TW201713623A - Derivatives of 1,2,3,4-tetrahydroisoquinoline, their preparation and use thereof - Google Patents

Derivatives of 1,2,3,4-tetrahydroisoquinoline, their preparation and use thereof Download PDF

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TW201713623A
TW201713623A TW105127662A TW105127662A TW201713623A TW 201713623 A TW201713623 A TW 201713623A TW 105127662 A TW105127662 A TW 105127662A TW 105127662 A TW105127662 A TW 105127662A TW 201713623 A TW201713623 A TW 201713623A
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孫廣俊
馬建斌
譚松良
高鵬
李成海
包如迪
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上海翰森生物醫藥科技有限公司
江蘇豪森藥業集團有限公司
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention discloses derivatives of 1,2,3,4-tetrahydroisoquinoline, their preparation and use thereof. In particular, the present invention relates to the derivatives of 1,2,3,4-tetrahydroisoquinoline represented by the formula (I), their preparation method and use thereof, and each substituent of formula (I) is the same as defined in the description. The series of compounds which have activity of treating, preventing or ameliorating neuropathy or neuropathic pain can be used as drugs with broad application prospects for treating primary neuropathy, neuropathy secondary, peripheral neuropathy, neuropathy caused by mechanical or biochemical nerve damage, painful diabetic neuropathy (PDN) or related neurological diseases.

Description

1,2,3,4-四氫異喹啉衍生物、其製備方法和應用 1,2,3,4-tetrahydroisoquinoline derivative, preparation method and application thereof

本發明屬於藥物開發領域，具體涉及1,2,3,4-四氫異喹啉衍生物、其製備方法和應用。 The invention belongs to the field of drug development, and particularly relates to a 1,2,3,4-tetrahydroisoquinoline derivative, a preparation method and application thereof.

神經性疼痛是一種由神經系統原發損害或功能障礙引起的慢性疼痛疾病，多種不同的損傷，如外傷、神經損傷或感染等疾病都可引起神經性疼痛。最常見的神經性疼痛類型包括糖尿病性神經痛(DNP)、帶狀皰疹後遺神經痛(PHN和愛滋病相關的神經性疼痛。與繼發性(損傷性疼痛)相反，神經性疼痛可能在外傷發生後數天，甚至數月後發生，常常為慢性疼痛，其特徵是痛覺過敏，感官對刺激過度敏感，異常性疼痛和自發性灼痛。目前神經性疼痛的治療藥物主要包括抗驚厥藥，抗抑鬱藥，麻醉性鎮痛藥和局部***。標準治療藥物如輝瑞公司的抗驚厥藥物Lyrica(普瑞巴林)。這些藥物能夠有效治療傷害感受性疼痛，但是對神經性疼痛的治療非常有限，而且伴隨有嚴重的副作用，包括認知改變，鎮靜作用，噁心以及產生耐藥性和依賴性。因此，需要提供一種能夠有效治療和預防 神經性疼痛且副作用較小的藥物。神經性疼的病理機制還不是很清楚，研究認為傷害性感受器和脊髓背角的敏感化交互作用可能就是神經性疼痛產生的基礎。 Neuropathic pain is a chronic painful disease caused by primary damage or dysfunction of the nervous system. A variety of different injuries, such as trauma, nerve damage or infection, can cause neuropathic pain. The most common types of neuropathic pain include diabetic neuropathic pain (DNP), postherpetic neuralgia (PHN and AIDS-related neuropathic pain. Contrary to secondary (injury pain), neuropathic pain may be traumatic Occurred several days or even months after the onset, often chronic pain, characterized by hyperalgesia, sensory hypersensitivity to irritation, allodynia and spontaneous burning. Currently, the treatment of neuropathic pain mainly includes anticonvulsants. Antidepressants, narcotic analgesics and local anesthetics. Standard treatments such as Pfizer's anticonvulsant Lyrica (pregain). These drugs are effective in treating nociceptive pain, but treatment of neuropathic pain is very limited, and Along with serious side effects, including cognitive changes, sedation, nausea, and drug resistance and dependence. Therefore, it is necessary to provide an effective treatment and prevention. A drug with neuropathic pain and fewer side effects. The pathological mechanism of neuropathic pain is not well understood. Studies suggest that sensitized interactions between nociceptors and spinal dorsal horn may be the basis for neuropathic pain.

腎素-血管緊張素系統(RAS)不僅存在於循環中，而且存在於許多組織器官如心血管、腎、腦中，並藉由自分泌和旁分泌發揮作用。RAS藉由血管緊張素II(AngII)與血管緊張素受體結合產生生物學效應。目前已明確的主要有血管緊張素II受體I型受體(AT1)，血管緊張素II受體II型受體(AT2)。AT1廣泛分佈於幾乎所有的組織器官。AT2主要分佈於胚胎組織、未成熟腦組織，成年正常組織較少分佈，但是組織損傷後，其表達升高。在神經性疼痛的動物模型和病人研究發現，其體內AngII，AngII受體AT2表達升高，而且，AT2的經常跟疼痛信號分子(如substance P,TRPV1)共表達。研究發現，小鼠腦組織血管緊張素Ⅱ受體激活後可對抗嗎啡的鎮痛作用；延髓尾端腹外側區血管緊張素Ⅱ受體激活後可引起痛覺過敏，給予血管緊張素Ⅱ受體拮抗劑可減輕這種痛覺過敏。EMA401，由澳大利亞生物醫藥公司Spinifex公司研究開發，是一種高選擇性血管緊張素II受體2拮抗劑，最早公開於US5246943，目前處於臨床II期實驗，現有研究表明該藥物具有較好鎮痛作用，尤其對包括糖尿病性神經痛(DNP)、帶狀皰疹後遺神經痛(PHN)等神經性疼痛治療效果顯著。 The renin-angiotensin system (RAS) exists not only in the circulation, but also in many tissues and organs such as the cardiovascular, renal, and brain, and functions by autocrine and paracrine. RAS produces a biological effect by binding angiotensin II (Ang II) to an angiotensin receptor. Currently, angiotensin II receptor type I receptor (AT1) and angiotensin II receptor type II receptor (AT2) have been identified. AT1 is widely distributed in almost all tissues and organs. AT2 is mainly distributed in embryonic tissues and immature brain tissues. Adult normal tissues are less distributed, but their expression is increased after tissue damage. In animal models and patient studies of neuropathic pain, the expression of AngII and AngII receptor AT2 is elevated in vivo, and AT2 is often co-expressed with pain signal molecules (such as substance P, TRPV1). The study found that the angiotensin II receptor in mouse brain tissue can resist the analgesic effect of morphine; the activation of angiotensin II receptor in the ventrolateral medulla of the medulla can cause hyperalgesia, and angiotensin II receptor antagonist It can alleviate this hyperalgesia. EMA401, developed by Australian biopharmaceutical company Spinifex, is a highly selective angiotensin II receptor 2 antagonist, first published in US 5,246,943, currently in clinical phase II trials, and existing studies have shown that the drug has a good analgesic effect, In particular, the treatment of neuropathic pain including diabetic neuropathic pain (DNP) and postherpetic neuralgia (PHN) is remarkable.

發明人在研究過程中發現了一類具有式(I)結構的1,2,3,4-四氫異喹啉衍生物、其製備方法和應用。該系列化合物具有治療、預防或緩解神經病或神經性疼痛方面的活性，可應用於原發性神經病、繼發性神經病、周圍神經病、由機械性神經損傷或生化神經損傷引起的神經病、疼痛性糖尿病神經病(PDN)或相關神經性疾病藥物的開發，具有廣闊的應用前景。 The inventors discovered a class of 1,2,3,4-tetrahydroisoquinoline derivatives having the structure of formula (I), their preparation methods and applications. This series of compounds has the activity of treating, preventing or relieving neuropathy or neuropathic pain, and can be applied to primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy caused by mechanical nerve injury or biochemical nerve injury, painful diabetes The development of drugs for neuropathy (PDN) or related neurological diseases has broad application prospects.

本發明一方面提供了一種具有如下式(I)結構的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽， In one aspect, the present invention provides a 1,2,3,4-tetrahydroisoquinoline derivative having the structure of the following formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

其中：R1、R2、R3各自獨立的選自氘、鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11，或者，R1與R2、R1與R3、R2與R3和直接相 連的碳原子一起形成C3-8環烷基或3-8員雜環基，該雜原子選自O、S、N，視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、鹵取代C1-8烷基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；R4選自氫、氘、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、鹼金屬、鹼土金屬或銨，視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、鹵取代C1-8烷基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；R5、R6、R9、R10各自獨立的選自氫、氘、鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8 鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11，視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；R7、R8各自獨立的選自氫、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基或5-10員雜芳基，視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取 代基所取代，視需要再進一步的被一個或多個選自鹵素、羥基、巰基、氰基、硝基、乙醯胺基、疊氮基、磺醯基、甲磺醯基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C1-8烷氧基、C1-8烷氧羰基、C1-8烷基羰基、C1-8烷基羰基氧基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、胺基、C1-8烷基單取代胺基或C1-8烷基雙取代胺基的取代基所取代；R12選自氫、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C1-8烷氧基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、C1-8烷基醯基、C1-8烷基胺基或C1-8烷基醯胺基，視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、乙醯胺基、疊氮基、磺醯基、甲磺醯基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C1-8烷氧基、C1-8烷氧羰基、C1-8烷基羰基、C1-8烷基羰基氧基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、胺基、C1-8烷基單取代胺基或C1-8烷基雙取代胺基的取代基所取代；R11、R13、R14選自自氫、氘、C1-8烷基、C3-8環烷基、鹵取代C1-8烷基、羥取代C1-8烷基、苯基或對甲基苯基； r為0、1、2。 Wherein: R 1, R 2, R 3 are each independently selected from deuterium, halogen, hydroxy, mercapto, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2 -8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 - OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N( R 13 )-C(O)OR 11 , or, R 1 and R 2 , R 1 and R 3 , R 2 and R 3 together with a directly attached carbon atom form a C 3-8 cycloalkyl group or a 3-8 member a heterocyclic group selected from O, S, N, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 alkyl, C 2 -8 alkenyl, C 2-8 alkynyl, halo substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3 -8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11, -C 0-8 -C (O) OR 11, -C 0-8 -C (O) R 12, -C 0-8 -OC (O) R 12, -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR Substituted by a substituent of 11 ; R 4 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 member a heterocyclic group, a C 5-10 aryl group, a 5-10 membered heteroaryl group, an alkali metal, an alkaline earth metal or an ammonium, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, and Nitro, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 member Heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0 -8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0 -8 -C (O) NR 13 R 14 -N (R 13) -C (O ) R 12 or -N (R 13) -C (O ) OR 11 group substituted by substituent; R 5, R 6, R 9, R 10 are each independently selected from hydrogen , deuterium, halogen, hydroxy, mercapto, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group, C 5-10 aryl group, C 5-10 aryloxy group, C 5-10 aryl group Thio group, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy group, 5-10 membered heteroarylthio group, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 , further if necessary One or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5 -10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) rR 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C( O) OR 11 group substituted with a substituent; R 7, R 8 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl An alkyl group, a 3-8 membered heterocyclic group, a C 5-10 aryl group or a 5-10 membered heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 member heteroaryl Alkoxy group, 5-10 membered heteroarylthio group, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14, -N (R 13) -C (O) R 12 or -N (R 13) -C (O ) oR 11, substituted by a substituent, still further optionally substituted by one or more substituents selected from halogen, hydroxy , 巯基, Group, nitro group, acetyl group, azido group, sulfo acyl, methanesulfonic acyl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 1-8 alkoxy, C 1-8 alkoxycarbonyl, C 1-8 alkylcarbonyl, C 1-8 alkylcarbonyloxy, 3-8 member Heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5 -10 membered heteroaryl group, 5-10-membered heteroaryl group, amino, mono-substituted C 1-8 alkyl group or C 1-8 alkyl disubstituted amine substituents; R & lt 12 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 1-8 alkoxy , 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 Heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, C 1-8 alkyl fluorenyl, C 1-8 alkylamino or C 1-8 alkyl hydrazine group, optionally further substituted by one or more substituents selected from halo, hydroxy, mercapto, cyano, nitro, acetyl amino, azido, acyl sulfonamide, methanesulfonamide acyl, C 1-8 Group, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 1-8 alkoxy, C 1-8 alkoxycarbonyl, C 1-8 alkylcarbonyl, C 1-8 alkylcarbonyloxy, 3-8 membered heterocyclic oxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryl Alkoxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amine, C 1-8 alkyl Substituted by a monosubstituted amino group or a C 1-8 alkyl disubstituted amine group; R 11 , R 13 , R 14 are selected from hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl And halogen substituted C 1-8 alkyl, hydroxy substituted C 1-8 alkyl, phenyl or p-methylphenyl; r is 0, 1, 2.

