WO2018210207A1 - Sulfonamide compound for treatment of gout or hyperuricemia, and method for preparing same - Google Patents

Sulfonamide compound for treatment of gout or hyperuricemia, and method for preparing same Download PDF

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WO2018210207A1
WO2018210207A1 PCT/CN2018/086731 CN2018086731W WO2018210207A1 WO 2018210207 A1 WO2018210207 A1 WO 2018210207A1 CN 2018086731 W CN2018086731 W CN 2018086731W WO 2018210207 A1 WO2018210207 A1 WO 2018210207A1
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group
compound
aryl
heterocycloalkyl
cycloalkyl
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PCT/CN2018/086731
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French (fr)
Chinese (zh)
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樊磊
胥珂馨
陈锞
张少华
杜武
李兴海
陈元伟
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成都海创药业有限公司
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Definitions

  • the invention belongs to the field of drug synthesis, and particularly relates to a sulfonamide compound and a preparation method thereof, and the use thereof for treating gout or hyperuricemia.
  • Gout is an inflammatory disease characterized by pain and swelling caused by deposition of monosodium urate (MSU) in joints and subcutaneous areas. It is one of the oldest diseases that plague humans.
  • MSU monosodium urate
  • the premise of gout in the MSU deposition instrument is hyperuricemia, a pathological condition in which the level of serum uric acid (sUA) is higher than the solubility of uric acid in the blood.
  • sUA serum uric acid
  • Hyperuricemia is usually caused by excessive uric acid production and/or reduced uric acid excretion, with the latter accounting for approximately 90% of patients with hyperuricemia.
  • hyperuricemia and gout treatment drugs mainly include: 1 anti-inflammatory analgesic drugs for symptomatic control of joint pain, pain, etc., such as colchicine and non-steroidal anti-inflammatory drugs (NSAID); A drug that inhibits uric acid production.
  • NSAID non-steroidal anti-inflammatory drugs
  • a drug that inhibits uric acid production Such as allopurinol, oxynium and nonbuxostat and other xanthine oxidase (XO) inhibitors; 3 for uric acid excretion drugs, such as probenecid and benzbromarone; 4 for acute gout attacks A uric acid-decomposing drug that rapidly lowers blood uric acid, such as uricase and PEGylase.
  • the urate transporter 1 (URAT1) is located on the brush border of the epithelial cells of the proximal convoluted tubules of the kidney. It is an important uric acid transporter found in the kidney in recent years and is responsible for the reabsorption of uric acid in the kidney. It has been proven that inhibition of URAT1 inhibits the reabsorption of uric acid in the kidney and increases the excretion of uric acid in the urine, thereby achieving the goal of lowering blood uric acid and controlling the onset of gout.
  • the present invention first provides a compound of the formula (I), or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, and alkyne.
  • a base a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heterocyclic aryl group, -OX, -S(O) 2 X, -COX, -COOX, -CONXY, -NXY or -NXCOY, wherein the alkane
  • the group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heterocyclic aryl group are each independently further selected from one or more selected from the group consisting of halogen, cyano, nitro, oxo, alkyl.
  • haloalkyl hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl group, heteroaryl group, -OX, -S (O) 2 X, -COX, -COOX, -CONXY Substituted by a substituent of -NXY or NXCOY,
  • R is selected from a 3- to 7-membered cycloalkyl group, a 3-membered-7-membered heterocycloalkyl group, a 6- to 12-membered heterocyclic aryl group, -NR p R q , wherein the cycloalkyl group, hetero
  • the cycloalkyl and heterocyclic aryl groups are each independently further selected from one or more selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkane.
  • R p and R q are each independently selected from the group consisting of hydrogen, a C 1 -C 6 alkyl group, a 3 member-6 membered cycloalkyl group, and a 3 member-6 membered heterocycloalkyl group;
  • X and Y are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, and alkyne.
  • cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, -OX, -S(O) 2 X, -COX, -COOX, -CONXY, -NXY or -NXCOY, X, Y are independent It is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, and alkyne.
  • R 1, R 2, R 3 , R 4, R 5, R 7, R 8, R 9 are hydrogen.
  • R 6 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, alkoxy.
  • R 6 is a cyano group.
  • the R is selected from a 3- to 7-membered cycloalkyl group, a 3-membered-7-membered heterocycloalkyl group, a 6-membered 12-membered heterocyclic aryl group, and -NR p R q , wherein the ring is
  • the alkyl group, heterocycloalkyl group, heterocyclic aryl group are each independently substituted by zero, one or more selected from the group consisting of halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, amino. Substituted.
  • heterocycloalkyl or heterocyclic aryl has 1 to 3 hetero atoms.
  • hetero atom is N, O or S.
  • R is selected from
  • the above groups are each independently substituted by zero, one or more substituents selected from the group consisting of halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, amino.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof is one of the following compounds:
  • the invention also provides a process for the preparation of the aforementioned compounds, comprising the steps of:
  • the present invention also provides the use of the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the preparation of a URAT1 inhibitor.
  • the drug is for preventing and/or treating gout, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lai-naphthalene syndrome, Kay-Sei's syndrome Symptoms, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis or hypoxanthine-guanine phosphoribosyltransferase deficiency
  • a drug preferably a drug for preventing and/or treating gout or hyperuricemia.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, together with a pharmaceutically acceptable adjuvant Prepared preparation.
  • the compound of the present invention is a URAT1 inhibitor, which has been proven to be useful for the treatment of gout and hyperuricemia, and can also be used for the treatment of recurrent gout attacks, gouty arthritis, hypertension, cardiovascular diseases, Coronary heart disease, Lai-naphthalene syndrome, Kay-Sei's syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, Sarcoidosis or hypoxanthine-guanine phosphoribosyltransferase deficiency.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C a - C b ) alkyl group indicates any alkyl group having "a" to "b” carbon atoms.
  • (C 1 -C 6 )alkyl means an alkyl group containing from 1 to 6 carbon atoms.
  • the C 1 -C 6 alkyl group means an alkyl group of C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , that is, a linear or branched alkyl group having 1 to 6 carbon atoms.
  • the 3- to 7-membered cycloalkyl group means a cyclic alkyl group composed of 3 to 7 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or the like.
  • the halogen means a fluorine atom, a bromine atom, a chlorine atom, or an iodine atom.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients which comprise a pharmaceutical dosage form, and It is physiologically compatible with the receptor.
  • the "salt" is an acid form and/or a base salt which forms a compound or a stereoisomer thereof with an inorganic and/or organic acid and a base, and also includes a zwitter ion salt (internal salt), and also includes a season.
  • An ammonium salt such as an alkylammonium salt.
  • the salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound.
  • Triethylamine West Asia reagent
  • Hydrochloric acid dichloromethane, ethyl acetate, petroleum ether, N,N-dimethylamine formamide, 1,4-dioxane, dimethyl sulfoxide, potassium acetate, sodium carbonate, all purchased from Chengdu Kelong Chemical reagent factory;
  • the above raw material reagent can be used as it is without being treated.
  • the starting material of the compound 4 was prepared by replacing the 4-cyclo-oxocyclopentane-3-sulfonyl chloride with 4-fluoro-oxocyclopentane-3-sulfonyl chloride.
  • Compound 12 was obtained according to the same preparation procedure as Compound 4, mass spectrum: 398.1 (M+H + ).
  • the starting material of the compound 4 was prepared by replacing the cyclobutylsulfonyl chloride with cyclohexane-1-sulfonyl chloride. According to the same preparation method as the compound 4, the compound 15 was obtained, mass spectrum: 392.1 (M+H + ).
  • the starting material was prepared cyclic compound 4-chloro-butylsulfonyl alternative is 1-piperidinyl 4-sulfonyl chloride according to the same method of preparation of compound 4 to give compound 18, MS: 393.1 (M + H +) .
  • the starting material cyclobutylsulfonyl chloride of the compound 4 was replaced with 1-pyrrolidine-3-sulfonyl chloride, and the compound 20 was obtained by the same preparation method as the compound 4, mass spectrum: 379.1 (M+H + ).
  • the starting material was prepared cyclic compound 4-chloro-butylsulfonyl replacement of cycloheptane-1-sulfonyl chloride, following the same production method to compound 4 to give compound 21, MS: 406.1 (M + H +) .
  • the starting material cyclobutylsulfonyl chloride of the compound 4 was replaced with 3-methylpyridazine-6-sulfonyl chloride, and the compound 30 was obtained by the same preparation method as the compound 4, mass spectrum: 402.1 (M+H + ).
  • the starting material of the compound 4 was prepared by replacing the starting material of cyclobutylsulfonyl chloride with 1,3,4-thiadiazole-2-sulfonyl chloride. According to the same preparation method as the compound 4, the compound 39 was obtained, mass spectrum: 394.1 (M+H + ).
  • the compound 40 can be obtained by the same preparation method as the compound 4, mass spectrum: 391.1 (M+H + ).
  • the compound 42 was obtained by the same preparation method as the compound 4, mass spectrum: 390.1 (M+H + ).
  • the starting material of the compound 4 was replaced with 1-ethylaminosulfonyl chloride, and the compound 44 was obtained by the same preparation method as the compound 4, mass spectrum: 353.1 (M+H + ).
  • Test Example 1 Determination of biological activity of the compound of the present invention
  • Test Example Determination of the inhibitory activity of the compound of the present invention on URAT1
  • Penicillin-streptomycin (Invitrogen, Cat. No. 15070-063)
  • HEK-293T cells stably expressing hURAT1 were cultured in 10% FBS and 1% P/S DMEM medium, and cultured overnight in a 37-degree incubator with 5% carbon dioxide.
  • the medium was removed, washed once with PBS, and then trypsinized for 2 minutes. After the cells were separated in the culture dish, 10 ml of the medium was added to terminate the digestion.
  • the 96-well plates inoculated with the cells were placed in a 37-degree cell culture incubator overnight.
  • test compound was dissolved in DMSO, and then the same concentration of DMSO was added to the HEK293/hURAT1 cell well containing no test compound. Uric acid uptake of cells at each test concentration was expressed as the average percent inhibition of the DMSO control. The radioactivity value obtained for the wells containing DMSO is considered to be 100% uptake of the cells. The IC50 value of a compound can be calculated from the inhibition rate at different concentrations.
  • the compounds of the examples of the present invention have good URAT1 inhibitory activity, can be used for the treatment of gout and hyperuricemia, and can also be used for recurrent gout attacks, gouty arthritis, hypertension, cardiovascular diseases, coronary heart disease. , Lai-naphthalene syndrome, Kay-Sei's syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, nodules Treatment of disease or secondary jaundice-guanine phosphoribosyltransferase deficiency and other diseases with abnormal URAT1 activity.
  • novel compound of the formula (A) disclosed in the present invention exhibits a good URAT1 inhibitory activity and provides a new medicinal possibility for clinical treatment of diseases associated with abnormal URAT1 activity.

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Abstract

A compound as represented by formula (I), and optical isomers, solvates, pharmaceutically-acceptable salts, or prodrugs thereof. The present invention has urate transporter 1 (URAT1) inhibitory activity, can be used for treatment of gout and hyperuricemia, and can also be used for treatment of diseases related to abnormal URAT1 activity, such as recurrent gout attacks, gouty arthritis, hypertension, cardiovascular diseases, coronary heart disease, Lesch-Nyhan syndrome, Kearns-Sayre syndrome, kidney diseases, kidney stones, kidney failure, joint inflammations, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, or hypoxanthine-guanine phosphoribosyltransferase deficiency. (I)

Description

用于治疗痛风或高尿酸血症的磺酰胺类化合物及其制备方法Sulfonamide compound for treating gout or hyperuricemia and preparation method thereof 技术领域Technical field
本发明属于药物合成领域，具体涉及磺酰胺类化合物及其制备方法，以及其用于治疗痛风或高尿酸血症的用途。The invention belongs to the field of drug synthesis, and particularly relates to a sulfonamide compound and a preparation method thereof, and the use thereof for treating gout or hyperuricemia.
