TW201620878A - Isoquinoline sulfanilamide derivatives, and pharmaceutical composition and pharmaceutical application thereof - Google Patents

Isoquinoline sulfanilamide derivatives, and pharmaceutical composition and pharmaceutical application thereof Download PDF

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TW201620878A
TW201620878A TW104113439A TW104113439A TW201620878A TW 201620878 A TW201620878 A TW 201620878A TW 104113439 A TW104113439 A TW 104113439A TW 104113439 A TW104113439 A TW 104113439A TW 201620878 A TW201620878 A TW 201620878A
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acid
group
pharmaceutically acceptable
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acceptable salt
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TWI650315B (en
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ling-yun Wu
Yuan-Shan Yao
zhao-guo Chen
Shu-Hui Chen
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Nanjing Mingde New Drug Res And Dev Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses a kind of isoquinoline sulfanilamide derivatives as an RHO kinases inhibitor and a pharmaceutical composition thereof, and also relates to pharmaceutical application of the derivatives. Concretely, the invention relates to compounds shown as a formula (I) or (II) or pharmaceutically acceptable salts.

Description

異喹啉磺胺衍生物及其藥物組合物和製藥用途Isoquinoline sulfonamide derivatives and pharmaceutical compositions thereof and pharmaceutical uses

本發明涉及一類作為RHO激酶抑制劑的異喹啉磺胺衍生物及其藥物組合物，並涉及其製藥用途。具體地，本發明涉及式(I)或(Ⅱ)所示化合物或其藥學上可接受的鹽。The present invention relates to a class of isoquinoline sulfonamide derivatives as RHO kinase inhibitors and pharmaceutical compositions thereof, and to their pharmaceutical use. In particular, the invention relates to a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

法舒地爾是一種具有廣泛藥理作用的新型藥物，為RHO激酶抑制物，通過增加肌球蛋白輕鏈磷酸酶的活性擴張血管，降低內皮細胞的張力，改善腦組織微循環，不產生和加重腦的盜血，同時可拮抗炎性因數，保護神經抗凋亡，促進神經再生。本結果表明鹽酸法舒地爾對促進神經功能的恢復，減輕臨床症狀，減少病殘率有一定療效。因此對於在基層由於受經濟條件的制約以及對疾病認識程度，而不能實現超早期溶栓治療，但為減少疾病的進一步進展，在治療時間窗內重建局部血循環顯得至關重要，而鹽酸法舒地爾具有對缺血性腦血管病的顯著神經保護和治療作用，值得在臨床尤其是基層的使用，減少致殘率，提高生活品質。Fasudil is a novel drug with a wide range of pharmacological effects. It is a RHO kinase inhibitor that dilates blood vessels by increasing the activity of myosin light chain phosphatase, reduces the tension of endothelial cells, improves brain microcirculation, and does not produce and aggravate Stealing blood from the brain can also antagonize the inflammatory factor, protect the nerve against apoptosis, and promote nerve regeneration. The results indicate that fasudil hydrochloride has a certain effect on promoting the recovery of nerve function, alleviating clinical symptoms and reducing the morbidity rate. Therefore, in the primary level due to economic constraints and awareness of the disease, it is impossible to achieve ultra-early thrombolytic therapy, but in order to reduce the further progress of the disease, it is crucial to reconstruct the local blood circulation within the treatment time window, while the phlegm hydrochloride Dilt has significant neuroprotective and therapeutic effects on ischemic cerebrovascular disease, and it is worthy of use in clinical, especially in the grassroots, reducing disability and improving quality of life.

WO2004106325公開了一類化合物，屬於法舒地爾的前藥，其結構通式如式(B-Ⅰ)所示：(B-Ⅰ)WO2004106325 discloses a class of compounds which are prodrugs of fasudil and have the structural formula shown as formula (B-I): (B-I)

儘管現有技術中存在上述化合物可作為RHO激酶抑制劑，但是它們在活性、溶解性、藥代動力學、成藥性的等方面有待改進。Although the above compounds exist in the prior art as RHO kinase inhibitors, they need to be improved in terms of activity, solubility, pharmacokinetics, drug-forming properties and the like.

本發明的目的在於提供式(I)或(Ⅱ)所示化合物或其藥學上可接受的鹽，(I)(Ⅱ) 其特徵是， R1 、R2 分別獨立地選自R3 C(=O)O-、(R4 O)2 P(=O)O-； R3 選自C1-6 烷基、(R5 )(R6 )N-、R7 O-、苯基、吡啶基、噻吩基、呋喃基； R4 、R5 、R6 、R7 分別獨立地選自選自H或C1-3 烷基； 所述C1-6 烷基、C1-3 烷基任選地被R01 所取代； R01 選自F、Cl、Br、I、OH、NH2 ，R01 的數目為1、2或3。It is an object of the present invention to provide a compound of the formula (I) or (II) or a pharmaceutically acceptable salt thereof, (I) (II) characterized in that R 1 and R 2 are each independently selected from R 3 C(=O)O-, (R 4 O) 2 P(=O)O-; R 3 is selected from C 1-6 alkane a group, (R 5 )(R 6 )N-, R 7 O-, phenyl, pyridyl, thienyl, furyl; R 4 , R 5 , R 6 , R 7 are each independently selected from H or C 1-3 alkyl; the C 1-6 alkyl group, C 1-3 alkyl group is optionally substituted by R 01 ; R 01 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , R 01 The number is 1, 2 or 3.

本發明的一個方案中，上述R3 選自丙基、丁基、二甲氨基；In one aspect of the present invention, the above R 3 is selected from propyl, butyl, dimethylamino;

本發明的一個方案中上述R3 選自異丙基、叔丁基、二甲氨基。In one embodiment of the invention, the above R 3 is selected from the group consisting of isopropyl, tert-butyl, and dimethylamino.

本發明的一個方案中，上述R1 、R2 分別獨立地選自、、、、、。In one aspect of the invention, the above R 1 and R 2 are each independently selected from the group consisting of , , , , , .

本發明的一個方案中，上述藥學上可接受的鹽如(Ⅲ)或(Ⅳ)所示：(Ⅲ)(Ⅳ) 其中，X選自無機酸或有機酸。In one embodiment of the invention, the above pharmaceutically acceptable salt is as shown in (III) or (IV): (III) (IV) wherein X is selected from a mineral acid or an organic acid.

本發明的一個方案中，上述的X選自三氟甲磺酸、鹽酸、氫溴酸、硝酸、碳酸，碳酸氫根、磷酸、磷酸一氫根、磷酸二氫根 、硫酸、硫酸氫根、氫碘酸、亞磷酸等、乙酸、丙酸、異丁酸、馬來酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、鄰苯二甲酸、苯磺酸、對甲苯磺酸、檸檬酸、酒石酸、甲磺酸、氨基酸或葡糖醛酸。In one embodiment of the present invention, the above X is selected from the group consisting of trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, Hydroiodic acid, phosphorous acid, etc., acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid , benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, amino acid or glucuronic acid.

本發明的一個方案中上述化合物或其藥學上可接受的鹽，其選自： 。In one embodiment of the invention, the above compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of .

本發明的另一個目的在於提供一種藥物組合物，其含有治療有效量的上述化合物或其藥學上可接受的鹽和藥學上可接受的載體。Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

本發明的另一個目的在於提供上述化合物或其藥學上可接受的鹽或上述藥物組合物在製備治療血管收縮引起的相關各種病症的藥物中的應用，其中所述相關的各種病症包括腦栓塞、腦缺血、腦損傷、椎底動脈供血不足、蛛網膜下腔出血所引起的腦血管痙攣、心絞痛、青光眼、高血壓、纖維化。Another object of the present invention is to provide the use of the above compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for the preparation of a medicament for treating various conditions associated with vasoconstriction, wherein the various conditions involved include cerebral embolism, Cerebral ischemia, brain damage, vertebral artery insufficiency, cerebral vasospasm caused by subarachnoid hemorrhage, angina pectoris, glaucoma, hypertension, fibrosis.

這裡所採用的術語“藥學上可接受的”，是針對那些化合物、材料、組合物和/或劑型而言，它們在可靠的醫學判斷的範圍之內，適用於與人類和動物的組織接觸使用，而沒有過多的毒性、刺激性、過敏性反應或其它問題或併發症，與合理的利益/風險比相稱。The term "pharmaceutically acceptable" as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

術語“藥學上可接受的鹽”是指本發明化合物的鹽，由本發明發現的具有特定取代基的化合物與相對無毒的酸或鹼製備。當本發明的化合物中含有相對酸性的功能團時，可以通過在純的溶液或合適的惰性溶劑中用足夠量的鹼與這類化合物的中性形式接觸的方式獲得鹼加成鹽。藥學上可接受的鹼加成鹽包括鈉、鉀、鈣、銨、有機氨或鎂鹽或類似的鹽。當本發明的化合物中含有相對鹼性的官能團時，可以通過在純的溶液或合適的惰性溶劑中用足夠量的酸與這類化合物的中性形式接觸的方式獲得酸加成鹽。藥學上可接受的酸加成鹽的實例包括無機酸鹽，所述無機酸包括例如鹽酸、氫溴酸、硝酸、碳酸，碳酸氫根，磷酸、磷酸一氫根、磷酸二氫根 、硫酸、硫酸氫根、氫碘酸、亞磷酸等；以及有機酸鹽，所述有機酸包括如乙酸、丙酸、異丁酸、馬來酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、鄰苯二甲酸、苯磺酸、對甲苯磺酸、檸檬酸、酒石酸和甲磺酸等類似的酸；還包括氨基酸(如精氨酸等)的鹽，以及如葡糖醛酸等有機酸的鹽(參見Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977))。本發明的某些特定的化合物含有鹼性和酸性的官能團，從而可以被轉換成任一鹼或酸加成鹽。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.

較佳地，以常規方式使鹽與鹼或酸接觸，再分離母體化合物，由此再生化合物的中性形式。化合物的母體形式與其各種鹽的形式的不同之處在於某些物理性質，例如在極性溶劑中的溶解度不同。Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.

本文所用的“藥學上可接受的鹽”屬於本發明化合物的衍生物，其中，通過與酸加成鹽或與鹼加成鹽的方式修飾所述母體化合物。藥學上可接受的鹽的實例包括但不限於：鹼基比如胺的無機酸或有機酸鹽、酸根比如羧酸的鹼金屬或有機鹽等等。藥學上可接受的鹽包括常規的無毒性的鹽或母體化合物的季銨鹽，例如無毒的無機酸或有機酸所形成的鹽。常規的無毒性的鹽包括但不限於那些衍生自無機酸和有機酸的鹽，所述的無機酸或有機酸選自2-乙醯氧基苯甲酸、2-羥基乙磺酸、乙酸、抗壞血酸、苯磺酸、苯甲酸、碳酸氫根、碳酸、檸檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富馬酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氫溴酸、鹽酸、氫碘酸鹽、羥基、羥萘、羥乙磺酸、乳酸、乳糖、十二烷基磺酸、馬來酸、蘋果酸、扁桃酸、甲烷磺酸、硝酸、草酸、雙羥萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水楊酸、硬脂酸、亞乙酸、琥珀酸、氨基磺酸、對氨基苯磺酸、硫酸、單寧、酒石酸和對甲苯磺酸。As used herein, a "pharmaceutically acceptable salt" is a derivative of a compound of the invention wherein the parent compound is modified by addition to an acid or to a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-ethyloxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid. , benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid , hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, nitric acid, oxalic acid , pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturaldehyde, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin , tartaric acid and p-toluenesulfonic acid.

本發明的藥學上可接受的鹽可由含有酸根或鹼基的母體化合物通過常規化學方法合成。一般情況下，這樣的鹽的製備方法是：在水或有機溶劑或兩者的混合物中，經由游離酸或鹼形式的這些化合物與化學計量的適當的鹼或酸反應來製備。一般地，優選醚、乙酸乙酯、乙醇、異丙醇或乙腈等非水介質。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

除了鹽的形式，本發明所提供的化合物還存在前藥形式。本文所​​描述的化合物的前藥容易地在生理條件下發生化學變化從而轉化成本發明的化合物。此外，前體藥物可以在體內環境中通過化學或生化方法被轉換到本發明的化合物。In addition to the form of the salt, the compounds provided herein also exist in the form of prodrugs. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention. Furthermore, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.

