WO2017036318A1 - 1,2,3,4-四氢异喹啉衍生物、其制备方法和应用 - Google Patents

1,2,3,4-四氢异喹啉衍生物、其制备方法和应用 Download PDF

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WO2017036318A1
WO2017036318A1 PCT/CN2016/096167 CN2016096167W WO2017036318A1 WO 2017036318 A1 WO2017036318 A1 WO 2017036318A1 CN 2016096167 W CN2016096167 W CN 2016096167W WO 2017036318 A1 WO2017036318 A1 WO 2017036318A1
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group
membered
alkyl
cycloalkyl
aryl
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PCT/CN2016/096167
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English (en)
French (fr)
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孙广俊
马建斌
谭松良
高鹏
李成海
包如迪
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上海翰森生物医药科技有限公司
江苏豪森药业集团有限公司
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Priority to CN201680050320.5A priority Critical patent/CN107922340B/zh
Publication of WO2017036318A1 publication Critical patent/WO2017036318A1/zh

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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

Definitions

  • 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.
  • Neuropathic pain is a chronic painful disease caused by primary damage or dysfunction of the nervous system.
  • the most common types of neuropathic pain include diabetic neuropathic pain (DNP), postherpetic neuralgia (PHN and AIDS-related neuropathic pain.
  • DNP diabetic neuropathic pain
  • PPN postherpetic neuralgia
  • 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.
  • the treatment of neuropathic pain mainly includes anticonvulsants. Antidepressants, narcotic analgesics and local anesthetics.
  • Standard treatments such as Pfizer's anticonvulsant Lyrica, which is effective in treating nociceptive pain, but has limited treatment for neuropathic pain. And with serious side effects, including cognitive changes, sedation, nausea, and drug resistance and dependence. Therefore, it is necessary to provide a drug that can effectively treat and prevent neuropathic pain with fewer side effects.
  • the pathological mechanism is still not very clear. The study suggests that the sensitizing interaction between nociceptors and spinal dorsal horn may be The basis for the development of neuropathic pain.
  • the renin-angiotensin system exists not only in the circulation, but also in many tissues and organs such as the cardiovascular, renal, and brain, and functions through autocrine and paracrine.
  • RAS produces a biological effect by binding angiotensin II (Ang II) to an angiotensin receptor.
  • Ang II angiotensin II
  • AT1 angiotensin II receptor type I receptor
  • AT2 angiotensin II receptor type II receptor
  • 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.
  • AngII and AngII receptor AT2 are elevated in vivo, and AT2 is often co-expressed with pain signal molecules (such as substance P, TRPV1).
  • pain signal molecules such as substance P, TRPV1
  • the agent 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 better town.
  • the painful effect is particularly effective in the treatment of neuropathic pain including diabetic neuropathic pain (DNP) and postherpetic neuralgia (PHN).
  • DNP diabetic neuropathic pain
  • PPN postherpetic neuralgia
  • 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
  • PDN neuropathy
  • 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,
  • 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, 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 -
  • R 1 and R 2 , R 1 and R 3 , R 2 and R 3 together with the directly attached carbon atom form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclic group selected from O. , S, N,
  • 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, C 5 - 10 aryl, 5-10 membered heteroaryl, alkali metal, alkaline earth metal or 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 heterocyclic ring Alkoxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 Nonheteroaryloxy
  • R 5 , R 6 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, deuterium, 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, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 , 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)OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8
  • 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 cycloalkyl, 3-8 membered heterocyclic group. , C 5-10 aryl or 5-10 membered heteroaryl, 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 group, C 2-8 alkynyl group, C 3-8 cycloalkyl group, 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 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroaryl Thiothio group, -C 0-8 -
  • R 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 heterocyclyl, C 1-8 alkane Oxyl, 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 1-8 alkyl acyl, C 1-8 alkylamino or C 1-8 alkyl amide , optionally further selected from one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, acetamido, azide, sulfonyl, methylsulfonyl, C 1-8 alkyl, C 2-8 chain Alkenyl, C 2-8 alky
  • R 11 , R 13 and 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 0, 1, 2.
  • the 1,2,3,4-tetrahydroisoquinoline derivative of the structure of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is Refers to 1-, 3-, 4- or 2 , - position contains stereo configuration, which can be R-configuration or S-configuration, respectively. or Preferred are "3R-" or "3S-" stereoisomers.
  • the 1,2,3,4-tetrahydroisoquinoline derivative of the structure 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 ,
  • 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).
  • the 1,2,3,4-tetrahydroisoquinoline derivative of the structure 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, methylsulfonyl, isopropylsulfonate Acyl, p-toluenesulfonyl, methoxycarbonyl, ethoxy
  • 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).
  • R 10 is independently selected from the group consisting of hydrogen, hydrazine, fluorine, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, isopropoxy, methoxycarbonyl. , ethoxycarbonyl, isopropoxycarbonyl, acetyl, acetoxy, amino 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 and r are as defined for the compound of the formula (I).
  • the 1,2,3,4-tetrahydroisoquinoline derivative of the structure of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following formula (II) ) Compound:
  • 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 15 is selected from the group consisting of hydrogen, halogen, hydroxy, decyl, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, halogen 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
  • n 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).
  • 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, 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 membered heteroaryl, 5-10 membered heteroaryloxy Base, 5-10 membered heteroarylthio group, -
  • 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, hydroxy, decyl, cyano, nitro, azide, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, ring Propyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methylsulfonyl, isopropylsulfonyl, p-toluenesulfonyl, Methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl, acetoxy, amino, dimethylamino, acetylamino 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.
  • the directly linked carbon atoms together form a C 3-8 cycloalkyl group, optionally further one or more selected from the group consisting of fluorine, chlorine, hydroxyl, sulfhydryl, cyano, nitro, azide, methyl, ethyl, iso Propyl, trifluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy Base, sulfonyl, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxy
  • 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, hydroxy, decyl, cyano, nitro, azide, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, ring Propyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methylsulfonyl, isopropylsulfonyl, p-toluenesulfonyl, Methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl, acetoxy, amino, dimethylamino, acetylamino 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.