背景技术Background technique
痛风是尿酸单钠盐(monosodium urate，MSU)在关节和皮下等部位沉积而引起的以疼痛和肿胀为主要特征的炎症性疾病，是困扰人类最老的疾病之一。MSU沉积仪器痛风的前提是高尿酸血症，即血尿酸(serum uric acid，sUA)水平高于尿酸在血液中的溶解度的一种病理状态。高尿酸血症通常是由于尿酸产生过多和/或尿酸排泄降低引起，其中后者在高尿酸血症患者中约占90％。Gout is an inflammatory disease characterized by pain and swelling caused by deposition of monosodium urate (MSU) in joints and subcutaneous areas. It is one of the oldest diseases that plague humans. The premise of gout in the MSU deposition instrument is hyperuricemia, a pathological condition in which the level of serum uric acid (sUA) is higher than the solubility of uric acid in the blood. Hyperuricemia is usually caused by excessive uric acid production and/or reduced uric acid excretion, with the latter accounting for approximately 90% of patients with hyperuricemia.
目前高尿酸血症及痛风治疗药物主要包括：①用于痛风急性发作关节肿痛、疼痛等症状控制的消炎止痛药物，如秋水仙碱和非甾体抗炎药物(NSAID)等；②用于抑制尿酸生成的的药物。如别嘌醇、奥昔嘌醇和非布索坦等黄嘌呤氧化酶(XO)抑制剂；③用于尿酸排泄的药物，如丙磺舒和苯溴马隆等；④用于急性痛风发作时迅速降低血尿酸的尿酸分解药，如尿酸酶(uricase)以及聚乙二醇的尿酸酶(pegloticase)。但是，这些药物均具有比较严重的副作用，如秋水仙碱具有腹泻、呕吐、腹痛性痉挛等常见的不良反应，治疗有效剂量与其引起胃肠道症状的剂量相近；丙磺舒能引起肾绞痛和肾功能损害；苯溴马隆有引起爆发性肝炎的危险；别嘌醇具有肝脏及骨髓毒性和变态反应等不良反应；尿酸酶制剂为注射给药，病人的顺应性不如口服制剂，只适用于急性痛风发作时降低血尿酸，不宜作为长期治疗。At present, hyperuricemia and gout treatment drugs mainly include: 1 anti-inflammatory analgesic drugs for symptomatic control of joint pain, pain, etc., such as colchicine and non-steroidal anti-inflammatory drugs (NSAID); A drug that inhibits uric acid production. Such as allopurinol, oxynium and nonbuxostat and other xanthine oxidase (XO) inhibitors; 3 for uric acid excretion drugs, such as probenecid and benzbromarone; 4 for acute gout attacks A uric acid-decomposing drug that rapidly lowers blood uric acid, such as uricase and PEGylase. However, these drugs have more serious side effects, such as colchicine has diarrhea, vomiting, abdominal pain and other common side effects, the effective dose is similar to the dose that causes gastrointestinal symptoms; probenecid can cause renal colic And renal dysfunction; benzbromarone has the risk of causing fulminant hepatitis; allopurinol has adverse reactions such as liver and bone marrow toxicity and allergic reaction; uric acid enzyme preparation is administered by injection, the patient's compliance is not as good as oral preparation, only applicable Lowering blood uric acid during acute gout attacks is not suitable for long-term treatment.
尿酸转运体1(urate transporter 1，URAT1)位于肾脏近曲小管的上皮细胞的刷状缘上，是近年来发现的位于肾脏的重要尿酸转运体，负责肾脏中尿酸的重吸收。经过证明，抑制URAT1就会抑制肾脏中尿酸的重吸收、增加尿液中尿酸的排泄，进而达到降低血尿酸和控制痛风发作的目的。例如，Lesinurad为阿斯利康研发的一种选择性尿酸在吸收抑制剂，通过抑制肾脏中URAT1转运体可以减少尿酸的分泌和降低血清中的尿酸含量，该药物于2015年12月份被FDA批准用于血中高水平尿酸(高尿酸血症)与痛风关联的治疗，2016年2月18日获得欧洲药品管理局(EMA)批准上市，将其与减少尿酸生成的药物(如别嘌呤醇和非布索坦)联用，可增加原本对上述药物应答不佳的痛风患者的应答率，但其单独用药仍然存在肾脏相关风险和疗效不佳，如何发挥URAT1抑制剂的最大效能并尽可能地克服其副作用，成为研究热点。The urate transporter 1 (URAT1) is located on the brush border of the epithelial cells of the proximal convoluted tubules of the kidney. It is an important uric acid transporter found in the kidney in recent years and is responsible for the reabsorption of uric acid in the kidney. It has been proven that inhibition of URAT1 inhibits the reabsorption of uric acid in the kidney and increases the excretion of uric acid in the urine, thereby achieving the goal of lowering blood uric acid and controlling the onset of gout. For example, Lesinurad developed a selective uric acid absorption inhibitor for AstraZeneca, which reduces uric acid secretion and lowers uric acid levels in serum by inhibiting the URAT1 transporter in the kidney. The drug was approved by the FDA in December 2015. High blood levels of uric acid (hyperuricemia) associated with gout in the blood, approved by the European Medicines Agency (EMA) on February 18, 2016, and associated with drugs that reduce uric acid production (such as allopurinol and non-Busso) Can be combined to increase the response rate of gout patients who have not responded well to the above drugs, but there are still kidney-related risks and poor efficacy in the treatment alone. How to maximize the efficacy of URAT1 inhibitors and overcome their side effects as much as possible Become a research hotspot.
发明内容Summary of the invention
本发明的目的在于提供一类可用于治疗痛风或高尿酸血症的磺酰胺类化合物及其制备方法。It is an object of the present invention to provide a class of sulfonamide compounds useful for the treatment of gout or hyperuricemia and methods for their preparation.
本发明首先提供了如式(Ⅰ)所示化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，The present invention first provides a compound of the formula (I), or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof,
Figure PCTCN2018086731-appb-000001
Figure PCTCN2018086731-appb-000001
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O) 2X、-COX、-COOX、-CONXY、-NXY或-NXCOY，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂环芳基分别独立地进一步被一个或多个任选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O) 2X、-COX、-COOX、-CONXY、-NXY或NXCOY的取代基所取代， Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, and alkyne. a base, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heterocyclic aryl group, -OX, -S(O) 2 X, -COX, -COOX, -CONXY, -NXY or -NXCOY, wherein the alkane The group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heterocyclic aryl group are each independently further selected from one or more selected from the group consisting of halogen, cyano, nitro, oxo, alkyl. , haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl group, heteroaryl group, -OX, -S (O) 2 X, -COX, -COOX, -CONXY Substituted by a substituent of -NXY or NXCOY,
R选自3元-7元的环烷基、3元-7元的杂环烷基、6元-12元的杂环芳基、-NR pR q，其中所述的环烷基、杂环烷基、杂环芳基分别独立地进一步被一个或多个任选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O) 2X、-COX、-COOX、-CONXY、-NXY或-NXCOY的取代基所取代； R is selected from a 3- to 7-membered cycloalkyl group, a 3-membered-7-membered heterocycloalkyl group, a 6- to 12-membered heterocyclic aryl group, -NR p R q , wherein the cycloalkyl group, hetero The cycloalkyl and heterocyclic aryl groups are each independently further selected from one or more selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkane. Substituted with a substituent of a heterocycloalkyl, aryl, heterocyclic aryl, -OX, -S(O) 2 X, -COX, -COOX, -CONXY, -NXY or -NXCOY;
R p、R q分别独立地选自氢、C 1-C 6的烷基、3元-6元的环烷基、3元-6元的杂环烷基； R p and R q are each independently selected from the group consisting of hydrogen, a C 1 -C 6 alkyl group, a 3 member-6 membered cycloalkyl group, and a 3 member-6 membered heterocycloalkyl group;
X、Y分别独立的选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基。X and Y are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl.
进一步地，所述R 1、R 2、R 3、R 4、R 5、R 7、R 8、R 9分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O) 2X、-COX、-COOX、-CONXY、-NXY或-NXCOY，X、Y分别独立的选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基。 Further, the R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, and alkyne. Base, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, -OX, -S(O) 2 X, -COX, -COOX, -CONXY, -NXY or -NXCOY, X, Y are independent It is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl.
进一步地，所述R 1、R 2、R 3、R 4、R 5、R 7、R 8、R 9分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、烷氧基。 Further, the R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, and alkyne. Alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, alkoxy.
进一步地，所述R 1、R 2、R 3、R 4、R 5、R 7、R 8、R 9均为氢。 Further, the R 1, R 2, R 3 , R 4, R 5, R 7, R 8, R 9 are hydrogen.
进一步地，所述R 6选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、烷氧基。 Further, the R 6 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, alkoxy.
进一步地，所述R 6为氰基。 Further, the R 6 is a cyano group.
进一步地，所述R选自3元-7元的环烷基、3元-7元的杂环烷基、6元-12元杂环芳 基、-NR pR q，其中所述的环烷基、杂环烷基、杂环芳基分别独立地被零个、一个或多个选自卤素、烷基、环烷基、杂环烷基、芳基、杂环芳基、氨基的取代基取代。 Further, the R is selected from a 3- to 7-membered cycloalkyl group, a 3-membered-7-membered heterocycloalkyl group, a 6-membered 12-membered heterocyclic aryl group, and -NR p R q , wherein the ring is The alkyl group, heterocycloalkyl group, heterocyclic aryl group are each independently substituted by zero, one or more selected from the group consisting of halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, amino. Substituted.
进一步地，所述杂环烷基或者杂环芳基上有1～3个杂原子。Further, the heterocycloalkyl or heterocyclic aryl has 1 to 3 hetero atoms.
进一步地，所述杂原子为N、O或S。Further, the hetero atom is N, O or S.
进一步地，所述R选自Further, the R is selected from
Figure PCTCN2018086731-appb-000002
Figure PCTCN2018086731-appb-000002
其中上述的基团分别独立地被零个、一个或多个选自卤素、烷基、环烷基、杂环烷基、芳基、杂环芳基、氨基的取代基取代。Wherein the above groups are each independently substituted by zero, one or more substituents selected from the group consisting of halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, amino.
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物为如下化合物之一：Further, the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, is one of the following compounds:
Figure PCTCN2018086731-appb-000003
Figure PCTCN2018086731-appb-000003
Figure PCTCN2018086731-appb-000004
Figure PCTCN2018086731-appb-000004
本发明还提供了制备前述化合物的方法，包括下述步骤：The invention also provides a process for the preparation of the aforementioned compounds, comprising the steps of:
Figure PCTCN2018086731-appb-000005
Figure PCTCN2018086731-appb-000005
本发明还提供了前述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物在制备URAT1抑制剂类药物上的用途。The present invention also provides the use of the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the preparation of a URAT1 inhibitor.
所述药物是预防和/或治疗痛风、复发性痛风发作、痛风性关节炎、高尿酸血症、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症的药物，优选预防和/或治疗痛风或高尿酸血症的药物。The drug is for preventing and/or treating gout, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lai-naphthalene syndrome, Kay-Sei's syndrome Symptoms, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis or hypoxanthine-guanine phosphoribosyltransferase deficiency A drug, preferably a drug for preventing and/or treating gout or hyperuricemia.
本发明还提供了一种药物组合物，它是以前述的化合物或其立体异构体、或其药学上可接受的盐、或其溶剂合物为活性成分，加上药学上可接受的辅料制备而成的制剂。The present invention also provides a pharmaceutical composition comprising the aforementioned compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, together with a pharmaceutically acceptable adjuvant Prepared preparation.
实验结果表明，本发明的化合物是一种URAT1抑制剂，经过证明，可以用于治疗痛风和高尿酸血症，还可用于治疗复发性痛风发作、痛风性关节炎、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症。The experimental results show that the compound of the present invention is a URAT1 inhibitor, which has been proven to be useful for the treatment of gout and hyperuricemia, and can also be used for the treatment of recurrent gout attacks, gouty arthritis, hypertension, cardiovascular diseases, Coronary heart disease, Lai-naphthalene syndrome, Kay-Sei's syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, Sarcoidosis or hypoxanthine-guanine phosphoribosyltransferase deficiency.
