WO2020063407A1 - N-芳香酰胺类化合物及其制备方法和用途 - Google Patents

N-芳香酰胺类化合物及其制备方法和用途 Download PDF

Info

Publication number
WO2020063407A1
WO2020063407A1 PCT/CN2019/106287 CN2019106287W WO2020063407A1 WO 2020063407 A1 WO2020063407 A1 WO 2020063407A1 CN 2019106287 W CN2019106287 W CN 2019106287W WO 2020063407 A1 WO2020063407 A1 WO 2020063407A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
cyano
trifluoromethyl
compound
group
Prior art date
Application number
PCT/CN2019/106287
Other languages
English (en)
French (fr)
Inventor
杨国宏
于丽俊
何君泽
段美娟
Original Assignee
深圳恩多凯医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 深圳恩多凯医药科技有限公司 filed Critical 深圳恩多凯医药科技有限公司
Priority to KR1020217011156A priority Critical patent/KR102606375B1/ko
Priority to JP2021542244A priority patent/JP7316362B2/ja
Priority to EP19866813.9A priority patent/EP3858811B1/en
Publication of WO2020063407A1 publication Critical patent/WO2020063407A1/zh
Priority to US17/214,834 priority patent/US11760727B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D231/16—Halogen atoms or nitro radicals
    • 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

Definitions

  • the invention relates to a class of N-aromatic amide compounds, a preparation method thereof and pharmaceutical applications thereof.
  • the compounds have the effects of resisting androgens and degrading androgen receptors, and can be used for prostate cancer, benign prostatic hyperplasia, breast cancer, bladder cancer, acne , Hairy, hair loss and other androgen-related diseases treatment.
  • the androgen receptor belongs to the nuclear receptor family and is a receptor for nuclear transcription factors induced by ligands. Androgen receptor is an important cell regulating protein. It plays an important role in a series of physiological processes through endogenous androgens, including the development and maintenance of male secondary sexual characteristics, including muscle and bone mass. Male hair, prostate growth, sperm development, etc. Endogenous steroidal androgens are called male sex hormones and include testosterone and dihydrotestosterone (DHT). Testosterone is the main steroidal androgen found in male serum and it is mainly secreted by the testes. In many peripheral tissues, such as the prostate and skin, testosterone can be converted by 5 ⁇ -reductase to the more active androgen dihydrotestosterone (DHT).
  • DHT dihydrotestosterone
  • prostate cancer is hormone-dependent, endocrine therapy for prostate cancer is the oldest, most mature, and most effective method.
  • surgical castration such as the surgical removal of bilateral testicles to eliminate testosterone sources, and estrogen could delay the progression of metastatic prostate cancer, and for the first time confirmed the response of prostate cancer to androgen removal. Sex.
  • clinical research shows that simply cutting off the testicles can reduce the content of androgens in the blood, but it cannot significantly reduce the content of androgens in prostate tissues, because prostate hormones use steroids secreted by the adrenal glands as raw materials to synthesize androgens.
  • Enzyme system and can convert the androgen testosterone into the more active androgen dihydrotestosterone. Therefore, even with castration therapy, anti-androgen medication for prostate cancer is necessary.
  • antiandrogen drugs androgen antagonists
  • antiandrogen antagonists to competitively block the binding of androgens to androgen receptors on prostate cells.
  • non-steroidal androgen receptor antagonists are:
  • Flutamide is the first generation of non-steroidal androgen receptor antagonists (Endocrinology 1972, 91,427-437; Biochemical Society Transactions 1979, 7,565-569; Journal of Steroid Biochemistry 1975, 6,815-819), which The metabolite 2-hydroxyflutamide is its main active form. It can bind to androgen receptors in target tissues, block the binding of dihydrotestosterone to androgen receptors, and inhibit testosterone uptake by target tissues. Androgenic effects. Due to large doses, long-term use can cause breast growth in men, accompanied by tumors and tenderness, and have nausea, vomiting, diarrhea, occasional skin reactions, degenerative red blood protein anemia, white blood cells and thrombocytopenia. In addition, flutamide is prone to produce anti-androgen withdrawal syndrome, and a few patients have liver toxicity and other problems.
  • Bicalutumide is a second-generation nonsteroidal androgen receptor antagonist (Journal of Endocrinology 1987, 113, R7-R9; Urologic Clinics of North America 1991, 18, 99-110). This drug is a racemic isomer and its active ingredient is the L-isomer.
  • bicalutamide has a higher efficacy than flutamide and a 70% reduction in side effects. Similar to flutamide, it can bind to androgen receptors in target tissues, block the binding of dihydrotestosterone to androgen receptors, and inhibit testosterone uptake by target tissues, thereby acting as an antiandrogen.
  • the disadvantage is that after a certain median period (generally 18-24 months), almost all patients will eventually develop hormone-resistant prostate cancer.
  • bicalutamide also causes problems such as anti-androgen withdrawal syndrome during treatment.
  • Enzalutamide (trade name: Xtandi) is a third-generation non-steroidal androgen receptor antagonist (Archives of Pharmacal Research 2015, 38 (11): 2076–82), the US FDA in 2012 Approved to market the drug. It has stronger androgen receptor antagonism, adding new drugs for endocrine therapy. The disadvantage is that it is expensive and can develop into hormone-resistant prostate cancer. In addition, enzalutamide has been found to cause side effects in patients with convulsions during treatment, so its application is limited.
  • N-aromatic amide compounds or their pharmaceutically acceptable salts can be used for preventing or treating androgen-related diseases, such as prostate cancer, prostate hyperplasia, breast cancer, bladder cancer, ovarian cancer, acne, hairy, hair loss, etc .;
  • the N-aromatic amide compound has the following chemistry Structural formula (I) or (II):
  • R 1 and R 2 are each independently a hydrogen atom, cyano, nitro, trifluoromethyl or halogen;
  • R 3 and R 4 are each independently a hydrogen atom, C 1 -C 6 alkyl, or R 3 and R 4 together with the carbon atom to which they are attached constitute a 3-6 membered cycloalkyl group;
  • R 5 and R 6 are each independently a hydrogen atom, halogen, trifluoromethyl, cyano, nitro, acetyl, N-methylcarbamoyl C 1 -C 6 alkyl, aryl or substituted aryl;
  • W 1 , W 2 , W 3 , W 4 and W 5 are each independently a carbon atom or a nitrogen atom; and in the general formula (I), W
  • the chemical bond between 2 and W 3 is a single or double bond, and R 5 and R 6 are each connected to the group Any connectable position of the middle benzene ring, such as the 2-, 3-, 4- or
  • the chemical bond between W 2 and W 3 is a double bond
  • the chemical bond between W 4 and W 5 is a double bond
  • R 5 and R 6 are each connected to a group Any connectable position of, such as the 2-, 3-, 4-, or 5-position shown below,
  • N-aromatic amide compound of the general formula (I) has the following chemical structure of the general formula (III):
  • R 1 and R 2 are each independently a hydrogen atom, cyano, nitro, trifluoromethyl or halogen;
  • R 3 and R 4 are each independently a hydrogen atom, C 1 -C 6 alkyl, or R 3 and R 4 together with the carbon atom to which they are attached constitute a 3-6 membered cycloalkyl group;
  • R 5 and R 6 are each independently a hydrogen atom, halogen, trifluoromethyl, cyano, nitro, acetyl, N-methylcarbamoyl C 1 -C 6 alkyl, aryl or substituted aryl;
  • W 1 is a carbon atom or a nitrogen atom;
  • W 2 and W 3 are carbon atoms, and R 5 and R 6 are each connected to the group Any connectable position of the middle benzene ring.
  • N-aromatic amide compound of the general formula (II) has the following chemical structure of the general formula (IV):
  • R 1 and R 2 are each independently a hydrogen atom, cyano, nitro, trifluoromethyl or halogen;
  • R 3 and R 4 are each independently a hydrogen atom, C 1 -C 6 alkyl, or R 3 and R 4 together with the carbon atom to which they are attached constitute a 3-6 membered cycloalkyl group;
  • R 5 and R 6 are each independently a hydrogen atom, halogen, trifluoromethyl, cyano, nitro, acetyl, N-methylcarbamoyl C 1 -C 6 alkyl, aromatic or substituted aromatic;
  • W 1 is a carbon atom or a nitrogen atom;
  • W 2 is a nitrogen atom;
  • W 3 , W 4 and W 5 are carbon atoms; and
  • R 5 and R 6 are each Attached to the group Any connectable position.
  • the stereo configuration may be a racemate, a left-handed (R configuration) and / or a right-handed ( S configuration). Therefore, the present invention also includes stereoisomers of the N-aromatic amide compounds of the general formulae (I) and (II) or pharmaceutically acceptable salts thereof, that is, their left-handed, right-handed, and / or racemic forms.
  • the compounds of general formulae (I), (II) are selected from the following N-aromatic amide compounds:
  • the present invention also includes the active metabolites of the N-aromatic amide compounds of the general formulae (I) and (II), their pharmaceutically acceptable salts or their stereoisomers, such as in vivo primary and / or secondary metabolites .
  • active metabolites of the N-aromatic amide compounds of the general formulae (I) and (II) their pharmaceutically acceptable salts or their stereoisomers, such as in vivo primary and / or secondary metabolites .
  • primary metabolites in the body are examples of the N-aromatic amide compounds of the general formulae (I) and (II), their pharmaceutically acceptable salts or their stereoisomers, such as in vivo primary and / or secondary metabolites .
  • the first and second metabolites in the body are identical to each other.
  • the N-aromatic amide compounds of the general formulae (I) and (II) of the present invention may also exist in the form of a solvate such as a hydrate. Therefore, the present invention also includes the N-aromatic amide compounds of the general formulae (I) and (II) , A pharmaceutically acceptable salt thereof, or a solvate of a stereoisomer thereof such as a hydrate.
  • N-aromatic amide compounds of the general formulae (I) and (II) of the present invention may also exist in the form of a prodrug, which is converted into N-aromatic amide compounds of the general formulae (I) and (II) in vivo.
  • the present invention also includes prodrugs of the N-aromatic amide compounds of the general formulae (I) and (II), pharmaceutically acceptable salts thereof, or stereoisomers thereof.
  • a prodrug for example, a prodrug:
  • R 7 CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , etc. alkyl
  • R 8 hydrogen atom, cyano, nitro, trifluoromethyl or halogen, etc.
  • Another object of the present invention is to provide a method for preparing the N-aromatic amide compound of the general formula (I). As shown in the following chemical reaction formula, the method includes the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , W 1 , W 2 , and W 3 shown in the chemical reaction formula are the same as the general formula (I) N-
  • the definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , W 1 , W 2 , and W 3 in the aromatic amide compound are the same;
  • R9 and R10 are each independently a hydrogen atom, a halogen, a trifluoro Methyl, cyano, nitro, acetyl, N-methylcarbamoyl Or C 1 -C 6 alkyl.
  • the catalyst is cuprous bromide dimethyl sulfide
  • the ligand is triphenylphosphine or tricyclohexylphosphine
  • the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate , Weak bases of potassium bicarbonate, trisodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, tripotassium phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate.
  • the catalyst is cuprous bromide dimethyl sulfide
  • the ligand is triphenylphosphine or tricyclohexylphosphine
  • the base is selected from the group consisting of sodium hydroxide and potassium hydroxide strong base.
  • Another object of the present invention is to provide a method for preparing the N-aromatic amide compound of the general formula (II). As shown in the following chemical reaction formula, the method includes the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , W 1 , W 2 , W 3 , W 4 , and W 5 shown in the chemical reaction formula are the same as those of the present invention.
  • the definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , W 1 , W 2 , W 3 , W 4 , and W 5 in the N-aromatic amide compound of formula (II) are the same;
  • R 11 and R 12 are each independently a hydrogen atom, halogen, trifluoromethyl, cyano, nitro, acetyl, N-methylcarbamoyl Or C 1 -C 6 alkyl.
  • the catalyst is cuprous bromide dimethyl sulfide
  • the ligand is triphenylphosphine or tricyclohexylphosphine
  • the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate , Weak bases of potassium bicarbonate, trisodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, tripotassium phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate.
  • the catalyst is cuprous bromide dimethyl sulfide
  • the ligand is triphenylphosphine or tricyclohexylphosphine
  • the base is selected from the group consisting of sodium hydroxide and potassium hydroxide strong base.
  • N-aromatic amide compounds of the general formulae (I) and (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of androgen-related diseases.
  • Another object of the present invention is to provide a method for treating or preventing androgen-related diseases, which comprises administering to a mammal in need thereof a therapeutic or preventive effective amount of a general formula (I) and (II) N-aromatic amide compound or Pharmaceutically acceptable salts.
  • the androgen-related diseases include, but are not limited to, prostate cancer, prostate hyperplasia, breast cancer, bladder cancer, ovarian cancer, acne, hairiness, and hair loss.
  • aromatic group refers to a 5- to 10-membered monocyclic or bicyclic carbocyclic group having aromaticity or containing a heteroatom selected from N, O, and S, which is unsubstituted or substituted by a substituent.
  • Monocyclic or bicyclic heterocyclic group wherein one ring of the bicyclic system may be hydrogenated; including, for example, phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, pyridyl, pyridazinyl, pyrimidinyl , Pyrazinyl, furyl, imidazolyl, pyranyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thienyl, purinyl, benzofuranyl, benzothienyl , Diazinyl, isobenzothienyl, isobenzofuranyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, etc .; the substituent is selected from a hydrogen atom, an alkyl group, a halogen, Trifluoromethyl, cyan
  • substituted aromatic group refers to an aromatic group substituted with one, two, three or more substituents, wherein the substituent is selected from the group consisting of alkyl, halogen, trifluoromethyl, Cyano and nitro etc.
  • alkyl refers to a linear or branched saturated hydrocarbon group, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Alkyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl, etc., preferably the alkyl group contains 1-6 carbon atoms, and can be expressed as a C 1 -C 6 alkyl group, more preferably an The group contains 1-4 carbon atoms and can be expressed as a C 1 -C 4 alkyl group.
  • 3-6 membered cycloalkyl refers to a monocyclic or bicyclic carbocyclic ring having 3 to 6 ring carbon atoms, including but not limited to: cyclopropyl, cyclobutyl, cyclopentyl and Cyclohexyl.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • copper (I) bromide dimethyl sulfide refers to CuBr ⁇ S (Me) 2 [Copper (I) bromide dimethyl sulfide].
  • the chemical bond between two terminal atoms is a single bond or a double bond.
  • mammals include, but is not limited to, primates (such as apes and humans), equines (including horses), canines (such as dogs), felines, domestic animals (if any Hoofed animals, like pigs, goats, sheep, etc.), as well as domestic pets and zoo-raised animals, mammals are preferably humans.
  • the "pharmaceutically acceptable salt” refers to a salt formed by reacting a pharmaceutically non-toxic acid with the basic part of the N-aromatic amide compound of the general formulae (I) and (II) of the present invention, Includes, for example, hydrochloride, acetate, hydrobromide, sulfate, bisulfate, carbonate, bicarbonate, sulfite, phosphate, hydrogen phosphate, oxalate, malonate, Valerate, borate, p-toluenesulfonate, mesylate, tartrate, benzoate, lactate, citrate, maleate, fumarate, malate, water Salicylate, mandelate, succinate, gluconate, lactate, etc.
  • Such salts can be prepared by methods known to those skilled in the art.
  • N-aromatic amide compounds of the general formulae (I) and (II) of the present invention can bind to androgen receptors, have significant resistance to androgens and degrade androgen receptor activity.
  • the compound can be used alone or as a composition for the prevention or treatment of various androgen-related diseases, including, for example, prostate cancer, prostate hyperplasia, breast cancer, bladder cancer, ovarian cancer, and can also be used for acne, hairy, hair loss, etc. Prevention or treatment of disease.
  • the present invention also provides a pharmaceutical composition containing the N-aromatic amide compounds of the general formulae (I) and (II) or a pharmaceutically acceptable salt thereof, and containing the general formulae (I) and (II) N -A pharmaceutical preparation of an aromatic amide compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may include a conventional pharmaceutical carrier in the art, such as a diluent, a filler, a binder, a disintegrant, a lubricant, a solvent, a solubilizer, and the like; including, but not limited to, for example, starch, Gelatinized starch, sodium carboxymethyl starch, sugar powder, lactose, calcium phosphate, magnesium stearate, talc, micronized silica gel, dextrin, cellulose and its derivatives (e.g.
  • hydroxyethyl cellulose hydroxypropyl fiber Cellulose, hydroxypropylmethyl cellulose (HPMC), etc.), microcrystalline cellulose, mannitol, polysorbate 80, polyethylene glycol, water, water for injection, physiological saline, glucose solution, and the like.
  • compositions and pharmaceutical preparation of the present invention may also include various other commonly used additives, such as preservatives, emulsifiers, suspending agents, flavoring agents, and the like.
  • composition of the present invention can be prepared into any suitable dosage form that is pharmaceutically acceptable, including but not limited to, for example, tablets, capsules, pills, granules, syrups, injections, solutions, suspensions and the like.
  • N-aromatic amide compounds of the general formulae (I) and (II) of the present invention or a pharmaceutically acceptable salt thereof can be administered to mammals, such as humans, by any effective route including oral, intravenous, intraperitoneal, muscle Internal, local, transdermal, ocular, nasal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, etc. They can be administered alone or in combination with other active ingredients.
  • An effective amount of the N-aromatic amide compounds of the general formulae (I) and (II) of the present invention or a pharmaceutically acceptable salt thereof can be determined by a person skilled in the art, such as a physician, by using a conventional method.
  • a compound of the present invention In determining the effective amount of a compound of the present invention, many factors should be considered by the attending physician, including but not limited to: the specific compound to be administered; combined use with other agents; the type, size, age and general health of the mammal; disease The severity of the disease; the response of the individual patient; the mode of administration; the bioavailability characteristics of the administered formulation; the chosen dosage regimen; the use of other concomitant drugs; and other relevant conditions.
  • the usual dose is 10-1000 mg.
  • THF represent tetrahydrofuran
  • DMSO-d 6 represents deuterated dimethyl sulfoxide
  • DMSO represents dimethyl sulfoxide
  • CDCl 3 represents deuterated chloroform
  • eq represents equivalent weight
  • HPLC high pressure liquid chromatography
  • PPh 3 stands for Triphenyl phosphine
  • PCy 3 stands for Tricyclohexyl phosphine
  • K 3 PO 4 stands for Potassium phosphate tribasic
  • DMF stands for dimethylformamide
  • Pd (PPh3) 4 Represents tetrakis (triphenylphosphine) palladium
  • DME represents ethylene glycol dimethyl ether.
  • Bruker AVANCE II 400MHz nuclear magnetic resonance apparatus was used for 1 H NMR measurement, where s represents a singlet, bs or brs represents a broad singlet, d represents a doublet, m represents a multiplet, and Ar is an aryl group.
  • Mass spectrometry was performed using a Bruker amaZon SL mass spectrometer. Waters Acquity HPLC + Xeno G2-S TOF Mass was used for high resolution mass spectrometry.
  • SHIMADZU CBM-20A was used for high pressure liquid chromatography. Thin layer chromatography was performed using a 60F254 silica gel plate (Merck).
  • the resulting mixture was heated to 50 ° C and stirred under argon for 12 hours. After confirming the completion of the reaction by thin-layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (30 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (20 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (30 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (20 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (30 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (20 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (30 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (20 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (30 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (20 ml). The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (30 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (20 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (30 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (20 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (30 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (20 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (30 ml) were added. After stirring briefly, the layers were separated. The organic phase was washed with brine (20 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred overnight under the protection of argon. After confirming the completion of the reaction by thin-layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (30 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (20 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred overnight under the protection of argon. After confirming the completion of the reaction by thin-layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (30 ml) were added. After stirring briefly, the layers were separated. The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred under argon for 14 hours. After confirming the completion of the reaction by thin-layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (30 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (20 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred under argon for 12 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred under argon for 12 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred under argon for 12 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred under argon for 12 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred under argon for 14 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred overnight under the protection of argon. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred overnight under the protection of argon. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred overnight under the protection of argon. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred overnight under the protection of argon. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred under argon for 15 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred under argon for 15 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred under argon for 15 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred under argon for 14 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred under argon for 14 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred under argon for 14 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the resulting mixture was heated to 50 ° C and stirred under argon for 14 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction solution was cooled to 20 ⁇ 5 ° C, and then water (30 ml) and ethyl acetate (35 ml) were added. After stirring briefly, the layers were separated, and the organic phase was washed with brine (25 ml), The magnesium sulfate was dried, filtered, and the organic phase was dried to obtain an oily substance.
  • the formula composition add the compound of Example 15, polysorbate 80 and mannitol to 4000m1 water for injection. After stirring and dissolving, add water for injection to the full amount of 5000ml, continue to stir, and filter through a 0.22 ⁇ m microporous filter. The filtrate was aseptically filled in 5ml ampoules (specification 25mg / piece) with 5ml of each, sealed and sterilized.
  • Example 15 The compound of Example 15, lactose and some microcrystalline cellulose were micronized at a ratio of 200: 100: 40, and the remaining microcrystalline cellulose, pregelatinized starch, micronized silica gel, and carboxymethyl starch were added to the 80 mesh sieve according to the formula ratio.
  • Radiolabeled dihydrotestosterone (DHT-d3) and unlabeled dihydrotestosterone (DHT) were purchased from Sigma-Aldrich (St. Louis, MO). A scintillation solution was purchased from Perkin Elmer Life Sciences (Boston, MA). Hydroxylapatite (HAP) suspension was purchased from Bio-Rad Laboratories (Hercules, CA). Buffer (containing 10 mM Tris, 1.5 mM disodium EDTA, 0.25 M sucrose, 10 mM sodium molybdate and 1 mM PMSF, pH adjusted to 7.4). Hydroxyapatite (HAP) wash solution (containing 50 mM Tris and 1 mM KH 2 PO 4 , pH adjusted to 7.4).
  • N-aromatic amide compounds of the general formulae (I) and (II) are measured according to the following methods.
  • the compound of the present invention and the control compound obtained in the preparation example were dissolved in DMSO to prepare a mother liquor of a certain concentration, which was diluted into several concentration gradients with DMSO, and each concentration was diluted with a buffer solution (10 -1 nM Up to 10 4 nM), 4 ° C refrigerator until use.
  • Androgen receptor prepared in prostate of male SD rats, male Sprague-Dawley rats 200-250 g
  • radiolabeled dihydrotestosterone DHT-d3, 84 Ci / mmol
  • HAP hydroxyapatite
  • Dihydrotestosterone bound to the androgen receptor is retained in the precipitated particles by adsorption on hydroxyapatite, thereby achieving the purpose of separating bound and unbound radiolabeled ligands.
  • a scintillation solution was added to the pellet, mixed well, and the radioactive intensity was measured using a WALLACE MicroBeta Trilux liquid scintillator (Perkin Elmer). Data processing was performed according to the detected radioactive intensity values of each concentration gradient to obtain IC 50 and K i values. Specific biological activities (androgen receptor ligands compete with radioligands) are shown in the table below:
  • bioactivity measurement results in the table above show that the compounds in the present invention can bind more strongly to the androgen receptor and have stronger resistance to androgen than the positive control group (bicalutamide and enzalutamide). Hormone receptor activity. Therefore, it is expected to develop new N-aromatic amide antiandrogen drugs that are safer and more effective than existing drugs, and have important value and status in the research of androgen-related diseases.
  • the compound of the present invention can be used alone or as a composition for the prevention or treatment of various androgen-related diseases, such as prostate cancer, prostate hyperplasia, breast cancer, bladder cancer, ovarian cancer, and can also be used for diseases such as acne, hairiness, hair loss Prevention or treatment.
  • various androgen-related diseases such as prostate cancer, prostate hyperplasia, breast cancer, bladder cancer, ovarian cancer, and can also be used for diseases such as acne, hairiness, hair loss Prevention or treatment.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

