基磺酰胺)苯甲酰胺(28.2mg,0.08mmol)。收率：28.2％。MS(ESI)m/e495.0(M+H) +。
实施例24：5-氯-N-(2-氯-4-三氟甲基苯基)-2-(三氟甲基磺酰胺基)苯甲酰胺(24)
25ml圆底烧瓶中，放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.2mmol,70mg),三氟甲基磺酰氯(2eq,68mg),二氯甲烷1ml和TEA(5eq,100mg),室温搅拌过夜，反应液稀盐酸洗，饱和食盐水洗，干燥，浓缩，pre-TLC纯化，正己烷打浆，过滤，得类白色固体10mg,产率10％。MS m/z(ESI):481.0(M+H) +。 1H NMR(400MHz,CDCl3)δ7.89(d,J＝2.4Hz,1H),7.87(d,J＝8.4Hz,1H),7.79(s,1H),7.62(d,J＝8.0Hz,1H),7.36(dd,J＝8.6,2.3Hz,1H),6.75(d,J＝8.6 Hz,1H)
实施例25：5-氯-N-(2-氯-4-三氟甲基苯基)-2-(氨基磺酰胺基)苯甲酰胺(25)
N-叔丁氧羰基-氨基磺酰氯的二氯甲烷溶液在冰浴下，加入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg)和TEA(2eq,50mg),自然升至室温，搅拌过夜，TLC显示原料消失，反应液稀盐酸洗，饱和食盐水洗，干燥，浓缩，pre-TLC纯化后，溶于二氯甲烷/三氟乙酸(1:1)中，室温搅拌0.5h脱去Boc保护基，旋干反应液，溶于乙酸乙酯中，饱和碳酸钠溶液洗，饱和食盐水洗，干燥，旋干得类白色固体25mg,产率23％。MS m/z(ESI):428.0(M+H) +
1H NMR(400MHz,DMSO-d6)δ14.77(s,1H),8.76(d,J＝8.7Hz,1H),7.93(d,J＝2.9Hz,1H),7.81(d,J＝1.7Hz,1H),7.64(dd,J＝8.8,2.0Hz,1H),7.54(d,J＝9.1Hz,1H),7.17(dd,J＝9.1,2.9Hz,1H),5.48(s,2H).
实施例26:5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-((N-甲胺磺酰基)胺基)苯甲酰胺(26)
氮气保护下，将甲胺磺酸(250.0mg,2.25mmol)加入到10mL甲苯中，加入五氯化磷(468.5g,2.25mmol)。加热110℃，搅拌2h。冷却至室温，溶剂浓缩干。加入二氯甲烷，抽滤，滤液旋干，得到粗品甲胺磺酰氯(250mg,1.93mmol)。氮气保护下，将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶，滴加粗品甲胺磺酰氯(250mg,1.93mmol)。室温搅拌过夜。加入二氯甲烷和水萃取，有机层用1N稀盐酸洗涤，再用饱和食盐水洗涤，干燥，旋干，硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(N-甲胺磺酰胺基)苯甲酰胺(60.0mg,0.14mmol)。收率：47.4％。MS(ESI)m/e442.0(M+H) +。
实施例27：5-氯-N-(2-氯-4-三氟甲基)苯基)-2-((N,N-二甲基磺酰基)氨基)苯甲酰胺(27)
氮气保护下，将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶，滴加二甲胺基磺酰氯(350.0mg,2.44mmol)。室温搅拌过夜。加入二氯甲烷和水萃取，有机层用1N稀盐酸洗涤，再用饱和食盐水洗涤，干燥，旋干，硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-三氟甲基)苯基)-(2-吗啉-4-磺酰胺)苯甲酰胺(40.0mg,0.01mmol)。收率：30.6％。MS(ESI)m/e 456.0(M+H) +。
实施例28：5-氯-N-(2-氯-4-三氟甲基苯基)-2-(吡咯烷-1-磺酰胺基)苯甲酰胺(28)
25ml圆底烧瓶中，放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.2mmol,70mg),吡咯烷-1-磺酰氯(3eq,102mg)和吡啶1ml,室温搅拌过夜，反应液以乙酸乙酯稀释，稀盐酸洗，饱和食盐水洗，干燥，浓缩，pre-TLC纯化，得类白色固体5mg,产率5％
MS m/z(ESI):482.0(M+H) +。 1H NMR(400MHz,DMSO)δ10.80(s,1H),10.33(s,1H),8.06-6.90(m,6H),2.99-2.90(m,4H),1.90-1.82(m,4H).