对于本发明的化合物而言，其同位素取代物，如氘代、氚代、 14C代以及 15N代也具有相同的活性和用途。上述同位素取代物均属于本发明的范围。 For the compounds of the invention, their isotopic substitutions, such as deuterated, deuterated, 14 C, and 15 N generations, also have the same activity and utility. The above isotopic substitutions are all within the scope of the invention.
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。Definitions of terms of use in connection with the present invention: Unless otherwise stated, the initial definitions provided herein by the group or term apply to the group or term of the entire specification; for terms not specifically defined herein, it should be based on the disclosure and context. Given the meanings that those skilled in the art can give to them.
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀(C a～C b)烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，(C 1～C 6)烷基是指包含1～6个碳原子的烷基。 The minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C a - C b ) alkyl group indicates any alkyl group having "a" to "b" carbon atoms. Thus, for example, (C 1 -C 6 )alkyl means an alkyl group containing from 1 to 6 carbon atoms.
所述C 1～C 6烷基是指C 1、C 2、C 3、C 4、C 5、C 6的烷基，即具有1～6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、己基等等。 The C 1 -C 6 alkyl group means an alkyl group of C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , that is, a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, and the like.
所述3元-7元的环烷基是指3个-7个碳原子组成的环状烷基，例如环丙基、环丁基、环戊基、环己基、环庚基等等。The 3- to 7-membered cycloalkyl group means a cyclic alkyl group composed of 3 to 7 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or the like.
所述卤素是指氟原子、溴原子、氯原子、碘原子。The halogen means a fluorine atom, a bromine atom, a chlorine atom, or an iodine atom.
本发明中，“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼 容。As used herein, "pharmaceutically acceptable" means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients which comprise a pharmaceutical dosage form, and It is physiologically compatible with the receptor.
本发明中，“盐”是将化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。In the present invention, the "salt" is an acid form and/or a base salt which forms a compound or a stereoisomer thereof with an inorganic and/or organic acid and a base, and also includes a zwitter ion salt (internal salt), and also includes a season. An ammonium salt such as an alkylammonium salt. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing a compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount). These salts may be precipitated in a solution and collected by filtration, or recovered after evaporation of the solvent, or may be obtained by lyophilization after reaction in an aqueous medium. The salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound. An acid salt, an oxalate salt, a malate salt, a succinate salt, a fumarate salt, a maleate salt, a tartrate salt or a trifluoroacetate salt.
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention.
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.
具体实施方式detailed description
本发明具体实施部分使用的原料和仪器均可通过市场购买得到。The materials and instruments used in the specific embodiments of the present invention are commercially available.
4-溴-1-萘腈：上海毕得医药科技有限公司；4-bromo-1-naphthonitrile: Shanghai Bied Pharmaceutical Technology Co., Ltd.;
联频哪醇硼酸酯：上海泽信化工科技有限公司；Terminated which alcohol borate: Shanghai Zexin Chemical Technology Co., Ltd.;
氯化钠：天津市瑞金特化学品有限公司；Sodium chloride: Tianjin Ruijinte Chemical Co., Ltd.;
碳酸氢钠：天津博迪化工股份有限公司；Sodium bicarbonate: Tianjin Bodi Chemical Co., Ltd.;
三乙胺：西亚试剂；Triethylamine: West Asia reagent;
盐酸、二氯甲烷、乙酸乙酯、石油醚、N,N-二甲胺甲酰胺、1,4-二氧六环、二甲亚砜、乙酸钾、碳酸钠、均购买自成都市科龙化工试剂厂；Hydrochloric acid, dichloromethane, ethyl acetate, petroleum ether, N,N-dimethylamine formamide, 1,4-dioxane, dimethyl sulfoxide, potassium acetate, sodium carbonate, all purchased from Chengdu Kelong Chemical reagent factory;
[1,1'-双(二苯基膦基)二茂铁]二氯化钯(简称：Pd(dppf)Cl 2)、四三苯基膦钯、4-氨基-3-溴吡啶、环丙基磺酰氯、1-甲基-1H-咪唑-4-磺酰氯、1,2-二甲基-1H-咪唑-4-磺酰氯、噻吩-2-磺酰氯、吡啶-3-磺酰氯、3-氧代环丁烷磺酰氯、环戊烷磺酰氯、环己烷-1-磺酰氯、1-氧代环己烷-3-磺酰氯、1-氧代环己烷-4-磺酰氯、环庚烷-1-磺酰氯、1-噻唑-2-磺酰氯、吡啶-4-磺酰氯、1-嘧啶-5-磺酰氯、1-嘧啶-2-磺酰氯、1-吡嗪-2-磺酰氯、1-恶唑-2-磺酰氯、1-异恶唑-5-磺酰氯、1-呋喃-3-磺酰氯、1-呋喃-2-磺酰氯、1-氨基磺酰氯、1-乙氨基磺酰氯、1-环丙基氨基磺酰氯、2-氯噻吩-5-磺酰氯、3,5-二甲基异恶唑-4-磺酰氯，均购买自百灵威科技有限公司； [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (abbreviation: Pd(dppf)Cl 2 ), tetrakistriphenylphosphine palladium, 4-amino-3-bromopyridine, ring Propylsulfonyl chloride, 1-methyl-1H-imidazole-4-sulfonyl chloride, 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride, thiophene-2-sulfonyl chloride, pyridine-3-sulfonyl chloride, 3-oxocyclobutanesulfonyl chloride, cyclopentanesulfonyl chloride, cyclohexane-1-sulfonyl chloride, 1-oxocyclohexane-3-sulfonyl chloride, 1-oxocyclohexane-4-sulfonyl chloride , cycloheptane-1-sulfonyl chloride, 1-thiazole-2-sulfonyl chloride, pyridine-4-sulfonyl chloride, 1-pyrimidine-5-sulfonyl chloride, 1-pyrimidine-2-sulfonyl chloride, 1-pyrazine-2 - sulfonyl chloride, 1-oxazole-2-sulfonyl chloride, 1-isoxazole-5-sulfonyl chloride, 1-furan-3-sulfonyl chloride, 1-furan-2-sulfonyl chloride, 1-aminosulfonyl chloride, 1 -ethylaminosulfonyl chloride, 1-cyclopropylaminosulfonyl chloride, 2-chlorothiophene-5-sulfonyl chloride, 3,5-dimethylisoxazole-4-sulfonyl chloride, all purchased from BEHRINGER TECHNOLOGY CO., LTD.;
2-氟环丙基磺酰氯、3-N-甲基吡咯烷磺酰氯、3-氧代环戊烷磺酰氯、4-氟环己烷磺酰氯、2-氟环己烷磺酰氯、4-氟-1甲基吡咯烷-3-磺酰氯、2-氟-环戊烷-1-磺酰氯、4-氟-氧代环戊烷-3-磺酰氯、1-哌啶-3-磺酰氯、1-甲基哌啶-3-磺酰氯、1-哌啶-4-磺酰氯、1-甲基哌啶-4-磺酰氯、1-吡咯烷-3-磺酰氯、1-氮代环庚烷-4-磺酰氯、3-甲基哒嗪-6-磺酰氯、1-甲基吡 唑-5-磺酰氯、1-咪唑-4-磺酰氯、1-甲基咪唑-5-磺酰氯、1,3,4-恶二唑-2-磺酰氯、1,3,4-噻二唑-2-磺酰氯、1-甲基-1,2,4-三氮唑-3-磺酰氯、1-甲基咪唑-4-磺酰氯，均购自成都普康生物科技有限公司；2-Fluorocyclopropylsulfonyl chloride, 3-N-methylpyrrolidinylsulfonyl chloride, 3-oxocyclopentanesulfonyl chloride, 4-fluorocyclohexanesulfonyl chloride, 2-fluorocyclohexanesulfonyl chloride, 4- Fluoro-1methylpyrrolidine-3-sulfonyl chloride, 2-fluoro-cyclopentane-1-sulfonyl chloride, 4-fluoro-oxocyclopentane-3-sulfonyl chloride, 1-piperidin-3-sulfonyl chloride , 1-methylpiperidine-3-sulfonyl chloride, 1-piperidin-4-sulfonyl chloride, 1-methylpiperidine-4-sulfonyl chloride, 1-pyrrolidine-3-sulfonyl chloride, 1-nitrogen ring Heptane-4-sulfonyl chloride, 3-methylpyridazine-6-sulfonyl chloride, 1-methylpyrazole-5-sulfonyl chloride, 1-imidazole-4-sulfonyl chloride, 1-methylimidazole-5-sulfonate Acid chloride, 1,3,4-oxadiazole-2-sulfonyl chloride, 1,3,4-thiadiazole-2-sulfonyl chloride, 1-methyl-1,2,4-triazole-3-sulfonate Acyl chloride, 1-methylimidazole-4-sulfonyl chloride, were purchased from Chengdu Pukang Biotechnology Co., Ltd.;
上述原料试剂可不进行处理，直接使用。The above raw material reagent can be used as it is without being treated.
实施例1、4-(4-氨基吡啶-3-基)-1-萘腈(Int 2)的合成Example 1. Synthesis of 4-(4-aminopyridin-3-yl)-1-naphthaleneonitrile (Int 2)
1)4-(频哪醇硼酸酯-3-基)-1-萘腈(Int1)的合成1) Synthesis of 4-(pinacol borate-3-yl)-1-naphthalene nitrile (Int1)
Figure PCTCN2018086731-appb-000006
Figure PCTCN2018086731-appb-000006
向100mL的反应瓶中加入4-溴-1-萘腈(232mg，1mmol)，乙酸钾(196mg，2mmol)，联频哪醇硼酸酯(380mg，1.5mmol)，Pd(dppf)Cl 2(73mg，0.1mmol),DMSO(5mL),氮气置换三次，加热到80℃搅拌反应6个小时。然后将反应液到入水中(30mL)，用乙酸乙酯萃取三次(3×15ml)，有机层合并，饱和食盐水洗，无水硫酸钠干燥，过滤，旋蒸后过柱得中间体1(176mg)，收率63％。 1H NMR(400MHz,Chloroform-d)δ8.88–8.72(m,1H),8.30–8.18(m,1H),8.08(d,J＝7.1Hz,1H),7.88(d,J＝7.2Hz,1H),7.72–7.56(m,2H),1.43(s,12H). To a 100 mL reaction vial was added 4-bromo-1-naphthonitrile (232 mg, 1 mmol), potassium acetate (196 mg, 2 mmol), carbaryl borate (380 mg, 1.5 mmol), Pd(dppf)Cl 2 ( 73 mg, 0.1 mmol), DMSO (5 mL), three times with nitrogen, and heated to 80 ° C to stir the reaction for 6 hours. Then, the reaction mixture was poured into water (30 mL), and extracted with EtOAc (3×15 mL). ), the yield was 63%. 1 H NMR (400 MHz, Chloroform-d) δ 8.88 - 8.72 (m, 1H), 8.30 - 8.18 (m, 1H), 8.08 (d, J = 7.1 Hz, 1H), 7.88 (d, J = 7.2 Hz) , 1H), 7.72–7.56 (m, 2H), 1.43 (s, 12H).