本发明涉及通式(I)和(II)N-芳香酰胺化合物及其制备方法、含有所述通式(I)或(II)化合物的药物组合物和药物制剂以及所述通式(I)和(II)化合物在制备治疗与雄激素相关疾病的药物方面的应用，通式中R1、R2、R3、R4、R5、R6、W1、W2、W3、W4和W5的定义与说明书中的相同。所述通式(I)和(II)化合物能够与雄激素受体结合，具有抵抗雄激素并且降解雄激素受体活性。所述化合物能够单独或作为组合物用于治疗各种与雄激素相关的疾病，如前列腺癌、前列腺增生、乳腺癌、膀胱癌、卵巢癌等，还能用于粉刺、多毛、脱发等疾病的治疗。

Description

N-芳香酰胺类化合物及其制备方法和用途 技术领域
本发明涉及一类N-芳香酰胺化合物及其制备方法以及其制药应用，所述化合物具有抵抗雄激素并且降解雄激素受体的作用，可用于前列腺癌、前列腺增生、乳腺癌、膀胱癌、粉刺、多毛、脱发等与雄激素相关的疾病治疗。
背景技术
雄激素受体属于核受体家族，是由配体诱导的核转录因子的受体。雄激素受体是一种重要的细胞调节蛋白，它通过内源性雄激素在一系列的生理过程中起着重要的作用，包括男性第二性征发育和维护，包括肌肉和骨骼的质量，男性毛发，前列腺的生长，精子发育等。内源性甾体雄激素被称为男性性激素，包括睾酮和二氢睾酮(DHT)。睾酮是在男性血清中发现的主要的甾体雄激素，它主要是由睾丸分泌的。在许多外周组织，如前列腺和皮肤，睾酮可被5α-还原酶转化为活性更强的雄激素二氢睾酮(DHT)。
许多疾病和雄激素水平有关。男性随着年龄的增长，体内雄激素水平会逐渐下降，伴随着肌肉减少、骨质疏松、性功能下降等。相反，体内雄激素水平过高也会引起一些疾病，如前列腺癌、前列腺增生、粉刺、多毛、脱发等与雄激素相关的疾病。
因前列腺癌是激素依赖性的，前列腺癌的内分泌治疗是最久使用、最成熟，也是最有效手段。早在1941年，Huggins和Hodges发现了手术去势，如手术切掉双侧睾丸以消除睾酮来源，和雌激素可延缓转移性前列腺癌的进展，并首次证实了前列腺癌对雄激素去除的反应性。但是临床研究表明，单纯切掉睾丸可以降低血液中雄激素的含量，但并不能大幅度的降低前列腺组织中雄激素的含量，因为前列腺组织中存在利用肾上腺分泌的甾体为原料合成雄激素的酶系统，并可转化雄激素睾酮为活性更强的雄激素二氢睾酮。因此，即使采取了去势疗法，对于前列腺癌抗雄激素药物治疗也是必须的。
应用抗雄激素药物(雄激素拮抗剂)竞争性阻断雄激素与前列腺细胞上雄激素受体的结合,是目前治疗前列腺癌的标准治疗方法。常用非甾体雄激素受体拮抗剂有：
1.氟他胺(Flutamide)是第一代非甾体雄激素受体拮抗剂(Endocrinology 1972，91,427–437；Biochemical Society Transactions 1979，7,565–569；Journal of Steroid Biochemistry 1975，6,815–819)，其代谢产物2–羟基氟他胺是其主要活性形式，能在靶组织内与雄激素受体结合，阻断二氢睾丸素与雄激素受体结合，抑制靶组织摄取睾丸素，从而起到抗雄激素 作用。因服用量较大，长期服用会造成男子乳房发育，伴有肿瘤和压痛，并有恶心、呕吐、腹泻、偶尔出现皮肤反应，变性红血蛋白性贫血，白细胞及血小板减少。另外，氟他胺在治疗中易产生抗雄激素撤除综合症，少数病人有肝毒性等问题。
Figure PCTCN2019106287-appb-000001
2.比卡鲁胺(Bicalutumide)是第二代非甾体雄激素受体拮抗剂(The Journal of Endocrinology 1987，113,R7–R9；Urologic Clinics of North America 1991，18,99–110)。此药物是一个消旋异构体，其活性成分为左旋异构体。比卡鲁胺除具有抗雄激素作用外，疗效高于氟他胺，而副作用减少了70％。与氟他胺类似，能在靶组织内与雄激素受体结合，阻断二氢睾丸素与雄激素受体结合，抑制靶组织摄取睾丸素，从而起到抗雄激素作用。其缺点是，经过一定中位期(一般18～24个月)后，几乎所有患者最终都会发展为激素抵抗性前列腺癌。另外，比卡鲁胺在治疗中也产生抗雄激素撤除综合症等问题。
Figure PCTCN2019106287-appb-000002
3.恩杂鲁胺(Enzalutamide，商品名：Xtandi)，是第三代非甾体雄激素受体拮抗剂(Archives of Pharmacal Research 2015，38(11):2076–82)，美国FDA于2012年批准该药上市。其具有更强的雄激素受体拮抗作用，为内分泌治疗增添了新的药物。缺点是价格昂贵，并且也会发展为激素抵抗性前列腺癌。另外，恩杂鲁胺在治疗中发现能引起患者抽搐的副作用，因此其应用受到一定限制。
Figure PCTCN2019106287-appb-000003
因此，开发比现有药物更安全有效的新型抗雄激素药物在治疗与雄激素相关疾病，如前列腺癌、前列腺增生、乳腺癌、膀胱癌、卵巢癌等疾病的研究中具有重要的价值和地位。
本发明人在研究抗雄激素药物的过程中，发现了一类具有抵抗雄激素活性并可降解雄激 素受体作用、比现有药物更安全、更有效的N-芳香酰胺化合物，由此完成了本发明。
发明内容
本发明的一个目的是提供比现有药物更安全有效的新一类具有抵抗雄激素活性而且可降解雄激素受体作用的N-芳香酰胺化合物或其药学上可接受的盐(以下亦称为本发明化合物)，可用于预防或治疗与雄激素相关的疾病，如前列腺癌、前列腺增生、乳腺癌、膀胱癌、卵巢癌、粉刺、多毛、脱发等；所述N-芳香酰胺化合物具有如下化学结构通式(I)或(II)：
Figure PCTCN2019106287-appb-000004
其中R 1和R 2各自独立地为氢原子、氰基、硝基、三氟甲基或卤素；R 3和R 4各自独立地为氢原子、C 1-C 6烷基或R 3和R 4与它们连接的碳原子一起构成3-6元环烷基；R 5和R 6各自独立地为氢原子、卤素、三氟甲基、氰基、硝基、乙酰基、
Figure PCTCN2019106287-appb-000005
N-甲基氨基甲酰基
Figure PCTCN2019106287-appb-000006
C 1-C 6烷基、芳香基或取代的芳香基；W 1、W 2、W 3、W 4和W 5各自独立地为碳原子或氮原子；且在通式(I)中，W 2和W 3之间的化学键为单键或双键，R 5和R 6各自连接在基团
Figure PCTCN2019106287-appb-000007
中苯环的任意可连接位置，如以下所示的2位、3位、4位或5位，
Figure PCTCN2019106287-appb-000008
在通式(II)中，W 2和W 3之间的化学键为双键，W 4和W 5之间的化学键为双键，R 5和R 6各自连接在基团
Figure PCTCN2019106287-appb-000009
的任意可连接位置，如以下所示的2位、3位、4位或5位，
Figure PCTCN2019106287-appb-000010
在一个优选的实施方案中，所述通式(I)N-芳香酰胺化合物具有以下化学结构通式(III)：
Figure PCTCN2019106287-appb-000011
其中R 1和R 2各自独立地为氢原子、氰基、硝基、三氟甲基或卤素；R 3和R 4各自独立地为氢原子、C 1-C 6烷基或R 3和R 4与它们连接的碳原子一起构成3-6元环烷基；R 5和R 6各自独立地为氢原子、卤素、三氟甲基、氰基、硝基、乙酰基、
Figure PCTCN2019106287-appb-000012
N-甲基氨基甲酰基
Figure PCTCN2019106287-appb-000013
C 1-C 6烷基、芳香基或取代的芳香基；W 1为碳原子或氮原子；W 2、W 3为碳原子，且R 5和R 6各自连接在基团
Figure PCTCN2019106287-appb-000014
中苯环的任意可连接位置。
在另一个优选的实施方案中，所述通式(II)N-芳香酰胺化合物具有以下化学结构通式(IV)：
Figure PCTCN2019106287-appb-000015
其中R 1和R 2各自独立地为氢原子、氰基、硝基、三氟甲基或卤素；R 3和R 4各自独立地为氢原子、C 1-C 6烷基或R 3和R 4与它们连接的碳原子一起构成3-6元环烷基；R 5和R 6各自独立地为氢原子、卤素、三氟甲基、氰基、硝基、乙酰基、
Figure PCTCN2019106287-appb-000016
N-甲基氨基甲酰基
Figure PCTCN2019106287-appb-000017
C 1-C 6烷基、芳香基或取代的芳香基；W 1为碳原子或氮原子；W 2为氮原子；W 3、W 4和W 5为碳原子；且R 5和R 6各自连接在基团
Figure PCTCN2019106287-appb-000018
的任意可连接位置。
在上述通式(I)、(II)、(III)和(IV)分子中含有手性原子的时候，其立体构型可为消旋体、左旋(R构型)和/或右旋(S构型)。因此，本发明还包括所述通式(I)和(II)N-芳香酰胺化合物或其药学上可接受的盐的立体异构体，即它们的左旋、右旋和/或消旋体。
在另一个优选的实施方案中，所述通式(I)、(II)化合物选自下列N-芳香酰胺化合物：
Figure PCTCN2019106287-appb-000019
Figure PCTCN2019106287-appb-000020
Figure PCTCN2019106287-appb-000021
Figure PCTCN2019106287-appb-000022
Figure PCTCN2019106287-appb-000023
本发明还包括所述通式(I)和(II)N-芳香酰胺化合物、其药学上可接受的盐或其立体异构体的活性代谢物，例如体内一级和/或二级代谢物。 例如，体内一级代谢物：
Figure PCTCN2019106287-appb-000024
例如，体内二级代谢物：
Figure PCTCN2019106287-appb-000025
例如，体内一级加二级代谢物：
Figure PCTCN2019106287-appb-000026
Figure PCTCN2019106287-appb-000027
本发明的通式(I)和(II)N-芳香酰胺化合物还可以溶剂化物例如水合物的形式存在，因此，本发明还包括所述通式(I)和(II)N-芳香酰胺化合物、其药学上可接受的盐或其立体异构体的溶剂化物例如水合物。
此外，本发明的通式(I)和(II)N-芳香酰胺化合物也可以前药的形式存在，该前药是在体内转化成通式(I)和(II)N-芳香酰胺化合物的化合物，因此，本发明还包括所述通式(I)和(II)N-芳香酰胺化合物、其药学上可接受的盐或其立体异构体的前药。
例如，前药：
Figure PCTCN2019106287-appb-000028
R 7＝CH 3,C 2H 5,C 3H 7,C 4H 9,等烷基
Figure PCTCN2019106287-appb-000029
R 8＝氢原子、氰基、硝基、三氟甲基或卤素,等基
本发明的另一个目的是提供所述通式(I)N-芳香酰胺化合物的制备方法，如以下化学反应式所示，所述方法包括以下步骤：
1)、使化合物(V)和化合物(VI)(均可直接商购得到)反应得到化合物(VII)；
2)、在催化剂、配体和碱存在的条件下，使化合物(VII)和化合物(VIII)(可直接商购得到或按文献Pure Appl.Chem.1991 63(3):419–422、Chemical Reviews.1979 95(7):2457–2483、和Journal of Organometallic Chemistry.1999 576:147–168方法合成)反应生成结构通式(I)所示的目标化合物，
Figure PCTCN2019106287-appb-000030
其中化合物VIII有些可直接商购得到，有些可按以下所述路线合成，例如合成相应的化合物(XII)。
Figure PCTCN2019106287-appb-000031
其中化学反应式中所示的R 1、R 2、R 3、R 4、R 5、R 6、W 1、W 2、和W 3的定义与上文中对本发明的通式(I)N-芳香酰胺化合物中的R 1、R 2、R 3、R 4、R 5、R 6、W 1、W 2、和W 3的定义相同；R9和R10各自独立地为氢原子、卤素、三氟甲基、氰基、硝基、乙酰基、
Figure PCTCN2019106287-appb-000032
N-甲基氨基甲酰基
Figure PCTCN2019106287-appb-000033
或C 1-C 6烷基。
在一个实施方案中，所述催化剂为溴化亚铜二甲基硫醚，所述配体为三苯基膦或三环己基膦，所述碱为选自碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、磷酸三钠、磷酸二氢钠、磷酸氢二钠、磷酸三钾、磷酸二氢钾和磷酸氢二钾的弱碱。
在另一个实施方案中，所述催化剂为溴化亚铜二甲基硫醚，所述配体为三苯基膦或三环己基膦，所述碱为选自氢氧化钠和氢氧化钾的强碱。
本发明的另一个目的是提供所述通式(II)N-芳香酰胺化合物的制备方法，如以下化学反应式所示，所述方法包括以下步骤：
1)、使化合物(V)和化合物(VI)(均可直接商购得到)反应得到化合物(VII)；
2)、在催化剂、配体和碱存在的条件下，使化合物(VII)和化合物(IX)(可直接商购得到或按文献Pure Appl.Chem.1991 63(3):419–422、Chemical Reviews.1979 95(7):2457–2483、和Journal of Organometallic Chemistry.1999 576:147–168方法合成)反应生成结构通 式(II)所示的目标化合物，
Figure PCTCN2019106287-appb-000034
其中化合物IX有些可直接商购得到，有些可按以下所述路线合成，例如合成相应的化合物(XV)。
Figure PCTCN2019106287-appb-000035
其中化学反应式中所示的R 1、R 2、R 3、R 4、R 5、R 6、W 1、W 2、W 3、W 4、和W 5的定义与上文中对本发明的通式(II)N-芳香酰胺化合物中的R 1、R 2、R 3、R 4、R 5、R 6、W 1、W 2、W 3、W 4、和W 5的定义相同；
R 11和R 12各自独立地为氢原子、卤素、三氟甲基、氰基、硝基、乙酰基、
Figure PCTCN2019106287-appb-000036
N-甲基氨基甲酰基
Figure PCTCN2019106287-appb-000037
或C 1-C 6烷基。
在一个实施方案中，所述催化剂为溴化亚铜二甲基硫醚，所述配体为三苯基膦或三环己基膦，所述碱为选自碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、磷酸三钠、磷酸二氢钠、磷酸氢二钠、磷酸三钾、磷酸二氢钾和磷酸氢二钾的弱碱。
在另一个实施方案中，所述催化剂为溴化亚铜二甲基硫醚，所述配体为三苯基膦或三环己基膦，所述碱为选自氢氧化钠和氢氧化钾的强碱。
本发明的再一个目的是提供所述通式(I)和(II)N-芳香酰胺化合物或其药学上可接受的盐在制备用于治疗或预防与雄激素相关的疾病的药物中的应用。
本发明的又一个目的是提供治疗或预防与雄激素相关的疾病的方法，包括给予有此需要 的哺乳动物治疗或预防有效量的通式(I)和(II)N-芳香酰胺化合物或其药学上可接受的盐。
在本申请中，所述与雄激素相关的疾病包括但不限于前列腺癌、前列腺增生、乳腺癌、膀胱癌、卵巢癌、粉刺、多毛和脱发。
在本申请中，术语“芳香基”是指未被取代或被取代基取代的5-10元具有芳香性的单环或双环系碳环基团或含有选自N、O和S的杂原子的单环或双环系杂环基团，其中双环系的一个环可以是被氢化的；包括例如苯基、萘基、二氢萘基、四氢萘基、吡啶基、哒嗪基、嘧啶基、吡嗪基、呋喃基、咪唑基、吡喃基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、噻吩基、嘌呤基、苯并呋喃基、苯并噻吩基、二嗪基、异苯并噻吩基、异苯并呋喃基、吲哚基、异吲哚基、喹啉基、异喹啉基等；所述取代基选自氢原子、烷基、卤素、三氟甲基、氰基、硝基等。
在本申请中，术语“取代的芳香基”是指被一个、两个、三个或者更多个取代基取代的芳香基，其中所述取代基选自烷基、卤素、三氟甲基、氰基和硝基等。
本文使用的术语“烷基”作为基团或基团的一部分是指直链或支化的饱和烃基，其实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或己基等，优选烷基含有1-6个碳原子，可表示为C 1-C 6烷基，更优选烷基含有1-4个碳原子，可表示为C 1-C 4烷基。
在本申请中，术语“3-6元环烷基”是指具有3至6个环碳原子的单环或双环碳环，包括但不限于：环丙基、环丁基、环戊基和环己基。
在本申请中，术语“卤素”是指氟、氯、溴或碘。
在本申请中，术语“溴化亚铜二甲基硫醚”是指CuBr·S(Me) 2[Copper(I)bromide dimethyl sulfide]。
在本申请中，
Figure PCTCN2019106287-appb-000038
表示两个端原子(在本发明化合物中，端原子为碳原子或氮原子)之间的化学键为单键或双键。
在本申请中，术语“哺乳动物”包括但不限于灵长类动物(例如猿猴和人类)、马科动物(包括马)、犬科动物(如狗)、猫科动物、家养牲畜(如有蹄动物，像猪、山羊、绵羊等)，以及家养宠物和动物园饲养的动物，哺乳动物优选为人。
在本申请中，所述“药学上可接受的盐”是指在药学上无毒的酸与本发明通式(I)和(II)N-芳香酰胺化合物的碱性部分反应形成的盐，包括例如盐酸盐、醋酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、碳酸盐、碳酸氢盐、亚硫酸盐、磷酸盐、磷酸氢盐、草酸盐、丙二酸盐、戊酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、酒石酸盐、苯甲酸盐、乳酸盐、柠檬酸盐、马来酸盐、富马酸盐、苹果酸盐、水杨酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐等。这种盐 可以通过本领域技术人员公知的方法来制备。
经实验证明，本发明通式(I)和(II)N-芳香酰胺化合物能够与雄激素受体结合，具有显著的抵抗雄激素并且降解雄激素受体活性。所述化合物能够单独或作为组合物用于预防或治疗各种与雄激素相关的疾病，包括例如前列腺癌、前列腺增生、乳腺癌、膀胱癌、卵巢癌，还能用于粉刺、多毛、脱发等疾病的预防或治疗。
因此，本发明还提供含有所述通式(I)和(II)N-芳香酰胺化合物或其药学上可接受的盐的药物组合物，和含有所述通式(I)和(II)N-芳香酰胺化合物或其药学上可接受的盐和药学上可接受的载体的药物制剂。
