WO2021047581A1 - 一种六氢化苯并吡唑衍生物及其制备 - Google Patents

一种六氢化苯并吡唑衍生物及其制备 Download PDF

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WO2021047581A1
WO2021047581A1 PCT/CN2020/114448 CN2020114448W WO2021047581A1 WO 2021047581 A1 WO2021047581 A1 WO 2021047581A1 CN 2020114448 W CN2020114448 W CN 2020114448W WO 2021047581 A1 WO2021047581 A1 WO 2021047581A1
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alkyl
compound
pain
ring
group
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French (fr)
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李瑶
陈雷
王文晶
张国彪
石宗军
王亚军
赵剑飞
唐平明
林洪军
叶飞
冯清伟
张晨
倪佳
严庞科
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四川海思科制药有限公司
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Priority to CN202080061781.9A priority Critical patent/CN114391011A/zh
Publication of WO2021047581A1 publication Critical patent/WO2021047581A1/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof

Definitions

  • the invention relates to a hexahydrobenzopyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides, prodrugs and pharmaceutical compositions thereof, preparation methods, and Use in the prevention and treatment of diseases mediated by the cannabinoid CB2 receptor.
  • Neuropathic pain is caused by damage to the peripheral or central nerve pathways. This pain leads to persistent spontaneous pain and hypersensitivity reactions to pain and harmless stimuli.
  • the underlying causes of neuropathic pain vary widely, but usually have similar clinical features. Some of the most common pathologies that cause neuropathic pain are diabetic neuropathy, amputation, surgery, and postherpetic neuralgia. Studies have shown that up to 7-8% of adults suffer from neuropathic pain, and the prevalence is rising, and it is expected to further increase in the aging population. In addition to personal pain, unemployment and loss of social ability have led to an increase in treatment costs. At the same time, it is often accompanied by complications such as anxiety and depression.
  • the main symptoms of Crohn's disease include abdominal pain, diarrhea and fatigue, weight loss, fever, growth retardation, anemia, recurrent anal fistulas or other extraintestinal manifestations.
  • Drug treatments include aminosalicylic acid preparations, glucocorticoids, immunosuppressants, antibacterial drugs, and anti-TNF- ⁇ monoclonal antibodies. There are currently no drugs to manage Crohn's disease-related abdominal pain.
  • painkillers widely used in the market can cause harmful side effects and have unsatisfactory therapeutic effects. Therefore, the development of new analgesics cannot be delayed.
  • Cannabis extract has been used for pain relief for centuries.
  • cannabidiol CBD
  • CBD cannabidiol
  • cannabinoid cannabinoid
  • cannabinoid receptor 1 cannabinoid receptor 1
  • CB2 cannabinoid receptor 2
  • CB1 is most expressed in neurons of the CNS, but it is also present in a variety of peripheral tissues and cells at lower concentrations (Matsuda, L.A. et al. (1990) Nature 346: 561-564).
  • CB2 is mainly but not absolutely expressed in non-neural tissues such as hematopoietic cells, endothelial cells, osteoblasts, osteoclasts, endocrine pancreas and cancer cell lines (Munro, S. et al. (1993) Nature 365 :61-65; and Pache, P. etal. (2006) Pharmacol. Rev. 58(3):389-462).
  • Central CB1 is distributed in the cerebral cortex and limbic system, and is responsible for the analgesic effect and causing behavioral changes after being activated by cannabinoid. Although CB1 can mediate a powerful analgesic effect, it can cause euphoria, ataxia, dizziness and other mental symptoms. At the same time, it may produce addiction and tolerance, so it limits its use in the field of analgesia.
  • Peripheral CB2 is mainly distributed in immune cells and plays a role in pain and inflammation signals. In addition, CB2 is also distributed in peripheral nerve fibers and injured nerve endings.
  • CB2 After CB2 is excited, it exerts analgesic effect by inhibiting the production of toxins and inflammatory mediators by neutrophils and macrophages, and can also block the excitatory conduction of injured nerves.
  • CB2 is expressed in the brainstem, cerebral cortex and cerebellum of mice, but the expression level is very low, about 3.4% of the spleen.
  • CB2 selective CB2 agonists can theoretically avoid CB1R-related central psychiatric side effects, and show good analgesic effects in multiple preclinical models.
  • CB2 selective agonists have been discontinued in the field of analgesia due to insufficient analgesic efficacy in clinical trials, including JBT-101, LY2828360, etc. The reasons may be as follows: Although it shows a certain selectivity, it still has an agonistic effect on CB1, so it may cause adverse events at the effective dose and insufficient efficacy at a safe dose; agonistic effects on CB1 may lead to significant drug effects in animal models. Insufficient efficacy after transformation.
  • CB2 agonists will have functional selectivity.
  • the downstream of CB1/2 includes adenosine cyclase synthesis, ERK signaling pathway activation, ion current changes, internalization, ⁇ -arrestin, etc. Different drugs have functional biases to downstream activation .
  • the purpose of the present invention is to introduce a new type of cannabinoid CB2 agonist which is effective, safe, highly selective, long-acting and good in pharmacokinetic characteristics.
  • the present invention relates to a hexahydrobenzopyrazole compound represented by formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs:
  • R 1 is selected from -L 1 -L 2 -L 3 -L 4 ;
  • L 1 is selected from C 1-6 alkylene, C 3-7 cycloalkenylene, C 3-7 cycloalkylene, C 3-6 unsaturated cycloalkylene, C 3-6 heterocyclylene, C 6-10 arylene group, C 5-10 heteroarylene group, C 4-12 bridged ring, C 4-12 parallel ring, C 5-10 spiro ring or not present, the alkylene group, cycloalkylene group Group, cycloalkylene, unsaturated cycloalkylene, heterocyclylene, arylene, heteroarylene, bridged ring, fused ring, and spiro ring are each independently optionally substituted with the following substituents: halogen, cyano, Hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 2-6 alkynyl-C 3-6 cycloalkyl, C 1-6 alkoxy, hydroxy substituted C 1-6 alkyl, halogenated C
  • L 2 is selected from C 1-6 alkylene, C 3-7 cycloalkylene, C 3-6 heterocyclylene, C 5-10 heteroarylene, -C(O)NH-, -C( O)-, -C(O)O- or not present, the alkylene, cycloalkylene, heterocyclylene, and heteroarylene are each independently optionally substituted by the following substituents: C 1-6 Alkyl or halogen;
  • L 3 is selected from C 1-6 alkylene or absent
  • L 4 is selected from H, halogen, hydroxyl, amino, ureido, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 3-6 heterocyclyl, C 2-6 alkynyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) C 1-6 alkyl, -NHC(O )C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -NH-C 6-10 aryl, -NH-C 3-7 cycloalkyl, -C(O)-C 6- 10 aryl, -OC 6-10 aryl, -OC 6-10 heteroaryl, -OC 1-6 alkylene-COOH, -C(O)NH 2 , -COOH, C 4-12 bridged ring, C 4-12 parallel ring or C 5-10 spiro ring, the alkyl, al
  • R 2 and R 3 are each independently selected from H, F, Cl, cyano, hydroxyl or C 1-6 alkyl;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, Cl, amino, cyano, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 8 and R 9 are each independently selected from H, F, Cl, C 1-6 alkyl, and the alkyl is optionally substituted by the following substituents: cyano, F or Cl, or R 8 and R 9 together form C 2-6 alkenyl or C 3-6 cycloalkyl;
  • R 10 is selected from H or C 1-6 alkyl
  • R 11 is selected from aryl or heteroaryl, said aryl or heteroaryl is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl or C 1-6 alkoxy, said Heteroaryl groups include heteroatoms selected from N, O, S and their oxidation states;
  • the present invention relates to a hexahydrobenzopyrazole compound represented by formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs:
  • R 1 is selected from -L 1 -L 2 -L 3 -L 4 ;
  • L 1 is selected from C 1-6 alkylene, C 3-7 cycloalkenylene, C 3-7 cycloalkylene, C 3-6 unsaturated cycloalkylene, C 3-6 heterocyclylene, C 6-10 arylene group, C 5-10 heteroarylene group, C 4-12 bridged ring, C 4-12 parallel ring, C 5-10 spiro ring or not present, the alkylene group, cycloalkylene group Group, cycloalkylene, unsaturated cycloalkylene, heterocyclylene, arylene, heteroarylene, bridged ring, fused ring, and spiro ring are each independently optionally substituted with the following substituents: halogen, cyano, Hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 alkynyl-C 3-6 cycloalkyl, C 1-6 alkoxy, hydroxy substituted C 1-6 alkyl, halo C 1-6 alky
  • L 2 is selected from C 1-6 alkylene, C 3-7 cycloalkylene, C 3-6 heterocyclylene, C 5-10 heteroarylene, -C(O)NH-, -C( O)-, -C(O)O- or not present, the alkylene, cycloalkylene, heterocyclylene, and heteroarylene are each independently optionally substituted by the following substituents: C 1-6 Alkyl or halogen;
  • L 3 is selected from C 1-6 alkylene or absent
  • L 4 is selected from H, halogen, hydroxyl, amino, ureido, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 3-6 heterocyclyl, C 1-6 haloalkyl, C 2-6 alkynyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) C 1-6 Alkyl, -NHC(O)C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -NH-C 6-10 aryl, -NH-C 3-7 cycloalkyl, -C (O)-C 6-10 aryl, -OC 6-10 aryl, -OC 6-10 heteroaryl, -OC 1-6 alkyl-COOH, -C(O)NH 2 , -COOH, C 4-12 bridged ring, C 4-12 parallel ring or C 5-10 spiro
  • R 2 and R 3 are each independently selected from H, F, Cl, cyano, hydroxyl or C 1-6 alkyl;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, Cl, amino, cyano, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 8 and R 9 are each independently selected from H, F, Cl, C 1-6 alkyl, and the alkyl is optionally substituted by the following substituents: cyano, F or Cl, or R 8 and R 9 together form C 2-6 alkenyl or C 3-6 cycloalkyl;
  • R 10 is selected from H or C 1-6 alkyl
  • R 11 is selected from aryl or heteroaryl, said aryl or heteroaryl is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl or C 1-6 alkoxy, said Heteroaryl groups include heteroatoms selected from N, O, S and their oxidation states;
  • the present invention relates to a hexahydrobenzopyrazole compound represented by formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs:
  • R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 3-6 unsaturated cyclic hydrocarbon group, C 6-10 aryl, C 5-10 heteroaryl Group, C 4-12 bridged ring, C 4-12 parallel ring, C 5-10 spiro ring, the alkyl group, cycloalkyl group, unsaturated cyclic hydrocarbon group, heterocycloalkyl group, aryl group, heteroaryl group, The bridged ring, fused ring or spiro ring is optionally substituted by the following substituents: F, Cl, hydroxy, cyano, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkyl, benzene ring, -C (O) OC 1-6 alkyl, -C 1-6 alkyl-OC 1-6 alkyl or C 3-6 cycloalkyl; R 1 is selected From
  • R 2 and R 3 are each independently selected from H, F, Cl, cyano, hydroxyl, C 1-6 alkoxy or C 1-6 alkyl; in some embodiments, R 2 and R 3 are each independently selected From H, F, Cl, cyano, hydroxy, or C 1-6 alkyl; in some embodiments, R 2 and R 3 are each independently selected from H, F, Cl, methyl, ethyl, isopropyl , Tert-butyl; In certain embodiments, R 2 and R 3 are each independently selected from H, F or methyl;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, Cl, amino, cyano, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl; in certain embodiments, R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, cyano, hydroxyl, or C 1-6 alkyl; R 4 , R 5 , R 6 , and R 7 are each independently selected from H or C 1- 6 Alkyl; In certain embodiments, R 4 , R 5 , R 6 , and R 7 are each independently selected from H, methyl, ethyl, and isopropyl;
  • R 8 and R 9 are each independently selected from H, F, Cl, cyano, hydroxyl, C 1-6 alkoxy or C 1-6 alkyl; R 8 , R 9 are each independently selected from H, F, Cl, C 1-6 alkyl, said alkyl is optionally substituted by the following substituents: cyano, F or Cl, or R 8 and R 9 together form a C 2-6 alkenyl or C 3-6 cycloalkyl;
  • R 10 is selected from H or C 1-6 alkyl
  • R 11 is selected from aryl or heteroaryl, said aryl or heteroaryl is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl or C 1-6 alkoxy; in some In the embodiment, R 11 is selected from or In certain embodiments, R 11 is selected from
  • the present invention relates to a hexahydrobenzopyrazole compound represented by formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs:
  • R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 3-6 unsaturated cyclic hydrocarbon group, C 6-10 aryl, C 5-10 heteroaryl Group, C 4-12 bridged ring, C 4-12 parallel ring, C 5-10 spiro ring, the alkyl group, cycloalkyl group, unsaturated cyclic hydrocarbon group, heterocycloalkyl group, aryl group, heteroaryl group, The bridged ring, fused ring or spiro ring is optionally substituted by the following substituents: F, Cl, hydroxy, cyano, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 heterocycloalkyl, benzene ring, -C (O) OC 1-6 alkyl, -C 1-6 alkyl-OC 1-6 alkyl or C 3-6 cycloalkyl; in some In an embodiment
  • R 2 and R 3 are each independently selected from H, F, Cl, cyano, hydroxyl, C 1-6 alkoxy or C 1-6 alkyl; in some embodiments, R 2 and R 3 are each independently selected From H, F, Cl, cyano, hydroxy, or C 1-6 alkyl; in some embodiments, R 2 and R 3 are each independently selected from H, F, Cl, methyl, ethyl, isopropyl , Tert-butyl; In certain embodiments, R 2 and R 3 are each independently selected from H, F or methyl;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, Cl, amino, cyano, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl; in certain embodiments, R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, cyano, hydroxyl, or C 1-6 alkyl; R 4 , R 5 , R 6 , and R 7 are each independently selected from H or C 1- 6 Alkyl; In certain embodiments, R 4 , R 5 , R 6 , and R 7 are each independently selected from H, methyl, ethyl, and isopropyl;
  • R 8 and R 9 are each independently selected from H, F, Cl, cyano, hydroxyl, C 1-6 alkoxy or C 1-6 alkyl; R 8 , R 9 are each independently selected from H, F, Cl, C 1-6 alkyl, said alkyl is optionally substituted by the following substituents: cyano, F or Cl, or R 8 and R 9 together form a C 2-6 alkenyl or C 3-6 cycloalkyl;
  • R 10 is selected from H or C 1-6 alkyl
  • R 11 is selected from aryl or heteroaryl, said aryl or heteroaryl is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl or C 1-6 alkoxy; in some In the embodiment, R 11 is selected from or In certain embodiments, R 11 is selected from
  • R 1 is selected from Indolyl, pyrrolyl, pyridyl, piperidinyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, adamantyl, piperazine, morpholinyl, or
  • R 1 is selected from
  • R 1 is selected from Indolyl, pyrrolyl, pyridyl, piperidinyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, adamantyl, piperazine, morpholinyl, or
  • R 1 is selected from Indolyl, pyrrolyl, pyridyl, piperidinyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, adamantyl, piperazine, morpholinyl, or
  • R 11 is selected from or
  • the condition is: when R 11 is selected from When, R 1 is selected from
  • R 11 is selected from
  • R 11 is selected from or
  • the condition is: when R 11 is selected from When, R 1 is selected from
  • R 11 is selected from
  • R 1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl, said alkyl or cycloalkyl is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl or hydroxy;
  • R 2 and R 3 are each independently selected from H, F, Cl or C 1-6 alkyl
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H or C 1-6 alkyl;
  • R 8 and R 9 are each independently selected from H, F, Cl, C 1-6 alkyl, and the alkyl is optionally substituted by the following substituents: cyano, F or Cl, or R 8 and R 9 together form C 2-6 alkenyl or C 3-6 cycloalkyl;
  • R 10 is selected from H
  • R 11 is selected from or
  • the condition is: when R 11 is selected from When, R 1 is selected from
  • R 1 is selected from or
  • R 2 and R 3 are each independently selected from H, F or methyl
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H;
  • R 8 and R 9 are each independently selected from H, F, isopropyl, Or R 8 and R 9 together form 2-methpropenyl or cyclopropyl;
  • R 10 is selected from H
  • R 11 is selected from
  • R 1 is selected from or
  • R 2 and R 3 are each independently selected from H, F or methyl
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H;
  • R 8 and R 9 are each independently selected from H, F, isopropyl, or R 8 and R 9 together form 2-methpropenyl or cyclopropyl;
  • R 10 is selected from H
  • R 11 is selected from
  • R 1 is selected from or
  • R 2 and R 3 are each independently selected from H, F or methyl
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H;
  • R 8 and R 9 are each independently selected from H, F, isopropyl, Or R 8 and R 9 together form 2-methpropenyl or cyclopropyl;
  • R 10 is selected from H
  • R 11 is selected from
  • R 1 is selected from or
  • R 2 and R 3 are each independently selected from H, F or methyl
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H;
  • R 8 and R 9 are each independently selected from H, F, and isopropyl
  • R 10 is selected from H
  • R 11 is selected from
  • hexahydrobenzopyrazole compound of the present invention and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, wherein the compound structure is as follows:
  • hexahydrobenzopyrazole compound of the present invention and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, wherein the compound structure is as follows:
  • hexahydrobenzopyrazole compound of the present invention and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, wherein the compound structure is as follows:
  • the present invention also relates to a pharmaceutical composition, said composition comprising: an effective dose of any compound of the present invention and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides Or prodrugs, or further include one or more other therapeutic agents and pharmaceutically acceptable carriers or excipients.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention Use of the compound composition in the preparation of a medicament for the treatment of diseases mediated by CB2 receptors.
