WO2021047583A1 - Tricyclic pyrazole derivative and preparation thereof - Google Patents

Tricyclic pyrazole derivative and preparation thereof Download PDF

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Publication number
WO2021047583A1
WO2021047583A1 PCT/CN2020/114451 CN2020114451W WO2021047583A1 WO 2021047583 A1 WO2021047583 A1 WO 2021047583A1 CN 2020114451 W CN2020114451 W CN 2020114451W WO 2021047583 A1 WO2021047583 A1 WO 2021047583A1
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alkyl
ring
hydroxy
pain
compound
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PCT/CN2020/114451
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French (fr)
Chinese (zh)
Inventor
李瑶
王文晶
张国彪
石宗军
陈雷
杜勇
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 CN202080061776.8A priority Critical patent/CN114391010A/en
Publication of WO2021047583A1 publication Critical patent/WO2021047583A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides, prodrugs and their pharmaceutical compositions, preparation methods, and Use in the prevention and treatment of cannabinoid CB2 receptor-mediated diseases.
  • 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, which 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 class of cannabinoid CB2 agonists with novel structure, effectiveness, safety, high selectivity and good pharmacokinetic characteristics.
  • the present invention relates to a tricyclic pyrazole 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
  • X is CR 2 'R 2, NR 3 or O;
  • R 2 and R 2 ' are selected from H, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy; or
  • R 2 and R 4 or R 3 and R 4 form a 3- to 6-membered ring and the C ring does not exist.
  • the ring may be further substituted by the following substituents: halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy;
  • R 3 is selected from H or C 1-6 alkyl
  • the C ring is a 3 to 6 membered ring, which is optionally substituted by R 7;
  • R 7 is each independently selected from F, Cl, hydroxyl, C 1-6 alkyl, cyano, C 1-6 alkoxy or C 1-6 haloalkyl;
  • R 4 , R 5 , R 6 , and R 9 are each independently selected from H, F, Cl, amino, cyano, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl; or
  • R 5 and R 6 form a 3- to 6-membered ring, and the C ring does not exist;
  • R 10 is selected from H or C 1-6 alkyl
  • R 11 is selected from -(CH 2 ) m -C 6-10 aryl, -(CH 2 ) m -C 5-10 heteroaryl, -(CH 2 ) m -C 3-6 heterocyclic group, said The aryl, heterocyclic or heteroaryl group is optionally substituted by the following substituents: F, Cl, hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy, the heteroaryl
  • the base contains 1-3 heteroatoms selected from N, O, S and their oxidation states;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • the condition is that the C ring is not a substituted or unsubstituted heteroaryl group.
  • the C ring is a 3 to 6 membered ring, which ring is optionally substituted with 0 to 3 R 7 .
  • R 1 is selected from a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 4-12 bridged ring, a C 4-12 hexacyclic ring, and a C 5-10 spiro ring.
  • Alkyl, cycloalkyl, bridged ring, fused ring or spiro ring is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl, hydroxy, hydroxy substituted C 1-6 alkyl, halo C 1 -6 alkyl, C 1-6 alkoxy, benzene ring, -C(O)OC 1-6 alkyl, or C 3-6 cycloalkyl.
  • R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted with the following substituents: F, Cl, C 1- 6 Alkyl, hydroxy, hydroxy substituted C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, benzene ring, -C (O) OC 1-6 alkyl or C 3 -6 cycloalkyl.
  • R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted with the following substituents: F, Cl, C 1- 6 Alkyl, hydroxy, hydroxy substituted C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, benzene ring, -C (O) OC 1-6 alkyl or C 3 -6 cycloalkyl.
  • R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted by the following substituents: C 1-6 alkyl, A hydroxy group or a C 1-6 alkyl group substituted by a hydroxy group; the definitions of other groups are the same as the above.
  • R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 3-6 unsaturated cyclic hydrocarbon group, C 6-10 Aryl, C 5-10 heteroaryl, C 4-12 bridged ring, C 4-12 parallel ring, C 5-10 spiro ring, the alkyl group, cycloalkyl group, unsaturated cyclic hydrocarbon group, heterocyclic group , Aryl, heteroaryl, bridged ring, fused ring or spiro ring are optionally substituted by the following substituents: F, Cl, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, hydroxy substituted C 1 -6 alkyl, C 3-6 heterocyclyl, halogenated C 1-6 alkyl, benzene ring, -C(O)OC 1-6 alkyl, or C 3-6 cycloalkyl.
  • R 1 is selected from a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 4-12 bridged ring, a C 4-12 hexacyclic ring, and a C 5-10 spiro ring.
  • Alkyl, cycloalkyl, bridged ring, fused ring or spiro ring is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl, hydroxy, hydroxy substituted C 1-6 alkyl, C 1-6 Alkoxy, C 3-6 heterocyclyl, benzene ring, -C(O)OC 1-6 alkyl or C 3-6 cycloalkyl.
  • R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted with the following substituents: F, Cl, C 1- 6 alkyl, hydroxy, hydroxy substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 heterocyclyl, benzene ring, -C (O) OC 1-6 alkyl or C 3- 6 cycloalkyl.
  • R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted with the following substituents: F, Cl, C 1- 6 alkyl, hydroxy, hydroxy substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 heterocyclyl, benzene ring, -C (O) OC 1-6 alkyl or C 3- 6 cycloalkyl.
  • R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted by the following substituents: C 1-6 alkyl, C 3-6 heterocyclyl, hydroxy or C 1-6 alkyl substituted with hydroxy; definition of other groups is the same as above.
  • R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted by the following substituents: F, Cl, hydroxy, halo Substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, phenyl; in certain embodiments, R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, the Alkyl and cycloalkyl are optionally substituted with the following substituents: F, Cl, hydroxy, halo C 1-6 alkyl, hydroxy substituted C 1-6 alkyl; in certain embodiments, R 1 is selected from C 1-6 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, said alkyl and cycloalkyl are optionally substituted by the following substituents: F, Cl, hydroxy, halo C 1-6 alkyl
  • R 1 is selected from methyl, ethyl, propyl, isopropyl, butyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantane, and these groups are optionally selected by Hydroxymethyl, hydroxyl, methyl, tert-butyl, fluorine atom, trifluoromethoxymethyl, fluoromethyl, cyclopropylethynyl, trifluoromethyl, trifluorosubstituted tert-butyl substituted.
  • R 1 is selected from the group consisting of ethyl, propyl, isopropyl, butyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted by hydroxymethyl, hydroxy, methyl, tert-butyl Substitution; the definition of other groups is the same as above.
  • R 1 is selected from methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantane.
  • Groups are optionally substituted by hydroxymethyl, hydroxyl, methyl, tert-butyl, fluorine atom, trifluoromethoxymethyl, fluoromethyl, cyclopropylethynyl, trifluoromethyl, trifluoromethyl replace.
  • R 1 is selected from ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally selected from hydroxymethyl, hydroxy, trifluoro Methyl, methyl, tert-butyl substitution; the definition of other groups is the same as above.
  • R 1 is selected from methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantane.
  • Groups are optionally substituted by hydroxymethyl, hydroxyl, methyl, tert-butyl, fluorine atom, trifluoromethoxymethyl, fluoromethyl, cyclopropylethynyl, trifluoromethyl, trifluoromethyl , replace.
  • R 1 is selected from ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally selected from hydroxymethyl, hydroxy, trifluoro Methyl, methyl, tert-butyl, Substitution; the definition of other groups is the same as above.
  • R 1 is selected from adamantane, and the adamantane is optionally substituted by hydroxyl, cyano, halogen, or hydroxymethyl; the definition of other groups is consistent with the foregoing.
  • R 1 is selected from Indolyl, pyrrolyl, pyridyl, piperidinyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, adamantyl, piperazine, morpholinyl, In certain embodiments, R 1 is selected from Adamantyl, In certain embodiments, R 1 is selected from Adamantyl, In the above embodiments, the other groups are the same as the above.
  • R 1 is selected from Indolyl, pyrrolyl, pyridyl, piperidinyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, adamantyl, piperazine, morpholinyl, In certain embodiments, R 1 is selected from Adamantyl, In certain embodiments, R 1 is selected from Adamantyl, In the above embodiments, the other groups are the same as the above.
  • R 1 is selected from In certain embodiments, R 1 is selected from In certain embodiments, R 1 is selected from or In certain embodiments, R 1 is selected from or In certain embodiments, R 1 is selected from or In certain embodiments, R 1 is selected from In certain embodiments, R 1 is selected from In certain embodiments, R 1 is selected from In certain embodiments, R 1 is selected from or In certain embodiments, R 1 is selected from In certain embodiments, R 1 is selected from In certain embodiments, R 1 is selected from or In certain embodiments, R 1 is selected from In certain embodiments, R 1 is selected from or In certain embodiments, R 1 is selected from In certain embodiments, R 1 is selected from In the above embodiments, the definitions of other groups are consistent with the foregoing.
  • X is CR 2 'R 2 or O; R 2, R 2' is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 Haloalkoxy or C 1-6 alkoxy.
  • X is CR 2 ′R 2 or O; R 2 , R 2 ′ are selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl. In certain embodiments, X is CR 2 'R 2 or O; R 2, R 2' is selected from H, F, Cl, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methyl Group, fluoroethyl, trifluoroethyl.
  • X is CR 2 ′R 2 ; R 2 , R 2 ′ are selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl.
  • X is CR 2 'R 2; R 2 , R 2' is selected from H, F, Cl, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, Fluoroethyl, trifluoroethyl.
  • X is CR 2 ′R 2 ; R 2 , R 2 ′ are selected from H, F, methyl, and fluoromethyl.
  • X is CR 2 ′R 2 ; R 2 is selected from H, F, methyl, fluoromethyl, and R 2 ′ is selected from H or F. In certain embodiments, X is CR 2 ′R 2 ; R 2 is selected from H, and R 2 ′ is selected from H. In the above embodiments, the definitions of other groups are consistent with the foregoing.
  • the C ring is a 3 to 6 membered cycloalkane, a 3 to 6 membered cycloalkene, or a 3 to 6 membered heterocyclic ring.
  • One R 7 is substituted.
  • the definitions of other groups are the same as above.
  • the C ring is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, 2-cyclopentene, 3-cyclopentene, 2,4-cyclopentadiene, 4-cyclopentene, 1-cyclohexene, 2-cyclohexene, 3-cyclohexene, 4-cyclohexene, 5-cyclohexene, 2,4-cyclodihexene, 3,5-cyclo Dihexene, ethylene oxide, azetane, azetidine, oxetane, pyrrolidine, pyrroline, pyrazoline, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, or
  • the C ring is cyclopropane, cyclobutane, cyclopentane; in certain embodiments, the C ring is cyclopropane, cyclobutane; in certain embodiments
  • R 7 is each independently selected from F, Cl, hydroxyl, C 1-6 alkyl, cyano, C 1-6 alkoxy or C 1-6 haloalkyl; In certain embodiments, R 7 is selected from F, Cl, C 1-6 alkyl or C 1-6 haloalkyl; in certain embodiments, R 7 is selected from F, Cl, methyl, ethyl, Isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl or trifluoroethyl; in some embodiments, R 7 is selected from F, Cl, methyl In certain embodiments, R 7 is selected from F.
  • R 7 is selected from F.
  • the definitions of other groups are the same as above.
  • the C ring is cyclopropane, cyclobutane or cyclopentane, and the cyclopropane, cyclobutane or cyclopentane is optionally substituted with 0 to 2 R 7 ;
  • Each R 7 is independently selected from F.
  • the definitions of other groups are the same as above.
  • R 4 , R 5 , R 6 , and R 9 are each independently selected from H or C 1-6 alkyl; or R 5 and R 6 form cyclopropane, and the C ring is not present.
  • the definitions of other groups are the same as above.
  • R 4 , R 5 , and R 9 are each independently selected from H;
  • R 6 is selected from H or methyl
  • R 5 and R 6 form cyclopropane, and the C ring does not exist.
  • the definitions of other groups are the same as above.
  • R 11 is selected from C 6-10 aryl or C 5-10 heteroaryl, and the aryl or heteroaryl is optionally substituted by the following substituents: F, Cl Or C 1-6 alkyl, the heteroaryl group contains 1-3 heteroatoms selected from N, O, S and their oxidation states.
  • substituents F, Cl Or C 1-6 alkyl
  • the heteroaryl group contains 1-3 heteroatoms selected from N, O, S and their oxidation states.
  • the definitions of other groups are the same as above.
  • R 11 is selected from phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrazinyl oxynitride Pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole; the above groups are optionally substituted by the following substituents: F, Cl or methyl. In certain embodiments, the above groups are optionally substituted with F. The definitions of other groups are the same as above.
  • R 11 is selected from or In certain embodiments, R 11 is selected from In certain embodiments, R 11 is selected from In certain embodiments, R 11 is selected from In certain embodiments, R 11 is selected from The definitions of other groups are the same as above.
  • R 1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by the following substituents: F, Cl , C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl or hydroxy; the compound of the present invention, in certain embodiments, 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, methyl, ethyl, isopropyl, hydroxymethyl, trifluoromethyl, di Fluoromethyl or hydroxy; or the compound of the present invention, in some embodiments, R 1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally Substituent substitution: F, Cl , C 1-6 alkyl, halogen
  • X is CR 2 'R 2 or O; In certain embodiments, X is CR 2' R 2;
  • R 2 , R 2 ′ are selected from H, F, methyl or fluoromethyl; in certain embodiments, R 2 , R 2 ′ are selected from H;
  • Ring C is cyclopropane, cyclobutane, or cyclopentane; in some embodiments, ring C is cyclopropane; in some embodiments, ring C is cyclobutane; in some embodiments, ring C is Cyclopentane; the cyclopropane, cyclobutane, or cyclopentane is optionally substituted with R 7 ; in some embodiments, the C ring is cyclopropane; in some embodiments, the C ring is cyclopentane, and any Optionally substituted by R 7 ; in some embodiments, the C ring is cyclopropane or cyclopentane;
  • R 7 is each independently selected from F
  • R 4 , R 5 , and R 9 are each independently selected from H;
  • R 6 is selected from H or methyl
  • R 5 and R 6 form cyclopropane, and the C ring does not exist;
  • R 10 is selected from H
  • R 11 is selected from or In certain embodiments, R 11 is selected from In certain embodiments, R 11 is selected from In certain embodiments, R 11 is selected from In certain embodiments, R 11 is selected from
  • R 1 is selected from or Or R 1 is selected from In certain embodiments, R 1 is selected from In certain embodiments, R 1 is selected from R 1 is selected from
  • X is CR 2 'R 2;
  • R 2 , R 2 ′ are selected from H
  • Ring C is cyclopropane, cyclobutane, or cyclopentane; in some embodiments, ring C is cyclopropane; in some embodiments, ring C is cyclobutane; in some embodiments, ring C is Cyclopentane; the cyclopropane, cyclobutane, or cyclopentane is optionally substituted with R 7 ; in some embodiments, the C ring is cyclopropane, cyclopentane; in some embodiments, the C ring is cyclopropane ;
  • R 7 is each independently selected from F
  • R 4 , R 5 , and R 9 are each independently selected from H;
  • R 6 is selected from H or methyl; in certain embodiments, R 6 is selected from H, and in certain embodiments, R 6 is selected from methyl;
  • R 10 is selected from H
  • R 11 is selected from
  • 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 tricyclic pyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention Use of the composition in the preparation of a medicament for treating diseases mediated by CB2 receptors.
  • the present invention relates to a tricyclic pyrazole compound represented by general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or combinations containing the compounds of the present invention In the preparation of medicines for the treatment of pain.
  • Pain can be selected from: bone pain, arthralgia, muscle pain, toothache, migraine, headache, inflammatory pain, neuropathic pain, Crohn’s disease-related abdominal pain, pain due to adverse effects of therapeutic agents, and selected from Pain related to the following diseases: 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 tricyclic pyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention Use of the composition in preparing a medicine for treating neuropathic pain.
  • the present invention also relates to the tricyclic pyrazole compound represented by general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention Use of the composition in the preparation of a medicine for treating Crohn's disease-related abdominal pain.
  • the present invention also relates to the tricyclic pyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention
  • the composition is used in a method of treating diseases mediated by CB2 receptors.
  • the present invention also relates to the tricyclic pyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention
  • the composition is used in a method of treating 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 caused by the adverse effects of the therapeutic agent, and the following Pain related to the diseases mentioned: 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 tricyclic pyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention
  • the composition is used to treat neuropathic pain.
  • the present invention also relates to the tricyclic pyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention A method for the composition to treat abdominal pain associated with Crohn's disease.
  • 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.
  • unsaturated bonds such as double bonds
  • Non-limiting examples include cyclopropenyl, cyclobutenyl, and 1,4-cyclohexanyl. Ene, 1,3-cyclopentadiene, etc.
  • 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 aziridine Group, oxetanyl, thietanyl, azetidinyl, oxetanyl, thietanyl, azetyl (also known as azetidinyl), pyrrolyl, pyrroline Group, 3-pyrrolinyl, 1-pyrrolinyl, pyrrolidinyl, pyrazolidinyl, 2-pyrazoline, imidazolyl, pyrazolyl, tetrahydrofuranyl, tetrahydrothienyl, 1,2,4 -Triazolyl and so on.
  • the heterocyclic group may be optionally further substituted with any substituent.
  • Heterocycle refers to a saturated or unsaturated cyclic hydrocarbon containing at least one heteroatom, a single ring, and the heteroatoms are N, O, S, P and their oxidized forms.
  • Non-limiting examples include aziridine, Oxetane, thietane, azetidine, oxetane, thietane, azetidine (also known as azetidine), pyrrole, pyrroline, 3-pyrroline , 1-pyrroline, pyrrolidine, pyrazolidine, 2-pyrazoline, imidazole, pyrazole, tetrahydrofuran, tetrahydrothiophene, 1,2,4-triazole, etc.