所述药学上可接受的载体可以包括本领域常规的药用载体，例如稀释剂、填充剂、粘合剂、崩解剂、润滑剂、溶剂、增溶剂等；包括但不限于例如淀粉、预胶化淀粉、羧甲基淀粉钠、糖粉、乳糖、磷酸钙、硬脂酸镁、滑石粉、微粉硅胶、糊精、纤维素及其衍生物(例如羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素(HPMC)等)、微晶纤维素、甘露醇、聚山梨醇80、聚乙二醇、水、注射用水、生理盐水、葡萄糖溶液等。
本发明药物组合物和药物制剂也可以包括各种其它常用的添加剂，例如防腐剂、乳化剂、助悬剂、矫味剂等。
本发明药物组合物可以制备成药学上可接受的任何适当的剂型，包括但不限于例如片剂、胶囊剂、丸剂、颗粒制剂、糖浆剂、注射剂、溶液剂、混悬剂等。
本发明通式(I)和(II)N-芳香酰胺化合物或其药学上可接受的盐可以通过任何有效途径施用于哺乳动物，例如人，所述途径包括口服、静脉内、腹膜内、肌肉内、局部、透皮、经眼、经鼻、吸入、皮下、肌内、口含、舌下、直肠等。它们可以单独给药，或者与其他活性成分联合给药。本发明通式(I)和(II)N-芳香酰胺化合物或其药学上可接受的盐的有效量可以由本领域技术人员例如主治医生等通过使用常规方法来确定。在确定本发明化合物的有效量时，许多因素应被主治医生考虑，包括但不限于：所要给予的具体化合物；与其它药剂的联合用药；哺乳动物的种类、大小、年龄和一般健康状况；疾病的严重程度；个体患者的反应；给药方式；所给予的制剂的生物利用度特性；所选择的剂量方案；其它伴随药物的使用；以及其它相关的情况等。通常剂量为10-1000毫克。
具体实施方式
下面用实施例进一步具体地描述本发明，显然，所描述的实施例仅是本发明的一部分，而不是全部。这些实施例仅用于例证本发明，不应将其理解为对本发明保护范围的限制。基于本发明的实施例，本领域技术人员在没有付出创造性劳动前提下所获得的所有其它技术方 案，都属于本发明保护的范围。
在实施例中，缩写THF代表四氢呋喃、DMSO-d 6代表氘代二甲基亚砜、DMSO代表二甲基亚砜、CDCl 3代表氘代氯仿、eq代表当量、HPLC代表高压液相色谱、PPh 3代表三苯基膦(Triphenyl phosphine)、PCy 3代表三环己基膦(Tricyclohexyl phosphine)、K 3PO 4代表磷酸三钾(Potassium phosphate tribasic)、DMF代表二甲基甲酰胺、Pd(PPh3)4代表四(三苯基膦)合钯、DME代表乙二醇二甲醚。
1H NMR测定用Bruker AVANCE II 400MHz核磁共振仪，其中s代表单峰、bs或brs代表宽单峰、d代表二重峰、m代表多重峰、Ar为芳基。质谱测定用Bruker amaZon SL质谱仪。高分辨质谱测定用Waters Acquity HPLC+Xeno G2-S TOF Mass。高压液相色谱测定用SHIMADZU CBM-20A。薄层层析测定用60F254硅胶板(Merck)。
I.化合物制备实施例
实施例1
N-(4-氰基-3-三氟甲基)苯基-2-[4-氟-6-(4-氟苯基)-1H-吲哚-1-基]-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000039
第一步反应
把二氯亚砜(2.62毫升，35.93毫摩尔,1.2eq)逐滴加入到2-溴-2-甲基丙酸(5.00克，29.94毫摩尔)在30毫升无水四氢呋喃(THF)的溶液中，滴加时的温度控制在0-12℃，用时间10分钟。将所得的混合物在相同条件下搅拌2小时。内温调整到-5℃左右，向反应的混合物缓慢加入三乙基氨(Et 3N)(5.42毫升,38.92mmol,1.3eq),加料过程中内温低于12℃。在相同的反应条件搅拌20分钟。随后向其中逐滴加入4–氰基-3-三氟甲基-苯胺(5.57克，29.94毫摩尔)在30mL无水四氢呋喃中的溶液，将所得混合物于50℃搅拌两个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(50毫升)和乙酸乙酯(50毫升)，短暂搅拌后分液，有机相用盐水洗(30毫升)、硫酸镁干燥、过滤、将 有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1)，纯化，得到8.68克2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺。产率86.8％,HPLC(流动相为水和乙氰)纯度99％(254nm)。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.57(s,1H,NH),8.38(s,1H,ArH),8.24(d,J＝8.4Hz,1H,ArH),8.15(d,J＝8.4Hz,1H,ArH),2.01(s,6H,2xCH 3)。
质谱：(ESI,Positive):335.00[M+H] +。
第二步反应
把6-溴-4-氟-1H-吲哚(1.00克，4.672毫摩尔)加入到四(三苯基膦)合钯([Pd(PPh 3) 4],0.54克，0.4672毫摩尔)在20毫升乙二醇二甲醚(DME)的混悬溶液中，在氩气保护下室温搅拌15分钟。将4-氟-苯硼酸(0.66克，4.672毫摩尔)在2.5毫升乙醇中的溶液加入到上述反应液中，将所得的混合物在相同条件下搅拌10分钟。再将碳酸钾(0.92克，7.008毫摩尔)溶于2.0毫升水中，并加入到上述反应液中。将所得的反应混合物在氩气保护下加热回流2-3小时。薄层色谱法确定反应完成后，然后加入盐水(20毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(15毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝3：1)，纯化，得棕色粉未物质0.66克，经鉴定为4-氟-6-(4-氟-苯基)-1H-吲哚。产率约为62％。
质谱：(ESI,positive):230.02[M+H] +。
第三步反应
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.17克,0.500毫摩尔)、4-氟-6-(4-氟-苯基)-1H-吲哚(0.22克,1.00毫摩尔)、溴化亚铜二甲基硫醚(11毫克,0.05毫摩尔)、三苯基膦(PPh3)(13毫克,0.05毫摩尔)、氢氧化钠(22毫克,0.56毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌12个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(20毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝3：1至2：1)，纯化，得到黄色粉未物质73毫克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-[4-氟-6-(4-氟苯基)-1H-吲哚-1-基]-2-甲基丙酰胺。产率30％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H,NH),8.20(d,J＝2.0Hz,1H,ArH),8.18-8.07(m,2H,ArH),7.75(d,J＝3.6Hz,1H,吲哚-H),7.52-7.48(m,2H,ArH),7.27-7.22(m,2H,ArH),7.17(d,J＝8.4Hz,1H,ArH),7.14(s,1H,ArH),6.68(d,J＝3.2Hz,1H,吲哚-H),1.91(s,6H, 2xCH 3)。
质谱：(ESI,Negative):482.26[M-H] -。
实施例2
N-(4-氰基-3-三氟甲基)苯基-2-(5-氟-6-苯基-1H-吲哚-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000040
第一步反应
同实施例1。
第二步反应
把6-溴-5-氟-1H-吲哚(1.00克，4.672毫摩尔)加入到四(三苯基膦)合钯[Pd(PPh3)4](0.54克，0.4672毫摩尔)在20毫升乙二醇二甲醚(DME)的混悬溶液中，在氩气保护下室温搅拌15分钟。将苯硼酸(0.57克，4.672毫摩尔)在2.5毫升乙醇中的溶液加入到上述反应液中，将所得的混合物在相同条件下搅拌10分钟。再将碳酸钾(0.97克，7.008毫摩尔)在2.0毫升水中，加入到上述反应液中。将所得的反应混合物在氩气保护下加热回流2-3小时。薄层色谱法确定反应完成后，加入盐水(20毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(15毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝3：1)，纯化，得棕色粉未物质0.79克，经鉴定为5-氟-6-苯基-1H-吲哚。产率约为80％。
质谱：(ESI,positive):212.03[M+H] +。
第三步反应
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.32克,0.9468毫摩尔)、5-氟-6-苯基-1H-吲哚(0.40克,1.8937毫摩尔)、溴化亚铜二甲基硫醚(20毫克,0.18937毫摩尔)、三苯基膦(25毫克,0.18937毫摩尔)、氢氧化钠(42毫克,1.0415毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌12个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(30 毫升)，短暂搅拌后分液，有机相用盐水洗(20毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1)，纯化，得到淡棕色粉未物质0.11克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(5-氟-6-苯基-1H-吲哚-1-基)-2-甲基丙酰胺。产率25％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H,NH),8.26(s,1H,ArH),8.14-8.08(m,2H,ArH),7.77(d,J＝3.2Hz,1H,吲哚-H),7.50(d,J＝11.6Hz,1H),7.42-7.33(m,3H,ArH),7.30(s,1H),7.28(d,J＝7.2Hz,1H),7.13(d,J＝6.4Hz,1H),6.62(d,J＝2.8Hz,1H,吲哚-H),1.89(s,6H,2xCH 3)。
质谱：(ESI,Negative):464.36[M-H] -。
实施例3
N-(4-氰基-3-三氟甲基)苯基-2-(5-氟-1H-吲哚-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000041
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.20克,0.5968毫摩尔)、5-氟-1H-吲哚(0.16克,1.1963毫摩尔)、溴化亚铜二甲基硫醚(12.3毫克,0.05868毫摩尔)、三苯基膦(15.7毫克,0.05968毫摩尔)、氢氧化钠(23.9毫克,0.5968毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌12个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(20毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1)，纯化，得到淡棕色粉未物质0.13克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(5-氟-1H-吲哚-1-基)-2-甲基丙酰胺。产率56％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.29(s,1H,NH),8.22(d,J＝2.0Hz,1H,ArH),8.19(dd,J＝8.4Hz,J＝2.0Hz,1H,ArH),8.09(d,J＝8.4Hz,1H,ArH),7.71(d,J＝3.6Hz,1H,吲哚-H),7.37(dd,J＝9.6Hz,J＝2.8Hz,1H),7.12(dd,J＝9.2Hz,J＝4.0Hz,1H),6.95(dt,J＝9.2Hz,J＝2.4Hz,1H),6.57(d,J＝3.6Hz,1H,吲哚-H),1.82(s,6H,2xCH 3)。
质谱：(ESI,Negative):388.27[M-H] -。
实施例4
N-(4-氰基-3-三氟甲基)苯基-2-(4-氟-1H-吲哚-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000042
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.20克,0.5968毫摩尔)、4-氟-1H-吲哚(0.16克,1.1963毫摩尔)、溴化亚铜二甲基硫醚(12.3毫克,0.05868毫摩尔)、三苯基膦(15.7毫克,0.05968毫摩尔)、氢氧化钠(23.9毫克,0.5968毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌过夜。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(20毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1)，纯化，得到黄色粉未物质0.11克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(4-氟-1H-吲哚-1-基)-2-甲基丙酰胺。产率47.3％。
核磁共振谱： 1H NMR(400MHz,CDCl 3)δ7.90(s,1H,ArH),7.72(d,J＝8.4Hz,1H,ArH),7.50(br s,1H,NH),7.38(d,J＝3.2Hz,1H,吲哚-H),7.28(m,1H,ArH),7.10(d,J＝8.4Hz,1H),6.99(dd,J＝9.2Hz,J＝2.0Hz,1H),6.77(dd,J＝9.2Hz,J＝2.0Hz,1H),6.74(d,J＝2.8Hz,1H,吲哚-H),1.93(s,6H,2xCH 3)。
质谱：(ESI,Negative):388.26[M-H] -。
实施例5
N-(4-氰基-3-三氟甲基)苯基-2-(6-氟-1H-吲哚-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000043
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.20克,0.5968毫摩尔)、6-氟-1H-吲哚(0.16克,1.1963毫摩尔)、溴化亚铜二甲基硫醚(12.3毫克,0.05868毫摩尔)、三苯基膦(15.7毫克,0.05968毫摩尔)、氢氧化钠(23.9毫克,0.5968毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌过夜。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(30毫升)， 短暂搅拌后分液，有机相用盐水洗(20毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1)，纯化，得到黄色粉未物质0.12克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(6-氟-1H-吲哚-1-基)-2-甲基丙酰胺。产率51.6％。
核磁共振谱： 1H NMR(400MHz,CDCl 3)δ7.87(d,J＝1.6Hz,1H,ArH),7.77(d,J＝8.4Hz,1H,ArH),7.61(dd,J＝8.4Hz,J＝1.6Hz,1H,ArH),7.51(br s,1H,NH),7.35(d,J＝3.2Hz,1H,吲哚-H),7.11(dd,J＝8.4H,J＝4.0Hz,1H,ArH),7.03(dd,J＝10.0Hz,J＝2.0Hz,1H),6.84(dd,J＝8.8Hz,J＝2.2Hz,1H),6.65(d,J＝3.0Hz,1H,吲哚-H),1.95(s,6H,2xCH 3)。
质谱：(ESI,Negative):388.30[M-H] -。
实施例6
N-(4-氰基-3-三氟甲基)苯基-2-(5-硝基-1H-吲哚-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000044
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.20克,0.5968毫摩尔)、5-硝基-1H-吲哚(0.194克,1.1963毫摩尔)、溴化亚铜二甲基硫醚(12.3毫克,0.05868毫摩尔)、三苯基膦(15.7毫克,0.05968毫摩尔)、氢氧化钠(24毫克,0.5968毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌过夜。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(20毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为二氯甲烷:乙酸乙酯＝9:1)，纯化，得到淡棕色粉未物质0.10克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(5-硝基-1H-吲哚-1-基)-2-甲基丙酰胺。产率40.2％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.45(s,1H,NH),8.24(s,1H,ArH),8.19(d,J＝8.4Hz,1H,ArH),8.09(d,J＝8.4Hz,1H,ArH),7.85-7.81(m,3H),7.50(d,J＝8.8Hz,1H),6.70(d,J＝3.2Hz,1H,吲哚-H),1.90(s,6H,2xCH 3)。
质谱：(ESI,Negative):415.29[M-H] -。
实施例7
N-(4-氰基-3-三氟甲基)苯基-2-(5-氯-1H-吲哚-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000045