作為進一步較佳的方案，該式(I)結構的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，該立體異構體是指1-、3-、4-或2’-位包含立體構型，可分別為R-構型或S-構型，結構對應表示為“”或“”；較佳為“3R-”或“3S-”立體異構體。 As a further preferred embodiment, the 1,2,3,4-tetrahydroisoquinoline derivative of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the stereoisomer means The 1-, 3-, 4- or 2' -positions contain stereoconfigurations, which may be R-configuration or S-configuration, respectively, and the structural correspondence is expressed as " "or" "; preferably a "3R-" or "3S-" stereoisomer.

作為進一步較佳的方案，該式(I)結構的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，R5、R6、R9、R10各自獨立的選自氫、氘、鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-4烷基、鹵取代C1-4烷基、C2-4鏈烯基、C2-4鏈炔基、C3-6環烷基、3-6員雜環基、3-6員雜環基氧基、3-6員雜環基硫基、C5-8芳基、C5-8芳基氧基、C5-8芳基硫基、5-8員雜芳基、5-8員雜芳基氧基、5-8員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11；視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫 基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代； R1、R2、R3、R4、R7、R8、R11、R12、R13、R14、r如式(I)化合物所定義。 As a further preferred embodiment, the 1,2,3,4-tetrahydroisoquinoline derivative of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 5 , R 6 , R 9 , R 10 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, hydroxy, fluorenyl, cyano, nitro, azide, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylthio, C 5 8 aryl, C 5-8 aryloxy, C 5-8 arylthio, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, 5-8 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 ,- C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 ; further optionally one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group , C 5-10 aryl, C 5-10 aryloxy, C 5-10 aryl sulfur , 5-10 membered heteroaryl, 5-10 membered heteroaryl group, 5-10-membered heteroaryl group, -C 0-8 -S (O) r R 11, -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14, -C 0-8 -C (O) NR 13 R 14, -N (R 13) -C (O) R 12 or -N (R 13) -C (O ) oR 11 group substituted with a substituent; R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 and r are as defined for the compound of the formula (I).

作為進一步較佳的方案，該式(I)結構的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，R5、R6、R9、R10各自獨立的選自氫、氘、氟、氯、羥基、巰基、氰基、硝基、疊氮基、甲基、乙基、異丙基、三氟甲基、乙烯基、烯丙基、乙炔基、環丙基、吡啶基、四氫呋喃基、嗎啉基、苯基、甲氧基、乙氧基、異丙氧基、苄氧基、磺醯基、甲磺醯基、異丙磺醯基、對甲苯磺醯基、甲氧羰基、乙氧羰基、異丙氧羰基、乙醯基、乙醯氧基、胺基、二甲胺基、乙醯胺基或二甲胺基羰基；R4選自氫、氘、C1-8烷基、鹵取代C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、鹼金屬、鹼土金屬或銨；R1、R2、R3、R7、R8、R11、R12、R13、R14、r如式(I)化合物所定義。 As a further preferred embodiment, the 1,2,3,4-tetrahydroisoquinoline derivative of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 5 , R 6 , R 9 , R 10 are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, hydroxyl, thiol, cyano, nitro, azide, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, alkene Propyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methanesulfonyl, iso Propisulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, ethyl hydrazine, ethoxylated, amine, dimethylamino, acetamino or dimethylamino a carbonyl group; R 4 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, halo-substituted C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, alkali metal, alkaline earth metal or ammonium; R 1 , R 2 , R 3 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , r are as defined for the compound of formula (I).

作為進一步較佳的方案，該式(I)結構的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，R5、R6、R9、R10各自獨立的選自氫、氘、氟、甲基、乙基、異丙基、三氟甲基、環丙基、甲氧基、乙氧基、異 丙氧基、甲氧羰基、乙氧羰基、異丙氧羰基、乙醯基、乙醯氧基、胺基或二甲胺基；R4選自氫、氘、甲基、乙基、異丙基、三氟甲基、環丙基、環己基、苯基、鹼金屬、鹼土金屬或銨；R1、R2、R3、R7、R8、R11、R12、R13、R14、r如式(I)化合物所定義。 As a further preferred embodiment, the 1,2,3,4-tetrahydroisoquinoline derivative of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 5 , R 6 , R 9. R 10 is independently selected from the group consisting of hydrogen, hydrazine, fluorine, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, isopropoxy, methoxycarbonyl. , ethoxycarbonyl, isopropoxycarbonyl, ethyl hydrazino, ethoxycarbonyl, amine or dimethylamino; R 4 is selected from the group consisting of hydrogen, hydrazine, methyl, ethyl, isopropyl, trifluoromethyl, Cyclopropyl, cyclohexyl, phenyl, alkali metal, alkaline earth metal or ammonium; R 1 , R 2 , R 3 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , r such as formula (I ) defined by the compound.

作為更進一步較佳的方案，該式(I)結構的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，選自如下式(Ⅱ)化合物： As a still further preferred embodiment, the 1,2,3,4-tetrahydroisoquinoline derivative of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the following formula (II) ) Compound:

其中，R4選自氫、氘、甲基、乙基、異丙基、三氟甲基、環丙基、環己基、苯基、鹼金屬、鹼土金屬或銨；R15選自氫、鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、鹵取代C1-8烷基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、 -N(R13)-C(O)R12或-N(R13)-C(O)OR11；m選自0、1、2、3、4或5；R2、R3、R7、R8、R11、R12、R13、R14、r如式(I)化合物所定義。 Wherein R 4 is selected from the group consisting of hydrogen, hydrazine, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclohexyl, phenyl, alkali metal, alkaline earth metal or ammonium; and R 15 is selected from the group consisting of hydrogen and halogen. , hydroxy, decyl, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, halo substituted C 1-8 alkyl, C 2-8 alkynyl, C 3 8 -cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 ; m is selected from 0, 1 , 2 , 3 , 4 or 5; R 2 , R 3 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , r are as defined for the compound of formula (I) .

作為更進一步較佳的方案，該式(Ⅱ)結構的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，R2與R3和直接相連的碳原子一起形成C3-8環烷基，視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、鹵取代C1-8烷基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；R4選自氫、甲基、乙基、異丙基、三氟甲基、環丙基、鈉、鉀、鈣或銨；R15選自氫、氟、氯、羥基、巰基、氰基、硝基、疊氮基、甲基、乙基、異丙基、三氟甲基、乙烯基、烯丙基、乙炔基、環丙基、吡啶基、四氫呋喃基、嗎啉基、苯基、甲氧基、乙氧基、異丙氧基、苄氧基、磺醯基、甲磺醯基、異丙磺醯基、對甲苯磺醯基、甲氧羰基、乙氧羰基、異丙氧羰基、乙醯基、乙醯氧基、胺基、二甲胺基、 乙醯胺基或二甲胺基羰基；R7、R8、R11、R12、R13、R14、r如式(I)化合物所定義；m如前述所定義。 As a still further preferred embodiment, the 1,2,3,4-tetrahydroisoquinoline derivative of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 2 and R 3 and The directly linked carbon atoms together form a C 3-8 cycloalkyl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 alkyl, C 2 -8 alkenyl, C 2-8 alkynyl, halo substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3 -8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy Base, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , Substituted by a substituent of -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 ; R 4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and tri fluoromethyl, cyclopropyl, sodium, potassium, calcium or ammonium; R 15 is selected from hydrogen, fluoro, chloro, hydroxy, mercapto, cyano, nitro, azido, methyl, ethyl, isopropyl, Fluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonium Base, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, ethoxylated, ethoxylated, amine, dimethylamino, B Amidino or dimethylaminocarbonyl; R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , r are as defined for the compound of formula (I); m is as defined above.

作為更進一步較佳的方案，該式(Ⅱ)結構的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，R2與R3和直接相連的碳原子一起形成C3-8環烷基，視需要進一步被一個或多個選自氟、氯、羥基、巰基、氰基、硝基、疊氮基、甲基、乙基、異丙基、三氟甲基、乙烯基、烯丙基、乙炔基、環丙基、吡啶基、四氫呋喃基、嗎啉基、苯基、甲氧基、乙氧基、異丙氧基、苄氧基、磺醯基、甲磺醯基、異丙磺醯基、對甲苯磺醯基、甲氧羰基、乙氧羰基、異丙氧羰基、乙醯基、乙醯氧基、胺基、二甲胺基、乙醯胺基或二甲胺基羰基的取代基所取代；R4選自氫、鈉、鉀、鈣或銨；R15選自氫、氟、氯、羥基、巰基、氰基、硝基、疊氮基、甲基、乙基、異丙基、三氟甲基、乙烯基、烯丙基、乙炔基、環丙基、吡啶基、四氫呋喃基、嗎啉基、苯基、甲氧基、乙氧基、異丙氧基、苄氧基、磺醯基、甲磺醯基、異丙磺醯基、對甲苯磺醯基、甲氧羰基、乙氧羰基、異丙氧羰基、乙醯基、乙醯氧基、胺基、二甲胺基、乙醯胺基或二甲胺基羰基；R7、R8、R11、R12、R13、R14、r如式(I)化合物所定義；m如前述所定義。 As a still further preferred embodiment, the 1,2,3,4-tetrahydroisoquinoline derivative of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 2 and R 3 and The directly linked carbon atoms together form a C 3-8 cycloalkyl group, optionally further selected from one or more selected from the group consisting of fluorine, chlorine, hydroxyl, sulfhydryl, cyano, nitro, azide, methyl, ethyl, and iso Propyl, trifluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy Base, sulfonyl, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, ethoxylated, ethoxylated, amine, dimethyl Substituted with a substituent of an amine group, an ethenyl group or a dimethylaminocarbonyl group; R 4 is selected from hydrogen, sodium, potassium, calcium or ammonium; and R 15 is selected from the group consisting of hydrogen, fluorine, chlorine, hydroxyl, thiol, cyano, Nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methyl Oxygen, ethoxy Base, isopropoxy, benzyloxy, sulfonyl, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, ethylidene, B a decyloxy group, an amine group, a dimethylamino group, an acetamino group or a dimethylaminocarbonyl group; R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , r are as defined for the compound of the formula (I) ;m is as defined above.