  • the heterocyclic ring may be optionally further substituted with any substituent.
  • Non-limiting examples include The fused ring may be further substituted with any substituent.
  • Bridged ring refers to a polycyclic group in which any two rings share atoms (such as carbon atoms) that are not directly connected, and can contain 0 or more double bonds, and can be substituted or unsubstituted, and a ring system
  • 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 on a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include phenyl, The aryl group may be further substituted with any substituent.
  • 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.
  • R can be independently and freely selected, can be the same or 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 4.6 mm).
  • 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
  • PE petroleum ether
  • EA ethyl acetate
  • DCM dichloromethane
  • mCPBA m-chloroperbenzoic acid
  • IBX o-iodobenzoic acid
  • LHMDS Lithium bis(trimethylsilyl)amide.
  • the reaction was quenched by adding saturated aqueous sodium bicarbonate (200mL) to the reaction, extracted with 300ml of ethyl acetate, allowed to stand and separate the layers, the aqueous phase was extracted three times with dichloromethane (200mL ⁇ 3)mL), and the combined organic phases were used After drying with anhydrous sodium sulfate and concentrating under reduced pressure, the residue is obtained as the crude product.
  • Dissolve compound 1b (20g, 0.18mol) in 400ml of ethanol solution, then add diethyl oxalate (26g, 0.18mol) and potassium tert-butoxide (20g, 0.18mol) with stirring, then heat to 40°C and stir to react After 2 hours, slowly add 6M hydrochloric acid solution (100ml), stir for 5 minutes, add pyrazine hydrazine (20g, 0.18mol), then raise the reaction solution to 50°C and continue the reaction for 2 hours.
  • Dissolve compound 1c (18g, 0.06mol) in a mixed solvent of 200ml methanol and 200ml tetrahydrofuran, then slowly add 20ml of aqueous solution of sodium hydroxide (3g, 0.08mol), stir overnight at room temperature after the addition is complete, add 2M Adjust the pH of the reaction solution to about 3 with dilute hydrochloric acid, then add 500ml of water, and then extract with dichloromethane (800mL ⁇ 3), then dry with anhydrous sodium sulfate and spin dry to obtain 15g (1d) of yellow powder solid, yield 92.5 %.
  • the fifth step 3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamyl)-5,5a,6, 6a-Tetrahydrocyclopropane[g]indazole-1(4hydro)-yl)pyrazine-1-oxide
  • Dissolve compound 1b (0.1g, 0.9mmol) in 2ml of ethanol solution, then add diethyl oxalate (0.13g, 0.9mmol) and potassium tert-butoxide (0.1g, 0.9mmol) under stirring, and then heat to 40 The reaction was stirred at °C for 2 hours, then 6M hydrochloric acid solution (0.5ml) was slowly added, after stirring for 5 minutes, 2,4-difluorophenylhydrazine (0.13g, 0.9mol) was added, and then the reaction solution was raised to 50°C to continue the reaction.
  • the reaction solution was poured into 100g of ice water, stirred for half an hour, and then filtered. The obtained filtrate was added with 150ml of water and used ethyl acetate. (200mL ⁇ 3) Extract, combine the organic phases, dry with anhydrous sodium sulfate, spin-dry in a water bath at 35°C to obtain 10g (5b) of the desired compound, and proceed directly to the next reaction. The yield was 89.3%.
  • the third step 5a-methyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropyl[g]indazole-3-carboxylic acid (5d)
  • the fifth step 3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbut-2-yl)carbamoyl)-5amethyl-5, 5a,6,6a-tetrahydrocyclopropane[g]indazole-1(4hydro)-yl)pyrazine-1-oxide
  • the raw material 5e (0.13g, 0.35mmol) was dissolved in 5ml of formic acid solution, and then 30% hydrogen peroxide solution (0.7ml) was added. The temperature was raised to 64°C and the reaction was stirred for 3 hours. Then 50ml of water was added and ethyl acetate ( 50mL ⁇ 3) extract, combine the organic phases, dry with anhydrous sodium sulfate, spin dry, dissolve the resulting brown oil in a mixed solvent of 3ml of methanol and 3ml of tetrahydrofuran, and then slowly add dropwise 2ml of sodium hydroxide aqueous solution ( 0.015g, 0.4mmol). After stirring and reacting at room temperature for 15 minutes, the reaction was checked by TLC.
  • Dissolve compound 6i (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 up to room temperature and react overnight. The reaction was quenched with dilute hydrochloric acid (1M, 30mL), and the organic phases were extracted and combined with ethyl acetate (50mL ⁇ 3).
  • 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: 11.3min.
  • Dissolve compound 8a (10g, 0.09mol) in 200ml of ethanol solution, then add diethyl oxalate (13g, 0.09mol) and potassium tert-butoxide (10g, 0.09mol) with stirring, then heat to 40°C and stir to react After 2 hours, slowly add 6M hydrochloric acid solution (50ml), stir for 5 minutes, add pyrazine hydrazine (10g, 0.09mol), then raise the reaction solution to 50°C and continue the reaction for 2 hours. TLC detects that the reaction is complete.
  • the second step (5aR,6aS)-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropane[g]indazole-3-carboxylic acid (8c) (5aR,6aS)-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylic acid
  • the third step 3-(((5aR,6aS)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1(4H)-yl)pyrazine 1-oxide( 8d)
  • the raw material 8c (10g, 0.04mol) was dissolved in 100ml of formic acid solution, and then 30% hydrogen peroxide solution (10ml) was added. The temperature was raised to 64°C and the reaction was stirred for 3 hours. Then 550ml of water was added, and ethyl acetate (500mL ⁇ 3) Extract three times, combine the organic phases, dry with anhydrous sodium sulfate, and spin-dry the resulting brown oil directly for the next step.
  • the first step 3-((5aR,6aS)-3-((2-phenylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole- 1(4H)-yl)pyrazine 1-oxide (Compound 10)
  • the first step 3-((5aR,6aS)-3-((1-methoxy-2-methyl-1-oxopropan-2-yl)carbamyl)-5,5a,6,6a- Tetrahydrocyclopropane[g]indazole-1(4H)-yl)pyrazine-1-oxide
  • the first step 3-((5aR,6aS)-3-((2-cyanopropane-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole- 1(4H)-yl)pyrazine 1-oxide
  • the first step 3-((5aR,6aS)-3-((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[ g)Indazole-1(4H)-yl)pyrazine 1-oxide
  • the first step 3-((5aR,6aS)-3-((tetrahydro-2H-pyran-4-yl)aminobenzyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole -1(4H)-yl)pyrazine 1-oxide
  • the first step 3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropyl[g]indole Azole-1(4H)-yl)pyrazine 1-oxide
  • the first step 3-((5aR,6aS)-3-((2-(hydroxymethyl)oxetan-2-yl)aminobenzyl)-5,5a,6,6a-tetrahydrocyclopropane[ g)Indazole-1(4H)-yl)pyrazine 1-oxide
  • the raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, and then (2-aminooxetan-2-yl)methanol (0.10g, 1mmol) and HATU (0.57g, 1.5mmol) were added.
  • the first step 3-((5aR,6aS)-3-((1-phenylcyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1( 4H)-yl)pyrazine 1-oxide
  • the first step 3-((5aR,6aS)-3-((S)-2,3-dihydroxypropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indole Azole-1(4H)-yl)pyrazine 1-oxide
  • the first step 3-((5aR,6aS)-3-((R)-1-hydroxy-4-methylpentan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydro Cyclopropane[g]indazole-1(4H)-yl)pyrazine-1-oxide
  • the first step 3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropyl[g]indole Azole-1(4H)-yl)pyrazine 1-oxide
  • the raw material 8d (1g, 3.7mmol) was dissolved in 10ml of DMF solution, and then 2-amino-2-methylpropane-1-ol (0.33g, 3.7mmol) and HATU (1.7g, 4.4mmol) were added.
  • the first step 3-((5aR,6aS)-3-(((R)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)aminomethyl Acyl-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1(4H)-yl)pyrazine-1-oxo
  • HBSS HBSS
  • APD-371 is compound 699 in patent document WO2011025541.
  • the compounds of the present invention show higher agonistic activity for CB 2 receptors. Some compounds, especially compounds 3, 4, 8, 22a, show higher selectivity for CB 2 /CB 1 receptors.
  • 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.

Abstract

Disclosed is a tricyclic pyrazole compound shown in formula (I), and a stereoisomer, a pharmaceutically acceptable salt, a solvate, a hydrate, an N-oxide, a prodrug, and a pharmaceutical composition thereof, a preparation method therefor, and the use in the prevention and treatment of diseases mediated by the cannabinoid CB2 receptor.

Description

一种三环吡唑衍生物及其制备A kind of tricyclic pyrazole derivative and its preparation 技术领域Technical field
本发明涉及一种三环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。The present invention relates to a tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides, prodrugs and their pharmaceutical compositions, preparation methods, and Use in the prevention and treatment of cannabinoid CB2 receptor-mediated diseases.
背景技术Background technique
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。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.
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。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-α monoclonal antibodies. There are currently no drugs to manage Crohn's disease-related abdominal pain.
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。Pain is one of the most common clinical symptoms and is one of the main factors for patients to seek medical services. Currently, 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.
***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％。Cannabis extract has been used for pain relief for centuries. In addition to Delta-9-THC, cannabidiol (CBD), there are also a variety of endogenous ligand substances, as well as chemically synthesized cannabinoids (cannabinoid), which play analgesic and euphoric effects by binding to cannabinoid receptors. . And cannabinoids are a type of extracellular signal transduction molecules found in plants and animals. Signals from these molecules are mediated in animals through two G protein-coupled receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). 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). On the contrary, 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, which 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. 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.
作用于CB2受体的研究目前有CN10259613、CN101014605、WO2006129178、US20090081123。There are currently CN10259613, CN101014605, WO2006129178, and US20090081123 studies on CB2 receptors.
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。Peripheral selective CB2 agonists can theoretically avoid CB1R-related central psychiatric side effects, and show good analgesic effects in multiple preclinical models. Several 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, β-arrestin, etc. Different drugs have functional biases to downstream activation .
发明内容Summary of the invention
本发明的目的是介绍一类结构新颖、有效、安全、选择性高、药代动力学特征好的***素CB2激动剂。The purpose of the present invention is to introduce a class of cannabinoid CB2 agonists with novel structure, effectiveness, safety, high selectivity and good pharmacokinetic characteristics.
本发明涉及一种式(I)所示的三环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：The present invention relates to a tricyclic pyrazole compound represented by formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs:
Figure PCTCN2020114451-appb-000001
Figure PCTCN2020114451-appb-000001
其中，among them,
R 1选自-L 1-L 2-L 3-L 4； R 1 is selected from -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 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 1-6 alkyl, benzene ring, -C 1-6 alkyl-O-haloalkyl, -C(O)OC 1-6 alkyl or C 3-6 cycloalkane base;
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 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选自C 1-6亚烷基或者不存在； L 3 is selected from C 1-6 alkylene or absent;
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、C 1-6烷基-OH、C 6-10芳基或者C 1-6烷氧基； 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, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkynyl, bridged ring, spiro ring, and double ring Optionally substituted by the following substituents: halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-OH, C 6-10 aryl or C 1- 6 alkoxy;
X为CR 2’R 2、NR 3或者O； X is CR 2 'R 2, NR 3 or O;
R 2、R 2’选自H、卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或者C 1-6烷氧基；或者 R 2 and R 2 'are selected from H, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy; or
R 2与R 4或者R 3与R 4形成3至6元环且C环不存在，所述的环任选进一步被以下取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或者C 1-6烷氧基； R 2 and R 4 or R 3 and R 4 form a 3- to 6-membered ring and the C ring does not exist. The ring may be further substituted by the following substituents: halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy;
R 3选自H或者C 1-6烷基； R 3 is selected from H or C 1-6 alkyl;
C环为3至6元环，所述环任选被R 7取代； The C ring is a 3 to 6 membered ring, which is optionally substituted by R 7;
R 7各自独立选自F、Cl、羟基、C 1-6烷基、氰基、C 1-6烷氧基或者C 1-6卤代烷基； R 7 is each independently selected from F, Cl, hydroxyl, C 1-6 alkyl, cyano, C 1-6 alkoxy or C 1-6 haloalkyl;
R 4、R 5、R 6、R 9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；或者 R 4 , R 5 , R 6 , and R 9 are each independently selected from H, F, Cl, amino, cyano, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl; or
R 5、R 6形成3至6元环，且C环不存在； R 5 and R 6 form a 3- to 6-membered ring, and the C ring does not exist;
R 10选自H或者C 1-6烷基； R 10 is selected from H or C 1-6 alkyl;
R 11选自-(CH 2) m-C 6-10芳基、-(CH 2) m-C 5-10杂芳基、-(CH 2) m-C 3-6杂环基，所述的芳基、杂环基或杂芳基任选被以下取代基取代：F、Cl、羟基、氰基、氨基、C 1-6烷基或者C 1-6烷氧基，所述的杂芳基包含1-3个选自N、O、S杂原子及其氧化态； R 11 is selected from -(CH 2 ) m -C 6-10 aryl, -(CH 2 ) m -C 5-10 heteroaryl, -(CH 2 ) m -C 3-6 heterocyclic group, said The aryl, heterocyclic or heteroaryl group is optionally substituted by the following substituents: F, Cl, hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy, the heteroaryl The base contains 1-3 heteroatoms selected from N, O, S and their oxidation states;
m选自0、1、2、3、4或者5；m is selected from 0, 1, 2, 3, 4 or 5;
条件是：C环不为取代或未取代杂芳基。The condition is that the C ring is not a substituted or unsubstituted heteroaryl group.
在某些实施方案中，C环为3至6元环，所述环任选被0至3个R 7取代。 In certain embodiments, the C ring is a 3 to 6 membered ring, which ring is optionally substituted with 0 to 3 R 7 .
在某些实施方案中，R 1选自C 1-6烷基、C 3-6环烷基、C 4-12桥环、C 4-12并环、C 5-10螺环，所述的烷基、环烷基、桥环、并环或者螺环任选被以下取代基取代：F、Cl、C 1-6烷基、羟基、羟基取代的C 1-6烷基、卤代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C 1-6烷基、C 3-6环烷基，所述的烷基、环烷基任选被以下取代基取代：F、Cl、C 1-6烷基、羟基、羟基取代的C 1-6烷基、卤代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C 1-6烷基、C 3-6环烷基，所述的烷基、环烷基任选被以下取代基取代：F、Cl、C 1-6烷基、羟基、羟基取代的C 1-6烷基、卤代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C 1-6烷基、C 3-6环烷基，所述的烷基、环烷基任选被以下取代基取代：C 1-6烷基、羟基或者羟基取代的C 1-6烷基；其他基团定义与前文一致。 In certain embodiments, R 1 is selected from a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 4-12 bridged ring, a C 4-12 hexacyclic ring, and a C 5-10 spiro ring. Alkyl, cycloalkyl, bridged ring, fused ring or spiro ring is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl, hydroxy, hydroxy substituted C 1-6 alkyl, halo C 1 -6 alkyl, C 1-6 alkoxy, benzene ring, -C(O)OC 1-6 alkyl, or C 3-6 cycloalkyl. In certain embodiments, R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted with the following substituents: F, Cl, C 1- 6 Alkyl, hydroxy, hydroxy substituted C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, benzene ring, -C (O) OC 1-6 alkyl or C 3 -6 cycloalkyl. In certain embodiments, R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted with the following substituents: F, Cl, C 1- 6 Alkyl, hydroxy, hydroxy substituted C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, benzene ring, -C (O) OC 1-6 alkyl or C 3 -6 cycloalkyl. In certain embodiments, R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted by the following substituents: C 1-6 alkyl, A hydroxy group or a C 1-6 alkyl group substituted by a hydroxy group; the definitions of other groups are the same as the above.
本发明化合物在某些实施方案中，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、C 1-6烷基、羟基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6杂环基、卤代C 1-6烷基、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C 1-6烷基、C 3-6环烷基、C 4-12桥环、C 4-12并环、C 5-10螺环，所述的烷基、环烷基、桥环、并环或者螺环任选被以下取代基取代：F、Cl、C 1-6烷基、羟基、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。在某些实施方案中，R 1选自C 1-6烷基、C 3-6环烷基，所述的烷基、环烷基任选被以下取代基取代：F、Cl、C 1-6烷基、羟基、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。在某些实施方案中，R 1选自C 1-6烷基、C 3-6环烷基，所述的烷基、环烷基任选被以下取代基取代：F、Cl、C 1-6烷基、羟基、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。在某些实施方案中，R 1选自C 1-6烷基、C 3-6环烷基，所述的烷基、环烷基任选被以下取代基取代：C 1-6烷基、C 3-6杂环基、羟基或者羟基取代的C 1-6烷基；其他基团定义与前文一致。 In certain embodiments of the compounds of the present invention, R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 3-6 unsaturated cyclic hydrocarbon group, C 6-10 Aryl, C 5-10 heteroaryl, C 4-12 bridged ring, C 4-12 parallel ring, C 5-10 spiro ring, the alkyl group, cycloalkyl group, unsaturated cyclic hydrocarbon group, heterocyclic group , Aryl, heteroaryl, bridged ring, fused ring or spiro ring are optionally substituted by the following substituents: F, Cl, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, hydroxy substituted C 1 -6 alkyl, C 3-6 heterocyclyl, halogenated C 1-6 alkyl, benzene ring, -C(O)OC 1-6 alkyl, or C 3-6 cycloalkyl. In certain embodiments, R 1 is selected from a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 4-12 bridged ring, a C 4-12 hexacyclic ring, and a C 5-10 spiro ring. Alkyl, cycloalkyl, bridged ring, fused ring or spiro ring is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl, hydroxy, hydroxy substituted C 1-6 alkyl, C 1-6 Alkoxy, C 3-6 heterocyclyl, benzene ring, -C(O)OC 1-6 alkyl or C 3-6 cycloalkyl. In certain embodiments, R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted with the following substituents: F, Cl, C 1- 6 alkyl, hydroxy, hydroxy substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 heterocyclyl, benzene ring, -C (O) OC 1-6 alkyl or C 3- 6 cycloalkyl. In certain embodiments, R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted with the following substituents: F, Cl, C 1- 6 alkyl, hydroxy, hydroxy substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 heterocyclyl, benzene ring, -C (O) OC 1-6 alkyl or C 3- 6 cycloalkyl. In certain embodiments, R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted by the following substituents: C 1-6 alkyl, C 3-6 heterocyclyl, hydroxy or C 1-6 alkyl substituted with hydroxy; definition of other groups is the same as above.