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.20克,0.5968毫摩尔)、5-氯-1H-吲哚(0.181克,1.1963毫摩尔)、溴化亚铜二甲基硫醚(12.3毫克,0.05868毫摩尔)、三苯基膦(15.7毫克,0.05968毫摩尔)、氢氧化钠(24毫克,0.5968毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌过夜。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(20毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1)，纯化，得到黄色粉未物质0.13克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(5-氯-1H-吲哚-1-基)-2-甲基丙酰胺。产率53.7％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.36(s,1H,NH),8.21(d，J＝2.0Hz,1H,ArH),8.18(dd,J＝8.4Hz,J＝2.0Hz,1H,ArH),8.07(d,J＝8.4Hz,1H,ArH),7.73(d,J＝3.2Hz,1H,吲哚-H),7.41(s,1H),7.11-7.08(m,2H),6.64(d,J＝3.2Hz,1H,吲哚-H),1.84(s,6H,2xCH 3)。
质谱：(ESI,Negative):403.12[M-H] -。
实施例8
N-(4-氰基-3-三氟甲基)苯基-2-(5-三氟甲基-1H-吲哚-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000046
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.20克,0.5968毫摩尔)、5-三氟甲基-1H-吲哚(0.22克,1.1963毫摩尔)、溴化亚铜二甲基硫醚(12.3毫克,0.05868毫摩尔)、三苯基膦(15.7毫克,0.05968毫摩尔)、氢氧化钠(24毫克,0.5968毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌过夜。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(20毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1)，纯化，得到黄色粉未物 质0.15克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(5-三氟甲基-1H-吲哚-1-基)-2-甲基丙酰胺。产率57％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H,NH),8.25(d，J＝1.6Hz,1H,ArH),8.17(dd,J＝8.4Hz,J＝1.6Hz,1H,ArH),8.10(d,J＝8.4Hz,1H,ArH),7.78(d,J＝3.2Hz,1H,吲哚-H),7.40(m,1H),7.12-7.07(m,2H),6.62(d,J＝3.2Hz,1H,吲哚-H),1.87(s,6H,2xCH 3)。
质谱：(ESI,Negative):438.25[M-H] -。
实施例9
N-(4-氰基-3-三氟甲基)苯基-2-(5-氰基-1H-吲哚-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000047
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.20克,0.5968毫摩尔)、5-氰基-1H-吲哚(0.17克,1.1963毫摩尔)、溴化亚铜二甲基硫醚(12.3毫克,0.05868毫摩尔)、三苯基膦(15.7毫克,0.05968毫摩尔)、氢氧化钠(24毫克,0.5968毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌过夜。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(20毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1)，纯化，得到黄色粉未物质90毫克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(5-氰基-1H-吲哚-1-基)-2-甲基丙酰胺。产率38％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.37(s,1H,NH),8.27(s,1H,ArH),8.19(d,J＝8.4Hz,1H,ArH),8.05(d,J＝8.4Hz,1H,ArH),7.78(d,J＝3.2Hz,1H,吲哚-H),7.51(d,J＝8.6Hz,1H),7.32(d,J＝8.6Hz,1H),6.60(d,J＝3.2Hz,1H,吲哚-H),1.85(s,6H,2xCH 3)。
质谱：(ESI,Negative):395.20[M-H] -。
实施例10
N-(4-氰基-3-三氟甲基)苯基-2-(5-氟-1H-2,3-二氢吲哚-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000048
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.20克,0.5968毫摩尔)、5-氟-1H-2,3-二氢吲哚(0.163克,1.1963毫摩尔)、溴化亚铜二甲基硫醚(12.3毫克,0.05868毫摩尔)、三环己基膦(16.7毫克,0.05968毫摩尔)、磷酸三钾(0.152克,0.7162毫摩尔)、氢氧化钠(24毫克,0.5968毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌过夜。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(20毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为二氯甲烷:乙酸乙酯＝9:1)，纯化，得到黄色粉未物质47毫克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(5-氟-1H-2,3-二氢吲哚-1-基)-2-甲基丙酰胺。产率20％。
核磁共振谱： 1H NMR(400MHz,CDCl 3)δ8.78(s,1H,NH),7.95(d,J＝2.0Hz,1H,ArH),7.60(d,J＝8.4Hz,1H,ArH),7.41(d,J＝8.4Hz,1H,ArH),6.85(m,1H),6.41-6.37(m,2H),3.36-3.33(m,1H),3.10-3.04(m,2H),2.98-2.95(m,1M),1.87(s,6H,2xCH 3)。
质谱：(ESI,Negative):390.29[M-H] -。
实施例11
N-(4-氰基-3-三氟甲基)苯基-2-(5,6-二氟-1H-2,3-二氢吲哚-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000049
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.20克,0.5968毫摩尔)、5,6-二氟-1H-2,3-二氢吲哚(0.185克,1.1963毫摩尔)、溴化亚铜二甲基硫醚(12.3毫克,0.05868毫摩尔)、三环己基膦(16.7毫克,0.05968毫摩尔)、磷酸三钾(0.152克,0.7162毫摩尔)、氢氧化钠(24毫克,0.5968毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌过夜。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗 (20毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为二氯甲烷:乙酸乙酯＝9:1)，纯化，得到黄色粉未物质54毫克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(5,6-二氟-1H-2,3-二氢吲哚-1-基)-2-甲基丙酰胺。产率22％。
核磁共振谱： 1H NMR(400MHz,CDCl 3)δ9.05(br s,1H,NH),8.05(d,J＝2.0Hz,1H,ArH),7.91(dd,J＝8.4Hz,J＝2.0Hz,1H,ArH),7.64(d,J＝8.4Hz,1H,ArH),6.68(t,J＝8.8Hz,1H),6.39(m,1H),3.42-3.37(m,2H),3.02-2.94(m,2H),1.88(s,6H,2xCH 3)。
质谱：(ESI,Negative):408.28[M-H] -。
实施例12
N-(3-氯-4-氰基)苯基-2-(5-氟-1H-吲哚-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000050
第一步反应
把二氯亚砜(2.62毫升，35.93毫摩尔,1.2eq)逐滴加入到2-溴-2-甲基丙酸(5.00克，29.94毫摩尔)在30毫升无水四氢呋喃的溶液中，滴加时的温度控制在0-12℃，用时间10分钟。将所得的混合物在相同条件下搅拌2小时。内温调整到-5℃左右，向反应的混合物缓慢加入三乙基氨(Et 3N)(5.42毫升,38.92mmol,1.3eq),加料过程中内温低于12℃。在相同的反应条件搅拌20分钟。随后向其中逐滴加入3-氯-4-氰基-苯胺(4.57克，29.94毫摩尔)在30mL无水四氢呋喃中的溶液，将所得混合物于50℃搅拌两个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(50毫升)和乙酸乙酯(50毫升)，短暂搅拌后分液，有机相用盐水洗(30毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为二氯甲烷:乙酸乙酯＝19:1)，纯化，得到淡黄色粉未物质6.77克，经鉴定为2-溴-N-(3-氯-4-氰基-苯基)-2-甲基丙酰胺。产率75％,HPLC(流动相为水和乙氰)纯度99％(254nm)。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H,NH),8.43(s,1H,ArH),8.34(d,J＝8.6Hz,1H,ArH),8.28(d,J＝8.6Hz,1H,ArH),2.05(s,6H,2xCH 3)。
质谱：(ESI,Positive):301.02[M+H] +。
第二步反应
在100mL园底烧瓶中加入2-溴-N-(3-氯-4-氰基-苯基)-2-甲基丙酰胺(0.30克,0.9948毫摩尔)、(5-氟-苯基)-1H-吲哚(0.269克,1.9896毫摩尔)、溴化亚铜二甲基硫醚(20.5毫克,0.0994毫摩尔)、三苯基膦(26.1毫克,0.09948毫摩尔)、磷酸三钾(0.25克,1.1938毫摩尔)、氢氧化钠(44毫克,0.56毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌14个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(20毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为二氯甲烷:乙酸乙酯＝19:1至9:1)，纯化，得到黄色粉未物质0.145克，经鉴定为N-(3-氯-4-氰基)苯基-2-(5-氟-1H-吲哚-1-基)-2-甲基丙酰胺。产率41％。
核磁共振谱： 1H NMR(400MHz,CDCl 3)δ8.60(br s,1H,NH),7.79(d,J＝2.0Hz,1H,ArH),7.52(d,J＝8.4Hz,1H,ArH),7.38-7.26(m,2H),7.22-7.18(m,3H),6.61(d,J＝3.2Hz,1H,吲哚-H),1.90(s,6H,2xCH 3)。
质谱：(ESI,Negative):354.02[M-H] -。
实施例13
N-(4-氰基-3-三氟甲基)苯基-2-[3-氟-4-(4-氟苯基)-1H-吡唑-1-基]-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000051
第一步反应
同实施例1。
第二步反应
在100mL园底烧瓶中加入3-氟-4-溴-1H-吡唑(2.00克,12.124毫摩尔)、4-氟-苯硼酸(2.04克,14.549毫摩尔)、乙酸钯(II)(54毫克,0.2424毫摩尔)、三苯基膦(0.128克,0.483毫摩尔)、碳酸钾(3.36克，24.248毫摩尔)，20mL乙嗪和10mL水作为溶剂。将所得混合物加热至回流，在氩气保护下搅拌3-4个小时。薄层色谱法确定反应完成后，然后加入水(30毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(30毫升)、硫酸镁干燥、过滤、 将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1至1：1)，纯化，得到淡黄色粉未物质0.66克，经鉴定为3-氟-4-(4-氟苯基)-1H-吡唑。产率约为30％。
质谱：(ESI,ositive):181.07[M+H] +。
第三步反应
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.40克,1.1936毫摩尔)、3-氟-4-(4-氟苯基)-1H-吡唑(0.43克,2.38727毫摩尔)、溴化亚铜二甲基硫醚(25毫克,0.11936毫摩尔)、三苯基膦(31毫克,0.11936毫摩尔)、磷酸三钾(0.304克,1.4323毫摩尔)、氢氧化钠(53毫克,1.3130毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌12个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝3:1至2：1)，纯化，得到淡黄色粉未物质0.26克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-[3-氟-4-(4-氟苯基)-1H-吡唑-1-基]-2-甲基丙酰胺。产率50％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.14(s,1H,NH),8.33(d,J＝1.6Hz,1H,ArH),8.21(dd,J＝8.2Hz,J＝1.6Hz,1H,ArH),8.11(d,J＝8.2Hz,1H,ArH),8.05(d,J＝3.0Hz,1H,吡唑-H),7.86-7.82(m,2H),7.25-7.21(m,2H),1.86(s,6H,2xCH 3)。
质谱：(ESI,Negative):433.27[M-H] -。
实施例14
N-(4-氰基-3-三氟甲基)苯基-2-[4-(4-氟苯基)-1H-吡唑-1-基]-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000052
第一步反应
同实施例1。
第二步反应
在100mL园底烧瓶中加入4-溴-1H-吡唑(1.00克,6.8041毫摩尔)、4-氟-苯硼酸(1.14克,8.1649毫摩尔)、乙酸钯(II)(30毫克,0.1361毫摩尔)、三苯基膦(71.4毫克,0.2722毫摩尔)、 碳酸钾(1.88克，13.6082毫摩尔)，20mL乙嗪和10mL水作为溶剂。将所得混合物加热至回流，在氩气保护下搅拌3-4个小时。薄层色谱法确定反应完成后，然后加入水(30毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(30毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1至1：1)，纯化，得到淡黄色粉未物质0.55克，经鉴定为4-(4-氟苯基)-1H-吡唑。产率约为50％。
质谱：(ESI,positive):163.02[M+H] +。
第三步反应
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.40克,1.1936毫摩尔)、4-(4-氟苯基)-1H-吡唑(0.39克,2.38727毫摩尔)、溴化亚铜二甲基硫醚(25毫克,0.11936毫摩尔)、三苯基膦(31毫克,0.11936毫摩尔)、磷酸三钾(0.304克,1.4323毫摩尔)、氢氧化钠(53毫克,1.3130毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌12个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝3:1至2：1)，纯化，得到白色粉未物质0.28克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-[4-(4-氟苯基)-1H-吡唑-1-基]-2-甲基丙酰胺。产率56.4％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.12(s,1H,NH),8.31(d,J＝2.0Hz,1H,ArH),8.18(dd,J＝8.4Hz,J＝2.0Hz,1H,ArH),8.10(d,J＝8.4Hz,1H,ArH),8.03(d,J＝3.0Hz,1H,吡唑-H),7.84-7.80(m,2H),7.23-7.19(m,2H),1.86(s,6H,2xCH 3)。
质谱：(ESI,Negative):415.27[M-H] -。
实施例15
N-(4-氰基-3-三氟甲基)苯基-2-(4-氟-1H-吡唑-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000053
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.40克,1.1936毫摩尔)、4-氟-1H-吡唑(0.21克,2.38727毫摩尔)、溴化亚铜二甲基硫醚(25毫克,0.11936毫摩尔)、三苯基膦(31毫克,0.11936毫摩尔)、磷酸三钾(0.304克,1.4323毫摩尔)、氢氧化钠(53毫克,1.3130毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃， 在氩气保护下搅拌12个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝3:1至2：1)，纯化，得到白色粉未物质0.15克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(4-氟-1H-吡唑-1-基)-2-甲基丙酰胺。产率37％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.05(s,1H,NH),8.27(d,J＝2.0Hz,1H,ArH),8.16(dd,J＝8.4Hz,J＝2.0Hz,1H,ArH),8.14(d,J＝4.4Hz,1H,吡唑-H),8.10(d,J＝8.4Hz,1H,ArH),7.57(d,J＝4.0Hz,1H,吡唑-H),1.77(s,6H,2xCH 3)。