实施例29:5-氯-N-(2-氯-4-三氟甲基)苯基)-(2-吗啉-4-磺酰胺基)苯甲酰胺(29)
将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶，滴加吗啉-4-磺酰氯(265.8mg,1.43mmol)。室温搅拌过夜。加入二氯甲烷和水萃取，有机层用1N稀盐酸洗涤，再用饱和食盐水洗涤，干燥，旋干，硅胶柱层析纯化。得到白色固体5- 氯-N-(2-氯-4-(三氟甲基)苯基)-2-(4-甲基苯磺酰胺基)苯甲酰胺(50.0mg,0.01mmol)。收率：35.0％。MS(ESI)m/e498.0(M+H) +。
实施例30:乙基(4-氯-2-((2-氯-4-(三氟甲基)苯基)氨基甲酰基)苯基)氨基磺酸酯(30)
用类似于实施例26的方法得到。MS m/z(ESI):457(M+H) +。
实施例31:异丙基(4-氯-2-((2-氯-4-(三氟甲基)苯基)氨基甲酰基)苯基)氨基磺酸酯(31)
用类似于实施例26的方法得到。MS m/z(ESI):471(M+H) +。
实施例32：5-氯-N-(2-氯-4-三氟甲基苯基)-2-苯磺酰胺基苯甲酰胺(32)
25ml圆底烧瓶中，放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),苯磺酰氯(1.2eq,53mg),二氯甲烷2ml和DMAP(1.5eq,45mg),室温搅拌过夜，反应液稀盐酸洗，饱和食盐水洗，干燥，旋干，少量冰二氯甲烷打浆，过滤，得白色固体24mg,产率20％。MS m/z(ESI):489.0(M+H) +。 1H NMR(400MHz,DMSO-d6)δ10.80–10.44(m,2H),8.01(d,J＝1.0Hz,1H),7.97(d,J＝8.4Hz,1H),7.92(d,J＝2.4Hz,1H),7.82(dd,J＝8.4,1.3Hz,1H),7.77–7.71(m,2H),7.66(t,J＝7.4Hz,1H),7.62–7.51(m,3H),7.31(d,J＝8.8Hz,1H).
实施例33：5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(4-甲基苯磺酰胺基)苯甲酰胺(33)
将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶，分批加入对甲基苯磺酰氯(65.6mg,0.57mmol)。加热到60℃，搅拌过夜。加入二氯甲烷和水萃取，有机层用1N稀盐酸洗涤，再用饱和食盐水洗涤，干燥，旋干，硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(4-甲基苯磺酰胺基)苯甲酰胺(50.0mg,0.10mmol)。收率：34.5％。MS(ESI)m/e503.0(M+H) +。
实施例34：5-氯-N-(2-氯-4-三氟甲基苯基)-2-(4-氰基苯磺酰胺基)苯甲酰胺(34)
25ml圆底烧瓶中，放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.22mmol,77mg),4-氰基苯磺酰氯(0.9eq,40mg),二氯甲烷1ml和吡啶(3eq,49mg),室温搅拌过夜，反应液稀盐酸洗，饱和食盐水洗，干燥，浓缩，pre-TLC纯化，得淡黄色固体40mg,产率40％。MS m/z(ESI):514.0(M+H) +。 1H NMR(400MHz,DMSO-d6)δ10.60(s,2H),8.16–7.92(m,4H),7.88(d,J＝8.4Hz,3H),7.79(d,J＝7.7Hz,1H),7.53(d,J＝5.6Hz,1H),7.28(d,J＝8.6Hz,1H).
实施例35：5-氯-N-(2-氯-4-三氟甲基苯基)-2-(吡啶-3-磺酰胺基)苯甲酰胺(35)
25ml圆底烧瓶中，放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),吡啶-3-磺酰氯(1.2eq,54mg),二氯甲烷2ml和TEA(2eq,50mg),室温搅拌过夜，反应液稀盐酸洗，饱和食盐水洗，干燥，旋干，少量冰二氯甲烷打浆，过滤，得黄色固体13mg,产率11％。MS m/z(ESI):490.0(M+H) +。 1H NMR(400MHz,DMSO)δ10.69(s,1H),8.86(d,J＝1.7Hz,1H),8.81(dd,J＝4.8,1.4Hz,1H),8.11(ddd,J＝8.1,2.3,1.6Hz,1H),8.04(d,J＝8.3Hz,1H),7.99(d,J＝1.3Hz,1H),7.87(d,J＝2.5Hz,1H),7.81(dd,J＝8.7,1.5Hz,1H),7.62–7.56(m,2H),7.30(d,J＝8.7Hz,1H).