在某些实施方案中，R 1选自C 1-6烷基、C 3-6环烷基，所述的烷基、环烷基任选被以下取代基取代：F、Cl、羟基、卤代C 1-6烷基、羟基取代的C 1-6烷基、苯基；在某些实施方案中，R 1选自C 1-6烷基、C 3-6环烷基，所述的烷基、环烷基任选被以下取代基取代：F、Cl、羟基、卤代C 1-6烷基、羟基取代的C 1-6烷基；在某些实施方案中，R 1选自C 1-6烷基、3元环烷基、4元环烷基、5元环烷基，所述的烷基、环烷基任选被以下取代基取代：F、Cl、羟基、卤代C 1-6烷基、羟基取代的C 1-6烷基；在某些实施方案中，R 1选自C 1-6烷基，所述的烷基任选被以下取代基取代：F、Cl、羟基、卤代C 1-6烷基、羟基取代的C 1-6烷基、苯基；在某些实施方案中，R 1选自C 1-6烷基，所述的烷基任选被以下取代基取代：F、Cl、羟基、卤代C 1-6烷基、C 1-6羟基烷基；在某些实施方案中，R 1选自C 1-6烷基，所述的烷基任选被以下取代基取代：F、Cl、羟基、卤代C 1-4烷基、羟基取代的C 1-4烷基；在某些实施方案中，R 1选自3元环烷基、4元环烷基、5元环烷基，所述的烷基、环烷基任选被以下取代基取代：F、Cl、羟基、卤代C 1-6烷基、羟基取代的C 1-6烷基；在某些实施方案中， R 1选自3元环烷基、4元环烷基、5元环烷基，所述的烷基、环烷基任选被以下取代基取代：F、Cl、羟基、卤代C 1-6烷基、羟基取代的C 1-6烷基；在某些实施方案中，R 1选自3元环烷基、5元环烷基，所述的环烷基任选被以下取代基取代：F、Cl、羟基、卤代C 1-4烷基、羟基取代的C 1-4烷基；在某些实施方案中，R 1选自3元环烷基、5元环烷基，所述的环烷基任选被以下取代基取代：羟基、卤代C 1-4烷基、羟基取代的C 1-4烷基；在某些实施方案中，R 1选自3元环烷基，所述的环烷基任选被以下取代基取代：F、Cl、羟基、卤代C 1-4烷基、羟基取代的C 1-4烷基；在某些实施方案中，R 1选自5元环烷基，所述的环烷基任选被以下取代基取代：F、Cl、羟基、卤代C 1-4烷基、羟基取代的C 1-4烷基；其他基团定义与前文一致。 In certain embodiments, R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and said alkyl and cycloalkyl are optionally substituted by the following substituents: F, Cl, hydroxy, halo Substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, phenyl; in certain embodiments, R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, the Alkyl and cycloalkyl are optionally substituted with the following substituents: F, Cl, hydroxy, halo C 1-6 alkyl, hydroxy substituted C 1-6 alkyl; in certain embodiments, R 1 is selected from C 1-6 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, said alkyl and cycloalkyl are optionally substituted by the following substituents: F, Cl, hydroxy, halo C 1-6 alkyl, hydroxy substituted C 1-6 alkyl; in certain embodiments, R 1 is selected from C 1-6 alkyl, and the alkyl is optionally substituted by the following substituents: F, Cl, hydroxy, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, phenyl; in some embodiments, R 1 is selected from C 1-6 alkyl, and the alkyl is any Optionally substituted by the following substituents: F, Cl, hydroxy, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl; in certain embodiments, R 1 is selected from C 1-6 alkyl, the The alkyl group of is optionally substituted with the following substituents: F, Cl, hydroxy, halogenated C 1-4 alkyl, hydroxy substituted C 1-4 alkyl; in certain embodiments, R 1 is selected from a 3-membered ring Alkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, said alkyl and cycloalkyl are optionally substituted by the following substituents: F, Cl, hydroxy, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl; in some embodiments, R 1 is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, said alkyl and cycloalkyl are optionally substituted by Group substitution: F, Cl, hydroxy, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl; in some embodiments, R 1 is selected from 3-membered cycloalkyl, 5-membered cycloalkyl , The cycloalkyl is optionally substituted by the following substituents: F, Cl, hydroxy, halogenated C 1-4 alkyl, hydroxy substituted C 1-4 alkyl; in some embodiments, R 1 is selected From a 3-membered cycloalkyl group and a 5-membered cycloalkyl group, the cycloalkyl group is optionally substituted by the following substituents: hydroxy, halogenated C 1-4 alkyl, hydroxy substituted C 1-4 alkyl; In some embodiments, R 1 is selected from a 3-membered cycloalkyl group, and the cycloalkyl group is optionally substituted with the following substituents: F, Cl, hydroxy, halogenated C 1-4 alkyl, hydroxy substituted C 1- 4- alkyl; In certain embodiments, R 1 is selected from 5-membered cycloalkyl, said cycloalkyl is optionally substituted by the following substituents: F, Cl, hydroxy, halogenated C 1-4 alkyl, C 1-4 alkyl substituted with hydroxy; other group definitions are the same as above.
本发明化合物在某些实施方案中，R 1选自甲基、乙基、丙基、异丙基、丁基、环丁基、环戊基、环己基或者金刚烷，这些基团任选被羟甲基、羟基、甲基、叔丁基、氟原子、三氟甲氧基甲基、氟代甲基、环丙基乙炔基、三氟甲基、三氟取代叔丁基取代。在某些实施方案中，R 1选自乙基、丙基、异丙基、丁基、环丁基、环戊基、环己基，任选被羟甲基、羟基、甲基、叔丁基取代；其他基团定义与前文一致。 In certain embodiments of the compounds of the present invention, R 1 is selected from methyl, ethyl, propyl, isopropyl, butyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantane, and these groups are optionally selected by Hydroxymethyl, hydroxyl, methyl, tert-butyl, fluorine atom, trifluoromethoxymethyl, fluoromethyl, cyclopropylethynyl, trifluoromethyl, trifluorosubstituted tert-butyl substituted. In certain embodiments, R 1 is selected from the group consisting of ethyl, propyl, isopropyl, butyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted by hydroxymethyl, hydroxy, methyl, tert-butyl Substitution; the definition of other groups is the same as above.
本发明化合物在某些实施方案中，R 1选自甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基或者金刚烷，这些基团任选被羟甲基、羟基、甲基、叔丁基、氟原子、三氟甲氧基甲基、氟代甲基、环丙基乙炔基、三氟甲基、三氟取代叔丁基取代。在某些实施方案中，R 1选自乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基，任选被羟甲基、羟基、三氟甲基、甲基、叔丁基取代；其他基团定义与前文一致。 In certain embodiments of the compounds of the present invention, R 1 is selected from methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantane. Groups are optionally substituted by hydroxymethyl, hydroxyl, methyl, tert-butyl, fluorine atom, trifluoromethoxymethyl, fluoromethyl, cyclopropylethynyl, trifluoromethyl, trifluoromethyl replace. In certain embodiments, R 1 is selected from ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally selected from hydroxymethyl, hydroxy, trifluoro Methyl, methyl, tert-butyl substitution; the definition of other groups is the same as above.
本发明化合物在某些实施方案中，R 1选自甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基或者金刚烷，这些基团任选被羟甲基、羟基、甲基、叔丁基、氟原子、三氟甲氧基甲基、氟代甲基、环丙基乙炔基、三氟甲基、三氟取代叔丁基、
Figure PCTCN2020114451-appb-000002
取代。在某些实施方案中，R 1选自乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基，任选被羟甲基、羟基、三氟甲基、甲基、叔丁基、
Figure PCTCN2020114451-appb-000003
取代；其他基团定义与前文一致。 In certain embodiments of the compounds of the present invention, R 1 is selected from methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantane. Groups are optionally substituted by hydroxymethyl, hydroxyl, methyl, tert-butyl, fluorine atom, trifluoromethoxymethyl, fluoromethyl, cyclopropylethynyl, trifluoromethyl, trifluoromethyl ,
Figure PCTCN2020114451-appb-000002
replace. In certain embodiments, R 1 is selected from ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally selected from hydroxymethyl, hydroxy, trifluoro Methyl, methyl, tert-butyl,
Figure PCTCN2020114451-appb-000003
Substitution; the definition of other groups is the same as above.
在某些实施方案中，R 1选自金刚烷，所述金刚烷任选被羟基、氰基、卤素、羟基甲基取代；其他基团定义与前文一致。 In certain embodiments, R 1 is selected from adamantane, and the adamantane is optionally substituted by hydroxyl, cyano, halogen, or hydroxymethyl; the definition of other groups is consistent with the foregoing.
本发明化合物，在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000004
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 PCTCN2020114451-appb-000005
Figure PCTCN2020114451-appb-000006
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000007
金刚烷基、
Figure PCTCN2020114451-appb-000008
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000009
金刚烷基、
Figure PCTCN2020114451-appb-000010
以上实施方案中，其他基团与前文一致。 In the compounds of the present invention, in certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000004
Indolyl, pyrrolyl, pyridyl, piperidinyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, adamantyl, piperazine, morpholinyl,
Figure PCTCN2020114451-appb-000005
Figure PCTCN2020114451-appb-000006
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000007
Adamantyl,
Figure PCTCN2020114451-appb-000008
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000009
Adamantyl,
Figure PCTCN2020114451-appb-000010
In the above embodiments, the other groups are the same as the above.
本发明化合物，在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000011
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 PCTCN2020114451-appb-000012
Figure PCTCN2020114451-appb-000013
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000014
金刚烷基、
Figure PCTCN2020114451-appb-000015
在某些 实施方案中，R 1选自
Figure PCTCN2020114451-appb-000016
金刚烷基、
Figure PCTCN2020114451-appb-000017
以上实施方案中，其他基团与前文一致。 In the compounds of the present invention, in certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000011
Indolyl, pyrrolyl, pyridyl, piperidinyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, adamantyl, piperazine, morpholinyl,
Figure PCTCN2020114451-appb-000012
Figure PCTCN2020114451-appb-000013
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000014
Adamantyl,
Figure PCTCN2020114451-appb-000015
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000016
Adamantyl,
Figure PCTCN2020114451-appb-000017
In the above embodiments, the other groups are the same as the above.
本发明化合物在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000018
Figure PCTCN2020114451-appb-000019
Figure PCTCN2020114451-appb-000020
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000021
Figure PCTCN2020114451-appb-000022
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000023
或者
Figure PCTCN2020114451-appb-000024
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000025
或者
Figure PCTCN2020114451-appb-000026
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000027
或者
Figure PCTCN2020114451-appb-000028
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000029
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000030
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000031
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000032
Figure PCTCN2020114451-appb-000033
或者
Figure PCTCN2020114451-appb-000034
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000035
Figure PCTCN2020114451-appb-000036
在某些实施方案中，R 1 选自
Figure PCTCN2020114451-appb-000037
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000038
或者
Figure PCTCN2020114451-appb-000039
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000040
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000041
以上实施方案中，其他基团定义与前文一致。 In certain embodiments of the compounds of the present invention, R 1 is selected from
Figure PCTCN2020114451-appb-000018
Figure PCTCN2020114451-appb-000019
Figure PCTCN2020114451-appb-000020
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000021
Figure PCTCN2020114451-appb-000022
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000023
or
Figure PCTCN2020114451-appb-000024
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000025
or
Figure PCTCN2020114451-appb-000026
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000027
or
Figure PCTCN2020114451-appb-000028
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000029
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000030
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000031
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000032
Figure PCTCN2020114451-appb-000033
or
Figure PCTCN2020114451-appb-000034
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000035
Figure PCTCN2020114451-appb-000036
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000037
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000038
or
Figure PCTCN2020114451-appb-000039
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000040
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000041
In the above embodiments, the definitions of other groups are consistent with the foregoing.
本发明化合物在某些实施方案中，X为CR 2’R 2或者O；R 2、R 2’选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或者C 1-6烷氧基。 Compounds of the invention in some embodiments, X is CR 2 'R 2 or O; R 2, R 2' is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 Haloalkoxy or C 1-6 alkoxy.
在某些实施方案中，X为CR 2’R 2或者O；R 2、R 2’选自H、卤素、C 1-6烷基或者C 1-6卤代烷基。在某些实施方案中，X为CR 2’R 2或者O；R 2、R 2’选自H、F、Cl、甲基、乙基、氟代甲基、二氟甲基、三氟甲基、氟代乙基、三氟乙基。 In certain embodiments, X is CR 2 ′R 2 or O; R 2 , R 2 ′ are selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl. In certain embodiments, X is CR 2 'R 2 or O; R 2, R 2' is selected from H, F, Cl, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methyl Group, fluoroethyl, trifluoroethyl.
在某些实施方案中，X为CR 2’R 2；R 2、R 2’选自H、卤素、C 1-6烷基或者C 1-6卤代烷基。在某些实施方案中，X为CR 2’R 2；R 2、R 2’选自H、F、Cl、甲基、乙基、氟代甲基、二氟甲基、三氟甲基、氟代乙基、三氟乙基。在某些实施方案中，X为CR 2’R 2；R 2、R 2’选自H、F、甲基、氟代甲基。在某些实施方案中，X为CR 2’R 2；R 2选自H、F、甲基、氟代甲基，R 2’选自H或者F。在某些实施方案中，X为CR 2’R 2；R 2选自H，R 2’选自H。以上实施方案中，其他基团定义与前文一致。 In certain embodiments, X is CR 2 ′R 2 ; R 2 , R 2 ′ are selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl. In certain embodiments, X is CR 2 'R 2; R 2 , R 2' is selected from H, F, Cl, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, Fluoroethyl, trifluoroethyl. In certain embodiments, X is CR 2 ′R 2 ; R 2 , R 2 ′ are selected from H, F, methyl, and fluoromethyl. In certain embodiments, X is CR 2 ′R 2 ; R 2 is selected from H, F, methyl, fluoromethyl, and R 2 ′ is selected from H or F. In certain embodiments, X is CR 2 ′R 2 ; R 2 is selected from H, and R 2 ′ is selected from H. In the above embodiments, the definitions of other groups are consistent with the foregoing.
本发明化合物在某些实施方案中，C环为3至6元环烷烃、3至6元环烯烃或者3至6元杂环，所述环烷烃、环烯烃、杂环任选被0至3个R 7取代。其他基团定义与前文一致。 In certain embodiments of the compound of the present invention, the C ring is a 3 to 6 membered cycloalkane, a 3 to 6 membered cycloalkene, or a 3 to 6 membered heterocyclic ring. One R 7 is substituted. The definitions of other groups are the same as above.
在某些实施方案中，C环为环丙烷、环丁烷、环戊烷、环己烷、环丁烯、2-环戊烯、3-环戊烯、2,4-环戊二烯、4-环戊烯、1-环己烯、2-环己烯、3-环己烯、4-环己烯、5-环己烯、2,4-环二己烯、3,5-环二己烯、环氧乙烷、环氮乙烷、氮杂环定烷、氧杂环丁烷、吡咯烷、吡咯啉、吡唑烷、四氢呋喃、哌啶、四氢吡喃、哌嗪或者吗啉；在某些实施方案中，C环为环丙烷、环丁烷、环戊烷；在某些实施方案中，C环为环丙烷、环丁烷；在某些实施方案中，C环为环丙烷；在某些实施方案中，C环为环丁烷；In certain embodiments, the C ring is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, 2-cyclopentene, 3-cyclopentene, 2,4-cyclopentadiene, 4-cyclopentene, 1-cyclohexene, 2-cyclohexene, 3-cyclohexene, 4-cyclohexene, 5-cyclohexene, 2,4-cyclodihexene, 3,5-cyclo Dihexene, ethylene oxide, azetane, azetidine, oxetane, pyrrolidine, pyrroline, pyrazoline, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, or In certain embodiments, the C ring is cyclopropane, cyclobutane, cyclopentane; in certain embodiments, the C ring is cyclopropane, cyclobutane; in certain embodiments, the C ring is Cyclopropane; in certain embodiments, the C ring is cyclobutane;
以上环任选被0至3个R 7取代；R 7各自独立选自F、Cl、羟基、C 1-6烷基、氰基、C 1-6烷氧基或者C 1-6卤代烷基；在某些实施方案中，R 7选自F、Cl、C 1-6烷基或者C 1-6卤代烷基；在某些实施方案中，R 7选自F、Cl、甲基、乙基、异丙基、氟代甲基、二氟甲基、三氟甲基、氟代乙基、二氟乙基或者三氟乙基；在某些实施方案中，R 7选自F、Cl、甲基；在某些实施方案中，R 7选自F。 其他基团定义与前文一致。 The above ring is optionally substituted with 0 to 3 R 7 ; R 7 is each independently selected from F, Cl, hydroxyl, C 1-6 alkyl, cyano, C 1-6 alkoxy or C 1-6 haloalkyl; In certain embodiments, R 7 is selected from F, Cl, C 1-6 alkyl or C 1-6 haloalkyl; in certain embodiments, R 7 is selected from F, Cl, methyl, ethyl, Isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl or trifluoroethyl; in some embodiments, R 7 is selected from F, Cl, methyl In certain embodiments, R 7 is selected from F. The definitions of other groups are the same as above.