作為最佳的方案，該式(Ⅱ)結構的1,2,3,4- 四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，選自如下化合物： As a preferred embodiment, the 1,2,3,4-tetrahydroisoquinoline derivative of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the group consisting of the following compounds:

作為更進一步較佳的方案，該式(Ⅱ)結構的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，R2、R3各自獨立的選自氘、鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11，視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、鹵取代C1-8烷基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代； R4選自氫、甲基、乙基、異丙基、三氟甲基、環丙基、鈉、鉀、鈣或銨；R15選自氫、氟、氯、羥基、巰基、氰基、硝基、疊氮基、甲基、乙基、異丙基、三氟甲基、乙烯基、烯丙基、乙炔基、環丙基、吡啶基、四氫呋喃基、嗎啉基、苯基、甲氧基、乙氧基、異丙氧基、苄氧基、磺醯基、甲磺醯基、異丙磺醯基、對甲苯磺醯基、甲氧羰基、乙氧羰基、異丙氧羰基、乙醯基、乙醯氧基、胺基、二甲胺基、乙醯胺基或二甲胺基羰基；R7、R8、R11、R12、R13、R14、r如式(I)化合物所定義；m如前述所定義。 As a still further preferred embodiment, the 1,2,3,4-tetrahydroisoquinoline derivative of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, each of R 2 and R 3 Independently selected from the group consisting of hydrazine, halogen, hydroxy, decyl, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 ring alkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclic thio group, C 5-10 aryl, C 5-10 aryloxy, C 5- 10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0- 8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 , Further optionally, one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen Substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl , C 5-10 aryloxy, C 5-10 arylthio, 5-10 Heteroaryl, 5-10 membered heteroaryl group, 5-10-membered heteroaryl group, -C 0-8 -S (O) r R 11, -C 0-8 -OR 11, -C 0 -8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0 Substituted with a substituent of -8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 ; R 4 is selected from hydrogen , methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, sodium, potassium, calcium or ammonium; R 15 is selected from hydrogen, fluoro, chloro, hydroxy, mercapto, cyano, nitro, azido Base, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy Base, isopropoxy, benzyloxy, sulfonyl, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, ethylidene, B a decyloxy group, an amine group, a dimethylamino group, an acetamino group or a dimethylaminocarbonyl group; R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , r are as defined for the compound of the formula (I) ;m is as defined above.

作為更進一步較佳的方案，該式(Ⅱ)結構的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，R2、R3各自獨立的選自氘、鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、鹵取代C1-8烷基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11；R4選自氫、鈉、鉀、鈣或銨；R15選自氫、氟、氯、羥基、巰基、氰基、硝基、疊氮基、甲基、乙基、異丙基、三氟甲基、乙烯基、 烯丙基、乙炔基、環丙基、吡啶基、四氫呋喃基、嗎啉基、苯基、甲氧基、乙氧基、異丙氧基、苄氧基、磺醯基、甲磺醯基、異丙磺醯基、對甲苯磺醯基、甲氧羰基、乙氧羰基、異丙氧羰基、乙醯基、乙醯氧基、胺基、二甲胺基、乙醯胺基或二甲胺基羰基；R7、R8、R11、R12、R13、R14、r如式(I)化合物所定義；m如前述所定義。 As a still further preferred embodiment, the 1,2,3,4-tetrahydroisoquinoline derivative of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, each of R 2 and R 3 Independently selected from the group consisting of hydrazine, halogen, hydroxy, decyl, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1- 8- alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group, C 5-10 aryl group, C 5 - 10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S (O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC( O) R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 -C(O)OR 11 ; R 4 is selected from hydrogen, sodium, potassium, calcium or ammonium; R 15 is selected from the group consisting of hydrogen, fluorine, chlorine, hydroxyl, sulfhydryl, cyano, nitro, azide, methyl, Ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy Base, benzyloxy, sulfonyl, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, ethyl hydrazine, ethoxylated, amine a dimethylamino group, an acetamino group or a dimethylaminocarbonyl group; R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , r are as defined for the compound of the formula (I); m is as defined above definition.

作為最較佳的方案，該式(Ⅱ)結構的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，選自如下化合物： As a most preferred embodiment, the 1,2,3,4-tetrahydroisoquinoline derivative of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the group consisting of the following compounds:

本發明另一方面提供式(I)化合物、其立體異構體或其藥學上可接受鹽的製備方法，包括如下步驟： In another aspect, the present invention provides a process for the preparation of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:

X選自羥基或鹵素，較佳為羥基或氯；R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、r如式(I)化合物所定義。 X is selected from a hydroxyl group or a halogen, preferably a hydroxyl group or chlorine; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , r are as defined for the compound of formula (I).

作為進一步較佳的方案，該縛酸劑為有機 鹼或無機鹼，該有機鹼選自三甲胺、三乙胺、吡啶、哌啶、嗎啉或其混合物，該無機鹼選自碳酸鉀、碳酸鈉、碳酸銫、碳酸氫鈉、碳酸氫鉀、氫氧化鈉，氫氧化鉀，氫氧化鋰，醋酸鈉或其混合物；該縮合劑選自DIC、DCC、HOBT、EDC．HCl、PyBOP、PyBroP、HATU、HCTU、DEPBT、EEDQ、CDI或其混合物。 As a further preferred solution, the acid binding agent is organic a base or an inorganic base selected from the group consisting of trimethylamine, triethylamine, pyridine, piperidine, morpholine or a mixture thereof, the inorganic base being selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, Sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate or a mixture thereof; the condensing agent is selected from the group consisting of DIC, DCC, HOBT, EDC. HCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI or mixtures thereof.

本發明另一方面提供醫藥組成物，其包括治療有效劑量的前述式(I)化合物、其立體異構體或其藥學上可接受鹽及可藥用的載體。 Another aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

本發明另一方面提供了前述式(I)化合物、其立體異構體或其藥學上可接受鹽，或前述醫藥組成物在製備用於治療、預防或緩解對象的神經病或神經性疼痛藥物中的應用。 According to another aspect of the present invention, there is provided a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use in the preparation of a medicament for the treatment, prevention or amelioration of a neuropathy or neuropathic pain in a subject Applications.

作為進一步較佳的方案，該神經病為原發性神經病、繼發性神經病、周圍神經病、由機械性神經損傷或生化神經損傷引起的神經病、疼痛性糖尿病神經病(PDN)或相關神經性疾病。 As a further preferred embodiment, the neuropathy is a primary neuropathy, a secondary neuropathy, a peripheral neuropathy, a neuropathy caused by mechanical nerve damage or biochemical nerve damage, a painful diabetic neuropathy (PDN) or a related neurological disease.

詳細說明：除非有相反陳述，下列用在說明書和申請專利範圍中的術語具有下述含義。 DETAILED DESCRIPTION: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

“C1-8烷基”指包括1至8個碳原子的直鏈烷基和含支鏈烷基，烷基指飽和的脂族烴基團，C0-8是指 不含碳原子或者C1-8烷基，例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各種支鏈異構體等。 "C 1-8 alkyl" means a straight-chain alkyl group having 1 to 8 carbon atoms and a branched alkyl group, the alkyl group means a saturated aliphatic hydrocarbon group, and C 0-8 means no carbon atom or C. 1-8 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, t-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-B 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl , 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, positive Heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2 - dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethyl Hexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4- Dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branches thereof Chain isomers, etc.

烷基可以是經取代的或未經取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，較佳為一個或多個以下基團，獨立地選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、 -N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；“環烷基指飽和或部分不飽和單環或多環環狀烴取代基，“C3-8環烷基”指包括3至8個碳原子的環烷基，“5-10員環烷基”指包括5至10個碳原子的環烷基，例如：單環環烷基的非限制性實施例包含環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等。 The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halo, hydroxy. , mercapto, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic ring , 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 Heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C Substituted by a substituent of 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 ; "cycloalkyl Refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, "C 3-8 cycloalkyl" refers to a cycloalkyl group containing from 3 to 8 carbon atoms, and "5-10 membered cycloalkyl" is included Non-limiting examples of cycloalkyl groups of 5 to 10 carbon atoms, for example, monocyclic cycloalkyl groups, include cyclopropyl, cyclobutyl, cyclopentyl, Pentenyl group, a cyclohexyl group, cyclohexenyl group, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like.

多環環烷基包括螺環、稠環和橋環的環烷基。“螺環烷基”指單環之間共用一個碳原子(稱螺原子)的多環基團，這些可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。根據環與環之間共用螺原子的數目將螺環烷基分為單螺環烷基、雙螺環烷基基或多螺環烷基，螺環烷基的非限制性實施例包含： Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spirocycloalkyl group is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of shared spiro atoms between the ring and the ring. Non-limiting examples of spirocycloalkyl groups include:

“稠環烷基”指系統中的每個環與體系中的其他環共享毗鄰的一對碳原子的全碳多環基團，其中一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。根據組成環的數目可以分為雙環、三環、四環或多環稠環烷基，稠環烷基的非限制性實施例包含： "Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated π-electron system. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and non-limiting examples of fused cycloalkyl groups include:

“橋環烷基”指任意兩個環共用兩個不直接連接的碳原子的全碳多環基團，這些可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。根據組成環的數目可以分為雙環、三環、四環或多環橋環烷基，橋環烷基的非限制性實施例包含： "Bridge cycloalkyl" refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

該環烷基環可以稠合於芳基、雜芳基或雜環烷基環上，其中與母體結構連接在一起的環為環烷基，非限制性實施例包括茚滿基、四氫萘基、苯并環庚烷基等。 The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.

環烷基可以是視需要經取代的或未經取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11 The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, Azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic Oxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 member Heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11

“雜環基”指飽和或部分不飽和單環或多環環狀烴取代基，其中一個或多個環原子選自氮、氧或S(O)r(其中r是整數0、1、2)的雜原子，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。“5-10員雜環 基”指包含5至10個環原子的環基，“3-8員雜環基”指包含3至8個環原子的環基。 "Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. The "5-10 membered heterocyclic group" means a ring group containing 5 to 10 ring atoms, and the "3-8 membered heterocyclic group" means a ring group containing 3 to 8 ring atoms.

單環雜環基的非限制性實施例包含吡咯烷基、哌啶基、哌嗪基、嗎啉基、硫代嗎啉基、高哌嗪基等。 Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.