本發明的某些化合物可以以非溶劑化形式或者溶劑化形式存在，包括水合物形式。一般而言，溶劑化形式與非溶劑化的形式相當，都包含在本發明的範圍之內。本發明的某些化合物可以以多晶或無定形形式存在。Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.

本發明的某些化合物可以具有不對稱碳原子(光學中心)或雙鍵。外消旋體、非對映異構體、幾何異構體和單個的異構體都包括在本發明的範圍之內。Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.

本文中消旋體、雙非外消旋(ambiscalemic)及非外消旋(scalemic)或者純的對映體化合物的圖示法來自Maehr, J. Chem. Ed. 1985, 62: 114-120。 1985年，62：114-120。除非另有說明，用楔形鍵和虛線鍵表示一個立體中心的絕對構型。當本文所述化合物含有烯屬雙鍵或其它幾何不對稱中心，除非另有規定，它們包括E 、 Z 幾何異構體。同樣地，所有的互變異構形式均包括在本發明的範圍之內。Graphical representations of racemates, bicscalemic and non-racemic or pure enantiomeric compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. 1985, 62: 114-120. The absolute configuration of a stereocenter is indicated by a wedge key and a dashed key unless otherwise stated. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E , Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.

本發明的化合物可以存在特定的幾何或立體異構體形式。本發明設想所有的這類化合物，包括順式和反式異構體、(-)- 和 (+)-對映體、(R )- 和 (S )-對映體、非對映異構體、(D )-異構體、(L )-異構體，及其外消旋混合物和其他混合物，例如對映異構體或非對映體富集的混合物，所有這些混合物都屬於本發明的範圍之內。烷基等取代基中可存在另外的不對稱碳原子。所有這些異構體以及它們的混合物，均包括在本發明的範圍之內。The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-enantiomers, the ( R )- and ( S )-enantiomers, diastereoisomers , ( D )-isomer, ( L )-isomer, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.

可以通過的掌性合成或掌性試劑或者其他常規技術製備光學活性的(R )-和(S )-異構體以及D 和L 異構體。如果想得到本發明某化合物的一種對映體，可以通過不對稱合成或者具有掌性助劑的衍生作用來製備，其中將所得非對映體混合物分離，並且輔助基團裂開以提供純的所需對映異構體。 或者，當分子中含有鹼性官能團(如氨基)或酸性官能團(如羧基)時，與適當的光學活性的酸或鹼形成非對映異構體的鹽，然後通過本領域所公知的分步結晶法或色譜法進行非對映異構體拆分，然後回收得到純的對映體。此外，對映異構體和非對映異構體的分離通常是通過使用色譜法完成的，所述色譜法採用掌性固定相，並任選地與化學衍生法相結合(例如由胺生成氨基甲酸鹽)。The optically active ( R )- and ( S )-isomers as well as the D and L isomers can be prepared by palm synthesis or palmitic reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a palmitic adjuvant, wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide a pure Enantiomers are required. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art. The diastereomeric resolution is carried out by crystallization or chromatography, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a palmitic stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).

本發明的化合物可以在一個或多個構成該化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素標記化合物，比如氚(3 H)，碘-125(125 I)或C-14(14 C)。本發明的化合物的所有同位素組成的變換，無論放射性與否，都包括在本發明的範圍之內。The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

術語“藥學上可接受的載體”是指能夠遞送本發明有效量活性物質、不干擾活性物質的生物活性並且對宿主或者患者無毒副作用的任何製劑或載體介質代表性的載體包括水、油、蔬菜和礦物質、膏基、洗劑基質、軟膏基質等。這些基質包括懸浮劑、增粘劑、透皮促進劑等。它們的製劑為化妝品領域或局部藥物領域的技術人員所周知。關於載體的其他資訊，可以參考Remington:  The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005)，該文獻的內容通過引用的方式併入本文。The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, vegetables. And minerals, cream bases, lotion bases, ointment bases, and the like. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the disclosure of which is incorporated herein by reference.

術語“賦形劑”通常是指配製有效的藥物組合物所需要載體、稀釋劑和/或介質。The term "excipient" generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.

針對藥物或藥理學活性劑而言，術語“有效量”或“治療有效量”是指無毒的但能達到預期效果的藥物或藥劑的足夠用量。對於本發明中的口服劑型，組合物中一種活性物質的“有效量”是指與該組合物中另一種活性物質聯用時為了達到預期效果所需要的用量。有效量的確定因人而異，取決於受體的年齡和一般情況，也取決於具體的活性物質，個案中合適的有效量可以由本領域技術人員根據常規試驗確定。The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect. For oral dosage forms in the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.

術語“活性成分”、“治療劑”，“活性物質”或“活性劑”是指一種化學實體，它可以有效地治療目標紊亂、疾病或病症。The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease or condition.

術語“被取代的”是指特定原子上的任意一個或多個氫原子被取代基取代，包括重氫和氫的變體，只要特定原子的價態是正常的並且取代後的化合物是穩定的。當取代基為酮基(即=O)時， 意味著兩個氫原子被取代。酮取代不會發生在芳香基上。術語“任選被取代的”是指可以被取代，也可以不被取代，除非另有規定，取代基的種類和數目在化學上可以實現的基礎上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. . When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on the aryl group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.

當任何變數(例如R)在化合物的組成或結構中出現一次以上時，其在每一種情況下的定義都是獨立的。因此，例如，如果一個基團被0-2個R所取代，則所述基團可以任選地至多被兩個R所取代，並且每種情況下的R都有獨立的選項。此外，取代基和/或其變體的組合只有在這樣的組合會產生穩定的化合物的情況下才是被允許的。When any variable (e.g., R) occurs more than once in the composition or structure of the compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

當一個取代基的鍵可以交叉連接到一個環上的兩個原子時，這種取代基可以與這個環上的任意原子相鍵合。當所列舉的取代基中沒有指明其通過哪一個原子連接到化學結構通式中包括但未具體提及的化合物時，這種取代基可以通過其任何原子相鍵合。取代基和/或其變體的組合只有在這樣的組合會產生穩定的化合物的情況下才是被允許的。When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

烴基和雜烴基原子團(包括通常被稱為亞烷基、鏈烯基、亞雜烷基、雜烯基、炔基、環烷基、雜環烷基、環烯基和雜環烯基的那些基團)的取代基一般被稱為“烴基取代基”，它們可以選自但不限於下列基團中的一個或多個： -R’、-OR’、 =O、=NR’、=N-OR’、-NR’R”、-SR’、鹵素、-SiR’R”R”’、OC(O)R’、-C(O)R’、 -CO2 R’、 -CONR’R”、-OC(O)NR’R”、 -NR”C(O)R’、NR’ C(O)NR”R”’、-NR”C(O)2 R’、-NR””’-C(NR’R”R’”)=NR””、NR”” C(NR’R”)=NR’”、-S(O)R’、-S(O)2 R’、-S(O)2 NR’R”、NR”SO2 R’、-CN、–NO2 、 -N3 、-CH(Ph)2 和氟代(C1 -C4 )烷基，取代基的數目為0～(2m’+1),其中m’是這類原子團中碳原子的總數。R'、R”、R”'、R’’’’和R’’’’’各自獨立地優選氫、被取代或未被取代的雜烷基、被取代或未被取代的芳基(例如被1～3個鹵素取代芳基)、被取代或未被取代的烷基、烷氧基、硫代烷氧基基團或芳烷基。當本發明的化合物包括一個以上的R基團時，例如，每一個R基團是獨立地加以選擇的，如同當存在一個以上的R'、R”、R”'、R’’’’和R’’’’’基團時的每個這些基團。當R'和R”附著於同一個氮原子時，它們可與該氮原子結合形成5-、6-或7-員環。例如，-NR'R“意在包括但不僅限於1-吡咯烷基和4-嗎啉基。根據上述關於取代基的討論中，本領域技術人員可以理解，術語“烷基”意在包括碳原子鍵合於非氫基團所構成的基團，如鹵代烷基(例如-CF3 、-CH2 CF3 )和醯基(例如-C(O)CH3 、-C(O)CF3 、-C(O)CH2 OCH3 等)。Hydrocarbyl and heterohydrocarbyl radicals (including those commonly referred to as alkylene, alkenyl, heteroalkyl, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) The substituents of the group are generally referred to as "hydrocarbyl substituents" which may be selected from, but are not limited to, one or more of the following groups: -R', -OR', =O, =NR', =N -OR', -NR'R", -SR', halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO 2 R', -CONR'R ", -OC(O)NR'R", -NR"C(O)R', NR'C(O)NR"R"',-NR"C(O) 2 R', -NR""'-C(NR'R"R'")=NR"",NR""C(NR'R")=NR'",-S(O)R', -S(O) 2 R', -S (O) 2 NR'R", NR"SO 2 R', -CN, -NO 2 , -N 3 , -CH(Ph) 2 and fluoro(C 1 -C 4 )alkyl, number of substituents Is 0 to (2m'+1), wherein m' is the total number of carbon atoms in such a group. R', R", R"', R'''' and R''''' are each independently preferably hydrogen. a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group (for example, an aryl group substituted by 1 to 3 halogens), a substituted or unsubstituted alkyl group, an alkoxy group, or a thio group Alkoxy group Or an aralkyl group. When the compound of the invention includes more than one R group, for example, each R group is independently selected, as when more than one R', R", R"', R are present Each of these groups in the ''' and R'''' groups. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form 5-, 6- or 7 - Member ring. For example, -NR'R" is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. In light of the above discussion of substituents, those skilled in the art will appreciate that the term "alkyl" is intended to include carbon. a group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and a mercapto group (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , etc.).

與烷基原子團所述取代基相似，芳基和雜芳基取代基一般統稱為“芳基取代基”，選自例如-R’、-OR’、-NR’R”、-SR’、-鹵素, -SiR’R”R”’、OC(O)R’、-C(O)R’、 -CO2R’、-CONR’R”、-OC(O)NR’R”、 -NR”C(O)R’、NR’ C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R’”)=NR””、NR”” C(NR’R”)=NR’”、-S(O)R’、-S(O)2 R’、-S(O)2 NR’R”、NR”SO2 R’、-CN、–NO2 、-N3 、-CH(Ph)2 、氟(C1 -C4 )烷氧基和氟(C1 -C4 )烷基等，取代基的數量為0到芳香環上開放化合價的總數之間；其中R’、R”、R”’、R”” 和R””’獨立地優選自氫、被取代或未被取代的烷基、被取代或未被取代的雜烷基、被取代或未被取代的芳基和被取代或未被取代的雜芳基。當本發明的化合物包括一個以上的R基團時，例如，每個R基團是獨立地加以選擇的，如同當存在一個以上R’、R”、R”’、R”” 和R””’基團時的每個這些基團。Similar to the substituents of the alkyl group, the aryl and heteroaryl substituents are generally collectively referred to as "aryl substituents" and are selected, for example, from -R', -OR', -NR'R", -SR', - Halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C (O) R', NR'C(O)NR"R"',-NR"C(O)2R',-NR""'-C(NR'R"R'")=NR"", NR "C(NR'R")=NR'", -S(O)R', -S(O) 2 R', -S(O) 2 NR'R", NR"SO 2 R',- CN, -NO 2 , -N 3 , -CH(Ph) 2 , fluorine (C 1 -C 4 ) alkoxy, and fluorine (C 1 -C 4 ) alkyl, etc., the number of substituents is 0 to an aromatic ring Between the total number of open valencies; wherein R', R", R"', R"" and R""' are independently preferred from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted a heteroalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group. When the compound of the present invention includes more than one R group, for example, each R group is independently added. Each of these groups is selected as when more than one R', R", R"', R"" and R"" group are present.