本发明化合物在某些实施方案中，C环为环丙烷、环丁烷或者环戊烷，所述环丙烷、环丁烷或者环戊烷任选被0至2个R 7取代； In certain embodiments of the compound of the present invention, the C ring is cyclopropane, cyclobutane or cyclopentane, and the cyclopropane, cyclobutane or cyclopentane is optionally substituted with 0 to 2 R 7 ;
R 7各自独立选自F。其他基团定义与前文一致。 Each R 7 is independently selected from F. The definitions of other groups are the same as above.
本发明化合物在某些实施方案中，R 4、R 5、R 6、R 9各自独立选自H或者C 1-6烷基；或者R 5、R 6形成环丙烷，且C环不存在。其他基团定义与前文一致。 In certain embodiments of the compounds of the present invention, R 4 , R 5 , R 6 , and R 9 are each independently selected from H or C 1-6 alkyl; or R 5 and R 6 form cyclopropane, and the C ring is not present. The definitions of other groups are the same as above.
在某些实施方案中，R 4、R 5、R 9各自独立选自H； In certain embodiments, R 4 , R 5 , and R 9 are each independently selected from H;
R 6选自H或者甲基；或者 R 6 is selected from H or methyl; or
R 5、R 6形成环丙烷，且C环不存在。其他基团定义与前文一致。 R 5 and R 6 form cyclopropane, and the C ring does not exist. The definitions of other groups are the same as above.
本发明化合物，在某些实施方案中，R 11选自C 6-10芳基或者C 5-10杂芳基，所述的芳基或杂芳基任选被以下取代基取代：F、Cl或者C 1-6烷基，所述的杂芳基包含1-3个选自N、O、S杂原子及其氧化态。其他基团定义与前文一致。 In the compound of the present invention, in certain embodiments, R 11 is selected from C 6-10 aryl or C 5-10 heteroaryl, and the aryl or heteroaryl is optionally substituted by the following substituents: F, Cl Or C 1-6 alkyl, the heteroaryl group contains 1-3 heteroatoms selected from N, O, S and their oxidation states. The definitions of other groups are the same as above.
在某些实施方案中，R 11选自苯基、吡啶基、哒嗪基、吡嗪基、氮氧化吡嗪基
Figure PCTCN2020114451-appb-000042
吡咯基、咪唑基、吡唑基、呋喃基、噻吩基、噁唑、噻唑、1,2,3-***、1,2,4-***；以上基团任选被以下取代基取代：F、Cl或者甲基，在某些实施方案中，以上基团任选被F取代。其他基团定义与前文一致。 In certain embodiments, R 11 is selected from phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrazinyl oxynitride
Figure PCTCN2020114451-appb-000042
Pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole; the above groups are optionally substituted by the following substituents: F, Cl or methyl. In certain embodiments, the above groups are optionally substituted with F. The definitions of other groups are the same as above.
本发明化合物在某些实施方案中，R 11选自
Figure PCTCN2020114451-appb-000043
或者
Figure PCTCN2020114451-appb-000044
在某些实施方案中，R 11选自
Figure PCTCN2020114451-appb-000045
在某些实施方案中，R 11选自
Figure PCTCN2020114451-appb-000046
在某些实施方案中，R 11选自
Figure PCTCN2020114451-appb-000047
在某些实施方案中，R 11选自
Figure PCTCN2020114451-appb-000048
其他基团定义与前文一致。 In certain embodiments of the compounds of the present invention, R 11 is selected from
Figure PCTCN2020114451-appb-000043
or
Figure PCTCN2020114451-appb-000044
In certain embodiments, R 11 is selected from
Figure PCTCN2020114451-appb-000045
In certain embodiments, R 11 is selected from
Figure PCTCN2020114451-appb-000046
In certain embodiments, R 11 is selected from
Figure PCTCN2020114451-appb-000047
In certain embodiments, R 11 is selected from
Figure PCTCN2020114451-appb-000048
The definitions of other groups are the same as above.
本发明化合物，在某些实施方案中，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、卤代C 1-6烷基、羟基取代的C 1-6烷基或者羟基；本发明化合物，在某些实施方案中，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、甲基、乙基、异丙基、羟甲基、三氟甲基、二氟甲基或者羟基；或者本发明化合物，在某些实施方案中，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、羟基取代的C 1-6烷基或者羟基；在某些实施方案中，R 1选自C 1-6烷基，所述烷基任选被以下取代基取代：F、Cl、C 1-6烷基、羟基取代的C 1-6烷基或者羟 基；在某些实施方案中，R 1选自C 1-6烷基，所述烷基任选被以下取代基取代：F、Cl、甲基、乙基、异丙基、羟甲基或者羟基；在某些实施方案中，R 1选自C 3-6环烷基，所述环烷基任选被以下取代基取代：F、Cl、C 1-6烷基、羟基取代的C 1-6烷基或者羟基；在某些实施方案中，R 1选自C 3-6环烷基，所述环烷基任选被以下取代基取代：羟基取代的C 1-6烷基或者羟基；在某些实施方案中，R 1选自C 3-6环烷基，所述环烷基任选被以下取代基取代：羟基取代的C 1-6烷基；在某些实施方案中，R 1选自C 3-6环烷基，所述环烷基任选被以下取代基取代：羟甲基；或者本发明化合物，在某些实施方案中，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、卤代C 1-6烷基、羟基取代的C 1-6烷基、羟基；本发明化合物，在某些实施方案中，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、甲基、乙基、异丙基、羟甲基、三氟甲基、二氟甲基、羟基；本发明化合物，在某些实施方案中，R 1选自C 1-6烷基、3元环烷基、4元环烷基、5元环烷基，所述的烷基或者环烷基任选被以下取代基取代：F、Cl、甲基、乙基、异丙基、羟甲基、三氟甲基、二氟甲基、羟基；本发明化合物，在某些实施方案中，R 1选自3元环烷基、4元环烷基、5元环烷基，所述的环烷基任选被以下取代基取代：F、Cl、甲基、乙基、异丙基、羟甲基、三氟甲基、二氟甲基、羟基；在某些实施方案中，R 1选自C 1-6烷基，所述的烷基任选被以下取代基取代：F、Cl、甲基、乙基、异丙基、羟甲基、三氟甲基、二氟甲基、羟基； In the compound of the present invention, in certain embodiments, R 1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by the following substituents: F, Cl , C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl or hydroxy; the compound of the present invention, in certain embodiments, 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, methyl, ethyl, isopropyl, hydroxymethyl, trifluoromethyl, di Fluoromethyl or hydroxy; or the compound of the present invention, in some embodiments, R 1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally Substituent substitution: F, Cl, C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, or hydroxy; in some embodiments, R 1 is selected from C 1-6 alkyl, and the alkyl is any Optionally substituted by the following substituents: F, Cl, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl or hydroxy; in certain embodiments, R 1 is selected from C 1-6 alkyl, the The alkyl group is optionally substituted with the following substituents: F, Cl, methyl, ethyl, isopropyl, hydroxymethyl or hydroxy; in certain embodiments, R 1 is selected from C 3-6 cycloalkyl, so The cycloalkyl is optionally substituted with the following substituents: F, Cl, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, or hydroxy; in certain embodiments, R 1 is selected from C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by the following substituents: hydroxy-substituted C 1-6 alkyl or hydroxy; in certain embodiments, R 1 is selected from C 3-6 cycloalkyl, the Cycloalkyl groups are optionally substituted with the following substituents: hydroxy-substituted C 1-6 alkyl; in certain embodiments, R 1 is selected from C 3-6 cycloalkyl, which cycloalkyl is optionally substituted Group substitution: hydroxymethyl; or a compound of the present invention, in certain embodiments, R 1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl, said alkyl or cycloalkyl is optionally The following substituents are substituted: F, Cl, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, hydroxy; the compound of the present invention, in certain embodiments, R 1 Selected from C 1-6 alkyl or C 3-6 cycloalkyl, said alkyl or cycloalkyl is optionally substituted by the following substituents: F, Cl, methyl, ethyl, isopropyl, hydroxymethyl Group, trifluoromethyl, difluoromethyl, hydroxy; the compound of the present invention, in some embodiments, R 1 is selected from C 1-6 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered Cycloalkyl, the alkyl or cycloalkyl is optionally substituted by the following substituents: F, Cl, methyl, ethyl, isopropyl, hydroxymethyl, trifluoromethyl, difluoromethyl, hydroxy The compound of the present invention, in certain embodiments, R 1 is selected from a 3-membered cycloalkyl group, a 4-membered cycloalkyl group, a 5-membered cycloalkyl group, and the cycloalkyl group is optionally substituted by the following substituents: F, Cl, methyl, ethyl, isopropyl, hydroxymethyl, Trifluoromethyl, difluoromethyl, hydroxy; in certain embodiments, R 1 is selected from C 1-6 alkyl, and the alkyl is optionally substituted with the following substituents: F, Cl, methyl, Ethyl, isopropyl, hydroxymethyl, trifluoromethyl, difluoromethyl, hydroxyl;
X为CR 2’R 2或者O；在某些实施方案中，X为CR 2’R 2； X is CR 2 'R 2 or O; In certain embodiments, X is CR 2' R 2;
R 2、R 2’选自选自H、F、甲基或者氟代甲基；在某些实施方案中，R 2、R 2’选自H； R 2 , R 2 ′ are selected from H, F, methyl or fluoromethyl; in certain embodiments, R 2 , R 2 ′ are selected from H;
C环为环丙烷、环丁烷或者环戊烷；在某些实施方案中，C环为环丙烷；在某些实施方案中，C环为环丁烷；在有些实施方案中，C环为环戊烷；所述环丙烷、环丁烷或者环戊烷任选被R 7取代；在有些实施方案中，C环为环丙烷；在有些实施方案中，C环为环戊烷，且任选被R 7取代；在有些实施方案中，C环为环丙烷或者环戊烷； Ring C is cyclopropane, cyclobutane, or cyclopentane; in some embodiments, ring C is cyclopropane; in some embodiments, ring C is cyclobutane; in some embodiments, ring C is Cyclopentane; the cyclopropane, cyclobutane, or cyclopentane is optionally substituted with R 7 ; in some embodiments, the C ring is cyclopropane; in some embodiments, the C ring is cyclopentane, and any Optionally substituted by R 7 ; in some embodiments, the C ring is cyclopropane or cyclopentane;
R 7各自独立选自F； R 7 is each independently selected from F;
R 4、R 5、R 9各自独立选自H； R 4 , R 5 , and R 9 are each independently selected from H;
R 6选自H或者甲基；或者 R 6 is selected from H or methyl; or
R 5、R 6形成环丙烷，且C环不存在； R 5 and R 6 form cyclopropane, and the C ring does not exist;
R 10选自H； R 10 is selected from H;
R 11选自
Figure PCTCN2020114451-appb-000049
或者
Figure PCTCN2020114451-appb-000050
在某些实施方案中，R 11选自
Figure PCTCN2020114451-appb-000051
在某些实施方 案中，R 11选自
Figure PCTCN2020114451-appb-000052
在某些实施方案中，R 11选自
Figure PCTCN2020114451-appb-000053
在某些实施方案中，R 11选自
Figure PCTCN2020114451-appb-000054
R 11 is selected from
Figure PCTCN2020114451-appb-000049
or
Figure PCTCN2020114451-appb-000050
In certain embodiments, R 11 is selected from
Figure PCTCN2020114451-appb-000051
In certain embodiments, R 11 is selected from
Figure PCTCN2020114451-appb-000052
In certain embodiments, R 11 is selected from
Figure PCTCN2020114451-appb-000053
In certain embodiments, R 11 is selected from
Figure PCTCN2020114451-appb-000054
本发明的化合物，在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000055
或者
Figure PCTCN2020114451-appb-000056
或者R 1选自
Figure PCTCN2020114451-appb-000057
在某些实施方案中，R 1选自
Figure PCTCN2020114451-appb-000058
在某些实施方案中，R 1选自R 1选自
Figure PCTCN2020114451-appb-000059
In the compound of the present invention, in certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000055
or
Figure PCTCN2020114451-appb-000056
Or R 1 is selected from
Figure PCTCN2020114451-appb-000057
In certain embodiments, R 1 is selected from
Figure PCTCN2020114451-appb-000058
In certain embodiments, R 1 is selected from R 1 is selected from
Figure PCTCN2020114451-appb-000059
X为CR 2’R 2； X is CR 2 'R 2;
R 2、R 2’选自H； R 2 , R 2 ′ are selected from H;
C环为环丙烷、环丁烷或者环戊烷；在某些实施方案中，C环为环丙烷；在某些实施方案中，C环为环丁烷；在有些实施方案中，C环为环戊烷；所述环丙烷、环丁烷或者环戊烷任选被R 7取代；在有些实施方案中，C环为环丙烷、环戊烷；在有些实施方案中，C环为环丙烷； Ring C is cyclopropane, cyclobutane, or cyclopentane; in some embodiments, ring C is cyclopropane; in some embodiments, ring C is cyclobutane; in some embodiments, ring C is Cyclopentane; the cyclopropane, cyclobutane, or cyclopentane is optionally substituted with R 7 ; in some embodiments, the C ring is cyclopropane, cyclopentane; in some embodiments, the C ring is cyclopropane ；
R 7各自独立选自F； R 7 is each independently selected from F;
R 4、R 5、R 9各自独立选自H； R 4 , R 5 , and R 9 are each independently selected from H;
R 6选自H或甲基；在某些实施方案中，R 6选自H，在某些实施方案中，R 6选自甲基； R 6 is selected from H or methyl; in certain embodiments, R 6 is selected from H, and in certain embodiments, R 6 is selected from methyl;
R 10选自H； R 10 is selected from H;
R 11选自
Figure PCTCN2020114451-appb-000060
R 11 is selected from
Figure PCTCN2020114451-appb-000060
本发明通式(I)所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs according to the general formula (I) of the present invention, wherein the compound structure is as follows:
Figure PCTCN2020114451-appb-000061
Figure PCTCN2020114451-appb-000061
Figure PCTCN2020114451-appb-000062
Figure PCTCN2020114451-appb-000062
优选，Preferably,
Figure PCTCN2020114451-appb-000063
Figure PCTCN2020114451-appb-000063
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。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.
本发明还涉及通式(I)所示的三环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。The present invention also relates to the tricyclic pyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention Use of the composition in the preparation of a medicament for treating diseases mediated by CB2 receptors.
本发明涉及通式(I)所示的三环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。The present invention relates to a tricyclic pyrazole compound represented by general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or combinations containing the compounds of the present invention In the preparation of medicines for the treatment of pain.
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。Pain can be selected from: bone pain, arthralgia, muscle pain, toothache, migraine, headache, inflammatory pain, neuropathic pain, Crohn’s disease-related abdominal pain, pain due to adverse effects of therapeutic agents, and selected from Pain related to the following diseases: osteoarthritis, cancer, multiple sclerosis, allergic response, nephritis syndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia, HIV-related neuropathy, sciatica And autoimmune diseases.
本发明还涉及通式(I)所示的三环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。The present invention also relates to the tricyclic pyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention Use of the composition in preparing a medicine for treating neuropathic pain.
本发明还涉及通式(I)所示的三环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。The present invention also relates to the tricyclic pyrazole compound represented by general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention Use of the composition in the preparation of a medicine for treating Crohn's disease-related abdominal pain.
本发明还涉及通式(I)所示的三环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。The present invention also relates to the tricyclic pyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention The composition is used in a method of treating diseases mediated by CB2 receptors.
本发明还涉及通式(I)所示的三环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。The present invention also relates to the tricyclic pyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention The composition is used in a method of treating pain.
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。The pain can be selected from: bone pain, arthralgia, muscle pain, toothache, migraine, headache, inflammatory pain, neuropathic pain, Crohn's disease-related abdominal pain caused by the adverse effects of the therapeutic agent, and the following Pain related to the diseases mentioned: osteoarthritis, cancer, multiple sclerosis, allergic response, nephritis syndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia, HIV-related neuropathy, sciatica and Autoimmune diseases.
本发明还涉及通式(I)所示的三环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。The present invention also relates to the tricyclic pyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention The composition is used to treat neuropathic pain.
本发明还涉及通式(I)所示的三环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。The present invention also relates to the tricyclic pyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, or those containing the compound of the present invention A method for the composition to treat abdominal pain associated with Crohn's disease.
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。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
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。 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, and the isotope of bromine includes 79 Br and 81 Br.
“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。"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.
“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。 "Alkylene" refers to straight and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v- (v is an integer from 1 to 10). Examples of 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.
“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。"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基-1-Butoxy and so on.
“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。"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, examples of 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-heptenyl, 4-heptenyl, 1-octene Base, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1, 4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group may be optionally further substituted with any group.
“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。"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 group may be optional It is further substituted by any substituent.
“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。"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.
“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。"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.
“杂环基”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。"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 aziridine Group, oxetanyl, thietanyl, azetidinyl, oxetanyl, thietanyl, azetyl (also known as azetidinyl), pyrrolyl, pyrroline Group, 3-pyrrolinyl, 1-pyrrolinyl, pyrrolidinyl, pyrazolidinyl, 2-pyrazoline, imidazolyl, pyrazolyl, tetrahydrofuranyl, tetrahydrothienyl, 1,2,4 -Triazolyl and so on. The heterocyclic group may be optionally further substituted with any substituent.