多環雜環基包括螺環、稠環和橋環的雜環基。“螺雜環基”指單環之間共用一個原子(稱螺原子)的多環雜環基團，其中一個或多個環原子選自氮、氧或S(O)r(其中r是整數0、1、2)的雜原子，其餘環原子為碳。這些可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。根據環與環之間共用螺原子的數目將螺環烷基分為單螺雜環基、雙螺雜環基或多螺雜環基。螺環烷基的非限制性實施例包含： Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of common spiro atoms between the ring and the ring. Non-limiting examples of spirocycloalkyl groups include:

“稠雜環基”指系統中的每個環與體系中的其他環共享毗鄰的一對原子的多環雜環基團，一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統，其中一個或多個環原子選自氮、氧或S(O)r(其中r是整數0、1、2)的雜原子，其餘環原子為碳。根據組成環的數目可以分為雙環、三環、四環或多環稠雜環烷基，稠雜環基的非限制性實施例包含： "Fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none The ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, the remaining ring atoms being carbon. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, and non-limiting examples of fused heterocyclic groups include:

“橋雜環基”指任意兩個環共用兩個不直接連接的原子的多環雜環基團，這些可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統，其中一個或多個環原子選自氮、氧或S(O)r(其中r是整數0、1、2)的雜原子，其餘環原子為碳。根據組成環的數目可以分為雙環、三環、四環或多環橋環烷基，橋環烷基的非限制性實施例包含： "Bridge heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

該雜環基環可以稠合於芳基、雜芳基或環烷基環上，其中與母體結構連接在一起的環為雜環基，非限制性實施例包含： The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:

雜環基可以是視需要經取代的或未經取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳 基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；“芳基”指全碳單環或稠合多環(也就是共享毗鄰碳原子對的環)基團，具有共軛的π電子體系的多環(即其帶有相鄰對碳原子的環)基團，“C5-10芳基”指含有5-10個碳的全碳芳基，“5-10員芳基”指含有5-10個碳的全碳芳基，例如苯基和萘基。該芳基環可以稠合於雜芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為芳基環，非限制性實施例包含： The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, Azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic Oxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 member Heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR Substituted by a substituent of 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 ; "aryl" means an all-carbon monocyclic or fused multi a ring (that is, a ring sharing a pair of adjacent carbon atoms) having a polycyclic ring of a conjugated π-electron system (ie, a ring having an adjacent pair of carbon atoms), and a "C 5-10 aryl group" An all-carbon aryl group having 5 to 10 carbons, and a "5-10 membered aryl group" means an all-carbon aryl group having 5 to 10 carbons such as a phenyl group and a naphthyl group. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:

芳基可以是經取代的或未經取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10 員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；“雜芳基”指包含1至4個雜原子的雜芳族體系，該雜原子包括氮、氧和S(O)r(其中r是整數0、1、2)的雜原子，5-7員雜芳基指含有5-7個環原子的雜芳族體系，5-10員雜芳基指含有5-10個環原子的雜芳族體系，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。該雜芳基環可以稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，非限制性實施例包含： The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide. , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryl Oxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 ,- C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 Substituted by a substituent of -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 ; "heteroaryl" means a heteroaryl containing 1 to 4 heteroatoms a family system comprising a hetero atom of nitrogen, oxygen and S(O) r (wherein r is an integer of 0, 1, 2), and a 5-7 membered heteroaryl group means a heteroaromatic group having 5 to 7 ring atoms The system, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5 to 10 ring atoms, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidine , Pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:

雜芳基可以是視需要經取代的或未經取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、 -C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；“烯基”指由至少兩個碳原子和至少一個碳-碳雙鍵組成的如上述定義的烷基，C2-8鏈烯基指含有2-8個碳的直鏈或含支鏈烯基。例如乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。 The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, Azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic Oxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 member Heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR Substituted by a substituent of 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 ; "alkenyl" means at least two carbon atoms and at least An alkyl group as defined above consisting of a carbon-carbon double bond, and a C 2-8 alkenyl group means a straight or branched chain alkenyl group having 2-8 carbons. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

烯基可以是經取代的或未經取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；“炔基”指至少兩個碳原子和至少一個碳-碳三鍵組成的如上所定義的烷基，C2-8鏈炔基指含有2-8個碳的直鏈或含支鏈炔基。例如乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。 The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide. , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryl Oxyl, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 ,- C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 Substituted by a substituent of -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 ; "alkynyl" means at least two carbon atoms and at least one carbon-carbon An alkyl group as defined above having a triple bond, and a C 2-8 alkynyl group means a straight-chain or branched alkynyl group having 2-8 carbons. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

炔基可以是經取代的或未經取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜 環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；“烷氧基”指-O-(烷基)，其中烷基的定義如上所述。C1-8烷氧基指含1-8個碳的烷基氧基，非限制性實施例包含甲氧基、乙氧基、丙氧基、丁氧基等。 The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide. , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryl Oxyl, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 ,- C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 Substituted by a substituent of -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 ; "alkoxy" means -O-(alkyl) wherein alkane The definition of the base is as described above. The C 1-8 alkoxy group means an alkyloxy group having 1-8 carbons, and the non-limiting examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like.

烷氧基可以是視需要經取代的或未經取代的，當被取代時，取代基，較佳為一個或多個以下基團，獨立地選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；“鹵取代的C1-8烷基”指烷基上的氫視需要的被氟、氯、溴、碘原子取代的1-8個碳烷基基團，例如二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。 The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro , azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic ring Alkoxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, -C 0-8 -S(O) r R 11 , -C 0-8 - OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 Substituted by a substituent of R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 "Hal-substituted C 1-8 alkyl" means a hydrogen of the alkyl group, preferably 1-8 alkylalkyl groups substituted by fluorine, chlorine, bromine or iodine atoms, such as difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

“鹵取代的C1-8烷氧基”烷基上的氫視需要的被氟、氯、溴、碘原子取代的1-8個碳烷氧基基團。 例如二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。 The hydrogen on the "halo-substituted C 1-8 alkoxy" alkyl group is preferably a 1-8 carbon alkoxy group substituted with a fluorine, chlorine, bromine or iodine atom. For example, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

“鹵素”指氟、氯、溴或碘。 "Halogen" means fluoro, chloro, bromo or iodo.

術語“縮合劑”是指能引起縮合反應的試劑。縮合反應是指兩個或多個有機分子相互作用後以共價鍵結合成一個大分子，同時失去水或其他比較簡單的無機或有機小分子的反應。其中的小分子物質通常是水、氯化氫、甲醇或乙酸等。本發明中各種縮合劑的簡稱對應的中文名稱如表1所示。 The term "condensing agent" means an agent capable of causing a condensation reaction. A condensation reaction refers to a reaction in which two or more organic molecules interact to form a macromolecule by covalent bonding while losing water or other relatively simple inorganic or organic small molecules. The small molecular substance is usually water, hydrogen chloride, methanol or acetic acid. The Chinese names corresponding to the abbreviations of the various condensing agents in the present invention are shown in Table 1.

“視需要”或“視需要地”意味著隨後所描述地事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生地場合。例如，“視需要被烷基取代的雜環基團”意味著烷基可以但不必須存在，該說明包括雜環基團被烷基取代的情形和雜環基團不被烷基取代的情形。 "As needed" or "as needed" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes a case where a heterocyclic group is substituted with an alkyl group and a case where a heterocyclic group is not substituted with an alkyl group. .

“經取代的”指基團中的一個或多個氫原子，較佳為最多5個，更佳為1~3個氫原子彼此獨立地被相應數目的取代基取代。不言而喻，取代基僅處在它們的可能的化學位置，本領域技術人員能夠在不付出過多努力的情況下確定(藉由實驗或理論)可能或不可能的取代。例如，具有游離氫的胺基或羥基與具有不飽和鍵(如烯屬)的碳原子結合時可能是不穩定的。 "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amine group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond such as an olefin.

“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上/可藥用的鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學/可藥用的載體和賦形劑。醫藥組成物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。 "Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, and to facilitate the absorption of the active ingredient to exert biological activity.

下面結合實施例對本發明做進一步詳細、完整地說明，但決非限制本發明，本發明也並非僅局限於實施例的內容。 The present invention is further described in detail with reference to the accompanying drawings, but by no way of limitation,

本發明的化合物結構是藉由核磁共振(NMR)或/和液質聯用色譜(LC-MS)來確定的。NMR化學位移(δ)以百萬分之一(ppm)的單位給出。NMR的測定是用Bruker AVANCE-400核磁儀，測定溶劑為氘代甲醇(CD3OD)和氘代氯仿(CDCl3)內標為四甲基矽烷(TMS)。 The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ) was internally labeled as tetramethyl decane (TMS).

液質聯用色譜LC-MS的測定用Agilent 1200 Infinity Series質譜儀。HPLC的測定使用安捷倫1200DAD高壓液相色譜儀(Sunfire C18 150×4.6mm色譜柱)和Waters 2695-2996高壓液相色譜儀(Gimini C18 150×4.6mm色譜柱)。 LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer. The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板，TLC採用的規格是0.15mm~0.20mm，薄層層析分離純化產品採用的規格是0.4mm~0.5mm。管柱層析一般使用煙臺黃海矽膠200~300目矽膠為載體。 The thin layer chromatography tantalum sheet uses Yantai Yellow Sea HSGF254 or Qingdao GF254 tantalum sheet. The specification for TLC is 0.15mm~0.20mm, and the specification for thin layer chromatography separation and purification is 0.4mm~0.5mm. Pipe column chromatography generally uses Yantai Huanghai Tanji 200~300 mesh silicone as carrier.

本發明實施例中的起始原料是已知的並且可以在市場上買到，或者可以採用或按照本領域已知的方法來合成。 Starting materials in the examples of the invention are known and commercially available or can be synthesized or synthesized according to methods known in the art.

在無特殊說明的情況下，本發明的所有反應均在連續的磁攪拌下，在乾燥氮氣或氬氣氛下進行，溶劑為乾燥溶劑。 Unless otherwise stated, all reactions of the present invention were carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, and the solvent was a dry solvent.

氬氣氛或氮氣氛是指反應瓶連接一個約1L容積的氬氣或氮氣氣球。氫氣氛是指反應瓶連接一個約1L容積的氫氣氣球。 An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L. The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

在無特殊說明的情況下，實施例中的溶液是指水溶液。反應的溫度為室溫。室溫為最適宜的反應溫度，為20℃~30℃。 The solution in the examples means an aqueous solution unless otherwise specified. The temperature of the reaction is room temperature. The optimum reaction temperature at room temperature is 20 ° C to 30 ° C.

實施例中的反應進程的監測採用薄層色譜 法(TLC)或液質聯用色譜(LC-MS)反應所使用的展開劑體系有：二氯甲烷和甲醇體系，正己烷和乙酸乙酯體系，石油醚和乙酸乙酯體系，丙酮，溶劑的體積比可根據化合物的極性不同而進行調節。柱層析的洗脫劑的體系包括：A：二氯甲烷和甲醇體系，B：正己烷和乙酸乙酯體系，C：二氯甲烷和乙酸乙酯體系，D：乙酸乙酯和甲醇，溶劑的體積比根據化合物的極性不同而進行調節，也可以加入少量的氨水和醋酸等進行調節。 TLC analysis of the reaction progress in the examples The solvent system used in the method (TLC) or liquid chromatography-mass spectrometry (LC-MS) is: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, acetone, solvent The volume ratio can be adjusted depending on the polarity of the compound. Column chromatography eluent system includes: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and ethyl acetate system, D: ethyl acetate and methanol, solvent The volume ratio is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of ammonia water and acetic acid.