  • the present invention relates to a hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the compounds of the present invention
  • the composition is used in the preparation of a medicine for the treatment of pain.
  • the pain can be selected from: bone pain, arthralgia, muscle pain, toothache, migraine, headache, inflammatory pain, neuropathic pain, Crohn’s disease-related abdominal pain, and dysfunction due to the therapeutic agent Pain caused by the action and pain associated with diseases selected from: osteoarthritis, cancer, multiple sclerosis, allergic response, nephritis syndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia , HIV-related neuropathy, sciatica and autoimmune diseases.
  • diseases selected from: osteoarthritis, cancer, multiple sclerosis, allergic response, nephritis syndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia , HIV-related neuropathy, sciatica and autoimmune diseases.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention Use of the compound composition in the preparation of a medicament for treating neuropathic pain.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention Use of the compound composition in the preparation of a medicament for treating Crohn's disease-related abdominal pain.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention
  • the composition of the compound is used in a method of treating diseases mediated by CB2 receptors.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention
  • the composition of the compound is used in a method of treating pain.
  • the pain may be selected from: bone pain, arthralgia, muscle pain, toothache, migraine, headache, inflammatory pain, neuropathic pain, Crohn’s disease-related abdominal pain due to adverse effects of the therapeutic agent
  • the pain caused and the pain associated with diseases selected from: osteoarthritis, cancer, multiple sclerosis, allergic response, nephritis syndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia, Neuropathy, sciatica and autoimmune diseases associated with HIV.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention A method of treating neuropathic pain with a combination of compounds.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention A method for the treatment of Crohn's disease-related abdominal pain with a combination of compounds.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, Nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, and hydrogen isotopes include protium (H) and deuterium (D, also known as heavy hydrogen).
  • tritium T, also known as superheavy hydrogen
  • oxygen isotopes include 16 O, 17 O and 18 O
  • sulfur isotopes include 32 S, 33 S, 34 S and 36 S
  • nitrogen isotopes include 14 N and 15 N
  • the isotope of fluorine is 19 F
  • the isotope of chlorine includes 35 Cl and 37 Cl
  • the isotope of bromine includes 79 Br and 81 Br.
  • Alkyl refers to a linear and branched monovalent saturated hydrocarbon group, the main chain includes 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, more preferably 1 Straight and branched groups of up to 4 carbon atoms, most preferably 1 to 2 carbon atoms, examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl Butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-heptyl Group, n-octyl, n-nonyl, n-decyl, etc.; the alkyl group may be further substituted with any substituent.
  • Alkylene refers to straight and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v- (v is an integer from 1 to 10).
  • alkylene include, but are not limited to, methylene, methylene, and Ethyl, propylene, butylene, etc.; the alkylene group may be optionally further substituted with any substituent. When the number of substituents in the alkylene group is greater than or equal to 2, the substituents may be fused together to form a cyclic structure.
  • Alkoxy refers to a monovalent group of O-alkyl (-O-alkyl), where alkyl is as defined herein, and examples of alkoxy include but are not limited to methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentoxy Group, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-1-butoxy and 2-methyl ⁇ -1-Butoxy and so on.
  • alkenyl refers to straight and branched monovalent unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain
  • alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2- Methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-hepten
  • Alkynyl refers to a linear and branched monovalent unsaturated hydrocarbon group, which has at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 To 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, examples of alkynyl groups include but are not limited to ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl Alkynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3 -Hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl and 4-decynyl, etc.; the alkynyl
  • Cycloalkyl refers to a monovalent saturated carbocyclic hydrocarbon group, a single ring, usually having 3 to 10 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl Base and so on.
  • the cycloalkyl group may be optionally further substituted with any substituent.
  • Unsaturated cyclic hydrocarbon group refers to a carbocyclic hydrocarbon group that contains unsaturated bonds (such as double bonds) and does not have aromaticity. Non-limiting examples include cyclopropenyl, cyclobutenyl, and 1,4-cyclohexanyl. Ene, 1,3-cyclopentadiene, etc.
  • the cycloalkyl group may be optionally further substituted with any substituent.
  • Heterocyclic group refers to a saturated or unsaturated cyclic hydrocarbon group containing at least one heteroatom, a single ring, and the heteroatoms are N, O, S, P and their oxidized forms.
  • Non-limiting examples include aza Cyclopropyl, oxetanyl, thietanyl, azetidinyl, oxetanyl, thietanyl, azetidine (also known as azetidinyl), pyrrolyl, Pyrrolinyl, 3-pyrrolinyl, 1-pyrrolinyl, pyrrolidinyl, pyrazolidinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, tetrahydrothienyl, 1,2 , 4-Triazolyl and so on.
  • the heterocyclic group may be optionally further substituted with any substituent.
  • the spiro ring may be further substituted with any substituent.
  • the ring atom contains 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12, and still more preferably 5 to 10 atoms.
  • Non-limiting examples include And adamantane.
  • the bridged ring may be further substituted with any substituent.
  • Aryl refers to a substituted or unsubstituted 6 to 14-membered cyclic aromatic group, including monocyclic aromatic groups and condensed ring aromatic groups.
  • a 6 to 14 membered aromatic ring is preferred, and a 6 to 10 membered aromatic ring is more preferred, and non-limiting examples thereof include phenyl, naphthyl, anthryl, phenanthryl and the like.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.
  • Non-limiting examples include: The aryl group may be further substituted with any substituent.
  • the ring is more preferably 5 to 6 members.
  • heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Piperidinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include
  • the heteroaryl group may be further substituted with any substituent.
  • “Pharmaceutically acceptable salt” refers to maintaining the biological effectiveness and characteristics of the free acid or free base, and the free acid is passed through with a non-toxic inorganic base or organic base, or the free base is passed through with the non-toxic inorganic base or organic base. Those salts obtained by the reaction of toxic inorganic or organic acids.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, ingredients Granules, lubricants, binders, disintegrants, etc.
  • Prodrug refers to a compound that can be converted into a compound of the present invention with biological activity under physiological conditions or by solvolysis.
  • the prodrug of the present invention is prepared by modifying the phenol group in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl groups.
  • Examples of prodrugs include, but are not limited to, the phenolic hydroxyl group of the compound of the present invention and sodium salt derivatives of phosphoric acid.
  • Effective dose refers to the amount of a compound that causes a physiological or medical response in a tissue, system, or subject. This amount is sought and includes one or more of the compounds that are sufficient to prevent the disease or condition being treated when administered to the subject. The amount of the compound that occurs or alleviates the symptoms to a certain degree.
  • solvents refer to the compounds of the present invention or their salts, and they also include stoichiometric or non-stoichiometric solvents bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate.
  • “Optional” or “optionally” means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur.
  • “Alkyl group optionally substituted by F” means that the alkyl group may but need not be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • Optionally substituted by R means that it can be substituted or unsubstituted by R.
  • the number of R is not limited, as long as the principle of chemical bond is satisfied, preferably 1-5, 1-3, 1-2, One; when replaced by two or more Rs, R can be independently and freely selected, can be the same, can be different, and are independent of each other.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • the NMR shift ( ⁇ ) is given in units of 10-6 (ppm).
  • NMR is measured with (Bruker ADVANCE III 400) nuclear magnetic instrument, the solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), the internal standard is Tetramethylsilane (TMS), 1 HNMR information is listed in the following format: chemical shift (multiple peaks (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), Number of protons).
  • DMSO-d6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Tetramethylsilane
  • 1 HNMR information is listed in the following format: chemical shift (multiple peaks (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), Number of protons).
  • HPLC determination uses Agilent 1260DAD high pressure liquid chromatograph (Zorba x SB-C18 100 x 4.6mm).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • TEA triethylamine
  • LHMDS Lithium bis(trimethylsilyl)amide
  • m-CPBA m-chloroperoxybenzoic acid
  • DIPEA N,N-diisopropylethylamine
  • PE petroleum ether
  • EA ethyl acetate
  • NIS N-iodosuccinimide
  • dichloromethane 100 mL was added to the known compound 1a (5.0 g, 32.0 mmol), and under water bath cooling, Dess Martin oxidant (13.6 g, 32 mmol) was added in batches, and the mixture was stirred at room temperature for 2 hours.
  • a saturated aqueous sodium bicarbonate solution 100 mL was added to the reaction to quench the reaction, and then stirred at room temperature for 30 minutes.
  • the first step (4R)-1-(2,4-difluorophenyl)-7-isopropyl-4-methyl-4,5,6,7-tetrahydro-1H-indazole-3- Formic acid (2a).
  • the first step 3-((4R)-3-carboxy-7-isopropyl-4-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine-1 -Oxide (3a).
  • the second step 3-((4R)-3-((1-hydroxy-2-methylpropanol-2-yl)carbamoyl)-7-isopropyl-4-methyl-4,5, 6,7-Tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide (Compound 3).
  • Dissolve compound 5b (3.0g, 21.4mmol) in tetrahydrofuran (30mL), cool to minus 78 degrees Celsius, add LHMDS (1M, 23.5mL) to it, and then add diethyl oxalate (3.4g) to it after half an hour , 23.5mmol), warm to room temperature and react overnight.
  • Preparative HPLC separation method 1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phase A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonium acetate); b. gradient elution, the content of mobile phase A ranges from 5% to 50% ; C. Flow rate 12mL/min; d Elution time 20min. Compound 6 retention time: 13.5min.
  • the first step 7,7-difluoro-N-(1-(hydroxymethyl)cyclopentyl)-1-(pyrazin-2-yl)-4,5,6,7-tetrahydro-1H- Indazole-3-carboxamide (8b)
  • compound 8b is obtained by reacting compound 5g.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phase A and B: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20%-75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 12.8min.
  • the first step 3-(7,7-difluoro-3-((4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamyl)- 4,5,6,7-tetrahydro-1H-indazol-1-yl)-1-oxopyrazine
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 13.2min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 13.8min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 13.7min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 12.9min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 12.6min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 12.5min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 12.3min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 12.4min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 13.1min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 13.3min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 13.5min.
  • APD-371 is compound 699 in patent document WO2011025541.
  • the compounds of the present invention especially 1, 4, 5, 6, 7, 8, 19, 20 show high agonistic activity for CB 2 receptors.
  • Some compounds, especially compound 5 and compound 8 have a higher agonistic activity on CB 2 /CB. 1 receptor shows high selectivity.
  • Experimental purpose to administer the test substance to SD rats by a single dose intravenously and intragastrically, determine the concentration of the test substance in the rat's plasma, and evaluate the pharmacokinetic characteristics and bioavailability of the test substance in the rat.
  • Test animals Male SD rats, about 220 g, 6-8 weeks old, 6 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Test method On the day of the test, 6 SD rats were randomly grouped according to their body weight. One day before administration, fasting without water for 12-14 hours, and 4 hours after administration. Dosing according to Table 2.
  • 0.1ml of blood was taken from the orbit with isoflurane anesthetized and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma.
  • Plasma collection time points in group G1 0, 2, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h.
  • Plasma collection time points in group G2 0,5,15,30min,1,2,4,6,8,24h.
  • APD-371 is compound 699 in patent document WO2011025541.
  • the compound of the present invention especially compound 5, has high bioavailability, good pharmacokinetic characteristics, and long half-life.
  • Pot dihydrogen phosphate buffer solution weigh 1.3961 g of potassium dihydrogen phosphate, dissolve in water, dilute to 100 ml, and adjust the pH to 6.8 with 0.1 mol/L sodium hydroxide solution.
  • Test animals Male SD rats, about 200g, 6-8 weeks old, 12 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Test method On the day of the test, 24 SD rats were randomly grouped according to their body weight. One day before administration, fasting without water for 12-14 hours, and 4 hours after administration. Dosing according to Table 6.
  • APD-371MTD is 300mg/kg; compound 5MTD is 1000mg/kg.