质谱：(ESI,Negative):339.26[M-H] -。
实施例16
N-(4-氰基-3-三氟甲基)苯基-2-(3-氟-1H-吡唑-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000054
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.40克,1.1936毫摩尔)、3-氟-1H-吡唑(0.21克,2.38727毫摩尔)、溴化亚铜二甲基硫醚(25毫克,0.11936毫摩尔)、三苯基膦(31毫克,0.11936毫摩尔)、磷酸三钾(0.304克,1.4323毫摩尔)、氢氧化钠(53毫克,1.3130毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌12个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝3:1至2：1)，纯化，得到白色粉未物质0.12克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(3-氟-1H-吡唑-1-基)-2-甲基丙酰胺。产率30％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.05(s,1H,NH),8.27(d,J＝2.0Hz,1H,ArH),8.16(dd,J＝8.4Hz,J＝2.0Hz,1H,ArH),8.10(d,J＝8.4Hz,1H,ArH),7.95(d,J＝3.0Hz,1H,吡唑-H),6.11(m,1H),1.79(s,6H,2xCH 3)。
质谱：(ESI,Negative):339.25[M-H] -。
实施例17
N-(4-氰基-3-三氟甲基)苯基-2-(4-氯-1H-吡唑-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000055
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.40克,1.1936毫摩尔)、4-氯-1H-吡唑(0.245克,2.38727毫摩尔)、溴化亚铜二甲基硫醚(25毫克,0.11936毫摩尔)、三苯基膦(31毫克,0.11936毫摩尔)、磷酸三钾(0.304克,1.4323毫摩尔)、氢氧化钠(53毫克,1.3130毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌14个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝3:1至2：1)，纯化，得到白色粉未物质0.233克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(4-氯-1H-吡唑-1-基)-2-甲基丙酰胺。产率55％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.04(s,1H,NH),8.26(s,1H,ArH),8.23(s,1H,吡唑-H),8.15(d,J＝8.6Hz,1H,ArH),8.10(d,J＝8.6Hz,1H,ArH),7.36(s,1H,吡唑-H),1.79(s,6H,2xCH 3)。
质谱：(ESI,Negative):355.08[M-H] -。
实施例18
N-(4-氰基-3-三氟甲基)苯基-2-(4-三氟甲基-1H-吡唑-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000056
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.40克,1.1936毫摩尔)、4-三氟甲基-1H-吡唑(0.325克,2.38727毫摩尔)、溴化亚铜二甲基硫醚(25毫克,0.11936毫摩尔)、三苯基膦(31毫克,0.11936毫摩尔)、磷酸三钾(0.304克,1.4323毫摩尔)、氢氧化钠(53毫克,1.3130毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌过夜。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁 干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1)，纯化，得到白色粉未物质0.144克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(4-三氟甲基-1H-吡唑-1-基)-2-甲基丙酰胺。产率31％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.04(s,1H,NH),8.42(s,1H,吡唑-H),8.25(d,J＝2.0Hz,1H,ArH),8.17(dd,J＝8.2Hz,J＝2.0Hz,1H,ArH),8.11(d,J＝8.2Hz,1H,ArH),7.90(s,1H,吡唑-H),1.85(s,6H,2xCH 3)。
质谱：(ESI,Negative):389.21[M-H] -。
实施例19
N-(4-氰基-3-三氟甲基)苯基-2-(4-硝基-1H-吡唑-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000057
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.40克,1.1936毫摩尔)、4-硝基-1H-吡唑(0.27克,2.38727毫摩尔)、溴化亚铜二甲基硫醚(25毫克,0.11936毫摩尔)、三苯基膦(31毫克,0.11936毫摩尔)、磷酸三钾(0.304克,1.4323毫摩尔)、氢氧化钠(53毫克,1.3130毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌过夜。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1)，纯化，得到淡黄色粉未物质0.17克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(4-硝基-1H-吡唑-1-基)-2-甲基丙酰胺。产率39％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.02(s,1H,NH),8.88(s,1H,吡唑-H),8.34(s,1H,吡唑-H),8.25(d,J＝1.2Hz,1H,ArH),8.16(dd,J＝8.6Hz,J＝1.2Hz,1H,ArH),8.11(d,J＝8.6Hz,1H,ArH),1.84(s,6H,2xCH 3)。
质谱：(ESI,Negative):366.19[M-H] -。
实施例20
N-(4-氰基-3-三氟甲基)苯基-2-(4-氰基-1H-吡唑-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000058
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.40克,1.1936毫摩尔)、4-氰基-1H-吡唑(0.222克,2.38727毫摩尔)、溴化亚铜二甲基硫醚(25毫克,0.11936毫摩尔)、三苯基膦(31毫克,0.11936毫摩尔)、磷酸三钾(0.304克,1.4323毫摩尔)、氢氧化钠(53毫克,1.3130毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌过夜。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1至1：1)，纯化，得到淡黄色粉未物质0.182克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-2-(4-氰基-1H-吡唑-1-基)-2-甲基丙酰胺。产率45％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.01(s,1H,NH),8.63(s,1H,吡唑-H),8.25(d,J＝1.2Hz,1H,ArH),8.14(dd,J＝8.8Hz,J＝1.2Hz,1H,ArH),8.13(s,1H,吡唑-H),8.10(d,J＝8.8Hz,1H,ArH),1.82(s,6H,2xCH 3)。
质谱：(ESI,Negative):346.23[M-H] -。
实施例21
1-{1-[(4-氰基-3-三氟甲基-苯基)-氨基]-2-甲基-1-氧代丙-2-基}-N-甲基-1H-吡唑-4-甲酰胺的制备
Figure PCTCN2019106287-appb-000059
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.40克,1.1936毫摩尔)、1H-吡唑-4-N-甲基甲酰胺(0.30克,2.38727毫摩尔)、溴化亚铜二甲基硫醚(25毫克,0.11936毫摩尔)、三苯基膦(31毫克,0.11936毫摩尔)、磷酸三钾(0.304克,1.4323毫摩尔)、氢氧化钠(53毫克,1.3130毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌过夜。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后 加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝3：1至2：1)，纯化，得到淡黄色粉未物质45毫克，经鉴定为1-{1-[(4-氰基-3-三氟甲基-苯基)-氨基]-2-甲基-1-氧代丙-2-基}-N-甲基-1H-吡唑-4-甲酰胺。产率10％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.03(s,1H,NH),8.52-8.48(m,2H,NH+吡唑-H),8.25(d,J＝1.2Hz,1H,ArH),8.15(dd,J＝8.0Hz,J＝1.2Hz,1H,ArH),8.09(d,J＝8.0Hz,1H,ArH),8.02(s,1H,吡唑-H),1.82(s,6H,2xCH 3),1.37(s,3H,CH 3)。
质谱：(ESI,Negative):378.31[M-H] -。
实施例22
N-(6-氰基-5-三氟甲基-吡啶-3-基)-2-(4-氟-1H-吡唑-1-基)-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000060
第一步反应
把二氯亚砜(2.62毫升，35.93毫摩尔)逐滴加入到2-溴-2-甲基丙酸(5.00克，29.94毫摩尔)在30毫升无水四氢呋喃的溶液中，滴加时的温度控制在0-12℃，用时间10分钟。将所得的混合物在相同条件下搅拌2小时。内温调整到-5℃左右，向反应的混合物缓慢加入三乙基氨(Et 3N)(5.42毫升,38.92mmol),加料过程中内温低于12℃。在相同的反应条件搅拌20分钟。随后向其中逐滴加入5-氨基-3-三氟甲基-2-氰基吡啶(5.60克，29.94毫摩尔)在20mL无水四氢呋喃中的溶液，将所得混合物于50℃搅拌两个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(50毫升)和乙酸乙酯(50毫升)，短暂搅拌后分液，有机相用盐水洗(30毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为二氯甲烷:乙酸乙酯＝9:1)，纯化，得到8.0克2-溴-N-(6-氰基-5-三氟甲基-吡啶-3-基)-2-甲基丙酰胺。产率80％,HPLC(流动相为水和乙氰)纯度99％(254nm)。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.73(s,1H,NH),9.39(d,J＝2.0Hz,1H,ArH), 8.81(d,J＝2.0Hz,1H,ArH),2.03(s,6H,2xCH 3)。
质谱：(ESI,Positive):335.9951[M+H] +。
第二步反应
在100mL园底烧瓶中加入2-溴-N-(6-氰基-5-三氟甲基-吡啶-3-基)-2-甲基丙酰胺(0.30克,0.8926毫摩尔)、4-氟-1H-吡唑(0.154克,1.7852毫摩尔)、溴化亚铜二甲基硫醚(18.3毫克,0.08926毫摩尔)、三苯基膦(23.4毫克,0.08926毫摩尔)、磷酸三钾(0.227克,1.0711毫摩尔)、氢氧化钠(39.3毫克,0.9818毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌15个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为二氯甲烷:乙酸乙酯＝9:1)，纯化，得到淡黄色粉未物质0.11克，经鉴定为N-(6-氰基-5-三氟甲基-吡啶-3-基)-2-(4-氟-1H-吡唑-1-基)-2-甲基丙酰胺。产率36％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.29(s,1H,NH),9.12(d,J＝2.0Hz,1H,ArH),8.47(d,J＝2.0Hz,1H,ArH),8.15(d,J＝4.8Hz,1H,吡唑-H),7.56(d,J＝4.0Hz,1H,吡唑-H),1.79(s,6H,2xCH 3)。
质谱：(ESI,Negative):340.19[M-H] -。
实施例23
N-(4-氰基-3-三氟甲基)苯基-1-(4-氟-1H-吡唑-1-基)-环丁烷甲酰胺的制备
Figure PCTCN2019106287-appb-000061
第一步反应
把二氯亚砜(2.45毫升，33.52毫摩尔)逐滴加入到1-溴-环丁烷甲酸(5.00克，27.93毫摩尔)在30毫升无水四氢呋喃的溶液中，滴加时的温度控制在0-12℃，用时间10分钟。将所得的混合物在相同条件下搅拌2小时。内温调整到-5℃左右，向反应的混合物缓慢加入 三乙基氨(Et 3N)(5.06毫升,36.31mmol),加料过程中内温低于12℃。在相同的反应条件搅拌20分钟。随后向其中逐滴加入4–氰基-3-三氟甲基-苯胺(5.20克，27.93毫摩尔)在20mL无水四氢呋喃中的溶液，将所得混合物于50℃搅拌三个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(50毫升)和乙酸乙酯(50毫升)，短暂搅拌后分液，有机相用盐水洗(30毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1)，纯化，得到黄色粉未物质7.95克，经鉴定为1-溴-N-(4-氰基-3-三氟甲基-苯基)-环丁烷甲酰胺。产率82％,HPLC(流动相为水和乙氰)纯度98.5％(254nm)。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.5(s,1H,NH),8.36(d,J＝1.6Hz,1H,ArH),8.23(dd,J＝8.4Hz,J＝1.6Hz,1H,ArH),8.13(d,J＝8.4Hz,1H,ArH),2.90-2.86(m,2H),2.65-2.60(m,2H),2.03-1.92(m,2H)。
质谱：(ESI,Positive):347.0002[M+H] +。
第二步反应
在100mL园底烧瓶中加入1-溴-N-(4-氰基-3-三氟甲基-苯基)-环丁烷甲酰胺(0.30克,0.8642毫摩尔)、4-氟-1H-吡唑(0.149克,1.7285毫摩尔)、溴化亚铜二甲基硫醚(17.8毫克,0.08642毫摩尔)、三苯基膦(22.7毫克,0.08642毫摩尔)、磷酸三钾(0.22克,1.0366毫摩尔)、氢氧化钠(38毫克,0.9507毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌15个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝2：1)，纯化，得到淡黄色粉未物质0.106克，经鉴定为N-(4-氰基-3-三氟甲基)苯基-1-(4-氟-1H-吡唑-1-基)-环丁烷甲酰胺。产率35％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.02(s,1H,NH),8.26(d,J＝2.0Hz,1H,ArH),8.15-8.15(m,2H,ArH+吡唑-H),8.11(d,J＝8.4Hz,1H,ArH),7.55(d,J＝4.0Hz,1H,吡唑-H),2.89-2.85(m,2H),2.65-2.59(m,2H),2.02-1.91(m,2H),1.78(s,6H,2xCH 3)。
质谱：(ESI,Negative):351.19[M-H] -。
实施例24
N-(6-氰基-5-三氟甲基-吡啶-3-基)-1-(4-氟-1H-吡唑-1-基)-环丁烷甲酰胺的制备
Figure PCTCN2019106287-appb-000062
第一步反应
把二氯亚砜(2.45毫升，33.52毫摩尔)逐滴加入到1-溴-环丁烷甲酸(5.00克，27.93毫摩尔)在30毫升无水四氢呋喃的溶液中，滴加时的温度控制在0-12℃，用时间10分钟。将所得的混合物在相同条件下搅拌2小时。内温调整到-5℃左右，向反应的混合物缓慢加入三乙基氨(Et 3N)(5.06毫升,36.31mmol),加料过程中内温低于12℃。在相同的反应条件搅拌20分钟。随后向其中逐滴加入5-氨基-3-三氟甲基-2-氰基吡啶(5.23克，27.93毫摩尔)在20mL无水四氢呋喃中的溶液，将所得混合物于50℃搅拌三个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(50毫升)和乙酸乙酯(50毫升)，短暂搅拌后分液，有机相用盐水洗(30毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为二氯甲烷:乙酸乙酯＝9:1)，纯化，得到黄色粉未物质7.70克，经鉴定为1-溴-N-(6-氰基-5-三氟甲基-吡啶-3-基)-环丁烷甲酰胺。产率75％,HPLC(流动相为水和乙氰)纯度98.5％(254nm)。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.77(s,1H,NH),9.40(d,J＝2.0Hz,1H,ArH),8.85(d,J＝2.0Hz,1H,ArH),2.82-2.78(m,2H),2.59-2.53(m,2H),2.04-1.95(m,2H)。