  • the 1,2,3,4-tetrahydroisoquinoline derivative of the structure of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:
  • 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 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 ,
  • 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, hydroxy, decyl, cyano, nitro, azide, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, ring Propyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methylsulfonyl, isopropylsulfonyl, p-toluenesulfonyl, Methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl, acetoxy, amino, dimethylamino, acetylamino 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.
  • 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, 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
  • 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, hydroxy, decyl, cyano, nitro, azide, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, ring Propyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methylsulfonyl, isopropylsulfonyl, p-toluenesulfonyl, Methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl, acetoxy, amino, dimethylamino, acetylamino 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.
  • the 1,2,3,4-tetrahydroisoquinoline derivative of the structure of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:
  • 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 is selected from a hydroxyl group or a halogen, preferably a hydroxyl group or a 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 such as the compound of the formula (I) definition.
  • the acid binding agent is an organic base or an inorganic base
  • 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 carbonic acid.
  • 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.
  • Another aspect of the invention provides a pharmaceutical composition
  • 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.
  • 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.
  • PDN painful diabetic neuropathy
  • 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, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 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, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhex
  • 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 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 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(
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and "C 3-8 cycloalkyl” refers to a cycloalkyl group of 3 to 8 carbon atoms, "5-10 membered ring.”
  • Alkyl means a cycloalkyl group of 5 to 10 carbon atoms, for example:
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like.
  • 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:
  • 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 ⁇ -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:
  • 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:
  • 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, tetrahydrogen Naphthyl, benzocycloheptyl and the like.
  • 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, azide.
  • 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
  • the "3-8 membered heterocyclic group” means a ring group containing 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • 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:
  • 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.
  • r is an integer of 0, 1, 2
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, and non-limiting examples of fused heterocyclic groups include:
  • 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:
  • 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:
  • 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, azide.
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated ⁇ -electron system (ie, having a ring adjacent to a carbon atom) a group
  • C 5-10 aryl means an all-carbon aryl group having 5 to 10 carbons
  • 5-10 membered aryl group means an all-carbon aryl group having 5 to 10 carbons, such as phenyl and Naphthyl.
  • 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:
  • the aryl group can be substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido group, 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 a heterocyclic heterothio group, a C 5-10 aryl group, a C 5-10 aryloxy group, a C 5-10 arylthio group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group, 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
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O) r (where r is an integer 0, 1, 2), 5-
  • a 7-membered heteroaryl group means a heteroaromatic system having 5 to 7 ring atoms
  • a 5-10 membered heteroaryl group means a heteroaromatic system having 5 to 10 ring atoms, such as furyl, thienyl, pyridyl, Pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may 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:
  • 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, azide.
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons. base.
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons. base.
  • vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like are examples of the alkenyl group.
  • Alkenyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido group, 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 a heterocyclic heterothio group, a C 5-10 aryl group, a C 5-10 aryloxy group, a C 5-10 arylthio group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group, 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
  • Alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond
  • C2-8 alkynyl refers to a straight or branched alkynyl group containing from 2 to 8 carbons.
  • ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • Alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido group, 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 a heterocyclic heterothio group, a C 5-10 aryl group, a C 5-10 aryloxy group, a C 5-10 arylthio group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group, 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
  • Alkoxy means -O-(alkyl) wherein alkyl is as defined 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.
  • 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, 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 0-8 -S(O) r R 11 , -C 0-8 -OR 11 , -C 0-8 -C(O)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
  • Halo-substituted C 1-8 alkyl means a hydrogen on the alkyl group optionally substituted with 1-8 carbon alkyl groups substituted by fluorine, chlorine, bromine or iodine atoms, such as difluoromethyl, dichloromethyl Base, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
  • the hydrogen on the "halo-substituted C 1-8 alkoxy" alkyl group is optionally a 1-8 carbon alkoxy group substituted with a fluorine, chlorine, bromine or iodine atom.
  • a fluorine chlorine, bromine or iodine atom.
  • Halogen means fluoro, chloro, bromo or iodo.
  • condensing agent means an agent capable of causing a condensation reaction. Condensation reaction refers to the interaction of two or more organic molecules to form a macromolecule by covalent bond, while losing water or other relatively simple inorganic or The reaction of small organic molecules.
  • the small molecular substance is usually water, hydrogen chloride, methanol or acetic acid.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted 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 amino 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.
  • “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, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) 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 ) internally labeled as tetramethylsilane (TMS).
  • LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer. HPLC The assay was performed 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).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification for TLC is 0.15mm ⁇ 0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • 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.
  • the solution in the examples means an aqueous solution unless otherwise specified.
  • the temperature of the reaction is room temperature.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • TLC thin layer chromatography
  • LC-MS liquid chromatography-mass spectrometry
  • 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
  • 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.
  • the 384-well Opti-Plate assay plate was purchased from Perkin Elmer, PE.
  • 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 fluid concentration is 0.1 nM, and it is stored at -20 degrees for use.
  • SPA scintillation beads purchased from Perkin Elmer, PE, dissolved in 25 mg/mL stock solution with 20 mL working solution, and the final concentration of the working solution was 250 ugbeads/well/25 uL.
  • Detection and analysis instrument ViewLux 1430 ultraHTS Microplate Imager (Perkin Elmer).
  • 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:
  • step 2 The premixed microbeads in step 2 were added to the experimental plate (25 uL/well) using an automatic dispenser Multidrop;
  • test plate 4. Quickly seal the test plate with a cover film, incubate at room temperature for 1 hour (shake bed);
  • test plate Quickly seal the test plate with a capping film, incubate overnight at room temperature, and mix well on a shaker;
  • hAT 2 IC 50 values of the compounds of other examples of the present invention are similar to those of the above examples, exhibiting approximate inhibitory activities and laws.