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Abstract

一种式(I)所示的六氢化苯并吡唑类化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物、前药及其药物组合物、制备方法，以及在由***素CB2受体介导的疾病的预防和治疗中的用途。

Description

一种六氢化苯并吡唑衍生物及其制备 技术领域
本发明涉及一种六氢化苯并吡唑类化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物、前药及其药物组合物、制备方法，以及在由***素CB2受体介导的疾病的预防和治疗中的用途。
背景技术
神经病理性疼痛是由于外周或中枢神经通路受到损伤而产生的，这种疼痛导致患者对于疼痛和无害刺激出现持续存在的自发性疼痛以及超敏反应。神经性疼痛的潜在病因差异很大，但通常具有相似的临床特征。一些导致神经性疼痛的最常见病理是糖尿病性神经病、截肢、手术以及疱疹后神经痛等。研究表明，高达7-8％的成人患有神经病性疼痛，患病率不断在上升，且预计在老龄化人群中将进一步增加。除个人痛苦之外，由于失业和社会能力的丧失导致治疗成本的增加，同时还常常伴随出现焦虑和抑郁等并发症。
克罗恩病的主要症状包括腹痛、腹泻和疲劳，体重减轻，发热，生长发育迟缓，贫血，反复发作的肛瘘或其他肠外表现。药物治疗包括氨基水杨酸制剂、糖皮质激素、免疫抑制剂、抗菌药物和抗TNF-α单抗等。目前尚无管理克罗恩病相关腹痛的药物。
疼痛作为一类临床最常见的病症，是患者寻求医疗服务的主要因素之一，目前市场上广泛使用的止痛药会引发有害副作用，治疗效果不理想，新型止痛药的开发刻不容缓。
***提取物被用于镇痛已有数个世纪的历史。除了Delta-9-THC,***二酚(CBD),还有多种内源性配体物质，以及化学合成的***素(cannabinoid)，通过结合***素受体发挥镇痛、产生欣快感等作用。而且***素是在植物和动物中均发现的一类细胞外信号传导分子。来自这些分子的信号在动物中通过两种G蛋白偶联受体即***素受体1(CB1)和***素受体2(CB2)来介导。CB1最大量地表达在CNS的神经元中，但也以较低浓度存在于多种外周组织和细胞中(Matsuda，L.A.et al.(1990)Nature 346：561-564)。相反地，CB2主要但不绝对地表达在非神经组织例如造血细胞、内皮细胞、成骨细胞、破骨细胞、内分泌胰腺及癌性细胞系中(Munro，S.et al.(1993)Nature 365:61-65；和Pache，P.etal.(2006)Pharmacol.Rev.58(3)：389-462)。中枢的CB1分布在大脑皮质和边缘***，负责在受到cannabinoid激活后发挥镇痛作用并引起行为学改变。CB1虽然可以介导强效的镇痛作用，但会引起欣快、共济失调、眩晕等精神类症状，同时可能产生成瘾和耐 受，所以限制了其在镇痛领域的使用。外周CB2主要分布在免疫细胞，在疼痛和炎症信号中发挥作用。此外，CB2在外周神经纤维和伤害神经末梢也有分布。CB2激动后通过抑制中性粒细胞、巨噬细胞等产生毒素和炎性介质来发挥镇痛作用，也可以阻断损伤性神经的兴奋传导。CB2在小鼠的脑干、大脑皮层和小脑中有表达，但表达量非常低，约为脾脏的3.4％。
外周选择性CB2激动剂理论上可以避免CB1R相关的中枢精神类副作用，并在多个临床前模型显示出良好的镇痛效果。数个CB2选择性激动剂因在临床试验中镇痛药效不足而中止在镇痛领域的开发，包括JBT-101、LY2828360等。原因可能如下：虽然表现出一定选择性，但对CB1仍有激动作用，所以可能导致有效剂量发生不良事件，安全剂量下药效不足；对CB1有激动作用可能导致在动物模型下药效显著而转化后药效不足的情况。CB2激动剂会具有功能选择性，CB1/2下游包括腺苷环化酶合成、ERK信号通路激活、离子流改变、内化作用、β-arrestin等，不同的药物对下游的激活有功能偏向性。
发明内容
本发明的目的是介绍一类新型的有效、安全、选择性高、长效、药代动力学特征好的***素CB2激动剂。
本发明涉及一种式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药：
Figure PCTCN2020114448-appb-000001
其中，
其中，
R 1选自-L 1-L 2-L 3-L 4；
L 1选自C 1-6亚烷基、C 3-7亚环烯基、C 3-7亚环烷基、C 3-6不饱和亚环烃基、C 3-6亚杂环基、C 6-10亚芳基、C 5-10亚杂芳基、C 4-12桥环、C 4-12并环、C 5-10螺环或者不存在，所述的亚烷基、亚环烯基、亚环烷基、不饱和亚环烃基、亚杂环基、亚芳基、亚杂芳基、桥环、并环、螺环各自独立任选被如下取代基取代：卤素、氰基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 2-6炔基-C 3-6环烷基、C 1-6烷氧基、羟基取代的C 1-6烷基、卤代C 1-6烷基、 苯环、-C 1-6烷基-O-卤代烷基、-C(O)O-C 1-6烷基或者C 3-6环烷基；
L 2选自C 1-6亚烷基、C 3-7亚环烷基、C 3-6亚杂环基、C 5-10亚杂芳基、-C(O)NH-、-C(O)-、-C(O)O-或者不存在，所述的亚烷基、亚环烷基、亚杂环基、亚杂芳基各自独立任选被如下取代基取代：C 1-6烷基或卤素；
L 3选自C 1-6亚烷基或者不存在；
L 4选自H、卤素、羟基、氨基、脲基、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷氧基、C 3-6杂环基、C 2-6炔基、C 6-10芳基、C 5-10杂芳基、-NHC 1-6烷基、-N(C 1-6烷基)C 1-6烷基、-NHC(O)C 1-6烷基、-C(O)NHC 1-6烷基、-NH-C 6-10芳基、-NH-C 3-7环烷基、-C(O)-C 6-10芳基、-O-C 6-10芳基、-O-C 6-10杂芳基、-O-C 1-6亚烷基-COOH、-C(O)NH 2、-COOH、C 4-12桥环、C 4-12并环或者C 5-10螺环，所述的烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、炔基、桥环、螺环、并环任选被如下取代基取代：卤素、氰基、羟基、氨基、C 1-6烷基、C 1-6卤代烷基或者C 1-6烷氧基；
R 2、R 3各自独立选自H、F、Cl、氰基、羟基或者C 1-6烷基；
R 4、R 5、R 6、R 7各自独立选自H、F、Cl、氨基、氰基、羟基、C 1-6烷基或者C 1-6卤代烷基；
R 8、R 9各自独立选自H、F、Cl、C 1-6烷基，所述的烷基任选被以下取代基取代：氰基、F或者Cl，或者R 8与R 9一起形成C 2-6烯基或者C 3-6环烷基；
R 10选自H或者C 1-6烷基；
R 11选自芳基或杂芳基，所述的芳基或杂芳基任选被以下取代基取代：F、Cl、C 1-6烷基或者C 1-6烷氧基，所述的杂芳基包含选自N、O、S杂原子及其氧化态；
条件是：当R 11选自芳基及取代芳基时，R 1选自
Figure PCTCN2020114448-appb-000002
或者
Figure PCTCN2020114448-appb-000003
本发明涉及一种式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药：
Figure PCTCN2020114448-appb-000004
其中，
R 1选自-L 1-L 2-L 3-L 4；
L 1选自C 1-6亚烷基、C 3-7亚环烯基、C 3-7亚环烷基、C 3-6不饱和亚环烃基、C 3-6亚杂环基、C 6-10亚芳基、C 5-10亚杂芳基、C 4-12桥环、C 4-12并环、C 5-10螺环或者不存在，所述的亚烷基、亚环烯基、亚环烷基、不饱和亚环烃基、亚杂环基、亚芳基、亚杂芳基、桥环、并环、螺环各自独立任选被如下取代基取代：卤素、氰基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 2-6炔基-C 3-6环烷基、C 1-6烷氧基、羟基取代的C 1-6烷基、卤代C 1-6烷基、苯环、C 1-6烷基-O-卤代烷基、-C(O)O-C 1-6烷基或者C 3-6环烷基；
L 2选自C 1-6亚烷基、C 3-7亚环烷基、C 3-6亚杂环基、C 5-10亚杂芳基、-C(O)NH-、-C(O)-、-C(O)O-或者不存在，所述的亚烷基、亚环烷基、亚杂环基、亚杂芳基各自独立任选被如下取代基取代：C 1-6烷基或卤素；
L 3选自C 1-6亚烷基或者不存在；
L 4选自H、卤素、羟基、氨基、脲基、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷氧基、C 3-6杂环基、C 1-6卤代烷基、C 2-6炔基、C 6-10芳基、C 5-10杂芳基、-NHC 1-6烷基、-N(C 1-6烷基)C 1-6烷基、-NHC(O)C 1-6烷基、-C(O)NHC 1-6烷基、-NH-C 6-10芳基、-NH-C 3-7环烷基、-C(O)-C 6-10芳基、-O-C 6-10芳基、-O-C 6-10杂芳基、-O-C 1-6烷基-COOH、-C(O)NH 2、-COOH、C 4-12桥环、C 4-12并环或者C 5-10螺环，所述的烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、炔基、桥环、螺环、并环任选被如下取代基取代：卤素、氰基、羟基、氨基、C 1-6烷基、C 1-6卤代烷基或者C 1-6烷氧基；
R 2、R 3各自独立选自H、F、Cl、氰基、羟基或者C 1-6烷基；
R 4、R 5、R 6、R 7各自独立选自H、F、Cl、氨基、氰基、羟基、C 1-6烷基或者C 1-6卤代烷基；
R 8、R 9各自独立选自H、F、Cl、C 1-6烷基，所述的烷基任选被以下取代基取代：氰基、F或者Cl，或者R 8与R 9一起形成C 2-6烯基或者C 3-6环烷基；
R 10选自H或者C 1-6烷基；
R 11选自芳基或杂芳基，所述的芳基或杂芳基任选被以下取代基取代：F、Cl、C 1-6烷基或者C 1-6烷氧基，所述的杂芳基包含选自N、O、S杂原子及其氧化态；
条件是：当R 11选自芳基及取代芳基时，R 1选自
Figure PCTCN2020114448-appb-000005
或者
Figure PCTCN2020114448-appb-000006
本发明涉及一种式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药：
Figure PCTCN2020114448-appb-000007
R 1选自C 1-6烷基、C 3-6环烷基、C 3-6杂环烷基、C 3-6不饱和环烃基、C 6-10芳基、C 5-10杂芳基、C 4-12桥环、C 4-12并环、C 5-10螺环，所述的烷基、环烷基、不饱和环烃基、杂环烷基、芳基、杂芳基、桥环、并环或者螺环任选被以下取代基取代：F、Cl、羟基、氰基、C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、苯环、-C(O)O-C 1-6烷基、-C 1-6烷基-OC 1-6烷基或者C 3-6环烷基；R 1选自C 1-6烷基、C 3-6环烷基、C 3-6杂环烷基、C 3-6不饱和环烃基、C 6-10芳基、C 5-10杂芳基、C 4-12桥环、C 4-12并环、C 5-10螺环，所述的烷基、环烷基、不饱和环烃基、杂环烷基、芳基、杂芳基、桥环、并环或者螺环任选被以下取代基取代：F、Cl、羟基、氰基、C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、苯环、-C(O)O-C 1-6烷基或者C 3-6环烷基；在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000008
吲哚基、吡咯基、吡啶基、哌啶基、苯基、环己基、环戊基、吡嗪、金刚烷基、哌嗪、吗啉基、
Figure PCTCN2020114448-appb-000009
Figure PCTCN2020114448-appb-000010
或者
Figure PCTCN2020114448-appb-000011
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000012
吲哚基、吡咯基、吡啶基、哌啶基、苯基、环己基、环戊基、吡嗪、金刚烷基、哌嗪、吗啉基、
Figure PCTCN2020114448-appb-000013
Figure PCTCN2020114448-appb-000014
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000015
吲哚基、吡咯基、吡啶基、哌啶基、苯基、环己基、环戊基、吡嗪、金刚烷基、哌嗪、吗啉基、
Figure PCTCN2020114448-appb-000016
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000017
Figure PCTCN2020114448-appb-000018
某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000019
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000020
金刚烷基、
Figure PCTCN2020114448-appb-000021
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000022
Figure PCTCN2020114448-appb-000023
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000024
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000025
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000026
R 2、R 3各自独立选自H、F、Cl、氰基、羟基、C 1-6烷氧基或者C 1-6烷基；在某些实 施方案中，R 2、R 3各自独立选自H、F、Cl、氰基、羟基或者C 1-6烷基；在某些实施方案中，R 2、R 3各自独立选自H、F、Cl、甲基、乙基、异丙基、叔丁基；在某些实施方案中，R 2、R 3各自独立选自H、F或者甲基；
R 4、R 5、R 6、R 7各自独立选自H、F、Cl、氨基、氰基、羟基、C 1-6烷基或者C 1-6卤代烷基；在某些实施方案中，R 4、R 5、R 6、R 7各自独立选自H、F、氰基、羟基或者C 1-6烷基；R 4、R 5、R 6、R 7各自独立选自H或者C 1-6烷基；在某些实施方案中，R 4、R 5、R 6、R 7各自独立选自H、甲基、乙基、异丙基；
R 8、R 9各自独立选自H、F、Cl、氰基、羟基、C 1-6烷氧基或者C 1-6烷基；R 8、R 9各自独立选自H、F、Cl、C 1-6烷基，所述的烷基任选被以下取代基取代：氰基、F或者Cl，或者R 8与R 9一起形成C 2-6烯基或者C 3-6环烷基；
R 10选自H或者C 1-6烷基；
R 11选自芳基或杂芳基，所述的芳基或杂芳基任选被以下取代基取代：F、Cl、C 1-6烷基或者C 1-6烷氧基；在某些实施方案中R 11选自
Figure PCTCN2020114448-appb-000027
或者
Figure PCTCN2020114448-appb-000028
在某些实施方案中，R 11选自
Figure PCTCN2020114448-appb-000029
条件是：当R 11选自芳基及取代芳基时，R 1选自
Figure PCTCN2020114448-appb-000030
或者
Figure PCTCN2020114448-appb-000031
本发明涉及一种式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药：
Figure PCTCN2020114448-appb-000032
R 1选自C 1-6烷基、C 3-6环烷基、C 3-6杂环烷基、C 3-6不饱和环烃基、C 6-10芳基、C 5-10杂芳基、C 4-12桥环、C 4-12并环、C 5-10螺环，所述的烷基、环烷基、不饱和环烃基、杂环烷基、芳基、杂芳基、桥环、并环或者螺环任选被以下取代基取代：F、Cl、羟基、氰基、C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、C 3-6杂环烷基、苯环、-C(O)O-C 1-6烷基、-C 1-6烷基-OC 1-6烷基或者C 3-6环烷基；在某些实施方案中，R 1选自C 1-6烷基、C 3-6环烷基、 C 3-6杂环烷基、C 3-6不饱和环烃基、C 6-10芳基、C 5-10杂芳基、C 4-12桥环、C 4-12并环、C 5-10螺环，所述的烷基、环烷基、不饱和环烃基、杂环烷基、芳基、杂芳基、桥环、并环或者螺环任选被以下取代基取代：F、Cl、羟基、氰基、C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、苯环、-C(O)O-C 1-6烷基、-C 1-6烷基-OC 1-6烷基或者C 3-6环烷基；在某些实施方案中，R 1选自C 1-6烷基、C 3-6环烷基、C 3-6杂环烷基、C 3-6不饱和环烃基、C 6-10芳基、C 5-10杂芳基、C 4-12桥环、C 4-12并环、C 5-10螺环，所述的烷基、环烷基、不饱和环烃基、杂环烷基、芳基、杂芳基、桥环、并环或者螺环任选被以下取代基取代：F、Cl、羟基、氰基、C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、苯环、-C(O)O-C 1-6烷基或者C 3-6环烷基；在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000033
吲哚基、吡咯基、吡啶基、哌啶基、苯基、环己基、环戊基、吡嗪、金刚烷基、哌嗪、吗啉基、
Figure PCTCN2020114448-appb-000034
Figure PCTCN2020114448-appb-000035
或者
Figure PCTCN2020114448-appb-000036
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000037
吲哚基、吡咯基、吡啶基、哌啶基、苯基、环己基、环戊基、吡嗪、金刚烷基、哌嗪、吗啉基、
Figure PCTCN2020114448-appb-000038
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000039
Figure PCTCN2020114448-appb-000040
在 某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000041
金刚烷基、
Figure PCTCN2020114448-appb-000042
