WO2021155781A1

WO2021155781A1 - Benzene sulfonamide compound containing five-membered heterocycle, preparation method therefor, and application thereof

Info

Publication number: WO2021155781A1
Application number: PCT/CN2021/074831
Authority: WO
Inventors: 何新华; 周涛; 杨朝福; 李爱玲; 陈亮; 李涛; 韩秋影; 王静
Original assignee: 中国人民解放军军事科学院军事医学研究院
Priority date: 2020-02-04
Filing date: 2021-02-02
Publication date: 2021-08-12
Also published as: CN111233786A; CN111233786B

Abstract

The present invention relates to a benzene sulfonamide compound containing a five-membered heterocycle represented by formula (I), and an enantiomer, a diastereomer, and a racemate thereof and a mixture thereof, and a pharmaceutically acceptable salt, crystalline hydrate, and solvate thereof, as well as a use of such a compound in the preparation of a CA inhibitor, and a pharmaceutical composition containing such a compound. As a carbonic anhydrase inhibitor, the compound of the present invention shows good development potential. In comparison with the commonly used carbonic anhydrase (CA) inhibitor, acetazolamide diamox, in clinical practice, the compound of the present invention has stronger inhibitory activity on CAI, and shows a strong inhibitory ability on both CAI and CAII, reaching an IC₅₀ of nanomolar levels, and is expected to avoid the loss of in vivo efficacy caused by the imbalance of acetazolamide diamox.

Description

含五元杂环的苯磺酰胺类化合物及其制备方法和用途Benzene sulfonamide compound containing five-membered heterocycle, and preparation method and application thereof

技术领域Technical field

本发明属于药学领域，具体涉及一种含五元杂环的苯磺酰胺类化合物或其药学上可接受的盐，及其制备方法，和包含该类化合物的药物组合物，以及其在制备治疗青光眼、高原缺氧、癫痫、癌症、白血病、肥胖、关节炎等药物中的用途。The present invention belongs to the field of pharmacy, and specifically relates to a five-membered heterocyclic ring-containing benzenesulfonamide compound or a pharmaceutically acceptable salt thereof, and a preparation method thereof, and a pharmaceutical composition containing the compound, and the preparation method Glaucoma, high altitude hypoxia, epilepsy, cancer, leukemia, obesity, arthritis and other medicines.

背景技术Background technique

人类碳酸酐酶(Carbonic Anhydrases,CA _S)是一种含锌的蛋白受体，它催化二氧化碳的可逆水合作用，形成质子和碳酸氢根，这种反应涉及许多生理和病理过程。包括二氧化碳的呼吸和运输，代谢组织和肺之间的碳酸氢盐转运；pH和CO ₂稳态；不同组织的电解质分泌和器官；因此与人体水肿、青光眼、肥胖、癌症、癫痫在内的疾病息息相关。人类碳酸酐酶分为16个亚型，其中CA I和CA II与青光眼、高原缺氧、癫痫等相关(Supuran CT.Nature Reviews Drug Discovery,2008,7,168-181；Arslan T,Turkoglu EA,Senturk M,Supuran CT.Bioorganic&Medicinal chemistry letters,2016,26(24):5867-5870；Ekinci D,Cavdar H,Talaz O,Senturk M,Supuran CT.Bioorganic&Medicinal Chemistry,2010,18(10):3559-3563)。 Human Carbonic Anhydrases (CA _S ) is a zinc-containing protein receptor, which catalyzes the reversible hydration of carbon dioxide to form protons and bicarbonate. This reaction involves many physiological and pathological processes. Including carbon dioxide respiration and transportation, bicarbonate transport between metabolic tissues and lungs; pH and CO ₂ homeostasis; electrolyte secretion and organs in different tissues; therefore, it is related to diseases such as edema, glaucoma, obesity, cancer, and epilepsy. Closely related. Human carbonic anhydrase is divided into 16 subtypes, of which CA I and CA II are related to glaucoma, high altitude hypoxia, epilepsy, etc. (Supuran CT. Nature Reviews Drug Discovery, 2008, 7, 168-181; Arslan T, Turkoglu EA, Senturk M , Supuran CT. Bioorganic & Medicinal chemistry letters, 2016, 26(24): 5867-5870; Ekinci D, Cavdar H, Talaz O, Senturk M, Supuran CT. Bioorganic & Medicinal Chemistry, 2010, 18(10): 3559-3563).

CA抑制剂作为利尿剂和治疗青光眼、癫痫和急性山地病的药物已在临床上应用数十年。特别值得一提的是乙酰唑胺(AAZ)，它是目前防治高原缺氧和癫痫的有效药物，是FDA批准的预防和治疗AMS最有效的药物(Jackson SJ,Varley J,Sellers C.Incidence and predictors of acute mountain sickness among trekkers on Mount Kilimanjaro.High Altitude Medicine&Biology,2010,11:217-222.)。乙酰唑胺的作用机制为增强呼吸驱动力、利尿和减少肾性代谢性酸中毒。但是乙酰唑胺副作用明显，如四肢麻木、全身不适、暂时性近视、胃肠道症状等，限制了其在长期治疗中的应用。目前已上市的药物包括醋氮酰胺、甲酰唑胺、双氯非那胺、依索唑胺、多佐胺、布林唑胺，但是它们存在水溶性差、眼部刺激、作用时间短等问题(庞鑫等，青光眼视神经保护治疗的研究进展，深圳中西医结合杂志，2018，28(24):196-198；宋春泽，磺胺类碳酸酐酶抑制剂研究进展，中国新药杂志2007，16(18)：1438-1444)。因此，开发具有低副作用的强效CAs抑制剂对青光眼、高原缺氧、癫痫、癌症、白血病、肥胖、关节炎具有重要意义。CA inhibitors have been used clinically for decades as diuretics and drugs for the treatment of glaucoma, epilepsy and acute mountain diseases. Particularly worth mentioning is acetazolamide (AAZ), which is currently an effective drug for the prevention and treatment of high altitude hypoxia and epilepsy. It is the most effective drug approved by the FDA for the prevention and treatment of AMS (Jackson SJ, Varley J, Sellers C. Incidence and predictors of acute mountain sickness among trekkers on Mount Kilimanjaro. High Altitude Medicine&Biology, 2010, 11:217-222.). Acetazolamide's mechanism of action is to enhance respiratory drive, diuresis and reduce renal metabolic acidosis. However, acetazolamide has obvious side effects, such as numbness of the limbs, general malaise, temporary myopia, gastrointestinal symptoms, etc., which limit its application in long-term treatment. The currently marketed drugs include acetazolamide, formazolamide, diclofenamide, esozolomide, dorzolamide, brinzolamide, but they have problems such as poor water solubility, eye irritation, and short action time. (Pang Xin et al. Research progress in the treatment of optic nerve protection for glaucoma, Shenzhen Journal of Integrated Traditional Chinese and Western Medicine, 2018, 28(24):196-198; Song Chunze, Research progress in sulfonamide carbonic anhydrase inhibitors, Chinese Journal of New Drugs 2007, 16(18) ): 1438-1444). Therefore, the development of potent CAs inhibitors with low side effects is of great significance for glaucoma, high altitude hypoxia, epilepsy, cancer, leukemia, obesity, and arthritis.

发明内容Summary of the invention

根据本发明的一个方面，本发明一个目的是提供式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物。According to one aspect of the present invention, an object of the present invention is to provide the enantiomers, diastereomers, racemates and mixtures of the five-membered heterocyclic benzenesulfonamide compounds represented by formula I , And its pharmaceutically acceptable salts, crystalline hydrates and solvates.

其中，Y为碳原子或者氮原子，Z和W中的至少一个为

其中取代基G选自NR1R2、OR3或取代或未取代的含有1至3个选自N和O的杂原子的五元、六元或七元杂环基，Z和W中的另一个不存在，或为氢原子、C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、被1至3个卤素原子取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、卤素原子、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的芳基； Among them, Y is a carbon atom or a nitrogen atom, and at least one of Z and W is

Wherein the substituent G is selected from NR1R2, OR3 or a substituted or unsubstituted five-membered, six-membered or seven-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, the other of Z and W does not exist , Or hydrogen atom, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl group, is C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl substituted with 1 to 3 halogen atoms , Halogen atom, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl group;

所述取代的含有1至3个选自N和O的杂原子的五元、六元或七元杂环基中的取代基选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、羟基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、含有1至3个选自N或O的杂原子的C5、C6、C7、C8、C9、C10、C11、C12、C13、C14或C15并环杂芳基的取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基和C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷氧基烷基；The substituents in the substituted five-membered, six-membered or seven-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O are selected from C1, C2, C3, C4, C5, C6, C7, C8 , C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl, hydroxy substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 , C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl, C5, C6, C7, C8, C9, C10, C5, C6, C7, C8, C9, C10, C18, C19 or C20 C11, C12, C13, C14 or C15 substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17 , C18, C19 or C20 alkyl and C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkoxy Alkyl;

R1、R2和R3各自独立地为：R1, R2, and R3 are each independently:

H、卤素原子、H, halogen atom,

卤素原子取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl substituted by halogen atoms,

C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷氧基、C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkoxy,

C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl,

C3至C20环烷基、C3 to C20 cycloalkyl,

C3至C20环烷基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl substituted with C3 to C20 cycloalkyl ,

C1、C2、C3、C4、C5、C6、C7、C8、C9或C10烷氧基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或 C20的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkoxy substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl groups,

C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20芳基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 , C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl groups,

含有1至3个选自N和O的杂原子的五元、六元或七元杂环基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12 substituted by a five-membered, six-membered or seven-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O , C13, C14, C15, C16, C17, C18, C19 or C20 alkyl groups,

含有1至3个卤素原子取代基的C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20芳基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl substituted C1, C2, C3, C4 containing 1 to 3 halogen atom substituents , C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl,

取代或未取代的C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20芳基，其中取代C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20芳基中的取代基选自含有1至3个C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、卤素原子、C7至C20芳烷基氧基和C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20烷氧基、Substituted or unsubstituted C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl groups, where C6, C7, C8, C9, C10, C11 are substituted The substituents in, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl groups are selected from containing 1 to 3 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 , C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl, halogen atom, C7 to C20 aralkyloxy and C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkoxy,

取代或未取代的含有1至3个选自N和O的杂原子的五元、六元或七元杂环基，其中取代的含有1至3个选自N和O的杂原子的五元、六元或七元杂环基中的取代基选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、羟基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基和C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷氧基烷基、A substituted or unsubstituted five-membered, six-membered or seven-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, wherein the substituted five-membered containing 1 to 3 heteroatoms selected from N and O The substituents in the six-membered or seven-membered heterocyclic group are selected from C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18 , C19 or C20 alkyl, hydroxy substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 And C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkoxyalkyl groups,

C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的氨基烷基；C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aminoalkyl;

所述卤素原子选自氟、氯、溴和碘。The halogen atom is selected from fluorine, chlorine, bromine and iodine.

作为优选的方案，其中，Z和W中的至少一个为

其中取代基G选自NR1R2、OR3或取代或未取代的含有1至3个选自N和O的杂原子的六元杂环基，Z和W中的另一个不存在，或为氢原子、C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、被1至3个卤素原子取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、卤素原子、C6、C7、C8、C9或C10的芳基； As a preferred solution, at least one of Z and W is

Wherein the substituent G is selected from NR1R2, OR3 or a substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, the other of Z and W does not exist, or is a hydrogen atom, C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl group, C1, C2, C3, C4, C5, C6, C7, C8, C9 or substituted by 1 to 3 halogen atoms C10 alkyl group, halogen atom, C6, C7, C8, C9 or C10 aryl group;

所述取代的含有1至3个选自N和O的杂原子的六元杂环基中的取代基选自C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、羟基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、含有1至3个选自N或O的杂原子的C5至C10并环杂芳基的取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基和C2至C10的烷氧基烷基；The substituents in the substituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O are selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkane C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl group, hydroxyl substituted C1, C2, C3, C4, C5, C6, C10, C5 to C10 heterocyclic heteroaryl containing 1 to 3 heteroatoms selected from N or O Substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl groups and C2 to C10 alkoxyalkyl groups;

R1、R2和R3各自独立地为：R1, R2, and R3 are each independently:

H、卤素原子、H, halogen atom,

卤素原子取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl substituted by halogen atoms,

C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷氧基、C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkoxy,

C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl groups,

C3至C10环烷基、C3 to C10 cycloalkyl,

C3至C10环烷基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl substituted by C3 to C10 cycloalkyl,

C1、C2、C3、C4、C5、C6、C7、C8、C9或C10烷氧基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkoxy substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl groups,

C6、C7、C8、C9或C10芳基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C6, C7, C8, C9 or C10 aryl substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl groups,

含有1至3个选自N和O的杂原子的六元杂环基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl substituted with a six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O,

含有1至3个卤素原子取代基的C6、C7、C8、C9或C10芳基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C6, C7, C8, C9 or C10 aryl substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl groups containing 1 to 3 halogen atom substituents,

取代或未取代的C6、C7、C8、C9或C10芳基，其中取代C6、C7、C8、C9或C10芳基中的取代基选自含有1至3个C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、卤素原子、C7、C8、C9或C10芳烷基氧基和C1、C2、C3、C4、C5、C6、C7、C8、C9或C10烷氧基、A substituted or unsubstituted C6, C7, C8, C9 or C10 aryl group, wherein the substituent in the substituted C6, C7, C8, C9 or C10 aryl group is selected from containing 1 to 3 C1, C2, C3, C4, C5 , C6, C7, C8, C9 or C10 alkyl, halogen atom, C7, C8, C9 or C10 aralkyloxy and C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkane Oxy,

取代或未取代的含有1至3个选自N和O的杂原子的六元杂环基，其中取代的含有1至3个选自N和O的杂原子的六元环基中的取代基选自C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、羟基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基和C2至C10的烷氧基烷基、A substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, wherein the substituted six-membered ring group containing 1 to 3 heteroatoms selected from N and O is a substituent Alkyl selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10, hydroxy substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl And C2 to C10 alkoxyalkyl groups,

C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的氨基烷基。C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 aminoalkyl.

作为优选的方案，其中，Z和W中的至少一个为

其中取代基G选自NR1R2、OR3或取代或未取代的含有1至3个选自N和O的杂原子的六元杂环基，Z和W中的另一个不存在，或为氢原子、C1、C2、C3、C4、C5或C6的烷基、被1至3个卤素原子取代的C1、C2、C3、C4、C5或C6的烷基、卤素原子、C6、C7、C8、C9或C10的芳基； As a preferred solution, at least one of Z and W is

Wherein the substituent G is selected from NR1R2, OR3 or a substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, the other of Z and W does not exist, or is a hydrogen atom, C1, C2, C3, C4, C5 or C6 alkyl group, C1, C2, C3, C4, C5 or C6 alkyl group substituted by 1 to 3 halogen atoms, halogen atom, C6, C7, C8, C9 or C10 aryl group;

所述取代的含有1至3个选自N和O的杂原子的六元杂环基中的取代基选自C1、C2、C3、C4、C5或C6的烷基、羟基取代的C1、C2、C3、C4、C5或C6的烷基和C2、C3、C4、C5或C6的烷氧基烷基；The substituents in the substituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O are selected from C1, C2, C3, C4, C5 or C6 alkyl, hydroxy substituted C1, C2 , C3, C4, C5 or C6 alkyl and C2, C3, C4, C5 or C6 alkoxyalkyl;

R1、R2和R3各自独立地为：R1, R2, and R3 are each independently:

H、卤素原子、H, halogen atom,

卤素原子取代的C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl substituted by halogen atoms,

C1、C2、C3或C4的烷氧基、C1, C2, C3 or C4 alkoxy group,

C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl group,

C3、C4、C5、C6、C7或C8环烷基、C3, C4, C5, C6, C7 or C8 cycloalkyl,

C3、C4、C5、C6、C7或C8环烷基取代的C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl substituted with C3, C4, C5, C6, C7 or C8 cycloalkyl,

C1、C2、C3或C4烷氧基取代的C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl substituted by C1, C2, C3 or C4 alkoxy,

C6、C7、C8、C9或C10芳基取代的C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl substituted with C6, C7, C8, C9 or C10 aryl,

含有1至3个选自N和O的杂原子的六元杂环基取代的C1、C2、C3或C4的烷基、A C1, C2, C3 or C4 alkyl group substituted with a six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O,

含有1至3个卤素原子取代基的C6、C7、C8、C9或C10芳基取代的C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl substituted by C6, C7, C8, C9 or C10 aryl groups containing 1 to 3 halogen atom substituents,

取代或未取代的C6、C7、C8、C9或C10芳基，其中取代C6、C7、C8、C9或C10芳基中的取代基选自含有1至3个C1、C2、C3或C4的烷基、卤素原子、C7、C8、C9或C10芳烷基氧基和C1至C3烷氧基、A substituted or unsubstituted C6, C7, C8, C9 or C10 aryl group, wherein the substituent in the substituted C6, C7, C8, C9 or C10 aryl group is selected from alkane containing 1 to 3 C1, C2, C3 or C4 Group, halogen atom, C7, C8, C9 or C10 aralkyloxy and C1 to C3 alkoxy,

取代或未取代的含有1至3个选自N和O的杂原子的六元杂环基，其中取代的含有1至3个选自N和O的杂原子的六元杂环基中的取代基选自C1、C2、C3、C4、C5或C6的烷基、羟基取代的C1、C2、C3、C4、C5或C6的烷基和C2、C3、C4、C5或C6的烷氧基烷基、The substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, and the substitution in the substituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O The group is selected from C1, C2, C3, C4, C5 or C6 alkyl, hydroxy substituted C1, C2, C3, C4, C5 or C6 alkyl and C2, C3, C4, C5 or C6 alkoxyalkyl base,

进一步优选地，其中，Z和W中的至少一个为

其中取代基G选自NR1R2、OR3或取代或未取代的含有1或2个选自N和O的杂原子的六元杂环基，Z和W中的另一个不存在，或为氢原子、甲基、乙基、丙基、丁基、Cl、Br、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、苯基或萘基； Further preferably, wherein at least one of Z and W is