  • the inhibitory activity against hAT 1 showed an inhibitory activity of more than 5000 nM as with the positive control compound.
  • 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.

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Abstract

提供了一种具有式(I)结构的1,2,3,4-四氢异喹啉衍生物、其制备方法和应用。该式(I)化合物可用于原发性神经病、继发性神经病、周围神经病、由机械性神经损伤或生化神经损伤引起的神经病、疼痛性糖尿病神经病(PDN)或相关神经性疾病药物的开发，具有广阔的应用前景。

Description

1,2,3,4-四氢异喹啉衍生物、其制备方法和应用 技术领域
本发明属于药物开发领域，具体涉及1,2,3,4-四氢异喹啉衍生物、其制备方法和应用。
背景技术
神经性疼痛是一种由神经系统原发损害或功能障碍引起的慢性疼痛疾病，多种不同的损伤，如外伤、神经损伤或感染等疾病都可引起神经性疼痛。最常见的神经性疼痛类型包括糖尿病性神经痛(DNP)、带状疱疹后遗神经痛(PHN和艾滋病相关的神经性疼痛。与继发性(损伤性疼痛)相反，神经性疼痛可能在外伤发生后数天，甚至数月后发生，常常为慢性疼痛，其特征是痛觉过敏，感官对刺激过度敏感，异常性疼痛和自发性灼痛。目前神经性疼痛的治疗药物主要包括抗惊厥药，抗抑郁药，麻醉性镇痛药和局部麻醉药。标准治疗药物如辉瑞公司的抗惊厥药物Lyrica(普瑞巴林)。这些药物能够有效治疗伤害感受性疼痛，但是对神经性疼痛的治疗非常有限，而且伴随有严重的副作用，包括认知改变，镇静作用，恶心以及产生耐药性和依赖性。因此，需要提供一种能够有效治疗和预防神经性疼痛且副作用较小的药物。神经性疼的病理机制还不是很清楚，研究认为伤害性感受器和脊髓背角的敏感化交互作用可能就是神经性疼痛产生的基础。
肾素-血管紧张素系统(RAS)不仅存在于循环中，而且存在于许多组织器官如心血管、肾、脑中，并通过自分泌和旁分泌发挥作用。RAS通过血管紧张素II(AngII)与血管紧张素受体结合产生生物学效应。目前已明确的主要有血管紧张素II受体I型受体(AT1)，血管紧张素II受体II型受体(AT2)。AT1广泛分布于几乎所有的组织器官。AT2主要分布于胚胎组织、未成熟脑组织，成年正常组织较少分布，但是组织损伤后，其表达升高。在神经性疼痛的动物模型和病人研究发现，其体内AngII，AngII受体AT2表达升高，而且，AT2的经常跟疼痛信号分子(如substance P,TRPV1)共表达。研究发现，小鼠脑组织血管紧张素Ⅱ受体激活后可对抗吗啡的镇痛作用；延髓尾端腹外侧区血管紧张素Ⅱ受体激活后可引起痛觉过敏，给予血管紧张素Ⅱ受体拮抗剂可减轻这种痛觉过敏。EMA401，由澳大利亚生物医药公司Spinifex公司研究开发，是一种高选择性血管紧张素II受体2拮抗剂，最早公开于US5246943，目前处于临床II期实验，现有研究表明该药物具有较好镇痛作用，尤其对包括糖尿病性神经痛(DNP)、带状疱疹后遗神经痛(PHN)等神经性疼痛治疗效果显著。
发明内容
发明人在研究过程中发现了一类具有式(I)结构的1,2,3,4-四氢异喹啉衍生物、其制备方法和应用。该系列化合物具有治疗、预防或缓解神经病或神经性疼痛方面的活性，可应用于原发性神经病、继发性神经病、周围神经病、由机械性神经损伤或生化神经损伤引起的神经病、疼痛性糖尿病神经病(PDN)或相关神经性疾病药物的开发，具有广阔的应用前景。
本发明一方面提供了一种具有如下式(I)结构的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，
Figure PCTCN2016096167-appb-000001
其中：
R1、R2、R3各自独立的选自氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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与R2、R1与R3、R2与R3和直接相连的碳原子一起形成C3-8环烷基或3-8元杂环基，所述杂原子选自O、S、N，
任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基、碱金属、碱土金属或铵，任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、 5-10元杂芳基氧基、5-10元杂芳基硫基、-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各自独立的选自氢、氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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，任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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各自独立的选自氢、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基或5-10元杂芳基，任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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，任选再进一步的被一个或多个选自卤素、羟基、巯基、氰基、硝基、乙酰胺基、叠氮基、磺酰基、甲磺酰基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、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元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、氨基、C1-8烷基单取代氨基或C1-8烷基双取代氨基的取代基所取代；
R12选自氢、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C1-8烷氧基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、C1-8烷基酰基、C1-8烷基氨基或C1-8烷基酰胺基，任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、乙酰胺基、叠氮基、磺酰基、甲磺酰基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、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元杂环基氧基、3-8元杂环基硫基、 C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、氨基、C1-8烷基单取代氨基或C1-8烷基双取代氨基的取代基所取代；
R11、R13、R14选自自氢、氘、C1-8烷基、C3-8环烷基、卤取代C1-8烷基、羟取代C1-8烷基、苯基或对甲基苯基；
r为0、1、2。
作为进一步优选的方案，所述式(I)结构的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，所述立体异构体是指1-、3-、4-或2，-位包含立体构型，可分别为R-构型或S-构型，结构对应表示为
Figure PCTCN2016096167-appb-000002
或
Figure PCTCN2016096167-appb-000003
优选“3R-”或“3S-”立体异构体。
Figure PCTCN2016096167-appb-000004
作为进一步优选的方案，所述式(I)结构的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，R5、R6、R9、R10各自独立的选自氢、氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-4烷基、卤取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C5-8芳基、C5-8芳基氧基、C5-8芳基硫基、5-8元杂芳基、5-8元杂芳基氧基、5-8元杂芳基硫基、-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；任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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)化合物所定义。
作为进一步优选的方案，所述式(I)结构的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，R5、R6、R9、R10各自独立的选自氢、氘、氟、氯、羟基、巯基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、乙烯基、烯丙基、乙炔基、环丙基、吡啶基、四氢呋喃基、吗啉基、苯基、甲氧基、乙氧基、异丙氧基、苄氧基、磺酰基、甲磺酰基、异丙磺酰基、对甲苯磺酰基、 甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基、乙酰氨基或二甲氨基羰基；