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000043
Figure PCTCN2020114448-appb-000044
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000045
Figure PCTCN2020114448-appb-000046
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000047
Figure PCTCN2020114448-appb-000048
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000049
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000050
在某些实施方案中，R 1选自
Figure PCTCN2020114448-appb-000051
R 2、R 3各自独立选自H、F、Cl、氰基、羟基、C 1-6烷氧基或者C 1-6烷基；在某些实施方案中，R 2、R 3各自独立选自H、F、Cl、氰基、羟基或者C 1-6烷基；在某些实施方案中，R 2、R 3各自独立选自H、F、Cl、甲基、乙基、异丙基、叔丁基；在某些实施方案中，R 2、R 3各自独立选自H、F或者甲基；
R 4、R 5、R 6、R 7各自独立选自H、F、Cl、氨基、氰基、羟基、C 1-6烷基或者C 1-6卤代烷基；在某些实施方案中，R 4、R 5、R 6、R 7各自独立选自H、F、氰基、羟基或者C 1-6烷基；R 4、R 5、R 6、R 7各自独立选自H或者C 1-6烷基；在某些实施方案中，R 4、R 5、R 6、R 7各自独立选自H、甲基、乙基、异丙基；
R 8、R 9各自独立选自H、F、Cl、氰基、羟基、C 1-6烷氧基或者C 1-6烷基；R 8、R 9各自独立选自H、F、Cl、C 1-6烷基，所述的烷基任选被以下取代基取代：氰基、F或者Cl，或者R 8与R 9一起形成C 2-6烯基或者C 3-6环烷基；
R 10选自H或者C 1-6烷基；
R 11选自芳基或杂芳基，所述的芳基或杂芳基任选被以下取代基取代：F、Cl、C 1-6烷基或者C 1-6烷氧基；在某些实施方案中R 11选自
Figure PCTCN2020114448-appb-000052
或者
Figure PCTCN2020114448-appb-000053
在某些实施方案中，R 11选自
Figure PCTCN2020114448-appb-000054
条件是：当R 11选自芳基及取代芳基时，R 1选自
Figure PCTCN2020114448-appb-000055
或者
Figure PCTCN2020114448-appb-000056
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
R 1选自
Figure PCTCN2020114448-appb-000057
吲哚基、吡咯基、吡啶基、哌啶基、苯基、环己基、环戊基、吡嗪、金刚烷基、哌嗪、吗啉基、
Figure PCTCN2020114448-appb-000058
Figure PCTCN2020114448-appb-000059
或者
Figure PCTCN2020114448-appb-000060
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：R 1选自
Figure PCTCN2020114448-appb-000061
Figure PCTCN2020114448-appb-000062
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
R 1选自
Figure PCTCN2020114448-appb-000063
吲哚基、吡咯基、吡啶基、哌啶基、苯基、环己基、环戊基、吡嗪、金刚烷基、哌嗪、吗啉基、
Figure PCTCN2020114448-appb-000064
Figure PCTCN2020114448-appb-000065
或者
Figure PCTCN2020114448-appb-000066
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
R 1选自
Figure PCTCN2020114448-appb-000067
吲哚基、吡咯基、吡啶基、哌啶基、苯基、环己基、环戊基、吡嗪、金刚烷基、哌嗪、吗啉基、
Figure PCTCN2020114448-appb-000068
Figure PCTCN2020114448-appb-000069
或者
Figure PCTCN2020114448-appb-000070
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
R 11选自
Figure PCTCN2020114448-appb-000071
或者
Figure PCTCN2020114448-appb-000072
条件是：当R 11选自
Figure PCTCN2020114448-appb-000073
时，R 1选自
Figure PCTCN2020114448-appb-000074
在某些实施方案中，R 11选自
Figure PCTCN2020114448-appb-000075
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
R 11选自
Figure PCTCN2020114448-appb-000076
或者
Figure PCTCN2020114448-appb-000077
条件是：当R 11选自
Figure PCTCN2020114448-appb-000078
时，R 1选自
Figure PCTCN2020114448-appb-000079
在某些实施方案中，R 11选自
Figure PCTCN2020114448-appb-000080
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
R 1选自C 1-6烷基或者C 3-6环烷基，所述的烷基或者环烷基任选被以下取代基取代：F、Cl、C 1-6烷基或者羟基；
R 2、R 3各自独立选自H、F、Cl或者C 1-6烷基；
R 4、R 5、R 6、R 7各自独立选自H或者C 1-6烷基；
R 8、R 9各自独立选自H、F、Cl、C 1-6烷基，所述的烷基任选被以下取代基取代：氰基、F或者Cl，或者R 8与R 9一起形成C 2-6烯基或者C 3-6环烷基；
R 10选自H；
R 11选自
Figure PCTCN2020114448-appb-000081
或者
Figure PCTCN2020114448-appb-000082
条件是：当R 11选自
Figure PCTCN2020114448-appb-000083
时，R 1选自
Figure PCTCN2020114448-appb-000084
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
R 1选自
Figure PCTCN2020114448-appb-000085
或者
Figure PCTCN2020114448-appb-000086
R 2、R 3各自独立选自H、F或者甲基；
R 4、R 5、R 6、R 7各自独立选自H；
R 8、R 9各自独立选自H、F、异丙基、
Figure PCTCN2020114448-appb-000087
或者R 8与R 9一起形成2-甲基丙烯基或者环丙基；
R 10选自H；
R 11选自
Figure PCTCN2020114448-appb-000088
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
R 1选自
Figure PCTCN2020114448-appb-000089
或者
Figure PCTCN2020114448-appb-000090
R 2、R 3各自独立选自H、F或者甲基；
R 4、R 5、R 6、R 7各自独立选自H；
R 8、R 9各自独立选自H、F、异丙基，或者R 8与R 9一起形成2-甲基丙烯基或者环丙基；
R 10选自H；
R 11选自
Figure PCTCN2020114448-appb-000091
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
R 1选自
Figure PCTCN2020114448-appb-000092
或者
Figure PCTCN2020114448-appb-000093
R 2、R 3各自独立选自H、F或者甲基；
R 4、R 5、R 6、R 7各自独立选自H；
R 8、R 9各自独立选自H、F、异丙基、
Figure PCTCN2020114448-appb-000094
或者R 8与R 9一起形成2-甲基丙烯基或者环丙基；
R 10选自H；
R 11选自
Figure PCTCN2020114448-appb-000095
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
R 1选自
Figure PCTCN2020114448-appb-000096
或者
Figure PCTCN2020114448-appb-000097
R 2、R 3各自独立选自H、F或者甲基；
R 4、R 5、R 6、R 7各自独立选自H；
R 8、R 9各自独立选自H、F、异丙基；
R 10选自H；
R 11选自
Figure PCTCN2020114448-appb-000098
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中化合物结构如下：
Figure PCTCN2020114448-appb-000099
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中化合物结构如下：
Figure PCTCN2020114448-appb-000100
本发明所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中化合物结构如下：
Figure PCTCN2020114448-appb-000101
Figure PCTCN2020114448-appb-000102
优选如下化合物：
Figure PCTCN2020114448-appb-000103
本发明还涉及一种药物组合物，所述的组合物包括：有效剂量的任一本发明的化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，或进一步包括一种或多种其他治疗剂以及药学上可接受的载体或赋形剂。
本发明还涉及通式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药或者含本发明化合物的组合物在制备用于治疗由CB2受体介导的疾病的药物中的用途。
本发明涉及通式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药或者含本发明化合物的组合物在制备用于治疗疼痛的药物中的用途。
在本发明一些具体实施方案中，疼痛可以选自：骨痛、关节痛、肌肉疼痛、牙痛、偏头痛、头痛、炎性疼痛、神经病理性疼痛、克罗恩病相关腹痛、由于治疗剂的不良作用而引起的疼痛及与选自下述的疾病相关的疼痛：骨关节炎、癌症、多发性硬化、变应性应答、肾炎综合征、硬皮病、甲状腺炎、糖尿病性神经病、纤维肌痛、与HIV相关的神经病、坐骨神经痛和自身免疫性疾病。
本发明还涉及通式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药或者含本发明化合物的组合物在制备用于治疗神经病理性疼痛药物中的用途。
本发明还涉及通式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药或者含本发明化合物的组合物在制备用于治 疗克罗恩病相关腹痛药物中的用途。
本发明还涉及通式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药或者含本发明化合物的组合物用于治疗由CB2受体介导的疾病的方法。
本发明还涉及通式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药或者含本发明化合物的组合物用于治疗疼痛的方法。
在本发明一些具体实施方案中，疼痛可以选自：骨痛、关节痛、肌肉疼痛、牙痛、偏头痛、头痛、炎性疼痛、神经病理性疼痛、克罗恩病相关腹痛由于治疗剂的不良作用而引起的疼痛及与选自下述的疾病相关的疼痛：骨关节炎、癌症、多发性硬化、变应性应答、肾炎综合征、硬皮病、甲状腺炎、糖尿病性神经病、纤维肌痛、与HIV相关的神经病、坐骨神经痛和自身免疫性疾病。
本发明还涉及通式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药或者含本发明化合物的组合物治疗神经病理性疼痛的方法。
本发明还涉及通式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药或者含本发明化合物的组合物治疗克罗恩病相关腹痛的方法。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。
“烷基”是指直链和支链的一价饱和烃基，主链包括1至10个碳原子，优选为1至8个碳原子，进一步优选为1至6个碳原子，更优选为1至4个碳原子的直链与支链基团，最优选1至2个碳原子，烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、正己基、正庚基、正辛基、正壬基和正癸基等；所述的烷基可以进一步被任意取代基取 代。
“亚烷基”是指直链和支链的二价饱和烃基，包括-(CH 2) v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等；所述的亚烷基可以任选进一步被任意取代基取代。当亚烷基中的取代基数量大于等于2个时，取代基可以稠合在一起形成环状结构。
“烷氧基”是指O-烷基的一价基团(-O-烷基)，其中，烷基如本文所定义，烷氧基实施例包括但不限于甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、1-戊氧基、2-戊氧基、3-戊氧基、2-甲基-2-丁氧基、3-甲基-2-丁氧基、3-甲基-1-丁氧基和2-甲基-1-丁氧基等。
“烯基”是指直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括2至10个碳原子，进一步优选2至6个碳原子，更优选在主链上有2至4个碳原子，烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；所述的烯基可以任选进一步被任意基团取代。
“炔基”是指直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，主链包括2至10个碳原子，进一步优选2至6个碳原子，更优选在主链上有2至4个碳原子，炔基实施例包括但不限于乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、4-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基和4-癸炔基等；所述的炔基可以任选进一步被任意取代基取代。
“环烷基”是指一价饱和的碳环烃基，单环，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。所述的环烷基可以任选进一步被任意取代基所取代。
“不饱和环烃基”是指含有不饱和键(比如双键)的、不具有芳香性的碳环烃基，非限制性实施例包括环丙烯基、环丁烯基、1,4-环己二烯、1,3-环戊二烯等。所述的环烷基可以任选进一步被任意取代基所取代。
“杂环基”是指是指饱和或不饱和的至少含1个杂原子的环烃基，单环，杂原子为N、 O、S、P及其氧化形态，非限制性实施例包括氮杂环丙基、氧杂环丙基、硫杂环丙基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吖丁基(又名氮杂环丁基)、吡咯基、吡咯啉基、3-吡咯啉基、1-吡咯啉基、吡咯烷基、吡唑烷基、2-吡唑啉基、咪唑基、吡唑基、四氢呋喃基、四氢噻吩基、1,2,4-***基等。所述的杂环基可以任选进一步被任意取代基所取代。
“螺环”是指取代的或未取代的单环之间共用一个原子(比如碳原子，称螺原子)的5至20元多环基团，其可以包含0至5个双键，且可以含有0至5个选自N、O或S(＝O)n的杂原子。优选为6至14元，进一步优选为6至12元，更有选6至10元，其非限定性实例包括
Figure PCTCN2020114448-appb-000104
。螺环可以被任意取代基进一步取代。
“并环”是指***中的每个环与体系中的其他环共享毗邻的一对原子(比如碳原子)的多环基团，其中一个或多个环可以含有0个或多个双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个选自N、S(＝O) n或O的杂原子。优选为5至20元，进一步优选为5至14元，更有选5至12元，再进一步优选5至10元。非限定性实例包括
Figure PCTCN2020114448-appb-000105
Figure PCTCN2020114448-appb-000106
并环可以进一步被任意取代基取代。
“桥环”是指任意两个环共用两个不直接连接的原子(比如碳原子)的多环基团，可以含有0个或多个双键，且可以是取代的或未取代的，并环体系中的任意环可以含0至5个选自N、S(＝O)n或O杂原子或基团(其中n为1、1、2)。环原子包含5至20个原子，优选为5至14个原子，进一步优选5至12个，在进一步优选5至10个。非限定性实例包括
Figure PCTCN2020114448-appb-000107
和金刚烷。桥环可以进一步被任意取代基取代。
“芳基”是指取代的或未取代的6至14元环状芳香基团，包括单环芳香基和稠环芳香基。优选6至14元芳香环，进一步优选6至10元芳香环，其非限制性实例包括苯基、萘基、蒽基和菲基等。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 PCTCN2020114448-appb-000108
Figure PCTCN2020114448-appb-000109
芳基可以进一步被任意取代基取代。
“杂芳基”是指取代或未取代的5至14元芳香环，且含有1至5个选自N、O或S(＝O) n杂原子或基团，优选5至10元杂芳香环，进一步优选5至6元。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉、硫代吗啉、1,3-二噻烷、苯并咪唑、苯并吡啶、吡咯并吡啶等。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 PCTCN2020114448-appb-000110