中間體的製備Preparation of intermediates 1、中間體1：乙基3-(2-(苄氧基)-3-甲氧苯基)-2-((二苯亞甲基)胺基)丙酸酯的製備1. Intermediate 1: Preparation of ethyl 3-(2-(benzyloxy)-3-methoxyphenyl)-2-((diphenylmethylene)amino)propionate

室溫下，往2-(苄氧基)-1-(氯甲基)-3-甲氧基苯(6.8g,25.88mmol)的乙腈溶液(60mL)中，加入碘化鉀(5.59g,33.65mmol)，碳酸銫(16.87g,51.76mmol)，乙基2-((二苯亞甲基)胺基)乙酸酯(6.92g,25.88mmol)，然後在氮氣保護下，在50℃油浴中攪拌過夜。冷卻後，減壓旋蒸除去有機溶劑，加入乙酸乙酯和水分層，乙酸乙酯相再用飽和食鹽水洗滌，用無水硫酸鈉乾燥，濃縮管柱層析(洗脫劑：石油醚/乙酸乙酯=10：1)，得到乙基3-(2-(苄氧基)-3-甲氧苯基)-2-((二苯亞甲基)胺基)丙酸酯(8.9g, 70%)。 To a solution of 2-(benzyloxy)-1-(chloromethyl)-3-methoxybenzene (6.8 g, 25.88 mmol) in EtOAc (60 mL), EtOAc. ), cesium carbonate (16.87 g, 51.76 mmol), ethyl 2-((diphenylmethylene)amino)acetate (6.92 g, 25.88 mmol), then in a 50 ° C oil bath under nitrogen. Stir overnight. After cooling, the organic solvent was evaporated under reduced pressure. ethyl acetate and aqueous layer was evaporated. Ethyl ester = 10:1) gave ethyl 3-(2-(benzyloxy)-3-methoxyphenyl)-2-((diphenylmethylene)amino)propanoate (8.9 g, 70%).

MS m/z(ESI)：494.6[M+H]+. MS m/z (ESI): 494.6 [M+H] + .

2、中間體2：乙基2-胺基-3-(2-(苄氧基)-3-甲氧苯基)丙酸酯的製備2. Intermediate 2: Preparation of ethyl 2-amino-3-(2-(benzyloxy)-3-methoxyphenyl) propionate

室溫下，往乙基3-(2-(苄氧基)-3-甲氧苯基)-2-((二苯亞甲基)胺基)丙酸酯(8.9g,18.03mmol)的四氫呋喃溶液(60mL)中，加入HCl(3M,30mL)，繼續在該溫度下攪拌2小時，然後減壓除去有機溶劑。加入約100mL水，用乙酸乙酯萃取。乙酸乙酯相用飽和食鹽水洗滌多次，無水硫酸鈉乾燥，濃縮得到乙基2-胺基-3-(2-(苄氧基)-3-甲氧苯基)丙酸酯(5.2g,88%)。 To ethyl 3-(2-(benzyloxy)-3-methoxyphenyl)-2-((diphenylmethylene)amino)propanoate (8.9 g, 18.03 mmol) at rt To a solution of tetrahydrofuran (60 mL) was added HCl (3M, 30 mL), and stirring at this temperature for 2 hr. About 100 mL of water was added and extracted with ethyl acetate. The ethyl acetate phase was washed several times with saturated brine, dried over anhydrous sodium sulfate and evaporated to ethyldiethyldiethyl 3-(2-(benzyloxy)-3-methoxyphenyl)propanoate (5.2 g) , 88%).

MS m/z(ESI)：330.5[M+H]+。 MS m/z (ESI): 330.5 [M+H] + .

3、中間體3：乙基5-(苄氧基)-6-甲氧基-1,2,3,4-四氫異喹啉-3-羧酸酯的製備3. Intermediate 3: Preparation of ethyl 5-(benzyloxy)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate

往乙基2-胺基-3-(2-(苄氧基)-3-甲氧苯基)丙酸酯(5g,15.18mmol)，多聚甲醛(2.28g,75.90mmol)的二氯甲烷溶液(50mL)中加入三氟醋酸(25mL)，然後室 溫攪拌過夜。減壓除去有機溶劑，加入約100mL水，用乙酸乙酯萃取。乙酸乙酯相用飽和食鹽水洗滌多次，有機相依次用飽和碳酸氫鈉水溶液、飽和食鹽水洗滌，無水硫酸鈉乾燥，濃縮，管柱層析(洗脫劑：石油醚/乙酸乙酯=3：1)，得到乙基5-(苄氧基)-6-甲氧基-1,2,3,4-四氫異喹啉-3-羧酸酯(3.2g,62%)。 To ethyl 2-amino-3-(2-(benzyloxy)-3-methoxyphenyl)propanoate (5 g, 15.18 mmol), methylene chloride (2.28 g, 75.90 mmol) Add trifluoroacetic acid (25 mL) to the solution (50 mL), then room Stir at room temperature overnight. The organic solvent was removed under reduced pressure, and water (100 mL) was added and ethyl acetate. The ethyl acetate phase was washed with saturated brine and the organic phase was washed sequentially with saturated aqueous sodium hydrogen sulfate and brine, dried over anhydrous sodium sulfate 3:1), ethyl 5-(benzyloxy)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (3.2 g, 62%) was obtained.

MS m/z(ESI)：342.4[M+H]+。 MS m/z (ESI): 342.4 [M+H] + .

實施例化合物的製備Preparation of example compounds 實施例1：5-(苄氧基)-6-甲氧基-2-(1-苯基環己烷-1-羰基)-1,2,3,4-四氫異喹啉-3-羧酸的製備Example 1: 5-(Benzyloxy)-6-methoxy-2-(1-phenylcyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3- Preparation of carboxylic acid

第一步：1-苯基環己烷-1-羰基醯氯的製備First step: Preparation of 1-phenylcyclohexane-1-carbonylindole chloride

室溫下，在1-苯基環己烷-1-羧酸(200mg,0.98mmol)的二氯甲烷(5mL)溶液中加入草醯氯(248mg,1.96mmol)，DMF(0.2mL)，反應在室溫下攪拌2小時，減壓除去溶劑，得到粗品1-苯基環己烷-1-羰基醯氯(230mg)，直接用於下一步反應。 To a solution of 1-phenylcyclohexane-l-carboxylic acid (200 mg, 0.98 mmol) in dichloromethane (5 mL), EtOAc (EtOAc, m. The mixture was stirred at room temperature for 2 hr.

第二步：乙基5-(苄氧基)-6-甲氧基-2-(1-苯基環己烷-1-羰基)-1,2,3,4-四氫異喹啉-3-羧酸酯的製備Second step: ethyl 5-(benzyloxy)-6-methoxy-2-(1-phenylcyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline- Preparation of 3-carboxylate

室溫下，在1-苯基環己烷-1-羰基醯氯(100mg,0.45mmol)的二氯甲烷(5mL)溶液中，加入乙基5-(苄氧基)-6-甲氧基-1,2,3,4-四氫異喹啉-3-羧酸酯(183mg,0.538mmol)，三乙胺(137mg,1.35mmol)。反應在室溫下攪拌兩個小時。加入約10mL水，用二氯甲烷萃取。有機相依次用飽和碳酸氫鈉水溶液、飽和食鹽水洗滌，無水硫酸鈉乾燥，濃縮，管柱層析(洗脫劑：石油醚/乙酸乙酯=1：1)，得到標題化合物乙基5-(苄氧基)-6-甲氧基-2-(1-苯基環己烷-1-羰基)-1,2,3,4-四氫異喹啉-3-羧酸酯(95mg,40%)。 Ethyl 5-(benzyloxy)-6-methoxyl was added to a solution of 1-phenylcyclohexane-1-carbonylindole chloride (100 mg, 0.45 mmol) in dichloromethane (5 mL) -1,2,3,4-tetrahydroisoquinoline-3-carboxylate (183 mg, 0.538 mmol), triethylamine (137 mg, 1.35 mmol). The reaction was stirred at room temperature for two hours. About 10 mL of water was added and extracted with dichloromethane. The organic phase was washed with aq. EtOAc (EtOAc m. (benzyloxy)-6-methoxy-2-(1-phenylcyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (95 mg, 40%).

MS m/z(ESI)：528.6[M+H]+。 MS m/z (ESI): 528.6 [M+H] + .

第三步：5-(苄氧基)-6-甲氧基-2-(1-苯基環己烷-1-羰基)-1,2,3,4-四氫異喹啉-3-羧酸的製備Third step: 5-(benzyloxy)-6-methoxy-2-(1-phenylcyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3- Preparation of carboxylic acid

在乙基5-(苄氧基)-6-甲氧基-2-(1-苯基環己烷-1-羰基)-1,2,3,4-四氫異喹啉-3-羧酸酯(70mg,0.133mmol)的四氫呋喃(6mL)溶液中分別加入甲醇(2mL)， 水(3mL)，接著加入氫氧化鋰(55.2mg,1.33mmol)，室溫下反應2個小時，減壓除去有機溶劑，加入約100mL水，用少量乙酸乙酯洗滌水相，收集水相用稀鹽酸調pH值到2，用乙酸乙酯萃取水相，收集乙酸乙酯相用飽和食鹽水洗滌，然後用無水硫酸鈉乾燥有機相，濃縮，得到標題化合物5-(苄氧基)-6-甲氧基-2-(1-苯基環己烷-1-羰基)-1,2,3,4-四氫異喹啉-3-羧酸(51mg,77%)。MS m/z(ESI)：500.2[M+H]+；1H NMR(400MHz,CDCl3)δ 7.41-7.17(m,11H),6.63-6.43(m,1H),5.94(d,J=6.3Hz,1H),4.94(dd,J=33.7,10.4Hz,2H),4.63(s,1H),4.18(d,J=14.7Hz,1H),3.80(s,3H),3.23-2.76(m,2H),2.44-2.21(m,2H),1.83-1.56(m,8H)。 Ethyl 5-(benzyloxy)-6-methoxy-2-(1-phenylcyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate To a solution of the acid ester (70 mg, 0.133 mmol) in tetrahydrofuran (6 mL) was added methanol (2 mL), water (3 mL), and then lithium hydroxide (55.2 mg, 1.33 mmol), and reacted at room temperature for 2 hours. The organic solvent was removed, about 100 mL of water was added, and the aqueous phase was washed with a small amount of ethyl acetate. The aqueous phase was collected, adjusted to pH 2 with dilute hydrochloric acid, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried (MgSO4) - Tetrahydroisoquinoline-3-carboxylic acid (51 mg, 77%). MS m/z (ESI): 500.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.41-7.17 (m, 11H), 6.63-6.43 (m, 1H), 5.94 (d, J = 6.3 Hz, 1H), 4.94 (dd, J = 33.7, 10.4 Hz, 2H), 4.63 (s, 1H), 4.18 (d, J = 14.7 Hz, 1H), 3.80 (s, 3H), 3.23 - 2.76 ( m, 2H), 2.44 - 2.21 (m, 2H), 1.83-1.56 (m, 8H).