Wherein the substituent G is selected from NR1R2, OR3 or a substituted or unsubstituted six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, the other of Z and W does not exist, or is a hydrogen atom, Methyl, ethyl, propyl, butyl, Cl, Br, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, phenyl or naphthalene base;

所述取代的含有1或2个选自N和O的杂原子的六元杂环基中的取代基选自甲基、乙基、丙基、丁基、羟甲基、羟乙基、羟丙基、羟丁基、甲氧基甲基、甲氧基乙基、甲氧基丙基、含有1或2个选自N或O的杂原子的C5、C6、C7、C8、C9、C10、C11、C12、C13、C14或C15苯并杂环芳基的取代的甲基、含有1或2个选自N或O的杂原子的C5、C6、C7、C8、C9、C10、C11、C12、C13、C14或C15苯并杂环芳基的取代的乙基和含有1或2个选自N或O的杂原子的C5、C6、C7、C8、C9、C10、C11、C12、C13、C14或C15苯并杂环芳基的取代的丙基；The substituent in the substituted six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxy Propyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, C5, C6, C7, C8, C9, C10 containing 1 or 2 heteroatoms selected from N or O , C11, C12, C13, C14 or C15 benzoheterocyclic aryl substituted methyl group, containing 1 or 2 heteroatoms selected from N or O C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 benzoheterocyclic aryl substituted ethyl group and C5, C6, C7, C8, C9, C10, C11, C12, C13 containing 1 or 2 heteroatoms selected from N or O , C14 or C15 benzoheterocyclic aryl substituted propyl group;

R1、R2和R3各自独立地为：R1, R2, and R3 are each independently:

H、氟、氯、溴、H, fluorine, chlorine, bromine,

一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、一氯甲基、二氯甲基、三氯甲基、一氯乙基、二氯乙基、三氯乙基、一溴甲基、二溴甲基、三溴甲基、一溴乙基、二溴乙基、三溴乙基、Monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, Dichloroethyl, trichloroethyl, monobromomethyl, dibromomethyl, tribromomethyl, monobromoethyl, dibromoethyl, tribromoethyl,

甲氧基、乙氧基、丙氧基、丁氧基、Methoxy, ethoxy, propoxy, butoxy,

甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,

环丙基、环丁基、环戊基、环己基、环庚基、环辛基、Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,

环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、环庚基甲基、环辛基甲基、环丙基乙基、环丁基乙基、环戊基乙基、环己基乙基、环庚基乙基、环辛基乙基、环丙基丙基、环丁基丙基、环戊基丙基、环己基丙基、环庚基丙基、环辛基丙基、环丙基丁基、环丁基丁基、环戊基丁基、环己基丁基、环庚基丁基、环辛基丁基、Cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl , Cyclohexylethyl, cycloheptylethyl, cyclooctylethyl, cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclooctyl Propyl, cyclopropylbutyl, cyclobutylbutyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptylbutyl, cyclooctylbutyl,

甲氧基甲基、乙氧基甲基、丙氧基甲基、丁氧基甲基、甲氧基乙基、乙氧基乙基、丙氧基乙基、丁氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基丙基、丁氧基丙基、甲氧基丁基、乙氧基丁基、丙氧基丁基、丁氧基丁基、Methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, methoxy Propyl propyl, ethoxy propyl, propoxy propyl, butoxy propyl, methoxy butyl, ethoxy butyl, propoxy butyl, butoxy butyl,

苯甲基、苯乙基、苯丙基、苯丁基、萘基甲基、萘基乙基、萘基丙基、萘基丁基、Benzyl, phenethyl, phenylpropyl, phenbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl,

含有1至3个氟、氯或溴卤素原子取代基的苯基或萘基取代的C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl substituted by phenyl or naphthyl with 1 to 3 fluorine, chlorine or bromine halogen atom substituents,

取代或未取代的苯基或萘基，其中取代的苯基或萘基中的取代基选自含有1至3个选自甲基、乙基、丙基、丁基、氟、氯、溴、苯氧基、苯甲氧基、苯乙氧基、苯丙氧基、苯丁氧基、萘氧基、萘甲氧基、萘乙氧基、萘丙氧基、萘丁氧基、甲氧基、乙氧基和丙氧基的取代基、A substituted or unsubstituted phenyl or naphthyl group, wherein the substituent in the substituted phenyl or naphthyl group is selected from the group consisting of 1 to 3 selected from methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, Phenoxy, benzyloxy, phenethoxy, phenylpropoxy, phenbutoxy, naphthyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, naphthylbutoxy, methoxy Group, ethoxy and propoxy substituents,

取代或未取代的含有1至3个选自N和O的杂原子的六元杂环基，其中取代的含有1至3个选自N和O的杂原子的六元杂环基中的取代基选自甲基、乙基、丙基、丁基、羟甲基、羟乙基、羟丙基、羟丁基、甲氧基甲基、乙氧基甲基和丙氧基甲基、甲氧基乙基、乙氧基乙基和丙氧基乙基、甲氧基丙基、乙氧基丙基和丙氧基丙基、The substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, and the substitution in the substituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O The group is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxymethyl, ethoxymethyl and propoxymethyl, methyl Oxyethyl, ethoxyethyl and propoxyethyl, methoxypropyl, ethoxypropyl and propoxypropyl,

甲胺基、乙胺基、丙胺基、丁胺基、戊胺基、二甲胺基、二乙胺基、二丙胺基、二丁胺基、二戊胺基、甲基乙基胺基、甲基丙基胺基、甲基丁基胺基、甲基戊基胺基、乙基丙基胺基、乙基丁基胺基、乙基戊基胺基、丙基丁基胺基、丙基戊基胺基、丁基戊基胺基。Methylamino, ethylamino, propylamino, butylamino, pentylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, methylethylamino, Methyl propyl amino, methyl butyl amino, methyl pentyl amino, ethyl propyl amino, ethyl butyl amino, ethyl pentyl amino, propyl butyl amino, propyl Benzyl pentyl amino, butyl pentyl amino.

进一步优选地，式I所述的含五元杂环的苯磺酰胺类化合物、其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物选自如下化合物：Further preferably, the five-membered heterocyclic ring-containing benzenesulfonamide compound of formula I, its enantiomers, diastereomers, racemates and mixtures thereof, and their pharmaceutically acceptable Salts, crystalline hydrates and solvates are selected from the following compounds:

(1)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸乙酯(1) 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid ethyl ester

(2)5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-羧酸乙酯(2) 5-[(4-sulfamoylphenyl) formyl]amino-1,3,4-thiadiazole-2-carboxylic acid ethyl ester

(3)N-环丙基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(3) N-Cyclopropyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(4)N-环戊基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(4) N-cyclopentyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(5)N-环己基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(5) N-cyclohexyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(6)N-环庚基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(6)N-cycloheptyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(7)N-环辛基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(7)N-cyclooctyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(8)N-正丙基-2-[(4-氨磺酰基苯甲酰基)胺基]噻唑-4-甲酰胺(8)N-n-propyl-2-[(4-sulfamoylbenzoyl)amino]thiazole-4-carboxamide

(9)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸酯己酯(9) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylate hexyl ester

(10)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸异丙酯(10) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid isopropyl ester

(11)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸(2-甲氧基)乙基酯(11) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid (2-methoxy) ethyl ester

(12)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环丙甲基酯(12) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid cyclopropylmethyl ester

(13)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环戊基甲基酯(13) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid cyclopentyl methyl ester

(14)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环丙基酯(14) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid cyclopropyl ester

(15)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环戊基酯(15) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid cyclopentyl ester

(16)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环己基酯(16) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid cyclohexyl ester

(17)N-正丙基-5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰胺(17) N-n-propyl-5-[(4-sulfamoylphenyl)formyl]amino-1,3,4-thiadiazole-2-carboxamide

(18)N-环己基-5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰胺(18)N-cyclohexyl-5-[(4-sulfamoylphenyl)formyl]amino-1,3,4-thiadiazole-2-carboxamide

(19)N-环庚基-5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰胺(19)N-Cycloheptyl-5-[(4-sulfamoylphenyl)formyl]amino-1,3,4-thiadiazole-2-carboxamide

(20)5-[(4-氨磺酰苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰胺(20) 5-[(4-sulfamoylphenyl) formyl]amino-1,3,4-thiadiazole-2-carboxamide

(21)5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰肼(21) 5-[(4-sulfamoylphenyl) formyl]amino-1,3,4-thiadiazole-2-carboxhydrazide

(22)N-(4-氟苄基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(22) N-(4-fluorobenzyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(23)N-(3,4-二甲基苯基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(23)N-(3,4-Dimethylphenyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(24)N-[3-(苄氧基)苯基]-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(24)N-[3-(Benzyloxy)phenyl]-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(25)(R)-N-(1-苯基丙基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(25)(R)-N-(1-phenylpropyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(26)N-甲基-N-苯基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(26)N-Methyl-N-phenyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(27)N-(2-吗啉乙基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(27)N-(2-morpholinoethyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(28)N-(2-甲氧基乙基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(28)N-(2-Methoxyethyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(29)N-{4-[4-(2-羟乙基)哌啶-1-羰基]噻唑-2-基}-4-氨磺酰基苯甲酰胺(29)N-{4-[4-(2-hydroxyethyl)piperidine-1-carbonyl]thiazol-2-yl}-4-sulfamoylbenzamide

(30)N-(2-甲氧基苯基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(30)N-(2-Methoxyphenyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(31)N-[4-(4-甲基哌嗪-1-羰基)噻唑-2-基]-4-氨磺酰基苯甲酰胺(31) N-[4-(4-Methylpiperazine-1-carbonyl)thiazol-2-yl]-4-sulfamoylbenzamide

(32)N-[4-(4-乙基哌嗪-1-羰基)噻唑-2-基]-4-氨磺酰基苯甲酰胺(32) N-[4-(4-Ethylpiperazine-1-carbonyl)thiazol-2-yl]-4-sulfamoylbenzamide

(33)N-{4-[(苯并[d][1,3]二氧-5-基甲基)哌嗪-1-羰基]噻唑-2-基}-4-氨磺酰基苯甲酰胺(33)N-{4-[(Benzo[d][1,3]dioxo-5-ylmethyl)piperazine-1-carbonyl]thiazol-2-yl}-4-sulfamoylbenzyl Amide

(34)N-{4-[(4-(2-甲氧基乙基)哌嗪-1-羰基]噻唑-2-基}-4-氨磺酰基苯甲酰胺(34) N-{4-[(4-(2-methoxyethyl)piperazine-1-carbonyl]thiazol-2-yl}-4-sulfamoylbenzamide

(35)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸[3-(4-甲基哌嗪-1-基)丙基]酯(35) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid [3-(4-methylpiperazin-1-yl)propyl] ester

(36)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸[2-(4-甲基哌嗪-1-基)乙基]酯(36) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid [2-(4-methylpiperazin-1-yl)ethyl] ester

(37)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸[(3-吗啉基)丙基]酯(37) 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid [(3-morpholinyl)propyl] ester

(38)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸[(2-吗啉基)乙基]酯(38) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid [(2-morpholinyl)ethyl] ester

(39)1-[(4-氨磺酰基苯甲基)甲酰胺基)噻唑-4-酰基]-4-(2-甲氧基乙基)哌嗪(39) 1-((4-sulfamoylbenzyl)carboxamido)thiazole-4-acyl)-4-(2-methoxyethyl)piperazine

(40)3-{[2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰基}-1-(叔丁氧羰基)胍(40) 3-{[2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-formyl}-1-(tert-butoxycarbonyl)guanidine

(41)N-{[(4-胺磺酰基苯基)甲酰基]胺基噻唑-4-酰基}甘氨酸苄酯(41) N-{[(4-Sulfonylphenyl)formyl]aminothiazole-4-acyl}glycine benzyl ester

(42)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-5-羧酸乙酯(42) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-5-carboxylic acid ethyl ester

(43)2-[(4-氨磺酰基苯基)甲酰基]胺基-4-甲基噻唑-5-羧酸乙酯(43) 2-[(4-sulfamoylphenyl)formyl]amino-4-methylthiazole-5-carboxylic acid ethyl ester

(44)2-[(4-氨磺酰基苯基)甲酰基]胺基-4-溴噻唑-5-羧酸乙酯(44) 2-[(4-sulfamoylphenyl)formyl]amino-4-bromothiazole-5-carboxylic acid ethyl ester

(45)2-[(4-氨磺酰基苯基)甲酰基]胺基-4-苯基噻唑-5-羧酸乙酯(45) 2-[(4-sulfamoylphenyl)formyl]amino-4-phenylthiazole-5-carboxylic acid ethyl ester

(46)2-[(4-氨磺酰基苯基)甲酰基]胺基-4-三氟甲基噻唑-5-羧酸乙酯(46) 2-[(4-sulfamoylphenyl) formyl]amino-4-trifluoromethylthiazole-5-carboxylic acid ethyl ester

(47)N-环庚基[2-(4-氨磺酰基苯基甲酰基)胺基]噻唑-5-甲酰胺(47) N-cycloheptyl[2-(4-sulfamoylphenylformyl)amino]thiazole-5-carboxamide

(48)N-(3-苄氧基)苯基2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-5-甲酰胺(48)N-(3-Benzyloxy)phenyl 2-[(4-sulfamoylphenyl)formyl]aminothiazole-5-carboxamide

(49)N-(2-吗啉基)乙基2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-5-甲酰胺(49)N-(2-morpholinyl)ethyl 2-[(4-sulfamoylphenyl)formyl]aminothiazole-5-carboxamide

(50)N-壬基2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-5-甲酰胺(50)N-nonyl 2-[(4-sulfamoylphenyl)formyl]aminothiazole-5-carboxamide

(51)N-(2-吗啉基)乙基2-[(4-氨磺酰基苯基)甲酰基]胺基-4-甲基噻唑-5-甲酰胺。(51) N-(2-morpholinyl)ethyl 2-[(4-sulfamoylphenyl)formyl]amino-4-methylthiazole-5-carboxamide.

根据本发明的另一个方面，本发明一个目的是提供式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物的制备方法，所述方法选自以下方法中的一种：According to another aspect of the present invention, an object of the present invention is to provide a five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates, and The mixture, and the preparation method of its pharmaceutically acceptable salt, crystalline hydrate and solvate, the method is selected from one of the following methods:

方法A：Method A:

方法B：Method B:

方法C：Method C:

其中以对羧基苯磺酰胺为原料，经过酰胺缩合、碱水解、酰胺缩合或酯缩合得目标产物含五元杂环的苯磺酰胺类化合物。其中，所述碱水解、酰胺缩合或酯缩合各个步骤的具体反应条件可以按照本领域中常规的设计进行，例如所述酰胺或酯缩合反应可以参照文献(Bioorganic&Medicinal Chemistry Letters,2007,17(5):1355-1357)，所述碱水解可以参照文献(Organic Letters,2012,14(20):5370-5373)。Among them, p-carboxybenzenesulfonamide is used as a raw material, through amide condensation, alkaline hydrolysis, amide condensation or ester condensation, the target product contains a five-membered heterocyclic benzenesulfonamide compound. Wherein, the specific reaction conditions of each step of the alkaline hydrolysis, amide condensation or ester condensation can be carried out according to the conventional design in the art. For example, the amide or ester condensation reaction can refer to the literature (Bioorganic&Medicinal Chemistry Letters, 2007, 17(5) :1355-1357), the alkali hydrolysis can refer to the literature (Organic Letters, 2012, 14(20): 5370-5373).

其中的取代基W和G同前面描述相同。The substituents W and G are the same as described above.

本发明的另一方面是提供式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物在制备CA抑制剂中的用途。Another aspect of the present invention is to provide a five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures thereof, and their pharmaceutically Use of acceptable salts, crystalline hydrates and solvates in the preparation of CA inhibitors.

本发明的另一方面是提供式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物在制备治疗青光眼、高原缺氧、癫痫、癌症、白血病、肥胖、关节炎等的药物中的用途。Another aspect of the present invention is to provide a five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures thereof, and their pharmaceutically The use of acceptable salts, crystalline hydrates and solvates in the preparation of medicines for the treatment of glaucoma, high altitude hypoxia, epilepsy, cancer, leukemia, obesity, arthritis and the like.

本发明的第四方面是提供含有式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物作为活性成分的药物组合物，所述药物组合物包括治疗有效量的式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物以及药物辅料。术语“有效量”可指为实现预期的效果所需的剂量和时段的有效的量。此有效量可能因某些因子而产生不同的变化，如疾病的种类或治疗时疾病的病症、被施用的特定标的器官的构造、病人个体大小、或疾病或症状的严重性。本领域具有通常知识者不需要过度实验即可凭经验决定特定化合物的有效量。所述“药物辅料”是指药物中常规采用的各种辅料，例如赋形剂、控释剂、稳定剂等，这属于本领域技术人员常规知识范围。这些药物组合物亦可含有一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂，使该药物组合物以可被接受的形式制造或使用。The fourth aspect of the present invention is to provide a five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures thereof, and their pharmaceuticals The above-acceptable salt, crystalline hydrate and solvate as the active ingredient of the pharmaceutical composition, the pharmaceutical composition comprises a therapeutically effective amount of the five-membered heterocyclic benzene sulfonamide compound shown in formula I and its enantiomers Isomers, diastereomers, racemates and mixtures thereof, as well as their pharmaceutically acceptable salts, crystalline hydrates and solvates, and pharmaceutical excipients. The term "effective amount" may refer to an effective amount for the dosage and time period required to achieve the desired effect. This effective amount may vary depending on certain factors, such as the type of disease or the condition of the disease during treatment, the structure of the specific target organ to be administered, the size of the patient, or the severity of the disease or symptom. Those with ordinary knowledge in the art can empirically determine the effective amount of a specific compound without undue experimentation. The "pharmaceutical excipients" refer to various excipients conventionally used in medicines, such as excipients, controlled release agents, stabilizers, etc., which belong to the conventional knowledge of those skilled in the art. These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreens, glidants, processing aids Agents, coloring agents, sweeteners, flavoring agents, flavoring agents or other known additives to enable the pharmaceutical composition to be manufactured or used in an acceptable form.