2)4-(4-氨基吡啶-3-基)-1-萘腈(Int 2)的合成2) Synthesis of 4-(4-aminopyridin-3-yl)-1-naphthalene nitrile (Int 2)
Figure PCTCN2018086731-appb-000007
Figure PCTCN2018086731-appb-000007
向100mL的反应瓶中加入Int 1(279mg，1mmol)，碳酸钠(212mg，2mmol)，4-氨基-3-溴吡啶(172mg，1mmol)，Pd(PPh 3) 4(58mg，0.05mmol),二氧六环(3mL),H2O(0.3ml),氮气置换三次，加热到110℃搅拌反应16个小时。然后将反应液到入水中(30mL)，用乙酸乙酯萃取三次(3×15ml)，有机层合并，饱和食盐水洗，无水硫酸钠干燥，过滤，旋蒸后过柱得中间体2(140mg)，收率57％。MS:246.1(M+H +)。 Into a 100 mL reaction flask was added Int 1 (279 mg, 1 mmol), sodium carbonate (212 mg, 2 mmol), 4-amino-3-bromopyridine (172 mg, 1 mmol), Pd (PPh 3 ) 4 (58 mg, 0.05 mmol). Dioxane (3 mL), H 2 O (0.3 mL), was replaced with nitrogen three times, and the mixture was stirred and stirred at 110 ° C for 16 hours. Then, the reaction mixture was poured into water (30 mL), and extracted with EtOAc (3×15 mL). ), the yield was 57%. MS: 246.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ8.25(d,J＝7.3Hz,1H),8.21(dt,J＝8.4,1.0Hz,1H),8.13(d,J＝5.7Hz,1H),7.94(s,1H),7.83(ddd,J＝8.3,6.4,1.7Hz,1H),7.72–7.62(m,2H),7.57(d,J＝7.4Hz,1H),6.72(d,J＝5.7Hz,1H),5.68(s,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.25 (d, J = 7.3 Hz, 1H), 8.21. (dt, J = 8.4, 1.0 Hz, 1H), 8.13 (d, J = 5.7 Hz, 1H) , 7.94 (s, 1H), 7.83 (ddd, J = 8.3, 6.4, 1.7 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.57 (d, J = 7.4 Hz, 1H), 6.72 (d, J =5.7 Hz, 1H), 5.68 (s, 2H).
实施例2、N-(3-(4-氰基萘-1-基)吡啶-4-基)环丁基磺酰胺(4)的合成Example 2 Synthesis of N-(3-(4-cyanophthalen-1-yl)pyridin-4-yl)cyclobutylsulfonamide (4)
Figure PCTCN2018086731-appb-000008
Figure PCTCN2018086731-appb-000008
向100mL的反应瓶中加入中间体2(245mg，1mmol)，二氯甲烷(8mL)，三乙胺(303mg，3mmol)，冰水浴条件下分批次加入环丁基磺酰氯(185mg,1.2mmol)，自然慢慢恢复至室温反应3个小时。反应完毕后，将反应液到入水中(30mL)，用二氯甲烷萃取三次(3×15ml)，有机层合并，饱和食盐水洗，无水硫酸钠干燥，过滤，旋蒸后过柱得化合物4(72mg)，收率20％。质谱:364.1(M+H +)。 Add intermediate 2 (245 mg, 1 mmol), dichloromethane (8 mL), triethylamine (303 mg, 3 mmol) to a 100 mL reaction flask and add cyclobutylsulfonyl chloride (185 mg, 1.2 mmol) in portions in ice water bath. ), naturally slowly returned to room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into water (30 mL), and extracted with dichloromethane (3×15 ml). The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, filtered, (72 mg), yield 20%. Mass spectrum: 364.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)1.45–1.01(m,6H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 2.74 - 2.81 (m, 1H) 1.45 - 1.01 (m, 6H).
实施例3、N-(3-(4-氰基萘-1-基)吡啶-4-基)环丙基磺酰胺(1)Example 3, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)cyclopropylsulfonamide (1)
Figure PCTCN2018086731-appb-000009
Figure PCTCN2018086731-appb-000009
将制备化合物4的原料环丁基磺酰氯替换为环丙基磺酰氯，按照与化合物4相同的制备方法即可得到化合物1，质谱：350.1(M+H +)。 Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with cyclopropylsulfonyl chloride, Compound 1 was obtained by the same preparation method as Compound 4, mass spectrum: 350.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)1.39–1.13(m,4H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 2.74 - 2.81 (m, 1H) 1.39 - 1.13 (m, 4H).
实施例4、N-(3-(4-氰基萘-1-基)吡啶-4-基)-2-氟环丙基磺酰胺(2)Example 4, N-(3-(4-cyanophthalen-1-yl)pyridin-4-yl)-2-fluorocyclopropylsulfonamide (2)
Figure PCTCN2018086731-appb-000010
Figure PCTCN2018086731-appb-000010
将制备化合物4的原料环丁基磺酰氯替换为2-氟环丙基磺酰氯，按照与化合物4相同的制备方法即可得到化合物2，质谱：368.1(M+H +)。 Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 2-fluorocyclopropylsulfonyl chloride, Compound 2 was obtained according to the same preparation procedure as Compound 4, mass spectrum: 368.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90– 7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)，1.74–1.81(m,1H)1.39–1.13(m,2H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90– 7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 2.74 - 2.81 (m, 1H), 1.74 - 1.81 (m, 1H) 1.39 - 1.13 (m , 2H).
实施例5、N-(3-(4-氰基萘-1-基)吡啶-4-基)-3-N-甲基吡咯烷磺酰胺(3)Example 5 N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-3-N-methylpyrrolidiniumsulfonamide (3)
Figure PCTCN2018086731-appb-000011
Figure PCTCN2018086731-appb-000011
将制备化合物4的原料环丁基磺酰氯替换为3-N-甲基吡咯烷磺酰氯，按照与化合物4相同的制备方法即可得到化合物3，质谱：393.1(M+H +)。 The starting material cyclobutylsulfonyl chloride of the compound 4 was replaced with 3-N-methylpyrrolidinylsulfonyl chloride, and Compound 3 was obtained by the same preparation method as Compound 4, mass spectrum: 393.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.9(s,3H)，2.74–2.81(m,1H)，1.74–1.81(m,2H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 3.34 - 3.51 (m, 4H), 2.9 (s, 3H), 2.74 - 2.81 (m, 1H), 1.74–1.81 (m, 2H).
实施例6、N-(3-(4-氰基萘-1-基)吡啶-4-基)-3-氧代环丁烷磺酰胺(5)Example 6. N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-3-oxocyclobutanesulfonamide (5)
Figure PCTCN2018086731-appb-000012
Figure PCTCN2018086731-appb-000012
将制备化合物4的原料环丁基磺酰氯替换为3-氧代环丁烷磺酰氯，按照与化合物4相同的制备方法即可得到化合物5，质谱：366.1(M+H +). The starting material cyclobutanesulfonyl chloride of compound 4 was replaced with 3-oxocyclobutanesulfonyl chloride, and compound 5 was obtained according to the same preparation method as compound 4, mass spectrum: 366.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.94–2.99(m,1H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 3.34 - 3.51 (m, 4H), 2.94 - 2.99 (m, 1H).
实施例7、N-(3-(4-氰基萘-1-基)吡啶-4-基)-环戊烷磺酰胺(6)Example 7, N-(3-(4-cyanophthalen-1-yl)pyridin-4-yl)-cyclopentanesulfonamide (6)
Figure PCTCN2018086731-appb-000013
Figure PCTCN2018086731-appb-000013
将制备化合物4的原料环丁基磺酰氯替换为环戊烷磺酰氯，按照与化合物4相同的制备方法即可得到化合物6，质谱：378.1(M+H +). The starting material cyclobutanesulfonyl chloride of compound 4 was replaced with cyclopentanesulfonyl chloride. Compound 6 was obtained according to the same preparation method as compound 4, mass spectrum: 378.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H), 7.37(s,1H),2.74–2.81(m,1H)1.45–1.01(m,8H) 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 2.74 - 2.81 (m, 1H) 1.45 - 1.01 (m, 8H)
实施例8、N-(3-(4-氰基萘-1-基)吡啶-4-基)-3-氧代环戊烷磺酰胺(7)Example 8, N-(3-(4-cyanophthalen-1-yl)pyridin-4-yl)-3-oxocyclopentanesulfonamide (7)
Figure PCTCN2018086731-appb-000014
Figure PCTCN2018086731-appb-000014
将制备化合物4的原料环丁基磺酰氯替换为3-氧代环戊烷磺酰氯，按照与化合物4相同的制备方法即可得到化合物7，质谱：380.1(M+H +). The starting material cyclobutanesulfonyl chloride of compound 4 was replaced with 3-oxocyclopentanesulfonyl chloride. Compound 7 was obtained according to the same preparation method as compound 4, mass spectrum: 380.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,2H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 3.34 - 3.51 (m, 4H), 2.74 - 2.81 (m, 1H), 1.74 - 1.81 ( m, 2H).
实施例9、N-(3-(4-氰基萘-1-基)吡啶-4-基)-4-氟环己烷磺酰胺(8)Example 9. N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-4-fluorocyclohexanesulfonamide (8)
Figure PCTCN2018086731-appb-000015
Figure PCTCN2018086731-appb-000015
将制备化合物4的原料环丁基磺酰氯替换为4-氟环己烷磺酰氯，按照与化合物4相同的制备方法即可得到化合物8，质谱：410.1(M+H +). The starting material of the compound 4 was replaced with 4-fluorocyclohexanesulfonyl chloride, and the same preparation method as the compound 4 was used to obtain the compound 8. Mass spectrum: 410.1 (M+H + ).
378.1(M+H +)， 1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)，1.99–1.78(m,4H)，1.74–1.66(m,1H)，1.45–1.01(m,4H). 378.1(M+H + ), 1 H NMR (400MHz, Chloroform-d) δ 8.74–8.66 (m, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.41 (dd, J=8.4, 5.2 Hz, 1H), 8.23 (dd, J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H) , 7.65 (dd, J = 7.4, 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 2.74 - 2.81 (m, 1H), 1.99 - 1.78 (m , 4H), 1.74–1.66 (m, 1H), 1.45–1.01 (m, 4H).
实施例10、N-(3-(4-氰基萘-1-基)吡啶-4-基)-2-氟环己烷磺酰胺(9)Example 10 N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-2-fluorocyclohexanesulfonamide (9)
Figure PCTCN2018086731-appb-000016
Figure PCTCN2018086731-appb-000016
将制备化合物4的原料环丁基磺酰氯替换为2-氟环己烷磺酰氯，按照与化合物4相同的制备方法即可得到化合物9，质谱：410.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 2-fluorocyclohexanesulfonyl chloride, according to the same preparation method as the compound 4, the compound 9 was obtained, mass spectrum: 410.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)，1.99–1.78(m,4H)，1.74–1.66(m,1H)，1.45–1.01(m, 4H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 2.74 - 2.81 (m, 1H), 1.99 - 1.78 (m, 4H), 1.74 - 1.66 ( m, 1H), 1.45–1.01 (m, 4H).
实施例11、N-(3-(4-氰基萘-1-基)吡啶-4-基)-4-氟-1甲基吡咯烷-3-磺酰胺(10)Example 11, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-4-fluoro-1methylpyrrolidin-3-sulfonamide (10)
Figure PCTCN2018086731-appb-000017
Figure PCTCN2018086731-appb-000017
将制备化合物4的原料环丁基磺酰氯替换为4-氟-1甲基吡咯烷-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物10，质谱：411.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 4-fluoro-1methylpyrrolidin-3-sulfonyl chloride, the compound was obtained by the same preparation method as the compound 4, mass spectrum: 411.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.9(s,3H)，2.74–2.81(m,1H)，1.74–1.81(m,1H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 3.34 - 3.51 (m, 4H), 2.9 (s, 3H), 2.74 - 2.81 (m, 1H), 1.74–1.81 (m, 1H).
实施例12、N-(3-(4-氰基萘-1-基)吡啶-4-基)-2-氟-环戊烷-1-磺酰胺(11)Example 12, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-2-fluoro-cyclopentane-1-sulfonamide (11)
Figure PCTCN2018086731-appb-000018
Figure PCTCN2018086731-appb-000018
将制备化合物4的原料环丁基磺酰氯替换为2-氟-环戊烷-1-磺酰氯，按照与化合物4相同的制备方法即可得到化合物11，质谱：396.1(M+H +). The starting material cyclobutanesulfonyl chloride of compound 4 was replaced by 2-fluoro-cyclopentane-1-sulfonyl chloride. Compound 11 was obtained according to the same preparation method as compound 4, mass spectrum: 396.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)1.45–1.01(m,7H). 1 H NMR (400MHz, Chloroform- d) δ8.74-8.66 (m, 1H), 8.49 (d, J = 5.1Hz, 1H), 8.41 (dd, J = 8.4,5.2Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 2.74 - 2.81 (m, 1H) 1.45 - 1.01 (m, 7H).