实施例36：5-氯-N-(2-氯-4-三氟甲基苯基)-2-(噻吩-2-磺酰胺基)苯甲酰胺(36)
25ml圆底烧瓶中，放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),噻吩-2-磺酰氯(1.2eq,55mg),二氯甲烷2ml和TEA(2eq,50mg),室温搅拌过夜，反应液稀盐酸洗，饱和食盐水洗，干燥，浓缩，pre-TLC纯化，得类白色固体7mg,产率6％。MS m/z(ESI):495.0(M+H) +。 1H NMR(400MHz,CDCl3)δ9.99(s,1H),8.53(d,J＝8.7Hz,1H),8.18(s,1H),7.83–7.77(m,1H),7.72(d,J＝1.5Hz,1H),7.62(dd,J＝8.7,1.3Hz,1H),7.54(dt,J＝6.0,2.9Hz,2H),7.48(ddd,J＝6.2,4.4,1.2Hz,2H),6.93(dd,J＝4.9,3.8Hz,1H).
实施例37：5-氯-N-(2-氯-4-三氟甲基苯基)-2-(5-氯噻吩-2-磺酰胺基)苯甲酰胺(37)
25ml圆底烧瓶中，放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),5-氯噻吩-2-磺酰氯(1.2eq,65mg),二氯甲烷2ml和TEA(2eq,50mg),室温搅拌过夜，反应液稀盐酸洗，饱和食盐水洗，干燥，浓缩，pre-TLC纯化，得类白色固体7mg,产率5％。MS m/z(ESI):528.9(M+H) +。 1H NMR(400MHz,CDCl3)δ8.54(d,J＝8.6Hz,1H),7.75(d,J＝8.8Hz,1H),7.72(d,J＝1.5Hz,1H),7.62(dd,J＝11.6,1.9Hz,2H),7.53(dd,J＝8.8,2.3Hz,1H),7.25(s,1H),6.76(d,J＝4.0Hz,1H).
实施例38：5-氯-N-(2-氯-4-三氟甲基苯基)-2-(3,5-二甲基异恶唑-4-磺酰胺基)苯甲酰胺(38)
25ml圆底烧瓶中，放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),3,5-二甲基异恶唑-4-磺酰氯(1.2eq,59mg),二氯甲烷2ml和TEA(2eq,50mg),室温搅拌过夜，反应液稀盐酸洗，饱和食盐水洗，干燥，浓缩，pre-TLC纯化，得淡黄色固体13mg,产率10％。MS m/z(ESI):508.0(M+H) +。 1H NMR(400MHz,DMSO)δ10.61(s,2H),8.05(s,1H),8.00(s,1H),7.92(d,J＝2.4Hz,1H),7.83(d,J＝8.4Hz,1H),7.66(d,J＝7.7Hz,1H),7.35(d,J＝8.7Hz,1H),2.40(s,3H),2.15(s,3H).
实施例39：5-氯-N-(2-氯-4-三氟甲基苯基)-2-(1-甲基-1H-咪唑-4-磺酰胺基)苯甲酰胺(39)
25ml圆底烧瓶中，放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.25mmol,87mg),1-甲基-1H-咪唑-4-磺酰氯(1.2eq,54mg),二氯甲烷2ml和TEA(2eq,50mg),室温搅拌过夜，反应液稀盐酸洗，饱和食盐水洗，干燥，旋干，少量冰二氯甲烷打浆，过滤，得白色固体25mg,产率20％。MS m/z(ESI):493.0(M+H) +。 1H NMR(400MHz,DMSO)δ10.70(s,1H),10.62(s,1H),8.06–7.74(m,6H),7.60(dd,J＝34.7,20.2Hz,2H),3.65(s,3H).
实施例40：5-氯-N-(2-氯-4-三氟甲基苯基)-(1,2-二甲基-1H-咪唑-4-磺酰胺基)苯甲酰胺(40)
25ml圆底烧瓶中，放入5-氯-N-(2-氯-4-三氟甲基苯基)-2-氨基苯甲酰胺(0.5mmol,174mg),1,2-二甲基-1H-咪唑-4-磺酰氯(1.2eq,117mg),二氯甲烷3ml和TEA(2eq,100mg),室温搅拌过夜，反应液浓缩，溶于乙酸乙酯中，稀盐酸洗，饱和食盐水洗，取EA层和EA层的沉淀，过滤，得白色固体67mg,产率27％。MS m/z(ESI):507.0(M+H) +。 1H NMR(400MHz,DMSO)δ10.98–10.18(m,2H),8.06–7.96(m,3H),7.88–7.81(m,2H),7.62(d,J＝10.2Hz,1H),7.56(d,J＝8.8Hz,1H),3.56(s,3H),2.22(d,J＝16.0Hz,3H).