芳基或雜芳基環的相鄰原子上的兩個取代基可以任選地被通式為–T-C(O)-(CRR’)q-U-的取代基所取代，其中T和U獨立地選自-NR-、-O-、CRR'-或單鍵，q是0到3的整數。作為替代選擇，芳基或雜芳基環的相鄰原子上的兩個取代基可以任選地被通式為–A (CH2)r B-的取代基所取代，其中A和B獨立的選自–CRR’-、-O-、-NR-、-S-、-S(O)-、S(O)2 -、-S(O)2 NR’-或單鍵，r是1～4的整數。任選地，由此形成的新環上的一個單鍵可以替換為雙鍵。作為替代選擇，芳基或雜芳基環的相鄰原子上的兩個取代基可以任選地被通式為–A (CH2)r B-的取代基所取代，其中s和d分別獨立的選自0～3的整數，X是–O-、-NR’、-S-、-S(O)-、-S(O)2 -或 –S(O)2 NR’-。取代基R、R’、R”和R”’分別獨立地優選自氫和被取代或未被取代的(C1 -C6 )烷基。Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, wherein T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) 2 -, -S(O) 2 NR'- or a single bond, r is 1 to 4 The integer. Optionally, a single bond on the new ring thus formed can be replaced with a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein s and d are each independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) 2 - or -S(O) 2 NR'-. The substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C 1 -C 6 )alkyl.

除非另有規定，術語“鹵代素”或“鹵素”本身或作為另一取代基的一部分表示氟、氯、溴或碘原子。此外，術語“鹵代烷基”意在包括單鹵代烷基和多鹵代烷基。例如，術語“鹵代(C1 -C4 )烷基”意在包括但不僅限於三氟甲基、2,2,2-三氟乙基、4-氯丁基和3-溴丙基等等。Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C 1 -C 4 )alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.

鹵代烷基的實例包括但不僅限於：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。“烷氧基”代表通過氧橋連接的具有特定數目碳原子的上述烷基。C1-6 烷氧基包括C1 、C2 、C3 、C4 、C5 和C6 的烷氧基。烷氧基的例子包括但不限於：甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S -戊氧基。“環烷基”包括飽和環基，如環丙基、環丁基或環戊基。3-7環烷基包括C3 、C4 、C5 、C6 和C7 環烷基。“鏈烯基”包括直鏈或支鏈構型的烴鏈，其中該鏈上任何的穩定位點上存在一個或多個碳-碳雙鍵，例如乙烯基和丙烯基。Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge. The C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy. "Cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl. The 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups. "Alkenyl" includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.

術語“鹵”或“鹵素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

除非另有規定，術語“雜”表示雜原子或雜原子團(即含有雜原子的原子團)，包括碳(C)和氫(H)以外的原子以及含有這些雜原子的原子團，例如包括氧(O)、氮(N)、硫(S)、矽(Si)、鍺(Ge)、鋁(Al)、硼(B)、-O-、-S-、=O、=S、-C(=O)O-、-C(=O) -、-C(=S)-、-S(=O) 、-S(=O)2 -，以及任選被被取代的-C(=O)N(H)-、-N(H)-、-C(=NH)-、-S(=O)2 N(H)-或-S(=O) N(H)-。Unless otherwise specified, the term "hetero" denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O). ), nitrogen (N), sulfur (S), antimony (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C (= O) O-, -C(=O) -, -C(=S)-, -S(=O), -S(=O) 2 -, and -C(=O) optionally substituted N(H)-, -N(H)-, -C(=NH)-, -S(=O) 2 N(H)- or -S(=O) N(H)-.

除非另有規定，“環”表示被取代或未被取代的環烷基、雜環烷基、環烯基、雜環烯基、環炔基、雜環炔基、芳基或雜芳基。所謂的環包括單環、聯環、螺環、並環或橋環。環上原子的數目通常被定義為環的員數，例如，“5～7員環”是指環繞排列5～7個原子。除非另有規定，該環任選地包含1～3個雜原子。因此，“5～7員環”包括例如苯基、吡啶基和呱啶基；另一方面，術語“5～7員雜環烷基環”包括吡啶基和呱啶基，但不包括苯基。術語“環”還包括含有至少一個環的環系，其中的每一個“環”均獨立地符合上述定義。Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of members of the ring. For example, "5 to 7 membered rings" means that 5 to 7 atoms are arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Therefore, the "5-7 membered ring" includes, for example, a phenyl group, a pyridyl group and an acridinyl group; on the other hand, the term "5-7 membered heterocycloalkyl ring" includes a pyridyl group and an acridinyl group, but does not include a phenyl group. . The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

除非另有規定，術語“雜環”或“雜環基”意指穩定的含雜原子或雜原子團的單環、雙環或三環，它們可以是飽和的、部分不飽和的或不飽和的(芳族的)，它們包含碳原子和1、2、3或4個獨立地選自N、O和S的環雜原子，其中上述任意雜環可以稠合到一個苯環上形成雙環。氮和硫雜原子可任選被氧化(即NO和S (O) p)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已經定義過的其他取代基)。該雜環可以附著到任何雜原子或碳原子的側基上從而形成穩定的結構。如果產生的化合物是穩定的，本文所述的雜環可以發生碳位或氮位上的取代。雜環中的氮原子任選地被季銨化。一個較佳的方案是，當雜環中S及O原子的總數超過1時，這些雜原子彼此不相鄰。另一個較佳的方案是，雜環中S及O原子的總數不超過1。如本文所用，術語“芳族雜環基團”或“雜芳基”意指穩定的5、6、7員單環或雙環或7、8、9或10員雙環雜環基的芳香環，它包含碳原子和1、2、3或4個獨立地選自N、O和S的環雜原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已經定義過的其他取代基)。氮和硫雜原子可任選被氧化(即NO和S (O) p)。值得注意的是，芳香雜環上S和O原子的總數不超過1。橋環也包含在雜環的定義中。當一個或多個原子(即C、O、N或S)連接兩個不相鄰的碳原子或氮原子時形成橋環。較佳的橋環包括但不限於：一個碳原子、兩個碳原子、一個氮原子、兩個氮原子和一個碳-氮基。值得注意的是，一個橋總是將單環轉換成三環。橋環中，環上的取代基也可以出現在橋上。Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites. The nitrogen atom in the heterocycle is optionally quaternized. A preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one. The term "aromatic heterocyclic group" or "heteroaryl" as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one. Bridged rings are also included in the definition of heterocycles. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.

雜環化合物的實例包括但不限於：吖啶基、吖辛因基、苯並咪唑基、苯並呋喃基、苯並巰基呋喃基、苯並巰基苯基、苯並噁唑基、苯並噁唑啉基、苯並噻唑基、苯並***基、苯並四唑基、苯並異噁唑基、苯並異噻唑基、苯並咪唑啉基、哢唑基、4aH -哢唑基、哢啉基、苯並二氫吡喃基、色烯、噌啉基十氫喹啉基、2H , 6H -1, 5,2-二噻嗪基、二氫呋喃並[2,3-b ]四氫呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H -吲唑基、吲哚烯基、二氫吲哚基、中氮茚基、3H -吲哚基、isatino基、異苯並呋喃基、異吲哚基、異二氫吲哚基、吲哚基、異喹啉基、異噻唑基、異噁唑基、亞甲二氧基苯基、嗎啉基、萘啶基，八氫異喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、異噁唑基、羥吲哚基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯並黃嘌呤基、酚噁嗪基、酞嗪基、呱嗪基、呱啶基、呱啶酮基、4-呱啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、噠嗪基、吡啶並噁唑、吡啶並咪唑、吡啶並噻唑、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H -吡咯基、吡咯基、吡唑基、喹唑啉基、喹啉基、4H -喹嗪基、喹喔啉基、奎寧環基、四氫呋喃基、四氫異喹啉基、四氫喹啉基、四唑基，6H -1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、異噻唑基噻吩基、噻吩並噁唑基、噻吩並噻唑基、噻吩並咪唑基、噻吩基、三嗪基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫噸基。還包括稠環和螺環化合物。Examples of heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4a H -carbazolyl , porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2 H , 6 H -1, 5,2-dithiazinyl, dihydrofuran [2,3 - b ] tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H -carbazolyl, nonenyl, indanyl, mesoindolyl, 3 H - Sulfhydryl, isatino, isobenzofuranyl, isodecyl, isoindoline, decyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl , morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- Diazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazolyl, hydroxyindenyl, phenanthryl, Porphyrin, phenazine, phenothiazine, benzoxanthyl, phenolzinyl, pyridazinyl, pyridazinyl, acridinyl, acridinone, 4-acridone, pepper, butterfly Pyridyl, fluorenyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridylthiazole, pyridyl, pyrimidinyl, pyrrolidinyl , pyrrolinyl, 2 H -pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolyl, 4 H -quinazinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroiso Quinolinyl, tetrahydroquinolyl, tetrazolyl, 6 H -1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thioxyl, thiazolyl, isothiazolylthiophenyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl , thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthene base. Also included are fused ring and spiro compounds.

除非另有規定，術語“烴基”或者其下位概念(比如烷基、烯基、炔基、苯基等等)本身或者作為另一取代基的一部分表示直鏈的、支鏈的或環狀的烴原子團或其組合，可以是完全飽和的、單元或多元不飽和的，可以是單取代、二取代或多取代的，可以包括二價或多價原子團，具有指定數量的碳原子(如C1 -C10 表示1至10個碳)。 “烴基”包括但不限於脂肪烴基和芳香烴基，所述脂肪烴基包括鏈狀和環狀，具體包括但不限於烷基、烯基、炔基，所述芳香烴基包括但不限於6-12員的芳香烴基，例如苯、萘等。在一些實施例中，術語“烴基”表示直鏈的或支鏈的原子團或它們的組合，可以是完全飽和的、單元或多元不飽和的，可以包括二價和多價原子團。飽和烴原子團的實例包括但不限於甲基、乙基、正丙基、異丙基、正丁基、叔丁基、異丁基、仲丁基、異丁基、環己基、(環己基)甲基、環丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子團的同系物或異構體。不飽和烴基具有一個或多個雙鍵或三鍵，其實例包括但不限於乙烯基、2 -丙烯基、丁烯基、巴豆基、2-異戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4 -戊二烯基)、乙炔基、1-和3-丙炔基、3-丁炔基，以及更高級的同系物和異構體。Unless otherwise specified, the term "hydrocarbyl" or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic The hydrocarbon radical or a combination thereof may be fully saturated, unitary or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may include divalent or polyvalent radicals having a specified number of carbon atoms (eg, C1 ) -C 10 represents 1 to 10 carbons). "Hydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members. An aromatic hydrocarbon group such as benzene, naphthalene or the like. In some embodiments, the term "hydrocarbyl" means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl). A homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl. The unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.

除非另有規定，術語“雜烴基”或者其下位概念(比如雜烷基、雜烯基、雜炔基、雜芳基等等)本身或者與另一術語聯合表示穩定的直鏈的、支鏈的或環狀的烴原子團或其組合，有一定數目的碳原子和至少一個雜原子組成。在一些實施例中，術語“雜烷基”本身或者與另一術語聯合表示穩定的直鏈的、支鏈的烴原子團或其組合物，有一定數目的碳原子和至少一個雜原子組成。在一個典型實施例中，雜原子選自B、O、N和S，其中氮和硫原子任選地被氧化，氮雜原子任選地被季銨化。雜原子B、O、N和S可以位於雜烴基的任何內部位置(包括該烴基附著于分子其餘部分的位置)。實例包括但不限於-CH2 -CH2 -O-CH3 、-CH2 -CH2 -NH-CH3 、-CH2 -CH2 -N(CH3 )-CH3 、-CH2 -S-CH2 -CH3 、-CH2 -CH2 、-S(O)-CH3 、-CH2 -CH2 -S(O)2 -CH3 、-CH=CH-O-CH3 、 -CH2 -CH=N-OCH3 和–CH=CH-N(CH3 )-CH3 。至多兩個雜原子可以是連續的，例如-CH2 -NH-OCH3 。Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. The heteroatoms B, O, N and S can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule). Examples include, but are not limited to, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S -CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 , -CH=CH-O-CH 3 , - CH 2 -CH=N-OCH 3 and -CH=CH-N(CH 3 )-CH 3 . Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.