杂芳基可以进一步被任意取代基取代。
“药学上可接受的盐”指的是保持游离酸或游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或有机碱，或所述的游离碱通过与无毒的无机酸或有机酸反应获得的那些盐。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括 微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
“前药”是指可以在生理条件下或通过溶剂解转化为具有生物活性的本发明化合物的化合物。本发明的前药通过修饰在该化合物中的酚基团来制备，该修饰可以按常规的操作或在体内被除去，而得到母体化合物。当本发明的前体药物被施予哺乳动物个体时，前体药物被割裂而分别形成游离的羟基。前药的例子包括，但不限于本发明化合物的酚羟基和磷酸成钠盐衍生物。
“有效剂量”指引起组织、***或受试者生理或医学反应的化合物的量，此量是所寻求的，包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
“溶剂化物”指本发明化合物或其盐，它们还包括以分子间非共价力结合的化学计量或非化学计量的溶剂。当溶剂为水时，则为水合物。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。
“任选被R取代”表示可以被R取代或不被取代，当取代时，R的个数不限定，满足化学键原则即可，优选1-5个、1-3个、1-2个、1个；当被2个及以上R取代时，R可以独立自由选择，可以相同，可以不相同，互相独立。
具体实施方式
以下结合实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。
NMR位移(δ)以10-6(ppm)的单位给出。
NMR的测定是用(Bruker ADVANCE III 400)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)， 1HNMR信息以下列格式来列表：化学位移(多重峰(s,单峰；d,双重峰；t,三重峰；q,四重峰；m,多重峰),质子数)。
MS的测定用(Agilent 6120B(ESI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorba x SB-C18 100 x 4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的 硅胶板采用的规格是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。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
简写说明：
HATU：2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐；
DMF：N,N-二甲基甲酰胺；
TEA：三乙胺；
LHMDS：双(三甲基硅基)氨基锂；
DCM：二氯甲烷；
m-CPBA：间氯过氧苯甲酸；
DIPEA：N,N-二异丙基乙胺；
PE：石油醚；EA：乙酸乙酯；
NIS：N-碘代琥珀酰亚胺。
中间体Int-1
2-氨基-4,4,4-三氟-3,3-二甲基丁-1-醇(中间体Int-1)
2-amino-4,4,4-trifluoro-3,3-dimethylbutan-1-ol
Figure PCTCN2020114448-appb-000111
第一步：3,3,3-三氟-N-甲氧-N,2,2-三甲基丙酰胺(Int-1-b)
3,3,3-trifluoro-N-methoxy-N,2,2-trimethylpropanamide
氮气保护，室温下，向3,3,3-三氟-2,2-二甲基丙酸(25g,0.16mol)，中依次加入DMF(50mL)，TEA(32mg,0.25mmol)，HATU(77mg,0.2mmol)，N-甲基-N-甲氧基胺盐酸盐(17.2g,0.176mol)，室温下搅拌过夜。向反应中加入饱和碳酸氢钠水溶液(200mL)淬灭 反应，300ml乙酸乙酯萃取，静置分层，水相再用二氯甲烷(200mL×3)萃取三次，合并后的有机相用无水硫酸钠干燥，减压浓缩后得到残留物，即粗品，粗品经柱层析(洗脱剂PE:EA＝10:1)得到Int-1-b(22g,收率69％)，淡黄色油状。
LC-MS(ESI)：m/z＝200.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ3.70(s,3H),3.21(s,3H),1.5(s,6H)。
第二步：3,3,3-三氟-2,2-二甲基丙醛(Int-1-c)
3,3,3-trifluoro-2,2-dimethylpropanal
氮气保护，室温下，250mL单口瓶中加入THF(50mL)，0℃下加入LiAlH 4(3.43g,90mmol)，缓慢滴入化合物Int-1-b(15g,75.3mmol)，室温下搅拌2h。在0℃下，向反应中依次加入水(3.5mL)、NaOH(15％,3.5mL)、水(3.5mL)淬灭反应，搅拌30min，再加入***200mL剧烈搅拌30min，经硅藻土过滤，减压浓缩后得到粗品Int-1-c(14g)，无色油状化合物，无需纯化，直接用于下一步反应。
LC-MS(ESI)：m/z＝141.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ9.69(s,1H),1.30(s,6H)。
第三步：2-氨基-4,4,4-三氟-3,3-二甲基丁腈(Int-1-d)
2-amino-4,4,4-trifluoro-3,3-dimethylbutanenitrile
氮气保护，室温下，向单口瓶中依次加入Int-1-c(4.5g)，NH 3/MeOH(10mL,70mmol)，NH 4Cl(1.62g,30mmol)，室温下搅拌30min，再加入KCN(1.95g,30mmol)，继续搅拌反应过夜。将反应液减压浓缩得到粗品。粗品溶于***10mL，0℃下缓慢加入2N HCl 1,4-二氧六环溶于搅拌析出白色固体Int-1-d(1.65g,收率34.78％)。
LC-MS(ESI)：m/z＝167.1[M+H] +。
第四步：2-氨基-4,4,4-三氟-3,3-二甲基丁酸(Int-1-e)
2-amino-4,4,4-trifluoro-3,3-dimethylbutanoic acid
氮气保护，室温下，向单口瓶中依次加入Int-1-d(2.05g,10.14mmol)，6N HCl(20mL)，回流下搅拌36h。冷却至室温，向反应中加入氢氧化钠水溶液调节pH至8，水相用二氯甲烷(20mL)洗涤回收原料0.4g，水相再调pH至7，减压浓缩至固体，得到粗品白色固体Int-1-e(1.3g)。
LC-MS(ESI)：m/z＝186.2[M+H] +。
第五步：2-氨基-4,4,4-三氟-3,3-二甲基丁-1-醇(Int-1)
2-amino-4,4,4-trifluoro-3,3-dimethylbutan-1-ol
氮气保护，室温下，50mL单口瓶中加入THF(20mL)，0℃下加入LiAlH 4(270mg,8.43 mmol)，缓慢滴入化合物Int-1-e(1.3g,7mmol)，回流下搅拌3h反应完全。在0℃下，向反应中依次加入水(0.27mL)、NaOH(15％,0.27mL)、水(0.27mL)淬灭反应，搅拌30min，再加入THF(50mL)剧烈搅拌30min，NaSO 4干燥，经硅藻土过滤，减压浓缩后得到Int-1(0.82g,68.23％)，淡黄色油状化合物，无需纯化，直接用于下一步反应。
LC-MS(ESI)：m/z＝172.2[M+H] +。
实施例1
3-((4R)-3-((s)-1-羟基-3,3-二甲基丁烷-2-基氨基甲酰)-7-异丙基-4-甲基-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物1)
3-((4R)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-7-isopropyl-4-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000112
第一步：(2S,5R)-2-异丙基-5-甲基环己酮
(2S,5R)-2-isopropyl-5-methylcyclohexanone(1b)
室温下，向已知化合物1a(5.0g,32.0mmol)中加入二氯甲烷(100mL)，水浴冷却下，分批次加入戴斯马丁氧化剂(13.6g,32mmol)，室温搅拌2小时。向反应中加入饱和碳酸氢钠水溶液(100mL)淬灭反应，再室温搅拌30分钟。垫硅藻土过滤，母液静置分层，水相用二氯甲烷(100mL)反萃，合并后的有机相用无水硫酸钠干燥，减压浓缩后残留物用硅胶柱层析(洗脱剂PE:EA＝20:1-5:1)分离提纯得到1b(3.4g,69％)。
LC-MS(ESI)：m/z＝155.2[M+H] +。
第二步：(4R)-7-异丙基-4-甲基-3a,4,5,6-四氢苯并呋喃-2,3-二酮(1c)
(4R)-7-isopropyl-4-methyl-3a,4,5,6-tetrahydrobenzofuran-2,3-dione
室温下，向化合物1b(1.0g,6.48mmol)中依次加入MeOH(10mL)、草酸二甲酯(0.92g,7.78mmol)，30％甲醇钠溶液(5ml,89.2mmol)。反应在50℃下搅拌18小时。用 1M盐酸将反应液pH调至5-6，加入水稀释(100mL)，用乙酸乙酯(100mL)萃取，静置分层，有机层用无水硫酸钠干燥，减压浓缩后残留物用硅胶柱层析(洗脱剂PE:EA＝10:1-5:1)分离提纯得到1c(0.84g,62％)。
LC-MS(ESI)：m/z＝209.2[M+H] +。
第三步：2-((6R)-3-异丙基-6-甲基-2-氧代环己基)-2-氧乙酸(1d)
2-((6R)-3-isopropyl-6-methyl-2-oxocyclohexyl)-2-oxoacetic acid
室温下，向化合物1c(1.0g,4.8mmol)中依次加入四氢呋喃(5mL)，水(5mL)，NaOH(2.0g,50mmol)，搅拌2小时，用1M HCl调pH至5-6，乙酸乙酯萃取，乙酸乙酯相用饱和食盐水(50mL)洗，无水硫酸钠干燥，减压浓缩后残留物得到1d(0.8g,70％)。
LC-MS(ESI)：m/z＝227.2[M+H] +。
第四步：(4R)-7-异丙基-4-甲基-1-(吡嗪-2-基)-4,5,6,7-四氢-1H-吲唑-3-甲酸(1e)
(4R)-7-isopropyl-4-methyl-1-(pyrazin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
室温下，向化合物1d(0.8g,4.0mmol)中依次加入MeOH(50mL)，2-肼基吡嗪(0.5g,5.0mmol)，再用6M盐酸调pH至1-2。50℃搅拌2小时，加水稀释，乙酸乙酯萃取，乙酸乙酯相用饱和食盐水(100mL)洗，无水硫酸钠干燥，减压浓缩后残留物用硅胶柱层析(洗脱剂PE:EA＝5:1-纯EA)分离提纯得到1e(0.2g,16.7％)。
LC-MS(ESI)：m/z＝301.2[M+H] +。
第五步：(4R)-N-((S)-1-羟基-3,3-二甲基丁烷-2-基)-7-异丙基-4-甲基-1-(吡嗪-2-基)-4,5,6,7-四氢-1H-吲唑-3-甲酰胺(1f)
(4R)-N-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-7-isopropyl-4-methyl-1-(pyrazin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide
室温下，向化合物1e(0.2g,0.66mmol)中依次加入DMF(2mL)，HATU(0.28g,0.73mmol)，(S)-2-氨基-3,3-二甲基丁醇(0.085g,0.72mmol)，三乙胺(0.2g,1.98mmol)。室温搅拌2小时，加水稀释，乙酸乙酯萃取，乙酸乙酯相用饱和食盐水(20mL)洗，无水硫酸钠干燥，减压浓缩后残留物用硅胶柱层析(洗脱剂PE:EA＝5:1-2:1)分离提纯得到1f(0.2g,75.5％)。
LC-MS(ESI)：m/z＝400.3[M+H] +。
第六步：3-((4R)-3-(((S)-1-羟基-3,3-二甲基丁烷-2-基)氨甲酰)-7-异丙基-4-甲基-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物1)
3-((4R)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-7-isopropyl-4-methyl-4,5, 6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
室温下，向化合物1f(0.05g,0.125mmol)中依次加入DCM(1mL)，m-CPBA(0.065g,0.376mmol)，室温搅拌18小时，用亚硫酸钠水溶液淬灭反应，加水稀释，乙酸乙酯萃取，乙酸乙酯相用饱和食盐水(20mL)洗，无水硫酸钠干燥，减压浓缩后残留物硅胶柱层析(PE:EA＝5:1-1:1)分离提纯得到化合物1(0.01g,19.2％)。
LC-MS(ESI)：m/z＝416.3[M+H] +。
1H NMR(400MHz,CD 3OD)δ8.99-8.98(m,1H),8.43-8.42(d,1H),8.22-8.21(m,1H),3.97-3.94(m,1H),3.86-3.82(m,1H),3.69-3.66(m,2H),3.28-3.25(m,1H),2.14-2.06(m,1H),1.86-1.76(m,3H),1.69-1.66(m,1H),1.29-1.27(d,3H),1.02(s,9H),0.94-0.92(d,3H),0.70-0.68(d,3H)。
实施例2
(4R)-1-(2,4-二氟苯基)-N-((S)-1-羟基-3,3-二甲基丁烷-2-基)-7-异丙基-4-甲基-4,5,6,7-四氢-1H-吲唑-3-甲酰胺(化合物2)。
(4R)-1-(2,4-difluorophenyl)-N-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-7-isopropyl-4-methyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide.
Figure PCTCN2020114448-appb-000113
第一步：(4R)-1-(2,4-二氟苯基)-7-异丙基-4-甲基-4,5,6,7-四氢-1H-吲唑-3-甲酸(2a)。
(4R)-1-(2,4-difluorophenyl)-7-isopropyl-4-methyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid.
室温下，向化合物1d(0.3g,1.3mmol)中依次加入甲醇(6mL)、2,4-二氟苯肼(0.22g,1.6mmol)，用盐酸(6M)调节pH值3-4，加热至50℃搅拌反应2小时。将反应液倒入(30mL)水中，用乙酸乙酯(20mL×2)萃取，有机相浓缩，柱层析(洗脱剂PE/EA＝10/1-5/1)分离纯化，得化合物2a(0.2g,收率46％)。
LC-MS(ESI)：m/z＝335.2[M+H] +。
第二步：(4R)-1-(2,4-二氟苯基)-N-((S)-1-羟基-3,3-二甲基丁烷-2-基)-7-异丙基-4-甲基-4,5,6,7-四氢-1H-吲唑-3-甲酰胺(化合物2)。
(4R)-1-(2,4-difluorophenyl)-N-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-7-isopropyl-4-me thyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide.
室温下，向化合物2a(0.1g,0.3mmol)中依次加入DMF(5mL)、S-叔亮氨醇(39mg,0.33mmol)、HATU(125mg,0.33mmol)、DIPEA(120mg,0.9mmol)。搅拌反应1小时。将反应液倒入(50mL)水中，乙酸乙酯(20mL×2)萃取，有机相浓缩，硅胶柱层析(洗脱剂PE/EA＝5/1-1/1)分离纯化，得化合物2(25mg,收率19％)。
LC-MS(ESI)：m/z＝434.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.45-7.39(m,1H),7.03-6.97(m,2H),3.99-3.89(m,2H),3.62-3.57(m,1H),3.41-3.99(m,1H),2.88-2.83(m,1H),1.80-1.68(m,4H),1.64-1.56(m,1H),1.31-1.29(d,3H),1.02(s,9H),0.81-0.79(d,3H),0.58-0.56(d,3H)。
实施例3
3-((4R)-3-((1-羟基-2-甲基丙醇-2-基)氨甲酰)-7-异丙基-4-甲基-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物3)。
3-((4R)-3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)-7-isopropyl-4-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide.
Figure PCTCN2020114448-appb-000114
第一步：3-((4R)-3-羧基-7-异丙基-4-甲基-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪-1-氧化物(3a)。
3-((4R)-3-carboxy-7-isopropyl-4-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide.
室温下，向化合物1d(0.4g,1.8mmol)中依次加入甲醇(8mL)、吡嗪-2-肼氧化物(0.27g,2.1mmol)，用盐酸(6M)调节pH值3-4，加热至50℃搅拌反应2小时。将反应液倒入(30mL)水中，用乙酸乙酯(20mL×2)萃取，有机相浓缩，柱层析(洗脱剂DCM/MeOH＝80/1-30/1)分离纯化，得化合物3a(0.12g,收率21％)。
LC-MS(ESI)：m/z＝317.2[M+H] +。
第二步：3-((4R)-3-((1-羟基-2-甲基丙醇-2-基)氨甲酰)-7-异丙基-4-甲基-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物3)。
3-((4R)-3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)-7-isopropyl-4-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide.