实施例41：2-乙酰氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(41)
用类似于实施例42的方法得到。MS m/z(ESI):391(M+H) +。
实施例42：5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(乙磺酰胺基)苯甲酰胺(42)
将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)溶于3mL吡啶，滴加乙酰氯(147.3mg,1.15mmol)。加热到40℃，搅拌过夜。加入二氯甲烷和水萃取，有机层用1N稀盐酸洗涤，再用饱和食盐水洗涤，干燥，旋干，硅胶柱层析纯化。得到白色固体5-氯-N-(2-氯-4-(三氟甲基)苯基)-2-(4-甲基苯磺酰胺基)苯甲酰胺(40.0mg,0.91mmol)。收率：31.6％。MS(ESI)m/e441.0(M+H) +。 1H NMR(400MHz,DMSO)δ10.51(s,2H),8.15(d,J＝8.8Hz,1H),8.01(s,1H),7.97(d,J＝8.3Hz,1H),7.90(d,J＝2.3Hz,1H),7.82(d,J＝8.5Hz,1H),7.65(dd,J＝8.9,2.4Hz,1H),2.36(q,J＝7.5Hz,2H),1.07(t,J＝7.5Hz,3H).
实施例43：5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(正丁酰胺基)-苯甲酰胺(43)
Figure PCTCN2019078725-appb-000041
将2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)-苯甲酰胺(80mg，0.23mmol)溶于2ml二氯甲烷，加入1ml吡啶，加入正丁酰氯(50.0mg，0.46mmol)，室温搅拌过夜，TLC监测反应(PE/Ea＝5:1)，反应完全，减压浓缩，加入0.5N HCl调节pH＝5.0，加入5mlEa萃取，有机层水洗，饱和食盐水洗涤，干燥，减压浓缩，薄层柱层析纯化(PE/Ea＝5:1)，得到目标产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(正丁酰胺基)-苯甲酰胺15mg。收率：15.6％。MS:224.1， 1H NMR(400MHz,CDCl 3)δ10.53(s,1H),8.69(d,J＝9.0Hz,1H),8.55(d,J＝8.7Hz,1H),8.42(s,1H),7.74(d,J＝1.7Hz,1H),7.64–7.60(m,2H),7.53(dd,J＝9.0,2.4Hz,1H),2.44–2.35(m,2H),1.82–1.72(m,2H),1.05–0.96(m,3H).
实施例44：5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(异丁酰胺基)-苯甲酰胺(44)
将2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)-苯甲酰胺(100mg，0.29mmol)溶于2ml二氯甲烷，加入1ml吡啶，加入异丁酰氯(61.1mg，0.57mmol)，45℃反应5h，TLC监测反应(PE/Ea＝5:1)，反应完全，减压浓缩，加入0.5N HCl调节pH＝5.0，加入5mlEa萃取，有机层水洗，饱和食盐水洗涤，干燥，减压浓缩，薄层柱层析纯化(PE/Ea＝2:1)，得到目标产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(异丁酰胺基)-苯甲酰胺20mg。收率：16.4％。MS:224.2， 1H NMR(400MHz,CDCl 3)δ10.64(s,1H),8.70(d,J＝9.0Hz,1H),8.57(d,J＝8.6Hz,1H),8.42(s,1H),7.74(d,J＝1.5Hz,1H),7.63(d,J＝2.3Hz,2H),7.53(dd,J＝8.9,2.2Hz,1H),2.60(s,1H),1.30–1.26(m,6H).
实施例45：5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(环丙甲酰胺基)-苯甲酰胺(45)
将2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)-苯甲酰胺(107mg，0.3mmol)，溶于1ml二 氯甲烷，加入1ml吡啶，加入环丙基甲酰氯(48mg，0.45mmol)，45℃反应过夜，TLC监测反应(PE/Ea＝5:1)，反应完全，减压浓缩，加入0.5N HCl调节pH＝5.0，加入5mlEa萃取，有机层水洗，饱和食盐水洗涤，干燥，减压浓缩，加入1mlEa打浆，过滤，得到20mg白色固体产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(环丙甲酰胺基)-苯甲酰胺。MS：222； 1H NMR(400MHz,DMSO)δ10.70(s,1H),10.46(s,1H),8.06(d,J＝8.9Hz,1H),8.00(d,J＝8.3Hz,2H),7.85(d,J＝2.5Hz,1H),7.80(dd,J＝8.5,1.5Hz,1H),7.62(dd,J＝8.9,2.5Hz,1H),1.75(tt,J＝6.9,5.4Hz,1H),0.90–0.73(m,4H).收率：15.6％。
实施例46：5-氯-N-(2-氯-4-三氟甲基苯基)-2-(环丁甲酰胺基)-苯甲酰胺(46)
用类似于实施例45的方法得到。MS m/z(ESI):431(M+H) +。
实施例47：5-氯-N-(2-氯-4-三氟甲基苯基)-2-(环戊甲酰胺基)-苯甲酰胺(47)
将2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)-苯甲酰胺(104.74mg，0.3mmol)溶于5mL二甲苯，待澄清后将体系移置于冰水浴中继续降温冷却搅拌，随后加入吡啶(4mL)以及加入环戊基甲酰氯(53.04mg，0.4mmol)，完毕体系在油浴中升温加热搅拌反应过夜。翌日，冷却至室温，向体系中加入10mL 0.5N HCl剧烈搅拌，静置分层，水相用10mL二氯甲烷萃取，合并有机相，分别用纯净水以及饱和食盐水洗涤，无水硫酸钠干燥，旋蒸除去溶剂，薄层层析分离纯化(PE/EA＝4:1)，得产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(环戊基甲酰胺基)苯胺85mg，收率：63.6％。 1HNMR(400Hz,DMSO-d 6):δ10.57(1H,s),10.52(1H,s),8.18-8.16(1H,d,J＝8.8Hz),8.0(1H,d,J＝1.6Hz),7.95-7.90(2H,m),7.82-7.79(1H,m),7.65-7.62(1H,m)，2.79-2.53(1H,m)，1.85-1.51(8H,m).