所述“药学上可接受的盐”为式I化合物与无机酸或有机酸反应形成的常规的无毒盐。例如，所述常规的无毒盐可通过式I化合物与无机酸或有机酸反应制得，所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者式I化合物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸或谷氨酸形成酯后再与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者式I化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐；或者式I化合物与赖氨酸、精氨酸、鸟氨酸形成酯后再与盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸形成的对应的无机酸盐或与甲酸、乙酸、苦味酸、甲磺酸和乙磺酸形成的对应的有机酸盐。The "pharmaceutically acceptable salt" is a conventional non-toxic salt formed by the reaction of a compound of formula I with an inorganic acid or an organic acid. For example, the conventional non-toxic salt can be prepared by reacting a compound of formula I with an inorganic acid or an organic acid. The inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, etc., and the Organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid Acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzene Sulfonic acid, 2-acetoxybenzoic acid and isethionic acid, etc.; or compound of formula I and propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, lemon The sodium, potassium, calcium, aluminum or ammonium salt formed with an acid, aspartic acid or glutamic acid after forming an ester with an inorganic base; or a methylamine salt or ethylamine salt formed by a compound of formula I with an organic base Or ethanolamine salt; or formula I compound forms ester with lysine, arginine, ornithine and then forms corresponding inorganic acid salt with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid or with formic acid , Acetic acid, picric acid, methanesulfonic acid and ethanesulfonic acid form the corresponding organic acid salt.

根据本发明的所述药物组合物可以是以下剂型：片剂，例如但不限于普通片剂、速释片、缓释片、控释片、薄膜衣片、糖衣片、***片、舌下片、生物粘附片等；胶囊剂，例如但不限于硬胶囊、软胶囊等；注射剂，例如但不限于无菌或者含抑菌剂的水性注射剂、油性注射剂、冷冻干粉针剂、注射用微球等；喷雾剂，例如但不限于口腔喷雾剂、鼻腔喷雾剂、局部皮肤喷雾剂等；气雾剂，例如但不限于肺吸入用气雾剂、局部皮肤气雾剂等；滴鼻剂，例如但不限于滴鼻用溶液、滴鼻用凝胶等；粉雾剂，例如但不限于空腔用粉雾剂、鼻腔用粉雾剂、局部皮肤用粉雾剂等；人体其他腔道如***、直肠、耳腔等用的栓剂、贴剂、凝胶剂。这些制剂的制备工艺是本领域技术人员根据已有的知识或者参考相关教科书或工具书或文献而可以制备的。The pharmaceutical composition according to the present invention can be in the following dosage forms: tablets, such as but not limited to ordinary tablets, immediate-release tablets, sustained-release tablets, controlled-release tablets, film-coated tablets, sugar-coated tablets, buccal tablets, sublingual tablets Tablets, bioadhesive tablets, etc.; capsules, such as but not limited to hard capsules, soft capsules, etc.; injections, such as but not limited to sterile or bacteriostatic-containing aqueous injections, oily injections, freeze-dried powder injections, and microspheres for injection Etc.; sprays, such as but not limited to oral sprays, nasal sprays, topical skin sprays, etc.; aerosols, such as but not limited to lung inhalation aerosols, topical skin aerosols, etc.; nasal drops, such as But not limited to nasal drops, nasal drops, gels, etc.; powder mists, such as but not limited to cavity powder mist, nasal powder mist, topical skin powder mist, etc.; other human cavities such as vagina Suppositories, patches, gels for rectum, ear cavity, etc. The preparation process of these preparations can be prepared by those skilled in the art based on existing knowledge or with reference to relevant textbooks or reference books or literature.

术语“药物辅料”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington：The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。The term "pharmaceutical excipient" refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic or side effects to the host or patient. Representative carriers include water, oil, vegetables, and minerals. , Ointment base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. For other information about the carrier, you can refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), and the content of this document is incorporated herein by reference.

有益效果Beneficial effect

本发明的化合物制备工艺简单、原料易得、收率高。本发明提供的制备式I所示的含五元杂环的苯磺酰胺类衍生物的合成方法科学合理，具有操作简便、成本低廉、反应易于控制等特点。本发明的化合物作为碳酸酐酶抑制剂，显示良好的开发潜力，与临床常用碳酸酐酶(CA)抑制剂醋氮酰胺相比，醋氮酰胺的抑制能力不平衡，抑制CA I能力相对较弱，IC ₅₀为微摩尔级、对CA II抑制能力强，IC ₅₀为纳摩尔级。所以它抑制CA II引起的效应容易被CA I代偿性折损，而本发明所述化合物对CA I的抑制活性更强，显示对CA I、CAII均具有很强的抑制能力，IC ₅₀均为纳摩尔级，有望避免醋氮酰胺的不平衡引起的体内药效损失。 The preparation process of the compound of the invention is simple, the raw materials are easily obtained, and the yield is high. The synthetic method for preparing the five-membered heterocyclic-containing benzenesulfonamide derivatives shown in formula I provided by the present invention is scientific and reasonable, and has the characteristics of simple operation, low cost, easy reaction control and the like. As a carbonic anhydrase inhibitor, the compound of the present invention shows good development potential. Compared with the commonly used carbonic anhydrase (CA) inhibitor acetazamide, the inhibitory ability of acetazamide is unbalanced, and the ability to inhibit CA I is relatively weak. , IC ₅₀ is at the micromolar level, and has a strong ability to inhibit CA II, and the IC ₅₀ is at the nanomolar level. Therefore, the effect caused by its inhibition of CA II is easily compromised by CA I. The compound of the present invention has stronger inhibitory activity on CA I, showing that it has a strong inhibitory ability on both CA I and CAII, and the IC ₅₀ is equal. The nanomolar level is expected to avoid the loss of efficacy in the body caused by the imbalance of acetazolamide.

具体实施方式Detailed ways

以下，将详细地描述本发明。在进行描述之前，应当理解的是，在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义，而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上，根据与本发明的技术方面相应的含义和概念进行解释。因此，这里提出的描述仅仅是出于举例说明目的的优选实例，并非意图限制本发明的范围，从而应当理解的是，在不偏离本发明的精神和范围的情况下，可以由其获得其他等价方式或改进方式。Hereinafter, the present invention will be described in detail. Before proceeding with the description, it should be understood that the terms used in this specification and the appended claims should not be construed as being limited to the general meaning and dictionary meaning, but should be allowed to allow the inventor to properly define the terms for the best interpretation. On the basis of the principle of the present invention, the explanation is based on the meaning and concept corresponding to the technical aspects of the present invention. Therefore, the description presented here is only a preferred example for illustrative purposes, and is not intended to limit the scope of the present invention. Therefore, it should be understood that, without departing from the spirit and scope of the present invention, others can be derived therefrom. Price method or improvement method.

以下实施例仅是作为本发明的实施方案的例子列举，并不对本发明构成任何限制，本领域技术人员可以理解在不偏离本发明的实质和构思的范围内的修改均落入本发明的保护范围。除非特别说明，以下实施例中使用的试剂和仪器均为市售可得产品。The following examples are only listed as examples of the embodiments of the present invention, and do not constitute any limitation to the present invention. Those skilled in the art can understand that modifications within the scope that do not deviate from the essence and concept of the present invention fall into the protection of the present invention. scope. Unless otherwise specified, the reagents and instruments used in the following examples are all commercially available products.

实施例1：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸乙酯Example 1: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid ethyl ester

将4-羧苯磺酰胺(10.0mmol)、1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI，12.0mmol)和1-羟基苯并***(HOBT，12.0mmol)添加到DMF(10ml)中并在室温下搅拌30分钟。然后加入2-氨基-4-乙氧羰基噻唑(12.0mmol)和DMAP(3.0mmol)。45℃下反应至TLC检测反应完全。将混合物冷却至室温，并用乙酸乙酯萃取。用盐水洗涤有机层，无水硫酸钠上干燥有机相，过滤，并在减压下浓缩。通过柱层析(DCM/MT60:1-30:1)纯化原料产物，得到白色固体化合物，收率69％。 ¹H NMR(DMSO-d6)δppm:13.30(s,1H,CONH),8.27(d,J＝8.0Hz,2H,Ar-H),8.18(s,1H,S-CH),7.98(d,J＝8.0Hz,2H,Ar-H),7.60(s,2H,SO ₂NH ₂),4.32(q,2H,OCH ₂),1.32(t,3H,CH ₃)； ¹³C NMR(DMSO-d6)δppm:165.18,161.56,159.06,147.99,141.72,135.03,129.55,126.36,123.96,61.24,14.75；ESI-MS:356.03[M+H] ⁺. Combine 4-carboxybenzenesulfonamide (10.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 12.0 mmol) and 1-hydroxybenzotriazole ( HOBT, 12.0 mmol) was added to DMF (10 ml) and stirred at room temperature for 30 minutes. Then 2-amino-4-ethoxycarbonylthiazole (12.0 mmol) and DMAP (3.0 mmol) were added. React at 45°C until TLC detects that the reaction is complete. The mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The raw material product was purified by column chromatography (DCM/MT60:1-30:1) to obtain a white solid compound with a yield of 69%. ¹ H NMR (DMSO-d6) δppm: 13.30 (s, 1H, CONH), 8.27 (d, J = 8.0 Hz, 2H, Ar-H), 8.18 (s, 1H, S-CH), 7.98 (d, J = 8.0Hz, 2H, Ar-H), 7.60 (s, 2H, SO ₂ NH ₂ ), 4.32 (q, 2H, OCH ₂ ), 1.32 (t, 3H, CH ₃ ); ¹³ C NMR (DMSO- d6)δppm:165.18,161.56,159.06,147.99,141.72,135.03,129.55,126.36,123.96,61.24,14.75; ESI-MS: 356.03[M+H] ⁺ .

实施例2：5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-羧酸乙酯Example 2: 5-[(4-sulfamoylphenyl)formyl]amino-1,3,4-thiadiazole-2-carboxylic acid ethyl ester

除了替换相应的反应起始原料以外，根据实施例1的方法制备目标化合物，白色固体，收率73％。 ¹H NMR(DMSO-d6)δppm:13.77(s,1H,CONH),8.29(d,J＝8.0Hz,2H,Ar-H),8.00(d,J＝8.0Hz,2H,Ar-H),7.61(s,2H,SO ₂NH ₂),4.43(q,2H,OCH ₂),1.37(t,3H,CH ₃)； ¹³C NMR(DMSO-d6)δppm:165.42,163.26,159.50,154.57,148.38,134.52,129.93,126.41,63.02,14.53；ESI-MS:357.01[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 1. A white solid, with a yield of 73%. ¹ H NMR(DMSO-d6)δppm: 13.77(s,1H,CONH), 8.29(d,J=8.0Hz,2H,Ar-H),8.00(d,J=8.0Hz,2H,Ar-H) , 7.61 (s, 2H, SO ₂ NH ₂ ), 4.43 (q, 2H, OCH ₂ ), 1.37 (t, 3H, CH ₃ ); ¹³ C NMR (DMSO-d6) δppm: 165.42,163.26,159.50,154.57 ,148.38,134.52,129.93,126.41,63.02,14.53; ESI-MS:357.01[M+H] ⁺ .

实施例3：N-环丙基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺Example 3: N-cyclopropyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

第一步：2-(4-氨磺酰苯甲酰胺基)噻唑-4-羧酸的制备Step 1: Preparation of 2-(4-sulfamoylbenzamide)thiazole-4-carboxylic acid

将2-(4-氨磺酰苯甲酰胺基)噻唑-4-羧酸乙酯(3.56mmol)溶于四氢呋喃(THF，15ml)中。然后加入氢氧化锂(10.68mmol)，室温下搅拌反应，TLC检测反应完成，用10％盐酸水溶液调整混合物的PH值5-6。过滤、并用甲醇洗涤滤饼，得到白色固体化合物，收率91％。 ¹H NMR(DMSO-d6)δppm:13.20-13.00(m,2H,CONH,COOH),8.27(d,J＝8.0H _Z,2H,Ar-H),8.10(s,1H,CH),7.98(d,J＝8.0H _Z,2H,Ar-H),7.59(s,2H,SO ₂NH ₂)；ESI-MS:328.00[M+H] ⁺. Ethyl 2-(4-sulfamoylbenzamide)thiazole-4-carboxylate (3.56 mmol) was dissolved in tetrahydrofuran (THF, 15 ml). Then lithium hydroxide (10.68 mmol) was added, and the reaction was stirred at room temperature. TLC detected that the reaction was complete, and the pH value of the mixture was adjusted to 5-6 with 10% aqueous hydrochloric acid. The filter cake was filtered and washed with methanol to obtain a white solid compound with a yield of 91%. ¹ H NMR (DMSO-d6) δppm: 13.20-13.00 (m, 2H, CONH, COOH), 8.27 (d, J = 8.0H _Z , 2H, Ar-H), 8.10 (s, 1H, CH), 7.98 (d,J=8.0H _Z ,2H,Ar-H), 7.59(s,2H,SO ₂ NH ₂ ); ESI-MS: 328.00[M+H] ⁺ .

第二步：N-环丙基-2-(4-氨磺酰苯甲酰胺基)噻唑-4-甲酰胺的制备Step 2: Preparation of N-cyclopropyl-2-(4-sulfamoylbenzamide)thiazole-4-carboxamide

将2-(4-氨磺酰苯甲酰胺基)噻唑-4-羧酸(1.53mmol)、EDCI(1.84mmol)、HOBT(1.84mmol)加入3ml DMF中，在室温下搅拌30分钟。然后加入2-氨基-4-乙氧羰基噻唑(1.53mmol)和DMAP(0.46mmol)。混合物在45℃下反应至反应完全，然后冷却至室温。乙酸乙酯萃取后用盐水洗涤，无水硫酸钠干燥，过滤并在减压条件下浓缩。用柱层析法(二氯甲烷-甲醇60:1-50:1)柱层析，得到白色固体化合物，收率53％。 ¹H NMR(DMSO-d6)δppm:13.01(s,1H,CONH),8.24(d,J＝8.0H _Z,2H,Ar-H),8.10(s,1H,CH),7.97(d,J＝8.0H _Z,2H,Ar-H),7.94(d,J＝4.0H _Z,1H,NH),7.88(s,1H,SCH),7.58(s,2H,SO ₂NH ₂),2.84(m,1H,NCH),0.73(m,2H,CH ₂),0.58(m,2H,CH ₂)；ESI-MS 367.05[M+H] ⁺。 2-(4-sulfamoylbenzamide)thiazole-4-carboxylic acid (1.53 mmol), EDCI (1.84 mmol), and HOBT (1.84 mmol) were added to 3 ml of DMF, and stirred at room temperature for 30 minutes. Then 2-amino-4-ethoxycarbonylthiazole (1.53 mmol) and DMAP (0.46 mmol) were added. The mixture was reacted at 45°C until the reaction was complete, and then cooled to room temperature. After extraction with ethyl acetate, it was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography (dichloromethane-methanol 60:1-50:1) was used to obtain a white solid compound with a yield of 53%. ¹ H NMR(DMSO-d6)δppm: 13.01(s,1H,CONH), 8.24(d,J=8.0H _Z ,2H,Ar-H), 8.10(s,1H,CH),7.97(d,J =8.0H _Z ,2H,Ar-H),7.94(d,J=4.0H _Z ,1H,NH),7.88(s,1H,SCH),7.58(s,2H,SO ₂ NH ₂ ), 2.84( m, 1H, NCH), 0.73 (m, 2H, CH ₂ ), 0.58 (m, 2H, CH ₂ ); ESI-MS 367.05 [M+H] ⁺ .

实施例4：N-环戊基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺Example 4: N-cyclopentyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率66％。 ¹H NMR(DMSO-d6)δppm:13.01(s,1H,CONH),8.25(d,J＝8.0H _Z,2H,Ar-H),7.98(d,J＝8.0H _Z,2H,Ar-H),7.89(s,1H,SCH),7.64(d,J＝8.0H _Z,1H,NH),7.58(s,2H,SO ₂NH ₂),4.16(m,1H,NCH),1.88(m,2H,CH ₂),1.53(m,6H,CH ₂)；ESI-MS 395.08[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 66%. ¹ H NMR (DMSO-d6) δppm: 13.01 (s, 1H, CONH), 8.25 (d, J = 8.0H _Z , 2H, Ar-H), 7.98 (d, J = 8.0H _Z , 2H, Ar- H), 7.89 (s, 1H, SCH), 7.64 (d, J = 8.0H _Z , 1H, NH), 7.58 (s, 2H, SO ₂ NH ₂ ), 4.16 (m, 1H, NCH), 1.88 ( m,2H,CH ₂ ),1.53(m,6H,CH ₂ ); ESI-MS 395.08[M+H] ⁺ .

实施例5：N-环己基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺Example 5: N-cyclohexyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率51％。 ¹H NMR(DMSO-d6)δppm:13.01(s,1H,CONH),8.25(d,J＝8.0H _Z,2H,Ar-H),7.97(d,J＝8.0H _Z,2H,Ar-H),7.89(s,1H,SCH),7.58-7.57(m,3H,SO ₂NH ₂,NH),3.74(m,1H,NCH),1.87-1.19(m,10H,CH ₂)；ESI-MS 409.10[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 51%. ¹ H NMR (DMSO-d6) δppm: 13.01 (s, 1H, CONH), 8.25 (d, J = 8.0H _Z , 2H, Ar-H), 7.97 (d, J = 8.0H _Z , 2H, Ar- H), 7.89 (s, 1H, SCH), 7.58-7.57 (m, 3H, SO ₂ NH ₂ , NH), 3.74 (m, 1H, NCH), 1.87-1.19 (m, 10H, CH ₂ ); ESI -MS 409.10[M+H] ⁺ .