實施例2：5-(苄氧基)-6-甲氧基-2-(1-苯基環丙烷-1-羰基)-1,2,3,4-四氫異喹啉-3-羧酸的製備Example 2: 5-(Benzyloxy)-6-methoxy-2-(1-phenylcyclopropane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate Acid preparation

5-(苄氧基)-6-甲氧基-2-(1-苯基環丙烷-1-羰基)-1,2,3,4-四氫異喹啉-3-羧酸的製備方法參照實施例1。MS m/z(ESI)：458.2[M+H]+；1H NMR(400MHz,CDCl3)δ 7.41-7.28(m,6H),7.23-7.13(m,4H),6.88-6.69(m,1H),6.68-6.44(m,1H),5.11-4.82(m,3H),4.66-4.13(m,2H),3.84(s,3H),3.40-2.75 (m,2H),1.54-1.19(m,4H)。 Method for preparing 5-(benzyloxy)-6-methoxy-2-(1-phenylcyclopropane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Refer to Example 1. MS m/z (ESI): 458.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.41-7.28 (m, 6H), 7.23 - 7.13 (m, 4H), 6.88-6.69 (m, 1H), 6.68-6.44 (m, 1H), 5.11-4.82 (m, 3H), 4.66-4.13 (m, 2H), 3.84 (s, 3H), 3.40-2.75 (m, 2H), 1.54-1.19 ( m, 4H).

實施例3：5-(苄氧基)-6-甲氧基-2-(1-苯基環戊烷-1-羰基)-1,2,3,4-四氫異喹啉-3-羧酸的製備Example 3: 5-(Benzyloxy)-6-methoxy-2-(1-phenylcyclopentane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3- Preparation of carboxylic acid

5-(苄氧基)-6-甲氧基-2-(1-苯基環戊烷-1-羰基)-1,2,3,4-四氫異喹啉-3-羧酸的製備方法參照實施例1。MS m/z(ESI)：486.3[M+H]+；1H NMR(400MHz,CDCl3)δ 7.42-7.32(m,6H),7.23-7.18(m,4H),6.60(t,J=14.1Hz,1H),6.08(d,J=8.2Hz,1H),4.95(dt,J=22.6,11.3Hz,2H),4.64(m,2H),4.17(d,J=15.0Hz,1H),3.82(s,3H),2.99(m,2H),2.51-2.33(m,2H),2.17-1.96(m,2H),1.79-1.70(m,4H)。 Preparation of 5-(benzyloxy)-6-methoxy-2-(1-phenylcyclopentane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid The method is referred to in Example 1. MS m/z (ESI): 486.3 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.42-7.32 (m, 6H), 7.23-7.18 (m, 4H), 6.60 (t, J = 14.1 Hz, 1H), 6.08 (d, J = 8.2 Hz, 1H), 4.95 (dt, J = 22.6, 11.3 Hz, 2H), 4.64 (m, 2H), 4.17 (d, J = 15.0 Hz, 1H) , 3.82 (s, 3H), 2.99 (m, 2H), 2.51-2.33 (m, 2H), 2.17-1.96 (m, 2H), 1.79-1.70 (m, 4H).

實施例4：5-(苄氧基)-2-(2,2-二苯基丙醯基)-6-甲氧基-1,2,3,4-四氫異喹啉-3-羧酸的製備Example 4: 5-(Benzyloxy)-2-(2,2-diphenylpropanyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate Acid preparation

5-(苄氧基)-2-(2,2-二苯基丙醯基)-6-甲氧基-1,2,3,4-四氫異喹啉-3-羧酸的製備方法參照實施例1。MS m/z(ESI)：522.3[M+H]+； 1H NMR(400MHz,CDCl3)δ 7.53-7.43(m,2H),7.43-7.26(m,12H),7.24-7.12(m,1H),6.55(d,J=8.4Hz,1H),6.01(d,J=8.3Hz,1H),4.98(dd,J=25.7,11.2Hz,1H),4.89(d,J=11.0Hz,1H),4.78-4.65(m,1H),4.04-3.89(m,1H),3.81(s,3H),3.75(d,J=15.0Hz,1H),3.08(dt,J=23.0,11.5Hz,1H),2.98-2.82(m,1H),1.97-1.86(m,3H)。 Process for preparing 5-(benzyloxy)-2-(2,2-diphenylpropanyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Refer to Example 1. MS m/z (ESI): 522.3 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.53-7.43 (m, 2H), 7.43 - 7.26 (m, 12H), 7.24 - 7.12 (m, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.01 (d, J = 8.3 Hz, 1H), 4.98 (dd, J = 25.7, 11.2 Hz, 1H), 4.89 (d, J = 11.0 Hz, 1H), 4.78-4.65 (m, 1H), 4.04-3.89 (m, 1H), 3.81 (s, 3H), 3.75 (d, J = 15.0 Hz, 1H), 3.08 (dt, J = 23.0, 11.5 Hz) , 1H), 2.98-2.82 (m, 1H), 1.97-1.86 (m, 3H).

實施例5：2-(2,2-二苯基丙醯基)-6-甲氧基-5-((4-甲氧基-3-甲基苯甲基)氧基)-1,2,3,4-四氫異喹啉-3-羧酸的製備Example 5: 2-(2,2-Diphenylpropanyl)-6-methoxy-5-((4-methoxy-3-methylbenzyl)oxy)-1,2 , Preparation of 3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(2,2-二苯基丙醯)-6-甲氧基-5-((4-甲氧基-3-甲基苯甲基)氧基)-1,2,3,4-四氫異喹啉-3-羧酸的製備方法參照實施例1。MS m/z(ESI)：566.2[M+H]+；1HNMR(400MHz,CD3OD)：δ 7.36-7.17(m,12H),6.96-6.85(m,3H),4.13-4.10(m,3H),3.98-3.95(m,1H),3.77(s,3H),3.70(s,3H),3.66-3.59(m,1H),2.80(m,2H),2.12(s,3H),2.02(s,3H)。 2-(2,2-diphenylpropanthene)-6-methoxy-5-((4-methoxy-3-methylbenzyl)oxy)-1,2,3,4- The preparation method of tetrahydroisoquinoline-3-carboxylic acid is as described in Example 1. MS m/z (ESI): 566.2 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD): δ 7.36-7.17 (m, 12H), 6.96-6.85 (m, 3H), 4.13-4.10 (m) , 3H), 3.98-3.95 (m, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 3.66-3.59 (m, 1H), 2.80 (m, 2H), 2.12 (s, 3H), 2.02 (s, 3H).

實施例6：5-((2,3-二氫苯并呋喃-5-基)甲氧基)-2-(2,2-二苯基丙醯基)-6-甲氧基-1,2,3,4-四氫異喹啉-3-羧酸的製備Example 6: 5-((2,3-Dihydrobenzofuran-5-yl)methoxy)-2-(2,2-diphenylpropanyl)-6-methoxy-1, Preparation of 2,3,4-tetrahydroisoquinoline-3-carboxylic acid

5-((2,3-二氫苯并呋喃-5-基)甲氧基)-2-(2,2-二苯基丙醯基)-6-甲氧基-1,2,3,4-四氫異喹啉-3-羧酸的製備方法參照實施例1。MS m/z(ESI)：564.2[M+H]+；1H NMR(400MHz,MeOD)：δ 7.46-7.29(m,11H),7.19(d,J=8.4Hz,1H),7.06-7.00(m,2H),6.77(d,J=8.0Hz,1H),4.58(t,J=8.4Hz,2H),4.22(m,3H),4.05(m,1H),3.79(s,3H),3.70(m,1H),3.23(t,J=8.8Hz,2H),2.89(m,2H),2.11(s,3H)。 5-((2,3-dihydrobenzofuran-5-yl)methoxy)-2-(2,2-diphenylpropanyl)-6-methoxy-1,2,3, The preparation method of 4-tetrahydroisoquinoline-3-carboxylic acid is referred to Example 1. MS m/z (ESI): 564.2 [M+H] + ; 1 H NMR (400 MHz,MeOD): δ 7.46-7.29 (m, 11H), 7.19 (d, J = 8.4 Hz, 1H), 7.06-7. (m, 2H), 6.77 (d, J = 8.0 Hz, 1H), 4.58 (t, J = 8.4 Hz, 2H), 4.22 (m, 3H), 4.05 (m, 1H), 3.79 (s, 3H) , 3.70 (m, 1H), 3.23 (t, J = 8.8 Hz, 2H), 2.89 (m, 2H), 2.11 (s, 3H).

生物活性測試Biological activity test 一、試驗試劑與儀器First, test reagents and instruments

1.儲存液(500mL)1. Storage solution (500mL)

1)50mM Tris：取25mL1M Tris(Sigma T2663)用蒸餾水稀釋為500mL備用；2)100mM NaCl：取10mLof 5M NaCl(購自西格瑪(Sigma))蒸餾水稀釋為500mL備用；3)5mM MgCl2：取2.5mLof 1M(購自Fluka)蒸餾水稀釋為500mL備用。 1) 50 mM Tris: Take 25 mL of 1 M Tris (Sigma T2663) diluted with distilled water to 500 mL for use; 2) 100 mM NaCl: 10 mL of 5 M NaCl (purchased from Sigma) diluted with distilled water to 500 mL for use; 3) 5 mM MgCl 2 : 2.5 The mLof 1M (purchased from Fluka) distilled water was diluted to 500 mL for use.

2.工作液(50mL)2. Working fluid (50mL)

1)取以上儲存液50mL，加入0.1% BSA和不含EDTA的蛋白酶抑制劑1片(購自羅氏Roche)。 1) 50 mL of the above stock solution was taken, and 1 piece of 0.1% BSA and EDTA-free protease inhibitor (purchased from Roche Roche) was added.

2)384孔Opti-Plate檢測板購自珀金埃爾默股份有限公司(Perkin Elmer，PE)。 2) The 384-well Opti-Plate assay plate was purchased from Perkin Elmer, PE.

3)碘標記配體：Sar1-Ile8-AngII,[125I]：購自PE(50uCi)。加1mL無菌水溶解為50uCi/mL儲存液，2200Ci/mmol。工作液濃度為0.1nM，-20℃凍存備用。 3) Iodine-labeled ligand: Sar1-Ile8-AngII, [ 125I ]: purchased from PE (50uCi). Add 1 mL of sterile water to dissolve into 50 uCi / mL stock solution, 2200 Ci / mmol. The working solution concentration was 0.1 nM, and stored at -20 ° C for use.

3.試驗儀器3. Test equipment

1)SPA閃爍微珠：購自珀金埃爾默股份有限公司(Perkin Elmer，PE)用20mL工作液溶解成25mg/mL儲存液，工作液最終濃度為250ug beads/well/25uL。 1) SPA scintillation beads: purchased from Perkin Elmer (PE) and dissolved into 25 mg/mL stock solution with 20 mL working solution. The final concentration of the working solution was 250 ug beads/well/25 uL.

2)384 well Opti-Plate(購自PE)。 2) 384 well Opti-Plate (available from PE).

3)自動分液器：Multidrop(Thermo Fisher)。 3) Automatic dispenser: Multidrop (Thermo Fisher).

4)檢測分析儀器：ViewLux 1430 ultraHTS Microplate Imager(Perkin Elmer)。 4) Detection and analysis instrument: ViewLux 1430 ultraHTS Microplate Imager (Perkin Elmer).