“杂环”是指饱和或不饱和的至少含1个杂原子的环烃，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烷、氧杂环丙烷、硫杂环丙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、吖丁烷(又名氮杂环丁烷)、吡咯、吡咯啉、3-吡咯啉、1-吡咯啉、吡咯烷、吡唑烷、2-吡唑啉、咪唑、吡唑、四氢呋喃、四氢噻吩、1,2,4-***等。所述的杂环可以任选进一步被任意取代基所取代。"Heterocycle" refers to a saturated or unsaturated cyclic hydrocarbon containing at least one heteroatom, a single ring, and the heteroatoms are N, O, S, P and their oxidized forms. Non-limiting examples include aziridine, Oxetane, thietane, azetidine, oxetane, thietane, azetidine (also known as azetidine), pyrrole, pyrroline, 3-pyrroline , 1-pyrroline, pyrrolidine, pyrazolidine, 2-pyrazoline, imidazole, pyrazole, tetrahydrofuran, tetrahydrothiophene, 1,2,4-triazole, etc. The heterocyclic ring may be optionally further substituted with any substituent.
“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 PCTCN2020114451-appb-000064
螺环可以被任意取代基进一步取代。 "Spiro ring" refers to a 5- to 20-membered polycyclic group sharing one atom (such as a carbon atom, called a spiro atom) between substituted or unsubstituted monocyclic rings, which may contain 0 to 5 double bonds, and may It contains 0 to 5 heteroatoms selected from N, O or S(=O)n. It is preferably 6 to 14 yuan, more preferably 6 to 12 yuan, more preferably 6 to 10 yuan, non-limiting examples thereof include
Figure PCTCN2020114451-appb-000064
The spiro ring may be further substituted with any substituent.
“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)、S(＝O) 2、S、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 PCTCN2020114451-appb-000065
Figure PCTCN2020114451-appb-000066
并环可以进一步被任意取代基取代。 "Polycyclic ring" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms (such as carbon atoms) with other rings in the system, wherein one or more rings may contain 0 or more double bonds , And may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms selected from N, S(=O), S(=O) 2 , S, or O. It is preferably 5 to 20 yuan, more preferably 5 to 14 yuan, more preferably 5 to 12 yuan, and still more preferably 5 to 10 yuan. Non-limiting examples include
Figure PCTCN2020114451-appb-000065
Figure PCTCN2020114451-appb-000066
The fused ring may be further substituted with any substituent.
“桥环”是指任意两个环共用不直接连接的原子(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 PCTCN2020114451-appb-000067
和金刚烷。桥环可以进一步被任意取代基取代。 "Bridged ring" refers to a polycyclic group in which any two rings share atoms (such as carbon atoms) that are not directly connected, and can contain 0 or more double bonds, and can be substituted or unsubstituted, and a ring system Any ring in can contain 0 to 5 heteroatoms or groups selected from N, S(=O)n or O (where n is 1, 1, 2). 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
Figure PCTCN2020114451-appb-000067
And adamantane. The bridged ring may be further substituted with any substituent.
“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苯基、
Figure PCTCN2020114451-appb-000068
Figure PCTCN2020114451-appb-000069
芳基可以进一步被任意取代基取代。 "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 on a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include phenyl,
Figure PCTCN2020114451-appb-000068
Figure PCTCN2020114451-appb-000069
The aryl group may be further substituted with any substituent.
“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 PCTCN2020114451-appb-000070
杂芳基可以进一步被任意取代基取代。 "Heteroaryl" refers to a substituted or unsubstituted 5- to 14-membered aromatic ring and contains 1 to 5 heteroatoms or groups selected from N, O or S(=O)n, preferably 5- to 10-membered heteroaromatic The ring is more preferably 5 to 6 members. Non-limiting examples of 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
Figure PCTCN2020114451-appb-000070
The heteroaryl group may be further substituted with any substituent.
“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。"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.
“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。"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.
“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。"Excipient" refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound. Examples of 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.
“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。"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. When 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.
“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。"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.
“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。"Solvates" 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.
“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。"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. For example: "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.
“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。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。"Optionally substituted by R" means that it can be substituted or unsubstituted by R. When substituted, the number of R is not limited, as long as the principle of chemical bond is satisfied. When replaced by two or more Rs, R can be independently and freely selected, can be the same or different, and are independent of each other.
具体实施方式detailed description
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。The technical solutions of the present invention will be described in detail below with reference to the embodiments, but the protection scope of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
NMR位移(δ)以10-6(ppm)的单位给出。The NMR shift (δ) is given in units of 10-6 (ppm).
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)。 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).
MS的测定用(Agilent 6120B(ESI))。For MS measurement (Agilent 6120B (ESI)).
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorba x SB-C18 100x 4.6mm)。HPLC determination uses Agilent 1260DAD high pressure liquid chromatograph (Zorba x SB-C18 100 x 4.6 mm).
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。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.
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
实施例中无特殊说明，溶液是指水溶液。There is no special description in the examples, and the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.
简写说明：Short description:
HATU：2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐；HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate;
DMF：N,N-二甲基甲酰胺；DMF: N,N-dimethylformamide;
TEA：三乙胺；PE：石油醚；EA：乙酸乙酯；DCM：二氯甲烷；TEA: triethylamine; PE: petroleum ether; EA: ethyl acetate; DCM: dichloromethane;
mCPBA：间氯过苯甲酸；IBX：邻碘酰苯甲酸；mCPBA: m-chloroperbenzoic acid; IBX: o-iodobenzoic acid;
LHMDS：双(三甲基硅基)氨基锂。LHMDS: Lithium bis(trimethylsilyl)amide.
中间体Int-1Intermediate 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 (Intermediate Int-1)
2-amino-4,4,4-trifluoro-3,3-dimethylbutan-1-ol2-amino-4,4,4-trifluoro-3,3-dimethylbutan-1-ol
Figure PCTCN2020114451-appb-000071
Figure PCTCN2020114451-appb-000071
第一步：3,3,3-三氟-N-甲氧-N,2,2-三甲基丙酰胺(Int-1-b)The first step: 3,3,3-trifluoro-N-methoxy-N,2,2-trimethylpropionamide (Int-1-b)
3,3,3-trifluoro-N-methoxy-N,2,2-trimethylpropanamide3,3,3-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)mL)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。Under nitrogen protection, at room temperature, to 3,3,3-trifluoro-2,2-dimethylpropionic acid (25g, 0.16mol), DMF (50mL), TEA (32mg, 0.25mmol), HATU( 77mg, 0.2mmol), N-methyl-N-methoxyamine hydrochloride (17.2g, 0.176mol), stirred overnight at room temperature. The reaction was quenched by adding saturated aqueous sodium bicarbonate (200mL) to the reaction, extracted with 300ml of ethyl acetate, allowed to stand and separate the layers, the aqueous phase was extracted three times with dichloromethane (200mL×3)mL), and the combined organic phases were used After drying with anhydrous sodium sulfate and concentrating under reduced pressure, the residue is obtained as the crude product. The crude product is subjected to column chromatography (eluent PE:EA=10:1) to obtain Int-1-b (22g, yield 69%). Yellow oily.
LC-MS(ESI)：m/z＝200.2[M+H] +。 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)。 1 H NMR (400MHz, CDCl 3 ) δ 3.70 (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)The second step: 3,3,3-trifluoro-2,2-dimethylpropanal (Int-1-c)
3,3,3-trifluoro-2,2-dimethylpropanal3,3,3-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。 Under nitrogen protection, THF (50 mL) was added to a 250 mL single-neck flask at room temperature, LiAlH 4 (3.43 g, 90 mmol) was added at 0° C., compound Int-1-b (15 g, 75.3 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 h. At 0°C, water (3.5mL), NaOH (15%, 3.5mL), and water (3.5mL) were added to the reaction to quench the reaction, stirred for 30min, then 200mL of ether was added and stirred vigorously for 30min, filtered through diatomaceous earth After concentration under reduced pressure, crude Int-1-c (14g) was obtained as a colorless oily compound, which was directly used in the next reaction without purification.
LC-MS(ESI)：m/z＝141.2[M+H] +。 LC-MS (ESI): m/z=141.2 [M+H] + .
1H NMR(400MHz,CDCl 3)δ9.69(s,1H),1.30(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ 9.69 (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)The third step: 2-amino-4,4,4-trifluoro-3,3-dimethylbutyronitrile (Int-1-d)
2-amino-4,4,4-trifluoro-3,3-dimethylbutanenitrile2-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％)。 Under nitrogen protection, at room temperature, add Int-1-c (4.5g), NH 3 /MeOH (10mL, 70mmol), NH 4 Cl (1.62g, 30mmol) to the single-necked flask, stir at room temperature for 30min, and then add KCN (1.95g, 30mmol), continue to stir and react overnight. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 10 mL of ether, and 2N HCl 1,4-dioxane was slowly added at 0°C to dissolve in stirring to precipitate a white solid Int-1-d (1.65g, yield 34.78%).
LC-MS(ESI)：m/z＝167.1[M+H] +。 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)The fourth step: 2-amino-4,4,4-trifluoro-3,3-dimethylbutanoic acid (Int-1-e)
2-amino-4,4,4-trifluoro-3,3-dimethylbutanoic acid2-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)。Under nitrogen protection, add Int-1-d (2.05g, 10.14mmol) and 6N HCl (20mL) to the single-necked flask at room temperature, and stir for 36h under reflux. After cooling to room temperature, sodium hydroxide aqueous solution was added to the reaction to adjust the pH to 8. The aqueous phase was washed with dichloromethane (20 mL) to recover 0.4 g of the raw material. The aqueous phase was adjusted to pH 7, and concentrated under reduced pressure to a solid to obtain a crude white solid. Int-1-e (1.3g).
LC-MS(ESI)：m/z＝186.2[M+H] +。 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)The fifth step: 2-amino-4,4,4-trifluoro-3,3-dimethylbutan-1-ol (Int-1)
2-amino-4,4,4-trifluoro-3,3-dimethylbutan-1-ol2-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，8.43mmol)，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。 Under nitrogen protection, add THF (20mL) to a 50mL single-neck flask at room temperature, add LiAlH 4 (270mg, 8.43mmol) at 0°C, slowly drop compound Int-1-e (1.3g, 7mmol), and stir for 3h under reflux for reaction complete. At 0℃, add water (0.27mL), NaOH (15%, 0.27mL) and water (0.27mL) to the reaction to quench the reaction, stir for 30min, then add THF (50mL) and stir vigorously for 30min, dry with NaSO 4 , Filtered through diatomaceous earth, and concentrated under reduced pressure to obtain Int-1 (0.82 g, 68.23%), a pale yellow oily compound, which was directly used in the next reaction without purification.
LC-MS(ESI)：m/z＝172.2[M+H] +。 LC-MS (ESI): m/z=172.2 [M+H] + .
实施例1Example 1
3-((5aR,6aS)-3-(((S)-1-羟基-3,3-二甲基丁烷-2-基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4氢)-基)吡嗪1-氧化物3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydro Cyclopropane[g]indazole-1(4hydro)-yl)pyrazine-1-oxide
3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1( 4H)-yl)pyrazine 1-oxide
3-((5aS,6aR)-3-(((S)-1-羟基-3,3-二甲基丁烷-2-基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4氢)-基)吡嗪1-氧化物3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydro Cyclopropane[g]indazole-1(4hydro)-yl)pyrazine-1-oxide
3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1( 4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000072
Figure PCTCN2020114451-appb-000072
第一步：[4.1.0]庚烷-2-酮(1b)The first step: [4.1.0] heptane-2-one (1b)
bicyclo[4.1.0]heptan-2-onebicyclo[4.1.0]heptan-2-one
500mL三口瓶中加入250mL的二甲基亚砜溶液，冰浴条件下缓慢加入钠氢(14.2g,0.35mol)，搅拌10分钟后加入三甲基碘化亚砜(78.3g,0.35mol)，然后搅拌半小时后缓慢滴入溶解于50mL的二甲基亚砜溶液中的环己-2-烯酮(30ml)溶液，反应液恢复至室温继续搅拌半小时后升温至50℃反应2小时，TLC检测反应完全以后，然后冷却反应液至室温，将反应液倒入300g的冰水中，搅拌半小时，过滤以后，得到的滤液加入500ml水，然后用(600mL×3)的乙酸乙酯溶液萃取合并有机相，无水硫酸钠干燥，35℃的水浴旋干得到所需的化合物32g(1b)直接进行下一步反应。收率93.2％。Add 250mL of dimethyl sulfoxide solution to a 500mL three-necked flask, slowly add sodium hydrogen (14.2g, 0.35mol) under ice bath conditions, stir for 10 minutes and then add trimethylsulfoxide iodide (78.3g, 0.35mol), Then, after stirring for half an hour, the cyclohex-2-enone (30ml) solution dissolved in 50mL of dimethyl sulfoxide solution was slowly dropped into it. The reaction solution was returned to room temperature and stirred for another half hour, and then heated to 50°C for 2 hours. After TLC detects that the reaction is complete, cool the reaction solution to room temperature, pour the reaction solution into 300g of ice water, stir for half an hour, after filtering, add 500ml of water to the obtained filtrate, and then extract with (600mL×3) ethyl acetate solution The organic phases were combined, dried with anhydrous sodium sulfate, and spin-dried in a water bath at 35° C. to obtain 32 g (1b) of the desired compound and proceed directly to the next reaction. The yield was 93.2%.
1H NMR(400MHz,CDCl 3)δ2.33-2.23(m,1H),2.11-1.85(m,3H),1.79-1.55(m,4H),1.25-1.15(m,1H),1.12-1.04(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ2.33-2.23 (m, 1H), 2.11-1.85 (m, 3H), 1.79-1.55 (m, 4H), 1.25-1.15 (m, 1H), 1.12-1.04 (m,1H).
第二步:乙基1-(吡嗪-2-基)-1,4,5,5a,6,6a-六氢环丙烷[g]吲唑-3-羧酸盐(1c)Step 2: Ethyl 1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropane[g]indazole-3-carboxylate (1c)
ethyl1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylateethyl1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylate
将化合物1b(20g,0.18mol)溶解于400ml的乙醇溶液中，然后搅拌下加入草酸二乙酯(26g,0.18mol)以及叔丁醇钾(20g,0.18mol)，然后升温至40℃搅拌反应2小时，然后缓慢加入6M的盐酸溶液(100ml)，搅拌5分钟以后加入吡嗪肼(20g,0.18mol)，然后将反应液升至50℃继续反应2小时，TLC检测反应完全以后，冷却至室温以后，加入饱和碳酸氢钠溶液调节pH至9左右，加入500ml的水中，用乙酸乙酯(500mL×3)萃取，无水硫酸钠干燥，旋干以后，柱层析(洗脱剂PE/EA＝5/1)纯化得到黄色油状物27g(1c)，收率53％。Dissolve compound 1b (20g, 0.18mol) in 400ml of ethanol solution, then add diethyl oxalate (26g, 0.18mol) and potassium tert-butoxide (20g, 0.18mol) with stirring, then heat to 40℃ and stir to react After 2 hours, slowly add 6M hydrochloric acid solution (100ml), stir for 5 minutes, add pyrazine hydrazine (20g, 0.18mol), then raise the reaction solution to 50°C and continue the reaction for 2 hours. After TLC detects that the reaction is complete, cool to After room temperature, add saturated sodium bicarbonate solution to adjust the pH to about 9, add 500ml of water, extract with ethyl acetate (500mL×3), dry with anhydrous sodium sulfate, spin dry, column chromatography (eluent PE/ EA=5/1) Purified to obtain 27 g (1c) of yellow oil, with a yield of 53%.
LC-MS(ESI)：m/z＝285.3[M+H] +。 LC-MS (ESI): m/z=285.3 [M+H] + .
第三步：1-(吡嗪-2-基)-1,4,5,5a,6,6a-六氢环丙烷[g]吲唑-3-羧酸(1d)The third step: 1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropane[g]indazole-3-carboxylic acid (1d)
1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylic acid1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylic acid
将化合物1c(18g,0.06mol)，溶解于200ml甲醇与200ml的四氢呋喃的混合溶剂中，然后缓慢加入氢氧化钠(3g,0.08mol)的水溶液20ml，滴加完毕以后室温搅拌过夜，加入2M的稀盐酸调节反应液的pH至3左右，然后加入500ml的水，再用二氯甲烷(800mL×3)萃取以后，无水硫酸钠干燥旋干，得到黄色粉末固体15g(1d)，收率92.5％。Dissolve compound 1c (18g, 0.06mol) in a mixed solvent of 200ml methanol and 200ml tetrahydrofuran, then slowly add 20ml of aqueous solution of sodium hydroxide (3g, 0.08mol), stir overnight at room temperature after the addition is complete, add 2M Adjust the pH of the reaction solution to about 3 with dilute hydrochloric acid, then add 500ml of water, and then extract with dichloromethane (800mL×3), then dry with anhydrous sodium sulfate and spin dry to obtain 15g (1d) of yellow powder solid, yield 92.5 %.
LC-MS(ESI)：m/z＝257.3[M+H] +。 LC-MS (ESI): m/z=257.3 [M+H] + .
第四步：N-((S)-1-羟基-3,3-二甲基丁-2-基)-1-(吡嗪-2-基)-1,4,5,5a,6,6a-六氢-环丙烷[g]吲唑-3-甲酰胺(1e)The fourth step: N-((S)-1-hydroxy-3,3-dimethylbut-2-yl)-1-(pyrazin-2-yl)-1,4,5,5a,6, 6a-hexahydro-cyclopropane[g]indazole-3-carboxamide(1e)
N-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxamideN-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole- 3-carboxamide
将化合物1d(0.3g,1.2mmol)溶解于25ml的DMF溶液中，然后加入S-叔亮胺醇(0.17g,1.44mmol)以及HATU(0.55g,1.44mmol)，三乙胺(0.36g,3.6mmol)，常温搅拌过夜，加入100ml的水至反应液中，然后用乙酸乙酯(100mL×3)萃取，合并有机相，无水硫酸钠干燥旋干，柱层析(洗脱剂MeOH/DCM＝1/10)纯化，得到淡黄色固体230mg(1e)，收率55.3％。Compound 1d (0.3g, 1.2mmol) was dissolved in 25ml of DMF solution, and then S-tertiary leucine alcohol (0.17g, 1.44mmol) and HATU (0.55g, 1.44mmol), triethylamine (0.36g, 3.6mmol), stir overnight at room temperature, add 100ml of water to the reaction solution, then extract with ethyl acetate (100mL×3), combine the organic phases, dry with anhydrous sodium sulfate and spin dry, and column chromatography (eluent MeOH/ DCM=1/10) was purified to obtain 230 mg (1e) as a pale yellow solid with a yield of 55.3%.