術語“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)屬於慣用表達，是指分別通過一個氧原子、氨基或硫原子連接到分子的其餘部分的那些烷基基團。The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are customary expressions and refer to those alkane which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively. Base group.

除非另有規定，術語“環烴基”、“雜環烴基”或者其下位概念(比如芳基、雜芳基、環烷基、雜環烷基、環烯基、雜環烯基、環炔基、雜環炔基等等)本身或與其他術語聯合分別表示環化的“烴基”、“雜烴基”。此外，就雜烴基或雜環烴基(比如雜烷基、雜環烷基)而言，雜原子可以佔據該雜環附著于分子其餘部分的位置。環烴基的實例包括但不限於環戊基、環己基、1-環己烯基、3-環己烯基、環庚基等。雜環基的非限制性實例包括1-(1,2,5,6-四氫吡啶基)、1-呱啶基、2-呱啶基、3-呱啶基、4-嗎啉基、3-嗎啉基、四氫呋喃-2-基、四氫呋喃吲哚-3-基、四氫噻吩-2-基、四氫噻吩-3 -基、1-呱嗪基和2-呱嗪基。Unless otherwise specified, the term "cycloalkyl", "heterocycloalkyl" or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) A heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized "hydrocarbyl group" or "heterohydrocarbyl group", respectively. Further, in the case of a heterohydrocarbyl group or a heterocycloalkyl group (such as a heteroalkyl group or a heterocycloalkyl group), a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-pyridazinyl and 2-pyridazinyl.

除非另有規定，術語“芳基”表示多不飽和的芳族烴取代基，可以是單取代、二取代或多取代的，它可以是單環或多環(較佳為1至3個環)，它們稠合在一起或共價連接。術語“雜芳基”是指含有一至四個雜原子的芳基(或環)。在一個示範性實例中，雜原子選自B、N、O和S，其中氮和硫原子任選地被氧化，氮原子任選地被季銨化。雜芳基可通過雜原子連接到分子的其餘部分。芳基或雜芳基的非限制性實施例包括苯基、1-萘基、2-萘基、4-聯苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-噁唑基、4-噁唑基、2-苯基-4-噁唑基、5-噁唑基、3 -異噁唑基、4-異噁唑基、5-異噁唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯並噻唑基、嘌呤基、2-苯並咪唑基、5-吲哚基、1-異喹啉基、5-異喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一個芳基和雜芳基環系的取代基選自下文所述的可接受的取代基。Unless otherwise specified, the term "aryl" denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, which may be monocyclic or polycyclic (preferably from 1 to 3 rings). ), they are fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolinyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

為簡便起見，芳基在與其他術語聯合使用時(例如芳氧基、芳硫基、芳烷基)包括如上定義的芳基和雜芳基環。因此，術語“芳烷基”意在包括芳基附著於烷基的那些原子團(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亞甲基)已經被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。For simplicity, aryl groups, when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen. Those alkyl groups substituted by an atom, such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.

術語“離去基團”是指可以被另一種官能團或原子通過取代反應(例如親和取代反應)所取代的官能團或原子。例如，代表性的離去基團包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、對溴苯磺酸酯、對甲苯磺酸酯等；醯氧基，如乙醯氧基、三氟乙醯氧基等等。The term "leaving group" refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Ester and the like; an oxime group such as an ethoxy group, a trifluoroacetoxy group or the like.

術語“保護基”包括但不限於“氨基保護基”、“羥基保護基”或“巰基保護基”。術語“氨基保護基”是指適合用於阻止氨基氮位上副反應的保護基團。代表性的氨基保護基包括但不限於：甲醯基；醯基，例如鏈烷醯基(如乙醯基、三氯乙醯基或三氟乙醯基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲矽烷基，如三甲基甲矽烷基(TMS)和叔丁基二甲基甲矽烷基(TBS)等等。術語“羥基保護基”是指適合用於阻止羥基副反應的保護基。代表性羥基保護基包括但不限於：烷基，如甲基、乙基和叔丁基；醯基，例如鏈烷醯基(如乙醯基)；芳基甲基，如苄基(Bn)，對甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲矽烷基，如三甲基甲矽烷基(TMS)和叔丁基二甲基甲矽烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, indolyl; indenyl, such as alkanealkyl (e.g., ethyl, trichloroethyl or trifluoroethyl); alkoxycarbonyl, such as tert-butyl Oxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr) 1,1-di-(4'-methoxyphenyl)methyl; formylalkyl, such as trimethylcarbinyl (TMS) and tert-butyldimethylformamidin (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing hydroxy side reactions. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; fluorenyl groups such as alkane fluorenyl groups (e.g., ethenyl); arylmethyl groups such as benzyl (Bn) , p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); germyl, such as trimethylmethanyl (TMS) and Tert-butyldimethylformamidinyl (TBS) and the like.

本發明的化合物可以通過本領域技術人員所熟知的多種合成方法來製備，包括下面列舉的具體實施方式、其與其他化學合成方法的結合所形成的實施方式以及本領域技術上人員所熟知的等同替換方式，較佳的實施方式包括但不限於本發明的實施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and equivalents well known to those skilled in the art. Alternatively, preferred embodiments include, but are not limited to, embodiments of the invention.

本發明所使用的所有溶劑是市售的，無需進一步純化即可使用。反應一般是在惰性氮氣下、無水溶劑中進行的。質子核磁共振資料記錄在Bruker Avance III 400 (400 MHz)分光儀上，化學位移以四甲基矽烷低場處的d (ppm)表示。質譜是在安捷倫1200系列加6110(&1956A)上測定。 LC/ MS或Shimadzu MS包含一個DAD：SPD-M20A(LC)和Shimadzu Micromass 2020檢測器。質譜儀配備有一個正或負模式下操作的電噴霧離子源(ESI)。All solvents used in the present invention are commercially available and can be used without further purification. The reaction is generally carried out under an inert nitrogen atmosphere in an anhydrous solvent. Proton nuclear magnetic resonance data was recorded on a Bruker Avance III 400 (400 MHz) spectrometer with chemical shifts expressed as d (ppm) at the low field of tetramethyl decane. Mass spectra were measured on an Agilent 1200 Series Plus 6110 (&1956A). LC/MS or Shimadzu MS contains a DAD: SPD-M20A (LC) and Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ionization source (ESI) operating in either positive or negative mode.

本發明採用下述縮略詞：aq代表水；HATU代表O-7-氮雜苯並***-1- 基)-N,N,N',N'-四甲基脲六氟磷酸鹽；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亞胺鹽酸鹽；m-CPBA代表3-氯過氧苯甲酸；eq代表當量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二異丙酯；DMF 代表N,N-二甲基甲醯胺；DMSO代表二甲亞碸；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一種胺保護基團；BOC代表叔丁基羰基是一種胺保護基團；HOAc代表乙酸； NaCNBH3 代表氰基硼氫化鈉；r.t.代表室溫；O/ N代表過夜；THF代表四氫呋喃；Boc2 O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二異丙基乙基胺；SOCl2 代表氯化亞碸；CS2 代表二硫化碳；TsOH代表對甲苯磺酸；NFSI代表N-氟-N-(苯磺醯基)苯磺醯胺；NCS代表1-氯吡咯烷-2,5-二酮；n -Bu4 NF代表氟化四丁基銨；iPrOH代表2-丙醇；mp代表熔點。The present invention employs the following abbreviations: aq for water; HATU for O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for carbonyl Diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl hydrazine; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for t-butylcarbonyl is an amine protecting group; HOAc for acetic acid; NaCNBH 3 for sodium cyanoborohydride; Represents room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc 2 O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl 2 stands for hydrazine chloride CS 2 stands for carbon disulfide; TsOH stands for p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n -Bu 4 NF represents a fluorinated Butylammonium; iPrOH represents 2-propanol; mp representative of melting point.

除非另有規定， 化合物經手工或者ChemDraw®軟體命名，市售化合物採用供應商目錄名稱。Unless otherwise specified, the compounds are named by hand or by ChemDraw® software, and the commercially available compounds are given the supplier's catalogue name.

與現有技術相比，本發明化合物高效、低毒，在活性、半衰期、溶解度和藥代動力學等方面均取得了顯著甚至預料不到的進步，更適合於製藥。Compared with the prior art, the compound of the present invention is highly efficient, low in toxicity, and has achieved remarkable and unexpected progress in activity, half-life, solubility and pharmacokinetics, and is more suitable for pharmaceuticals.

下面通過實施例對本發明進行詳細描述，但並不意味著對本發明任何不利限制。本文已經詳細地描述了本發明，其中也公開了其具體實施例方式，對本領域的技術人員而言，在不脫離本發明精神和範圍的情況下針對本發明具體實施方式進行各種變化和改進將是顯而易見的。The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, and the specific embodiments thereof are disclosed, and various changes and modifications may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It is obvious.

實施例1 (5-((1,4-二氮雜環庚烷-1-基)磺醯基)-1-氧代異喹啉-2(1H)-基)甲基異丁酯 Example 1 (5-((1,4-Diazepane-1-yl)sulfonyl)-1-oxoisoquinolin-2(1H)-yl)methyl isobutyl ester

第一步first step

將異喹啉1a (47.5 mL,405 mmol)緩慢加入到22 mL濃硫酸中，充分攪拌成小塊，然後加入到200 mL 20%的發煙硫酸中，室溫放置兩天。然後倒入700 g冰水中並靜置過夜，得到的懸濁液過濾，濾餅用水洗滌兩遍(100 mL x 2)，乾燥，得到異喹啉-5-磺酸1b (50 g，產率：60%)，直接用於下一步反應1 H NMR (400 MHz, D2 O): δ 9.66 (s, 1H), 8.94-8.92 (m, 1H), 8.62-8.60 (m, 2H), 8.58-8.56 (m, 1H), 8.50-8.48 (m, 1H), 7.99-7.95 (m, 1H)。 MS-ESI 計算值 [M + H]+ 210，實測值 210。Isoquinoline 1a (47.5 mL, 405 mmol) was slowly added to 22 mL of concentrated sulfuric acid, stirred well into small pieces, then added to 200 mL of 20% fuming sulfuric acid and allowed to stand at room temperature for two days. Then, it was poured into 700 g of ice water and allowed to stand overnight, and the obtained suspension was filtered, and the filter cake was washed twice with water (100 mL x 2), and dried to give isoquinoline-5-sulfonic acid 1b (50 g, yield :60%), directly for the next reaction 1 H NMR (400 MHz, D 2 O): δ 9.66 (s, 1H), 8.94-8.92 (m, 1H), 8.62-8.60 (m, 2H), 8.58 -8.56 (m, 1H), 8.50-8.48 (m, 1H), 7.99-7.95 (m, 1H). MS-ESI calcd for [M + H] + 210, found 210.

第二步Second step

室溫下將異喹啉-5-磺酸1b (4.0 g, 0.019 mol)加入到25 mL的氯化亞碸中，然後加入0.1 mL的N,N-二甲基甲醯胺。反應加熱回流兩小時後，減壓蒸掉多餘的氯化亞碸，蒸發殘渣用冷的二氯甲烷洗滌(10 mL x 2)。乾燥得到目標產物異喹啉-5-磺醯氯1c (3.9 g，黃色固體，產率：100%)。  MS-ESI計算值[M + H]+ 227實測值227。Isoquinoline-5-sulfonic acid 1b (4.0 g, 0.019 mol) was added to 25 mL of cerium chloride at room temperature, followed by the addition of 0.1 mL of N,N-dimethylformamide. After the reaction was heated to reflux for two hours, excess chlorinium chloride was evaporated under reduced pressure and the residue was evaporated and washed with cold methylene chloride (10 mL x 2). Drying gave the desired product isoquinoline-5-sulfonyl chloride 1c (3.9 g, yellow solid, yield: 100%). MS-ESI calculated [M + H] + 227 found 227.