二、試驗步驟Second, the test steps

本發明採用鄰近閃爍分析(SPA)技術來檢測化合物對AT2的抑制活性，碘標記AT2配體：Sar1-Ile8-AngII,[125I]，SPA微珠及384孔檢測板均購自PE公司(PE(50uCi))。檢測分析儀器：ViewLux 1430 ultraHTS Microplate Imager(Perkin Elmer)。試驗步驟如下： 1.將化合物包括質控陽性化合物接到384孔實驗板中(Optiplate)2.將工作液、微珠混合到離心管中，室溫避光孵育混合1小時，搖床混勻；3.用自動分液器Multidrop將步驟2中的預混合的微珠加入到實驗板中(25uL/孔)；4.用封蓋薄膜迅速密封實驗板，避光室溫混合孵育1小時(搖床混勻)；5.用自動分液器(Multidrop)在每孔中加入25uL的顯影劑(tracer)；6.用封蓋薄膜迅速密封實驗板，避光室溫混合孵育過夜，搖床混勻；7.第二天早上，離心實驗板，使微珠沉澱到板底；8.將實驗板放入ViewLux，檢測、讀數分析，計算IC50。 The present invention uses the proximity scintillation analysis (SPA) technique to detect the inhibitory activity of the compound on AT 2 , the iodine-labeled AT 2 ligand: Sar1-Ile8-AngII, [ 125 I], SPA microbeads and 384-well assay plates are all purchased from PE. Company (PE (50uCi)). Detection and analysis instrument: ViewLux 1430 ultraHTS Microplate Imager (Perkin Elmer). The test procedure is as follows: 1. Connect the compound including the quality control positive compound to the 384-well experimental plate (Optiplate). 2. Mix the working solution and the microbead into the centrifuge tube, incubate at room temperature for 1 hour in the dark, and mix by shaker. 3. The premixed microbeads from step 2 were added to the experimental plate (25 uL/well) using an automatic dispenser Multidrop; 4. The test plates were quickly sealed with a capping film and incubated for 1 hour at room temperature in the dark ( Shake the bed to mix); 5. Add 25uL of developer (tracer) to each well with an automatic dispenser (Multidrop); 6. Quickly seal the test plate with a cover film, incubate at room temperature overnight, shaker Mixing; 7. The next morning, centrifuge the plate to precipitate the beads to the bottom of the plate; 8. Place the plate into ViewLux, test, read and analyze, calculate IC 50 .

三、試驗結果：Third, the test results:

本發明實施例化合物及陽性對照化合物(EMA-400，參照US5246943實施例20製備得到)的生化學活性藉由以上的試驗進行測定，測得的IC50值見下表。 The biochemical activity of the compound of the present invention and the positive control compound (EMA-400, prepared in accordance with Example 20 of US Pat. No. 5,246,943) was determined by the above test, and the IC 50 values measured are shown in the following table.

本發明其它實施例化合物hAT2 IC50值與上述實施例的效果類似，表現出了近似的抑制活性和規律。 The compound hAT2 IC50 values of the other examples of the present invention are similar to those of the above examples, exhibiting approximate inhibitory activities and laws.

結論：本發明實施例化合物相對於陽性對照化合物，部分化合物對hAT2表現出很強的抑制活性，提高了一倍以上的抑制效果。 Conclusion: The compounds of the examples of the present invention showed strong inhibitory activity against hAT 2 relative to the positive control compound, and the inhibitory effect was more than doubled.

對於hAT1的抑制活性，與陽性對照化合物一樣均表現為大於5000nM的抑制活性。 The inhibitory activity against hAT 1 showed an inhibitory activity of more than 5000 nM as with the positive control compound.

綜上所述，本發明實施例化合物對於hAT2與hAT1的抑制效果相應也具有更高的選擇性，更加適合hAT2疾病的藥學或臨床上的應用。 In summary, the compounds of the present invention have higher selectivity for the inhibitory effect of hAT 2 and hAT 1 , and are more suitable for the pharmaceutical or clinical application of hAT 2 disease.

Claims (16)