室温下，向化合物3a(120mg,0.38mmol)中依次加入DMF(5mL)、2-氨基-2-甲基-1-丙醇(37mg,0.42mmol)、HATU(160mg,0.42mmol)、DIPEA(147mg,1.14mmol)。搅拌反应1小时。将反应液倒入(50mL)水中，乙酸乙酯(20mL×2)萃取，有机相浓缩，硅胶柱层析分离纯化(洗脱剂PE/EA＝5/1-1/1)，得化合物3(30mg,收率20％)。
LC-MS(ESI)：m/z＝388.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.78(s,1H),8.28-8.27(m,1H),8.02-8.01(m,1H),6.98(s,1H),3.75-3.70(m,2H),3.64-3.60(m,1H),3.37-3.31(m,2H),1.80-1.73(m,4H),1.42-1.41(m,6H),1.31-1.29(m,3H),0.92-0.90(m,3H),0.65-0.63(m,3H)。
实施例4：
(4R)-N-(1-(羟甲基)环戊基)-7-异丙基-4-甲基-1-(吡嗪-2-基)-4,5,6,7-四氢-1H-吲唑-3-甲酰胺-氧化物(化合物4)
(4R)-N-(1-(hydroxymethyl)cyclopentyl)-7-isopropyl-4-methyl-1-(pyrazin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide-oxide
Figure PCTCN2020114448-appb-000115
第一步：(4R)-N-(1-(羟甲基)环戊基)-7-异丙基-4-甲基-1-(吡嗪-2-基)-4,5,6,7-四氢-1H-吲唑-3-甲酰胺-氧化物(化合物4)
(4R)-N-(1-(hydroxymethyl)cyclopentyl)-7-isopropyl-4-methyl-1-(pyrazin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide-oxide
室温下，向化合物3a(0.1g,0.316mmol)中依次加入DCM(2mL)，HATU(0.14g,0.35mmol)，(1-氨基环戊基)甲醇(0.045g,0.38mmol)，三乙胺(0.1g,0.95mmol)。室温搅拌2小时，加水稀释，乙酸乙酯萃取，乙酸乙酯相用饱和食盐水(20mL)洗，无水硫酸钠干燥，减压浓缩后残留物用硅胶柱层析(洗脱剂PE/EA＝5/1-1/1)分离提纯得到化合物4(0.06g,50％)。
LC-MS(ESI)：m/z＝414.3[M+H] +。
1H NMR(400MHz,CD 3OD)δ8.79-8.72(m,1H),8.26-8.24(m,1H),8.01-7.98(m,1H),7.07-7.06(m,1H),3.80-3.72(m,2H),3.66-3.59(m,1H),3.39-3.29(m,1H),2.06-1.96(m, 3H),1.92-1.64(m,9H),1.31-1.22(m,3H),0.92-0.83(m,3H),0.82-0.60(m,3H)。
实施例5
(S)-3-(7,7-二氟-3-((1-羟基-3,3-二甲基丁-2-基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物5)
(S)-3-(7,7-difluoro-3-((1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000116
第一步：2-乙氧基环己烷-2-烯-1-酮(5b)
2-ethoxycyclohex-2-en-1-one
将化合物5a(10g,89.3mmol)溶解在甲苯(100mL)中，室温下向其中依次加入乙醇(50mL)，对甲苯磺酸(23.1g,133.0mmol)。升温回流24小时。将反应液旋干加硅胶拌样，柱层析(洗脱剂：石油醚/乙酸乙酯＝10:1～5:1)分离得到化合物5b(6.5g,52％)。
LC-MS(ESI)：m/z＝141.2[M+H] +。
第二步：2-(3-乙氧基-2-氧代环己-3-烯-1-基)-2-氧代乙酸乙酯(5c)
ethyl 2-(3-ethoxy-2-oxocyclohex-3-en-1-yl)-2-oxoacetate
将化合物5b(3.0g,21.4mmol)溶解在四氢呋喃(30mL)中，降温至零下78摄氏度，向其中加入LHMDS(1M，23.5mL)，半个小时后再向其中加入草酸二乙酯(3.4g,23.5mmol)，升温至室温反应过夜。使用稀盐酸淬灭反应，乙酸乙酯(100mL×2)萃取水相，无水硫酸钠干燥，加入硅胶拌样柱层析(洗脱剂：石油醚/乙酸乙酯＝10:1～5:1)分离，得到化合物5c(1.9g,37.0％)。
LC-MS(ESI)：m/z＝241.2[M+H] +。
第三步：(7-氧代-1-(吡嗪-2-基)-4,5,6,7-四氢-1H-吲唑-3-羧酸乙酯(5d)
ethyl 7-oxo-1-(pyrazin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate
将化合物5c(2.1g,8.8mmol)溶解在硫酸乙醇溶液中(1:100(v/v),21mL)中，室温下 向其中加入吡嗪-2-肼(1.45g,13.2mmol)，升温回流反应半个小时。将反应液旋干，加入硅胶拌样柱层析(洗脱剂：石油醚/乙酸乙酯＝5:1～3:1)分离，得到化合物5d(1.85g,73.4％)。
1H NMR(400MHz,Chloroform-d)δ9.16(d,1H),8.64(d,1H),8.55(dd,1H),4.45(q,2H),2.95(t,2H),2.37–2.20(m,2H),2.16–2.03(m,2H),1.43(t,3H)。
第四步：1-(吡嗪-2-基)-1,4,5,6-四氢螺[1-吲唑-7,2'-[1,3]二硫戊环]-3-羧酸乙酯(5e)
ethyl 1-(pyrazin-2-yl)-1,4,5,6-tetrahydrospiro[indazole-7,2'-[1,3]dithiolane]-3-carboxylate
将化合物5d(0.9g,3.15mmol)溶解在无水二氯甲烷(10mL)中，室温下依次向其中加入三氟化硼***溶液(2M，10mL)，乙二硫醇(1.45g,13.2mmol)，室温反应过夜。饱和碳酸氢钠溶液淬灭反应，乙酸乙酯(70mL×2)萃取水相，无水硫酸钠干燥，加入硅胶拌样，柱层析(洗脱剂：石油醚/乙酸乙酯＝5:1～3:1)分离，得到化合物5e(0.9g,78.7％)。
LC-MS(ESI)：m/z＝363.3[M+H] +。
第五步：1-(吡嗪-2-基)-1,4,5,6-四氢螺[1-吲唑-7,2'-[1,3]二硫戊环]-3-羧酸乙酯(5f)
ethyl 7,7-difluoro-1-(pyrazin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate
将NIS(0.9g,2.49mmol)溶解在无水二氯甲烷(10mL)中，降温至零下78摄氏度，向其中加入氢氟酸吡啶盐溶液，反应十分钟后，再向其中滴加化合物5e(0.9g,2.49mmol)的二氯甲烷(10mL)溶液，在此温度下反应二十分钟。将反应液旋干，加硅胶拌样，柱层析(洗脱剂：石油醚/乙酸乙酯＝2:1～1:1)分离，得到化合物5f(0.48g,47％)。
LC-MS(ESI)：m/z＝309.1[M+H] +。
第六步：2-羧基7,7-二氟-1-(吡嗪-2-基)-4,5,6,7-四氢-1H-吲唑-3-羧酸(5g)
7,7-difluoro-1-(pyrazin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
将化合物5f(0.15g,0.54mmol)溶解在四氢呋喃(10mL)和甲醇(10mL)混合溶剂中，室温下向其中加入氢氧化钠溶液(2M,10mL)。室温下反应两个小时。调节反应液pH＝6，二氯化甲烷(30mL×2)萃取水相，旋干得到化合物5g，无需纯化，备用。
LC-MS(ESI)：m/z＝281.2[M+H] +。
第七步：(S)-7,7-二氟-N-(1-羟基-3,3-二甲基丁-2-基)-1-(吡嗪-2-基)-4,5,6,7-四氢-1H-吲唑-3-甲酰胺(5h)
(S)-7,7-difluoro-N-(1-hydroxy-3,3-dimethylbutan-2-yl)-1-(pyrazin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide
将化合物5g(5.0g,32.5mmol)溶解在二氯甲烷(10mL)中，室温下向其中加入HATU(2M,10mL)，TEA(2M,10mL)，(S)-叔亮氨醇(3.97g,39mmol)。室温下反应两个小时。 稀盐酸调节至中性，二氯甲烷(100mL×2)萃取水相，硫酸钠干燥，柱层析(洗脱剂：石油醚/乙酸乙酯＝2:1～1:1)分离得到化合物5h(0.1g,52％)。
LC-MS(ESI)：m/z＝380.2[M+H] +。
第八步：(S)-3-(7,7-二氟-3-((1-羟基-3,3-二甲基丁-2-基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物5)
(S)-3-(7,7-difluoro-3-((1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
将原料5h(100mg,0.35mmol)溶解于5ml的甲酸溶液中，然后加入30％的双氧水溶液(0.5ml)，升温至64℃搅拌反应3小时以后，加入50ml的水，用50ml的乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，旋干以后将得到的棕色油状物溶解于3ml的甲醇与3ml的四氢呋喃的混合溶剂中，然后缓慢滴加氢氧化钠的水溶液2ml(2M)，常温搅拌反应15分钟以后，TLC检测，反应完全，加入50ml的水，用50ml的乙酸乙酯萃取三次，合并有机相无水硫酸钠干燥旋干，高效液相制备分离后得到终产物白色粉末32mg(化合物5),收率26％。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％至75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：13.8min。LC-MS(ESI)：m/z＝396.2[M+H] +。
1H NMR(400MHz,Chloroform-d)δ8.70(dd,1H),8.40(dd,1H),8.08(dd,1H),7.04(d,1H),4.06–3.87(m,2H),3.69(dd,1H),3.00(dd,2H),2.38–2.14(m,2H),2.10–1.99(m,3H),1.04(s,9H)。
实施例6
(S)-3-(3'-((1-羟基-3,3-二甲基丁烷-2-基)氨甲酰基)-5',6'-二氢螺[环丙基-1,7'-吲唑]-1'(4'H)-基)吡嗪1-氧化物(化合物6)
(S)-3-(3'-((1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5',6'-dihydrospiro[cyclopropane-1,7'-indazol]-1'(4'H)-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000117
第一步：2-(2-氯乙基)环己酮(6b)
2-(2-chloroethyl)cyclohexanone
室温下，向化合物6a(3.3g,23.24mmol)中加入乙腈(3.3mL)，0℃下加入浓盐酸(16.5ml)，升温至100℃反应3小时，反应液降至室温后用乙酸乙酯萃取，有机相浓缩干，得化合物6b(3.68g,收率99％)。
第二步：螺[2.5]辛-4-酮(6c)。
spiro[2.5]octan-4-one.
室温下，向化合物6b(3.65g,23mmol)中加入乙醇(16mL)、氢氧化钾(1.8g,32mmol)，室温反应5小时。将反应夜倒入(50mL)水中，乙酸乙酯(50mL×2)萃取，有机相浓缩，残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(v/v)＝0:1～1:8)，得化合物6c(1g,收率35％)。
第三步：2-氧代-2-(4-氧代螺[2.5]辛-5-基)乙酸甲酯(6d)
methyl 2-oxo-2-(4-oxospiro[2.5]octan-5-yl)acetate
将化合物6c(500mg,4mmol)加入四氢呋喃(10mL)中，-78℃下加入双三甲基硅基胺基锂(5ml,5mmol)，-78℃搅拌30min，加入2-氯-2-氧代乙酸甲酯(740mg,6.1mmol)，继续反应1h，缓慢升至室温，反应液用氯化铵水溶液淬灭，倒入水(20mL)中，乙酸乙酯(30mL×3)萃取，有机相浓缩，残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(v/v)＝0:1～1:6)，得化合物6d(700mg,收率83％)。
LC-MS(ESI)：m/z＝211.1[M+H] +。
第四步：1'-(吡嗪-2-基)-1',4',5',6'-四氢螺[环丙烷-1,7'-吲唑]-3'-羧酸甲酯(6e)
methyl 1'-(pyrazin-2-yl)-1',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-indazole]-3'-carboxylate
室温下，向化合物6d(400mg,1.9mmol)中依次加入甲醇(6mL)、2,4-二氟苯肼(252mg,2.3mmol)，用盐酸(6M)调节pH值4-5，加热至50℃搅拌反应2小时。将反应液倒入(30mL)水中，用乙酸乙酯(20mL×2)萃取，有机相浓缩，残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(v/v)＝0:1～1:3)，得化合物6e(300mg,收率56％)。
LC-MS(ESI)：m/z＝285.1[M+H] +。
第五步：1'-(吡嗪-2-基)-1',4',5',6'-四氢螺[环丙烷-1,7'-吲唑]-3'-羧酸(6f)
1'-(pyrazin-2-yl)-1',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-indazole]-3'-carboxylic acid
室温下，向化合物6e(180mg,0.63mmol)加入甲醇(3ml)和水(1ml)，再加入氢氧化钠(120mg,3mmol)，搅拌反应1小时。将反应液用稀盐酸调制pH值4-5，乙酸乙酯(20mL×2)萃取，有机相浓缩，得化合物6f(165mg,收率97％)。。
LC-MS(ESI)：m/z＝271.1[M+H] +。
第六步：3-(3'-羧基-5',6'-二氢螺[环丙烷-1,7'-吲唑]-1'(4'H)-基)吡嗪1-氧化物(6g)
3-(3'-carboxy-5',6'-dihydrospiro[cyclopropane-1,7'-indazol]-1'(4'H)-yl)pyrazine 1-oxide
室温下，向化合物6f(165mg,0.61mmol)中依次加入甲酸(5mL)、30％双氧水(0.5ml)，加热至50℃搅拌反应2小时。将反应液倒入(20mL)水中，用乙酸乙酯(20mL×2)萃取，有机相浓缩，得化合物6g(140mg,收率80％)。
LC-MS(ESI)：m/z＝287.1[M+H] +。
第七步：(S)-3-(3’-((1-羟基-3,3-二甲基丁-2-基)氨基甲酰基)-5’,6'-二氢螺[环丙烷-1,7'-吲唑]-1'(4'H)-基)吡嗪1-氧化物(化合物6)
(S)-3-(3'-((1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5',6'-dihydrospiro[cyclopropane-1,7'-indazol]-1'(4'H)-yl)pyrazine 1-oxide
室温下，向化合物6g(140mg,0.49mmol)中依次加入DMF(5mL)、S-叔亮氨醇(60mg,0.0.51mmol)、HATU(223mg,0.0.58mmol)、DIPEA(160mg,1.2mmol)。搅拌反应1小时。将反应液倒入(50mL)水中，乙酸乙酯(20mL×2)萃取，有机相浓缩，制备HPLC分离纯化，得化合物6(35mg,收率19％)。
制备HPLC分离方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈；流动相B：水(含0.1％乙酸铵)；b.梯度洗脱，流动相A含量从5％-50％；c.流量12mL/min；d洗脱时间20min。化合物6保留时间：13.5min。
LC-MS(ESI)：m/z＝386.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.49(s,1H),8.27(d,1H),8.13–8.07(m,1H),7.03(d,1H),4.03-3.94(m,2H),3.7-3.65(m,1H),2.98(t,2H),2.41(s,1H),1.95-1.88(m,2H),1.64-1.61(m,2H),1.41-1.38(m,2H),1.03(s,9H),0.71-0.68(m,2H)。
实施例7
3-((R)-3-((S)-1-羟基-3,3-二甲基丁烷-2-基)氨甲酰-4-甲基-7-(丙-2-亚基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物7)
3-((R)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-4-methyl-7-(propan-2-ylidene)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide.