LC-MS(ESI)：m/z＝356.4[M+H] +。 LC-MS (ESI): m/z=356.4 [M+H] + .
第五步：3-((5aR,6aS)-3-(((S)-1-羟基-3,3-二甲基丁烷-2-基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4氢)-基)吡嗪1-氧化物The fifth step: 3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamyl)-5,5a,6, 6a-Tetrahydrocyclopropane[g]indazole-1(4hydro)-yl)pyrazine-1-oxide
3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1( 4H)-yl)pyrazine 1-oxide
3-((5aS,6aR)-3-(((S)-1-羟基-3,3-二甲基丁烷-2-基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4氢)-基)吡嗪1-氧化物3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydro Cyclopropane[g]indazole-1(4hydro)-yl)pyrazine-1-oxide
3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1( 4H)-yl)pyrazine 1-oxide
将化合物1e(0.13g,0.37mmol)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，用二氯甲烷(50mL×3)萃取，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(0.015g,0.4mmol)，常温搅拌反应15分钟以后，TLC检测，反应完全，加入50ml的水，用二氯甲烷(50mL×3)萃取，合并有机相并用无水硫酸钠干燥，然后旋干，硅胶柱层析(洗脱剂MeOH/DCM＝1/10)以后得到终产物白色粉末10mg(化合物1-a)，HPLC出峰时间(t＝3.948)；收率7.35％，以及白色粉末8mg(化合物1-b)，HPLC出峰时间(t＝4.272)，收率5.88％。Compound 1e (0.13g, 0.37mmol) was dissolved in 5ml of formic acid solution, and then 30% hydrogen peroxide solution (0.5ml) was added. The temperature was raised to 64°C and the reaction was stirred for 3 hours. After that, 50ml of water was added and dichloromethane ( 50mL×3) extract, combine the organic phases, dry with anhydrous sodium sulfate, spin dry, dissolve the resulting brown oil in a mixed solvent of 3ml of methanol and 3ml of tetrahydrofuran, and then slowly add dropwise 2ml of sodium hydroxide aqueous solution ( 0.015g, 0.4mmol), stirred and reacted at room temperature for 15 minutes, TLC detection, the reaction is complete, add 50ml of water, extract with dichloromethane (50mL×3), combine the organic phases and dry with anhydrous sodium sulfate, then spin dry. After silica gel column chromatography (eluent MeOH/DCM=1/10), the final product white powder 10mg (compound 1-a), HPLC peak time (t=3.948); yield 7.35%, and white powder 8mg ( Compound 1-b), HPLC peak time (t=4.272), yield 5.88%.
化合物1-a：Compound 1-a:
LC-MS(ESI)：m/z＝372.4[M+H] +。 LC-MS (ESI): m/z=372.4 [M+H] + .
1H NMR(400MHz,CDCl 3)δ9.66-9.79(m,3H),8.03(s,1H),3.50-3.52(m,3H),2.75-2.85(m,2H),1.46-1.71(m,3H),0.96(s,9H),0.31-0.61(m,3H)。 1 H NMR (400MHz, CDCl 3 ) δ9.66-9.79 (m, 3H), 8.03 (s, 1H), 3.50-3.52 (m, 3H), 2.75-2.85 (m, 2H), 1.46-1.71 (m ,3H),0.96(s,9H),0.31-0.61(m,3H).
化合物1-b：Compound 1-b:
LC-MS(ESI)：m/z＝372.4[M+H] +。 LC-MS (ESI): m/z=372.4 [M+H] + .
1H NMR(400MHz,CDCl 3)δ9.62-9.79(m,2H),9.59-9.61(s,1H),8.03(s,1H),3.25-3.65(m,3H),2.75-2.95(m,2H),1.56-1.82(m,3H),0.94(s,9H),0.34-0.59(m,3H)。 1 H NMR(400MHz, CDCl 3 )δ9.62-9.79(m,2H), 9.59-9.61(s,1H), 8.03(s,1H), 3.25-3.65(m,3H), 2.75-2.95(m , 2H), 1.56-1.82 (m, 3H), 0.94 (s, 9H), 0.34-0.59 (m, 3H).
实施例2Example 2
1-(2,4-二氟苯基)-N-((S)-1-羟基-3,3-二甲基丁烷-2-基)-1,4,5,5a,6,6a-六氢环丙烷[g]吲唑-3-甲酰胺(化合物2)1-(2,4-Difluorophenyl)-N-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-1,4,5,5a,6,6a -Hexahydrocyclopropane[g]indazole-3-carboxamide (Compound 2)
1-(2,4-difluorophenyl)-N-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxamide1-(2,4-difluorophenyl)-N-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole- 3-carboxamide
Figure PCTCN2020114451-appb-000073
Figure PCTCN2020114451-appb-000073
第一步：乙基1-(2,4-二氟苯基)-1,4,5,5a,6,6a-六氢环丙基[g]吲唑-3-羧酸盐(2a)The first step: ethyl 1-(2,4-difluorophenyl)-1,4,5,5a,6,6a-hexahydrocyclopropyl[g]indazole-3-carboxylate (2a)
ethyl 1-(2,4-difluorophenyl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylateethyl 1-(2,4-difluorophenyl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylate
将化合物1b(0.1g,0.9mmol)溶解于2ml的乙醇溶液中，然后搅拌下加入草酸二乙酯(0.13g,0.9mmol)以及叔丁醇钾(0.1g,0.9mmol)，然后升温至40℃搅拌反应2小时，然后缓慢加入6M的盐酸溶液(0.5ml)，搅拌5分钟以后加入2,4-二氟苯肼(0.13g,0.9mol)，然后将反应液升至50℃继续反应2小时，TLC检测反应完全以后，反应液冷却至室温以后，加入饱和碳酸氢钠溶液调节反应液pH至9左右，加入50ml的水中，用乙酸乙酯(50mL×3)萃取无水硫酸钠干燥，旋干以后，柱层析(洗脱剂PE/EA＝3/1)纯化得到黄色油状物0.1g(2a)，收率34.6％。.Dissolve compound 1b (0.1g, 0.9mmol) in 2ml of ethanol solution, then add diethyl oxalate (0.13g, 0.9mmol) and potassium tert-butoxide (0.1g, 0.9mmol) under stirring, and then heat to 40 The reaction was stirred at ℃ for 2 hours, then 6M hydrochloric acid solution (0.5ml) was slowly added, after stirring for 5 minutes, 2,4-difluorophenylhydrazine (0.13g, 0.9mol) was added, and then the reaction solution was raised to 50℃ to continue the reaction. 2 After hours, TLC detected the completion of the reaction, and after the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution was added to adjust the pH of the reaction solution to about 9, then added to 50ml of water, extracted with ethyl acetate (50mL×3) and dried with anhydrous sodium sulfate. After spin-drying, purification by column chromatography (eluent PE/EA=3/1) yielded 0.1 g (2a) of yellow oil with a yield of 34.6%. .
LC-MS(ESI)：m/z＝317.3[M+H] +。 LC-MS (ESI): m/z=317.3 [M+H] + .
第二步：1-(2,4-二氟苯基)-1,4,5,5a,6,6a-六氢环丙基[g]吲唑-3-羧酸(2b)The second step: 1-(2,4-difluorophenyl)-1,4,5,5a,6,6a-hexahydrocyclopropyl[g]indazole-3-carboxylic acid (2b)
1-(2,4-difluorophenyl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylic acid1-(2,4-difluorophenyl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylic acid
将化合物2a(0.3g,1mmol)，溶解于3ml甲醇与3ml的四氢呋喃的混合溶剂中，然后缓慢加入氢氧化钠(0.048g,1.2mmol)的水溶液，滴加完毕以后室温搅拌过夜，加入2M的稀盐酸调节反应液的pH至3左右，然后加入25ml水，再用二氯甲烷(30mL×3)萃取以后，有机相用无水硫酸钠干燥，然后旋干，得到黄色固体250mg(2b)，收率91.6％。Compound 2a (0.3g, 1mmol) was dissolved in a mixed solvent of 3ml of methanol and 3ml of tetrahydrofuran, and then slowly added an aqueous solution of sodium hydroxide (0.048g, 1.2mmol). After the addition, it was stirred overnight at room temperature, and 2M was added. Adjust the pH of the reaction solution to about 3 with dilute hydrochloric acid, then add 25ml of water and extract with dichloromethane (30mL×3). The organic phase is dried with anhydrous sodium sulfate and then spin-dried to obtain 250mg (2b) of a yellow solid. The yield was 91.6%.
LC-MS(ESI)：m/z＝291.2[M+H] +。 LC-MS (ESI): m/z=291.2 [M+H] + .
第三步：乙基1-(2,4-二氟苯基)-1,4,5,5a,6,6a-六氢环丙基[g]吲唑-3-羧酸盐(化合物2)The third step: ethyl 1-(2,4-difluorophenyl)-1,4,5,5a,6,6a-hexahydrocyclopropyl[g]indazole-3-carboxylate (compound 2 )
ethyl 1-(2,4-difluorophenyl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylateethyl 1-(2,4-difluorophenyl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylate
将原料2b(0.1g,0.34mmol)溶解于3ml的DMF溶液中，然后加入S-叔亮胺醇(0.056g,0.48mmol)以及HATU(0.18g,0.47mmol)，三乙胺(0.12g,1.09mmol)，常温搅拌过夜，加入50ml的水至反应液中，然后用乙酸乙酯(100mL×3)萃取，合并有机相，无水硫酸钠干燥并旋干，柱层析(洗脱剂MeOH/DCM＝1/10)纯化，得到淡黄色固体230mg(化合物2)，收率55.3％。Dissolve the raw material 2b (0.1g, 0.34mmol) in 3ml of DMF solution, then add S-tertiary leucine alcohol (0.056g, 0.48mmol) and HATU (0.18g, 0.47mmol), triethylamine (0.12g, 1.09mmol), stir overnight at room temperature, add 50ml of water to the reaction solution, then extract with ethyl acetate (100mL×3), combine the organic phases, dry with anhydrous sodium sulfate and spin dry, column chromatography (eluent MeOH /DCM=1/10) to obtain 230 mg of light yellow solid (compound 2) with a yield of 55.3%.
LC-MS(ESI)：m/z＝390.4[M+H] +。 LC-MS (ESI): m/z=390.4 [M+H] + .
1H NMR(400MHz,CDCl 3)δ7.58-7.68(m,1H),7.01-7.14(m,1H),6.86-6.90(m,1H),3.65-3.68(m,1H),3.25-3.50(m,2H),2.75-2.85(m,2H),1.46-1.71(m,3H),0.94-1.11(m,9H),0.34-0.59(m,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 7.58-7.68 (m, 1H), 7.01-7.14 (m, 1H), 6.86-6.90 (m, 1H), 3.65-3.68 (m, 1H), 3.25-3.50 (m, 2H), 2.75-2.85 (m, 2H), 1.46-1.71 (m, 3H), 0.94-1.11 (m, 9H), 0.34-0.59 (m, 3H).
实施例3Example 3
3-(3-((1-羟基-2-甲基丙烷-2-基)氨基甲酰基)-5,5a,6,6a-四氢环丙基[g]吲唑-1(4氢)-基)吡嗪1-氧化物(化合物3)3-(3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropyl[g]indazole-1(4hydro) -Yl)pyrazine 1-oxide (compound 3)
3-(3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-(3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000074
Figure PCTCN2020114451-appb-000074
第一步：N-(1-羟基-2-甲基丙-2-基)-1-(吡嗪-2-基)-1,4,5,5a,6,6a-六氢环丙烷[g]吲唑-3-甲酰胺(3a)The first step: N-(1-hydroxy-2-methylprop-2-yl)-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropane[ g)Indazole-3-carboxamide (3a)
(1-hydroxy-2-methylpropan-2-yl)-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxamide(1-hydroxy-2-methylpropan-2-yl)-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxamide
将原料1d(0.3g,1.2mmol)溶解于10ml的DMF溶液中，然后加入2-氨基-2-甲基丙-1-醇(0.12g,1.44mmol)以及HATU(0.53g,1.44mmol)，三乙胺(0.36g,3.6mmol)，常温搅拌过夜，加入100ml的水至反应液中，然后用乙酸乙酯(100mL×3)萃取，合并有机相，无水硫酸钠干燥旋干，柱层析(洗脱剂MeOH/DCM＝1/10)纯化，得到淡黄色固体200mg(3a)，收率52.2％。Dissolve the raw material 1d (0.3g, 1.2mmol) in 10ml of DMF solution, then add 2-amino-2-methylpropan-1-ol (0.12g, 1.44mmol) and HATU (0.53g, 1.44mmol), Triethylamine (0.36g, 3.6mmol), stir overnight at room temperature, add 100ml of water to the reaction solution, and then extract with ethyl acetate (100mL×3), combine the organic phases, dry with anhydrous sodium sulfate and spin-dry the column layer It was purified by analysis (eluent MeOH/DCM=1/10) to obtain 200 mg (3a) of light yellow solid with a yield of 52.2%.
LC-MS(ESI)：m/z＝328.3[M+H] +。 LC-MS (ESI): m/z=328.3 [M+H] + .
第二步：3-(3-((1-羟基-2-甲基丙烷-2-基)氨基甲酰基)-5,5a,6,6a-四氢环丙基[g]吲唑-1(4氢)-基)吡嗪1-氧化物(化合物3)The second step: 3-(3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropyl[g]indazole-1 (4Hydroxy)-yl)pyrazine 1-oxide (compound 3)
3-(3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-(3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
将原料3a(0.2g,0.61mmol)溶解于25ml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，用乙酸乙酯(50mL×3)萃取，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(0.03g,0.8mmol)，常温搅拌反应15分钟以后，TLC检测，反应完全，加入50ml的水，用乙酸乙酯(50mL×3)萃取，合并有机相无水硫酸钠干燥旋干，柱层析(洗脱剂MeOH/DCM＝1/5)分离纯化以后得到终产物白色粉末17mg(化合物3)，收率7.7％。The raw material 3a (0.2g, 0.61mmol) was dissolved in 25ml of formic acid solution, and then 30% hydrogen peroxide solution (0.5ml) was added. The temperature was raised to 64°C and the reaction was stirred for 3 hours. After that, 50ml of water was added and ethyl acetate ( 50mL×3) extract, combine the organic phases, dry with anhydrous sodium sulfate, spin dry, dissolve the resulting brown oil in a mixed solvent of 3ml of methanol and 3ml of tetrahydrofuran, and then slowly add dropwise 2ml of sodium hydroxide aqueous solution ( 0.03g, 0.8mmol), stirred and reacted at room temperature for 15 minutes, TLC detection, the reaction was complete, 50ml of water was added, extracted with ethyl acetate (50mL×3), the combined organic phases were dried with anhydrous sodium sulfate and spin-dried, column chromatography (Eluent MeOH/DCM=1/5) After separation and purification, 17 mg of the final product (compound 3) was obtained as a white powder with a yield of 7.7%.
LC-MS(ESI)：m/z＝344.3[M+H] +。 LC-MS (ESI): m/z=344.3 [M+H] + .
1H NMR(400MHz,CDCl3)δ9.66-9.79(m,3H),8.03(s,1H),3.50-3.52(m,2H),2.75-2.85(m,2H),1.46-1.71(m,3H),1.38-1.40(m,6H),0.34-0.64(m,4H)。 1 H NMR(400MHz,CDCl3)δ9.66-9.79(m,3H), 8.03(s,1H), 3.50-3.52(m,2H), 2.75-2.85(m,2H), 1.46-1.71(m, 3H), 1.38-1.40 (m, 6H), 0.34-0.64 (m, 4H).
实施例4Example 4
3-(3-((1-(羟甲基)环戊基)氨基甲酰基)-5,5a,6,6a-四氢环丙基[g]吲唑-1(4氢)-基)吡嗪1-氧化物(化合物4)3-(3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropyl[g]indazole-1(4hydro)-yl) Pyrazine 1-oxide (Compound 4)
3-(3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-(3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000075
Figure PCTCN2020114451-appb-000075
第一步：3-(3-羧基-5,5a,6,6a-四氢氯丙烷[g]吲唑-1(4氢)-基)吡嗪1-氧化物(4a)The first step: 3-(3-carboxy-5,5a,6,6a-tetrahydrochloropropane[g]indazole-1(4hydro)-yl)pyrazine 1-oxide (4a)
3-(3-carboxy-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-(3-carboxy-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
将原料1d(2g,7.8mmol)溶解于25ml的甲酸溶液中，然后加入30％的双氧水溶液(5ml)，升温至64℃搅拌反应3小时以后，加入250ml的水，用乙酸乙酯(50mL×3)萃取，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4a直接进行下一步反应。Dissolve the raw material 1d (2g, 7.8mmol) in 25ml of formic acid solution, then add 30% hydrogen peroxide solution (5ml), heat up to 64℃ and stir the reaction for 3 hours, add 250ml of water, and use ethyl acetate (50mL× 3) Extraction, combine the organic phases, dry with anhydrous sodium sulfate, and spin-dry the resulting brown oil 4a directly for the next reaction.