质谱：(ESI,Positive):347.09951[M+H] +。
第二步反应
在100mL园底烧瓶中加入1-溴-N-(6-氰基-5-三氟甲基-吡啶-3-基)-环丁烷甲酰胺(0.30克,0.8618毫摩尔)、4-氟-1H-吡唑(0.148克,1.7236毫摩尔)、溴化亚铜二甲基硫醚(17.7毫克,0.08618毫摩尔)、三苯基膦(22.6毫克,0.08618毫摩尔)、磷酸三钾(0.22克,1.0341毫摩尔)、氢氧化钠(38毫克,0.9480毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌15个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为二氯甲烷:乙酸乙酯＝9:1)，纯化，得到黄色粉未物质82毫克，经鉴定为N-(4-氰基-3-三氟甲基)苯 基-1-(4-氟-1H-吡唑-1-基)-环丁烷甲酰胺。产率27％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.25(s,1H,NH),9.10(d,J＝2.0Hz,1H,ArH),8.72(d,J＝2.0Hz,1H,ArH),8.13(d,J＝4.8Hz,1H,吡唑-H),7.51(d,J＝4.0Hz,1H,吡唑-H),2.91-2.86(m,2H),2.67-2.60(m,2H),2.05-1.93(m,2H),1.89(s,6H,2xCH 3)。
质谱：(ESI,Negative):352.21[M-H] -。
实施例25
2-(4-溴-3-氟-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000063
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.40克,1.1936毫摩尔)、4-溴-3-氟-1H-吡唑(0.394克,2.38727毫摩尔)、溴化亚铜二甲基硫醚(25毫克,0.11936毫摩尔)、三苯基膦(31毫克,0.11936毫摩尔)、磷酸三钾(0.304克,1.4323毫摩尔)、氢氧化钠(53毫克,1.3130毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌14个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝3:1至2：1)，纯化，得到类白色粉未物质0.24克，经鉴定为2-(4-溴-3-氟-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2-甲基丙酰胺。产率48％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.04(s,1H,NH),8.25(d,J＝2.0Hz,1H,ArH),8.16-8.14(m,2H,ArH+吡唑-H),8.10(d,J＝8.4Hz,1H,ArH),1.84(s,6H,2xCH 3)。
质谱：(ESI,Negative):417.02[M-H] -。
实施例26
2-(3,4-二氟-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000064
在100mL园底烧瓶中加入2-(4-溴-3-氟-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2- 甲基丙酰胺(0.20克,0.4771毫摩尔)，4mL无水四氢呋喃作为溶剂，在氩气保护下搅拌5分钟,然后用干冰丙酮浴将反应液冷却至-78℃。将2.5摩尔的正丁基锂溶液(0.382毫升,0.9542毫摩尔)加入到上述反应液中，将所得的混合物在相同条件下搅拌15分钟。再将N-氟代双苯磺酰胺(0.15克，0.4771毫摩尔)在2.0毫升无水四氢呋喃中的溶液加入到上述反应液中。将所得的反应混合物逐渐回温至室温，在氩气保护下搅拌15个小时。薄层色谱法确定反应完成后，然后加入盐水(20毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为二氯甲烷:乙酸乙酯＝9:1)，纯化，得到淡黄色粉未物质43毫克，经鉴定为2-(3,4-二氟-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2-甲基丙酰胺。产率25％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.36(s,1H,NH),8.43(d,J＝2.0Hz,1H,ArH),8.22(dd,J＝8.0Hz,J＝2.0Hz,1H,ArH),8.10(d,J＝8.0Hz,1H,ArH),7.85(m,1H,吡唑-H),1.90(s,6H,2xCH 3)。
质谱：(ESI,Negative):357.16[M-H] -。
实施例27
2-(3-氯-4-甲基-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000065
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.40克,1.1936毫摩尔)、3-氯-4-甲基-1H-吡唑(0.278克,2.38727毫摩尔)、溴化亚铜二甲基硫醚(25毫克,0.11936毫摩尔)、三苯基膦(31毫克,0.11936毫摩尔)、磷酸三钾(0.304克,1.4323毫摩尔)、氢氧化钠(53毫克,1.3130毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌14个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝3:1至2：1)，纯化，得到类白色粉未物质0.16克，经鉴定为2-(3-氯-4-甲基-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2-甲基丙酰胺。产率36.4％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.00(s,1H,NH),8.22(d,J＝1.0Hz,1H,ArH),8.13(dd,J＝8.4Hz,1H,ArH),8.10(d,J＝8.4Hz,1H,ArH),7.91(s,1H,吡唑-H),1.91(s,3H,CH 3),1.82(s,6H,2xCH 3)。
质谱：(ESI,Negative):369.12[M-H] -。
实施例28
2-(3-溴-4-氯-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000066
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.40克,1.1936毫摩尔)、3-溴-4-氯-1H-吡唑(0.433克,2.38727毫摩尔)、溴化亚铜二甲基硫醚(25毫克,0.11936毫摩尔)、三苯基膦(31毫克,0.11936毫摩尔)、磷酸三钾(0.304克,1.4323毫摩尔)、氢氧化钠(53毫克,1.3130毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌14个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝3:1至2：1)，纯化，得到白色粉未物质0.22克，经鉴定为2-(3-溴-4-氯-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2-甲基丙酰胺。产率42.3％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.01(s,1H,NH),8.24-8.21(m,2H,ArH+吡唑-H),8.13(d,J＝8.8Hz,1H,ArH),8.10(d,J＝8.8Hz,1H,ArH),1.81(s,6H,2xCH 3)。
质谱：(ESI,Negative):433.01[M-H] -。
实施例29
2-(3-氟-4-氯-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000067
在100mL园底烧瓶中加入2-(3-溴-4-氯-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2-甲基丙酰胺(0.20克,0.4591毫摩尔)，4mL无水四氢呋喃作为溶剂，在氩气保护下搅拌5分钟,然后用干冰丙酮浴将反应液冷却至-78℃。将2.5摩尔的正丁基锂溶液(0.367毫升,0.9182毫摩尔)加入到上述反应液中，将所得的混合物在相同条件下搅拌15分钟。再将N-氟代双苯磺酰胺(0.145克，0.4591毫摩尔)在2.0毫升无水四氢呋喃中的溶液加入到上述反应液中。 将所得的反应混合物逐渐回温至室温，在氩气保护下搅拌15个小时。薄层色谱法确定反应完成后，加入盐水(20毫升)和乙酸乙酯(30毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为二氯甲烷:乙酸乙酯＝9:1)，纯化，得到黄色粉未物质50毫克，经鉴定为2-(3-氟-4-氯-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2-甲基丙酰胺。产率29％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H,NH),8.44(d,J＝1.6Hz,1H,ArH),8.23(dd,J＝8.2Hz,J＝1.6Hz,1H,ArH),8.11(d,J＝8.2Hz,1H,ArH),7.97(d,J＝3.6Hz,1H,吡唑-H),1.89(s,6H,2xCH 3)。
质谱：(ESI,Negative):373.10[M-H] -。
实施例30
2-(3-氯-4-氰基-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2-甲基丙酰胺的制备
Figure PCTCN2019106287-appb-000068
在100mL园底烧瓶中加入2-溴-N-(4-氰基-3-三氟甲基-苯基)-2-甲基丙酰胺(0.40克,1.1936毫摩尔)、3-氯-4-氰基-1H-吡唑(0.304克,2.38727毫摩尔)、溴化亚铜二甲基硫醚(25毫克,0.11936毫摩尔)、三苯基膦(31毫克,0.11936毫摩尔)、磷酸三钾(0.304克,1.4323毫摩尔)、氢氧化钠(53毫克,1.3130毫摩尔)，10mL无水甲苯作为溶剂。将所得混合物加热至50℃，在氩气保护下搅拌14个小时。薄层色谱法确定反应完成后，反应液冷却至20±5℃，然后加入水(30毫升)和乙酸乙酯(35毫升)，短暂搅拌后分液，有机相用盐水洗(25毫升)、硫酸镁干燥、过滤、将有机相抽干，得到油状物质。硅胶柱层析分离(流动相为己烷：乙酸乙酯＝3:1至2：1)，纯化，得到白色粉未物质0.16克，经鉴定为2-(3-氯-4-氰基-1H-吡唑-1-基)-N-(4-氰基-3-三氟甲基)苯基-2-甲基丙酰胺。产率35％。
核磁共振谱： 1H NMR(400MHz,DMSO-d 6)δ9.99(s,1H,NH),8.69(s,1H,吡唑-H),8.21(s,1H,ArH),8.12(d,J＝8.4Hz,H,ArH),8.10(d,J＝8.4Hz,1H,ArH),1.83(s,6H,2xCH 3)。
质谱：(ESI,Negative):380.15[M-H] -。
II.制剂制备实施例
制剂实施例A：注射剂的制备
(一)配方组成:
Figure PCTCN2019106287-appb-000069
(二)制备方法:
按配方组成，将实施例15化合物、聚山梨醇80和甘露醇，加到4000m1注射用水中，搅拌溶解后，加注射用水至全量5000ml，继续搅拌，通过0.22μm微孔滤膜进行除菌过滤，滤液以每支5m1无菌灌装于5ml安瓶中(规格25mg/支)，封口，灭菌。
制剂实施例B：片剂的制备
(一)配方组成
配方2-1 通式I片剂配方(每1000片用量)
Figure PCTCN2019106287-appb-000070
配方2-2 通式I片剂配方(每1000片用量)
Figure PCTCN2019106287-appb-000071
Figure PCTCN2019106287-appb-000072
配方2-3 通式I片剂配方(每1000片用量)
Figure PCTCN2019106287-appb-000073
(二)制备工艺
将实施例15化合物、乳糖及部分微晶纤维素按200:100:40比例微粉化，按配方比例加入过80目筛的剩余微晶纤维素、预胶化淀粉、微粉硅胶及羧甲基淀粉钠，混合均匀后，加入0.3％HPMC溶液适量，制软材，18目筛制粒，60℃干燥(控制颗粒水分含量在3％左右)，加入过80目筛的硬脂酸镁，与颗粒混匀，16目筛整粒，压片，包装。
III.生物活性检测
试剂与仪器设备：带有放射性标记的二氢睾酮(DHT-d3)和未标记的二氢睾酮(DHT)购于Sigma-Aldrich(St.Louis,MO)。闪烁液(scintillation solution)购于Perkin Elmer Life Sciences(Boston,MA)。羟基磷灰石(Hydroxylapatite)(HAP)悬浮液购于Bio-Rad Laboratories(Hercules,CA)。缓冲液(含有10mM Tris,1.5mM EDTA二钠,0.25M sucrose,10mM钼酸钠和1mM PMSF，pH调至7.4)。羟基磷灰石(HAP)洗液(含有50mM Tris和1mM KH 2PO 4，pH调至7.4)。
在本发明中，通式(I)和(II)N-芳香酰胺化合物生物活性按照下述方法检测。将制备实施例所得到的本发明化合物和对照化合物溶于DMSO中，配制成一定浓度的母液，以DMSO将其稀释成几个浓度梯度，再用缓冲液将各浓度进行稀释(10 -1nM至10 4nM)，4℃冰箱保存直至使用。将雄激素受体(制备于雄性SD大鼠的前列腺，雄性Sprague-Dawley大鼠200-250克)和带有放射性标记的二氢睾酮(DHT-d3，84Ci/mmol)加入到缓冲液中，混和均匀， 配制成反应液，将各化合物浓度梯度稀释液分别加入到反应液中，混和均匀，4℃孵育15小时，使化合物及二氢睾酮与雄激素受体充分反应，加入羟基磷灰石(HAP)悬浮液，混和均匀，4℃孵育10分钟，离心，弃去含有游离二氢睾酮的上清液。与雄激素受体结合的二氢睾酮通过吸附于羟基磷灰石上而保留在沉淀颗粒中，从而达到分离结合与未结合的放射性标记的配体的目的。向沉淀中加入闪烁液(scintillation solution)，混和均匀，用WALLACE MicroBeta Trilux液闪仪(Perkin Elmer)进行放射性强度检测。根据检测到的各浓度梯度的放射性强度数值进行数据处理，得到IC 50和K i值。具体的生物活性(雄激素受体配体与放射性配体竞争结果)见下表：
Figure PCTCN2019106287-appb-000074
Figure PCTCN2019106287-appb-000075
Figure PCTCN2019106287-appb-000076
Figure PCTCN2019106287-appb-000077
Figure PCTCN2019106287-appb-000078
根据测试物与阳性对照组的比较，可以得到以下结论：
实施例1(IC 50＝0.546μM)、实施例2(IC 50＝0.337μM)、实施例3(IC 50＝0.215μM)、实施例4(IC 50＝0.246μM)、实施例5(IC 50＝0.227μM)、实施例6(IC 50＝0.261μM)、实施例7(IC 50＝0.253μM)、实施例8(IC 50＝0.357μM)、实施例9(IC 50＝0.232μM)、实施例10(IC 50＝0.437μM)、、实施例11(IC 50＝0.505μM)、实施例12(IC 50＝0.205μM)和实施例13(IC 50＝0.416μM)对雄激素受体的拮抗作用明显强于比卡鲁胺(IC 50＝0.637μM)阳性对照组。
实施例15(IC 50＝0.125μM)、实施例16(IC 50＝0.147μM)、实施例17(IC 50＝0.116μM)、实施例18(IC 50＝0.168μM)、实施例20(IC 50＝0.107μM)、实施例22(IC 50＝0.073μM)、实施例23(IC 50＝0.115μM)、实施例24(IC 50＝0.068μM)、实施例25(IC 50＝0.091μM)、实施例26(IC 50＝0.075μM)、实施例27(IC 50＝0.133μM)、实施例 28(IC 50＝0.159μM)、实施例29(IC 50＝0.105μM)和实施例30(IC 50＝0.088μM)对雄激素受体的拮抗作用甚至明显强于最新一代抗前列腺癌新药恩杂鲁胺(IC 50＝0.215μM)阳性对照组。
实施例3(K i＝0.367μM)、实施例4(IC 50＝0.491μM)、实施例5(K i＝0.314μM)、实施例6(K i＝0.421μM)、实施例7(K i＝0.295μM)、实施例8(K i＝0.440μM)、实施例9(K i＝0.445μM)、实施例10(K i＝0.387μM)、实施例11(K i＝0.505μM)和实施例12(K i＝0.351μM)对雄激素受体的结合活性作用强于比卡鲁胺(K i＝1.25μM)对照组,更强于恩杂鲁胺(K i＝2.75μM)对照组。
上表中的生物活性测定结果表明,与阳性对照组(比卡鲁胺，和恩杂鲁胺)比较,本发明中的化合物能够更强地与雄激素受体结合，具有更强地抵抗雄激素受体活性。因此，有望开发成比现有药物更安全、有效的新型N-芳香酰胺类抗雄激素药物，并在治疗与雄激素相关疾病的研究中具有重要的价值和地位。
本发明化合物能够单独或作为组合物用于预防或治疗各种与雄激素相关的疾病，如前列腺癌、前列腺增生、乳腺癌、膀胱癌、卵巢癌，还能用于粉刺、多毛、脱发等疾病的预防或治疗。
以上所述仅为本发明的示例性实施方案和实施例，并非因此限制本发明的范围，凡是利用本说明书内容所作的等效结构或等效流程变换，或直接或间接运用在其它相关的技术领域，均同理包括在本发明的范围内。