R4选自氢、氘、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基、碱金属、碱土金属或铵；
R1、R2、R3、R7、R8、R11、R12、R13、R14、r如如式(I)化合物所定义。
作为进一步优选的方案，所述式(I)结构的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，R5、R6、R9、R10各自独立的选自氢、氘、氟、甲基、乙基、异丙基、三氟甲基、环丙基、甲氧基、乙氧基、异丙氧基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基、乙酰氧基、氨基或二甲氨基；
R4选自氢、氘、甲基、乙基、异丙基、三氟甲基、环丙基、环己基、苯基、碱金属、碱土金属或铵；
R1、R2、R3、R7、R8、R11、R12、R13、R14、r如式(I)化合物所定义。
作为更进一步优选的方案，所述式(I)结构的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，选自如下式(Ⅱ)化合物：
Figure PCTCN2016096167-appb-000005
其中，R4选自氢、氘、甲基、乙基、异丙基、三氟甲基、环丙基、环己基、苯基、碱金属、碱土金属或铵；
R15选自氢、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、卤取代C1-8烷基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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选自0、1、2、3、4或5；
R2、R3、R7、R8、R11、R12、R13、R14、r如式(I)化合物所定义。
作为更进一步优选的方案，所述式(Ⅱ)结构的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，R2与R3和直接相连的碳原子一起形成C3-8环烷基，任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环 基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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选自氢、甲基、乙基、异丙基、三氟甲基、环丙基、钠、钾、钙或铵；
R15选自氢、氟、氯、羟基、巯基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、乙烯基、烯丙基、乙炔基、环丙基、吡啶基、四氢呋喃基、吗啉基、苯基、甲氧基、乙氧基、异丙氧基、苄氧基、磺酰基、甲磺酰基、异丙磺酰基、对甲苯磺酰基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基、乙酰氨基或二甲氨基羰基；
R7、R8、R11、R12、R13、R14、r如式(I)化合物所定义；m如前述所定义。
作为更进一步优选的方案，所述式(Ⅱ)结构的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，R2与R3和直接相连的碳原子一起形成C3-8环烷基，任选进一步被一个或多个选自氟、氯、羟基、巯基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、乙烯基、烯丙基、乙炔基、环丙基、吡啶基、四氢呋喃基、吗啉基、苯基、甲氧基、乙氧基、异丙氧基、苄氧基、磺酰基、甲磺酰基、异丙磺酰基、对甲苯磺酰基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基、乙酰氨基或二甲氨基羰基的取代基所取代；
R4选自氢、钠、钾、钙或铵；
R15选自氢、氟、氯、羟基、巯基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、乙烯基、烯丙基、乙炔基、环丙基、吡啶基、四氢呋喃基、吗啉基、苯基、甲氧基、乙氧基、异丙氧基、苄氧基、磺酰基、甲磺酰基、异丙磺酰基、对甲苯磺酰基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基、乙酰氨基或二甲氨基羰基；
R7、R8、R11、R12、R13、R14、r如式(I)化合物所定义；m如前述所定义。
作为最优选的方案，所述式(Ⅱ)结构的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，选自如下化合物：
Figure PCTCN2016096167-appb-000006
作为更进一步优选的方案，所述式(Ⅱ)结构的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，R2、R3各自独立的选自氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、 C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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，
任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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选自氢、甲基、乙基、异丙基、三氟甲基、环丙基、钠、钾、钙或铵；
R15选自氢、氟、氯、羟基、巯基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、乙烯基、烯丙基、乙炔基、环丙基、吡啶基、四氢呋喃基、吗啉基、苯基、甲氧基、乙氧基、异丙氧基、苄氧基、磺酰基、甲磺酰基、异丙磺酰基、对甲苯磺酰基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基、乙酰氨基或二甲氨基羰基；
R7、R8、R11、R12、R13、R14、r如式(I)化合物所定义；m如前述所定义。
作为更进一步优选的方案，所述式(Ⅱ)结构的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，R2、R3各自独立的选自氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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选自氢、钠、钾、钙或铵；
R15选自氢、氟、氯、羟基、巯基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、乙烯基、烯丙基、乙炔基、环丙基、吡啶基、四氢呋喃基、吗啉基、苯基、甲氧基、乙氧基、异丙氧基、苄氧基、磺酰基、甲磺酰基、异丙磺酰基、对甲苯磺酰基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基、乙酰氨基或二甲氨基羰基；
R7、R8、R11、R12、R13、R14、r如式(I)化合物所定义；m如前述所定义。
作为最优选的方案，所述式(Ⅱ)结构的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，选自如下化合物：
Figure PCTCN2016096167-appb-000007
本发明另一方面提供式(I)化合物、其立体异构体或其药学上可接受盐的制备方法，包括如下步骤：
Figure PCTCN2016096167-appb-000008
X选自羟基或卤素，优选羟基或氯；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、r如式(I)化合物所定义。
作为进一步优选的方案，所述的缚酸剂为有机碱或无机碱，所述有机碱选自三甲胺、三乙胺、吡啶、哌啶、吗啉或其混合物，所述无机碱选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠，氢氧化钾，氢氧化锂，醋酸钠或其混合物；所述的缩合剂选自DIC、DCC、HOBT、EDC·HCl、PyBOP、PyBroP、HATU、HCTU、DEPBT、EEDQ、CDI或其混合物。
本发明另一方面提供药物组合物，其包括治疗有效剂量的前述式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。
本发明另一方面提供了前述式(I)化合物、其立体异构体或其药学上可接受盐，或前述药物组合物在制备用于治疗、预防或缓解对象的神经病或神经性疼痛药物中的应用。
作为进一步优选的方案，所述的神经病为原发性神经病、继发性神经病、周围神经病、由机械性神经损伤或生化神经损伤引起的神经病、疼痛性糖尿病神经病(PDN)或相关神经性疾病。
具体实施方式
详细说明：除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。
“C1-8烷基”指包括1至8个碳原子的直链烷基和含支链烷基，烷基指饱和的脂族烃基团，C0-8是指不含碳原子或者C1-8烷基，例如甲基、乙基、正丙基、异 丙基、正丁基、异丁基、叔丁基、仲丁基、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-乙基戊基或其各种支链异构体等。
烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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；
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，“C3-8环烷基”指包括3至8个碳原子的环烷基，“5-10元环烷基”指包括5至10个碳原子的环烷基，例如：
单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基基或多螺环烷基，螺环烷基的非限制性实施例包含：
Figure PCTCN2016096167-appb-000009
“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，稠环烷基的非限制性实施例包含：
Figure PCTCN2016096167-appb-000010
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基的非限制性实施例包含：
Figure PCTCN2016096167-appb-000011
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。“5-10元杂环基”指包含5至10个环原子的环基，“3-8元杂环基”指包含3至8个环原子的环基。
单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基。螺环烷基的非限制性实施例包含：
Figure PCTCN2016096167-appb-000012
“稠杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，稠杂环基的非限制性实施例包含：
Figure PCTCN2016096167-appb-000013
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基的非限制性实施例包含：
Figure PCTCN2016096167-appb-000014
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，非限制性实施例包含：
Figure PCTCN2016096167-appb-000015
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，“C5-10芳基”指含有5-10个碳的全碳芳基，“5-10元芳基”指含有5-10个碳的全碳芳基，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结 构连接在一起的环为芳基环，非限制性实施例包含：
Figure PCTCN2016096167-appb-000016
芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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；
“杂芳基”指包含1至4个杂原子的杂芳族体系，所述杂原子包括氮、氧和S(O)r(其中r是整数0、1、2)的杂原子，5-7元杂芳基指含有5-7个环原子的杂芳族体系，5-10元杂芳基指含有5-10个环原子的杂芳族体系，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。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含：
Figure PCTCN2016096167-appb-000017
杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷 基，C2-8链烯基指含有2-8个碳的直链或含支链烯基。例如乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。
烯基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，C2-8链炔基指含有2-8个碳的直链或含支链炔基。例如乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。
炔基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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)，其中烷基的定义如上所述。C1-8烷氧基指含1-8个碳的烷基氧基，非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基等。
烷氧基可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、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；
“卤取代的C1-8烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷基基团，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。
“卤取代的C1-8烷氧基”烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷氧基基团。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。
“卤素”指氟、氯、溴或碘。
术语“缩合剂”是指能引起缩合反应的试剂。缩合反应是指两个或多个有机分子相互作用后以共价键结合成一个大分子，同时失去水或其他比较简单的无机或 有机小分子的反应。其中的小分子物质通常是水、氯化氢、甲醇或乙酸等。本发明中各种缩合剂的简称对应的中文名称如表1所示。
表1各种缩合剂的简称对应的中文名称
简称 中文名称
DIC N,N-二异丙基碳二亚胺
DCC N,N-二环己基碳二亚胺
HOBT 1-羟基苯并三唑
EDC·HCl 1-乙基-3-(3-二甲氨丙基)碳二亚胺盐酸盐
PyBOP 六氟磷酸苯并三唑-1-基-氧基三吡咯烷基
PyBroP 三吡咯烷基溴化鏻六氟磷酸盐
HATU 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
HCTU 6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯
DEPBT 3-(二乙氧基磷酰氧基)-1,2,3-苯并三嗪-4-酮
EEDQ 2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉
CDI 羰基二咪唑
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键(如烯属)的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代甲醇(CD3OD)和氘代氯仿(CDCl3)内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 1200 Infinity Series质谱仪。HPLC的 测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下，本发明的所有反应均在连续的磁搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。氢气氛是指反应瓶连接一个约1L容积的氢气气球。
在无特殊说明的情况下，实施例中的溶液是指水溶液。反应的温度为室温。室温为最适宜的反应温度，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)或液质联用色谱(LC-MS)反应所使用的展开剂体系有：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，石油醚和乙酸乙酯体系，丙酮，溶剂的体积比可根据化合物的极性不同而进行调节。柱层析的洗脱剂的体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：二氯甲烷和乙酸乙酯体系，D：乙酸乙酯和甲醇，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的氨水和醋酸等进行调节。
中间体的制备
1、中间体1：乙基3-(2-(苄氧基)-3-甲氧苯基)-2-((二苯亚甲基)氨基)丙酸酯的制备
Figure PCTCN2016096167-appb-000018
室温下，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，加入碘化钾(5.59g,33.65mmol)，碳酸铯(16.87g,51.76mmol),乙基2-((二苯亚甲基)氨基)乙酸酯(6.92g,25.88mmol),然后在氮气保护下，在50℃油浴中搅拌过夜。冷却后，减压旋蒸除去有机溶剂，加入乙酸乙酯和水分层，乙酸乙酯相再用饱和食盐水洗涤，用无水硫酸钠干燥，浓缩柱层析(洗脱剂:石油醚/乙酸乙酯＝10:1)，得到乙基3-(2-(苄氧基)-3-甲氧苯基)-2-((二苯亚甲基)氨基)丙酸酯(8.9g,70％)。
MS m/z(ESI):494.6[M+H]+.