Figure PCTCN2020114448-appb-000118
第一步：2-((6R)-6-甲基-2-氧代-3-(丙烷-2-亚基)环己基)-2-氧乙酸甲酯(7b)
methyl 2-((6R)-6-methyl-2-oxo-3-(propan-2-ylidene)cyclohexyl)-2-oxoacetate
氮气保护下，向化合物7a(0.5g,3.3mmol)中加入四氢呋喃(10mL)，冷却至-70至-80℃，将双三甲基硅基胺基锂(4.3mL,4.3mmol)于-70至-80℃间滴加至反应液中，保温反应半小时，将草酰氯单甲酯(0.5g,4.3mmol)于-70至-80℃间滴加至反应液中，保温反应半小时。将反应液倒入(50mL)水中，用盐酸(6M)调节pH值5-6，乙酸乙酯(30mL×2)萃取，有机相浓缩，柱层析(洗脱剂PE/EA＝10/1-3/1)分离纯化，得化合物7b(0.3g,收率38％)。
LC-MS(ESI)：m/z＝239.1[M+H] +。
第二步：(R)-3-(3-(甲氧基羰基)-4-甲基-7-(丙烷-2-亚基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(7c)
(R)-3-(3-(methoxycarbonyl)-4-methyl-7-(propan-2-ylidene)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
室温下，向化合物7b(0.3g,1.3mmol)中依次加入甲醇(5mL)、吡嗪-2-肼氧化物(0.2g,1.6mmol)，用盐酸(6M)调节pH值3-4，加热至50℃搅拌反应2小时。将反应液倒入(30mL)水中，用乙酸乙酯(20mL×2)萃取，有机相浓缩，柱层析(洗脱剂PE/EA＝5/1-1/1)分离纯化，得化合物7c(0.2g,收率50％)。
LC-MS(ESI)：m/z＝329.1[M+H] +。
第三步：(R)-3-(3-羧基-4-甲基-7-(丙烷-2-亚基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧 化物(7d)
(R)-3-(3-carboxy-4-methyl-7-(propan-2-ylidene)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
室温下，向化合物7c(0.2g,0.6mmol)中依次加入MeOH(2mL)、水(2mL)、氢氧化钠(73.1mg,1.8mmol)，搅拌反应1小时。将反应液倒入(10mL)水中，用盐酸(6M)调节pH值3-4，乙酸乙酯(10mL×2)萃取，有机相浓缩，得化合物7d(150mg,收率80％)。
LC-MS(ESI)：m/z＝315.1[M+H] +。
第四步：3-((R)-3-((S)-1-羟基-3,3-二甲基丁烷-2-基)氨甲酰-4-甲基-7-(丙-2-亚基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物7)
3-((R)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-4-methyl-7-(propan-2-ylidene)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
室温下，向化合物7d(150mg,0.48mmol)中依次加入DMF(5mL)、S-叔亮氨醇(62mg,0.53mmol)、HATU(200mg,0.53mmol)、DIPEA(185mg,1.44mmol)。搅拌反应1小时。将反应液倒入(50mL)水中，乙酸乙酯(20mL×2)萃取，有机相浓缩，硅胶柱层析(洗脱剂PE/EA＝5/1-1/1)分离纯化，得化合物7(50mg,收率25％)。
LC-MS(ESI)：m/z＝414.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.60(s,1H),8.31-8.30(d,1H),8.04-8.02(m,1H),7.10-7.08(d,1H),4.03-3.95(m,2H),3.69-3.65(m,1H),3.45-3.41(m,1H),2.54-2.51(m,2H),2.05-2.00(m,1H),1.81(s,3H),1.72-1.65(m,1H),1.35(s,3H),1.30-1.28(d,3H),1.03(s,9H)。
实施例8
3-(7,7-二氟-3-((1-(羟甲基)环戊基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物8)
3-(7,7-difluoro-3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000119
第一步：7,7-二氟-N-(1-(羟甲基)环戊基)-1-(吡嗪-2-基)-4,5,6,7-四氢-1H-吲唑-3-甲酰胺(8b)
7,7-difluoro-N-(1-(hydroxymethyl)cyclopentyl)-1-(pyrazin-2-yl)-4,5,6,7-tetrahydro-1H-in dazole-3-carboxamide
参照化合物5的第七步，由化合物5g反应得到化合物8b。
第二步：(S)-3-(7,7-二氟-3-((1-羟基-3,3-二甲基丁-2-基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物8)
(S)-3-(7,7-difluoro-3-((1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
参照化合物5的第八步，由化合物8b反应得到化合物8(30mg,32％)。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％-75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：12.8min。
LC-MS(ESI)：m/z＝394.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.75(t,1H),8.43(d,1H),8.11(dd,1H),7.10(s,1H),3.79(s,2H),3.27(s,1H),2.99(t,2H),2.37–2.22(m,2H),2.12–1.96(m,4H),1.96–1.66(m,6H)。
实施例9
3-(7,7-二氟-3-((4,4,4-三氟-1-羟基-3,3-二甲基丁烷-2-基)氨甲酰)-4,5,6,7-四氢-1H-吲唑-1-基)-1-氧代吡嗪
3-(7,7-difluoro-3-((4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine-1-oxide
Figure PCTCN2020114448-appb-000120
第一步：3-(7,7-二氟-3-((4,4,4-三氟-1-羟基-3,3-二甲基丁烷-2-基)氨甲酰)-4,5,6,7-四氢-1H-吲唑-1-基)-1-氧代吡嗪
3-(7,7-difluoro-3-((4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine-1-oxide
氮气保护，室温下，向化合物10a(0.05g,0.17mmol)，中依次加入DMF(3mL)， DIPEA(32mg,0.25mmol)，HATU(77mg,0.2mmol)，2-氨基-4,4,4-三氟-3,3-二甲丁烷-1-醇(Int-1)(43mg,0.25mmol)，室温下搅拌3h。向反应中加入饱和碳酸氢钠水溶液(30mL)淬灭反应，乙酸乙酯(20mL×2)萃取水相，静置分层，水相再用二氯甲烷(20mL)萃取，合并后的有机相用无水硫酸钠干燥，减压浓缩后残留物得到粗品，粗品经高效液相制备分离得到化合物9(30mg,收率39.64％)，白色固体。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％至75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：12.5min。LC-MS(ESI)：m/z＝450.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ9.14(s,1H),8.53(s,1H),8.41(d,J＝8.0Hz,1H),8.13(d,J＝8.0Hz,1H),4.81(s,1H),4.34-4.29(m,2H),4.08-3.70(m,1H),3.63-3.51(m,1H),3.31-3.17(m,1H),2.90-2.73(m,2H),2.34-2.27(m,2H),1.24-1.17(s,6H)。
实施例10：
(S)-3-(7,7-二氟-3-((2-羟基-1-苯乙基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物10)
(S)-3-(7,7-difluoro-3-((2-hydroxy-1-phenylethyl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000121
第一步：3-(3-羧基-7,7-二氟-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(10a)
3-(3-carboxy-7,7-difluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
将中间体5g(2g,7.14mmol)溶解于甲酸(20ml)中，然后加入30％的双氧水溶液(2ml)，升温至64℃搅拌反应3小时以后，加入50ml水，并且冷却至室温，减压抽滤得到化合物10a(800mg,38％)。
LC-MS(ESI)：m/z＝297.3[M+H] +。
第二步：(S)-3-(7,7-二氟-3-((2-羟基-1-苯乙基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物10)
(S)-3-(7,7-difluoro-3-((2-hydroxy-1-phenylethyl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
将化合物10a(200mg,0.68mmol)溶解在二氯甲烷(10mL)中，室温下向其中加入HATU(334mg，0.88mL)，DIPEA(2.0mL)，(S)-2-氨基-2-苯基乙烷-1-醇(102mg,0.75mmol)。室温下反应两个小时。稀盐酸调节至中性，二氯甲烷(20mL×2)萃取水相，硫酸钠干燥有机相，旋干经高效液相制备分离纯化。得到化合物10(0.11g,38％)。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％至75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：13.2min。
LC-MS(ESI)：m/z＝416.4[M+H] +。
1H NMR(400MHz,Chloroform-d)δ8.76(dd,1H),8.38(dd,1H),8.06(dd,1H),7.60(d,1H),7.39(d,3H),7.35–7.28(m,1H),5.25(t,1H),4.01(d,2H),2.97(tt,2H),2.27(t,2H),2.16–1.84(m,3H)。
实施例11：
3-(7,7-二氟-3-((2-苯丙-2-基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物11)
3-(7,7-difluoro-3-((2-phenylpropan-2-yl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000122
将化合物10a(200mg,0.68mmol)溶解在二氯甲烷(10mL)中，室温下向其中加入HATU(334mg，0.88mL)，DIPEA(2.0mL)，2-苯基丙-2-胺(101mg,0.75mmol)。室温下反应两个小时。稀盐酸调节至中性，二氯甲烷(20mL×2)萃取水相，硫酸钠干燥有机相，旋干经高效液相制备分离纯化。得到化合物11(0.03g,11％)。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％至75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：13.8min。
LC-MS(ESI)：m/z＝414.3[M+H] +。
1H NMR(400MHz,Chloroform-d)δ8.72(dd,1H),8.40(dd,1H),8.07(dd,1H),7.49–7.41(m,2H),7.35(dd,2H),7.25–7.17(m,1H),2.93(tt,2H),2.25(t,2H),2.04–1.95(m,2H),1.82(s,6H),1.66(s,1H)。
实施例12：
3-(7,7-二氟-3-((2-甲基-1-吗啉代丙烷-2-基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物12)
3-(7,7-difluoro-3-((2-methyl-1-morpholinopropan-2-yl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000123
将化合物10a(200mg,0.68mmol)溶解在二氯甲烷(10mL)中，室温下向其中加入HATU(334mg，0.88mmol)，DIPEA(2.0mL)，2-甲基-1-吗啉代丙烷-2-胺(215mg,1.36mmol)。室温下反应两个小时。稀盐酸调节至中性，二氯甲烷(20mL×2)萃取水相，无水硫酸钠干燥有机相，减压除去溶剂，高效液相制备分离纯化。得到化合物12(20mg,5％)。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％至75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：13.7min。
LC-MS(ESI)：m/z＝437.3[M+H] +。
1H NMR(400MHz,Chloroform-d)δ8.65(s,1H),8.38(d,1H),8.06(dd,1H),7.32(s,1H),3.71(s,4H),2.98(s,2H),2.61(d,4H),2.27(t,2H),2.05(t,2H),1.46(s,6H)。
实施例13：
3-(7,7-二氟-3-((1-甲氧基-2-甲基-1-氧丙烷-2-基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物13)
3-(7,7-difluoro-3-((1-methoxy-2-methyl-1-oxopropan-2-yl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000124
将化合物10a(100mg,0.34mmol)溶解在二氯甲烷(5mL)中，室温下向其中加入HATU(194mg，0.51mmol)，DIPEA(0.2mL)，2-氨基-2-甲基丙酸甲酯(40mg,0.34mmol)。室温下反应两个小时。稀盐酸调节至中性，二氯甲烷(20mL×2)萃取水相，硫酸钠干燥有机相，减压除去溶剂，经高效液相制备分离纯化，得到化合物13(20mg,14％)。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％至75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：12.9min。
LC-MS(ESI)：m/z＝396.1[M+H] +。
1H NMR(400MHz,Chloroform-d)δ8.73(s,1H),8.40(d,1H),8.08(dd,1H),7.36(s,1H),3.78(s,3H),2.97(t,2H),2.39–2.13(m,2H),2.11–1.90(m,2H),1.67(s,6H)。
实施例14：
3-(3-((2-氰基丙烷-2-基)氨基甲酰基)-7,7-二氟-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物14)
3-(3-((2-cyanopropan-2-yl)carbamoyl)-7,7-difluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000125
将化合物10a(100mg,0.34mmol)溶解在二氯甲烷(5mL)中，室温下向其中加入HATU(194mg，0.51mmol)，DIPEA(0.2mL)，2-氨基-2-甲基丙腈(29mg,0.34mmol)。室温下反应两个小时。稀盐酸调节至中性，二氯甲烷(20mL×2)萃取水相，硫酸钠干燥有机相，减压除去溶剂，高效液相制备分离纯化，得到化合物14(10mg,7％)。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。 2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％至75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：12.6min。
LC-MS(ESI)：m/z＝363.1[M+H] +。
1H NMR(400MHz,Chloroform-d)δ8.68(dd,1H),8.48–8.35(m,1H),8.09(dd,1H),6.92(s,1H),3.01(t,2H),2.42–2.17(m,2H),2.15–1.96(m,2H),1.58(s,6H)。
实施例15：
3-(3-((2-氰基丙烷-2-基)氨基甲酰基)-7,7-二氟-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物15)
3-(3-((2-cyanopropan-2-yl)carbamoyl)-7,7-difluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000126
将化合物10a(100mg,0.34mmol)溶解在二氯甲烷(5mL)中，室温下向其中加入HATU(194mg，0.51mmol)，DIPEA(0.2mL)，(四氢-2H-吡喃-4-基)甲胺(39mg,0.34mmol)。室温下反应两个小时。稀盐酸调节至中性，二氯甲烷(20mL×2)萃取水相，硫酸钠干燥有机相，减压除去溶剂，高效液相制备分离纯化，得到化合物15(10mg,7％)。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％至75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：12.5min。
LC-MS(ESI)：m/z＝394.1[M+H] +。
1H NMR(400MHz,Chloroform-d)δ8.69(s,1H),8.40(d,1H),8.07(dd,1H),6.98(s,1H),4.00(dd,2H),3.46–3.29(m,2H),2.99(t,2H),2.39–2.17(m,2H),2.13–1.95(m,2H),1.68(d,8H),1.39(t,2H)。
实施例16：
3-(7,7-二氟-3-((四氢-2H-吡喃-4-基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物16)
3-(7,7-difluoro-3-((tetrahydro-2H-pyran-4-yl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000127
将化合物10a(100mg,0.34mmol)溶解在二氯甲烷(5mL)中，室温下向其中加入HATU(194mg，0.51mmol)，DIPEA(0.2mL)，四氢-2H-吡喃-4-胺(34mg,0.34mmol)。室温下反应两个小时。稀盐酸调节至中性，二氯甲烷(20mL×2)萃取水相，硫酸钠干燥有机相，减压除去溶剂，高效液相制备分离纯化，得到化合物16(20mg,15％)。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％至75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：12.3min。
LC-MS(ESI)：m/z＝380.1[M+H] +。
1H NMR(400MHz,Chloroform-d)δ8.72(dd,1H),8.40(dd,1H),8.08(dd,1H),6.80(d,1H),4.02(dd,2H),3.53(t,2H),3.00(tq,2H),2.36–2.21(m,2H),1.98(t,1H),1.63(t,6H)。
实施例17：
3-(7,7-二氟-3-((2-(羟甲基)氧杂环丁-2-基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物17)
3-(7,7-difluoro-3-((2-(hydroxymethyl)oxetan-2-yl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000128
将化合物10a(100mg,0.34mmol)溶解在二氯甲烷(5mL)中，室温下向其中加入HATU(194mg，0.51mmol)，DIPEA(0.2mL)，(2-氨基氧杂环丁-2-基)甲醇(35mg,0.34mmol)。室温下反应两个小时。稀盐酸调节至中性，二氯甲烷(20mL×2)萃取水相，硫酸钠干燥有机相，减压除去溶剂，高效液相制备分离纯化，得到化合物17(34mg,22％)。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％至75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：12.4min。