Claims (19)

  1. 下述通式(I)和(II)N-芳香酰胺化合物或其药学上可接受的盐：
    Figure PCTCN2019106287-appb-100001
    其中R 1和R 2各自独立地为氢原子、氰基、硝基、三氟甲基或卤素；
    R 3和R 4各自独立地为氢原子、C 1-C 6烷基或R 3和R 4与它们连接的碳原子一起构成3-6元环烷基；
    R 5和R 6各自独立地为氢原子、卤素、三氟甲基、氰基、硝基、乙酰基、
    Figure PCTCN2019106287-appb-100002
    N-甲基氨基甲酰基、C 1-C 6烷基、芳香基或取代的芳香基；
    W 1、W 2、W 3、W 4和W 5各自独立地为碳原子或氮原子，且
    在通式(I)中，W 2和W 3之间的化学键为单键或双键，R 5和R 6各自连接在基团
    Figure PCTCN2019106287-appb-100003
    中苯环的任意可连接位置；
    在通式(II)中，W 2和W 3之间的化学键为双键，W 4和W 5之间的化学键为双键，R 5和R 6各自连接在基团
    Figure PCTCN2019106287-appb-100004
    的任意可连接位置。
  2. 根据权利要求1所述的通式(I)N-芳香酰胺化合物或其药学上可接受的盐，所述化合物具有以下化学结构通式(III)：
    Figure PCTCN2019106287-appb-100005
    其中R 1和R 2各自独立地为氢原子、氰基、硝基、三氟甲基或卤素；
    R 3和R 4各自独立地为氢原子、C 1-C 6烷基或R 3和R 4与它们连接的碳原子一起构成3-6元环烷基；
    R 5和R 6各自独立地为氢原子、卤素、三氟甲基、氰基、硝基、乙酰基、
    Figure PCTCN2019106287-appb-100006
    甲基氨基甲酰基、C 1-C 6烷基、芳香基或取代的芳香基；
    W 1为碳原子或氮原子；且
    在通式(III)中，
    Figure PCTCN2019106287-appb-100007
    表示两个端碳原子之间的化学键为单键或双键；
    R 5和R 6各自连接在基团
    Figure PCTCN2019106287-appb-100008
    中苯环的任意可连接位置。
  3. 根据权利要求1所述的通式(II)N-芳香酰胺化合物或其药学上可接受的盐，所述化合物具有以下化学结构通式(IV)：
    Figure PCTCN2019106287-appb-100009
    其中R 1和R 2各自独立地为氢原子、氰基、硝基、三氟甲基或卤素；
    R 3和R 4各自独立地为氢原子、C 1-C 6烷基或R 3和R 4与它们连接的碳原子一起构成3-6元环烷基；
    R 5和R 6各自独立地为氢原子、卤素、三氟甲基、氰基、硝基、乙酰基、
    Figure PCTCN2019106287-appb-100010
    甲基氨基甲酰基、C 1-C 6烷基、芳香基或取代的芳香基；
    W 1为碳原子或氮原子；且
    R 5和R 6各自连接在基团
    Figure PCTCN2019106287-appb-100011
    的任意可连接位置。
  4. 根据权利要求1-3之任一项所述的N-芳香酰胺化合物或其药学上可接受的盐，其特征在于，其光学异构体为消旋、左旋和/或右旋异构体。
  5. 根据权利要求1所述的N-芳香酰胺化合物或其药学上可接受的盐，所述化合物选自下列化合物：
    Figure PCTCN2019106287-appb-100012
    Figure PCTCN2019106287-appb-100013
    Figure PCTCN2019106287-appb-100014
    Figure PCTCN2019106287-appb-100015
    Figure PCTCN2019106287-appb-100016
  6. 根据权利要求1-5之任一项所述的N-芳香酰胺化合物或其药学上可接受的盐的水合物、前药或体内一级和/或二级代谢物。
  7. 权利要求1所述的通式(I)N-芳香酰胺化合物的制备方法，如以下化学反应式所示，所述方法包括以下步骤：
    1)使化合物(V)和化合物(VI)反应得到化合物(VII)；
    2)在催化剂、配体和碱存在的条件下，使化合物(VII)和化合物(VIII)反应生成结构通式(I)所示的目标化合物，
    Figure PCTCN2019106287-appb-100017
    其中化学反应式中所示的R 1、R 2、R 3、R 4、R 5、R 6、W 1、W 2和W 3的定义与权利要求1中的对R 1、R 2、R 3、R 4、R 5、R 6、W 1、W 2和W 3的定义相同。
  8. 权利要求7所述的制备方法，其中所述催化剂为溴化亚铜二甲基硫醚，所述配体为三苯基膦或三环己基膦，所述碱为选自碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、磷酸三钠、磷酸二氢钠、磷酸氢二钠、磷酸三钾、磷酸二氢钾和磷酸氢二钾的弱碱。
  9. 权利要求7所述的制备方法，其中所述催化剂为溴化亚铜二甲基硫醚，所述配体为三苯基膦或三环己基膦，所述碱为选自氢氧化钠和氢氧化钾的强碱。
  10. 权利要求1所述的通式(II)N-芳香酰胺化合物的制备方法，如以下化学反应式所示，所述方法包括以下步骤：
    1)使化合物(V)和化合物(VI)反应得到化合物(VII)；
    2)使化合物(VII)和化合物(IX)反应生成结构通式(II)所示的目标化合物，
    Figure PCTCN2019106287-appb-100018
    其中化学反应式中所示的R 1、R 2、R 3、R 4、R 5、R 6、W 1、W 2、W 3、W 4和W 5的定义与权利要求1中的对R 1、R 2、R 3、R 4、R 5、R 6、W 1、W 2、W 3、W 4和W 5的定义相同。
  11. 权利要求10所述的制备方法，其中所述催化剂为溴化亚铜二甲基硫醚，所述配体 为三苯基膦或三环己基膦，所述碱为选自碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、磷酸三钠、磷酸二氢钠、磷酸氢二钠、磷酸三钾、磷酸二氢钾和磷酸氢二钾的弱碱。
  12. 权利要求10所述的制备方法，其中所述催化剂为溴化亚铜二甲基硫醚，所述配体为三苯基膦或三环己基膦，所述碱为选自氢氧化钠和氢氧化钾的强碱。
  13. 一种药物组合物，所述组合物含有权利要求1-5之任一项所述的N-芳香酰胺化合物或其药学上可接受的盐。
  14. 一种药物制剂，其包含药学上可接受的载体或稀释剂和权利要求1-5之任一项所述的N-芳香酰胺化合物或其药学上可接受的盐。
  15. 权利要求1-5之任一项所述的N-芳香酰胺化合物或其药学上可接受的盐在制备用于预防或治疗与雄激素相关的疾病的药物中的用途。
  16. 根据权利要求15所述的用途，其中所述与雄激素相关的疾病为前列腺癌、前列腺增生、乳腺癌、膀胱癌、卵巢癌、粉刺、多毛或脱发。
  17. 一种预防或治疗哺乳动物的与雄激素相关的疾病的方法，所述方法包括给予所述哺乳动物权利要求1-5之任一项所述的N-芳香酰胺化合物或其药学上可接受的盐。
  18. 权利要求17所述的方法，其中所述与雄激素相关的疾病为前列腺癌、前列腺增生、乳腺癌、膀胱癌、卵巢癌、粉刺、多毛或脱发。
  19. 权利要求17或18所述的方法，其中所述哺乳动物为人。
PCT/CN2019/106287 2018-09-28 2019-09-17 N-芳香酰胺类化合物及其制备方法和用途 WO2020063407A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
KR1020217011156A KR102606375B1 (ko) 2018-09-28 2019-09-17 N-방향족 아미드류 화합물 및 이의 제조 방법과 용도
JP2021542244A JP7316362B2 (ja) 2018-09-28 2019-09-17 Ｎ－芳香族アミド系化合物及びその製造方法と用途
EP19866813.9A EP3858811B1 (en) 2018-09-28 2019-09-17 N-aromatic amides compound and preparation method and use thereof
US17/214,834 US11760727B2 (en) 2018-09-28 2021-03-27 N-aromatic amide compounds, preparation methods and uses thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811138268.6A CN110963957B (zh) 2018-09-28 2018-09-28 N-芳香酰胺类化合物及其制备方法和用途
CN201811138268.6 2018-09-28