2、中间体2：乙基2-氨基-3-(2-(苄氧基)-3-甲氧苯基)丙酸酯的制备
Figure PCTCN2016096167-appb-000019
室温下，往乙基3-(2-(苄氧基)-3-甲氧苯基)-2-((二苯亚甲基)氨基)丙酸酯(8.9g,18.03mmol)的四氢呋喃溶液(60mL)中，加入HCl(3M,30mL)，继续在该温度下搅拌2小时，然后减压除去有机溶剂。加入约100mL水，用乙酸乙酯萃取。乙酸乙酯相用饱和食盐水洗涤多次，无水硫酸钠干燥，浓缩得到乙基2-氨基-3-(2-(苄氧基)-3-甲氧苯基)丙酸酯(5.2g,88％)。
MS m/z(ESI):330.5[M+H]+。
3、中间体3：乙基5-(苄氧基)-6-甲氧基-1,2,3,4-四氢异喹啉-3-羧酸酯的制备
Figure PCTCN2016096167-appb-000020
往乙基2-氨基-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)，然后室温搅拌过夜。减压除去有机溶剂，加入约100mL水，用乙酸乙酯萃取。乙酸乙酯相用饱和食盐水洗涤多次，有机相依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(洗脱剂:石油醚/乙酸乙酯＝3:1)，得到乙基5-(苄氧基)-6-甲氧基-1,2,3,4-四氢异喹啉-3-羧酸酯(3.2g,62％)。
MS m/z(ESI):342.4[M+H]+。
实施例化合物的制备
实施例1：5-(苄氧基)-6-甲氧基-2-(1-苯基环己烷-1-羰基)-1,2,3,4-四氢异喹啉-3-羧酸的制备
Figure PCTCN2016096167-appb-000021
第一步：1-苯基环己烷-1-羰基酰氯的制备
Figure PCTCN2016096167-appb-000022
室温下，在1-苯基环己烷-1-羧酸(200mg,0.98mmol)的二氯甲烷(5mL)溶液中加入草酰氯(248mg,1.96mmol)，DMF(0.2mL)，反应在室温下搅拌2小时，减压除去溶剂，得到粗品1-苯基环己烷-1-羰基酰氯(230mg)，直接用于下一步反应。
第二步：乙基5-(苄氧基)-6-甲氧基-2-(1-苯基环己烷-1-羰基)-1,2,3,4-四氢异喹啉-3-羧酸酯的制备
Figure PCTCN2016096167-appb-000023
室温下，在1-苯基环己烷-1-羰基酰氯(100mg,0.45mmol)的二氯甲烷(5mL)溶液中，加入乙基5-(苄氧基)-6-甲氧基-1,2,3,4-四氢异喹啉-3-羧酸酯(183mg,0.538mmol)，三乙胺(137mg,1.35mmol)。反应在室温下搅拌两个小时。加入约10mL水，用二氯甲烷萃取。有机相依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(洗脱剂:石油醚/乙酸乙酯＝1:1),得到标题化合物乙基5-(苄氧基)-6-甲氧基-2-(1-苯基环己烷-1-羰基)-1,2,3,4-四氢异喹啉-3-羧酸酯(95mg,40％)。
MS m/z(ESI):528.6[M+H]+。
第三步：5-(苄氧基)-6-甲氧基-2-(1-苯基环己烷-1-羰基)-1,2,3,4-四氢异喹啉-3-羧酸的制备
Figure PCTCN2016096167-appb-000024
在乙基5-(苄氧基)-6-甲氧基-2-(1-苯基环己烷-1-羰基)-1,2,3,4-四氢异喹啉-3-羧酸酯(70mg,0.133mmol)的四氢呋喃(6mL)溶液中分别加入甲醇(2mL)，水(3mL)，接着加入氢氧化锂(55.2mg,1.33mmol)，室温下反应2个小时，减压除去有机溶剂，加入约100mL水，用少量乙酸乙酯洗涤水相，收集水相用稀盐酸调pH值到2，用乙酸乙酯萃取水相，收集乙酸乙酯相用饱和食盐水洗涤，然后用无水硫酸钠干燥有机相，浓缩，得到标题化合物5-(苄氧基)-6-甲氧基-2-(1-苯基环己烷-1-羰基)-1,2,3,4-四氢异喹啉-3-羧酸(51mg,77％)。MS m/z(ESI):500.2[M+H]+；
1H NMR(400MHz,CDCl3)δ7.41-7.17(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)。
实施例2：5-(苄氧基)-6-甲氧基-2-(1-苯基环丙烷-1-羰基)-1,2,3,4-四氢异喹啉-3-羧酸的制备
Figure PCTCN2016096167-appb-000025
5-(苄氧基)-6-甲氧基-2-(1-苯基环丙烷-1-羰基)-1,2,3,4-四氢异喹啉-3-羧酸的制备方法参照实施例1。MS m/z(ESI):458.2[M+H]+；
1H NMR(400MHz,CDCl3)δ7.41-7.28(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)。
实施例3：5-(苄氧基)-6-甲氧基-2-(1-苯基环戊烷-1-羰基)-1,2,3,4-四氢异喹啉-3-羧酸的制备
Figure PCTCN2016096167-appb-000026
5-(苄氧基)-6-甲氧基-2-(1-苯基环戊烷-1-羰基)-1,2,3,4-四氢异喹啉-3-羧酸的制备方法参照实施例1。MS m/z(ESI):486.3[M+H]+；
1H NMR(400MHz,CDCl3)δ7.42-7.32(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)。
实施例4：5-(苄氧基)-2-(2,2-二苯基丙酰)-6-甲氧基-1,2,3,4-四氢异喹啉-3-羧酸的制备
Figure PCTCN2016096167-appb-000027
5-(苄氧基)-2-(2,2-二苯基丙酰)-6-甲氧基-1,2,3,4-四氢异喹啉-3-羧酸的制备方法参照实施例1。MS m/z(ESI):522.3[M+H]+；
1H NMR(400MHz,CDCl3)δ7.53-7.43(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)。
实施例5：2-(2,2-二苯基丙酰)-6-甲氧基-5-((4-甲氧基-3-甲基苯甲基)氧代)-1,2,3,4-四氢异喹啉-3-羧酸的制备
Figure PCTCN2016096167-appb-000028
2-(2,2-二苯基丙酰)-6-甲氧基-5-((4-甲氧基-3-甲基苯甲基)氧代)-1,2,3,4-四氢异喹啉-3-羧酸的制备方法参照实施例1。MS m/z(ESI):566.2[M+H]+；
1HNMR(400MHz,CD3OD):δ7.36-7.17(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)。
实施例6：5-((2,3-二氢苯并呋喃-5-基)甲氧基)-2-(2,2-二苯基丙酰)-6-甲氧基-1,2,3,4-四氢异喹啉-3-羧酸的制备
Figure PCTCN2016096167-appb-000029
5-((2,3-二氢苯并呋喃-5-基)甲氧基)-2-(2,2-二苯基丙酰)-6-甲氧基-1,2,3,4-四氢异喹啉-3-羧酸的制备方法参照实施例1。MS m/z(ESI):564.2[M+H]+；
1H NMR(400MHz,MeOD):δ7.46-7.29(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)。
生物活性测试
一、试验试剂与仪器
1.储存液(500mL)
1)50mM Tris:取25mL1M Tris(Sigma T2663)用蒸馏水稀释为500mL备用；
2)100mM NaCl：取10mLof 5M NaCl(购自西格玛(Sigma))蒸馏水稀释为500mL备用；