实施例13、N-(3-(4-氰基萘-1-基)吡啶-4-基)-4-氟-氧代环戊烷-3-磺酰胺(12)Example 13, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-4-fluoro-oxocyclopentane-3-sulfonamide (12)
Figure PCTCN2018086731-appb-000019
Figure PCTCN2018086731-appb-000019
将制备化合物4的原料环丁基磺酰氯替换为4-氟-氧代环戊烷-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物12，质谱：398.1(M+H +)。 The starting material of the compound 4 was prepared by replacing the 4-cyclo-oxocyclopentane-3-sulfonyl chloride with 4-fluoro-oxocyclopentane-3-sulfonyl chloride. Compound 12 was obtained according to the same preparation procedure as Compound 4, mass spectrum: 398.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,1H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 3.34 - 3.51 (m, 4H), 2.74 - 2.81 (m, 1H), 1.74 - 1.81 ( m, 1H).
实施例14、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-哌啶-3-磺酰胺(13)Example 14, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-piperidine-3-sulfonamide (13)
Figure PCTCN2018086731-appb-000020
Figure PCTCN2018086731-appb-000020
将制备化合物4的原料环丁基磺酰氯替换为1-哌啶-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物13，质谱：393.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-piperidine-3-sulfonyl chloride, the compound was obtained by the same preparation method as the compound 4, mass spectrum: 393.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,4H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 3.34 - 3.51 (m, 4H), 2.74 - 2.81 (m, 1H), 1.74 - 1.81 ( m, 4H).
实施例15、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-甲基哌啶-3-磺酰胺(14)Example 15. N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-methylpiperidine-3-sulfonamide (14)
Figure PCTCN2018086731-appb-000021
Figure PCTCN2018086731-appb-000021
将制备化合物4的原料环丁基磺酰氯替换为1-甲基哌啶-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物14，质谱：407.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-methylpiperidine-3-sulfonyl chloride, the compound 14 was obtained by the same preparation method as the compound 4, mass spectrum: 407.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.9(s,3H)，2.74–2.81(m,1H)，1.74–1.81(m,4H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 3.34 - 3.51 (m, 4H), 2.9 (s, 3H), 2.74 - 2.81 (m, 1H), 1.74–1.81 (m, 4H).
实施例16、N-(3-(4-氰基萘-1-基)吡啶-4-基)-环己烷-1-磺酰胺(15)Example 16. N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-cyclohexane-1-sulfonamide (15)
Figure PCTCN2018086731-appb-000022
Figure PCTCN2018086731-appb-000022
将制备化合物4的原料环丁基磺酰氯替换为环己烷-1-磺酰氯，按照与化合物4相同的制备方法即可得到化合物15，质谱：392.1(M+H +). The starting material of the compound 4 was prepared by replacing the cyclobutylsulfonyl chloride with cyclohexane-1-sulfonyl chloride. According to the same preparation method as the compound 4, the compound 15 was obtained, mass spectrum: 392.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.34–2.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,6H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 2.34 - 2.51 (m, 4H), 2.74 - 2.81 (m, 1H), 1.74 - 1.81 ( m, 6H).
实施例17、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-氧代环己烷-3-磺酰胺(16)Example 17, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-oxocyclohexane-3-sulfonamide (16)
Figure PCTCN2018086731-appb-000023
Figure PCTCN2018086731-appb-000023
将制备化合物4的原料环丁基磺酰氯替换为1-氧代环己烷-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物16，质谱：394.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-oxocyclohexane-3-sulfonyl chloride, the compound was obtained by the same preparation method as the compound 4, mass spectrum: 394.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,4H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 3.34 - 3.51 (m, 4H), 2.74 - 2.81 (m, 1H), 1.74 - 1.81 ( m, 4H).
实施例18、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-氧代环己烷-4-磺酰胺(17)Example 18, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-oxocyclohexane-4-sulfonamide (17)
Figure PCTCN2018086731-appb-000024
Figure PCTCN2018086731-appb-000024
将制备化合物4的原料环丁基磺酰氯替换为1-氧代环己烷-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物17，质谱：394.1(M+H +)。 Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-oxocyclohexane-4-sulfonyl chloride, Compound 17 was obtained according to the same preparation procedure as Compound 4, mass spectrum: 394.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,4H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 3.34 - 3.51 (m, 4H), 2.74 - 2.81 (m, 1H), 1.74 - 1.81 ( m, 4H).
实施例19、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-哌啶-4-磺酰胺(18)Example 19, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-piperidin-4-sulfonamide (18)
Figure PCTCN2018086731-appb-000025
Figure PCTCN2018086731-appb-000025
将制备化合物4的原料环丁基磺酰氯替换为1-哌啶-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物18，质谱：393.1(M+H +). The starting material was prepared cyclic compound 4-chloro-butylsulfonyl alternative is 1-piperidinyl 4-sulfonyl chloride according to the same method of preparation of compound 4 to give compound 18, MS: 393.1 (M + H +) .
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),4.14–4.31(m,1H)，3.14–3.31(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,4H). 1 H NMR (400MHz, Chloroform- d) δ8.74-8.66 (m, 1H), 8.49 (d, J = 5.1Hz, 1H), 8.41 (dd, J = 8.4,5.2Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 4.14 - 4.31 (m, 1H), 3.14 - 3.31 (m, 4H), 2.74 - 2.81 ( m, 1H), 1.74–1.81 (m, 4H).
实施例20、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-甲基哌啶-4-磺酰胺(19)Example 20, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-methylpiperidine-4-sulfonamide (19)
Figure PCTCN2018086731-appb-000026
Figure PCTCN2018086731-appb-000026
将制备化合物4的原料环丁基磺酰氯替换为1-甲基哌啶-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物19，质谱：407.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-methylpiperidine-4-sulfonyl chloride, according to the same preparation method as the compound 4, the compound 19 was obtained, mass spectrum: 407.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),4.14(s,3H)，3.14–3.31(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,4H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 4.14 (s, 3H), 3.14 - 3.31 (m, 4H), 2.74 - 2.81 (m, 1H), 1.74–1.81 (m, 4H).
实施例21、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-吡咯烷-3-磺酰胺(20)Example 21, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-pyrrolidin-3-sulfonamide (20)
Figure PCTCN2018086731-appb-000027
Figure PCTCN2018086731-appb-000027
将制备化合物4的原料环丁基磺酰氯替换为1-吡咯烷-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物20，质谱：379.1(M+H +). The starting material cyclobutylsulfonyl chloride of the compound 4 was replaced with 1-pyrrolidine-3-sulfonyl chloride, and the compound 20 was obtained by the same preparation method as the compound 4, mass spectrum: 379.1 (M+H + ).
393.1(M+H +)， 1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),4.14–4.31(m,1H)，3.14–3.31(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,2H). 393.1(M+H + ), 1 H NMR (400MHz, Chloroform-d) δ 8.74–8.66 (m, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.41 (dd, J=8.4, 5.2 Hz, 1H), 8.23 (dd, J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H) , 7.65 (dd, J = 7.4, 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 4.14 - 4.31 (m, 1H), 3.14 - 3.31 (m , 4H), 2.74–2.81 (m, 1H), 1.74–1.81 (m, 2H).
实施例22、N-(3-(4-氰基萘-1-基)吡啶-4-基)-环庚烷-1-磺酰胺(21)Example 22, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-cycloheptane-1-sulfonamide (21)
Figure PCTCN2018086731-appb-000028
Figure PCTCN2018086731-appb-000028
将制备化合物4的原料环丁基磺酰氯替换为环庚烷-1-磺酰氯，按照与化合物4相同的制备方法即可得到化合物21，质谱：406.1(M+H +). The starting material was prepared cyclic compound 4-chloro-butylsulfonyl replacement of cycloheptane-1-sulfonyl chloride, following the same production method to compound 4 to give compound 21, MS: 406.1 (M + H +) .
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.34–2.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,8H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 2.34 - 2.51 (m, 4H), 2.74 - 2.81 (m, 1H), 1.74 - 1.81 ( m, 8H).
实施例23、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-氮代环庚烷-4-磺酰胺(22)Example 23, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-azacycloheptane-4-sulfonamide (22)
Figure PCTCN2018086731-appb-000029
Figure PCTCN2018086731-appb-000029
将制备化合物4的原料环丁基磺酰氯替换为1-氮代环庚烷-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物22，质谱：407.1(M+H +). The starting material cyclobutylsulfonyl chloride of compound 4 was replaced by 1-nitrocycloheptane-4-sulfonyl chloride. Compound 22 was obtained according to the same preparation procedure as compound 4, mass spectrum: 407.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),4.14–4.31(m,1H)，3.14–3.31(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,6H) 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 4.14 - 4.31 (m, 1H), 3.14 - 3.31 (m, 4H), 2.74 - 2.81 ( m, 1H), 1.74–1.81 (m, 6H)
实施例24、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-噻唑-2-磺酰胺(23)Example 24 N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-thiazole-2-sulfonamide (23)
Figure PCTCN2018086731-appb-000030
Figure PCTCN2018086731-appb-000030
将制备化合物4的原料环丁基磺酰氯替换为1-噻唑-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物23，质谱：393.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-thiazole-2-sulfonyl chloride, the compound was obtained by the same preparation method as the compound 4, mass spectrum: 393.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H) 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 3H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.1 Hz) , 1H), 7.03 (dd, J=4.9, 3.6 Hz, 1H)
实施例25、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-噻唑-2-磺酰胺(24)Example 25, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-thiazole-2-sulfonamide (24)
Figure PCTCN2018086731-appb-000031
Figure PCTCN2018086731-appb-000031
将制备化合物4的原料环丁基磺酰氯替换为噻吩-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物24，质谱：393.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with thiophene-2-sulfonyl chloride, the compound was obtained by the same preparation method as the compound 4, mass spectrum: 393.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H) 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 3H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.1 Hz) , 1H), 7.35 (dd, J = 3.6, 1.4 Hz, 1H), 7.03 (dd, J = 4.9, 3.6 Hz, 1H)
实施例26、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-吡啶-3-磺酰胺(25)Example 26, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-pyridine-3-sulfonamide (25)
Figure PCTCN2018086731-appb-000032
Figure PCTCN2018086731-appb-000032
将制备化合物4的原料环丁基磺酰氯替换为吡啶-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物25，质谱：387.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with pyridine-3-sulfonyl chloride, the compound was obtained by the same preparation method as the compound 4, mass spectrum: 387.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.27(s,1H),8.68–8.62(m,2H),8.24(d,J＝7.4Hz,1H),8.21–8.11(m,3H),7.89–7.78(m,2H),7.62–7.53(m,2H),7.47(ddd,J＝11.4,8.0,4.5Hz,3H). 1 H NMR (400MHz, DMSO- d 6) δ13.27 (s, 1H), 8.68-8.62 (m, 2H), 8.24 (d, J = 7.4Hz, 1H), 8.21-8.11 (m, 3H), 7.89–7.78 (m, 2H), 7.62–7.53 (m, 2H), 7.47 (ddd, J=11.4, 8.0, 4.5 Hz, 3H).
实施例27、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-吡啶-4-磺酰胺(26)Example 27, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-pyridine-4-sulfonamide (26)
Figure PCTCN2018086731-appb-000033
Figure PCTCN2018086731-appb-000033
将制备化合物4的原料环丁基磺酰氯替换为吡啶-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物26，质谱：387.1(M+H +). The starting material cyclobutanesulfonyl chloride of compound 4 was replaced with pyridine-4-sulfonyl chloride. Compound 26 was obtained according to the same preparation method as compound 4, mass spectrum: 387.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.27(s,1H),8.68–8.62(m,2H),8.24(d,J＝7.4Hz,1H),8.21–8.11(m,3H),7.89–7.78(m,2H),7.62–7.53(m,2H),7.47(ddd,J＝11.4,8.0,4.5Hz,3H). 1 H NMR (400MHz, DMSO- d 6) δ13.27 (s, 1H), 8.68-8.62 (m, 2H), 8.24 (d, J = 7.4Hz, 1H), 8.21-8.11 (m, 3H), 7.89–7.78 (m, 2H), 7.62–7.53 (m, 2H), 7.47 (ddd, J=11.4, 8.0, 4.5 Hz, 3H).