实施例48：5-氯-N-(2-氯-4-三氟甲基-5-氟苯基)-2-环丙磺酰胺基苯甲酰胺(48)
25ml圆底烧瓶中，放入2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)-苯甲酰胺(0.2mmol,70mg),苯甲酸(1.2eq,30mg)和1ml二甲苯，室温搅拌下滴加三氯化磷(0.3eq,8mg),滴加完毕后升温至140℃搅拌过夜。搅拌下冷却至室温，pre-TLC纯化，得类白色固体10mg，产率11％
MS m/z(ESI):258.0。 1H NMR(400MHz,DMSO)δ11.67(s,1H),10.74(s,1H),8.50(d,J＝8.5Hz,1H),8.16–7.47(m,10H).
实施例49：5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(四氢呋喃甲酰胺基)-苯甲酰胺(49)
将2-四氢呋喃甲酸(232mg，2.0mmol)溶于2ml二氯亚砜，95℃回流3h，减压浓缩，加入5ml二氯甲烷，减压浓缩，再次加入5ml二氯甲烷，加入2-氨基-5-氯-N-(2-氯-4-三氟甲基-苯基)-苯甲酰胺(175mg，0.5mmol)，室温反应过夜，TLC监测，原料大部分反应完全，减压浓缩，加入0.5N HCl调节pH＝5.0，加入5mlEa萃取，有机层水洗，饱和食盐水洗涤，干燥，减压浓缩，加入2ml混合溶液(正己烷/Ea＝10:1)打浆，过滤，得到30mg白色固体产品5-氯-N-(2-氯-4-三氟甲基-苯基)-2-(四氢呋喃甲酰胺基)-苯甲酰胺，收率：13.4％。MS：252.2， 1H NMR(400MHz,CDCl 3)δ11.27(s,1H),8.69(d,J＝9.0Hz,1H),8.64(d,J＝8.7Hz,1H),8.40(s,1H),7.72(s,1H),7.63(dd,J＝9.0,5.7Hz,2H),7.54(dd,J＝9.0,2.3Hz,1H),4.50 (dd,J＝8.5,5.3Hz,1H),4.17(dd,J＝14.1,7.1Hz,1H),4.00(dd,J＝15.1,7.1Hz,1H),2.36(dd,J＝12.8,8.1Hz,1H),2.17(dd,J＝13.0,7.3Hz,1H),2.04–1.83(m,2H).
实施例50：5-氯-N-(2-氯-4-三氟甲基-苯基)-3-(四氢呋喃甲酰胺基)-苯甲酰胺(50)
用类似于实施例49的方法得到。MS m/z(ESI):447(M+H) +。
实施例51:N-(4-氯-2-((2-氯-4-(三氟甲基)苯基)胺甲酰基)苯基)四氢吡喃-4-甲酰胺(51)
氮气保护下，将2-氨基-5-氯-N-(2-氯-4-(三氟甲基)苯基)苯甲酰胺(100.0mg,0.28mmol)和三乙胺(87.0mg,0.86mmol)溶于3mL二氯甲烷，滴加四氢吡喃-4-甲酰氯(64.0mg,0.43mmol)。室温搅拌2h。加入二氯甲烷和水萃取，有机层用1N稀盐酸洗涤，再用饱和食盐水洗涤，干燥，旋干，硅胶柱层析纯化。得到白色固体N-(4-氯-2-((2-氯-4-(三氟甲基)苯基)胺甲酰基)苯基)四氢吡喃-4-甲酰胺(80.0mg,0.17mmol)。收率：60.5％。MS(ESI)m/e461.0(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ10.64(s,1H),10.57(s,1H),8.21(d,J＝8.9Hz,1H),8.00(d,J＝1.5Hz,1H),7.92(t,J＝5.5Hz,2H),7.81(dd,J＝8.5,1.6Hz,1H),7.65(dd,J＝8.9,2.5Hz,1H),3.92–3.82(m,2H),3.35(dd,J＝11.7,2.3Hz,2H),2.65–2.53(m,1H),1.72(dd,J＝12.8,2.0Hz,2H),1.67–1.53(m,2H)。
以下通过实验例证明本发明的有益效果。
实验例1 本发明化合物抑制癌细胞增殖
实验目的：测定化合物对癌细胞增殖的抑制作用
1.实验材料及仪器：
RIPM1640培养基(Hyclone Cat#308090.01)
胎牛血清(FBS)(Gibco Cat#10099-141)
青-链霉素Pen Strep(Hyclone Cat#SV30010)
22RV1细胞(中国科学院细胞库TCHu100)
CCK8试剂盒(Signalway Antibody Cat#CP002)
酶标仪(Thermo Multiskan MK3型)
细胞培养液：RIPM1640培养基，10％FBS，1％Pen Strep。
2.实验步骤：
22RV1细胞用细胞培养液传代培养后，接种于96孔板，每孔80μl，每孔细胞数为2万，放在37℃，5％CO 2培养箱中培养过夜。
将药物用二甲基亚砜(DMSO)配置成30mM的储存液。临用前再用DMSO稀释3倍，再按3倍梯度稀释，得到9个浓度梯度，再用培养液将各浓度的化合物稀释200倍(以此保证培养体系中DMSO浓度为0.1％)，每个浓度做2个孔重复。取20μl稀释好的化合物加到细 胞培养孔，轻轻振荡混匀。另外设置3个只加细胞的阴性对照孔和3个只加培养液的空白对照孔(6孔各加20μl培养液稀释200倍的DMSO)，氯硝柳氨为参照化合物。
3.结果检测：
培养48小时后，每孔滴加10μl CCK-8溶液，放37℃，5％CO 2培养箱继续培养2.5小时。
用多功能酶标仪在450nm处测吸光度(OD值)。