实施例6：N-环庚基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺Example 6: N-cycloheptyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率63％。 ¹H NMR(DMSO-d6)δppm:13.00(s,1H,CONH),8.25(d,J＝8.0H _Z,2H,Ar-H),7.98(d,J＝8.0H _Z,2H,Ar-H),7.88(s,1H,SCH),7.62-7.58(m,3H,SO ₂NH ₂,NH),3.94(m,1H,NCH),1.91-1.44(m,12H,CH ₂)；ESI-MS 423.11[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 63%. ¹ H NMR (DMSO-d6) δppm: 13.00 (s, 1H, CONH), 8.25 (d, J = 8.0H _Z , 2H, Ar-H), 7.98 (d, J = 8.0H _Z , 2H, Ar- H),7.88(s,1H,SCH),7.62-7.58(m,3H,SO ₂ NH ₂ ,NH),3.94(m,1H,NCH),1.91-1.44(m,12H,CH ₂ ); ESI -MS 423.11[M+H] ⁺ .

实施例7：N-环辛基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺Example 7: N-cyclooctyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率63％。 ¹H NMR(DMSO-d6)δppm:13.00(s,1H,CONH),8.25(d,J＝8.0H _Z,2H,Ar-H),7.98(d,J＝8.0H _Z,2H,Ar-H),7.88(s,1H,SCH),7.61-7.58(m,3H,SO ₂NH ₂,NH),3.99(m,1H,NCH),1.80-1.52(m,14H,CH ₂)；ESI-MS 437.13[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 63%. ¹ H NMR (DMSO-d6) δppm: 13.00 (s, 1H, CONH), 8.25 (d, J = 8.0H _Z , 2H, Ar-H), 7.98 (d, J = 8.0H _Z , 2H, Ar- H),7.88(s,1H,SCH),7.61-7.58(m,3H,SO ₂ NH ₂ ,NH),3.99(m,1H,NCH),1.80-1.52(m,14H,CH ₂ ); ESI -MS 437.13[M+H] ⁺ .

实施例8：N-正丙基-2-[(4-氨磺酰基苯甲酰基)胺基]噻唑-4-甲酰胺Example 8: N-n-propyl-2-[(4-sulfamoylbenzoyl)amino]thiazole-4-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率75％。 ¹H NMR(DMSO-d6)δppm:13.01(s,1H,CONH),8.25(d,J＝8.0H _Z,2H,Ar-H),7.98(d,J＝8.0H _Z,2H,Ar-H),7.89-7.87(m,2H,SCH,NH),7.59(s,2H,SO ₂NH ₂),3.26(q,1H,NCH),1.55(m,2H,CH ₂),0.90(t,3H,CH ₃)；ESI-MS 369.09[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 75%. ¹ H NMR (DMSO-d6) δppm: 13.01 (s, 1H, CONH), 8.25 (d, J = 8.0H _Z , 2H, Ar-H), 7.98 (d, J = 8.0H _Z , 2H, Ar- H), 7.89-7.87 (m, 2H, SCH, NH), 7.59 (s, 2H, SO ₂ NH ₂ ), 3.26 (q, 1H, NCH), 1.55 (m, 2H, CH ₂ ), 0.90 (t ,3H,CH ₃ ); ESI-MS 369.09[M+H] ⁺ .

实施例9：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸酯己酯Example 9: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylate hexyl ester

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率42％。 ¹H NMR(DMSO-d6)δppm:13.27(s,1H,Ar-CONH),8.26(d,J＝8.0H _Z,2H,Ar-H),8.16(s,1H,CH),7.97(d,J＝8.0H _Z,2H,Ar-H),7.58(s,2H,SO ₂NH ₂),4.26(t,2H,OCH ₂),1.70(m,2H,CH ₂),1.35(m,4H,CH ₂),0.90(t,3H,CH ₃)；ESI-MS 398.08[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 42%. ¹ H NMR(DMSO-d6)δppm: 13.27(s,1H,Ar-CONH), 8.26(d,J=8.0H _Z ,2H,Ar-H), 8.16(s,1H,CH),7.97(d ,J=8.0H _Z ,2H,Ar-H), 7.58 (s, 2H, SO ₂ NH ₂ ), 4.26 (t, 2H, OCH ₂ ), 1.70 (m, 2H, CH ₂ ), 1.35 (m, 4H,CH ₂ ),0.90(t,3H,CH ₃ ); ESI-MS 398.08[M+H] ⁺ .

实施例10：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸异丙酯Example 10: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid isopropyl ester

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率47％。 ¹H NMR(DMSO-d6)δppm:13.28(s,1H,Ar-CONH),8.27(d,J＝8.0H _Z,2H,Ar-H),8.15(s,1H,CH),7.98(d,J＝8.0H _Z,2H,Ar-H),7.59(s,2H,SO ₂NH ₂),5.15(m,1H,OCH),1.32(d,J＝4.0H _Z,6H,CH3)；ESI-MS 370.06[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 47%. ¹ H NMR(DMSO-d6)δppm: 13.28(s,1H,Ar-CONH), 8.27(d,J=8.0H _Z ,2H,Ar-H), 8.15(s,1H,CH),7.98(d ,J=8.0H _Z ,2H,Ar-H),7.59(s,2H,SO ₂ NH ₂ ), 5.15(m,1H,OCH),1.32(d,J=4.0H _Z ,6H,CH3); ESI-MS 370.06[M+H] ⁺ .

实施例11：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸(2-甲氧基)乙基酯Example 11: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid (2-methoxy)ethyl ester

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率74％。 ¹H NMR(DMSO-d6)δppm:13.30(s,1H,Ar-CONH),8.27(d,J＝8.0H _Z,2H,Ar-H),8.18(s,1H,CH),7.97(d,J＝8.0H _Z,2H,Ar-H),7.59(s,2H,SO ₂NH ₂),4.39(m,2H,OCH ₂),3.65(m,2H,CH ₂),3.30(s,3H,CH ₃)；ESI-MS 386.05[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 74%. ¹ H NMR(DMSO-d6)δppm: 13.30(s,1H,Ar-CONH), 8.27(d,J=8.0H _Z ,2H,Ar-H), 8.18(s,1H,CH),7.97(d ,J=8.0H _Z ,2H,Ar-H),7.59(s,2H,SO ₂ NH ₂ ), 4.39(m,2H,OCH ₂ ), 3.65(m,2H,CH ₂ ), 3.30(s, 3H,CH ₃ ); ESI-MS 386.05[M+H] ⁺ .

实施例12：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环丙甲基酯Example 12: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid cyclopropylmethyl ester

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率42％。 ¹H NMR(DMSO-d6)δppm:13.30(s,1H,Ar-CONH),8.27(d,J＝8.0H _Z,2H,Ar-H),8.18(s,1H,SCH),7.97(d,J＝8.0H _Z,2H,Ar-H),7.58(s,2H,SO ₂NH ₂),4.10(d,2H,OCH ₂),1.23(m,1H,OCCH),0.58(m,2H,CH ₂),0.35(m,3H,CH ₂)；ESI-MS 382.05[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 42%. ¹ H NMR(DMSO-d6)δppm: 13.30(s,1H,Ar-CONH), 8.27(d,J=8.0H _Z ,2H,Ar-H), 8.18(s,1H,SCH),7.97(d ,J=8.0H _Z ,2H,Ar-H),7.58(s,2H,SO ₂ NH ₂ ),4.10(d,2H,OCH ₂ ),1.23(m,1H,OCCH),0.58(m,2H ,CH ₂ ),0.35(m,3H,CH ₂ ); ESI-MS 382.05[M+H] ⁺ .

实施例13：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环戊基甲基酯Example 13: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid cyclopentyl methyl ester

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率64％。 ¹H NMR(DMSO-d6)δppm:13.27(s,1H,Ar-CONH),8.27(d,J＝8.0H _Z,2H,Ar-H),8.16(s,1H,SCH),7.97(d,J＝8.0H _Z,2H,Ar-H),7.58(s,2H,SO ₂NH ₂),4.16(d,J＝8H _Z,2H,OCH ₂),2.29(m,1H,OCCH),1.76-1.30(m,8H,CH ₂)；ESI-MS 410.08[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 64%. ¹ H NMR(DMSO-d6)δppm: 13.27(s,1H,Ar-CONH), 8.27(d,J=8.0H _Z ,2H,Ar-H), 8.16(s,1H,SCH),7.97(d ,J=8.0H _Z ,2H,Ar-H),7.58(s,2H,SO ₂ NH ₂ ), 4.16(d,J=8H _Z ,2H,OCH ₂ ), 2.29(m,1H,OCCH), 1.76-1.30(m,8H,CH ₂ ); ESI-MS 410.08[M+H] ⁺ .

实施例14：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环丙基酯Example 14: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid cyclopropyl ester

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率43％。 ¹H NMR(DMSO-d6)δppm:13.28(s,1H,Ar-CONH),8.26(d,J＝8.0H _Z,2H,Ar-H),8.16(s,1H,SCH),7.97(d,J＝8.0H _Z,2H,Ar-H),7.58(s,2H,SO ₂NH ₂),4.30(m,1H,OCH),0.80(m,4H,CH ₂)；ESI-MS 368.03[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 43%. ¹ H NMR(DMSO-d6)δppm: 13.28(s,1H,Ar-CONH), 8.26(d,J=8.0H _Z ,2H,Ar-H), 8.16(s,1H,SCH),7.97(d ,J=8.0H _Z ,2H,Ar-H),7.58(s,2H,SO ₂ NH ₂ ), 4.30(m,1H,OCH),0.80(m,4H,CH ₂ ); ESI-MS 368.03[ M+H] ⁺ .

实施例15：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环戊基酯Example 15: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid cyclopentyl ester

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率48％。 ¹H NMR(DMSO-d6)δppm:13.25(s,1H,Ar-CONH),8.26(d,J＝8.0H _Z,2H,Ar-H),8.14(s,1H,SCH),7.96(d,J＝8.0H _Z,2H,Ar-H),7.57(s,2H,SO ₂NH ₂),5.30(m,1H,OCH),1.96-1.61(m,8H,CH ₂)；ESI-MS 396.06[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 48%. ¹ H NMR(DMSO-d6)δppm: 13.25(s,1H,Ar-CONH), 8.26(d,J=8.0H _Z ,2H,Ar-H), 8.14(s,1H,SCH),7.96(d ,J=8.0H _Z ,2H,Ar-H),7.57(s,2H,SO ₂ NH ₂ ),5.30(m,1H,OCH),1.96-1.61(m,8H,CH ₂ ); ESI-MS 396.06[M+H] ⁺ .

实施例16：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环己基酯Example 16: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid cyclohexyl ester

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率57％。 ¹H NMR(DMSO-d6)δppm:13.27(s,1H,Ar-CONH),8.27(d,J＝8.0H _Z,2H,Ar-H),8.16(s,1H,SCH),7.97(d,J＝8.0H _Z,2H,Ar-H),7.58(s,2H,SO ₂NH ₂),4.90(m,1H,OCH),1.92-1.23(m,10H,CH ₂)；ESI-MS 410.08[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 57%. ¹ H NMR(DMSO-d6)δppm: 13.27(s,1H,Ar-CONH), 8.27(d,J=8.0H _Z ,2H,Ar-H), 8.16(s,1H,SCH),7.97(d ,J=8.0H _Z ,2H,Ar-H),7.58(s,2H,SO ₂ NH ₂ ), 4.90(m,1H,OCH),1.92-1.23(m,10H,CH ₂ ); ESI-MS 410.08[M+H] ⁺ .

实施例17：N-正丙基-5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰胺Example 17: N-n-propyl-5-[(4-sulfamoylphenyl)formyl]amino-1,3,4-thiadiazole-2-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率72％。 ¹H NMR(DMSO-d6)δppm:13.56(s,1H,Ar-CONH),9.18(t,1H,NH),8.29(d,J＝8.0H _Z,2H,Ar-H),7.99(d,J＝8.0H _Z,2H,Ar-H),7.60(s,2H,SO ₂NH ₂),3.24(m,2H,NCH ₂),1.56(m,2H,CH ₂),0.89(t,3H,CH ₃)；ESI-MS 370.07[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 72%. ¹ H NMR(DMSO-d6)δppm: 13.56(s,1H,Ar-CONH), 9.18(t,1H,NH), 8.29(d,J=8.0H _Z ,2H,Ar-H),7.99(d ,J=8.0H _Z ,2H,Ar-H), 7.60 (s, 2H, SO ₂ NH ₂ ), 3.24 (m, 2H, NCH ₂ ), 1.56 (m, 2H, CH ₂ ), 0.89 (t, 3H,CH ₃ ); ESI-MS 370.07[M+H] ⁺ .

实施例18：N-环己基-5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰胺Example 18: N-cyclohexyl-5-[(4-sulfamoylphenyl)formyl]amino-1,3,4-thiadiazole-2-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率47％。 ¹H NMR(DMSO-d6)δppm:13.58(s,1H,Ar-CONH),8.99(d,J＝8.0H _Z,1H,NH),8.29(d,J＝8.0H _Z,2H,Ar-H),7.99(d,J＝8.0H _Z,2H,Ar-H),7.60(s,2H,SO ₂NH ₂),3.76(m,1H,NCH),1.81-1.09(m,10H,CH ₂)；ESI-MS 410.10[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 47%. ¹ H NMR (DMSO-d6) δppm: 13.58 (s, 1H, Ar-CONH), 8.99 (d, J = 8.0H _Z , 1H, NH), 8.29 (d, J = 8.0H _Z , 2H, Ar- H),7.99(d,J=8.0H _Z ,2H,Ar-H), 7.60(s,2H,SO ₂ NH ₂ ), 3.76(m,1H,NCH),1.81-1.09(m,10H,CH ₂ ); ESI-MS 410.10[M+H] ⁺ .

实施例19：N-环庚基-5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰胺Example 19: N-cycloheptyl-5-[(4-sulfamoylphenyl)formyl]amino-1,3,4-thiadiazole-2-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率62％。 ¹H NMR(DMSO-d6)δppm:13.53(s,1H,Ar-CONH),8.93(d,J＝8.0H _Z,1H,NH),8.28(d,J＝8.0H _Z,2H,Ar-H),7.97(d,J＝8.0H _Z,2H,Ar-H),7.57(s,2H,SO ₂NH ₂),3.94(m,1H,NCH),1.86-1.41(m,12H,CH ₂)；ESI-MS 424.11[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 62%. ¹ H NMR (DMSO-d6) δppm: 13.53 (s, 1H, Ar-CONH), 8.93 (d, J = 8.0H _Z , 1H, NH), 8.28 (d, J = 8.0H _Z , 2H, Ar- H),7.97(d,J=8.0H _Z ,2H,Ar-H),7.57(s,2H,SO ₂ NH ₂ ),3.94(m,1H,NCH),1.86-1.41(m,12H,CH ₂ ); ESI-MS 424.11[M+H] ⁺ .

实施例20：5-[(4-氨磺酰苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰胺Example 20: 5-[(4-sulfamoylphenyl)formyl]amino-1,3,4-thiadiazole-2-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率73％。 ¹H NMR(DMSO-d6)δppm:13.58(s,1H,CONH),8.44(s,1H,CONH ₂),8.28(d,J＝8.0H _Z,2H,Ar-H),7.97(m,3H,Ar-H,CONH ₂),7.57(s,2H,SO ₂NH ₂)；ESI-MS 327.99[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 73%. ¹ H NMR (DMSO-d6) δppm: 13.58 (s, 1H, CONH), 8.44 (s, 1H, CONH ₂ ), 8.28 (d, J = 8.0H _Z , 2H, Ar-H), 7.97 (m, 3H,Ar-H,CONH ₂ ),7.57(s,2H,SO ₂ NH ₂ ); ESI-MS 327.99[M+H] ⁺ .

实施例21：5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰肼Example 21: 5-[(4-sulfamoylphenyl)formyl]amino-1,3,4-thiadiazole-2-carboxhydrazide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率85％。 ¹H NMR(DMSO-d6)δppm:9.83(s,1H,CONH),8.29(d,J＝8.0H _Z,2H,Ar-H),7.88(d,J＝8.0H _Z,2H,Ar-H),7.35(brs,5H,SO ₂NH ₂,NHNH ₂)；ESI-MS 343.00[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3, a white solid, with a yield of 85%. ¹ H NMR (DMSO-d6) δ ppm: 9.83 (s, 1H, CONH), 8.29 (d, J = 8.0H _Z , 2H, Ar-H), 7.88 (d, J = 8.0H _Z , 2H, Ar- H),7.35(brs,5H,SO ₂ NH ₂ ,NHNH ₂ ); ESI-MS 343.00[M+H] ⁺ .

实施例22：N-(4-氟苄基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺Example 22: N-(4-Fluorobenzyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率43％。 ¹H NMR(DMSO-d6)δppm:13.00(s,1H,CONHC),8.43(t,1H,CH ₂-NHCO),8.23(d,J＝8.0Hz,2H,Ar-H),7.97(d,J＝8.0Hz,2H,Ar-H),7.93(s,1H,SCH),7.58(s,2H,SO ₂NH ₂),7.37(m,2H,Ar-H),7.16(m,2H,Ar-H),4.47(d,2H,J＝4.0Hz,CH ₂)；ESI-MS 435.06[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 43%. ¹ H NMR (DMSO-d6) δppm: 13.00 (s, 1H, CONHC), 8.43 (t, 1H, CH ₂ -NHCO), 8.23 (d, J = 8.0 Hz, 2H, Ar-H), 7.97 (d ,J=8.0Hz,2H,Ar-H),7.93(s,1H,SCH),7.58(s,2H,SO ₂ NH ₂ ),7.37(m,2H,Ar-H),7.16(m,2H ,Ar-H),4.47(d,2H,J=4.0Hz,CH ₂ ); ESI-MS 435.06[M+H] ⁺ .