3)5mM MgCl2：取2.5mLof 1M(购自Fluka)蒸馏水稀释为500mL备用。
2.工作液(50mL)
1)取以上储存液50mL,加入0.1％BSA和不含EDTA的蛋白酶抑制剂1片(购自罗氏Roche)。
2)384孔Opti-Plate检测板购自珀金埃尔默股份有限公司(Perkin Elmer，PE)。
3)碘标记配体:Sar1-Ile8-AngII,[125I]:购自PE(50uCi)。加1mL无菌水溶解为50uCi/mL储存液,2200Ci/mmol。工作液浓度为0.1nM，-20度冻存备用。
3.试验仪器
1)SPA闪烁微珠：购自珀金埃尔默股份有限公司(Perkin Elmer，PE)用20mL工作液溶解成25mg/mL储存液，工作液最终浓度为250ugbeads/well/25uL。
2)384 well Opti-Plate(购自PE)。
3)自动分液器：Multidrop(Thermo Fisher)。
4)检测分析仪器：ViewLux 1430 ultraHTS Microplate Imager(Perkin Elmer)。
二、试验步骤
本发明采用邻近闪烁分析(SPA)技术来检测化合物对AT2的抑制活性，碘标记AT2配体:Sar1-Ile8-AngII,[125I]，SPA微珠及384孔检测板均购自PE公司(PE(50uCi))。检测分析仪器：ViewLux 1430 ultraHTS Microplate Imager(Perkin Elmer)。试验步骤如下：
1.将化合物包括质控阳性化合物接到384孔实验板中(Optiplate)
2.将工作液、微珠混合到离心管中，室温避光孵育混合1小时，摇床混匀；
3.用自动分液器Multidrop将步骤2中的预混合的微珠加入到实验板中(25uL/孔)；
4.用封盖薄膜迅速密封实验板，避光室温混合孵育1小时(摇床混匀)；
5.用自动分液器(Multidrop)在每孔中加入25uL的显影剂(tracer)；
6.用封盖薄膜迅速密封实验板，避光室温混合孵育过夜，摇床混匀；
7.第二天早上，离心实验板，使微珠沉淀到板底；
8.将实验板放入ViewLux，检测、读数分析,计算IC50。
三、试验结果：
本发明实施例化合物及阳性对照化合物(EMA-400，参照US5246943实施例20制备得到)的生化学活性通过以上的试验进行测定，测得的IC50值见下表。
Figure PCTCN2016096167-appb-000030
Figure PCTCN2016096167-appb-000031
本发明其它实施例化合物hAT2IC50值与上述实施例的效果类似，表现出了近似的抑制活性和规律。
结论：本发明实施例化合物相对于阳性对照化合物，部分化合物对hAT2表现出很强的抑制活性，提高了一倍以上的抑制效果。
对于hAT1的抑制活性，与阳性对照化合物一样均表现为大于5000nM的抑制活性。
综上所述，本发明实施例化合物对于hAT2与hAT1的抑制效果相应也具有更高的选择性，更加适合hAT2疾病的药学或临床上的应用。

Claims (14)

  1. 一种具有如下式(I)结构的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，
    Figure PCTCN2016096167-appb-100001
    其中：
    R1、R2、R3各自独立的选自氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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与R2、R1与R3、R2与R3和直接相连的碳原子一起形成C3-8环烷基或3-8元杂环基，所述杂原子选自O、S、N，
    任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基、碱金属、碱土金属或铵，任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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各自独立的选自氢、氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8 元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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，任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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各自独立的选自氢、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基或5-10元杂芳基，任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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，任选再进一步的被一个或多个选自卤素、羟基、巯基、氰基、硝基、乙酰胺基、叠氮基、磺酰基、甲磺酰基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、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元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、氨基、C1-8烷基单取代氨基或C1-8烷基双取代氨基的取代基所取代；
    R12选自氢、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C1-8烷氧基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、C1-8烷基酰基、C1-8烷基氨基或C1-8烷基酰胺基，任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、乙酰胺基、叠氮基、磺酰基、甲磺酰基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、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元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、氨基、C1-8烷基单取代氨基或C1-8烷基双取代氨基的取代基所取代；
    R11、R13、R14选自氢、氘、C1-8烷基、C3-8环烷基、卤取代C1-8烷基、羟取代C1-8烷基、苯基或对甲基苯基；
    r为0、1、2。
  2. 根据权利要求1所述的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，其特征在于，所述立体异构体是指1-、3-、4-或2’-位包含立体构型，可分别为R-构型或S-构型；优选“3R-”或“3S-”立体异构体，
    Figure PCTCN2016096167-appb-100002
  3. 根据权利要求1所述的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，其特征在于，