实施例28、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-嘧啶-5-磺酰胺(27)Example 28, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-pyrimidine-5-sulfonamide (27)
Figure PCTCN2018086731-appb-000034
Figure PCTCN2018086731-appb-000034
将制备化合物4的原料环丁基磺酰氯替换为1-嘧啶-5-磺酰氯，按照与化合物4相同的制备方法即可得到化合物27，质谱：388.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-pyrimidin-5-sulfonyl chloride, the compound 27 was obtained according to the same preparation method as the compound 4, mass spectrum: 388.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.27(s,1H),8.68–8.62(m,2H),8.24(d,J＝7.4Hz,1H),8.21–8.11(m,3H),7.89–7.78(m,2H),7.62–7.53(m,1H),7.47(ddd,J＝11.4,8.0,4.5Hz,3H). 1 H NMR (400MHz, DMSO- d 6) δ13.27 (s, 1H), 8.68-8.62 (m, 2H), 8.24 (d, J = 7.4Hz, 1H), 8.21-8.11 (m, 3H), 7.89–7.78 (m, 2H), 7.62–7.53 (m, 1H), 7.47 (ddd, J=11.4, 8.0, 4.5 Hz, 3H).
实施例29、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-嘧啶-2-磺酰胺(28)Example 29, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-pyrimidine-2-sulfonamide (28)
Figure PCTCN2018086731-appb-000035
Figure PCTCN2018086731-appb-000035
将制备化合物4的原料环丁基磺酰氯替换为1-嘧啶-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物28，质谱：388.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-pyrimidine-2-sulfonyl chloride, according to the same preparation method as the compound 4, the compound 28 was obtained, mass spectrum: 388.1 (M+H + ).
388.1(M+H +)， 1H NMR(400MHz,DMSO-d 6)δ13.27(s,1H),8.68–8.62(m,2H),8.24(d,J＝7.4Hz,1H),8.21–8.11(m,3H),7.89–7.78(m,2H),7.62–7.53(m,1H),7.47(ddd,J＝11.4,8.0,4.5Hz,3H). 388.1(M+H + ), 1 H NMR (400MHz, DMSO-d 6 ) δ 13.27 (s, 1H), 8.68 - 8.62 (m, 2H), 8.24 (d, J = 7.4 Hz, 1H), 8.21. –8.11 (m, 3H), 7.89–7.78 (m, 2H), 7.62–7.53 (m, 1H), 7.47 (ddd, J=11.4, 8.0, 4.5 Hz, 3H).
实施例30、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-吡嗪-2-磺酰胺(29)Example 30, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-pyrazine-2-sulfonamide (29)
Figure PCTCN2018086731-appb-000036
Figure PCTCN2018086731-appb-000036
将制备化合物4的原料环丁基磺酰氯替换为1-吡嗪-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物29，质谱：388.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-pyrazine-2-sulfonyl chloride, according to the same preparation method as the compound 4, the compound 29 was obtained, mass spectrum: 388.1 (M+H + ).
388.1(M+H +)， 1H NMR(400MHz,DMSO-d 6)δ13.27(s,1H),8.68–8.62(m,2H),8.24(d,J＝7.4Hz,1H),8.21–8.11(m,3H),7.89–7.78(m,2H),7.62–7.53(m,1H),7.47(ddd,J＝11.4,8.0,4.5Hz,3H). 388.1(M+H + ), 1 H NMR (400MHz, DMSO-d 6 ) δ 13.27 (s, 1H), 8.68 - 8.62 (m, 2H), 8.24 (d, J = 7.4 Hz, 1H), 8.21. –8.11 (m, 3H), 7.89–7.78 (m, 2H), 7.62–7.53 (m, 1H), 7.47 (ddd, J=11.4, 8.0, 4.5 Hz, 3H).
实施例31、N-(3-(4-氰基萘-1-基)吡啶-4-基)-3-甲基哒嗪-6-磺酰胺(30)Example 31, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-3-methylpyridazine-6-sulfonamide (30)
Figure PCTCN2018086731-appb-000037
Figure PCTCN2018086731-appb-000037
将制备化合物4的原料环丁基磺酰氯替换为3-甲基哒嗪-6-磺酰氯，按照与化合物4相同的制备方法即可得到化合物30，质谱：402.1(M+H +)。 The starting material cyclobutylsulfonyl chloride of the compound 4 was replaced with 3-methylpyridazine-6-sulfonyl chloride, and the compound 30 was obtained by the same preparation method as the compound 4, mass spectrum: 402.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.27(s,1H),8.68–8.62(m,2H),8.24(d,J＝7.4Hz,1H),8.21–8.11(m,3H),7.89–7.78(m,2H),7.62–7.53(m,1H),7.47(ddd,J＝11.4,8.0,4.5Hz,2H),3.61(s,3H). 1 H NMR (400MHz, DMSO- d 6) δ13.27 (s, 1H), 8.68-8.62 (m, 2H), 8.24 (d, J = 7.4Hz, 1H), 8.21-8.11 (m, 3H), 7.89–7.78 (m, 2H), 7.62–7.53 (m, 1H), 7.47 (ddd, J=11.4, 8.0, 4.5 Hz, 2H), 3.61 (s, 3H).
实施例32、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-恶唑-2-磺酰胺(31)Example 32, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-oxazole-2-sulfonamide (31)
Figure PCTCN2018086731-appb-000038
Figure PCTCN2018086731-appb-000038
将制备化合物4的原料环丁基磺酰氯替换为1-恶唑-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物31，质谱：377.1(M+H +). The preparation of the compounds 4-chloro-replacement materials cyclobutylsulfonyl 1-oxazol-2-sulfonyl chloride and following the same preparation of compound 4 to give compound 31, MS: 377.1 (M + H +) .
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H) 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 3H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.1 Hz) , 1H), 7.03 (dd, J=4.9, 3.6 Hz, 1H)
实施例33、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-异恶唑-5-磺酰胺(32)Example 33, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-isoxazole-5-sulfonamide (32)
Figure PCTCN2018086731-appb-000039
Figure PCTCN2018086731-appb-000039
将制备化合物4的原料环丁基磺酰氯替换为1-异恶唑-5-磺酰氯，按照与化合物4相同的制备方法即可得到化合物32，质谱：377.1(M+H +). The starting material cyclobutylsulfonyl chloride of compound 4 was replaced with 1-isoxazole-5-sulfonyl chloride. Compound 32 was obtained according to the same preparation procedure as compound 4, mass spectrum: 377.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H) 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 3H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.1 Hz) , 1H), 7.03 (dd, J=4.9, 3.6 Hz, 1H)
实施例34、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-甲基吡唑-5-磺酰胺(33)Example 34, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-methylpyrazole-5-sulfonamide (33)
Figure PCTCN2018086731-appb-000040
Figure PCTCN2018086731-appb-000040
将制备化合物4的原料环丁基磺酰氯替换为1-甲基吡唑-5-磺酰氯，按照与化合物4相同的制备方法即可得到化合物33，质谱：390.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-methylpyrazole-5-sulfonyl chloride, the compound was obtained by the same preparation method as the compound 4, mass spectrum: 390.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.13(s,3H) 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 3H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.1 Hz) , 1H), 7.03 (dd, J=4.9, 3.6 Hz, 1H), 3.13 (s, 3H)
实施例35、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-咪唑-4-磺酰胺(34)Example 35, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-imidazole-4-sulfonamide (34)
Figure PCTCN2018086731-appb-000041
Figure PCTCN2018086731-appb-000041
将制备化合物4的原料环丁基磺酰氯替换为1-咪唑-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物34，质谱：376.1(M+H +). The starting material cyclobutylsulfonyl chloride of compound 4 was replaced with 1-imidazole-4-sulfonyl chloride. Compound 34 was obtained according to the same preparation method as compound 4, mass spectrum: 376.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)。 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 3H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.1 Hz) , 1H), 7.03 (dd, J = 4.9, 3.6 Hz, 1H).
实施例36、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-甲基咪唑-5-磺酰胺(35)Example 36, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-methylimidazole-5-sulfonamide (35)
Figure PCTCN2018086731-appb-000042
Figure PCTCN2018086731-appb-000042
将制备化合物4的原料环丁基磺酰氯替换为1-甲基咪唑-5-磺酰氯，按照与化合物4相同的制备方法即可得到化合物35，质谱：390.1(M+H +). The starting material cyclobutylsulfonyl chloride of compound 4 was replaced by 1-methylimidazolium-5-sulfonyl chloride. Compound 35 was obtained according to the same preparation method as compound 4, mass spectrum: 390.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.13(s,3H) 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 3H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.1 Hz) , 1H), 7.03 (dd, J=4.9, 3.6 Hz, 1H), 3.13 (s, 3H)
实施例37、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-呋喃-3-磺酰胺(36)Example 37, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-furan-3-sulfonamide (36)
Figure PCTCN2018086731-appb-000043
Figure PCTCN2018086731-appb-000043
将制备化合物4的原料环丁基磺酰氯替换为1-呋喃-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物36，质谱：376.1(M+H +). The starting material cyclobutylsulfonyl chloride of compound 4 was replaced with 1-furan-3-sulfonyl chloride. Compound 36 was obtained according to the same preparation procedure as compound 4, mass spectrum: 376.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H) 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 3H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.1 Hz) , 1H), 7.35 (dd, J = 3.6, 1.4 Hz, 1H), 7.03 (dd, J = 4.9, 3.6 Hz, 1H)
实施例38、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-呋喃-2-磺酰胺(37)Example 38, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-furan-2-sulfonamide (37)
Figure PCTCN2018086731-appb-000044
Figure PCTCN2018086731-appb-000044
将制备化合物4的原料环丁基磺酰氯替换为1-呋喃-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物37，质谱：376.1(M+H +). The starting material cyclobutylsulfonyl chloride of compound 4 was replaced with 1-furan-2-sulfonyl chloride. Compound 37 was obtained according to the same preparation procedure as compound 4, mass spectrum: 376.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H) 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 3H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.1 Hz) , 1H), 7.35 (dd, J = 3.6, 1.4 Hz, 1H), 7.03 (dd, J = 4.9, 3.6 Hz, 1H)
实施例39、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1,3,4-恶二唑-2-磺酰胺(38)Example 39, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1,3,4-oxadiazol-2-sulfonamide (38)
Figure PCTCN2018086731-appb-000045
Figure PCTCN2018086731-appb-000045
将制备化合物4的原料环丁基磺酰氯替换为1,3,4-恶二唑-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物38，质谱：378.1(M+H +). The starting material cyclobutylsulfonyl chloride of the compound 4 was replaced with 1,3,4-oxadiazole-2-sulfonyl chloride, and the compound 38 was obtained by the same preparation method as the compound 4, mass spectrum: 378.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,2H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H) 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 2H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.1 Hz) , 1H), 7.35 (dd, J = 3.6, 1.4 Hz, 1H), 7.03 (dd, J = 4.9, 3.6 Hz, 1H)
实施例40、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1,3,4-噻二唑-2-磺酰胺(39)Example 40, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1,3,4-thiadiazole-2-sulfonamide (39)
Figure PCTCN2018086731-appb-000046
Figure PCTCN2018086731-appb-000046
将制备化合物4的原料环丁基磺酰氯替换为1,3,4-噻二唑-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物39，质谱：394.1(M+H +). The starting material of the compound 4 was prepared by replacing the starting material of cyclobutylsulfonyl chloride with 1,3,4-thiadiazole-2-sulfonyl chloride. According to the same preparation method as the compound 4, the compound 39 was obtained, mass spectrum: 394.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,2H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H) 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 2H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.1 Hz) , 1H), 7.35 (dd, J = 3.6, 1.4 Hz, 1H), 7.03 (dd, J = 4.9, 3.6 Hz, 1H)