数据用软件GraphPad Prism5中Dose-response-inhibition方程分析，得出IC50值，结果见表1：
表1 本发明化合物对22RV1癌细胞增殖的抑制作用
实施例 22RV1细胞抑制活性(IC 50,M) 实施例 22RV1细胞抑制活性(IC 50,M)
1 >10 27 0.61
2 3.7 28 1.2
3 1.1 29 2.9
4 1.1 32 4.5
5 1.2 33 8.5
6 1 34 >10
7 1 35 >10
8 >10 36 2.8
9 2.6 37 5.9
10 1.2 38 >10
12 7.3 39 >10
13 1.1 40 >10
14 3.9 41 >10
15 1.8 42 >10
16 1.1 43 >10
20 5.8 44 >10
21 9.7 45 >10
22 1.9 46 >10
23 2.3 47 >10
24 4.3 48 >10
25 >10 49 >10
26 2.3 50 >10
27 0.61 51 >10
应用类似的检测方法我们发现本发明的化合物对其他癌细胞系，包括卵巢癌细胞系SKOV-3，也有显著的抑制增殖活性：
表2.本发明化合物对其他癌细胞增殖的抑制作用
Figure PCTCN2019078725-appb-000042
上述实验结果表明，本发明的化合物能够显著抑制多个癌细胞系，尤其是能够显著抑制前列腺癌细胞22RV1、乳腺癌细胞、卵巢癌细胞、肝癌细胞的增殖。本发明的化合物有潜力应用于各种癌症，特别是前列腺癌、乳腺癌、卵巢癌和肝癌的治疗。
试验例2：本发明化合物的小鼠药代动力学
1)实验材料及仪器：
LC-20AD高效液相色谱系统(日本SHIMADZU(岛津)公司)
API4000三重四极杆质谱仪，(美国Applied Biosystem公司)
PhenixWinnolin药动学软件(Version 6.3，美国Certara公司)
高速冷冻离心机(Thermo Fisher Scientific)
分析天平(赛多利斯，SECURA225D-1CN)
实验动物：ICR小鼠(成都达硕实验动物有限公司)
DMA(Sigma)
CMC-Na(成都科龙化工)
肝素(成都科龙化工)
2)实验方法及结果
精密称取化合物6加入相应的溶媒至终体积10ml，超声涡旋混匀。配置成浓度为0.5mg/ml的溶液。取配制的终溶液0.2ml，于-20℃保存，用于浓度测定。健康成年ICR小鼠9只(20-30g)，禁食过夜(自由饮水)后，灌胃给药，给药体积0.2ml/10g；于给药前及给药后0.5,1,2,4,6,8,12,24h由眼眶后静脉丛采血0.1ml，4℃离心5min分离血浆，于-20℃保 存待测。然后采用LC/MS/MS法测定血浆中的待测化合物浓度。口服生物利用度由PO给药测得的药物暴露量和IV给药测得的药物暴露量计算得到。
表3.本发明化合物的药代动力学参数
Figure PCTCN2019078725-appb-000043
化合物6做了小鼠PK实验。本发明的化合物显示出达到较高的暴露量(AUC)，相比于类似发明参照化合物有更长的半衰期和更佳的口服生物利用度，在药代动力学上有显著提高。
综上，本发明提供了一种结构新颖的酰胺类化合物及其在治疗癌症中的用途。实验结果表明，本发明化合物能够抑制前列腺癌细胞的增殖，尤其是对耐药性前列腺癌细胞系(22RV1)有明显抑制作用。同时，本发明化合物还能够显著抑制多种癌细胞的增殖。此外，本发明化合物具有良好的药代动力学。对癌症，尤其是前列腺癌具有潜在的治疗作用，为临床上筛选和/或制备癌症药物提供了一种新的选择。

Claims (30)

  1. 式Ⅰ所示的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物：
    Figure PCTCN2019078725-appb-100001
    式中，
    R 1～R 9各自独立地选自氢、氘、氚、卤素、羟基、氨基、酰胺基、氰基、硝基、-CO 2R a、取代或未取代的C 1～C 12烷基、取代或未取代的C 1～C 12烷氧基、环烷基、芳基；
    其中，R a选自C 1～C 12烷基；所述取代基为氘、氚、卤素、C 1～C 12烷基、芳基；
    R 10选自氢、C 1～C 12烷基；
    R 11选自OR、SR’、NR 12R 13；
    R、R’、R 12、R 13各自独立地选自氢、氘、氚、
    Figure PCTCN2019078725-appb-100002
    其中，R 14选自取代或未取代的C 1～C 12烷基、取代或未取代的3～8元环烷基、取代或未取代的3～8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-O-R 15、
    Figure PCTCN2019078725-appb-100003
    所述取代基为氘、氚、卤素、氰基、C 1～C 12烷基、C 1～C 12烷氧基；
    R 15选自取代或未取代的C 1～C 12烷基，取代或未取代的3～8元环烷基；
    R 16、R 17各自独立地选自氢、取代或未取代的C 1～C 12烷基、取代或未取代的3～8元环烷基；或者，R 16、R 17相连形成取代或未取代的3～8元环。
  2. 根据权利要求1所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    R 1～R 9各自独立地选自氢、氘、氚、卤素、羟基、氨基、酰胺基、氰基、硝基、-CO 2R a、取代或未取代的C 1～C 8烷基、取代或未取代的C 1～C 8烷氧基、环烷基、芳基；