    R5、R6、R9、R10各自独立的选自氢、氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-4烷基、卤取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C5-8芳基、C5-8芳基氧基、C5-8芳基硫基、5-8元杂芳基、5-8元杂芳基氧基、5-8元杂芳基硫基、-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；任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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。
  4. 根据权利要求1所述的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，其特征在于，
    R4选自氢、氘、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基、碱金属、碱土金属或铵；
    R5、R6、R9、R10各自独立的选自氢、氘、氟、氯、羟基、巯基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、乙烯基、烯丙基、乙炔基、环丙基、吡啶基、四氢呋喃基、吗啉基、苯基、甲氧基、乙氧基、异丙氧基、苄氧基、磺酰基、甲磺酰基、异丙磺酰基、对甲苯磺酰基、甲氧羰基、乙氧羰基、异丙氧 羰基、乙酰基、乙酰氧基、氨基、二甲氨基、乙酰氨基或二甲氨基羰基。
  5. 根据权利要求1所述的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，其特征在于，
    R4选自氢、氘、甲基、乙基、异丙基、三氟甲基、环丙基、环己基、苯基、碱金属、碱土金属或铵；
    R5、R6、R9、R10各自独立的选自氢、氘、氟、甲基、乙基、异丙基、三氟甲基、环丙基、甲氧基、乙氧基、异丙氧基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基、乙酰氧基、氨基或二甲氨基。
  6. 根据权利要求1所述的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下式(II)化合物：
    Figure PCTCN2016096167-appb-100003
    其中，R4选自氢、氘、甲基、乙基、异丙基、三氟甲基、环丙基、环己基、苯基、碱金属、碱土金属或铵；
    R15选自氢、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、卤取代C1-8烷基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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选自0、1、2、3、4或5。
  7. 根据权利要求6所述的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，其特征在于，
    R2、R3各自独立的选自氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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与R3和直接相连的碳原子一起形成C3-8环烷基，
    任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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选自氢、甲基、乙基、异丙基、三氟甲基、环丙基、钠、钾、钙或铵；
    R15选自氢、氟、氯、羟基、巯基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、乙烯基、烯丙基、乙炔基、环丙基、吡啶基、四氢呋喃基、吗啉基、苯基、甲氧基、乙氧基、异丙氧基、苄氧基、磺酰基、甲磺酰基、异丙磺酰基、对甲苯磺酰基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基、乙酰氨基或二甲氨基羰基；
    m选自0、1、2、3、4或5。
  8. 根据权利要求6所述的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，其特征在于，
    R2、R3各自独立的选自氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-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与R3和直接相连的碳原子一起形成C3-8环烷基，
    任选进一步被一个或多个选自氟、氯、羟基、巯基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、乙烯基、烯丙基、乙炔基、环丙基、吡啶基、四氢呋喃基、吗啉基、苯基、甲氧基、乙氧基、异丙氧基、苄氧基、磺酰基、甲磺酰基、异丙磺酰基、对甲苯磺酰基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基、乙酰氨基或二甲氨基羰基的取代基所取代；
    R4选自氢、钠、钾、钙或铵；
    R15选自氢、氟、氯、羟基、巯基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、乙烯基、烯丙基、乙炔基、环丙基、吡啶基、四氢呋喃基、吗啉基、苯基、甲氧基、乙氧基、异丙氧基、苄氧基、磺酰基、甲磺酰基、异丙磺 酰基、对甲苯磺酰基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰基、乙酰氧基、氨基、二甲氨基、乙酰氨基或二甲氨基羰基；
    m选自0、1、2、3、4或5。
  9. 根据权利要求6所述的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物：
    Figure PCTCN2016096167-appb-100004
  10. 根据权利要求1-9中任一项所述的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐的制备方法，包括如下步骤：
    Figure PCTCN2016096167-appb-100005
    X选自羟基或卤素，优选羟基或氯。
  11. 根据权利要求10所述的制备方法，其特征在于，所述的缚酸剂为有机碱或无机碱，所述有机碱选自三甲胺、三乙胺、吡啶、哌啶、吗啉或其混合物，所述无机碱选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠，氢氧化钾，氢氧化锂，醋酸钠或其混合物；所述的缩合剂选自DIC、DCC、HOBT、EDC·HCl、PyBOP、PyBroP、HATU、HCTU、DEPBT、EEDQ、CDI或其混合物。
  12. 一种药物组合物，其包括治疗有效剂量的根据权利要求1-9中任一项所述的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐及可药用的 载体。
  13. 根据权利要求1-9中任一项所述的1,2,3,4-四氢异喹啉衍生物、其立体异构体或其药学上可接受盐、或权利要求12所述的药物组合物在制备用于治疗、预防或缓解对象的神经病或神经性疼痛药物中的应用。
  14. 根据权利要求13所述的应用，其特征在于，所述的神经病为原发性神经病、继发性神经病、周围神经病、由机械性神经损伤或生化神经损伤引起的神经病、疼痛性糖尿病神经病(PDN)或相关神经性疾病。
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