LC-MS(ESI)：m/z＝382.1[M+H] +。
1H NMR(400MHz,Chloroform-d)δ8.73(d,1H),8.41(d,1H),8.09(t,1H),7.44(s,1H),4.88–4.81(m,2H),4.69(d,2H),4.17(s,2H),3.01–2.89(m,2H),2.35–2.16(m,2H),2.13–1.94(m,2H)。
实施例18：
3-(7,7-二氟-3-((1-苯基环丙基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物18)
3-(7,7-difluoro-3-((1-phenylcyclopropyl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000129
将化合物10a(100mg,0.34mmol)溶解在二氯甲烷(5mL)中，室温下向其中加入HATU(194mg，0.51mmol)，DIPEA(0.2mL)，1-苯基环丙烷-1-胺(45mg,0.34mmol)。室温下反应两个小时。稀盐酸调节至中性，二氯甲烷(20mL×2)萃取水相，硫酸钠干燥有机相，减压除去溶剂，高效液相制备分离纯化，得到化合物18(33mg,24％)。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％至75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：13.1min。
LC-MS(ESI)：m/z＝412.1[M+H] +。
1H NMR(400MHz,Chloroform-d)δ8.79(d,1H),8.37(d,1H),8.05(dd,1H),7.67(s,1H),7.37–7.24(m,4H),7.24–7.15(m,1H),2.98(t,2H),2.27(t,2H),2.07–1.99(m,2H),1.38(t,2H)。
实施例19：
3-(7,7-二氟-3-((1-苯基环丙基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物19)
3-(7,7-difluoro-3-((1-phenylcyclopropyl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000130
将化合物10a(100mg,0.34mmol)溶解在二氯甲烷(5mL)中，室温下向其中加入HATU(194mg，0.51mmol)，DIPEA(0.2mL)，(S)-3-氨基丙烷-1,2-二醇(31mg,0.34mmol)。室温下反应两个小时。稀盐酸调节至中性，二氯甲烷(20mL×2)萃取水相，硫酸钠干燥有机相，减压除去溶剂，高效液相制备分离纯化，得到化合物19(42mg,36％)。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％至75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：13.3min。
LC-MS(ESI)：m/z＝370.1[M+H] +。
1H NMR(400MHz,Chloroform-d)δ8.72(s,1H),8.40(d,1H),8.13–8.04(m,1H),7.37(s,1H),3.97–3.84(m,1H),3.75–3.53(m,2H),2.98(s,2H),2.36–2.19(m,2H),2.12–1.95(m,2H),1.26(s,2H)。
实施例20：
3-(7,7-二氟-3-((1-苯基环丙基)氨基甲酰基)-4,5,6,7-四氢-1H-吲唑-1-基)吡嗪1-氧化物(化合物20)
3-(7,7-difluoro-3-((1-phenylcyclopropyl)carbamoyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide
Figure PCTCN2020114448-appb-000131
将化合物10a(100mg,0.34mmol)溶解在二氯甲烷(5mL)中，室温下向其中加入HATU(194mg，0.51mmol)，DIPEA(0.2mL)，(R)-2-氨基-4-甲基戊-1-醇(40mg,0.34mmol)。室温下反应两个小时。稀盐酸调节至中性，二氯甲烷(20mL×2)萃取水相，硫酸钠干燥有机相，减压除去溶剂，高效液相制备分离纯化，得到化合物20(24mg,18％)。
制备方法：1.仪器：waters 2767制备液相；色谱柱：SunFire@Prep C18(19mm×250mm)。2.样品用DMF溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：乙腈，流动相B：水；b.梯度洗脱，流动相A含量从20％至75％；c.流量12ml/min；d.洗脱时间20min。出峰时间：13.5min。
LC-MS(ESI)：m/z＝396.1[M+H] +。
1H NMR(400MHz,Chloroform-d)δ8.74(s,1H),8.39(d,1H),8.08(dd,1H),6.99(d,1H),4.24(t,1H),3.79(dd,1H),3.66(dd,1H),2.99(d,2H),2.34–2.20(m,2H),2.14–1.90(m,4H),1.71(d,1H),1.51(t,2H),0.97(dd,6H)。
生物测试
1、CB2激动剂活性
实验对象：化合物1-20。
高表达人CB2的CHO细胞悬于HBSS buffer(含20mM HEPES，pH＝7.4)中，以每孔7.5×10 3个细胞(细胞密度为1.5×10 6个/mL)接种于已加入样品(HBSS，阳性对照WIN55212-2或不同浓度实施例化合物)的384孔白板中。向上述384孔板中加入终浓度为3μM腺苷酸环化酶活化剂NKH 477。于37℃孵育10分钟后，裂解细胞，加入D2-labeled cAMP与anti-cAMP antibody labeled with europium cryptate。室温孵育1小时后，用酶标仪(Envison,Perkin Elmer)进行HTRF检测(λex＝337nm，λem＝620与665nm)。计算信号比值Ratio(Signal 665/Signal 620*10 4)，结果表示为相对于100nM WIN 55212-2的百分比值，采用DoseResp函数拟合EC 50值。结果见表1。
表1 CB2受体活性
Figure PCTCN2020114448-appb-000132
Figure PCTCN2020114448-appb-000133
注：ND表示未测试。
APD-371为专利文献WO2011025541化合物699。
结论：本发明化合物，特别是1、4、5、6、7、8、19、20对于CB 2受体显示了较高的激动活性，部分化合物特别是化合物5、化合物8对CB 2/CB 1受体显示了较高的选择性。
2、大鼠药代动力学测试
实验目的：通过单剂量静脉和灌胃给予受试物于SD大鼠，测定大鼠血浆中受试物的浓度，评价受试物在大鼠体内药代特征和生物利用度。
实验对象：APD-371及化合物5。
试验动物：雄性SD大鼠，220g左右，6～8周龄，6只/化合物。购于成都达硕实验动物有限公司。
试验方法：试验当天，6只SD大鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。按照表2给药。
表2给药信息
Figure PCTCN2020114448-appb-000134
*剂量以游离碱计。
取样
于给药前及给药后异氟烷麻醉经眼眶取血0.1ml，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。
G1组采集血浆时间点：0,2,5,15,30min,1,2,4,6,8,24h。
G2组采集血浆时间点：0,5,15,30min,1,2,4,6,8,24h。
分析检测前，所有样品存于-80℃。
样品前处理
取30μL血浆样品、标曲和质控样品，加入200μL的含内标乙腈溶液，涡旋混匀之后，4℃，12000rpm离心10min。取170μL上清于96孔板中，LC-MS/MS分析，进样量为5μL。
主要药代动力学参数用WinNonlin 8.0软件非房室模型分析。实验结果如表3所示。
表3化合物5大鼠药代动力学
Figure PCTCN2020114448-appb-000135
APD-371为专利文献WO2011025541化合物699。
结论：本发明化合物，特别是化合物5，具有较高的生物利用度，良好的药代动力学特征，半衰期长。
3、稳定性测试
实验方法：
溶液稳定性：(进样量20ul)
人工胃液：取稀盐酸16.4ml，加水约800ml与胃蛋白酶10g，摇均后，加水稀释成1000ml，即得。
人工肠液：磷酸二氢钾缓冲溶液：称取磷酸二氢钾1.3961g，加水溶解，稀释成100 ml，用0.1mol/L氢氧化钠溶液调节pH至6.8。
另取胰蛋白酶2.0307g，加水适量溶解，与磷酸二氢钾缓冲溶液混合，加水至200ml，摇匀，即可。
取本品APD-371适量，加入人工胃液稀释制成每ml约含0.6mg的供试品溶液，于常温下放置，分别于0、2、4、8、12、24、36、48h取供试品溶液适量，注入液相色谱仪，进样分析考察人工胃液下供试品溶液稳定性。以相对0h峰面积计算样品稳定性，并关注是否具有新增杂质。
取本品化合物5适量，加入人工肠液稀释制成每ml约含0.6mg的供试品溶液，于常温下放置，分别于0、2、4、8、12、24、36、48h取供试品溶液适量，注入液相色谱仪，进样分析考察人工肠液下供试品溶液稳定性。以相对0h峰面积计算样品稳定性，并关注是否具有新增杂质。
化学稳定性：(进样量2ul)
分别取APD-371和化合物5适量，分别平铺与无色透明扁形称量瓶中，密封。密封后的供试品分别放置与光照、40℃+75％RH条件下，分别与7天、33天取样考察。
分别取各条件下样品适量，加入乙腈制成约0.2mg/ml的供试品溶液，进样分析，以峰面积百分比考察样品稳定性，并关注是否有新增杂质。
实验条件见表4，实验结果见表5。
表4实验条件
Figure PCTCN2020114448-appb-000136
表5化合物5稳定性
Figure PCTCN2020114448-appb-000137
4、大鼠组织分布实验
4.1.试验动物：雄性SD大鼠，200g左右，6～8周龄，12只/化合物。购于成都达硕实验动物有限公司。
4.2实验方案：
试验方法：试验当天，24只SD大鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。按照表6给药。
表6给药信息
Figure PCTCN2020114448-appb-000138
*剂量以游离碱计。
于给药前及给药后异氟烷麻醉经眼眶取血0.20mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。采血时间点：10min,0.5,1,4h。分析检测前，所有血浆样品存于-80℃。
给药后组织(心、肝、脾、肺、肾、脑、结肠、直肠)样本采集时间点：10min,0.5,1,4h。动物放血干净安乐死后取组织，生理盐水清洗干净后用50％甲醇按m/v＝1:3比例匀浆后-80°冰箱保存待分析。
4.3实验结果如表7：
表7大鼠组织分布实验结果
Figure PCTCN2020114448-appb-000139
结论：运用本发明技术所合成的化合物5的组织分布结果显示，脑中暴露量低于APD-371。
5、SD大鼠单次经口灌胃给药最大耐受剂量(MTD)试验
试验设计：
共50只大鼠，雌雄各半，分5组，每组5只/性别，溶媒对照组(20％SBE-β-CD)，APD-371低剂量组300mg/kg，APD-371高剂量组1000mg/kg，化合物5低剂量组300 mg/kg，化合物5高剂量组1000mg/kg，经口灌胃，给药体积10mL/kg。
结果及结论：
APD-371MTD为300mg/kg；化合物5MTD为1000mg/kg。

Claims (17)

  1. 一种式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药：
    Figure PCTCN2020114448-appb-100001
    其中，
    R 1选自-L 1-L 2-L 3-L 4；
    L 1选自C 1-6亚烷基、C 3-7亚环烯基、C 3-7亚环烷基、C 3-6不饱和亚环烃基、C 3-6亚杂环基、C 6-10亚芳基、C 5-10亚杂芳基、C 4-12桥环、C 4-12并环、C 5-10螺环或者不存在，所述的亚烷基、亚环烯基、亚环烷基、不饱和亚环烃基、亚杂环基、亚芳基、亚杂芳基、桥环、并环、螺环各自独立任选被如下取代基取代：卤素、氰基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 2-6炔基-C 3-6环烷基、C 1-6烷氧基、羟基取代的C 1-6烷基、卤代C 1-6烷基、苯环、-C 1-6烷基-O-卤代烷基、-C(O)O-C 1-6烷基或者C 3-6环烷基；
    L 2选自C 1-6亚烷基、C 3-7亚环烷基、C 3-6亚杂环基、C 5-10亚杂芳基、-C(O)NH-、-C(O)-、-C(O)O-或者不存在，所述的亚烷基、亚环烷基、亚杂环基、亚杂芳基各自独立任选被如下取代基取代：C 1-6烷基或卤素；
    L 3选自C 1-6亚烷基或者不存在；
    L 4选自H、卤素、羟基、氨基、脲基、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷氧基、C 3-6杂环基、C 2-6炔基、C 6-10芳基、C 5-10杂芳基、-NHC 1-6烷基、-N(C 1-6烷基)C 1-6烷基、-NHC(O)C 1-6烷基、-C(O)NHC 1-6烷基、-NH-C 6-10芳基、-NH-C 3-7环烷基、-C(O)-C 6-10芳基、-O-C 6-10芳基、-O-C 6-10杂芳基、-O-C 1-6亚烷基-COOH、-C(O)NH 2、-COOH、C 4-12桥环、C 4-12并环或者C 5-10螺环，所述的烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、炔基、桥环、螺环、并环任选被如下取代基取代：卤素、氰基、羟基、氨基、C 1-6烷基、C 1-6卤代烷基或者C 1-6烷氧基；
    R 2、R 3各自独立选自H、F、Cl、氰基、羟基或者C 1-6烷基；
    R 4、R 5、R 6、R 7各自独立选自H、F、Cl、氨基、氰基、羟基、C 1-6烷基或者C 1-6卤代烷基；
    R 8、R 9各自独立选自H、F、Cl、C 1-6烷基，所述的烷基任选被以下取代基取代：氰基、F或者Cl；或者R 8与R 9一起形成C 2-6烯基或者C 3-6环烷基；
    R 10选自H或者C 1-6烷基；
    R 11选自芳基或杂芳基，所述的芳基或杂芳基任选被以下取代基取代：F、Cl、C 1-6烷基或者C 1-6烷氧基，所述的杂芳基包含选自N、O、S杂原子或其氧化态；
    条件是：当R 11选自芳基及取代芳基时，R 1选自
    Figure PCTCN2020114448-appb-100002
    或者
    Figure PCTCN2020114448-appb-100003
  2. 根据权利要求1所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
    R 1选自C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 3-6不饱和环烃基、C 6-10芳基、C 5-10杂芳基、C 4-12桥环、C 4-12并环、C 5-10螺环，所述的烷基、环烷基、不饱和环烃基、杂环基、芳基、杂芳基、桥环、并环或者螺环任选被以下取代基取代：F、Cl、羟基、氰基、C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、C 3-6杂环基、苯环、-C(O)O-C 1-6烷基或者C 3-6环烷基。
  3. 根据权利要求2所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
    R 1选自
    Figure PCTCN2020114448-appb-100004
    吲哚基、吡咯基、吡啶基、哌啶基、苯基、环己基、环戊基、吡嗪、金刚烷基、哌嗪、吗啉基、
    Figure PCTCN2020114448-appb-100005
    Figure PCTCN2020114448-appb-100006
    或者
    Figure PCTCN2020114448-appb-100007
    或者
    R 1选自
    Figure PCTCN2020114448-appb-100008
  4. 根据权利要求1所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
    R 11选自
    Figure PCTCN2020114448-appb-100009
    或者
    Figure PCTCN2020114448-appb-100010
    或者
    R 11选自
    Figure PCTCN2020114448-appb-100011
  5. 根据权利要求1所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
    R 1选自C 1-6烷基或者C 3-6环烷基，所述的烷基或者环烷基任选被以下取代基取代：F、Cl、C 1-6烷基或者羟基；
    R 2、R 3各自独立选自H、F、Cl或者C 1-6烷基；
    R 4、R 5、R 6、R 7各自独立选自H或者C 1-6烷基；
    R 8、R 9各自独立选自H、F、Cl、C 1-6烷基，所述的烷基任选被以下取代基取代：氰基、F或者Cl，或者R 8与R 9一起形成C 2-6烯基或者C 3-6环烷基；
    R 10选自H；
    R 11选自
    Figure PCTCN2020114448-appb-100012
    或者
    Figure PCTCN2020114448-appb-100013
  6. 根据权利要求5所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中：
    R 1选自
    Figure PCTCN2020114448-appb-100014
    或者
    Figure PCTCN2020114448-appb-100015
    R 2、R 3各自独立选自H、F或者甲基；
    R 4、R 5、R 6、R 7各自独立选自H；
    R 8、R 9各自独立选自H、F、异丙基，或者R 8与R 9一起形成2-甲基丙烯基或者环丙 基；
    R 10选自H；
    R 11选自
    Figure PCTCN2020114448-appb-100016
  7. 根据权利要求1所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中化合物结构如下：
    Figure PCTCN2020114448-appb-100017
  8. 根据权利要求7所述的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，其中化合物结构如下：
    Figure PCTCN2020114448-appb-100018
  9. 一种药物组合物，所述的组合物包括：有效剂量的根据权利要求1至8中任一项所述通式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药，或进一步包括一种或多种其他治疗剂以及药学上可接受的载体或赋形剂。
  10. 权利要求1至8中任一项所述通式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药或者权利要求9所述的组合物在制备用于治疗由CB2受体介导的疾病的药物中的用途。
  11. 根据权利要求10所述的用途，其中所述的由CB2受体介导的疾病为疼痛。
  12. 根据权利要求11所述的用途，其中疼痛选自：骨痛、关节痛、肌肉疼痛、牙痛、偏头痛、头痛、炎性疼痛、神经病理性疼痛、克罗恩病相关腹痛、由于治疗剂的不良作用而引起的疼痛及与选自下述的疾病相关的疼痛：骨关节炎、癌症、多发性硬化、变应性应答、肾炎综合征、硬皮病、甲状腺炎、糖尿病性神经病、纤维肌痛、与HIV相关的神经病、坐骨神经痛和自身免疫性疾病。
  13. 根据权利要求12所述的用途，其中疼痛选自神经病理性疼痛、克罗恩病相关腹痛。
  14. 一种治疗CB2受体介导的疾病的方法，所述方法包括给药权利要求1至8中任一项所述通式(I)所示的六氢化苯并吡唑化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N-氧化物或前药或者权利要求9所述的组合物。
  15. 根据权利要求14所述的方法，其中由CB2受体介导的疾病为疼痛。
  16. 根据权利要求15所述的方法，其中疼痛选自：骨痛、关节痛、肌肉疼痛、牙痛、偏头痛、头痛、炎性疼痛、神经病理性疼痛、克罗恩病相关腹痛由于治疗剂的不良作用 而引起的疼痛及与选自下述的疾病相关的疼痛：骨关节炎、癌症、多发性硬化、变应性应答、肾炎综合征、硬皮病、甲状腺炎、糖尿病性神经病、纤维肌痛、与HIV相关的神经病、坐骨神经痛和自身免疫性疾病。
  17. 根据权利要求16所述的方法，其中疼痛选自神经病理性疼痛、克罗恩病相关腹痛。
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