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US17/214,834 Continuation US11760727B2 (en) 2018-09-28 2021-03-27 N-aromatic amide compounds, preparation methods and uses thereof

Publications (1)

Publication Number Publication Date
WO2020063407A1 true WO2020063407A1 (zh) 2020-04-02

Family

ID=69951004

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/106287 WO2020063407A1 (zh) 2018-09-28 2019-09-17 N-芳香酰胺类化合物及其制备方法和用途

Country Status (6)

Country Link
US (2) US11760727B2 (zh)
EP (1) EP3858811B1 (zh)
JP (1) JP7316362B2 (zh)
KR (1) KR102606375B1 (zh)
CN (1) CN110963957B (zh)
WO (1) WO2020063407A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022007903A1 (zh) 2020-07-09 2022-01-13 四川海思科制药有限公司 一种能够抑制并降解雄激素受体的化合物及其药物组合物和药学上的应用
WO2023016518A1 (zh) 2021-08-11 2023-02-16 四川海思科制药有限公司 一种杂环衍生物及其组合物和药学上的应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007038444A2 (en) * 2005-09-26 2007-04-05 Merck & Co., Inc. N-(4-oxo-3,4-dihydroquinazolin-2-yl)butanamides as androgen receptor modulators
CN104245675A (zh) * 2012-04-04 2014-12-24 默克专利股份公司 作为MetAP-2抑制剂的环酰胺

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ178996A (en) * 1974-11-15 1978-06-02 Kornis G Pyrfazole amides and thioamides;herbicidal compositions
CA1053231A (en) * 1974-11-15 1979-04-24 Malcolm W. Moon Pyrazole amides and thioamides
US5486534A (en) * 1994-07-21 1996-01-23 G. D. Searle & Co. 3,4-substituted pyrazoles for the treatment of inflammation
US9814698B2 (en) 2015-04-21 2017-11-14 University Of Tennessee Research Foundation Selective androgen receptor degrader (SARD) ligands and methods of use thereof
CN107400088B (zh) 2017-08-16 2020-04-28 山东大学 1,3-二取代吡唑类衍生物及其制备方法与应用
WO2019081477A1 (de) * 2017-10-26 2019-05-02 Bayer Cropscience Aktiengesellschaft Substituierte pyrazole sowie deren salze und ihre verwendung als herbizide wirkstoffe

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007038444A2 (en) * 2005-09-26 2007-04-05 Merck & Co., Inc. N-(4-oxo-3,4-dihydroquinazolin-2-yl)butanamides as androgen receptor modulators
CN104245675A (zh) * 2012-04-04 2014-12-24 默克专利股份公司 作为MetAP-2抑制剂的环酰胺

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
ARCHIVES OF PHARMACAL RESEARCH, vol. 38, no. 11, 2015, pages 2076 - 82
BIOCHEMICAL SOCIETY TRANSACTIONS, vol. 7, 1979, pages 565 - 569
CHEMICAL REVIEWS, vol. 95, no. 7, 1979, pages 2457 - 2483
DATABASE Registry CAS; 1 May 2011 (2011-05-01), retrieved from STN Database accession no. RN1288359-74-9 *
DATABASE Registry CAS; 24 May 2011 (2011-05-24), retrieved from STN Database accession no. RN1299363-11-3 *
DATABASE Registry CAS; 28 April 2011 (2011-04-28), retrieved from STN Database accession no. RN1287181-00-3 *
DATABASE Registry CAS; 8 August 2012 (2012-08-08), retrieved from STN Database accession no. RN1387940-35-3 *
ENDOCRINOLOGY, vol. 91, 1972, pages 427 - 437
FERRONI, CLAUDIA ET AL.: "1, 4-Substituted Triazoles as Nonsteroidal Anti-An- drogens for Prostate", JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, no. 7, 8 March 2017 (2017-03-08), pages 3082 - 3093, XP055406231, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b00105 *
ISHIDA, SYO ET AL.: "Copper-Catalyzed Amination of Congested and Functionalized a-Bromocarboxamides with either Amines or Ammonia at Room Temperature", ANGEWANDTE CHEMIE, vol. 56, no. 38, 15 August 2017 (2017-08-15), pages 11610 - 11614, XP055699618, ISSN: 1433-7851, DOI: 10.1002/anie.201706293 *
JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 576, 1999, pages 147 - 168
JOURNAL OF STEROID BIOCHEMISTRY, vol. 6, 1975, pages 815 - 819
PURE APPL. CHEM., vol. 63, no. 3, 1991, pages 419 - 422
THE JOURNAL OF ENDOCRINOLOGY, vol. 113, 1987, pages R7 - R9
UROLOGIC CLINICS OF NORTH AMERICA, vol. 18, 1991, pages 99 - 110

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022007903A1 (zh) 2020-07-09 2022-01-13 四川海思科制药有限公司 一种能够抑制并降解雄激素受体的化合物及其药物组合物和药学上的应用
WO2023016518A1 (zh) 2021-08-11 2023-02-16 四川海思科制药有限公司 一种杂环衍生物及其组合物和药学上的应用

Also Published As

Publication number Publication date
EP3858811A1 (en) 2021-08-04
JP7316362B2 (ja) 2023-07-27
EP3858811A4 (en) 2022-05-11
CN110963957A (zh) 2020-04-07
EP3858811C0 (en) 2024-07-17
EP3858811B1 (en) 2024-07-17
US20230382870A1 (en) 2023-11-30
KR20210090615A (ko) 2021-07-20
US11760727B2 (en) 2023-09-19
CN110963957B (zh) 2021-10-22
KR102606375B1 (ko) 2023-11-24
JP2022501442A (ja) 2022-01-06
US20210214311A1 (en) 2021-07-15

Similar Documents

Publication Publication Date Title
TWI394571B (zh) 螺旋１２取向性之非類固醇抗雄激素及包含其之醫藥組合物、以及其等之用途
JP5346292B2 (ja) ５−ｈｔ２ａセロトニン受容体に関連する障害の処置に有用な５−ｈｔ２ａセロトニン受容体の調整因子としてのピラゾール誘導体
JP2003508380A (ja) スルホニルカルボキサミド誘導体、その調製方法および医薬としてのその使用
JPH082870B2 (ja) ピペラジニルカンファースルフォニルオキシトシン拮抗物質の置換誘導体
TW201016671A (en) Novel imidazolidine compounds as androgen receptor modulators
TW201000467A (en) Novel 1,2,4-triazole derivatives and process of manufacturing thereof
EA022619B1 (ru) Ариламидные производные, обладающие антиандрогенными свойствами
TW201240662A (en) Ester pro-drugs of [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl] methanol for treating retinal diseases
US20230382870A1 (en) N-aromatic amide compounds, preparation methods and uses thereof
TWI260222B (en) Anthranilic acid amides and pharmacological use thereof
WO2015109666A1 (zh) 一类新的含酯基芳香丙酰胺化合物及其制备方法和用途
JP7446460B2 (ja) 新規ｅｐ４拮抗薬の合成及びその癌及び炎症における使用
EA028063B1 (ru) N-[4-(хинолин-4-илокси)циклогексил(метил)](гетеро)арилкарбоксамиды в качестве антагонистов андрогенного рецептора, их получение и применение в качестве лекарственных средств
CN108558760B (zh) 一类芳香酰胺化合物及其制备方法和用途
US10093609B2 (en) TAK1 kinase inhibitors, compositions, and uses related thereto
JP2021513963A (ja) 異常増殖性疾患を治療するための薬剤および方法
JP2023541434A (ja) エストロゲン受容体の標的化分解のための化合物の結晶性形態
JP2022501435A (ja) 肥満に対する処置
TWI738162B (zh) 稠合三環氘代衍生物及其組合物和用途
JP2010155802A (ja) ５−ｈｔ２ｂ受容体拮抗活性を有する新規５−エチニルピラゾール−３−カルボキサミド誘導体
JP2022532186A (ja) 非晶質のｐｉ３ｋ阻害剤及びこれを含有する医薬組成物
JP2021151996A (ja) フェニル酢酸化合物を含有する医薬組成物
TWI398440B (zh) 雙芳基組成物與調節激酶級聯之方法
EA029007B1 (ru) Новые гетероариламидные производные, обладающие антиандрогенными свойствами
TW200524863A (en) Novel N-substituted indolyl-3-glyoxylamides, their use as medicaments and process for their preparation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19866813

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021542244

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2019866813

Country of ref document: EP

Effective date: 20210428