    其中，R a选自C 1～C 8烷基；
    所述取代基为氘、氚、卤素、C 1～C 8烷基、芳基；
    R 10选自氢、C 1～C 8烷基。
  3. 根据权利要求2所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    R 1～R 9各自独立地选自氢、氘、氚、卤素、取代或未取代的C 1～C 4烷基、取代或未取代的C 1～C 4烷氧基；
    所述取代基为氘、氚、卤素、C 1～C 4烷基；
    R 10选自氢、C 1～C 4烷基。
  4. 根据权利要求3所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    R 1～R 9各自独立地选自氢、氘、氚、卤素、取代或未取代的C 1～C 2烷基；
    所述取代基为氘、氚、卤素；
    R 10选自氢。
  5. 根据权利要求1所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    R 11选自OR、SR’、NR 12R 13；
    R、R’、R 12、R 13各自独立地选自氢、氘、氚、
    Figure PCTCN2019078725-appb-100004
    其中，R 14选自取代或未取代的C 1～C 8烷基、取代或未取代的3～8元环烷基、取代或未取代的3～8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-O-R 15、
    Figure PCTCN2019078725-appb-100005
    所述取代基为氘、氚、卤素、氰基、C 1～C 8烷基、C 1～C 8烷氧基；
    R 15选自C 1～C 8烷基；
    R 16、R 17各自独立地选自氢、C 1～C 8烷基；或者，R 16、R 17相连形成3～8元环。
  6. 根据权利要求1～5任意一项所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物Ⅰ如式Ⅱ所示：
    Figure PCTCN2019078725-appb-100006
    其中，
    R 1～R 9各自独立地选自氢、氘、氚、F、Cl、Br、CF 3、CH 3；
    R 12、R 13各自独立地选自氢、氘、氚、
    Figure PCTCN2019078725-appb-100007
    其中，R 14选自取代或未取代的C 1～C 4烷基、取代或未取代的3～6元环烷基、取代或未取代的3～6元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-O-R 15、
    Figure PCTCN2019078725-appb-100008
    所述取代基为氘、氚、卤素、氰基、C 1～C 2烷基；
    R 15选自C 1～C 4烷基；
    R 16、R 17各自独立地选自氢、C 1～C 6烷基；或者，R 16、R 17相连形成3～6元环。
  7. 根据权利要求6所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    R 1、R 3、R 6各自独立地选自氢、氘、氚。
  8. 根据权利要求6所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物Ⅱ如式ⅢA所示：
    Figure PCTCN2019078725-appb-100009
    式中，
    R 14’选自取代或未取代的C 1～C 4烷基；所述取代基为氘、氚、卤素。
  9. 根据权利要求8所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢA如式ⅢA-1所示：
    Figure PCTCN2019078725-appb-100010
    式中，
    R 14’选自C 1～C 3烷基、CF 3。
  10. 根据权利要求8或9所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢA-1为下述结构式之一：
    Figure PCTCN2019078725-appb-100011
    Figure PCTCN2019078725-appb-100012
  11. 根据权利要求6所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物Ⅱ如式ⅢB所示：
    Figure PCTCN2019078725-appb-100013
    式中，
    A环选自取代或未取代的3～6元环烷基、取代或未取代的3～6元杂环基、取代或未取代的芳基、取代或未取代的杂芳基；所述取代基选自氘、氚、卤素、氰基、C 1～C 2烷基。
  12. 根据权利要求11所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢB如式ⅢB-1所示：
    Figure PCTCN2019078725-appb-100014
    式中，
    R 2、R 3、R 5、R 7、R 8、R 9各自独立地选自F、Cl、Br、CF 3、CH 3；
    A环选自3～6元环烷基、取代或未取代的4～6元杂环基、取代或未取代的苯基、取代或未取代的杂芳基；