实施例23：N-(3,4-二甲基苯基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺Example 23: N-(3,4-Dimethylphenyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率64％。 ¹H NMR(DMSO-d6)δppm:13.07(s,1H,CONH),9.69(s,1H,NHCO),8.27(d,J＝8.0Hz,2H,Ar-H),8.05(s,1H,SCH),7.99(d,J＝8.0Hz,2H,Ar-H),7.59(s,2H,SO ₂NH ₂),7.53(m,1H,Ar-H),7.47(m,1H,Ar-H),7.12(d,1H,J＝8.0Hz,Ar-H),2.23(s,3H,CH ₃),2.20(s,3H,CH ₃)；ESI-MS 431.08[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 64%. ¹ H NMR (DMSO-d6) δppm: 13.07 (s, 1H, CONH), 9.69 (s, 1H, NHCO), 8.27 (d, J = 8.0 Hz, 2H, Ar-H), 8.05 (s, 1H, SCH), 7.99 (d, J = 8.0 Hz, 2H, Ar-H), 7.59 (s, 2H, SO ₂ NH ₂ ), 7.53 (m, 1H, Ar-H), 7.47 (m, 1H, Ar- H), 7.12(d,1H,J=8.0Hz,Ar-H), 2.23(s,3H,CH ₃ ), 2.20(s,3H,CH ₃ ); ESI-MS 431.08[M+H] ⁺ .

实施例24：N-[3-(苄氧基)苯基]-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺Example 24: N-[3-(Benzyloxy)phenyl]-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率71％。 ¹H NMR(DMSO-d6)δppm:13.16(s,1H,CONH),9.88(s,1H,NHCO),8.27(d,J＝8.0Hz,2H,Ar-H),8.10(s,1H,SCH),7.99(d,J＝8.0Hz,2H,Ar-H),7.59(s,2H,SO ₂NH ₂),7.57(m,1H,Ar-H),7.48-7.27(m,6H,Ar-H),6.78(m,1H,Ar-H),5.11(s,2H,CH ₂)；ESI-MS509.09[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 71%. ¹ H NMR (DMSO-d6) δppm: 13.16 (s, 1H, CONH), 9.88 (s, 1H, NHCO), 8.27 (d, J = 8.0 Hz, 2H, Ar-H), 8.10 (s, 1H, SCH), 7.99 (d, J = 8.0 Hz, 2H, Ar-H), 7.59 (s, 2H, SO ₂ NH ₂ ), 7.57 (m, 1H, Ar-H), 7.48-7.27 (m, 6H, Ar-H), 6.78(m,1H,Ar-H), 5.11(s,2H,CH ₂ ); ESI-MS509.09[M+H] ⁺ .

实施例25：(R)-N-(1-苯基丙基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺Example 25: (R)-N-(1-phenylpropyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率68％。 ¹H NMR(DMSO-d6)δppm:13.04(s,1H,CONH),8.25(d,J＝8.0Hz,2H,Ar-H),8.08(d,J＝8.0Hz,1H,CONH),7.97(d,J＝8.0Hz,2H,Ar-H),7.93(s,1H,SCH),7.59(s,2H,SO ₂NH ₂),7.40-7.24(m,5H,Ar-H),4.89(q,1H,NCH),1.88(m,2H,CH ₂),0.88(t,3H,CH ₃)；ESI-MS 445.10[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 68%. ¹ H NMR(DMSO-d6)δppm: 13.04(s,1H,CONH), 8.25(d,J=8.0Hz,2H,Ar-H), 8.08(d,J=8.0Hz,1H,CONH),7.97 (d, J=8.0Hz, 2H, Ar-H), 7.93 (s, 1H, SCH), 7.59 (s, 2H, SO ₂ NH ₂ ), 7.40-7.24 (m, 5H, Ar-H), 4.89 (q,1H,NCH),1.88(m,2H,CH ₂ ),0.88(t,3H,CH ₃ ); ESI-MS 445.10[M+H] ⁺ .

实施例26：N-甲基-N-苯基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺Example 26: N-methyl-N-phenyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率51％。 ¹H NMR(DMSO-d6)δppm:13.02(s,1H,CONH),8.20(d,J＝8.0Hz,2H,Ar-H),7.95(d,J＝8.0Hz,2H,Ar-H),7.57(s,2H,SO ₂NH ₂),7.35(m,2H,Ar-H),7.48-7.27(m,6H,Ar-H),7.22(m,3H,Ar-H),7.03(s,1H,SCH),3.40(s,3H,CH ₃)；ESI-MS 417.06[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 51%. ¹ H NMR(DMSO-d6)δppm: 13.02(s,1H,CONH), 8.20(d,J=8.0Hz,2H,Ar-H),7.95(d,J=8.0Hz,2H,Ar-H) , 7.57 (s, 2H, SO ₂ NH ₂ ), 7.35 (m, 2H, Ar-H), 7.48-7.27 (m, 6H, Ar-H), 7.22 (m, 3H, Ar-H), 7.03 ( s,1H,SCH),3.40(s,3H,CH ₃ ); ESI-MS 417.06[M+H] ⁺ .

实施例27：N-(2-吗啉乙基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺Example 27: N-(2-morpholinethyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率68％。 ¹H NMR(DMSO-d6)δppm:13.00(s,1H,CONH),8.25(d,J＝8.0Hz,2H,Ar-H),7.98(d,J＝8.0Hz,2H,Ar-H),7.89(s,1H,SCH),7.82(t,1H,CONH),7.59(s,2H,SO ₂NH ₂),3.60(m,4H,OCH ₂),3.44(m,2H,CONH-CH ₂),2.43(m,6H,NCH ₂)；ESI-MS 440.11[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 68%. ¹ H NMR(DMSO-d6)δppm: 13.00(s,1H,CONH), 8.25(d,J=8.0Hz,2H,Ar-H),7.98(d,J=8.0Hz,2H,Ar-H) ,7.89(s,1H,SCH),7.82(t,1H,CONH),7.59(s,2H,SO ₂ NH ₂ ), 3.60(m,4H,OCH ₂ ), 3.44(m,2H,CONH-CH ₂ ),2.43(m,6H,NCH ₂ ); ESI-MS 440.11[M+H] ⁺ .

实施例28：N-(2-甲氧基乙基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺Example 28: N-(2-Methoxyethyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率70％。 ¹H NMR(DMSO-d6)δppm:13.04(s,1H,CONH),8.24(d,J＝8.0Hz,2H,Ar-H),7.97(d,J＝8.0Hz,2H,Ar-H),7.92(s,1H,SCH),7.79(t,1H,CONH),7.59(s,2H,SO ₂NH ₂),3.47(m,4H,CH ₂CH ₂),3.29(s,3H,OCH ₃)；ESI-MS 385.06[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 70%. ¹ H NMR(DMSO-d6)δppm: 13.04(s,1H,CONH), 8.24(d,J=8.0Hz,2H,Ar-H),7.97(d,J=8.0Hz,2H,Ar-H) ,7.92(s,1H,SCH),7.79(t,1H,CONH),7.59(s,2H,SO ₂ NH ₂ ), 3.47(m,4H,CH ₂ CH ₂ ), 3.29(s,3H,OCH ₃ ); ESI-MS 385.06[M+H] ⁺ .

实施例29：N-{4-[4-(2-羟乙基)哌啶-1-羰基]噻唑-2-基}-4-氨磺酰基苯甲酰胺Example 29: N-{4-[4-(2-hydroxyethyl)piperidine-1-carbonyl]thiazol-2-yl}-4-sulfamoylbenzamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率61％。 ¹H NMR(DMSO-d6)δppm:13.01(s,1H,CONH),8.24(d,J＝8.0Hz,2H,Ar-H),7.97(d,J＝8.0Hz,2H,Ar-H),7.59(m,3H,SCH,SO ₂NH ₂),4.42(m,2H,OCH ₂),4.10(s,1H,OH),3.46(m,2H,CH ₂),3.07-2.75(m,2H,CH ₂),1.72(m,3H,CH,CH ₂),1.38(m,2H,CH ₂),1.10(m,2H,CH ₂)；ESI-MS 439.10[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 61%. ¹ H NMR(DMSO-d6)δppm: 13.01(s,1H,CONH), 8.24(d,J=8.0Hz,2H,Ar-H),7.97(d,J=8.0Hz,2H,Ar-H) , 7.59 (m, 3H, SCH, SO ₂ NH ₂ ), 4.42 (m, 2H, OCH ₂ ), 4.10 (s, 1H, OH), 3.46 (m, 2H, CH ₂ ), 3.07-2.75 (m, 2H,CH ₂ ),1.72(m,3H,CH,CH ₂ ),1.38(m,2H,CH ₂ ),1.10(m,2H,CH ₂ ); ESI-MS 439.10[M+H] ⁺ .

实施例30：N-(2-甲氧基苯基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺Example 30: N-(2-Methoxyphenyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率63％。 ¹H NMR(DMSO-d6)δppm:13.12(s,1H,CONH),9.57(s,1H,CONH),8.39(d,1H,Ar-H),8.29(d,J＝8.0Hz,2H,Ar-H),8.09(s,1H,SCH),7.99(d,J＝8.0Hz,2H,Ar-H),7.60(s,2H,SO ₂NH ₂),7.13(m,2H,Ar-H),7.00(m,1H,Ar-H),3.94(s,3H,CH ₃)；ESI-MS 433.06[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 63%. ¹ H NMR(DMSO-d6)δppm: 13.12(s,1H,CONH), 9.57(s,1H,CONH), 8.39(d,1H,Ar-H), 8.29(d,J=8.0Hz,2H, Ar-H), 8.09 (s, 1H, SCH), 7.99 (d, J = 8.0 Hz, 2H, Ar-H), 7.60 (s, 2H, SO ₂ NH ₂ ), 7.13 (m, 2H, Ar- H),7.00(m,1H,Ar-H),3.94(s,3H,CH ₃ ); ESI-MS 433.06[M+H] ⁺ .

实施例31：N-[4-(4-甲基哌嗪-1-羰基)噻唑-2-基]-4-氨磺酰基苯甲酰胺Example 31: N-[4-(4-Methylpiperazine-1-carbonyl)thiazol-2-yl]-4-sulfamoylbenzamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率64％。 ¹H NMR(DMSO-d6)δppm:12.98(s,1H,CONH),8.25(d,J＝8.0Hz,2H,Ar-H),7.97(d,J＝8.0Hz,2H,Ar-H),7.66(s,1H,SCH),7.59(s,2H,SO ₂NH ₂),3.66(m,4H,NCH ₂),2.35(m,4H,NCH ₂),2.22(s,3H,CH ₃)；ESI-MS 410.09[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 64%. ¹ H NMR(DMSO-d6)δppm: 12.98(s,1H,CONH), 8.25(d,J=8.0Hz,2H,Ar-H),7.97(d,J=8.0Hz,2H,Ar-H) , 7.66 (s, 1H, SCH), 7.59 (s, 2H, SO ₂ NH ₂ ), 3.66 (m, 4H, NCH ₂ ), 2.35 (m, 4H, NCH ₂ ), 2.22 (s, 3H, CH ₃ ); ESI-MS 410.09[M+H] ⁺ .

实施例32：N-[4-(4-乙基哌嗪-1-羰基)噻唑-2-基]-4-氨磺酰基苯甲酰胺Example 32: N-[4-(4-ethylpiperazine-1-carbonyl)thiazol-2-yl]-4-sulfamoylbenzamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率54％。 ¹H NMR(DMSO-d6)δppm:12.95(s,1H,CONH),8.24(d,J＝8.0Hz,2H,Ar-H),7.96(d,J＝8.0Hz,2H,Ar-H),7.65(s,1H,SCH),7.58(s,2H,SO ₂NH ₂),3.65(m,4H,NCH ₂),2.37(m,6H,NCH ₂),1.01(t,3H,CH ₃)；ESI-MS 424.11[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 54%. ¹ H NMR(DMSO-d6)δppm: 12.95(s,1H,CONH), 8.24(d,J=8.0Hz,2H,Ar-H),7.96(d,J=8.0Hz,2H,Ar-H) , 7.65 (s, 1H, SCH), 7.58 (s, 2H, SO ₂ NH ₂ ), 3.65 (m, 4H, NCH ₂ ), 2.37 (m, 6H, NCH ₂ ), 1.01 (t, 3H, CH ₃ ); ESI-MS 424.11[M+H] ⁺ .

实施例33：N-{4-[(苯并[d][1,3]二氧-5-基甲基)哌嗪-1-羰基]噻唑-2-基}-4-氨磺酰基苯甲酰胺Example 33: N-{4-[(benzo[d][1,3]dioxo-5-ylmethyl)piperazine-1-carbonyl]thiazol-2-yl}-4-sulfamoylbenzene Formamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率51％。 ¹H NMR(DMSO-d6)δppm:12.86(s,1H,CONH),8.24(d,J＝8.0Hz,2H,Ar-H),7.97(d,J＝8.0Hz,2H,Ar-H),7.64(s,1H,SCH),7.58(s,2H,SO ₂NH ₂),6.87(m,2H,Ar-H),6.76(m,2H,Ar-H),5.99(s,2H,Ar-H),3.64(m,4H,NCH ₂),3.42(s,2H,NCH ₂),2.38(m,4H,NCH ₂)；ESI-MS 530.11[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 51%. ¹ H NMR(DMSO-d6)δppm: 12.86(s,1H,CONH), 8.24(d,J=8.0Hz,2H,Ar-H),7.97(d,J=8.0Hz,2H,Ar-H) , 7.64 (s, 1H, SCH), 7.58 (s, 2H, SO ₂ NH ₂ ), 6.87 (m, 2H, Ar-H), 6.76 (m, 2H, Ar-H), 5.99 (s, 2H, Ar-H), 3.64(m,4H,NCH ₂ ),3.42(s,2H,NCH ₂ ),2.38(m,4H,NCH ₂ ); ESI-MS 530.11[M+H] ⁺ .

实施例34：N-{4-[(4-(2-甲氧基乙基)哌嗪-1-羰基]噻唑-2-基}-4-氨磺酰基苯甲酰胺Example 34: N-{4-[(4-(2-methoxyethyl)piperazine-1-carbonyl]thiazol-2-yl}-4-sulfamoylbenzamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率64％。 ¹H NMR(DMSO-d6)δppm:13.15(s,1H,CONH),8.24(d,J＝8.0Hz,2H,Ar-H),7.97(d,J＝8.0Hz,2H,Ar-H),7.67(s,1H,SCH),7.59(s,2H,SO ₂NH ₂),3.66(m,4H,NCH ₂),3.46(t,2H,OCH ₂),3.24(s,3H,OCH ₃),2.48(m,6H,NCH ₂)；ESI-MS 454.12[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 64%. ¹ H NMR(DMSO-d6)δppm: 13.15(s,1H,CONH), 8.24(d,J=8.0Hz,2H,Ar-H),7.97(d,J=8.0Hz,2H,Ar-H) , 7.67 (s, 1H, SCH), 7.59 (s, 2H, SO ₂ NH ₂ ), 3.66 (m, 4H, NCH ₂ ), 3.46 (t, 2H, OCH ₂ ), 3.24 (s, 3H, OCH ₃ ),2.48(m,6H,NCH ₂ ); ESI-MS 454.12[M+H] ⁺ .

实施例35：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸[3-(4-甲基哌嗪-1-基)丙基]酯Example 35: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid [3-(4-methylpiperazin-1-yl)propyl] ester

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率63％。 ¹H NMR(DMSO-d6)δppm:8.27(d,J＝8.0Hz,2H,Ar-H),8.14(s,1H,SCH),7.96(d,J＝8.0Hz,2H,Ar-H),7.58(s,2H,SO ₂NH ₂),4.28(t,2H,OCH ₂),2.42-2.33(m,10H,NCH ₂),2.18(s,3H,CH ₃),1.85(m,2H,CCH ₂C)；ESI-MS 468.13[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 63%. ¹ H NMR(DMSO-d6)δppm: 8.27(d,J=8.0Hz,2H,Ar-H), 8.14(s,1H,SCH),7.96(d,J=8.0Hz,2H,Ar-H) , 7.58 (s, 2H, SO ₂ NH ₂ ), 4.28 (t, 2H, OCH ₂ ), 2.42-2.33 (m, 10H, NCH ₂ ), 2.18 (s, 3H, CH ₃ ), 1.85 (m, 2H ,CCH ₂ C); ESI-MS 468.13[M+H] ⁺ .

实施例36：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸[2-(4-甲基哌嗪-1-基)乙基]酯Example 36: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid [2-(4-methylpiperazin-1-yl)ethyl] ester

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率49％。 ¹H NMR(DMSO-d6)δppm:12.54(s,1H,CONH),8.22(d,J＝8.0Hz,2H,Ar-H),8.09(s,1H,SCH),7.92(d,J＝8.0Hz,2H,Ar-H),7.54(s,2H,SO ₂NH ₂),4.32(t,2H,OCH ₂),2.62(t,2H,NCH ₂),2.33(m,8H,NCH ₂),2.15(s,3H,CH ₃)；ESI-MS 454.12[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 49%. ¹ H NMR (DMSO-d6) δppm: 12.54 (s, 1H, CONH), 8.22 (d, J = 8.0 Hz, 2H, Ar-H), 8.09 (s, 1H, SCH), 7.92 (d, J = 8.0Hz, 2H, Ar-H), 7.54 (s, 2H, SO ₂ NH ₂ ), 4.32 (t, 2H, OCH ₂ ), 2.62 (t, 2H, NCH ₂ ), 2.33 (m, 8H, NCH ₂ ), 2.15(s,3H,CH ₃ ); ESI-MS 454.12[M+H] ⁺ .