第三步third step

將異喹啉-5-磺醯氯1c (3.00 g, 11.3 mmol) 溶解於20 mL二氯甲烷中，在氮氣保護下0℃先後加入1,4-二氮雜環庚烷-1-羧酸叔丁酯( 2.60 g, 13.0 mmol)和N,N-二異丙基乙基胺(7.5 mL, 35.0 mmol)。所得反應液室溫攪拌16小時直到反應結束。用二氯甲烷(100 mL)和水(100 mL)稀釋，二氯甲烷萃取(100 mL x 2),合併有機相用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用矽膠柱 (0-100% 乙酸乙酯/石油醚) 純化得目標化合物4-(異喹啉-5-基磺醯基)-1,4-二氮雜環庚烷-1-羧酸叔丁酯1d (4.5 g, 無色油狀物，產率：100%)。 MS-ESI 計算值[M + H]+ 392，實測值392。Dissolve isoquinoline-5-sulfonyl chloride 1c (3.00 g, 11.3 mmol) in 20 mL of dichloromethane and add 1,4-diazepane-1-carboxylic acid at 0 ° C under nitrogen. tert-Butyl ester ( 2.60 g, 13.0 mmol) and N,N-diisopropylethylamine (7.5 mL, 35.0 mmol). The resulting reaction solution was stirred at room temperature for 16 hours until the reaction was completed. Diluted with dichloromethane (100 mL) and water (100 mL), dichloromethane (100 mL EtOAc) Purification of the title compound 4-(isoquinolin-5-ylsulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 1d (4.5 g, EtOAc/EtOAc) Colorless oil, yield: 100%). MS-ESI calcd for [M + H] + 392.

第四步the fourth step

0°C將4-(異喹啉-5-基磺醯基)-1,4-二氮雜環庚烷-1-羧酸叔丁酯1d (5.38 g, 13.8 mmol)的200 mL二氯甲烷溶液中分批加入間氯過氧苯羧酸(4.80 g，27.6 mmol)，然後升至室溫攪拌2小時直至反應結束。直接蒸乾溶劑後用色譜矽膠柱純化(0-100% 乙酸乙酯／石油醚) 得到5-((4-(叔丁氧基羰基)-1,4- 二氮雜環庚烷-1 -基)磺醯基)異喹啉-2-氧化物1e (4.9 g, 黃色油狀液體，產率：86%)。1 H NMR (400 MHz, DMSO-d6 ): δ 9.11 (s, 1H), 8.40-8.35 (m, 1H), 8.35-8.30 (m, 1H), 8.20-8.15 (m, 1H), 7.80-7.75 (m, 2H), 3.52-3.42 (m, 8H), 1.85-1.65 (m, 2H) , 1.37 (s, 9H)。  MS-ESI 計算值[M + H]+ 408，實測值408。4-(isoquinolin-5-ylsulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 1d (5.38 g, 13.8 mmol) in 200 mL of dichloro To the methane solution, m-chloroperoxybenzenecarboxylic acid (4.80 g, 27.6 mmol) was added portionwise, and then the mixture was stirred at room temperature for 2 hours until the end of the reaction. The solvent is directly evaporated to dryness and purified by chromatography (yield: 0-100% ethyl acetate / petroleum ether) to give 5-((4-(tert-butoxycarbonyl)-1,4-diazepan-1 - yl) sulfonylurea yl) isoquinoline 2-oxide 1e (4.9 g, as a yellow oily liquid, yield: 86%). 1 H NMR (400 MHz, DMSO- d6 ): δ 9.11 (s, 1H), 8.40-8.35 (m, 1H), 8.35-8.30 (m, 1H), 8.20-8.15 (m, 1H), 7.80-7.75 (m, 2H), 3.52-3.42 (m, 8H), 1.85-1.65 (m, 2H), 1.37 (s, 9H). MS-ESI calcd [M + H] + 408, Found 408.

第五步the fifth step

將5-((4-(叔丁氧基羰基)-1,4- 二氮雜環庚烷-1 -基)磺醯基)異喹啉-2-氧化物1e (5.70 g, 14.0 mmol)溶於50 mL乙酸酐中在100℃下攪拌2小時直到反應結束。反應液減壓濃縮除去溶劑後將殘餘物溶解於50 mL的四氫呋喃中，加入100 mL30%的氫氧化鈉水溶液後於室溫攪拌0.5小時。減壓除去四氫呋喃後用稀鹽酸調節反應液的pH到7，將得到的懸濁液過濾，濾餅用水(10 mL x 2)洗滌，乾燥，得到4-((1-氧代-1,2 -二氫異喹啉-5-基)磺醯基)-1,4 -二氮雜環庚烷-1-羧酸叔丁酯1f (3 g，淺紅色固體，產率：75%)。1 H NMR (400 MHz, CDCl3 ): δ 11.57 (s, 1H), 8.50-8.45 (m, 1H), 8.20-8.15 (m, 1H), 8.08 (s, 1H), 7.85-7.80 (m, 1H) , 7.65-7.60 (m, 1H) , 3.50-3.30 (m, 8H), 2.05-1.95 (m, 2H) , 1.44 (s, 9H)。  MS-ESI計算值 [M + H]+ 408，實測值408。5-((4-(tert-Butoxycarbonyl)-1,4-diazepan-1-yl)sulfonyl)isoquinoline-2-oxide 1e (5.70 g, 14.0 mmol) Dissolved in 50 mL of acetic anhydride and stirred at 100 ° C for 2 hours until the end of the reaction. The reaction mixture was concentrated under reduced pressure to dryness crystals. After removing tetrahydrofuran under reduced pressure, the pH of the reaction mixture was adjusted to 7 with dilute hydrochloric acid, and the obtained suspension was filtered. The filter cake was washed with water (10 mL x 2) and dried to give 4-((1-oxo-1,2) -Dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 1f (3 g, light red solid, yield: 75%). 1 H NMR (400 MHz, CDCl 3 ): δ 11.57 (s, 1H), 8.50-8.45 (m, 1H), 8.20-8.15 (m, 1H), 8.08 (s, 1H), 7.85-7.80 (m, 1H), 7.65-7.60 (m, 1H), 3.50-3.30 (m, 8H), 2.05-1.95 (m, 2H), 1.44 (s, 9H). MS-ESI calcd [M + H] + 408

第六步Step 6

在氮氣保護下將4-((1-氧代-1,2 -二氫異喹啉-5-基)磺醯基)-1,4 -二氮雜環庚烷-1-羧酸叔丁酯1f (5.50 g, 13.5 mmol)溶解於110 mL六甲基磷醯三胺中，於0℃條件下緩慢加入氫化鈉(0.595 g, 14.9 mmol)並在同一溫度下反應15分鐘，然後向反應液滴加氯甲基異丁酸酯(2.24 g, 14.9 mmol)，加完後升至室溫並反應1小時。待反應結束後將反應液慢慢滴加到冰水(200 mL)中，用乙酸乙酯(100 mL´3)萃取，有機相用無水硫酸鈉乾燥，過濾，濃縮，殘餘物通過色譜矽膠柱純化(0-100% 乙酸乙酯／石油醚)得到4-((2-((異丁醯氧基)甲基)-1-氧代-1,2-二氫異喹啉-5-基)磺醯基)-1,4-二氮雜環庚烷-1-羧酸叔丁酯1g (5.8 g，白色固體，產率： 85%)。 MS-ESI計算值 [M + H]+ 508，實測值508。4-((1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl under nitrogen protection Ester 1f (5.50 g, 13.5 mmol) was dissolved in 110 mL of hexamethylphosphonium triamine, and sodium hydride (0.595 g, 14.9 mmol) was slowly added at 0 ° C and reacted at the same temperature for 15 minutes, then reacted to the reaction. A solution of chloromethyl isobutyrate (2.24 g, 14.9 mmol) was added dropwise, and the mixture was allowed to warm to room temperature and reacted for 1 hour. After the reaction was completed, the reaction solution was slowly added dropwise to ice water (200 mL), extracted with ethyl acetate (100 mL s3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification (0-100% ethyl acetate / petroleum ether) afforded 4-((2-((isobutyloxy)methyl)-1-oxo-1,2-dihydroisoquinolin-5-yl) Tert-butyl sulfonyl)-1,4-diazepane-1-carboxylate 1 g (5.8 g, white solid, yield: 85%). MS-ESI calcd for [M + H] + 508.

第七步Seventh step

將4-((2-((異丁醯氧基)甲基)-1-氧代-1,2-二氫異喹啉-5-基)磺醯基)-1,4-二氮雜環庚烷-1-羧酸叔丁酯1g (5.80 g, 11.4 mmol)溶解於690 mL的二氯甲烷中，在0℃和氮氣保護下緩慢滴加三氟甲磺醯基三甲基矽烷(5.06 g, 22.8 mmol)，控制溫度在0-5℃範圍內。反應液反應45分鐘後向其中滴加2,6-二甲基吡啶(3.66 g, 34.2 mmol)，在0-5℃繼續反應1小時直到反應結束。把反應液緩慢加入到冰水(200 mL)中，用二氯甲烷(100 mL´3)萃取，有機相用無水硫酸鈉乾燥，過濾，濃縮得到的殘留物用乙酸乙酯重結晶得到(5-((1,4-二氮雜環庚烷-1-基)磺醯基)-1-氧代異喹啉-2(1H)-基)甲基異丁酯1 (2.5 g，淡黃色固體，產率：54%)。1 H NMR (400 MHz, D2 O): δ 8.41 (d,J = 8.4 Hz, 1H), 8.13 (d,J = 8.0 Hz, 1H), 7.58-7.54 (m, 2H), 7.14 (d,J = 8.0 Hz, 1H), 5.92 (s, 2H), 3.67-3.64 (m, 2H), 3.50-3.40 (m, 2H), 3.35-3.30 (m, 4H), 2.65-2.55 (m, 1H), 2.15-2.00 (m, 2H), 1.07 (d,J = 7.2 Hz, 6H)。  MS-ESI 計算值[M + H]+ 408，實測值 408。4-((2-((isobutyloxy)methyl)-1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diaza 1 g of cyclo-heptane-1-carboxylic acid tert-butyl ester (5.80 g, 11.4 mmol) was dissolved in 690 mL of dichloromethane, and trifluoromethanesulfonyltrimethyldecane was slowly added dropwise at 0 ° C under nitrogen. 5.06 g, 22.8 mmol), control temperature in the range of 0-5 °C. After reacting the reaction solution for 45 minutes, 2,6-lutidine (3.66 g, 34.2 mmol) was added dropwise thereto, and the reaction was continued at 0 to 5 ° C for 1 hour until the end of the reaction. The reaction mixture was slowly added to ice water (200 mL), EtOAc (EtOAc) -((1,4-Diazepane-1-yl)sulfonyl)-1-oxoisoquinolin-2(1H)-yl)methylisobutyl ester 1 (2.5 g, light yellow Solid, yield: 54%). 1 H NMR (400 MHz, D 2 O): δ 8.41 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.58-7.54 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 5.92 (s, 2H), 3.67-3.64 (m, 2H), 3.50-3.40 (m, 2H), 3.35-3.30 (m, 4H), 2.65-2.55 (m, 1H) , 2.15-2.00 (m, 2H), 1.07 (d, J = 7.2 Hz, 6H). MS-ESI calcd [M + H] + 408, Found 408.