实施例41.N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-甲基-1,2,4-三氮唑-3-磺酰胺(40)Example 41. N-(3-(4-Cyanonaphthalen-1-yl)pyridin-4-yl)-1-methyl-1,2,4-triazole-3-sulfonamide (40)
Figure PCTCN2018086731-appb-000047
Figure PCTCN2018086731-appb-000047
将制备化合物4的原料环丁基磺酰氯替换为1-甲基-1,2,4-三氮唑-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物40，质谱：391.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-methyl-1,2,4-triazole-3-sulfonyl chloride, the compound 40 can be obtained by the same preparation method as the compound 4, mass spectrum: 391.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,2H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.13(s,3H), 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 2H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.1 Hz) , 1H), 7.35 (dd, J = 3.6, 1.4 Hz, 1H), 7.03 (dd, J = 4.9, 3.6 Hz, 1H), 3.13 (s, 3H),
实施例42、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1,2-二甲基咪唑-4-磺酰胺(41)Example 42, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1,2-dimethylimidazolium-4-sulfonamide (41)
Figure PCTCN2018086731-appb-000048
Figure PCTCN2018086731-appb-000048
将制备化合物4的原料环丁基磺酰氯替换为1,2-二甲基-1H-咪唑-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物41，质谱：404.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride, the compound 41 was obtained by the same preparation method as the compound 4, mass spectrum: 404.1 (M+ H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,2H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.33(s,3H),3.13(s,3H), 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 2H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.1 Hz) , 1H), 7.35 (dd, J = 3.6, 1.4 Hz, 1H), 7.03 (dd, J = 4.9, 3.6 Hz, 1H), 3.33 (s, 3H), 3.13 (s, 3H),
实施例43、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-甲基咪唑-4-磺酰胺(42)Example 43, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-methylimidazole-4-sulfonamide (42)
Figure PCTCN2018086731-appb-000049
Figure PCTCN2018086731-appb-000049
将制备化合物4的原料环丁基磺酰氯替换为1-甲基咪唑-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物42，质谱：390.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-methylimidazole-4-sulfonyl chloride, the compound 42 was obtained by the same preparation method as the compound 4, mass spectrum: 390.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H), 7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.13(s,3H), 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 3H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.1 Hz) , 1H), 7.35 (dd, J = 3.6, 1.4 Hz, 1H), 7.03 (dd, J = 4.9, 3.6 Hz, 1H), 3.13 (s, 3H),
实施例44、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-氨基磺酰胺(43)Example 44, N-(3-(4-Cyanonaphthalen-1-yl)pyridin-4-yl)-1-aminosulfonamide (43)
Figure PCTCN2018086731-appb-000050
Figure PCTCN2018086731-appb-000050
将制备化合物4的原料环丁基磺酰氯替换为1-氨基磺酰氯，按照与化合物4相同的制备方法即可得到化合物43，质谱：325.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-aminosulfonyl chloride, according to the same preparation method as the compound 4, the compound 43 was obtained, mass spectrum: 325.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,2H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.13(s,2H), 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 2H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.1 Hz, 1H), 7.35 (dd, J =3.6, 1.4 Hz, 1H), 7.03 (dd, J=4.9, 3.6 Hz, 1H), 3.13 (s, 2H),
实施例45、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-乙氨基磺酰胺(44)Example 45, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-ethylaminosulfonamide (44)
Figure PCTCN2018086731-appb-000051
Figure PCTCN2018086731-appb-000051
将制备化合物4的原料环丁基磺酰氯替换为1-乙氨基磺酰氯，按照与化合物4相同的制备方法即可得到化合物44，质谱：353.1(M+H +). The starting material of the compound 4 was replaced with 1-ethylaminosulfonyl chloride, and the compound 44 was obtained by the same preparation method as the compound 4, mass spectrum: 353.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,2H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.13(m,2H)，1.13(m,3H), 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 2H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.1 Hz, 1H), 7.35 (dd, J =3.6, 1.4 Hz, 1H), 7.03 (dd, J=4.9, 3.6 Hz, 1H), 3.13 (m, 2H), 1.13 (m, 3H),
实施例46、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-环丙基氨基磺酰胺(45)Example 46, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-1-cyclopropylaminosulfonamide (45)
Figure PCTCN2018086731-appb-000052
Figure PCTCN2018086731-appb-000052
将制备化合物4的原料环丁基磺酰氯替换为1-环丙基氨基磺酰氯，按照与化合物4相同的制备方法即可得到化合物45，质谱：365.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 1-cyclopropylsulfamoyl chloride, the compound 45 was obtained by the same preparation method as the compound 4, mass spectrum: 365.1 (M+H + ).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H), 7.37(s,1H),2.74–2.81(m,1H)1.39–1.13(m,4H). 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.66 (m, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 8.4, 5.2 Hz, 1H), 8.23 (dd , J=6.9, 5.4 Hz, 1H), 8.11 (dd, J=7.4, 5.4 Hz, 1H), 7.90–7.80 (m, 1H), 7.77–7.68 (m, 1H), 7.65 (dd, J=7.4) , 5.3 Hz, 1H), 7.58 (dd, J = 8.5, 5.2 Hz, 1H), 7.37 (s, 1H), 2.74 - 2.81 (m, 1H) 1.39 - 1.13 (m, 4H).
实施例47、N-(3-(4-氰基萘-1-基)吡啶-4-基)-2-氯噻吩-5-磺酰胺(46)Example 47, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-2-chlorothiophene-5-sulfonamide (46)
Figure PCTCN2018086731-appb-000053
Figure PCTCN2018086731-appb-000053
将制备化合物4的原料环丁基磺酰氯替换为2-氯噻吩-5-磺酰氯，按照与化合物4相同的制备方法即可得到化合物46，质谱：426.1(M+H +). Substituting the starting material of the compound 4, cyclobutylsulfonyl chloride, with 2-chlorothiophene-5-sulfonyl chloride, the compound 46 was obtained by the same preparation method as the compound 4, mass spectrum: 426.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H). 1 H NMR (400MHz, DMSO- d 6) δ13.25 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 8.22-8.13 (m, 3H), 7.82 (ddd, J = 8.3,6.7 , 1.4 Hz, 1H), 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.1 Hz, 1H), 7.35 (dd, J =3.6, 1.4 Hz, 1H), 7.03 (dd, J = 4.9, 3.6 Hz, 1H).
实施例48、N-(3-(4-氰基萘-1-基)吡啶-4-基)-3,5-二甲基异恶唑-4-磺酰胺(47)Example 48, N-(3-(4-Cyanophthalen-1-yl)pyridin-4-yl)-3,5-dimethylisoxazole-4-sulfonamide (47)
Figure PCTCN2018086731-appb-000054
Figure PCTCN2018086731-appb-000054
将制备化合物4的原料环丁基磺酰氯替换为3,5-二甲基异恶唑-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物47，质谱：405.1(M+H +). The starting material cyclobutanesulfonyl chloride of the compound 4 was replaced with 3,5-dimethylisoxazole-4-sulfonyl chloride, and the compound 47 was obtained by the same preparation method as the compound 4, mass spectrum: 405.1 (M+H + ).
1H NMR(400MHz,DMSO-d 6)δ8.25(d,J＝7.3Hz,1H),8.21(dt,J＝8.4,1.0Hz,1H),8.13(d,J＝5.7Hz,1H),7.94(s,1H),7.83(ddd,J＝8.3,6.4,1.7Hz,1H),7.72–7.62(m,2H),7.57(d,J＝7.4Hz,1H),6.72(d,J＝5.7Hz,1H),5.68(s,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.25 (d, J = 7.3 Hz, 1H), 8.21. (dt, J = 8.4, 1.0 Hz, 1H), 8.13 (d, J = 5.7 Hz, 1H) , 7.94 (s, 1H), 7.83 (ddd, J = 8.3, 6.4, 1.7 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.57 (d, J = 7.4 Hz, 1H), 6.72 (d, J =5.7 Hz, 1H), 5.68 (s, 1H).
以下通过试验例的方式来说明本发明的有益效果。The advantageous effects of the present invention will be described below by way of test examples.
试验例1、本发明化合物的生物学活性测定Test Example 1. Determination of biological activity of the compound of the present invention
测试例：本发明化合物对URAT1抑制活性的测定Test Example: Determination of the inhibitory activity of the compound of the present invention on URAT1
1)实验材料：1) Experimental materials:
胎牛血清(Invitrogen,Cat.No.10099141)Fetal bovine serum (Invitrogen, Cat. No. 10099141)
胰酶(Invitrogen,Cat.No.25200056)Trypsin (Invitrogen, Cat. No. 25200056)
磷酸盐缓冲液(Invitrogen,Cat.No.14190250)Phosphate buffer (Invitrogen, Cat. No. 14190250)
杜尔伯科改良伊格尔培养基(Invitrogen,Cat.No.10564)Durbuco Modified Eagle Medium (Invitrogen, Cat. No. 10564)
青霉素-链霉素(Invitrogen,Cat.No.15070-063)Penicillin-streptomycin (Invitrogen, Cat. No. 15070-063)
转IT-293转染试剂(MIRUS BIO,Cat.No.MIR2706)Transfer to IT-293 Transfection Reagent (MIRUS BIO, Cat. No. MIR2706)
无血清优化改良伊格尔培养基(Invitrogen,Cat.No.31985-070)Serum-free optimized and improved Eagle's medium (Invitrogen, Cat. No. 31985-070)
尿酸盐阴离子转运体1质粒(Genecopoeia,Cat.No.EX-T4563-M03)Urate Anion Transporter 1 Plasmid (Genecopoeia, Cat. No. EX-T4563-M03)
尿酸[8-14C](ARC,Cat.No.ARC0513-250UCI)Uric acid [8-14C] (ARC, Cat. No. ARC0513-250UCI)
终极金 TMXR闪烁液(PerkinElmer,Cat.No.6013111) Ultimate TM XR gold scintillation fluid (PerkinElmer, Cat.No.6013111)
苯溴马隆(百灵威科技,Cat.No.3562-84-3)Benzobromarone (Belling Technology, Cat. No. 3562-84-3)
D-葡萄糖酸钠盐(阿拉丁,Cat.No.527-07-1)D-gluconate sodium salt (Aladdin, Cat. No. 527-07-1)
D-葡萄糖酸钾(阿拉丁,Cat.No.299-27-4)D-Gluconophosphate (Aladdin, Cat. No. 299-27-4)
葡萄糖酸钙(阿拉丁,Cat.No.299-28-5)Calcium gluconate (Aladdin, Cat. No. 299-28-5)
二甲基亚砜(Sigma,Cat.No.D2650)Dimethyl sulfoxide (Sigma, Cat. No. D2650)
离心管,15ml(Greiner,Cat.No.07030115)Centrifuge tube, 15ml (Greiner, Cat.No.07030115)
离心管,50ml(BD Falcon,Cat.No.352098)Centrifuge tube, 50ml (BD Falcon, Cat. No. 352098)
多聚D-赖氨酸96微孔板(BD,Cat.No.356461)Poly D-lysine 96 microplate (BD, Cat. No. 356461)
隔离96微孔板(PERKIN ELMER,Cat.No.6005040)Isolation of 96 microplates (PERKIN ELMER, Cat. No. 6005040)
2)实验方法：2) Experimental method:
i)缓冲液配制i) Buffer preparation
Figure PCTCN2018086731-appb-000055
Figure PCTCN2018086731-appb-000055
ii)细胞培养：Ii) Cell culture:
①将稳定表达hURAT1的HEK-293T细胞培养于10％FBS和1％P/S的DMEM培养基中，在5％二氧化碳的37度培养箱中培养过夜。1 HEK-293T cells stably expressing hURAT1 were cultured in 10% FBS and 1% P/S DMEM medium, and cultured overnight in a 37-degree incubator with 5% carbon dioxide.
②将培养基去掉后用PBS清洗一次，然后加入胰酶消化2分钟，待细胞于培养皿分离后加入10毫升培养基终止消化。2 The medium was removed, washed once with PBS, and then trypsinized for 2 minutes. After the cells were separated in the culture dish, 10 ml of the medium was added to terminate the digestion.
③把细胞放入离心机1000转离心2分钟，加入新的10毫升培养基来重悬细胞，并计算细胞个数。将细胞个数调整为4x10 5个细胞每毫升。 3 Place the cells in a centrifuge for 1000 minutes at 1000 rpm, add a new 10 ml medium to resuspend the cells, and count the number of cells. The number of cells was adjusted to 4 x 10 5 cells per ml.