    所述取代基选自Cl、氰基、甲基。
  13. 根据权利要求12所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：A环为环丙烷。
  14. 根据权利要求11～13任意一项所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢB-1为下述结构式之一：
    Figure PCTCN2019078725-appb-100015
    Figure PCTCN2019078725-appb-100016
  15. 根据权利要求6所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物Ⅱ如式ⅢC所示：
    Figure PCTCN2019078725-appb-100017
    式中，
    R 15选自C 1～C 4烷基。
  16. 根据权利要求15所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢC如式ⅢC-1所示：
    Figure PCTCN2019078725-appb-100018
    式中，
    R 15选自C 1～C 4烷基。
  17. 根据权利要求15或16所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢC-1为下述结构式之一：
    Figure PCTCN2019078725-appb-100019
  18. 根据权利要求6所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物Ⅱ如式ⅢD所示：
    Figure PCTCN2019078725-appb-100020
    式中，
    R 16、R 17各自独立地选自氢、C 1～C 2烷基；
    或者，R 16、R 17相连形成4～6元环。
  19. 根据权利要求18所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢD如式ⅢD-1所示：
    Figure PCTCN2019078725-appb-100021
    式中，
    R 16、R 17各自独立地选自氢、甲基；
    或者，R 16、R 17相连形成5～6元杂环基。
  20. 根据权利要求18或19所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢD-1为下述结构式之一：
    Figure PCTCN2019078725-appb-100022
  21. 根据权利要求6所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其立体化学异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物Ⅱ如式ⅢE所示：
    Figure PCTCN2019078725-appb-100023
    式中，
    R 14”选自C 1～C 4烷基、3～6元环烷基、3～6元杂环基、芳基。
  22. 根据权利要求21所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢE如式ⅢE-1所示：
    Figure PCTCN2019078725-appb-100024
    式中，
    R 14”选自C 1～C 3烷基、3～5元环烷基、5～6元杂环基、苯基。
  23. 根据权利要求21或22所述的化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢE-1为下述结构式之一：
    Figure PCTCN2019078725-appb-100025
    Figure PCTCN2019078725-appb-100026
  24. 权利要求1～23任意一项所述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗和/或预防癌症的药物中的用途。
  25. 根据权利要求24所述的用途，其特征在于：所述癌症为乳腺癌、脑癌、前列腺癌，肺癌、卵巢癌、骨癌、神经癌、肝癌、血癌、食道癌、恶性胶质瘤、多发性骨髓瘤、套细胞淋巴瘤、急性骨髓性白血病及并发的癌症。
  26. 根据权利要求25所述的用途，其特征在于：所述癌症为前列腺癌、卵巢癌、骨癌或神经癌。
  27. 权利要求1～23任意一项所述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备减少全长雄激素受体、变异雄激素受体表达的药物中的用途。
  28. 权利要求1～23任意一项所述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备抑制癌细胞增殖的药物中的用途。
  29. 根据权利要求28所述的用途，其特征在于：所述癌细胞是下述癌症的癌细胞：乳腺癌、脑癌、前列腺癌，肺癌、卵巢癌、骨癌、神经癌、肝癌、血癌、食道癌、恶性胶质瘤、多发性骨髓瘤、套细胞淋巴瘤、急性骨髓性白血病及并发的癌症。
  30. 根据权利要求29所述的用途，其特征在于：所述癌细胞为前列腺癌细胞、卵巢癌细胞、骨癌细胞或神经癌细胞。
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