LC-MS(ESI)：m/z＝273.2[M+H] +。 LC-MS (ESI): m/z=273.2 [M+H] + .
第二步：3-(3-((1-(羟甲基)环戊基)氨基甲酰基)-5,5a,6,6a-四氢环丙基[g]吲唑-1(4氢)-基)吡嗪1-氧化物(化合物4)The second step: 3-(3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropyl[g]indazole-1(4hydro )-Yl)pyrazine 1-oxide (Compound 4)
3-(3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-(3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
将原料4a(0.7g,2.57mmol)溶解于25ml的DMF溶液中，然后加入(1-氨基环戊基)甲醇(0.35g, 3.08mmol)以及HATU(1.17g,3.08mmol)，三乙胺(1.1g,10.9mmol)，常温搅拌过夜，加入200ml的水至反应液中，然后用乙酸乙酯(70mL×3)萃取，合并有机相，无水硫酸钠干燥后旋干，硅胶柱层析纯化(洗脱剂MeOH/DCM＝1/10)，得到淡黄色固体350mg(化合物4)，收率36.9％。Dissolve the raw material 4a (0.7g, 2.57mmol) in 25ml of DMF solution, then add (1-aminocyclopentyl) methanol (0.35g, 3.08mmol) and HATU (1.17g, 3.08mmol), triethylamine ( 1.1g, 10.9mmol), stir overnight at room temperature, add 200ml of water to the reaction solution, then extract with ethyl acetate (70mL×3), combine the organic phases, dry with anhydrous sodium sulfate, spin dry, and purify by silica gel column chromatography (Eluent MeOH/DCM=1/10) to obtain 350 mg of light yellow solid (Compound 4) with a yield of 36.9%.
LC-MS(ESI)：m/z＝370.4[M+H] +。 LC-MS (ESI): m/z=370.4 [M+H] + .
1H NMR(400MHz,CDCl 3)δ8.83-8.84(m,1H),8.27-8.28(m,1H),7.99-8.01(m,1H)7.06(s,1H),3.72-3.78(m,2H),3.21-3.26(m,1H),3.03-3.09(m,1H),1.71-1.98(m,12H),1.13-1.18(m,1H),0.83-0.87(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ8.83-8.84 (m, 1H), 8.27-8.28 (m, 1H), 7.99-8.01 (m, 1H) 7.06 (s, 1H), 3.72-3.78 (m, 2H), 3.21-3.26 (m, 1H), 3.03-3.09 (m, 1H), 1.71-1.98 (m, 12H), 1.13-1.18 (m, 1H), 0.83-0.87 (m, 1H).
实施例5Example 5
3-((5aR,6aS)-3-(((S)-1-羟基-3,3-二甲基丁-2-基)氨基甲酰基)-5a甲基代-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4氢)-基)吡嗪1-氧化物3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbut-2-yl)carbamoyl)-5amethyl-5,5a,6, 6a-Tetrahydrocyclopropane[g]indazole-1(4hydro)-yl)pyrazine-1-oxide
3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5a-methyl-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5a-methyl-5,5a,6,6a-tetrahydrocyclopropa[g] indazol-1(4H)-yl)pyrazine 1-oxide
3-((5aS,6aR)-3-(((S)-1-羟基-3,3-二甲基丁-2-基)氨基甲酰基)-5a甲基代-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4氢)-基)吡嗪1-氧化物3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbut-2-yl)carbamoyl)-5amethyl-5,5a,6, 6a-Tetrahydrocyclopropane[g]indazole-1(4hydro)-yl)pyrazine-1-oxide
3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5a-methyl-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5a-methyl-5,5a,6,6a-tetrahydrocyclopropa[g] indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000076
Figure PCTCN2020114451-appb-000076
第一步：6-甲基双环[4.1.0]庚烷-2-酮(5b)The first step: 6-methylbicyclo[4.1.0]heptan-2-one (5b)
6-methylbicyclo[4.1.0]heptan-2-one6-methylbicyclo[4.1.0]heptan-2-one
250mL三口瓶中加入100mL的二甲基亚砜溶液，冰浴条件下缓慢加入钠氢(4.73g,0.20mol)，搅拌10分钟后加入三甲基碘化亚砜(26.1g,0.12mol)，然后搅拌半小时以后缓慢滴入溶解于20mL的二甲基亚砜溶液中的3-甲基环己-2-烯酮(10ml)，继续搅拌十分钟，然后反应液恢复至室温继续 搅拌半小时，再升温至50℃反应2小时，TLC检测反应完全以后，冷却反应液至室温，将反应液倒入100g的冰水中，搅拌半小时，然后过滤，得到的滤液加入150ml水，用乙酸乙酯(200mL×3)萃取，合并有机相，无水硫酸钠干燥，35℃的水浴旋干得到所需的化合物10g(5b)，直接进行下一步反应。收率89.3％。Add 100mL of dimethyl sulfoxide solution to a 250mL three-necked flask, slowly add sodium hydrogen (4.73g, 0.20mol) under ice bath conditions, stir for 10 minutes and then add trimethylsulfoxide iodide (26.1g, 0.12mol), Then, after stirring for half an hour, slowly drop in 3-methylcyclohex-2-enone (10ml) dissolved in 20mL of dimethyl sulfoxide solution, continue stirring for ten minutes, then return the reaction solution to room temperature and continue stirring for half an hour Then the temperature was raised to 50°C and reacted for 2 hours. After the reaction was completed by TLC, the reaction solution was cooled to room temperature. The reaction solution was poured into 100g of ice water, stirred for half an hour, and then filtered. The obtained filtrate was added with 150ml of water and used ethyl acetate. (200mL×3) Extract, combine the organic phases, dry with anhydrous sodium sulfate, spin-dry in a water bath at 35°C to obtain 10g (5b) of the desired compound, and proceed directly to the next reaction. The yield was 89.3%.
1H NMR(400MHz,CDCl 3)δ2.17-2.27(m,2H),1.60-1.85(m,4H),1.06-1.17(m,1H),0.99(s,3H)),0.26-0.54(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ 2.17-2.27 (m, 2H), 1.60-1.85 (m, 4H), 1.06-1.17 (m, 1H), 0.99 (s, 3H)), 0.26-0.54 ( m,2H).
第二步：5a-甲基-1-(吡嗪-2-基)-1,4,5,5a,6,6a-六氢环丙基[g]吲唑-3-羧酸乙酯(5c)The second step: 5a-methyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropyl[g]indazole-3-carboxylic acid ethyl ester ( 5c)
ethyl 5a-methyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylateethyl 5a-methyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylate
将化合物5b(1g,8mmol)溶解于20ml的乙醇溶液中，然后搅拌下加入草酸二乙酯(1.17g,8mmol)以及叔丁醇钾(0.9g,8mmol)，然后升温至40℃搅拌反应2小时，然后缓慢加入6M的盐酸溶液(5ml)，搅拌5分钟以后加入吡嗪肼(0.88g,0.18mol)，然后将反应液升至50℃继续反应2小时，TLC检测反应完全以后，冷却至室温以后，加入饱和碳酸氢钠溶液调节pH至9左右，将反应液加入100ml的水中，然后用乙酸乙酯(100mL×3)萃取，有机相用无水硫酸钠干燥，旋干以后，柱层析(洗脱剂EA/PE＝1/5)纯化得到黄色油状物0.18g(5c)，收率7.5％。Dissolve compound 5b (1g, 8mmol) in 20ml of ethanol solution, then add diethyl oxalate (1.17g, 8mmol) and potassium tert-butoxide (0.9g, 8mmol) with stirring, then heat to 40℃ and stir for reaction 2. Then slowly add 6M hydrochloric acid solution (5ml), stir for 5 minutes, add pyrazine hydrazine (0.88g, 0.18mol), then raise the reaction solution to 50℃ and continue to react for 2 hours. After TLC detects the reaction is complete, cool to After room temperature, add saturated sodium bicarbonate solution to adjust the pH to about 9, add the reaction solution to 100ml of water, and then extract with ethyl acetate (100mL×3). The organic phase is dried with anhydrous sodium sulfate. After spin-drying, the column layer Analyze (eluent EA/PE=1/5) to obtain 0.18 g (5c) of yellow oil with a yield of 7.5%.
LC-MS(ESI)：m/z＝299.3[M+H] +。 LC-MS (ESI): m/z=299.3 [M+H] + .
第三步：5a-甲基-1-(吡嗪-2-基)-1,4,5,5a,6,6a-六氢环丙基[g]吲唑-3-羧酸(5d)The third step: 5a-methyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropyl[g]indazole-3-carboxylic acid (5d)
5a-methyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylic acid5a-methyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylic acid
将化合物5c(0.18g,0.6mmol)，溶解于5ml甲醇与5ml的四氢呋喃的混合溶剂中，然后缓慢加入氢氧化钠(0.029g,0.72mmol)的水溶液，滴加完毕以后室温搅拌过夜，加入2M的稀盐酸调节反应液的pH至3左右，然后加入30ml的水，用二氯甲烷(50mL×3)萃取以后，有机相用无水硫酸钠干燥并旋干，得到黄色油状物0.14g(5d)，收率85.9％。Compound 5c (0.18g, 0.6mmol) was dissolved in a mixed solvent of 5ml of methanol and 5ml of tetrahydrofuran, and then slowly added an aqueous solution of sodium hydroxide (0.029g, 0.72mmol). After the addition, it was stirred at room temperature overnight, and 2M was added. Adjust the pH of the reaction solution to about 3 with the diluted hydrochloric acid, then add 30ml of water and extract with dichloromethane (50mL×3). The organic phase is dried with anhydrous sodium sulfate and spin-dried to obtain a yellow oil 0.14g (5d ), the yield is 85.9%.
LC-MS(ESI)：m/z＝271.3[M+H] +。 LC-MS (ESI): m/z=271.3 [M+H] + .
第四步：N-((S)-1-羟基-3,3-二甲基丁-2-基)-5a甲基-1-(吡嗪-2-基)-1,4,5,5a,6,6a-六氢环丙烷[g]吲唑-3-甲酰胺(5e)The fourth step: N-((S)-1-hydroxy-3,3-dimethylbut-2-yl)-5amethyl-1-(pyrazin-2-yl)-1,4,5, 5a,6,6a-hexahydrocyclopropane[g]indazole-3-carboxamide(5e)
N-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-5a-methyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxamideN-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-5a-methyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[ g]indazole-3-carboxamide
将原料5d(0.14g,0.52mmol)溶解于5ml的DMF溶液中，然后加入S-叔亮胺醇(0.073g,0.62mmol)以及HATU(0.24g,0.62mmol)，三乙胺(0.16g,1.6mmol)，常温搅拌过夜，TLC监测反应完全，然后加入20ml的水至反应液中，然后用乙酸乙酯(30mL×3)萃取，合并有机相，无水硫酸钠干燥并旋干，柱层析(洗脱剂MeOH/DCM＝1/10)纯化，得到淡黄色固体130mg(5e)，收率68.4％。The raw material 5d (0.14g, 0.52mmol) was dissolved in 5ml of DMF solution, and then S-tertiary leucine alcohol (0.073g, 0.62mmol) and HATU (0.24g, 0.62mmol), triethylamine (0.16g, 1.6mmol), stirred overnight at room temperature, TLC monitored the completion of the reaction, then added 20ml of water to the reaction solution, and then extracted with ethyl acetate (30mL×3), combined the organic phases, dried with anhydrous sodium sulfate and spin-dried, the column layer It was purified by analysis (eluent MeOH/DCM=1/10) to obtain 130 mg (5e) of light yellow solid, with a yield of 68.4%.
LC-MS(ESI)：m/z＝370.4[M+H] +。 LC-MS (ESI): m/z=370.4 [M+H] + .
第五步：3-((5aR,6aS)-3-(((S)-1-羟基-3,3-二甲基丁-2-基)氨基甲酰基)-5a甲基代-5,5a,6,6a-四氢 环丙烷[g]吲唑-1(4氢)-基)吡嗪1-氧化物The fifth step: 3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbut-2-yl)carbamoyl)-5amethyl-5, 5a,6,6a-tetrahydrocyclopropane[g]indazole-1(4hydro)-yl)pyrazine-1-oxide
3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5a-methyl-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5a-methyl-5,5a,6,6a-tetrahydrocyclopropa[g] indazol-1(4H)-yl)pyrazine 1-oxide
3-((5aS,6aR)-3-(((S)-1-羟基-3,3-二甲基丁-2-基)氨基甲酰基)-5a甲基代-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbut-2-yl)carbamoyl)-5amethyl-5,5a,6, 6a-Tetrahydrocyclopropane[g]indazole-1(4H)-yl)pyrazine 1-oxide
3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5a-methyl-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5a-methyl-5,5a,6,6a-tetrahydrocyclopropa[g] indazol-1(4H)-yl)pyrazine 1-oxide
将原料5e(0.13g,0.35mmol)溶解于5ml的甲酸溶液中，然后加入30％的双氧水溶液(0.7ml)，升温至64℃搅拌反应3小时以后，加入50ml的水，用乙酸乙酯(50mL×3)萃取，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(0.015g,0.4mmol)，常温搅拌反应15分钟以后，TLC检测，反应完全，加入50ml的水，用乙酸乙酯(50mL×3)萃取，合并有机相用无水硫酸钠干燥并旋干，硅胶柱层析(洗脱剂MeOH/DCM＝1/10)纯化分离以后得到终产物白色粉末10mg(化合物5-a)，HPLC(保留时间t＝3.885)，收率7.4％，以及白色粉末8mg(化合物5-b)，HPLC(保留时间t＝4.042)，收率5.9％。The raw material 5e (0.13g, 0.35mmol) was dissolved in 5ml of formic acid solution, and then 30% hydrogen peroxide solution (0.7ml) was added. The temperature was raised to 64°C and the reaction was stirred for 3 hours. Then 50ml of water was added and ethyl acetate ( 50mL×3) extract, combine the organic phases, dry with anhydrous sodium sulfate, spin dry, dissolve the resulting brown oil in a mixed solvent of 3ml of methanol and 3ml of tetrahydrofuran, and then slowly add dropwise 2ml of sodium hydroxide aqueous solution ( 0.015g, 0.4mmol). After stirring and reacting at room temperature for 15 minutes, the reaction was checked by TLC. The reaction was complete. Add 50ml of water and extract with ethyl acetate (50mL×3). The combined organic phases were dried with anhydrous sodium sulfate and spin-dried. After purification and separation by column chromatography (eluent MeOH/DCM=1/10), the final product white powder 10mg (compound 5-a), HPLC (retention time t=3.885), yield 7.4%, and white powder 8mg ( Compound 5-b), HPLC (retention time t=4.042), yield 5.9%.
化合物5-a:Compound 5-a:
LC-MS(ESI)：m/z＝386.4[M+H] +。 LC-MS (ESI): m/z=386.4 [M+H] + .
1H NMR(400MHz,CDCl 3)δ9.66-9.89(m,2H),9.66(s,1H),8.03(s,1H),3.25-3.65(m,4H),2.75-2.85(m,4H),1.42-1.67(m,3H),0.94-0.99(m,10H),0.30-0.55(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ9.66-9.89 (m, 2H), 9.66 (s, 1H), 8.03 (s, 1H), 3.25-3.65 (m, 4H), 2.75-2.85 (m, 4H) ), 1.42-1.67 (m, 3H), 0.94-0.99 (m, 10H), 0.30-0.55 (m, 2H).
化合物5-b：Compound 5-b:
LC-MS(ESI)：m/z＝386.4[M+H] +。 LC-MS (ESI): m/z=386.4 [M+H] + .
1H NMR(400MHz,CDCl 3)δ9.62-9.91(m,2H),9.63(s,1H),3.85-3.75(m,4H),2.77-2.95(m,4H),1.43-1.72(m,3H),0.91-0.97(m,10H),0.31-0.52(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ9.62-9.91 (m, 2H), 9.63 (s, 1H), 3.85-3.75 (m, 4H), 2.77-2.95 (m, 4H), 1.43-1.72 (m ,3H),0.91-0.97(m,10H),0.31-0.52(m,2H).
实施例6Example 6
3-(3-(((S)-1-羟基-3,3-二甲基丁-2-基)氨基甲酰基)-4,5,5a,6,7,7a-六氢-1氢-环己并[g]吲唑1-氧基)吡嗪1-氧化物(化合物6)3-(3-(((S)-1-hydroxy-3,3-dimethylbut-2-yl)carbamoyl)-4,5,5a,6,7,7a-hexahydro-1 hydrogen -Cyclohexano[g]indazole 1-oxy)pyrazine 1-oxide (Compound 6)
3-(3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-4,5,5a,6,7,7a-hexahydro-1H-cyclobuta[g]indazol-1-yl)pyrazine 1-oxide3-(3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-4,5,5a,6,7,7a-hexahydro-1H-cyclobuta[g]indazol- 1-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000077
Figure PCTCN2020114451-appb-000077
第一步：8,8-二氯双环[4.2.0]辛-2-烯-7-酮(6b)The first step: 8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one (6b)
8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one
将化合物6a(3.5g,24.5mmol)溶解在四氢呋喃(50mL)中，向其中加入锌粉(1.6g,24.5mmol)，室温反应过夜。过滤除去锌粉，旋干溶剂加硅胶拌样，柱层析(洗脱剂：石油醚/乙酸乙酯＝10:1～5:1)分离得到化合物6b(3.0g,66％)。Compound 6a (3.5 g, 24.5 mmol) was dissolved in tetrahydrofuran (50 mL), zinc powder (1.6 g, 24.5 mmol) was added thereto, and reacted at room temperature overnight. The zinc powder was removed by filtration, the sample was mixed with silica gel in a spin-drying solvent, and column chromatography (eluent: petroleum ether/ethyl acetate = 10:1 to 5:1) was separated to obtain compound 6b (3.0 g, 66%).