實施例 2 ((5-((1,4-二氮雜環庚烷-1-基)磺醯基)-1- 氧代異喹啉-2(1H)-基)甲基)膦酸 Example 2 ((5-((1,4-Diazepane-1-yl)sulfonyl)-1-oxoisoquinolin-2(1H)-yl)methyl)phosphonic acid

第一步first step

4-(異喹啉-5-基磺醯基)-1,4-二氮雜環庚烷-1-羧酸叔丁酯1d (4.10 g,11.2 mmol) 溶解於30 mL的乙酸乙酯中，於0℃滴加20 mL乙酸乙酯的飽和氯化氫溶液，反應液於室溫反應0.5小時。把得到的懸濁液過濾，濾餅用乙酸乙酯洗滌(10 mL x 2)，乾燥得到5-((1,4-二氮雜環庚烷-1-基)磺醯基)異喹啉2a (2.6 g，白色固體，產率：87%)。tert-Butyl 4-(isoquinolin-5-ylsulfonyl)-1,4-diazepane-1-carboxylate 1d (4.10 g, 11.2 mmol) dissolved in 30 mL of ethyl acetate 20 mL of a saturated hydrogen chloride solution of ethyl acetate was added dropwise at 0 ° C, and the reaction solution was reacted at room temperature for 0.5 hour. The obtained suspension was filtered, and the filter cake was washed with ethyl acetate (10 mL x 2) and dried to give 5-((1,4-diazepan-1-yl)sulfonyl)isoquinoline 2a (2.6 g, white solid, yield: 87%).

第二步Second step

氮氣保護下向5-((1,4-二氮雜環庚烷-1-基)磺醯基)異喹啉2a (4.00 g, 11.1 mmol) 的80 mL二氯甲烷溶液中加入N,N-二甲基甲醯胺(5.90 mL, 33.3 mmol), 然後於0℃滴加氯甲酸苄酯(2.10 g, 12.2 mmol)。滴加完畢後將反應液升至室溫並反應2小時後，用50 mL水稀釋反應液，二氯甲烷(30 mL x 2)萃取，有機相用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用矽膠色譜法純化(0~100% 乙酸乙酯/石油醚)得到4-(異喹啉-5-基磺醯基)-1,4-二氮雜-1-羧酸苄酯2b (6.4 g，無色油狀液體，產率：100%)。1 H NMR (400 MHz, CDCl3 ): δ 9.36 (s, 1H), 8.75-8.65 (m, 1H), 8.45-8.35 (m, 1H), 8.32-8.25 (m, 1H), 8.23-8.15 (m, 1H), 7.82-7.62 (m, 1H), 7.40-7.20 (m, 5H), 5.09 (s, 2H), 3.75-3.54 (m, 4H), 3.50-3.32 (m, 4H), 2.11-1.92 (m, 2H)。  MS-ESI 計算值[M + H]+ 426，實測值426。Add N,N to a solution of 5-((1,4-diazepan-1-yl)sulfonyl)isoquinoline 2a (4.00 g, 11.1 mmol) in 80 mL of dichloromethane under N2 - dimethylformamide (5.90 mL, 33.3 mmol), then benzyl chloroformate (2.10 g, 12.2 mmol). After the completion of the dropwise addition, the reaction mixture was warmed to room temperature and then reacted for 2 hrs. The reaction mixture was diluted with 50 mL of water, dichloromethane (30 mL? Purification by gel chromatography (0~100% ethyl acetate/petroleum ether) affords 4-(isoquinolin-5-ylsulfonyl)-1,4-diaza-1-carboxylic acid benzyl ester 2b ( 6.4 g, colorless oily liquid, yield: 100%). 1 H NMR (400 MHz, CDCl 3 ): δ 9.36 (s, 1H), 8.75-8.65 (m, 1H), 8.45-8.35 (m, 1H), 8.32-8.25 (m, 1H), 8.23-8.15 ( m, 1H), 7.82-7.62 (m, 1H), 7.40-7.20 (m, 5H), 5.09 (s, 2H), 3.75-3.54 (m, 4H), 3.50-3.32 (m, 4H), 2.11- 1.92 (m, 2H). MS-ESI calcd for [M + H] + 426, found 426.

第三步third step

4-(異喹啉-5-基磺醯基)-1,4-二氮雜-1-羧酸苄酯2b (7.4 g, 17.4 mmol)按照實施例1的合成方法得到5-((4-((苄氧基)羰基)-1,4-二氮雜環庚烷-1-基)磺醯基)異喹啉-2-氧化物2c (5.0 g，黃色油狀物，產率：65%)。 MS-ESI 計算值[M + H]+ 442，實測值442。4-(isoquinolin-5-ylsulfonyl)-1,4-diaza-1-carboxylic acid benzyl ester 2b (7.4 g, 17.4 mmol) was obtained according to the procedure of Example 1. -((Benzyloxy)carbonyl)-1,4-diazepan-1-yl)sulfonyl)isoquinoline-2-oxide 2c (5.0 g, yellow oil, yield: 65%). MS-ESI calcd for [M + H] + 422.

第四步the fourth step

將5-((4-((苄氧基)羰基)-1,4-二氮雜環庚烷-1-基)磺醯基)異喹啉-2-氧化物2c (5.00 g, 11.3 mmol)溶解於70 mL醋酸酐中，加熱到130℃反應4小時。待反應結束後減壓蒸餾除去多餘的乙酸酐，殘餘物溶解於50 mL的四氫呋喃中，並加入100 mL30%的氫氧化鈉。反應液室溫攪拌0.5小時，然後減壓蒸餾除去四氫呋喃並將反應液調pH到中性，得到的懸濁液過濾，濾餅乾燥得到4-((1-氧代-1,2-二氫異喹啉-5-基)磺醯基)-1,4-二氮雜-1-羧酸苄酯2d (4.5 g，棕色固體，產率：90%)。 MS-ESI 計算值[M + H]+ 442，實測值 442。5-((4-((Benzyloxy)carbonyl)-1,4-diazepan-1-yl)sulfonyl)isoquinoline-2-oxide 2c (5.00 g, 11.3 mmol Dissolved in 70 mL of acetic anhydride and heated to 130 ° C for 4 hours. After the reaction was completed, excess acetic anhydride was distilled off under reduced pressure, and the residue was dissolved in 50 mL of tetrahydrofuran, and 100 mL of 30% sodium hydroxide was added. The reaction solution was stirred at room temperature for 0.5 hour, then the tetrahydrofuran was distilled off under reduced pressure and the reaction mixture was adjusted to pH. The obtained suspension was filtered, and the filter cake was dried to give 4-((1-oxo-1,2-dihydro) Isoquinolin-5-yl)sulfonyl)-1,4-diaza-1-carboxylic acid benzyl ester 2d (4.5 g, brown solid, yield: 90%). MS-ESI calcd for [M + H] + 422.

第五步the fifth step

4-((1-氧代-1,2-二氫異喹啉-5-基)磺醯基)-1,4-二氮雜-1-羧酸苄酯2d (1.00 g, 2.27 mmol)和氯甲基磷酸二苄酯(816 mg, 2.5 mmol)按照實施例1的合成方法得到4-((2-((雙(苄氧基)磷醯基)甲基)-1-氧代-1,2-二氫異喹啉-5-基)磺醯基)-1,4-二氮雜-1-羧酸苄酯2e (140 mg， 棕色油狀物，產率： 8.5%)。1 H NMR (400 MHz, CDCl3 ): δ 8.41 (d,J = 8.0 Hz, 1H), 8.26 (d,J = 8.0 Hz, 1H), 8.20-8.10 (m, 1H), 8.05-8.00 (m, 1H), 7.55-7.50 (m, 1H), 7.40-7.15 (m, 15H), 6.25-6.20 (m 2H), 5.15-5.10 (m, 2H), 5.05 (s, 2H), 5.04 (s, 2H), 3.70-3.50 (m, 4H), 3.45-3.30 (m, 4H), 2.00-1.90 (m, 2H)。  MS-ESI 計算值[M + H]+ 716，實測值716。4-((1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diaza-1-carboxylic acid benzyl ester 2d (1.00 g, 2.27 mmol) And dibenzyl chloromethyl phosphate (816 mg, 2.5 mmol) according to the synthesis method of Example 1 to give 4-((2-((bis(benzyloxy)phosphonyl)methyl)-1-oxo- 1,2-Dihydroisoquinolin-5-yl)sulfonyl)-1,4-diaza-1-carboxylic acid benzyl ester 2e (140 mg, brown oil, yield: 8.5%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.41 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.20-8.10 (m, 1H), 8.05-8.00 (m , 1H), 7.55-7.50 (m, 1H), 7.40-7.15 (m, 15H), 6.25-6.20 (m 2H), 5.15-5.10 (m, 2H), 5.05 (s, 2H), 5.04 (s, 2H), 3.70-3.50 (m, 4H), 3.45-3.30 (m, 4H), 2.00-1.90 (m, 2H). MS-ESI calcd for [M + H] + 716.

第六步Step 6

向4-((2-((雙(苄氧基)磷醯基)甲基)-1-氧代-1,2-二氫異喹啉-5-基)磺醯基)-1,4-二氮雜-1-羧酸苄酯2e (100 mg, 0.140 mmol)的20 mL四氫呋喃和2.5 mL水的混合溶劑中加入濕鈀碳(70 mg, 10%)，在一個大氣壓氫氣氛中室溫反應4小時。反應結束後矽藻土過濾，濃縮，得((5-((1,4-二氮雜環庚烷-1-基)磺醯基)-1- 氧代異喹啉-2(1H)-基)甲基)膦酸2 (63 mg，白色固體，產率：100%)。1 H NMR (400 MHz, D2 O): δ 8.60 (d,J = 8.0 Hz, 1H), 8.31-8.23 (m, 1H), 7.80-7.60 (m, 2H), 7.31 (d,J = 7.6 Hz, 1H), 5.64 (s, 2H), 3.60-3.30 (m, 6H), 3.10-3.00 (m, 2H), 1.95-1.70 (m, 2H)。 MS-ESI 計算值[M + H]+ 402，實測值402。To 4-((2-((bis(benzyloxy)phosphonyl)methyl)-1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4 - a mixture of benzyl diaza-1-carboxylate 2e (100 mg, 0.140 mmol) in 20 mL of tetrahydrofuran and 2.5 mL of water was added wet palladium on carbon (70 mg, 10%) in a hydrogen atmosphere atmosphere The temperature was reacted for 4 hours. After the reaction, the diatomaceous earth was filtered and concentrated to give ((5-((1,4-diazepan-1-yl)sulfonyl)-1-oxoisoquinoline-2(1H)- Methyl)phosphonic acid 2 (63 mg, white solid, yield: 100%). 1 H NMR (400 MHz, D 2 O): δ 8.60 (d, J = 8.0 Hz, 1H), 8.31-8.23 (m, 1H), 7.80-7.60 (m, 2H), 7.31 (d, J = 7.6 Hz, 1H), 5.64 (s, 2H), 3.60-3.30 (m, 6H), 3.10-3.00 (m, 2H), 1.95-1.70 (m, 2H). MS-ESI calcd for [M+H] + 402, found 402.

實施例 3 Example 3

第一步first step

4-((1-氧代-1,2 -二氫異喹啉-5-基)磺醯基)-1,4 -二氮雜環庚烷-1-羧酸叔丁酯1f (200 mg, 0.49 mmol)按照實施例1的合成方法得到4-((2-((苯甲醯氧基)甲基)-1-氧代-1,2-二氫異喹啉-5-基)磺醯基)-1,4-二氮雜環庚烷-1-羧酸叔丁酯3a (150 mg，白色固體，產率：56%)。1 H NMR (400 MHz, DMSO-6d ): δ 8.54 (d,J = 8.0 Hz, 1H), 8.23 (d,J = 8.0 Hz, 1H), 7.93-7.98 (m, 2H), 7.85 (d,J = 8.0 Hz, 1H), 7.51-7.55 (m, 2H), 7.20-7.15 (m, 1H), 6.18 (s, 2H), 4.05-4.02 (m, 1H), 3.41-3.47(m, 4H), 3.37-3.41 (m, 2H), 2.69- 2.67 (m, 1H), 2.00-1.98 (m, 2H), 1.78-1.75 (m, 2H), 1.36 (s, 9H)。4-((1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 1f (200 mg , 0.49 mmol) 4-((2-((benzylideneoxy)methyl)-1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonate obtained according to the procedure of Example 1. Tert-butyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 3a (150 mg, white solid, yield: 56%). 1 H NMR (400 MHz, DMSO- 6d ): δ 8.54 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.93-7.98 (m, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.51-7.55 (m, 2H), 7.20-7.15 (m, 1H), 6.18 (s, 2H), 4.05-4.02 (m, 1H), 3.41-3.47 (m, 4H) , 3.37-3.41 (m, 2H), 2.69- 2.67 (m, 1H), 2.00-1.98 (m, 2H), 1.78-1.75 (m, 2H), 1.36 (s, 9H).