一種具有如下式(I)結構的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽， 其中：R1、R2、R3各自獨立的選自氘、鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11，或者R1與R2、R1與R3、R2與R3和直接相連的碳原子一起形成C3-8環烷基或3-8員雜環基，該雜原子選自O、S、N，視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、鹵取代C1-8烷基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳 基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；R4選自氫、氘、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、鹼金屬、鹼土金屬或銨，視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、鹵取代C1-8烷基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；R5、R6、R9、R10各自獨立的選自氫、氘、鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11，視需要進一步被一個或多個選自鹵 素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；R7、R8各自獨立的選自氫、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基或5-10員雜芳基，視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代，視需要再進一步的被一個或多個選自鹵素、羥基、巰基、氰基、硝基、乙醯胺基、疊氮基、磺醯基、甲磺醯基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C1-8烷氧基、C1-8烷氧羰基、C1-8烷基羰基、C1-8烷基羰基氧基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、 C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、胺基、C1-8烷基單取代胺基或C1-8烷基雙取代胺基的取代基所取代；R12選自氫、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C1-8烷氧基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、C1-8烷基醯基、C1-8烷基胺基或C1-8烷基醯胺基，視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、乙醯胺基、疊氮基、磺醯基、甲磺醯基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C1-8烷氧基、C1-8烷氧羰基、C1-8烷基羰基、C1-8烷基羰基氧基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、胺基、C1-8烷基單取代胺基或C1-8烷基雙取代胺基的取代基所取代；R11、R13、R14選自氫、氘、C1-8烷基、C3-8環烷基、鹵取代C1-8烷基、羥取代C1-8烷基、苯基或對甲基苯基；r為0、1、2。 A 1,2,3,4-tetrahydroisoquinoline derivative having the structure of the following formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Wherein: R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrazine, halogen, hydroxy, fluorenyl, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2 -8 alkynyl group, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclic thio group, C at 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 - OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N( R 13 )-C(O)OR 11 , or R 1 and R 2 , R 1 and R 3 , R 2 and R 3 together with a directly bonded carbon atom form a C 3-8 cycloalkyl group or a 3-8 member hetero a cyclic group, the hetero atom is selected from O, S, N, and further optionally one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 alkyl, C 2 - 8 alkenyl, C 2-8 alkynyl, halo substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3- 8-membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-1 0 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0- 8 -NR 13 R 14, -C 0-8 -C (O) NR 13 R 14, -N (R 13) -C (O) R 12 or -N (R 13) -C (O ) oR 11 is Substituted by a substituent; R 4 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic ring a C 5-10 aryl group, a 5-10 membered heteroaryl group, an alkali metal, an alkaline earth metal or an ammonium, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3 -8 membered heterocyclooxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 member heteroaryl Base, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 ,- Substituted by a substituent of N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 ; R 5 , R 6 , R 9 , R 10 are each independently selected from hydrogen, Anthracene, halogen, hydroxy, decyl, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3 -8-membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclic thio group, C 5-10 aryl, C 5-10 aryloxy, C 5-10 aryl sulfur Base, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 - OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 , further as needed One or more selected from the group consisting of halogen, hydroxy, decyl, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5 10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C( O) Substituted by a substituent of OR 11 ; R 7 and R 8 are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 ring alkyl, 3-8 membered heterocyclyl, C 5-10 aryl or 5-10 membered heteroaryl group, optionally further substituted by one or more substituents selected from halo, hydroxy, mercapto, cyano, nitro, azido , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 member heteroaryl Alkoxy group, 5-10 membered heteroarylthio group, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14, -N (R 13) -C (O) R 12 or -N (R 13) -C (O ) oR 11, substituted by a substituent, still further optionally substituted by one or more substituents selected from halogen, hydroxy , 巯基, Group, nitro group, acetyl group, azido group, sulfo acyl, methanesulfonic acyl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 1-8 alkoxy, C 1-8 alkoxycarbonyl, C 1-8 alkylcarbonyl, C 1-8 alkylcarbonyloxy, 3-8 member Heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5 Substituted by a substituent of a 10-membered heteroaryloxy group, a 5-10 membered heteroarylthio group, an amine group, a C 1-8 alkyl monosubstituted amine group or a C 1-8 alkyl disubstituted amine group; 12 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 1-8 alkoxy , 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryl group, 5-10-membered heteroaryl group, acyl C 1-8 alkyl, C 1-8 alkylamino C 1-8 alkyl or acyl group, optionally further substituted by one or more substituents selected from halo, hydroxy, mercapto, cyano, nitro, acetyl amino, azido, acyl sulfonamide, methanesulfonamide acyl, C 1-8 Group, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 1-8 alkoxy, C 1-8 alkoxycarbonyl, C 1-8 alkylcarbonyl, C 1-8 alkylcarbonyloxy, 3-8 membered heterocyclic oxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryl Alkoxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amine, C 1-8 alkyl Substituted by a monosubstituted amino group or a C 1-8 alkyl disubstituted amine group; R 11 , R 13 , R 14 are selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl, Halogen substituted C 1-8 alkyl, hydroxy substituted C 1-8 alkyl, phenyl or p-methylphenyl; r is 0, 1, 2. 如申請專利範圍第1項所述的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，其中，該立體異構體是指1-、3-、4-或2’-位包含立體構型，可分別為R-構型或S-構型， The 1,2,3,4-tetrahydroisoquinoline derivative, the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to the first aspect of the invention, wherein the stereoisomer is 1- , the 3-, 4- or 2' -positions comprise a stereo configuration, which may be in the R-configuration or the S-configuration, respectively. 如申請專利範圍第2項所述的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，其中，該立體異構體是指“3R-”或“3S-”立體異構體。 The 1,2,3,4-tetrahydroisoquinoline derivative, the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 2, wherein the stereoisomer means "3R" -" or "3S-" stereoisomers. 如申請專利範圍第1項所述的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，其中，R5、R6、R9、R10各自獨立的選自氫、氘、鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-4烷基、鹵取代C1-4烷基、C2-4鏈烯基、C2-4鏈炔基、C3-6環烷基、3-6員雜環基、3-6員雜環基氧基、3-6員雜環基硫基、C5-8芳基、C5-8芳基氧基、C5-8芳基硫基、5-8員雜芳基、5-8員雜芳基氧基、5-8員雜芳基硫基、-C0-4-S(O)rR11、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11；視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、 -C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代。 The 1,2,3,4-tetrahydroisoquinoline derivative, the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to the first aspect of the invention, wherein R 5 , R 6 , R 9 , R 10 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, decyl, cyano, nitro, azide, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 2-4 alkenyl , C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylthio, C 5-8 , C 5-8 aryloxy, C 5-8 arylthio, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, 5-8 membered heteroarylthio, -C 0-4 -S(O)rR 11 , -C 0-4 -OR 11 , -C 0-4 -C(O)OR 11 , -C 0-4 -C(O)R 12 , -C 0- 4 -OC(O)R 12 , -C 0-4 -NR 13 R 14 , -C 0-4 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or- N(R 13 )-C(O)OR 11 ; further optionally one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 alkyl, C 2-8 Alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5 -10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-1 0 member heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 ,- C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 ,- Substituents of C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 are substituted. 如申請專利範圍第1項所述的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，其中，R4選自氫、氘、C1-8烷基、鹵取代C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、鹼金屬、鹼土金屬或銨；R5、R6、R9、R10各自獨立的選自氫、氘、氟、氯、羥基、巰基、氰基、硝基、疊氮基、甲基、乙基、異丙基、三氟甲基、乙烯基、烯丙基、乙炔基、環丙基、吡啶基、四氫呋喃基、嗎啉基、苯基、甲氧基、乙氧基、異丙氧基、苄氧基、磺醯基、甲磺醯基、異丙磺醯基、對甲苯磺醯基、甲氧羰基、乙氧羰基、異丙氧羰基、乙醯基、乙醯氧基、胺基、二甲胺基、乙醯胺基或二甲胺基羰基。 The 1,2,3,4-tetrahydroisoquinoline derivative, the stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R 4 is selected from the group consisting of hydrogen, hydrazine, and C. 1-8 alkyl, halo substituted C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5 10 aryl, 5-10 membered heteroaryl, alkali metal, alkaline earth metal or ammonium; R 5 , R 6 , R 9 , R 10 are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, hydroxyl, thiol, cyano , nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, Methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl Ethylene, ethoxylated, amine, dimethylamino, etidinyl or dimethylaminocarbonyl. 如申請專利範圍第1項所述的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，其中，R4選自氫、氘、甲基、乙基、異丙基、三氟甲基、環丙基、環己基、苯基、鹼金屬、鹼土金屬或銨；R5、R6、R9、R10各自獨立的選自氫、氘、氟、甲基、乙基、異丙基、三氟甲基、環丙基、甲氧基、乙氧基、異丙氧基、甲氧羰基、乙氧羰基、異丙氧羰基、乙醯基、乙醯氧基、胺基或二甲胺基。 The 1,2,3,4-tetrahydroisoquinoline derivative, the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R 4 is selected from the group consisting of hydrogen, hydrazine, and A a group, an ethyl group, an isopropyl group, a trifluoromethyl group, a cyclopropyl group, a cyclohexyl group, a phenyl group, an alkali metal, an alkaline earth metal or an ammonium; and R 5 , R 6 , R 9 and R 10 are each independently selected from the group consisting of hydrogen,氘, fluorine, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, B Mercapto, ethoxylated, amine or dimethylamino. 如申請專利範圍第1項所述的1,2,3,4-四氫異喹啉衍生 物、其立體異構體或其藥學上可接受鹽，係選自如下式(II)化合物： 其中，R4選自氫、氘、甲基、乙基、異丙基、三氟甲基、環丙基、環己基、苯基、鹼金屬、鹼土金屬或銨；R15選自氫、鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、鹵取代C1-8烷基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11；m選自0、1、2、3、4或5。 The 1,2,3,4-tetrahydroisoquinoline derivative, the stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of the following compounds of the formula (II): Wherein R 4 is selected from the group consisting of hydrogen, hydrazine, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclohexyl, phenyl, alkali metal, alkaline earth metal or ammonium; and R 15 is selected from the group consisting of hydrogen and halogen. , hydroxy, decyl, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, halo substituted C 1-8 alkyl, C 2-8 alkynyl, C 3 8 -cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 ; m is selected from 0, 1, 2, 3, 4 or 5. 如申請專利範圍第7項所述的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，其中，R2、R3各自獨立的選自氘、鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、 5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11，或者，R2與R3和直接相連的碳原子一起形成C3-8環烷基，視需要進一步被一個或多個選自鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、鹵取代C1-8烷基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12或-N(R13)-C(O)OR11的取代基所取代；R4選自氫、甲基、乙基、異丙基、三氟甲基、環丙基、鈉、鉀、鈣或銨；R15選自氫、氟、氯、羥基、巰基、氰基、硝基、疊氮基、甲基、乙基、異丙基、三氟甲基、乙烯基、烯丙基、乙炔基、環丙基、吡啶基、四氫呋喃基、嗎啉基、苯基、甲氧基、乙氧基、異丙氧基、苄氧基、磺醯基、甲磺醯基、異丙磺醯基、對甲苯磺醯基、甲氧羰基、乙氧羰基、異丙氧羰基、乙醯基、乙醯氧基、胺基、二甲胺基、乙醯胺基或二甲胺基羰基； m選自0、1、2、3、4或5。 The 1,2,3,4-tetrahydroisoquinoline derivative, the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 7, wherein R 2 and R 3 are each independently selected. From hydrazine, halogen, hydroxy, decyl, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group, C 5-10 aryl group, C 5-10 aryloxy group, C 5-10 aryl group Thio group, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy group, 5-10 membered heteroarylthio group, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C(O)R 12 or -N(R 13 )-C(O)OR 11 , or, R 2 together with R 3 and a directly attached carbon atom to form a C 3-8 cycloalkyl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic ring Alkoxy group, 3-8 membered heterocyclic thio group C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryl group, 5-10-membered heteroaryl Sulfur group, -C 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -N(R 13 )-C( O) is substituted with a substituent of R 12 or -N(R 13 )-C(O)OR 11 ; R 4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, sodium , potassium, calcium or ammonium; R 15 is selected from the group consisting of hydrogen, fluorine, chlorine, hydroxyl, sulfhydryl, cyano, nitro, azide, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, alkene Propyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methanesulfonyl, iso Propisulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, ethyl hydrazine, ethoxylated, amine, dimethylamino, acetamino or dimethylamino a carbonyl group; m is selected from 0, 1, 2, 3, 4 or 5. 如申請專利範圍第7項所述的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，其中，R2、R3各自獨立的選自氘、鹵素、羥基、巰基、氰基、硝基、疊氮基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、鹵取代C1-8烷基、C3-8環烷基、3-8員雜環基、3-8員雜環基氧基、3-8員雜環基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、-C0-8-S(O)rR10、-C0-8-O-R10、-C0-8-C(O)OR10、-C0-8-C(O)R11、-C0-8-O-C(O)R11、-C0-8-NR12R13、-C0-8-C(O)NR12R13、-N(R13)-C(O)R11或-N(R13)-C(O)OR10，或者，R2與R3和直接相連的碳原子一起形成C3-8環烷基，視需要進一步被一個或多個選自氟、氯、羥基、巰基、氰基、硝基、疊氮基、甲基、乙基、異丙基、三氟甲基、乙烯基、烯丙基、乙炔基、環丙基、吡啶基、四氫呋喃基、嗎啉基、苯基、甲氧基、乙氧基、異丙氧基、苄氧基、磺醯基、甲磺醯基、異丙磺醯基、對甲苯磺醯基、甲氧羰基、乙氧羰基、異丙氧羰基、乙醯基、乙醯氧基、胺基、二甲胺基、乙醯胺基或二甲胺基羰基的取代基所取代；R4選自氫、鈉、鉀、鈣或銨；R15選自氫、氟、氯、羥基、巰基、氰基、硝基、 疊氮基、甲基、乙基、異丙基、三氟甲基、乙烯基、烯丙基、乙炔基、環丙基、吡啶基、四氫呋喃基、嗎啉基、苯基、甲氧基、乙氧基、異丙氧基、苄氧基、磺醯基、甲磺醯基、異丙磺醯基、對甲苯磺醯基、甲氧羰基、乙氧羰基、異丙氧羰基、乙醯基、乙醯氧基、胺基、二甲胺基、乙醯胺基或二甲胺基羰基；m選自0、1、2、3、4或5。 The 1,2,3,4-tetrahydroisoquinoline derivative, the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 7, wherein R 2 and R 3 are each independently selected. From hydrazine, halogen, hydroxy, decyl, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group, C 5-10 aryl group, C 5-10 aryl group Oxyl, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 10 , -C 0-8 -OR 10 , -C 0-8 -C(O)OR 10 , -C 0-8 -C(O)R 11 , -C 0-8 -OC(O)R 11 , -C 0-8 -NR 12 R 13 , -C 0-8 -C(O)NR 12 R 13 , -N(R 13 )-C(O)R 11 or -N(R 13 )-C (O)OR 10 , or R 2 and R 3 together with a directly attached carbon atom form a C 3-8 cycloalkyl group, optionally further selected from one or more selected from the group consisting of fluorine, chlorine, hydroxyl, sulfhydryl, cyano, Nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, Base, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl Substituted with a substituent of isopropoxycarbonyl, ethyl hydrazino, ethoxylated, amine, dimethylamino, acetamino or dimethylaminocarbonyl; R 4 is selected from the group consisting of hydrogen, sodium, potassium, calcium Or ammonium; R 15 is selected from the group consisting of hydrogen, fluorine, chlorine, hydroxyl, sulfhydryl, cyano, nitro, azide, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, acetylene Base, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methanesulfonyl, isopropylsulfonyl , p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, ethyl hydrazine, ethoxylated, amine, dimethylamino, acetaminophen or dimethylaminocarbonyl; From 0, 1, 2, 3, 4 or 5. 如申請專利範圍第7項所述的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽，係選自如下化合物： The 1,2,3,4-tetrahydroisoquinoline derivative, the stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 7, is selected from the group consisting of the following compounds: 一種申請專利範圍第1至10項中任一項所述的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽的製備方法，包括如下步驟： X選自羥基或鹵素。 A method for producing a 1,2,3,4-tetrahydroisoquinoline derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which comprises the following step: X is selected from a hydroxyl group or a halogen. 如申請專利範圍第11項所述的製備方法，其中，X選自羥基或氯。 The production method according to claim 11, wherein X is selected from a hydroxyl group or chlorine. 如申請專利範圍第11項所述的製備方法，其中，該縛酸劑為有機鹼或無機鹼，該有機鹼選自三甲胺、三乙胺、吡啶、哌啶、嗎啉或其混合物，該無機鹼選自碳酸鉀、碳酸鈉、碳酸銫、碳酸氫鈉、碳酸氫鉀、氫氧化鈉，氫氧化鉀，氫氧化鋰，醋酸鈉或其混合物；該縮合劑選自DIC、DCC、HOBT、EDC．HCl、PyBOP、PyBroP、HATU、HCTU、DEPBT、EEDQ、CDI或其混合物。 The preparation method according to claim 11, wherein the acid binding agent is an organic base or an inorganic base, and the organic base is selected from the group consisting of trimethylamine, triethylamine, pyridine, piperidine, morpholine or a mixture thereof. The inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate or a mixture thereof; the condensing agent is selected from the group consisting of DIC, DCC, HOBT, EDC. HCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI or mixtures thereof. 一種醫藥組成物，其包括治療有效劑量的如申請專利範圍第1至10項中任一項所述的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽及可藥用的載體。 A pharmaceutical composition comprising a therapeutically effective amount of a 1,2,3,4-tetrahydroisoquinoline derivative, a stereoisomer thereof, or a stereoisomer thereof, according to any one of claims 1 to 10 A pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. 一種申請專利範圍第1至10項中任一項所述的1,2,3,4-四氫異喹啉衍生物、其立體異構體或其藥學上可接受鹽、或申請專利範圍第14項所述的醫藥組成物的用途，係用在製備用於治療、預防或緩解對象的神經病或神經性疼痛的藥物。 A 1,2,3,4-tetrahydroisoquinoline derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, or a patent application scope The use of the pharmaceutical composition according to item 14 is for the preparation of a medicament for treating, preventing or ameliorating a neuropathy or neuropathic pain in a subject. 如申請專利範圍第15項所述的用途，其中，該神經病為原發性神經病、繼發性神經病、周圍神經病、由機械性神經損傷或生化神經損傷引起的神經病、疼痛性糖尿病神經病(PDN)或相關神經性疾病。 The use according to claim 15, wherein the neuropathy is a primary neuropathy, a secondary neuropathy, a peripheral neuropathy, a neuropathy caused by a mechanical nerve injury or a biochemical nerve injury, and a painful diabetic neuropathy (PDN). Or related neurological diseases.
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