实施例37：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸[(3-吗啉基)丙基]酯Example 37: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid [(3-morpholinyl)propyl] ester

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率69％。 ¹H NMR(DMSO-d6)δppm:13.26(s,1H,CONH),8.27(d,J＝8.0Hz,2H,Ar-H),8.18(s,1H,SCH),7.97(d,J＝8.0Hz,2H,Ar-H),7.60(s,2H,SO ₂NH ₂),4.31(t,2H,OCH ₂),3.58(t,4H,OCH ₂),2.40(m,6H,NCH ₂),1.87(m,2H,CCH ₂C)；ESI-MS 455.10[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 69%. ¹ H NMR (DMSO-d6) δppm: 13.26 (s, 1H, CONH), 8.27 (d, J = 8.0 Hz, 2H, Ar-H), 8.18 (s, 1H, SCH), 7.97 (d, J = 8.0Hz, 2H, Ar-H), 7.60 (s, 2H, SO ₂ NH ₂ ), 4.31 (t, 2H, OCH ₂ ), 3.58 (t, 4H, OCH ₂ ), 2.40 (m, 6H, NCH ₂ ),1.87(m,2H,CCH ₂ C); ESI-MS 455.10[M+H] ⁺ .

实施例38：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸[(2-吗啉基)乙基]酯Example 38: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid [(2-morpholinyl)ethyl] ester

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率56％。 ¹H NMR(DMSO-d6)δppm:13.28(s,1H,CONH),8.27(d,J＝8.0Hz,2H,Ar-H),8.17(s,1H,SCH),7.97(d,J＝8.0Hz,2H,Ar-H),7.59(s,2H,SO ₂NH ₂),4.39(t,2H,OCH ₂),3.58(t,4H,OCH ₂),2.68(t,2H,NCH ₂),2.47(m,4H,NCH ₂)；ESI-MS 441.09[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 56%. ¹ H NMR (DMSO-d6) δppm: 13.28 (s, 1H, CONH), 8.27 (d, J = 8.0 Hz, 2H, Ar-H), 8.17 (s, 1H, SCH), 7.97 (d, J = 8.0Hz, 2H, Ar-H), 7.59 (s, 2H, SO ₂ NH ₂ ), 4.39 (t, 2H, OCH ₂ ), 3.58 (t, 4H, OCH ₂ ), 2.68 (t, 2H, NCH ₂ ),2.47(m,4H,NCH ₂ ); ESI-MS 441.09[M+H] ⁺ .

实施例39：1-[(4-氨磺酰基苯甲基)甲酰胺基)噻唑-4-酰基]-4-(2-甲氧基乙基)哌嗪Example 39: 1-[(4-sulfamoylbenzyl)carboxamido)thiazole-4-acyl]-4-(2-methoxyethyl)piperazine

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率59％。 ¹H NMR(DMSO-d6)δppm:13.08(br s,1H,CONH),8.21(d,J＝8.0Hz,2H,Ar-H),7.94(d,J＝8.0Hz,2H,Ar-H),7.87(s,1H,SCH),7.54(s,2H,SO ₂NH ₂),3.63(m,4H,NCH ₂), 3.42(t,2H,OCH ₂),3.21(s,3H,OCH ₃),2.46(m,6H,NCH ₂)；ESI-MS 454.12[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 59%. ¹ H NMR(DMSO-d6)δppm: 13.08(br s,1H,CONH), 8.21(d,J=8.0Hz,2H,Ar-H),7.94(d,J=8.0Hz,2H,Ar-H ), 7.87(s,1H,SCH),7.54(s,2H,SO ₂ NH ₂ ),3.63(m,4H,NCH ₂ ), 3.42(t,2H,OCH ₂ ),3.21(s,3H,OCH ₃ ), 2.46(m,6H,NCH ₂ ); ESI-MS 454.12[M+H] ⁺ .

实施例40：3-{[2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰基}-1-(叔丁氧羰基)胍Example 40: 3-{[2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-formyl}-1-(tert-butoxycarbonyl)guanidine

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率58％。 ¹H NMR(DMSO-d6)δppm:13.81(br s,1H,NH),10.9(br s,1H,NH),9.12(br s,1H,NH),8.56(br s,1H,NH),8.24(d,J＝8.0Hz,2H,Ar-H),8.08(s,1H,SCH),7.94(d,J＝8.0Hz,2H,Ar-H),7.55(br s,2H,SO ₂NH ₂),1.42(s,9H,C(CH ₃) ₃).ESI-MS 469.10[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 58%. ¹ H NMR (DMSO-d6) δppm: 13.81 (br s, 1H, NH), 10.9 (br s, 1H, NH), 9.12 (br s, 1H, NH), 8.56 (br s, 1H, NH), 8.24(d,J=8.0Hz,2H,Ar-H),8.08(s,1H,SCH),7.94(d,J=8.0Hz,2H,Ar-H),7.55(br s,2H,SO ₂ NH ₂ ),1.42(s,9H,C(CH ₃ ) ₃ ).ESI-MS 469.10[M+H] ⁺ .

实施例41：N-{[(4-胺磺酰基苯基)甲酰基]胺基噻唑-4-酰基}甘氨酸苄酯Example 41: N-{[(4-Sulfonylphenyl)formyl]aminothiazole-4-acyl}glycine benzyl ester

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率66％。 ¹H NMR(DMSO-d6)δppm:13.05(br s,1H,CONH),8.25(br t,J＝5.96Hz,1H,CON HCH ₂),8.21(d,J＝8.0Hz,2H,Ar-H),7.94(d,J＝8.0Hz,2H,Ar-H),7.92(s,1H,SCH),7.55(br s,2H,SO ₂NH ₂),7.28-7.38(m,5H,Ph),5.15(s,2H,PhCH ₂),4.12(d,J＝5.96Hz,2H,CONHC H ₂ )；ESI-MS 475.07[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 66%. ¹ H NMR (DMSO-d6) δppm: 13.05 (br s, 1H, CONH), 8.25 (br t, J = 5.96 Hz, 1H, CON H CH ₂ ), 8.21 (d, J = 8.0 Hz, 2H, Ar -H), 7.94 (d, J = 8.0 Hz, 2H, Ar-H), 7.92 (s, 1H, SCH), 7.55 (br s, 2H, SO ₂ NH ₂ ), 7.28-7.38 (m, 5H, Ph),5.15(s,2H,PhCH ₂ ),4.12(d,J=5.96Hz,2H,CONHC H ₂ ); ESI-MS 475.07[M+H] ⁺ .

实施例42：2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-5-羧酸乙酯Example 42: 2-[(4-sulfamoylphenyl)formyl]aminothiazole-5-carboxylic acid ethyl ester

除了替换相应的反应起始原料以外，根据实施例1的方法制备目标化合物，白色固体，收率86％。 ¹H NMR(DMSO-d6)δppm:13.35(br s,1H,CONH),8.27(s,1H,SCH),8.26(d,J＝8.0Hz,2H,Ar-H),7.99(d,J＝8.0Hz,2H,Ar-H),7.60(s,2H,SO ₂NH ₂),4.31(q,J＝7.0Hz,2H,OC H ₂ CH ₃),1.32(t,J＝7.0Hz,3H,OCH ₂ CH ₃ )；ESI-MS 356.04[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 1, a white solid, with a yield of 86%. ¹ H NMR(DMSO-d6)δppm: 13.35(br s,1H,CONH), 8.27(s,1H,SCH), 8.26(d,J=8.0Hz,2H,Ar-H),7.99(d,J =8.0Hz,2H,Ar-H),7.60(s,2H,SO ₂ NH ₂ ),4.31(q,J=7.0Hz,2H,OC H ₂ CH ₃ ),1.32(t,J=7.0Hz, 3H,OCH ₂ CH ₃ ); ESI-MS 356.04[M+H] ⁺ .

实施例43：2-[(4-氨磺酰基苯基)甲酰基]胺基-4-甲基噻唑-5-羧酸乙酯Example 43: 2-[(4-sulfamoylphenyl)formyl]amino-4-methylthiazole-5-carboxylic acid ethyl ester

除了替换相应的反应起始原料以外，根据实施例1的方法制备目标化合物，白色固体，收率81％。 ¹H NMR(DMSO-d6)δppm:13.2(br s,1H),8.24(d,J＝8.0Hz,2H,Ar-H),7.99(d,J＝8.0Hz,2H,Ar-H),7.58(s,2H,SO ₂NH ₂),4.27(q,J＝7.0Hz,2H,OC H ₂ CH ₃),2.60(s,3H,CH ₃),1.31(t,J＝7.0Hz,3H,OCH ₂ CH ₃ )；ESI-MS 370.05[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 1. A white solid, with a yield of 81%. ¹ H NMR(DMSO-d6)δppm: 13.2(br s,1H), 8.24(d,J=8.0Hz,2H,Ar-H),7.99(d,J=8.0Hz,2H,Ar-H), 7.58(s,2H,SO ₂ NH ₂ ), 4.27(q,J=7.0Hz,2H,OC H ₂ CH ₃ ), 2.60(s,3H,CH ₃ ),1.31(t,J=7.0Hz,3H ,OCH ₂ CH ₃ ); ESI-MS 370.05[M+H] ⁺ .

实施例44：2-[(4-氨磺酰基苯基)甲酰基]胺基-4-溴噻唑-5-羧酸乙酯Example 44: 2-[(4-sulfamoylphenyl)formyl]amino-4-bromothiazole-5-carboxylic acid ethyl ester

除了替换相应的反应起始原料以外，根据实施例1的方法制备目标化合物，白色固体，收率62％。 ¹H NMR(DMSO-d6)δppm:13.5(br s,1H),8.22(d,J＝8.0Hz,2H,Ar-H),7.93(d,J＝8.0Hz,2H,Ar-H),7.55(s,2H,SO ₂NH ₂),4.28(q,J＝7.0Hz,2H,OC H ₂ CH ₃),1.28(t,J＝7.0Hz,3H,OCH ₂ CH ₃ )；ESI-MS 433.95[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 1. A white solid, with a yield of 62%. ¹ H NMR(DMSO-d6)δppm: 13.5(br s,1H), 8.22(d,J=8.0Hz,2H,Ar-H),7.93(d,J=8.0Hz,2H,Ar-H), 7.55(s,2H,SO ₂ NH ₂ ), 4.28(q,J=7.0Hz,2H,OC H ₂ CH ₃ ), 1.28(t,J=7.0Hz,3H,OCH ₂ CH ₃ ); ESI-MS 433.95[M+H] ⁺ .

实施例45：2-[(4-氨磺酰基苯基)甲酰基]胺基-4-苯基噻唑-5-羧酸乙酯Example 45: 2-[(4-sulfamoylphenyl)formyl]amino-4-phenylthiazole-5-carboxylic acid ethyl ester

除了替换相应的反应起始原料以外，根据实施例1的方法制备目标化合物，白色固体，收率82％。 ¹H NMR(DMSO-d6)δppm:13.4(br s,1H),8.23(d,J＝8.0Hz,2H,Ar-H),7.94(d,J＝8.0Hz,2H,Ar-H),7.77(m,2H,Ph-H),7.56(s,2H,SO ₂NH ₂),7.42(m,3H,Ph-H),4.18(q,J＝7.0Hz,2H,OC H ₂ CH ₃),1.19(t,J＝7.0Hz,3H,OCH ₂ CH ₃ )；ESI-MS 432.07[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 1. A white solid, with a yield of 82%. ¹ H NMR (DMSO-d6) δppm: 13.4 (br s, 1H), 8.23 (d, J = 8.0 Hz, 2H, Ar-H), 7.94 (d, J = 8.0 Hz, 2H, Ar-H), 7.77(m,2H,Ph-H),7.56(s,2H,SO ₂ NH ₂ ),7.42(m,3H,Ph-H), 4.18(q,J=7.0Hz,2H,OC H ₂ CH ₃ ), 1.19(t,J=7.0Hz,3H,OCH ₂ CH ₃ ); ESI-MS 432.07[M+H] ⁺ .

实施例46：2-[(4-氨磺酰基苯基)甲酰基]胺基-4-三氟甲基噻唑-5-羧酸乙酯Example 46: 2-[(4-sulfamoylphenyl)formyl]amino-4-trifluoromethylthiazole-5-carboxylic acid ethyl ester

除了替换相应的反应起始原料以外，根据实施例1的方法制备目标化合物，白色固体，收率73％。 ¹H NMR(DMSO-d6)δppm:13.7(br s,1H),8.24(d,J＝8.0Hz,2H,Ar-H),7.95(d,J＝8.0Hz,2H,Ar-H),7.57(s,2H,SO ₂NH ₂),4.30(q,J＝7.0Hz,2H,OC H ₂ CH ₃),1.28(t,J＝7.0Hz,3H,OCH ₂ CH ₃ )；ESI-MS 424.02[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 1. A white solid, with a yield of 73%. ¹ H NMR(DMSO-d6)δppm: 13.7(br s,1H), 8.24(d,J=8.0Hz,2H,Ar-H),7.95(d,J=8.0Hz,2H,Ar-H), 7.57(s,2H,SO ₂ NH ₂ ), 4.30(q,J=7.0Hz,2H,OC H ₂ CH ₃ ), 1.28(t,J=7.0Hz,3H,OCH ₂ CH ₃ ); ESI-MS 424.02[M+H] ⁺ .

实施例47：N-环庚基[2-(4-氨磺酰基苯基甲酰基)胺基]噻唑-5-甲酰胺Example 47: N-cycloheptyl[2-(4-sulfamoylphenylformyl)amino]thiazole-5-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率56％。 ¹H NMR(DMSO-d6)δppm:13.35(br s,1H,CONH),9.52(s,1H,CONH),8.84(s,1H,NCH),8.26(d,J＝8.0Hz,2H,Ar-H),7.99(d,J＝8.0Hz,2H,Ar-H),7.60(s,2H,SO ₂NH ₂), 3.41(m,1H,

),1.35-1.52(m,12H)；ESI-MS 437.13[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 56%. ¹ H NMR (DMSO-d6) δppm: 13.35 (br s, 1H, CONH), 9.52 (s, 1H, CONH), 8.84 (s, 1H, NCH), 8.26 (d, J = 8.0 Hz, 2H, Ar -H),7.99(d,J=8.0Hz,2H,Ar-H),7.60(s,2H,SO ₂ NH ₂ ), 3.41(m,1H,

),1.35-1.52(m,12H); ESI-MS 437.13[M+H] ⁺ .

实施例48：N-(3-苄氧基)苯基2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-5-甲酰胺Example 48: N-(3-Benzyloxy)phenyl 2-[(4-sulfamoylphenyl)formyl]aminothiazole-5-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率61％。 ¹H NMR(DMSO-d6)δppm:13.4(br s,1H,CONH),10.2(br s,1H,CONH),8.84(s,1H,NCH-C),8.28(d,J＝8.0Hz,2H,Ar-H),7.91(d,J＝8.0Hz,2H,Ar-H),7.56(s,2H,SO ₂NH ₂),7.08-7.48(m,9H,Ph-H),5.14(s,2H,Ph-CH ₂O)；ESI-MS 509.10[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 61%. ¹ H NMR(DMSO-d6)δppm: 13.4(br s,1H,CONH), 10.2(br s,1H,CONH), 8.84(s,1H,NCH-C), 8.28(d,J=8.0Hz, 2H, Ar-H), 7.91 (d, J = 8.0 Hz, 2H, Ar-H), 7.56 (s, 2H, SO ₂ NH ₂ ), 7.08-7.48 (m, 9H, Ph-H), 5.14 ( s,2H,Ph-CH ₂ O); ESI-MS 509.10[M+H] ⁺ .

实施例49：N-(2-吗啉基)乙基2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-5-甲酰胺Example 49: N-(2-morpholinyl)ethyl 2-[(4-sulfamoylphenyl)formyl]aminothiazole-5-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率54％。 ¹H NMR(DMSO-d6)δppm:13.0(br s,1H,CONH),8.46(s,1H,CONH),8.21(d,J＝8.0Hz,2H,Ar-H),8.11(s,1H,NCHC)7.92(d,J＝8.0Hz,2H,Ar-H),7.54(s,2H,SO ₂NH ₂),3.55(m,4H,CH ₂OCH ₂),3.31(m,2H),3.13(m,2H),2.41(m,4H)；ESI-MS 440.10[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 54%. ¹ H NMR (DMSO-d6) δppm: 13.0 (br s, 1H, CONH), 8.46 (s, 1H, CONH), 8.21 (d, J = 8.0 Hz, 2H, Ar-H), 8.11 (s, 1H) ,NCHC)7.92(d,J=8.0Hz,2H,Ar-H),7.54(s,2H,SO ₂ NH ₂ ),3.55(m,4H,CH ₂ OCH ₂ ),3.31(m,2H), 3.13(m,2H),2.41(m,4H); ESI-MS 440.10[M+H] ⁺ .

实施例50：N-壬基2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-5-甲酰胺Example 50: N-nonyl 2-[(4-sulfamoylphenyl)formyl]aminothiazole-5-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率86％。 ¹H NMR(DMSO-d6)δppm:13.0(br s,1H,CONH),8.45(s,1H,CONH),8.21(d,J＝8.0Hz,2H,Ar-H),8.11(s,1H,NCHC)7.92(d,J＝8.0Hz,2H,Ar-H),7.54(s,2H,SO ₂NH ₂),3.18(m,2H,NH-C H ₂ -CH ₂-),1.47(m,2H,NH-CH ₂- CH ₂ -),1.22(m,2H,CH ₂×6),0.81(m,3H,-CH ₃)；ESI-MS 453.16[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 86%. ¹ H NMR(DMSO-d6)δppm: 13.0(br s,1H,CONH),8.45(s,1H,CONH),8.21(d,J=8.0Hz,2H,Ar-H),8.11(s,1H) ,NCHC)7.92(d,J=8.0Hz,2H,Ar-H),7.54(s,2H,SO ₂ NH ₂ ), 3.18(m,2H,NH-C H ₂ -CH ₂ -), 1.47( m,2H,NH-CH ₂ - CH ₂ -),1.22(m,2H,CH ₂ ×6),0.81(m,3H,-CH ₃ ); ESI-MS 453.16[M+H] ⁺ .