第二步Second step

4-((2-((苯甲醯氧基)甲基)-1-氧代-1,2-二氫異喹啉-5-基)磺醯基)-1,4-二氮雜環庚烷-1-羧酸叔丁酯3a (150 mg, 0.28 mmol)按照實施例1的合成方法得到(5-(1,4-二氮雜環庚烷-1-基)磺醯基)-1-氧代異喹啉-2(1H)-基)苯羧酸甲酯3 (50 mg，白色固體，產率：41%)。1 H NMR (400 MHz, D2 O): δ 8.48 (d,J = 8.0 Hz, 1H), 8.11 (d,J = 7.6 Hz, 1H), 8.00-7.95 (m, 2H), 7.70 (d,J = 8.0 Hz, 1H), 7.60-7.55 (m, 2H), 7.43 (d,J = 7.6 Hz, 2H), 7.16 (d,J = 8.0 Hz, 1H), 6.16 (s, 2H), 3.59-3.56 (m, 2H), 3.38-3.36 (m, 2H), 3.29-3.23 (m, 4H), 2.02-2.00 (m, 2H)。4-((2-((benzylideneoxy)methyl)-1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazacyclocycle tert-Butyl-1-carboxylic acid tert-butyl ester 3a (150 mg, 0.28 mmol) was obtained according to the procedure of Example 1 (5-(1,4-diazepan-1-yl)sulfonyl)- Methyl 1-oxoisoquinoline-2(1H)-yl)benzoate 3 (50 mg, white solid, yield: 41%). 1 H NMR (400 MHz, D 2 O): δ 8.48 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 8.00-7.95 (m, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.60-7.55 (m, 2H), 7.43 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 8.0 Hz, 1H), 6.16 (s, 2H), 3.59- 3.56 (m, 2H), 3.38-3.36 (m, 2H), 3.29-3.23 (m, 4H), 2.02-2.00 (m, 2H).

實施例 4 5-((1,4-二氮雜環庚烷-1-基)磺醯基)-1-氧代異喹啉-2(1H)-基) 氧基)甲基新戊酸酯4 、((5-((1,4-二氮雜環庚烷-1-基)磺醯基)異喹啉-1-基)氧基) 甲基新戊酸酯4’ Example 4 5-((1,4-Diazepane-1-yl)sulfonyl)-1-oxoisoquinolin-2(1H)-yl)oxy)methylpivalic acid Ester 4 , ((5-((1,4-diazepan-1-yl)sulfonyl)isoquinolin-1-yl)oxy)methyl pivalate 4'

第一步first step

4-((1-氧代-1,2 -二氫異喹啉-5-基)磺醯基)-1,4 -二氮雜環庚烷-1-羧酸叔丁酯1f (0.50 g, 1.23 mmol)按照實施例1的合成方法得到4-((1-氧代-2-((新戊醯氧基)甲基)-1,2-二氫異喹啉-5-基)磺醯基)-1,4-二氮雜-1- 羧酸叔丁酯4a1 和 4-((1-((新戊醯氧基)甲氧基)異喹啉-5-基)磺醯基)-1,4-二氮雜環庚烷-1-羧酸叔丁酯4a2 的混合物(0.34 g， 白色固體，產率： 50%)。4a1 :1 H NMR (400 MHz, CDCl3 ): δ 8.53 (d,J = 8.4 Hz, 1H), 8.42-8.30 (m, 1H), 8.18 (d,J = 6.4 Hz, 1H), 8.04 (d,J = 6.4 Hz, 1H), 7.65-7.60 (m, 1H), 6.31 (s, 2H), 3.64-3.45 (m, 4H), 3.40-3.30 (m, 4H), 2.05-1.90 (m, 2H), 1.43 (s, 9H), 1.21 (s, 9H)。  MS-ESI計算值 [M + H]+ 522，實測值522。4a2 :1 H NMR (400 MHz, CDCl3 ): δ 8.72 (d,J = 8.0 Hz，1H), 8.25-8.20  (m, 1H), 7.60-7.55 (m, 1H), 7.46 (d,J = 8.0 Hz, 1H), 7.30-7.27 (m, 1H), 5.98 (s, 2H), 3.64-3.45 (m, 4H), 3.40-3.30 (m, 4H), 2.05-1.90 (m, 2H), 1.47 (s, 9H), 1.23 (s, 9H)。  MS-ESI計算值 [M + H]+ 522，實測值 522。4-((1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 1f (0.50 g , 1.23 mmol) 4-((1-oxo-2-((pentopentoxy)methyl)-1,2-dihydroisoquinolin-5-yl)sulfonate was obtained according to the procedure of Example 1. Tert-butyl)-1,4-diaza-1-carboxylic acid tert-butyl ester 4a1 and 4-((1-((pentyloxy)methoxy)isoquinolin-5-yl)sulfonyl) a mixture of -1,4-diazepane-1-carboxylic acid tert-butyl ester 4a2 (0.34 g, white solid, yield: 50%). 4a1 : 1 H NMR (400 MHz, CDCl 3 ): δ 8.53 (d, J = 8.4 Hz, 1H), 8.42-8.30 (m, 1H), 8.18 (d, J = 6.4 Hz, 1H), 8.04 (d , J = 6.4 Hz, 1H), 7.65-7.60 (m, 1H), 6.31 (s, 2H), 3.64-3.45 (m, 4H), 3.40-3.30 (m, 4H), 2.05-1.90 (m, 2H ), 1.43 (s, 9H), 1.21 (s, 9H). MS-ESI calcd for [M + H] + 522. 4a2 : 1 H NMR (400 MHz, CDCl 3 ): δ 8.72 (d, J = 8.0 Hz, 1H), 8.25-8.20 (m, 1H), 7.60-7.55 (m, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.30-7.27 (m, 1H), 5.98 (s, 2H), 3.64-3.45 (m, 4H), 3.40-3.30 (m, 4H), 2.05-1.90 (m, 2H), 1.47 (s, 9H), 1.23 (s, 9H). MS-ESI calcd for [M + H] + 522.

第二步Second step

4-((1-氧代-2-((新戊醯氧基)甲基)-1,2-二氫異喹啉-5-基)磺醯基)-1,4-二氮雜-1- 羧酸叔丁酯4a1 和 4-((1-((新戊醯氧基)甲氧基)異喹啉-5-基)磺醯基)-1,4-二氮雜環庚烷-1-羧酸叔丁酯4a2 (100 mg, 0.19 mmol)按照實施例1的合成方法得到5-((1,4-二氮雜環庚烷-1-基)磺醯基)-1-氧代異喹啉-2(1H)-基) 氧基)甲基新戊酸酯4 和((5-((1,4-二氮雜環庚烷-1-基)磺醯基)異喹啉-1-基)氧基) 甲基新戊酸酯4’ (50 mg，淡黃色固體，產率：53%)。4 :1 H NMR (400 MHz, CDCl3 ): δ 8.65 (d,J = 8.0 Hz, 1H), 8.19 (d,J = 7.6 Hz, 1H), 7.53 (t,J = 6.0 Hz, 1H), 7.39 (d,J = 8.0 Hz, 1H), 7.26 (d,J = 8.0 Hz, 1H), 5.93 (s, 2H), 3.50-3.30 (m, 4H), 3.05-2.90 (m, 4H), 1.90-1.75 (m, 2H), 1.18 (s, 9H)。  MS-ESI 計算值[M + H]+ 422，實測值 422。4’ :1 H NMR (400 MHz, CDCl3 ): δ 8.55 (d,J = 8.0 Hz，1H), 8.31 (m, 1H), 8.19 (d,J = 6.4 Hz, 1H), 8.00 (d,J = 6.4 Hz, 1H), 7.64 (t,J = 8.0 Hz, 1H), 6.31 (s, 2H), 3.70-3.60 (m, 2H), 3.58-3.50 (m, 2H), 3.36-3.25 (m, 4H), 2.20-2.10 (m, 2H), 1.21 (s, 9H)。 MS-ESI 計算值[M + H]+ 422，實測值422。4-((1-oxo-2-((pentyloxy)methyl)-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diaza- 1-carboxylic acid tert-butyl ester 4a1 and 4-((1-((pentylmethoxy)methoxy)isoquinolin-5-yl)sulfonyl)-1,4-diazepane 4- (carboxylic acid tert-butyl ester 4a2 (100 mg, 0.19 mmol) was obtained according to the procedure of Example 1 to give 5-((1,4-diazepan-1-yl)sulfonyl)-1- Oxoisoquinoline-2(1H)-yl)oxy)methylpivalate 4 and ((5-((1,4-diazepan-1-yl)sulfonyl)) Quinoline-1-yl)oxy)methyl pivalate 4' (50 mg, pale yellow solid, yield: 53%). 4 : 1 H NMR (400 MHz, CDCl 3 ): δ 8.65 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 6.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 5.93 (s, 2H), 3.50-3.30 (m, 4H), 3.05-2.90 (m, 4H), 1.90 -1.75 (m, 2H), 1.18 (s, 9H). MS-ESI calcd for [M + H] + 422. 4' : 1 H NMR (400 MHz, CDCl 3 ): δ 8.55 (d, J = 8.0 Hz, 1H), 8.31 (m, 1H), 8.19 (d, J = 6.4 Hz, 1H), 8.00 (d, J = 6.4 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 6.31 (s, 2H), 3.70-3.60 (m, 2H), 3.58-3.50 (m, 2H), 3.36-3.25 (m , 4H), 2.20-2.10 (m, 2H), 1.21 (s, 9H). MS-ESI calcd for [M + H] + 422.

實施例 5 (5-((1,4-二氮雜環庚烷-1-基)磺醯基)-1-氧代異喹啉-2(1H)基)二甲氨基羧酸甲酯 Example 5 (5-((1,4-Diazepane-1-yl)sulfonyl)-1-oxoisoquinolin-2(1H)yl)dimethylaminocarboxylic acid methyl ester

第一步first step

在氮氣保護下將4-((1-氧代-1,2 -二氫異喹啉-5-基)磺醯基)-1,4 -二氮雜環庚烷-1-羧酸叔丁酯1f (200 mg, 0.49 mmol)、二甲氨基羧酸氯甲酯(149 mg, 0.98 mmol)和碳酸鉀(224 mg, 1.47 mmol)的20 mL四氫呋喃溶液加熱回流24小時。待反應結束後將反應液冷卻至室溫，除去溶劑，用製備薄層層析 (50% 乙酸乙酯/石油醚) 得到4-((2-(((二甲氨基甲醯基)氧基)甲基)-1-氧代-1,2-二氫異喹啉-5-基)磺醯基)-1,4-二氮雜環庚烷-1-羧酸叔丁酯5a (100 mg，白色固體，產率：39%)。 MS-ESI 計算值[M + H]+ 509，實測值509。4-((1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl under nitrogen protection A solution of the ester 1f (200 mg, 0.49 mmol), dimethyl dimethylaminocarboxylate (149 mg, 0.98 mmol) and potassium carbonate (224 mg, 1.47 mmol) in 20 mL of THF. After completion of the reaction, the reaction solution was cooled to room temperature, the solvent was removed, and a thin layer chromatography (50% ethyl acetate / petroleum ether) was used to give 4-((2-((dimethylaminomethyl)methyl) )methyl)-1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 5a (100 Mg, white solid, yield: 39%). MS-ESI calcd [M + H] + 509, found 509.