④将上述计数好的细胞接种到96孔板中，每孔100微升。4 The above counted cells were seeded into 96-well plates at 100 μL per well.
⑤将接种好细胞的96孔板放置于37度细胞培养箱中培养过夜。5 The 96-well plates inoculated with the cells were placed in a 37-degree cell culture incubator overnight.
ⅲ)同位素碳14标记的尿酸吸收实验：Iii) Isotope carbon 14 labeled uric acid absorption experiment:
①在15毫升离心管中加入5毫升Cl-free HBSS缓冲液，然后加入碳14标记的尿酸，使尿酸的浓度达到2uCi/ml.1 Add 5 ml of Cl-free HBSS buffer to a 15 ml centrifuge tube, then add carbon 14-labeled uric acid to bring the concentration of uric acid to 2 uCi/ml.
②将之前培养过夜的96孔板中的培养基吸干净，加入100毫升预热过的Cl-free HBSS缓冲液清洗三次。2 The medium in the 96-well plate that had been cultured overnight was sucked up and washed three times with 100 ml of pre-warmed Cl-free HBSS buffer.
③将清洗好后的96孔板中的所以缓冲液吸干净。3 Soak the buffer in the cleaned 96-well plate.
④清洗好的96孔板上每孔中加入50微升含有碳14标记的尿酸的Cl-free HBSS缓冲液，然后加入需要测试的化合物的DMSO溶液。On each of the cleaned 96-well plates, 50 μl of Cl-free HBSS buffer containing carbon 14-labeled uric acid was added to each well, followed by the addition of the DMSO solution of the compound to be tested.
⑤把上述96孔板在室温下静置5分钟后，将里面所有的液体吸干。5 After the above 96-well plate was allowed to stand at room temperature for 5 minutes, all the liquid inside was drained.
⑥加入100毫升预冷的无Cl离子Hanks平衡盐溶液缓冲液清洗三次。6 Wash three times with 100 ml of pre-cooled Cl-free Hanks balanced salt solution buffer.
⑦把板里残留的液体吸干净后，于每孔中加入50微升的细胞裂解液，在混匀器上以每分钟600转的速度振荡10分钟。7 After sucking up the remaining liquid in the plate, add 50 μl of cell lysate to each well and shake at a speed of 600 rpm for 10 minutes on a mixer.
⑧加入50微升Ultima Gold TMXR scitillation cocktail闪烁液后，继续振荡10分钟。 ⑧ 50 l Ultima Gold TM XR scitillation cocktail after scintillation fluid, shaking continued for 10 minutes.
将振荡好的板用封板膜贴好后，于MicroBeta Trilux上读数。After the oscillating plate was pasted with a sealing film, it was read on a MicroBeta Trilux.
⑨将测试化合物溶解在DMSO中，然后将相同浓度的DMSO加入不包含测试化合物的HEK293/hURAT1细胞孔中。将各测试浓度下的细胞的尿酸摄取表示为相对DMSO对照的平均百分比抑制率。将对包含DMSO的孔得到的放射性值视为细胞的100％摄取。化合物的IC50值可通过不同浓度下的抑制率计算得出。9 The test compound was dissolved in DMSO, and then the same concentration of DMSO was added to the HEK293/hURAT1 cell well containing no test compound. Uric acid uptake of cells at each test concentration was expressed as the average percent inhibition of the DMSO control. The radioactivity value obtained for the wells containing DMSO is considered to be 100% uptake of the cells. The IC50 value of a compound can be calculated from the inhibition rate at different concentrations.
本发明上述化合物的活性数据如下表：The activity data of the above compounds of the present invention are as follows:
Figure PCTCN2018086731-appb-000056
Figure PCTCN2018086731-appb-000056
Figure PCTCN2018086731-appb-000057
Figure PCTCN2018086731-appb-000057
Figure PCTCN2018086731-appb-000058
Figure PCTCN2018086731-appb-000058
Figure PCTCN2018086731-appb-000059
Figure PCTCN2018086731-appb-000059
试验表明，本发明实施例的化合物具有良好的URAT1抑制活性，可以用于痛风和高尿酸血症的治疗，还可用于复发性痛风发作、痛风性关节炎、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症等与URAT1活性异常疾病的治疗。Tests have shown that the compounds of the examples of the present invention have good URAT1 inhibitory activity, can be used for the treatment of gout and hyperuricemia, and can also be used for recurrent gout attacks, gouty arthritis, hypertension, cardiovascular diseases, coronary heart disease. , Lai-naphthalene syndrome, Kay-Sei's syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, nodules Treatment of disease or secondary jaundice-guanine phosphoribosyltransferase deficiency and other diseases with abnormal URAT1 activity.
综上所述，本发明公开的式(A)所示的新化合物，表现出了良好的URAT1抑制活 性，为临床治疗与URAT1活性异常相关的疾病提供了一种新的药用可能。In summary, the novel compound of the formula (A) disclosed in the present invention exhibits a good URAT1 inhibitory activity and provides a new medicinal possibility for clinical treatment of diseases associated with abnormal URAT1 activity.

Claims (15)

  1. 式(Ⅰ)所示化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，a compound of the formula (I), or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof,
    Figure PCTCN2018086731-appb-100001
    Figure PCTCN2018086731-appb-100001
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O) 2X、-COX、-COOX、-CONXY、-NXY或-NXCOY，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂环芳基分别独立地进一步被一个或多个任选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O) 2X、-COX、-COOX、-CONXY、-NXY或-NXCOY的取代基所取代， Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, and alkyne. a base, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heterocyclic aryl group, -OX, -S(O) 2 X, -COX, -COOX, -CONXY, -NXY or -NXCOY, wherein the alkane The group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heterocyclic aryl group are each independently further selected from one or more selected from the group consisting of halogen, cyano, nitro, oxo, alkyl. , haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, -OX, -S(O) 2 X, -COX, -COOX, -CONXY Substituted by a substituent of -NXY or -NXCOY,
    R选自3元-7元的环烷基、3元-7元的杂环烷基、6元-12元的杂环芳基、-NR pR q，其中所述的环烷基、杂环烷基、杂环芳基分别独立地进一步被一个或多个任选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O) 2X、-COX、-COOX、-CONXY、-NXY或-NXCOY的取代基所取代； R is selected from a 3- to 7-membered cycloalkyl group, a 3-membered-7-membered heterocycloalkyl group, a 6- to 12-membered heterocyclic aryl group, -NR p R q , wherein the cycloalkyl group, hetero The cycloalkyl and heterocyclic aryl groups are each independently further selected from one or more selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkane. Substituted with a substituent of a heterocycloalkyl, aryl, heterocyclic aryl, -OX, -S(O) 2 X, -COX, -COOX, -CONXY, -NXY or -NXCOY;
    R p、R q分别独立地选自氢、C 1-C 6的烷基、3元-6元的环烷基、3元-6元的杂环烷基； R p and R q are each independently selected from the group consisting of hydrogen, a C 1 -C 6 alkyl group, a 3 member-6 membered cycloalkyl group, and a 3 member-6 membered heterocycloalkyl group;
    X、Y分别独立的选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基。X and Y are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl.
  2. 根据权利要求1所述的化合物，其特征在于：所述R 1、R 2、R 3、R 4、R 5、R 7、R 8、R 9分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O) 2X、-COX、-COOX、-CONXY、-NXY或-NXCOY，X、Y分别独立的选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基。 The compound according to claim 1, wherein said R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, halogen, and cyano. Nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, -OX, -S(O) 2 X, -COX, -COOX, -CONXY, - NXY or -NXCOY, X and Y are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl.
  3. 根据权利要求2所述的化合物，其特征在于：所述R 1、R 2、R 3、R 4、R 5、R 7、R 8、R 9分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、烷氧基。 The compound according to claim 2, wherein said R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, halogen, and cyano. Nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, alkoxy.
  4. 根据权利要求3所述的化合物，其特征在于：所述R 1、R 2、R 3、R 4、R 5、R 7、R 8、R 9均为氢。 The compound according to claim 3, wherein said R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are all hydrogen.
  5. 根据权利要求1所述的化合物，其特征在于：所述R 6选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、烷氧基。 The compound according to claim 1, wherein said R 6 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, Heterocyclic aryl, alkoxy.
  6. 根据权利要求5所述的化合物，其特征在于：所述R 6为氰基。 The compound according to claim 5, wherein said R 6 is a cyano group.
  7. 根据权利要求1所述的化合物，其特征在于：所述R选自3元-7元的环烷基、3元-7元的杂环烷基、6元-12元的杂环芳基、-NR pR q，其中所述的环烷基、杂环烷基、杂环芳基分别独立地被零个、一个或多个选自卤素、烷基、环烷基、杂环烷基、芳基、杂环芳基、氨基的取代基取代。 The compound according to claim 1, wherein said R is selected from the group consisting of a 3- to 7-membered cycloalkyl group, a 3-membered-7-membered heterocycloalkyl group, and a 6- to 12-membered heterocyclic aryl group. -NR p R q , wherein said cycloalkyl, heterocycloalkyl, heterocyclic aryl are each independently zero, one or more selected from the group consisting of halogen, alkyl, cycloalkyl, heterocycloalkyl, A substituent of an aryl group, a heterocyclic aryl group or an amino group is substituted.
  8. 根据权利要求7所述的化合物，其特征在于：所述杂环烷基或者杂环芳基上有1～3个杂原子。The compound according to claim 7, wherein the heterocycloalkyl or heterocyclic aryl has 1 to 3 hetero atoms.
  9. 根据权利要求8所述的化合物，其特征在于：所述杂原子为N、O或S。The compound according to claim 8, wherein the hetero atom is N, O or S.
  10. 根据权利要求9所述的化合物，其特征在于：所述R选自The compound according to claim 9, wherein said R is selected from the group consisting of
    Figure PCTCN2018086731-appb-100002
    Figure PCTCN2018086731-appb-100002
    其中上述的基团分别独立地被零个、一个或多个选自卤素、烷基、环烷基、杂环烷基、芳基、杂环芳基、氨基的取代基取代。Wherein the above groups are each independently substituted by zero, one or more substituents selected from the group consisting of halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic aryl, amino.
  11. 根据权利要求1-10任一项所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，所述化合物为如下化合物之一：The compound according to any one of claims 1 to 10, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein the compound is the following compound one:
    Figure PCTCN2018086731-appb-100003
    Figure PCTCN2018086731-appb-100003
    Figure PCTCN2018086731-appb-100004
    Figure PCTCN2018086731-appb-100004
    Figure PCTCN2018086731-appb-100005
    Figure PCTCN2018086731-appb-100005
  12. 制备权利要求1-11任一项所述的化合物的方法，其特征在于：包括下述步骤：A method of preparing a compound according to any one of claims 1-11, comprising the steps of:
    Figure PCTCN2018086731-appb-100006
    Figure PCTCN2018086731-appb-100006
  13. 权利要求1-12任一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物在制备URAT1抑制剂类药物中的用途。Use of a compound according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the manufacture of a URAT1 inhibitor.
  14. 根据权利要求13所述的用途，其特征在于：所述药物是预防和/或治疗痛风、复发性痛风发作、痛风性关节炎、高尿酸血症、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症的药物，优选预防和/或治疗痛风或高尿酸血症的药物。The use according to claim 13, characterized in that the medicament is for preventing and/or treating gout, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lai -naphthalene syndrome, Kay-Sei's syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis or A drug of hypoxanthine-guanine phosphoribosyltransferase deficiency, preferably a drug for preventing and/or treating gout or hyperuricemia.
  15. 一种药物组合物，其特征在于：它是以权利要求1-11任一项所述的化合物或其立体异构体、或其药学上可接受的盐、或其溶剂合物为活性成分，加上药学上可接受的辅料制备而成的制剂。A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient, Formulations prepared with pharmaceutically acceptable excipients.
PCT/CN2018/086731 2017-05-16 2018-05-14 Sulfonamide compound for treatment of gout or hyperuricemia, and method for preparing same WO2018210207A1 (en)

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