实施例51：N-(2-吗啉基)乙基2-[(4-氨磺酰基苯基)甲酰基]胺基-4-甲基噻唑-5-甲酰胺Example 51: N-(2-morpholinyl)ethyl 2-[(4-sulfamoylphenyl)formyl]amino-4-methylthiazole-5-carboxamide

除了替换相应的反应起始原料以外，根据实施例3的方法制备目标化合物，白色固体，收率56％。 ¹H NMR(DMSO-d6)δppm:13.2(br s,1H),8.24(d,J＝8.0Hz,2H,Ar-H),7.99(d,J＝8.0Hz,2H,Ar-H),7.58(s,2H,SO ₂NH ₂),3.52(m,4H,CH ₂OCH ₂),3.36(m,2H,CONH-C H ₂ -CH ₂-N)2.50(s,3H,CH ₃),2.46(m,2H,CONH-CH ₂- CH ₂ -N),2.38(m,4H,-C H ₂ NC H ₂- ,morpholine)；ESI-MS 454.12[M+H] ⁺. Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 56%. ¹ H NMR(DMSO-d6)δppm: 13.2(br s,1H), 8.24(d,J=8.0Hz,2H,Ar-H),7.99(d,J=8.0Hz,2H,Ar-H), 7.58 (s, 2H, SO ₂ NH ₂ ), 3.52 (m, 4H, CH ₂ OCH ₂ ), 3.36 (m, 2H, CONH-C H ₂ -CH ₂ -N) 2.50 (s, 3H, CH ₃ ) ,2.46(m,2H,CONH-CH ₂ - CH ₂ -N), 2.38(m,4H,-C H ₂ NC H _2- ,morpholine); ESI-MS 454.12[M+H] ⁺ .

测试实施例1：化合物对碳酸酐酶的抑制试验Test Example 1: Inhibition test of compound on carbonic anhydrase

根据碳酸酐酶可催化4-硝基邻苯二甲酸成邻苯二甲酸根离子产生颜色变化的原理，采用分光光度计测定405nm的数值变化。实验中以15mM Hepes(pH 7.5)为缓冲液，100mM NaCl为离子强度调节剂。以市售乙酰唑胺为对照，每项实验重复3次。化合物的测试浓度为30.0000,10.0000,3.3333,1.1111,0.3704,0.1235,0.0412,0.0137,0.0046,0.0015,0.0000uM/L，CAⅠ、Ⅱ酶溶液与化合物混合液在25℃下孵育15分钟，之后加入邻苯二甲酸反应60分钟，记录吸光度值，并以抑制剂浓度为横坐标绘制曲线，计算IC ₅₀，利用Chenge-Prusoff方程计算Ki，结果见表1。 According to the principle that carbonic anhydrase can catalyze 4-nitrophthalic acid to phthalate ion to produce color change, a spectrophotometer is used to measure the value change of 405nm. In the experiment, 15mM Hepes (pH 7.5) was used as the buffer, and 100mM NaCl was used as the ionic strength regulator. With commercially available acetazolamide as a control, each experiment was repeated 3 times. The test concentration of the compound is 30.0000, 10.0000, 3.3333, 1.1111, 0.3704, 0.1235, 0.0412, 0.0137, 0.0046, 0.0015, 0.0000uM/L, CAⅠ, Ⅱ enzyme solution and compound mixture are incubated at 25°C for 15 minutes, and then added to The phthalic acid was reacted for 60 minutes, the absorbance value was recorded, and the curve was drawn with the concentration of the inhibitor as the abscissa, IC _{50 was} calculated, and Ki was calculated using the Chenge-Prusoff equation. The results are shown in Table 1.

表1碳酸酐酶抑制活性测试结果Table 1 Carbonic anhydrase inhibitory activity test results

从表1的数据可以看出，根据本发明制备的化合物相对于现有技术中临床应用的乙酰唑胺，针对CAⅠ、Ⅱ具有更为显著的抑制作用。It can be seen from the data in Table 1 that the compound prepared according to the present invention has a more significant inhibitory effect on CAI and II compared to the acetazolamide clinically used in the prior art.

测试实施例2：密闭缺氧试验Test Example 2: Airtight Hypoxia Test

乙酰唑胺(AAZ)是美国药品食品监督管理局(FDA)唯一批准的用于治疗和预防高原缺氧的药物。本发明优选代表性化合物与乙酰唑胺进行对比性药效研究。C57小鼠根据体重随机分组，每组10只，受试化合物用羧甲基纤维素钠配成混悬溶液，灌胃给药，连续三天，末次给药之后，将小鼠分别置于磨口玻璃瓶，进行密闭缺氧实验，用钠石灰吸收实验过程中密封玻璃瓶里的二氧化碳。结果显示，与乙酰唑胺，代表性化合物可以更好的延长小鼠的生存时间，显示更强的抗缺氧作用(表2)，具备发展成为更强的抗高原缺氧药物的潜力。Acetazolamide (AAZ) is the only drug approved by the US Food and Drug Administration (FDA) for the treatment and prevention of high altitude hypoxia. The preferred representative compounds of the present invention and acetazolamide are used for comparative efficacy studies. C57 mice were randomly divided into groups according to their body weight, 10 mice in each group. The test compound was prepared into a suspension solution with sodium carboxymethyl cellulose and administered by gavage for three consecutive days. After the last administration, the mice were placed in the grinding mill. Open the glass bottle, conduct the airtight hypoxia experiment, use soda lime to absorb the carbon dioxide in the sealed glass bottle during the experiment. The results showed that, with acetazolamide, representative compounds can better extend the survival time of mice, show stronger anti-hypoxia effects (Table 2), and have the potential to develop into stronger anti-altitude hypoxia drugs.

表2抗缺氧实验测试结果.Table 2 Anti-hypoxia experimental test results.

c无明显毒性效应的剂量c Dose without obvious toxic effect

CA抑制剂作为利尿剂和治疗青光眼、癫痫、黄斑水肿和急性山地病的药物已在临床上广泛应用(Supuran CT.Nature Reviews Drug Discovery,2008,7,168-181；闵靖宇等，碳酸酐酶抑制剂治疗黄斑水肿的机制与进展，眼科新进展，2016，36(7):684-687)。研究显示本发明的新的碳酸酐酶抑制剂化合物具有良好的医药用途，能够作为新型的强效低毒CAI/II抑制剂。CA inhibitors have been widely used clinically as diuretics and drugs for the treatment of glaucoma, epilepsy, macular edema and acute mountain diseases (Supuran CT. Nature Reviews Drug Discovery, 2008, 7, 168-181; Min Jingyu, etc., carbonic anhydrase inhibitors) The mechanism and progress of the treatment of macular edema, New Advances in Ophthalmology, 2016, 36(7):684-687). Studies have shown that the new carbonic anhydrase inhibitor compound of the present invention has good medical applications and can be used as a new type of potent and low-toxic CAI/II inhibitor.

尽管已经对本发明的具体实施方式进行了描述，但对本领域普通技术人员来说，显然在不脱离由如下权利要求所限定的本发明实质和范围的情况下，可对本发明进行各种变通和修改。Although the specific embodiments of the present invention have been described, it is obvious to those skilled in the art that various variations and modifications can be made to the present invention without departing from the spirit and scope of the present invention as defined by the following claims .

Claims

一类式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物，A class of five-membered heterocyclic ring-containing benzenesulfonamide compounds represented by formula I, their enantiomers, diastereomers, racemates and mixtures thereof, and their pharmaceutically acceptable salts and crystals Hydrates and solvates,

其中，Y为碳原子或者氮原子，Z和W中的至少一个为
其中取代基G选自NR1R2、OR3或取代或未取代的含有1至3个选自N和O的杂原子的五元、六元或七元杂环基，Z和W中的另一个不存在，或为氢原子、C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、被1至3个卤素原子取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、卤素原子或C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的芳基； Among them, Y is a carbon atom or a nitrogen atom, and at least one of Z and W is
Wherein the substituent G is selected from NR1R2, OR3 or a substituted or unsubstituted five-membered, six-membered or seven-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, the other of Z and W does not exist , Or hydrogen atom, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl group, is C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl substituted with 1 to 3 halogen atoms , Halogen atom or C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl group;

所述取代的含有1至3个选自N和O的杂原子的五元、六元或七元杂环基中的取代基选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、羟基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、含有1至3个选自N或O的杂原子的C5、C6、C7、C8、C9、C10、C11、C12、C13、C14或C15并环杂芳基的取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基和C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷氧基烷基；The substituents in the substituted five-membered, six-membered or seven-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O are selected from C1, C2, C3, C4, C5, C6, C7, C8 , C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl, hydroxy substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 , C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl, C5, C6, C7, C8, C9, C10, C5, C6, C7, C8, C9, C10, C18, C19 or C20 C11, C12, C13, C14 or C15 substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17 , C18, C19 or C20 alkyl and C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkoxy Alkyl;

R1、R2和R3各自独立地为：R1, R2, and R3 are each independently:

H、卤素原子、H, halogen atom,

卤素原子取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl substituted by halogen atoms,

C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷氧基、C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkoxy,

C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl,

C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20环烷基、C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 cycloalkyl,

C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20环烷基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 cycloalkyl substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl,

C1、C2、C3、C4、C5、C6、C7、C8、C9或C10烷氧基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkoxy substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl groups,

C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20芳基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 , C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl groups,

含有1至3个选自N和O的杂原子的五元、六元或七元杂环基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12 substituted by a five-membered, six-membered or seven-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O , C13, C14, C15, C16, C17, C18, C19 or C20 alkyl groups,

含有1至3个卤素原子取代基的C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20芳基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl substituted C1, C2, C3, C4 containing 1 to 3 halogen atom substituents , C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl,

取代或未取代的C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20芳基，其中取代C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20芳基中的取代基选自含有1至3个C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、卤素原子、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20芳烷基氧基和C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20烷氧基、Substituted or unsubstituted C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl groups, where C6, C7, C8, C9, C10, C11 are substituted The substituents in, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl groups are selected from containing 1 to 3 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 , C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl, halogen atom, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18 , C19 or C20 aralkyloxy and C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkane Oxy,

取代或未取代的含有1至3个选自N和O的杂原子的五元、六元或七元杂环基，其中取代的含有1至3个选自N和O的杂原子的五元、六元或七元杂环基中的取代基选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基、羟基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷基和C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的烷氧基烷基、A substituted or unsubstituted five-membered, six-membered or seven-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, wherein the substituted five-membered containing 1 to 3 heteroatoms selected from N and O The substituents in the six-membered or seven-membered heterocyclic group are selected from C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18 , C19 or C20 alkyl, hydroxy substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 And C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkoxyalkyl groups,

C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19或C20的氨基烷基；C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aminoalkyl;

所述卤素原子选自氟、氯、溴和碘。The halogen atom is selected from fluorine, chlorine, bromine and iodine.
根据权利要求1所述的式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物，其特征在于，According to claim 1, the five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures thereof, and their pharmaceutically acceptable Accepted salts, crystalline hydrates and solvates are characterized in that:

其中，Z和W中的至少一个为
其中取代基G选自NR1R2、OR3或取代或未取代的含有1至3个选自N和O的杂原子的六元杂环基，Z和W中的另一个不存在，或为氢原子、C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、被1至3个卤素原子取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、卤素原子或C6、C7、C8、C9或C10的芳基； Among them, at least one of Z and W is
Wherein the substituent G is selected from NR1R2, OR3 or a substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, the other of Z and W does not exist, or is a hydrogen atom, C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl group, C1, C2, C3, C4, C5, C6, C7, C8, C9 or substituted by 1 to 3 halogen atoms C10 alkyl group, halogen atom or C6, C7, C8, C9 or C10 aryl group;

所述取代的含有1至3个选自N和O的杂原子的六元杂环基中的取代基选自C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、羟基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、含有1至3个选自N或O的杂原子的C5、C6、C7、C8、C9或C10并环杂芳基的取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基和C2、C3、C4、C5、C6、C7、C8、C9或C10的烷氧基烷基；The substituents in the substituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O are selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkane C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl groups, hydroxy substituted C5, C6, C7, C8, C5, C6, C7, C8, C8, C9 or C10 C9 or C10 substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl and C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkoxyalkyl;

R1、R2和R3各自独立地为：R1, R2, and R3 are each independently:

H、卤素原子、H, halogen atom,

卤素原子取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl substituted by halogen atoms,

C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷氧基、C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkoxy,

C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl groups,

C3、C4、C5、C6、C7、C8、C9或C10环烷基、C3, C4, C5, C6, C7, C8, C9 or C10 cycloalkyl,

C3、C4、C5、C6、C7、C8、C9或C10环烷基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C3, C4, C5, C6, C7, C8, C9 or C10 cycloalkyl substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl,

C1、C2、C3、C4、C5、C6、C7、C8、C9或C10烷氧基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkoxy substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl groups,

C6、C7、C8、C9或C10芳基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C6, C7, C8, C9 or C10 aryl substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl groups,

含有1至3个选自N和O的杂原子的六元杂环基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl substituted with a six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O,

含有1至3个卤素原子取代基的C6、C7、C8、C9或C10芳基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、C6, C7, C8, C9 or C10 aryl substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl groups containing 1 to 3 halogen atom substituents,

取代或未取代的C6、C7、C8、C9或C10芳基，其中取代C6、C7、C8、C9或C10芳基中的取代基选自含有1至3个C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、卤素原子、C7、C8、C9或C10芳烷基氧基和C1、C2、C3、C4、C5、C6、C7、C8、C9或C10烷氧基、A substituted or unsubstituted C6, C7, C8, C9 or C10 aryl group, wherein the substituent in the substituted C6, C7, C8, C9 or C10 aryl group is selected from containing 1 to 3 C1, C2, C3, C4, C5 , C6, C7, C8, C9 or C10 alkyl, halogen atom, C7, C8, C9 or C10 aralkyloxy and C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkane Oxy,

取代或未取代的含有1至3个选自N和O的杂原子的六元杂环基，其中取代的含有1至3个选自N和O的杂原子的六元环基中的取代基选自C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、羟基取代的C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基和C2至C10的烷氧基烷基、A substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, wherein the substituted six-membered ring group containing 1 to 3 heteroatoms selected from N and O is a substituent Alkyl selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10, hydroxy substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl And C2 to C10 alkoxyalkyl groups,

C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的氨基烷基。C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 aminoalkyl.
根据权利要求1所述的式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物，其特征在于，According to claim 1, the five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures thereof, and their pharmaceutically acceptable Accepted salts, crystalline hydrates and solvates are characterized in that:

其中，Z和W中的至少一个为
其中取代基G选自NR1R2、OR3或取代或未取代的含有1至3个选自N和O的杂原子的六元杂环基，Z和W中的另一个不存在，或为氢原子、C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的烷基、被1至3个卤素原子取代的C1、C2、C3、C4、C5或C6的烷基、卤素原子或C6、C7、C8、C9或C10的芳基； Among them, at least one of Z and W is
Wherein the substituent G is selected from NR1R2, OR3 or a substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, the other of Z and W does not exist, or is a hydrogen atom, C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl group, C1, C2, C3, C4, C5 or C6 alkyl group substituted by 1 to 3 halogen atoms, halogen atom or C6, C7, C8, C9 or C10 aryl groups;

所述取代的含有1至3个选自N和O的杂原子的六元杂环基中的取代基选自C1、C2、C3、C4、C5或C6的烷基、羟基取代的C1、C2、C3、C4、C5或C6的烷基和C2、C3、C4、C5或C6的烷氧基烷基；The substituents in the substituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O are selected from C1, C2, C3, C4, C5 or C6 alkyl, hydroxy substituted C1, C2 , C3, C4, C5 or C6 alkyl and C2, C3, C4, C5 or C6 alkoxyalkyl;

R1、R2和R3各自独立地为：R1, R2, and R3 are each independently:

H、卤素原子、H, halogen atom,

卤素原子取代的C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl substituted by halogen atoms,

C1、C2、C3或C4的烷氧基、C1, C2, C3 or C4 alkoxy group,

C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl group,

C3、C4、C5、C6、C7或C8环烷基、C3, C4, C5, C6, C7 or C8 cycloalkyl,

C3、C4、C5、C6、C7或C8环烷基取代的C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl substituted with C3, C4, C5, C6, C7 or C8 cycloalkyl,

C1、C2、C3或C4烷氧基取代的C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl substituted by C1, C2, C3 or C4 alkoxy,

C6、C7、C8、C9或C10芳基取代的C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl substituted with C6, C7, C8, C9 or C10 aryl,

含有1至3个选自N和O的杂原子的六元杂环基取代的C1、C2、C3或C4的烷基、A C1, C2, C3 or C4 alkyl group substituted with a six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O,

含有1至3个卤素原子取代基的C6、C7、C8、C9或C10芳基取代的C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl substituted by C6, C7, C8, C9 or C10 aryl groups containing 1 to 3 halogen atom substituents,

取代或未取代的C6、C7、C8、C9或C10芳基，其中取代C6、C7、C8、C9或C10芳基中的取代基选自含有1至3个C1、C2、C3或C4的烷基、卤素原子、C7、C8、C9或C10芳烷基氧基和C1至C3烷氧基、A substituted or unsubstituted C6, C7, C8, C9 or C10 aryl group, wherein the substituent in the substituted C6, C7, C8, C9 or C10 aryl group is selected from alkane containing 1 to 3 C1, C2, C3 or C4 Group, halogen atom, C7, C8, C9 or C10 aralkyloxy and C1 to C3 alkoxy,

取代或未取代的含有1至3个选自N和O的杂原子的六元杂环基，其中取代的含有1至3个选自N和O的杂原子的六元杂环基中的取代基选自C1、C2、C3、C4、C5或C6的烷基、羟基取代的C1、C2、C3、C4、C5或C6的烷基和C2、C3、C4、C5或C6的烷氧基烷基、C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的氨基烷基。The substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, and the substitution in the substituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O The group is selected from C1, C2, C3, C4, C5 or C6 alkyl, hydroxy substituted C1, C2, C3, C4, C5 or C6 alkyl and C2, C3, C4, C5 or C6 alkoxyalkyl Group, C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 aminoalkyl.
根据权利要求1所述的式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物，其特征在于，According to claim 1, the five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures thereof, and their pharmaceutically acceptable Accepted salts, crystalline hydrates and solvates are characterized in that:

其中，Z和W中的至少一个为
其中取代基G选自NR1R2、OR3或取代或未取代的含有1或2个选自N和O的杂原子的六元杂环基，Z和W中的另一个不存在，或为氢原子、甲基、乙基、丙基、丁基、Cl、Br、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、苯基或萘基； Among them, at least one of Z and W is
Wherein the substituent G is selected from NR1R2, OR3 or a substituted or unsubstituted six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, the other of Z and W does not exist, or is a hydrogen atom, Methyl, ethyl, propyl, butyl, Cl, Br, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, phenyl or naphthalene base;

所述取代的含有1或2个选自N和O的杂原子的六元杂环基中的取代基选自甲基、乙基、丙基、丁基、羟甲基、羟乙基、羟丙基、羟丁基、甲氧基甲基、甲氧基乙基、甲氧基丙基、含有1或2个选自N或O的杂原子的C5、C6、C7、C8、C9、C10、C11、C12、C13、C14或C15苯并杂环芳基的取代的甲基、含有1或2个选自N或O的杂原子的C5、C6、C7、C8、C9、C10、C11、C12、C13、C14或C15苯并杂环芳基的取代的乙基和含有1或2个选自N或O的杂原子的C5、C6、C7、C8、C9、C10、C11、C12、C13、C14或C15苯并杂环芳基的取代的丙基；The substituent in the substituted six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxy Propyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, C5, C6, C7, C8, C9, C10 containing 1 or 2 heteroatoms selected from N or O , C11, C12, C13, C14 or C15 benzoheterocyclic aryl substituted methyl group, containing 1 or 2 heteroatoms selected from N or O C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 benzoheterocyclic aryl substituted ethyl group and C5, C6, C7, C8, C9, C10, C11, C12, C13 containing 1 or 2 heteroatoms selected from N or O , C14 or C15 benzoheterocyclic aryl substituted propyl group;

R1、R2和R3各自独立地为：R1, R2, and R3 are each independently:

H、氟、氯、溴、H, fluorine, chlorine, bromine,

一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、一氯甲基、二氯甲基、三氯甲基、一氯乙基、二氯乙基、三氯乙基、一溴甲基、二溴甲基、三溴甲基、一溴乙基、二溴乙基、三溴乙基、Monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, Dichloroethyl, trichloroethyl, monobromomethyl, dibromomethyl, tribromomethyl, monobromoethyl, dibromoethyl, tribromoethyl,

甲氧基、乙氧基、丙氧基、丁氧基、Methoxy, ethoxy, propoxy, butoxy,

甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,

环丙基、环丁基、环戊基、环己基、环庚基、环辛基、Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,

环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、环庚基甲基、环辛基甲基、环丙基乙基、环丁基乙基、环戊基乙基、环己基乙基、环庚基乙基、环辛基乙基、环丙基丙基、环丁基丙基、环戊基丙基、环己基丙基、环庚基丙基、环辛基丙基、环丙基丁基、环丁基丁基、环戊基丁基、环己基丁基、环庚基丁基、环辛基丁基、Cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl , Cyclohexylethyl, cycloheptylethyl, cyclooctylethyl, cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclooctyl Propyl, cyclopropylbutyl, cyclobutylbutyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptylbutyl, cyclooctylbutyl,

甲氧基甲基、乙氧基甲基、丙氧基甲基、丁氧基甲基、甲氧基乙基、乙氧基乙基、丙氧基乙基、丁氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基丙基、丁氧基丙基、甲氧基丁基、乙氧基丁基、丙氧基丁基、丁氧基丁基、Methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, methoxy Propyl propyl, ethoxy propyl, propoxy propyl, butoxy propyl, methoxy butyl, ethoxy butyl, propoxy butyl, butoxy butyl,

苯甲基、苯乙基、苯丙基、苯丁基、萘基甲基、萘基乙基、萘基丙基、萘基丁基、Benzyl, phenethyl, phenylpropyl, phenbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl,

含有1至3个选自N和O的杂原子的六元杂环基取代的C1、C2、C3或C4的烷基、A C1, C2, C3 or C4 alkyl group substituted with a six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O,

含有1至3个氟、氯或溴卤素原子取代基的苯基或萘基取代的C1、C2、C3或C4的烷基、C1, C2, C3 or C4 alkyl substituted by phenyl or naphthyl with 1 to 3 fluorine, chlorine or bromine halogen atom substituents,

取代或未取代的苯基或萘基，其中取代的苯基或萘基中的取代基选自含有1至3个选自甲基、乙基、丙基、丁基、氟、氯、溴、苯氧基、苯甲氧基、苯乙氧基、苯丙氧基、苯丁氧基、萘氧基、萘甲氧基、萘乙氧基、萘丙氧基、萘丁氧基、甲氧基、乙氧基和丙氧基的取代基、A substituted or unsubstituted phenyl or naphthyl group, wherein the substituent in the substituted phenyl or naphthyl group is selected from the group consisting of 1 to 3 selected from methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, Phenoxy, benzyloxy, phenethoxy, phenylpropoxy, phenbutoxy, naphthyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, naphthylbutoxy, methoxy Group, ethoxy and propoxy substituents,

取代或未取代的含有1至3个选自N和O的杂原子的六元杂环基，其中取代的含有1至3个选自N和O的杂原子的六元杂环基中的取代基选自甲基、乙基、丙基、丁基、羟甲基、羟乙基、羟丙基、羟丁基、甲氧基甲基、乙氧基甲基和丙氧基甲基、甲氧基乙基、乙氧基乙基和丙氧基乙基、甲氧基丙基、乙氧基丙基和丙氧基丙基、The substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, and the substitution in the substituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O The group is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxymethyl, ethoxymethyl and propoxymethyl, methyl Oxyethyl, ethoxyethyl and propoxyethyl, methoxypropyl, ethoxypropyl and propoxypropyl,

甲胺基、乙胺基、丙胺基、丁胺基、戊胺基、二甲胺基、二乙胺基、二丙胺基、二丁胺基、二戊胺基、甲基乙基胺基、甲基丙基胺基、甲基丁基胺基、甲基戊基胺基、乙基丙基胺基、乙基丁基胺基、乙基戊基胺基、丙基丁基胺基、丙基戊基胺基、丁基戊基胺基。Methylamino, ethylamino, propylamino, butylamino, pentylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, methylethylamino, Methyl propyl amino, methyl butyl amino, methyl pentyl amino, ethyl propyl amino, ethyl butyl amino, ethyl pentyl amino, propyl butyl amino, propyl Benzyl pentyl amino, butyl pentyl amino.
根据权利要求1所述的式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物，其特征在于，其选自如下化合物：According to claim 1, the five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures thereof, and their pharmaceutically acceptable Accepted salts, crystalline hydrates and solvates are characterized in that they are selected from the following compounds:

(1)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸乙酯(1) 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid ethyl ester

(2)5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-羧酸乙酯(2) 5-[(4-sulfamoylphenyl) formyl]amino-1,3,4-thiadiazole-2-carboxylic acid ethyl ester

(3)N-环丙基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(3) N-Cyclopropyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(4)N-环戊基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(4) N-cyclopentyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(5)N-环己基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(5) N-cyclohexyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(6)N-环庚基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(6)N-cycloheptyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(7)N-环辛基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(7)N-cyclooctyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(8)N-正丙基-2-[(4-氨磺酰基苯甲酰基)胺基]噻唑-4-甲酰胺(8)N-n-propyl-2-[(4-sulfamoylbenzoyl)amino]thiazole-4-carboxamide

(9)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸酯己酯(9) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylate hexyl ester

(10)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸异丙酯(10) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid isopropyl ester

(11)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸(2-甲氧基)乙基酯(11) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid (2-methoxy) ethyl ester

(12)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环丙甲基酯(12) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid cyclopropylmethyl ester

(13)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环戊基甲基酯(13) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid cyclopentyl methyl ester

(14)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环丙基酯(14) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid cyclopropyl ester

(15)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环戊基酯(15) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid cyclopentyl ester

(16)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸环己基酯(16) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid cyclohexyl ester

(17)N-正丙基-5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰胺(17) N-n-propyl-5-[(4-sulfamoylphenyl)formyl]amino-1,3,4-thiadiazole-2-carboxamide

(18)N-环己基-5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰胺(18)N-cyclohexyl-5-[(4-sulfamoylphenyl)formyl]amino-1,3,4-thiadiazole-2-carboxamide

(19)N-环庚基-5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰胺(19)N-Cycloheptyl-5-[(4-sulfamoylphenyl)formyl]amino-1,3,4-thiadiazole-2-carboxamide

(20)5-[(4-氨磺酰苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰胺(20) 5-[(4-sulfamoylphenyl) formyl]amino-1,3,4-thiadiazole-2-carboxamide

(21)5-[(4-氨磺酰基苯基)甲酰基]胺基-1,3,4-噻二唑-2-甲酰肼(21) 5-[(4-sulfamoylphenyl) formyl]amino-1,3,4-thiadiazole-2-carboxhydrazide

(22)N-(4-氟苄基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(22) N-(4-fluorobenzyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(23)N-(3,4-二甲基苯基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(23)N-(3,4-Dimethylphenyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(24)N-[3-(苄氧基)苯基]-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(24)N-[3-(Benzyloxy)phenyl]-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(25)(R)-N-(1-苯基丙基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(25)(R)-N-(1-phenylpropyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(26)N-甲基-N-苯基-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(26)N-Methyl-N-phenyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(27)N-(2-吗啉乙基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(27)N-(2-morpholinoethyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(28)N-(2-甲氧基乙基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(28)N-(2-Methoxyethyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(29)N-{4-[4-(2-羟乙基)哌啶-1-羰基]噻唑-2-基}-4-氨磺酰基苯甲酰胺(29)N-{4-[4-(2-hydroxyethyl)piperidine-1-carbonyl]thiazol-2-yl}-4-sulfamoylbenzamide

(30)N-(2-甲氧基苯基)-2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰胺(30)N-(2-Methoxyphenyl)-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide

(31)N-[4-(4-甲基哌嗪-1-羰基)噻唑-2-基]-4-氨磺酰基苯甲酰胺(31) N-[4-(4-Methylpiperazine-1-carbonyl)thiazol-2-yl]-4-sulfamoylbenzamide

(32)N-[4-(4-乙基哌嗪-1-羰基)噻唑-2-基]-4-氨磺酰基苯甲酰胺(32) N-[4-(4-Ethylpiperazine-1-carbonyl)thiazol-2-yl]-4-sulfamoylbenzamide

(33)N-{4-[(苯并[d][1,3]二氧-5-基甲基)哌嗪-1-羰基]噻唑-2-基}-4-氨磺酰基苯甲酰胺(33)N-{4-[(Benzo[d][1,3]dioxo-5-ylmethyl)piperazine-1-carbonyl]thiazol-2-yl}-4-sulfamoylbenzyl Amide

(34)N-{4-[(4-(2-甲氧基乙基)哌嗪-1-羰基]噻唑-2-基}-4-氨磺酰基苯甲酰胺(34) N-{4-[(4-(2-methoxyethyl)piperazine-1-carbonyl]thiazol-2-yl}-4-sulfamoylbenzamide

(35)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸[3-(4-甲基哌嗪-1-基)丙基]酯(35) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid [3-(4-methylpiperazin-1-yl)propyl] ester

(36)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸[2-(4-甲基哌嗪-1-基)乙基]酯(36) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid [2-(4-methylpiperazin-1-yl)ethyl] ester

(37)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸[(3-吗啉基)丙基]酯(37) 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylic acid [(3-morpholinyl)propyl] ester

(38)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-羧酸[(2-吗啉基)乙基]酯(38) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-4-carboxylic acid [(2-morpholinyl)ethyl] ester

(39)1-[(4-氨磺酰基苯甲基)甲酰胺基)噻唑-4-酰基]-4-(2-甲氧基乙基)哌嗪(39) 1-((4-sulfamoylbenzyl)carboxamido)thiazole-4-acyl)-4-(2-methoxyethyl)piperazine

(40)3-{[2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-4-甲酰基}-1-(叔丁氧羰基)胍(40) 3-{[2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-formyl}-1-(tert-butoxycarbonyl)guanidine

(41)N-{[(4-胺磺酰基苯基)甲酰基]胺基噻唑-4-酰基}甘氨酸苄酯(41) N-{[(4-Sulfonylphenyl)formyl]aminothiazole-4-acyl}glycine benzyl ester

(42)2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-5-羧酸乙酯(42) 2-[(4-sulfamoylphenyl) formyl]aminothiazole-5-carboxylic acid ethyl ester

(43)2-[(4-氨磺酰基苯基)甲酰基]胺基-4-甲基噻唑-5-羧酸乙酯(43) 2-[(4-sulfamoylphenyl)formyl]amino-4-methylthiazole-5-carboxylic acid ethyl ester

(44)2-[(4-氨磺酰基苯基)甲酰基]胺基-4-溴噻唑-5-羧酸乙酯(44) 2-[(4-sulfamoylphenyl)formyl]amino-4-bromothiazole-5-carboxylic acid ethyl ester

(45)2-[(4-氨磺酰基苯基)甲酰基]胺基-4-苯基噻唑-5-羧酸乙酯(45) 2-[(4-sulfamoylphenyl)formyl]amino-4-phenylthiazole-5-carboxylic acid ethyl ester

(46)2-[(4-氨磺酰基苯基)甲酰基]胺基-4-三氟甲基噻唑-5-羧酸乙酯(46) 2-[(4-sulfamoylphenyl) formyl]amino-4-trifluoromethylthiazole-5-carboxylic acid ethyl ester

(47)N-环庚基[2-(4-氨磺酰基苯基甲酰基)胺基]噻唑-5-甲酰胺(47) N-cycloheptyl[2-(4-sulfamoylphenylformyl)amino]thiazole-5-carboxamide

(48)N-(3-苄氧基)苯基2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-5-甲酰胺(48)N-(3-Benzyloxy)phenyl 2-[(4-sulfamoylphenyl)formyl]aminothiazole-5-carboxamide

(49)N-(2-吗啉基)乙基2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-5-甲酰胺(49)N-(2-morpholinyl)ethyl 2-[(4-sulfamoylphenyl)formyl]aminothiazole-5-carboxamide

(50)N-壬基2-[(4-氨磺酰基苯基)甲酰基]胺基噻唑-5-甲酰胺(50)N-nonyl 2-[(4-sulfamoylphenyl)formyl]aminothiazole-5-carboxamide

(51)N-(2-吗啉基)乙基2-[(4-氨磺酰基苯基)甲酰基]胺基-4-甲基噻唑-5-甲酰胺。(51) N-(2-morpholinyl)ethyl 2-[(4-sulfamoylphenyl)formyl]amino-4-methylthiazole-5-carboxamide.
根据权利要求1至5中任意一项所述的式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物在制备CA抑制剂中的用途。According to any one of claims 1 to 5, the five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures thereof , And the use of its pharmaceutically acceptable salts, crystalline hydrates and solvates in the preparation of CA inhibitors.
根据权利要求1至5中任意一项所述的式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物在制备治疗青光眼、抗高原缺氧、癫痫、癌症、白血病、肥胖、关节炎的药物中的用途。According to any one of claims 1 to 5, the five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures thereof , And the use of its pharmaceutically acceptable salts, crystal hydrates and solvates in the preparation of drugs for treating glaucoma, anti-altitude hypoxia, epilepsy, cancer, leukemia, obesity, and arthritis.
一种药物组合物，所述药物组合物包括治疗有效量的根据权利要求1至5中任意一项所述的式I所示的含五元杂环的苯磺酰胺类化合物其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物作为活性成分以及药物辅料。A pharmaceutical composition comprising a therapeutically effective amount of the five-membered heterocyclic-containing benzenesulfonamide compound represented by formula I according to any one of claims 1 to 5 and its enantiomers Forms, diastereomers, racemates and mixtures thereof, as well as their pharmaceutically acceptable salts, crystalline hydrates and solvates as active ingredients and pharmaceutical excipients.
根据权利要求8所述的药物组合物，其特征在于，所述药物组合物是以下剂型：片剂，胶囊剂，注射剂，喷雾剂，气雾剂，滴鼻剂，粉雾剂，栓剂、贴剂、凝胶剂。The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is in the following dosage forms: tablets, capsules, injections, sprays, aerosols, nasal drops, powder mists, suppositories, patches Agents, gels.
根据权利要求8所述的药物组合物，其特征在于，所述片剂选自普通片剂、速释片、缓释片、控释片、薄膜衣片、糖衣片、***片、舌下片、生物粘附片；所述胶囊剂选自硬胶囊、软胶囊；所述注射剂选自无菌或者含抑菌剂的水性注射剂、油性注射剂、冷冻干粉针剂、注射用微球；所述喷雾剂选自口腔喷雾剂、鼻腔喷雾剂、局部皮肤喷雾剂；所述气雾剂选自肺吸入用气雾剂、局部皮肤气雾剂；所述滴鼻剂选自滴鼻用溶液、滴鼻用凝胶；所述粉雾剂选自空腔用粉雾剂、鼻腔用粉雾剂、局部皮肤用粉雾剂。The pharmaceutical composition according to claim 8, wherein the tablet is selected from the group consisting of ordinary tablets, immediate-release tablets, sustained-release tablets, controlled-release tablets, film-coated tablets, sugar-coated tablets, buccal tablets, and sublingual tablets. Tablets, bioadhesive tablets; the capsules are selected from hard capsules and soft capsules; the injections are selected from sterile or bacteriostatic-containing aqueous injections, oily injections, freeze-dried powder injections, and microspheres for injection; the spray The agent is selected from oral sprays, nasal sprays, and topical skin sprays; the aerosol is selected from lung inhalation aerosols and topical skin aerosols; the nasal drops are selected from nasal drops and nasal drops With gel; the powder mist is selected from the group consisting of powder mist for cavity, powder mist for nasal cavity, powder mist for topical skin.