第二步Second step

室溫下，將4-((2-(((二甲氨基甲醯基)氧基)甲基)-1-氧代-1,2-二氫異喹啉-5-基)磺醯基)-1,4-二氮雜環庚烷-1-羧酸叔丁酯5a (0.25 g, 0.45 mmol)加入到4 mL氯化氫氣體的飽和1,4-二氧六環溶液中，並在室溫持續攪拌0.5小時。待反應結束後將反應液濃縮，用製備薄層層析板(乙酸乙酯)分離得到(5-((1,4-二氮雜環庚烷-1-基)磺醯基)-1-氧代異喹啉-2(1H)基)二甲氨基羧酸甲酯5 (150 mg， 淡黃色固體，產率：74%)。1 H NMR (400 MHz, DMSO-d6 ): δ 8.92 (brs, 1H), 8.52-8.59 (m, 1H), 8.25 (d,J = 7.6 Hz, 1H), 7.69-7.75 (m, 1H), 7.18 (d,J = 7.6 Hz, 1H), 5.93 (s, 2H), 4.85-4.80 (m, 1H), 3.65-3.60 (m, 2H), 3.46 (t,J = 5.73 Hz, 2H), 3.21 (brs, 4H), 2.00 (brs, 2H), 1.38 (d,J = 6.39 Hz, 2H), 1.25-1.20 (m, 3H)。 MS-ESI  計算值[M + H]+ 409，實測值409。4-((2-(((dimethylaminomethyl)methyl)oxy)methyl)-1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl) at room temperature )-1,4-Diazepane-1-carboxylic acid tert-butyl ester 5a (0.25 g, 0.45 mmol) was added to a saturated solution of 4 mL of hydrogen chloride gas in 1,4-dioxane and in the chamber Stirring was continued for 0.5 hours. After the reaction was completed, the reaction solution was concentrated and separated (5-((1,4-diazepan-1-yl)sulfonyl)-1- Methyl oxoisoquinoline-2(1H)yl)dimethylaminocarboxylate 5 (150 mg, pale yellow solid, yield: 74%). 1 H NMR (400 MHz, DMSO- d6 ): δ 8.92 (brs, 1H), 8.52-8.59 (m, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.69-7.75 (m, 1H), 7.18 (d, J = 7.6 Hz, 1H), 5.93 (s, 2H), 4.85-4.80 (m, 1H), 3.65-3.60 (m, 2H), 3.46 (t, J = 5.73 Hz, 2H), 3.21 (brs, 4H), 2.00 (brs, 2H), 1.38 (d, J = 6.39 Hz, 2H), 1.25-1.20 (m, 3H). MS-ESI calcd [M + H] + 409, Found 409.

實施例 6 (5-((1,4-二氮雜環庚烷-1-基)磺醯基)-1-氧代異喹啉-2(1H)-基)甲基碳酸異丙酯 Example 6 (5-((1,4-Diazepane-1-yl)sulfonyl)-1-oxoisoquinolin-2(1H)-yl)methyl isopropyl carbonate

第一步first step

4-((1-氧代-1,2 -二氫異喹啉-5-基)磺醯基)-1,4 -二氮雜環庚烷-1-羧酸叔丁酯1f (150 mg, 0.39 mmol)和氯甲基碳酸異丙酯(77 mg, 0.51 mmol)按照實施例1的合成方法經過兩步反應得到(5-((1,4-二氮雜環庚烷-1-基)磺醯基)-1-氧代異喹啉-2(1H)-基)甲基碳酸異丙酯6 (53 mg, 白色固體，產率：32%)。1 H NMR (400 MHz, DMSO-d6 ): δ 8.92 (brs, 1H), 8.60-8.55 (m, 1H), 8.25 (d,J = 7.6 Hz, 1H), 7.73 (t,J = 7.6 Hz, 1H), 7.17 (d,J = 7.6 Hz, 1H), 5.93 (s, 2H), 4.84-4.78 (m, 1H), 3.62 (brs, 2H), 3.48-3.45 (m, 2H), 3.21 (brs, 4H), 2.00 (brs, 2H), 1.37 (d,J = 6.4 Hz, 2H), 1.23 (d,J = 6.4 Hz, 4H)。 MS-ESI 計算值[M + H]+ 424，實測值424。4-((1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 1f (150 mg , 0.39 mmol) and isopropyl chloromethyl carbonate (77 mg, 0.51 mmol) were obtained by a two-step reaction according to the synthesis method of Example 1 (5-((1,4-diazepan-1-yl) Sulfomethyl)-1-oxoisoquinoline-2(1H)-yl)methyl isopropyl carbonate 6 (53 mg, white solid, yield: 32%). 1 H NMR (400 MHz, DMSO- d6 ): δ 8.92 (brs, 1H), 8.60-8.55 (m, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 5.93 (s, 2H), 4.84-4.78 (m, 1H), 3.62 (brs, 2H), 3.48-3.45 (m, 2H), 3.21 (brs , 4H), 2.00 (brs, 2H), 1.37 (d, J = 6.4 Hz, 2H), 1.23 (d, J = 6.4 Hz, 4H). MS-ESI calcd for [M + H] + 424, found 424.

實驗例1：大鼠動力學測試Experimental Example 1: Rat Dynamics Test

實驗目的： 檢測化合物在體內產生活性藥物成分的速度和活性藥物成分暴露量。Experimental purposes: To test the rate at which a compound produces an active pharmaceutical ingredient in the body and the exposure of the active pharmaceutical ingredient.

實驗材料: 雄性SD大鼠，體重200 - 250g，購自上海斯萊克實驗動物有限公司。Experimental materials: Male Sprague-Dawley rats weighing 200-250 g were purchased from Shanghai Slack Laboratory Animal Co., Ltd.

實驗操作: 實驗前，動物進行頸動脈插管(用於血漿樣品採集)，大鼠術後至少恢復3天，觀察無異常後用於實驗。口服給藥給藥劑量為10 mg/kg，給藥後0、 5min、15min、30min、60min、2h、4h、6h、8h、24h採集全血並製備血漿樣品。所有樣品運用液相色譜偶聯質譜質譜聯用技術對給藥化合物在實驗動物血漿中含量進行定量檢測，所測濃度值運用WinNonlin 非房室模型, 根據血漿濃度-時間資料，計算T1/2 、Cmax 、Tmax 、AUC(0-t) 和 AUC(0- ∞ ) 等參數, 並且繪製血漿濃度-時間曲線。Experimental operation: Before the experiment, the animals were subjected to carotid cannulation (for plasma sample collection), and the rats were restored to at least 3 days after surgery, and the experiment was performed after no abnormality was observed. The oral administration dose was 10 mg/kg, and whole blood was collected at 0, 5 min, 15 min, 30 min, 60 min, 2 h, 4 h, 6 h, 8 h, and 24 h after administration, and plasma samples were prepared. All samples were quantitatively detected in the plasma of the experimental animals by liquid chromatography coupled-mass spectrometry. The measured concentrations were calculated using the WinNonlin non-compartment model and the plasma concentration-time data was used to calculate T 1/2. Parameters such as C max , T max , AUC (0-t), and AUC (0- ∞ ) , and plot the plasma concentration-time curve.

實驗結果： 表1大鼠動力血測試結果 注：血藥峰值濃度: + ＞ 1000 nM；血藥峰值時間:  + ＜ 20 min；單位暴露量:+ ＞ 100 nM.hr/mmol。Experimental results: Table 1 rat dynamic blood test results Note: Peak plasma concentration: + > 1000 nM; peak plasma time: + < 20 min; unit exposure: + > 100 nM.hr/mmol.

無。no.

無。no.

無。no.

Claims (9)

一種式(I)或(Ⅱ)所示化合物或其藥學上可接受的鹽，(I)(Ⅱ) R1 、R2 分別獨立地選自R3 C(=O)O-、(R4 O)2 P(=O)O-； R3 選自C1-6 烷基、(R5 )(R6 )N-、R7 O-、苯基、吡啶基、噻吩基、呋喃基； R4 、R5 、R6 、R7 分別獨立地選自選自H或C1-3 烷基； 所述C1-6 烷基、C1-3 烷基任選地被R01 所取代； R01 選自F、Cl、Br、I、OH、NH2 ，R01 的數目為1、2或3。a compound of the formula (I) or (II) or a pharmaceutically acceptable salt thereof, (I) (II) R 1 and R 2 are each independently selected from R 3 C(=O)O-, (R 4 O) 2 P(=O)O-; R 3 is selected from C 1-6 alkyl, (R 5 ) (R 6 )N-, R 7 O-, phenyl, pyridyl, thienyl, furyl; R 4 , R 5 , R 6 , R 7 are each independently selected from H or C 1-3 alkane The C 1-6 alkyl group, the C 1-3 alkyl group is optionally substituted by R 01 ; R 01 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , and the number of R 01 is 1. 2 or 3. 如申請專利範圍第1項所述之化合物或其藥學上可接受的鹽，R3 選自丙基、丁基、二甲氨基。A compound as defined in claim 1 of the scope of the item, or a pharmaceutically acceptable salt thereof, R 3 is selected from propyl, butyl, dimethylamino. 如申請專利範圍第2項所述之化合物或其藥學上可接受的鹽，R3 選自異丙基、叔丁基、二甲氨基。The compound of claim 2, wherein R 3 is selected from the group consisting of isopropyl, tert-butyl, and dimethylamino, or a pharmaceutically acceptable salt thereof. 如申請專利範圍第1項所述之化合物或其藥學上可接受的鹽， R1 、R2 分別獨立地選自、、、、、。The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently selected from the group consisting of , , , , , . 如申請專利範圍第1項所述之化合物或其藥學上可接受的鹽，所述藥學上可接受的鹽如(Ⅲ)或(Ⅳ)所示：(Ⅲ)(Ⅳ) 其中，X選自無機酸或有機酸。The compound of claim 1, or a pharmaceutically acceptable salt thereof, as shown in (III) or (IV): (III) (IV) wherein X is selected from a mineral acid or an organic acid. 如申請專利範圍第5項所述之化合物或其藥學上可接受的鹽，X選自三氟甲磺酸、鹽酸、氫溴酸、硝酸、碳酸，碳酸氫根、磷酸、磷酸一氫根、磷酸二氫根 、硫酸、硫酸氫根、氫碘酸、亞磷酸等、乙酸、丙酸、異丁酸、馬來酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、鄰苯二甲酸、苯磺酸、對甲苯磺酸、檸檬酸、酒石酸、甲磺酸、氨基酸或葡糖醛酸。The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, Dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc., acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, antibutene Acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, amino acid or glucuronic acid. 如申請專利範圍第1項所述之化合物或其藥學上可接受的鹽，其選自： 。The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: . 一種藥物組合物，其含有治療有效量的如申請專利範圍第1項至第7項中之任一項所述之化合物或其藥學上可接受的鹽和藥學上可接受的載體。A pharmaceutical composition comprising a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in a therapeutically effective amount. 一種如申請專利範圍第1項至第7項中之任一項所述之化合物或其藥學上可接受的鹽或如申請專利範圍第8項所述之藥物組合物在製備治療血管收縮引起的相關各種病症的藥物中的應用，其中相關的各種病症包括腦栓塞、腦缺血、腦損傷、椎底動脈供血不足、蛛網膜下腔出血所引起的腦血管痙攣、心絞痛、青光眼、高血壓、纖維化。A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8 of the invention, in the preparation of a treatment for vasoconstriction The application of drugs related to various diseases, including various diseases including cerebral embolism, cerebral ischemia, brain injury, vertebral artery insufficiency, cerebral vasospasm caused by subarachnoid hemorrhage, angina pectoris, glaucoma, hypertension, Fibrosis.
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