1H NMR(500MHz,Chloroform-d)：δ1.61(1H,m),1.95(1H,m),2.00(1H,m),2.07(1H,m),3.41(1H,m),4.07(1H,m),5.84(1H,m),6.05(1H,m)。 1 H NMR (500MHz, Chloroform-d): δ 1.61 (1H, m), 1.95 (1H, m), 2.00 (1H, m), 2.07 (1H, m), 3.41 (1H, m), 4.07 ( 1H, m), 5.84 (1H, m), 6.05 (1H, m).
第二步：双环[4.2.0]辛-2-烯-7-酮(6c)Step 2: Bicyclo[4.2.0]oct-2-en-7-one (6c)
bicyclo[4.2.0]oct-2-en-7-onebicyclo[4.2.0]oct-2-en-7-one
将化合物6b(1.0g,5.3mmol)溶于乙酸(40mL)中。加入锌粉(3.44g,53mmol)，使反应混合物回流3小时。冷却至室温后，加入30mL水淬灭反应，二氯甲烷(50mL×3)萃取并合并有机相，并将合并的有机萃取液用饱和碳酸氢钠溶液洗涤，经无水硫酸钠干燥并真空浓缩。柱层析(洗脱剂：石油醚/乙酸乙酯＝10:1～5:1)得到化合物6c(0.5g，80％)。Compound 6b (1.0 g, 5.3 mmol) was dissolved in acetic acid (40 mL). Zinc powder (3.44 g, 53 mmol) was added, and the reaction mixture was refluxed for 3 hours. After cooling to room temperature, 30 mL of water was added to quench the reaction, dichloromethane (50 mL×3) was extracted and the organic phases were combined, and the combined organic extracts were washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo . Column chromatography (eluent: petroleum ether/ethyl acetate = 10:1 to 5:1) to obtain compound 6c (0.5 g, 80%).
1H NMR(400MHz,Chloroform-d)δ1.49(1H,m),1.94(3H,m),2.53(1H,t),2.85(1H,m),3.20(1H,t),3.49(1H,m),5.78(1H,m),5.87(1H,m)。 1 H NMR (400MHz, Chloroform-d) δ 1.49 (1H, m), 1.94 (3H, m), 2.53 (1H, t), 2.85 (1H, m), 3.20 (1H, t), 3.49 (1H) ,m), 5.78 (1H, m), 5.87 (1H, m).
第三步：螺[二环[4.2.0]辛烷7,2'-[1,3]二氧戊环]-2-烯(6d)The third step: Spiro[bicyclo[4.2.0]octane 7,2'-[1,3]dioxolane]-2-ene (6d)
spiro[bicyclo[4.2.0]octane-7,2'-[1,3]dioxolan]-2-enespiro[bicyclo[4.2.0]octane-7,2'-[1,3]dioxolan]-2-ene
将化合物6c(450mg,3.68mmol)溶解在甲苯(1.5mL)中，向其中加入乙二醇(1.5mL)和对甲苯磺酸(633mg,3.68mmol)，升温至120摄氏度回流分水四个小时。待反应液冷却至室温，旋蒸除去甲苯，柱层析(洗脱剂：石油醚/乙酸乙酯＝10:1～5:1)分离得到化合物6d(0.65g,80％)。Compound 6c (450mg, 3.68mmol) was dissolved in toluene (1.5mL), ethylene glycol (1.5mL) and p-toluenesulfonic acid (633mg, 3.68mmol) were added to it, and the temperature was raised to 120 degrees Celsius and refluxed for four hours. . After the reaction solution was cooled to room temperature, the toluene was removed by rotary evaporation, and column chromatography (eluent: petroleum ether/ethyl acetate = 10:1 to 5:1) was separated to obtain compound 6d (0.65 g, 80%).
1H NMR(400MHz,Chloroform-d)δ5.98–5.75(m,2H),3.93–3.69(m,4H),3.47–3.30(m,1H),2.72(t,1H),2.46–2.35(m,2H),2.23–1.85(m,4H)。 1 H NMR (400MHz, Chloroform-d) δ 5.98--5.75 (m, 2H), 3.93 - 3.69 (m, 4H), 3.47 - 3.30 (m, 1H), 2.72 (t, 1H), 2.46 - 2.35 ( m, 2H), 2.23–1.85 (m, 4H).
第四步：3'-氧杂螺[[1,3]二氧戊环2,8'-三环[5.2.0.0 2,4]壬烷](6e) The fourth step: 3'-oxaspiro[[1,3]dioxolane 2,8'-tricyclo[5.2.0.0 2,4 ]nonane](6e)
将mCPBA(85％,136mg,0.67mmol)加入到化合物6d(100mg,0.56mmol)的二氯甲烷(5mL)溶液中，室温下搅拌反应5小时。加5ml水淬灭反应，二氯甲烷(20mL×3)萃取并合并有机相，将合并后的有机相使用饱和碳酸氢钠溶液洗涤，旋干溶剂，柱层析(洗脱剂：石油醚/乙酸乙酯＝10:1～5:1)分离得到化合物6e(86mg，78.6％)。MCPBA (85%, 136 mg, 0.67 mmol) was added to a dichloromethane (5 mL) solution of compound 6d (100 mg, 0.56 mmol), and the reaction was stirred at room temperature for 5 hours. Add 5ml of water to quench the reaction, extract with dichloromethane (20mL×3) and combine the organic phases, wash the combined organic phases with saturated sodium bicarbonate solution, spin dry the solvent, and column chromatography (eluent: petroleum ether/ Ethyl acetate=10:1～5:1) was isolated to obtain compound 6e (86 mg, 78.6%).
1H NMR(400MHz,Chloroform-d)δ1.2-2.82(m,8H),3.10(t,2H),3.23(t,3H),3.26-3.30(m,1H),3.7-3.95(m,4H)。 1 H NMR (400MHz, Chloroform-d) δ 1.2-2.82 (m, 8H), 3.10 (t, 2H), 3.23 (t, 3H), 3.26 3.30 (m, 1H), 3.7-3.95 (m, 4H).
第五步：螺[二环[4.2.0]辛烷7,2'-[1,3]二氧戊环]-2-醇(6f)Step 5: Spiro[Bicyclo[4.2.0]octane 7,2'-[1,3]dioxolane]-2-ol (6f)
将化合物6e(450mg,3.68mmol)溶解在四氢呋喃(1.5mL)中，降温至零摄氏度向其中加入四氢铝锂(450mg,3.68mmol)，升温至65摄氏度反应两个小时。向反应液中分别缓慢滴加水(1.5mL)，氢氧化钠溶液(15％,1.5mL)以及水(1.5mL)。过滤除去不溶物，再向其中加入20ml饱和碳酸氢钠溶液淬灭反应，二氯甲烷(50mL×3)萃取并合并有机相，有机相用无水硫酸钠干燥，柱层析(洗脱剂：石油醚/乙酸乙酯＝8:1～3:1)分离得到化合物6f(420mg,77％)。Compound 6e (450 mg, 3.68 mmol) was dissolved in tetrahydrofuran (1.5 mL), the temperature was lowered to zero degrees Celsius, lithium aluminum tetrahydrogen (450 mg, 3.68 mmol) was added thereto, and the temperature was raised to 65 degrees Celsius to react for two hours. Water (1.5 mL), sodium hydroxide solution (15%, 1.5 mL) and water (1.5 mL) were slowly added dropwise to the reaction solution. The insoluble matter was removed by filtration, and the reaction was quenched by adding 20ml of saturated sodium bicarbonate solution, extracted with dichloromethane (50mL×3) and combined the organic phases, the organic phase was dried with anhydrous sodium sulfate, and column chromatography (eluent: Petroleum ether/ethyl acetate=8:1～3:1) Compound 6f (420mg, 77%) was isolated.
1H NMR(400MHz,Chloroform-d)δ4.06–3.83(m,4H),3.63(tt,1H),2.58(d,1H),2.38(dd,1H),2.19(dd,1H),2.01t,1H),1.80(p,1H),1.75–1.67(m,1H),1.66–1.48(m,5H)。 1 H NMR (400MHz, Chloroform-d) δ 4.06-3.83 (m, 4H), 3.63 (tt, 1H), 2.58 (d, 1H), 2.38 (dd, 1H), 2.19 (dd, 1H), 2.01 t,1H), 1.80(p,1H), 1.75–1.67(m,1H), 1.66–1.48(m,5H).
第六步：2-羟基双环[4.2.0]辛-7-酮(6g)The sixth step: 2-hydroxybicyclo[4.2.0]octan-7-one (6g)
2-hydroxybicyclo[4.2.0]octan-7-one2-hydroxybicyclo[4.2.0]octan-7-one
将化合物6f(120mg,2.36mmol)溶解在浓盐酸的甲醇溶液(1M,1.5mL)中，室温反应两个小时。加入15ml水，二氯甲烷(50mL×3)萃取并合并有机相，有机相用无水硫酸钠干燥，柱层析(洗脱剂：石油醚/乙酸乙酯＝8:1～3:1)分离得到化合物6g(89mg,79％)。Compound 6f (120mg, 2.36mmol) was dissolved in a methanol solution (1M, 1.5mL) of concentrated hydrochloric acid and reacted at room temperature for two hours. Add 15ml of water, extract with dichloromethane (50mL×3) and combine the organic phases, dry the organic phase with anhydrous sodium sulfate, and column chromatography (eluent: petroleum ether/ethyl acetate=8:1～3:1) Compound 6g (89mg, 79%) was isolated.
1H NMR(400MHz,Chloroform-d)δ4.15(tt,1H),2.82(dt,1H),2.75(dd,1H),2.67(dd,1H),2.59(d,1H),2.28(t,1H),1.91–1.81(m,1H),1.81–1.74(m,2H),1.74–1.66(m,1H),1.55(t,1H),1.50–1.40(m,1H)。 1 H NMR(400MHz, Chloroform-d)δ4.15(tt,1H), 2.82(dt,1H), 2.75(dd,1H), 2.67(dd,1H), 2.59(d,1H), 2.28(t ,1H), 1.91–1.81(m,1H), 1.81–1.74(m,2H), 1.74–1.66(m,1H), 1.55(t,1H), 1.50–1.40(m,1H).
第七步：双环[4.2.0]辛-2-醇(6h)The seventh step: Bicyclo[4.2.0]octan-2-ol (6h)
bicyclo[4.2.0]octan-2-olbicyclo[4.2.0]octan-2-ol
将化合物6g(320mg,3.56mmol)溶解在乙二醇(1M,1.5mL)中，依次向其中加入水合肼，氢氧化钾(140mg,4.5mmol)，升温至160℃反应一个小时。旋蒸除去过量的水合肼以及水。随后升温至200摄氏度反应两个小时。向反应体系中加入大量水，二氯甲烷萃取并合并有机相，有机相用无水硫酸钠干燥，柱层析分离得到化合物6h(270mg，69％)。Compound 6g (320mg, 3.56mmol) was dissolved in ethylene glycol (1M, 1.5mL), hydrazine hydrate and potassium hydroxide (140mg, 4.5mmol) were sequentially added to it, and the temperature was raised to 160° C. for reaction for one hour. Rotary evaporation to remove excess hydrazine hydrate and water. Then the temperature was raised to 200 degrees Celsius for two hours. A large amount of water was added to the reaction system, extracted with dichloromethane and combined the organic phases, the organic phases were dried with anhydrous sodium sulfate, and column chromatography was separated to obtain compound 6h (270 mg, 69%).
1H NMR(400MHz,Chloroform-d)δ3.70(t,1H),2.49(d,1H),2.00–1.90(m,1H),1.85–1.76(m,3H),1.74–1.65(m,3H),1.61–1.50(m,3H),1.49–1.36(m,2H)。 1 H NMR (400MHz, Chloroform-d) δ 3.70 (t, 1H), 2.49 (d, 1H), 2.00-1.90 (m, 1H), 1.85-1.76 (m, 3H), 1.74-1.65 (m, 3H), 1.61–1.50 (m, 3H), 1.49–1.36 (m, 2H).
第八步：双环[4.2.0]辛-2-醇(6i)Step 8: Bicyclo[4.2.0]octan-2-ol (6i)
bicyclo[4.2.0]octan-2-olbicyclo[4.2.0]octan-2-ol
将化合物6g(150mg,1.35mmol)溶解在乙酸乙酯(15mL)中，向其中加入IBX(250mg,2.7mmol)，升温至80摄氏度反应一个小时。过滤除去不溶物向滤液中加入硅胶拌样，柱层析(洗脱剂：石油醚/乙酸乙酯＝8:1～3:1)分离得到化合物6i(79mg，77％)。Compound 6g (150 mg, 1.35 mmol) was dissolved in ethyl acetate (15 mL), IBX (250 mg, 2.7 mmol) was added thereto, and the temperature was raised to 80 degrees Celsius to react for one hour. The insoluble matter was removed by filtration, silica gel was added to the filtrate, and the sample was mixed, and column chromatography (eluent: petroleum ether/ethyl acetate = 8:1 to 3:1) was used to isolate compound 6i (79 mg, 77%).
1H NMR(400MHz,Chloroform-d)δ2.92(t,1H),2.43(t,1H),2.39–2.25(m,2H),2.05(t,1H),1.89–1.67(m,5H),1.66–1.45(m,2H)。 1 H NMR (400MHz, Chloroform-d) δ 2.92 (t, 1H), 2.43 (t, 1H), 2.39-2.25 (m, 2H), 2.05 (t, 1H), 1.89-1.67 (m, 5H) ,1.66–1.45(m,2H).
第九步：2-氧代-2-(2-氧代双环[4.2.0]辛-3-基)乙酸乙酯(6j)The ninth step: ethyl 2-oxo-2-(2-oxobicyclo[4.2.0]oct-3-yl)acetate (6j)
ethyl 2-oxo-2-(2-oxobicyclo[4.2.0]octan-3-yl)acetateethyl 2-oxo-2-(2-oxobicyclo[4.2.0]octan-3-yl)acetate
将化合物6i(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(1M，30mL)淬灭反应，乙酸乙酯(50mL×3)萃取并合并有机相，有机相用无水硫酸钠干燥，加入硅胶拌样柱层析(洗脱剂：石油醚/乙酸乙酯＝5:1～2:1)分离，得到化合物6j(1.9g,37.0％)。Dissolve compound 6i (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 up to room temperature and react overnight. The reaction was quenched with dilute hydrochloric acid (1M, 30mL), and the organic phases were extracted and combined with ethyl acetate (50mL×3). The organic phases were dried with anhydrous sodium sulfate and added to silica gel and mixed with column chromatography (eluent: petroleum ether/ Ethyl acetate = 5:1 to 2:1) to obtain compound 6j (1.9 g, 37.0%).
LC-MS(ESI)：m/z＝225.2[M+H] +。 LC-MS (ESI): m/z=225.2 [M+H] + .
第十步：1-(吡嗪-2-基)-4,5,5a,6,7,7a-六氢-1氢-环丁基[g]吲唑-3-羧酸乙酯(6k)The tenth step: 1-(pyrazin-2-yl)-4,5,5a,6,7,7a-hexahydro-1hydro-cyclobutyl[g]indazole-3-carboxylic acid ethyl ester (6k )
ethyl 1-(pyrazin-2-yl)-4,5,5a,6,7,7a-hexahydro-1H-cyclobuta[g]indazole-3-carboxylateethyl 1-(pyrazin-2-yl)-4,5,5a,6,7,7a-hexahydro-1H-cyclobuta[g]indazole-3-carboxylate
将化合物6j(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＝5:1～2:1)分离，得到化合物6k(1.85g,73.4％)。Compound 6j (2.1g, 8.8mmol) was dissolved in sulfuric acid ethanol solution (1:100(v/v), 21mL), pyrazine-2-hydrazine (1.45g, 13.2mmol) was added to it at room temperature, and the temperature was increased. Reflux for half an hour. The reaction solution was spin-dried and added to silica gel sample-mixed column chromatography (eluent: petroleum ether/ethyl acetate = 5:1 to 2:1) for separation to obtain compound 6k (1.85 g, 73.4%).
LC-MS(ESI)：m/z＝299.4[M+H] +。 LC-MS (ESI): m/z=299.4 [M+H] + .
第十一步：1-(吡嗪-2-基)-4,5,5a,6,7,7a-六氢-1氢-环丁基[g]吲唑-3-羧酸乙酯(6l)The eleventh step: 1-(pyrazin-2-yl)-4,5,5a,6,7,7a-hexahydro-1hydro-cyclobutyl[g]indazole-3-carboxylic acid ethyl ester ( 6l)
1-(pyrazin-2-yl)-4,5,5a,6,7,7a-hexahydro-1H-cyclobuta[g]indazole-3-carboxylic acid1-(pyrazin-2-yl)-4,5,5a,6,7,7a-hexahydro-1H-cyclobuta[g]indazole-3-carboxylic acid
将化合物6k(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(50mL×3)萃取并合并有机相，有机相旋干得到化合物6l，无需纯化，备用。Compound 6k (0.15 g, 0.54 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL), and sodium hydroxide solution (2M, 10 mL) was added thereto at room temperature. React at room temperature for two hours. The pH of the reaction solution was adjusted to 6, the organic phases were extracted and combined with dichloromethane (50 mL×3), and the organic phases were spin-dried to obtain 6 liters of compound, without purification, for use.
LC-MS(ESI)：m/z＝271.2[M+H] + LC-MS(ESI): m/z=271.2[M+H] +
第十二步：3-(3-羧基-4,5,5a,6,7,7a-六氢-1氢-环丁[g]吲唑-1-基)吡嗪1-氧化物(6m)The twelfth step: 3-(3-carboxy-4,5,5a,6,7,7a-hexahydro-1hydro-cyclobutane[g]indazol-1-yl)pyrazine 1-oxide (6m )
3-(3-carboxy-4,5,5a,6,7,7a-hexahydro-1H-cyclobuta[g]indazol-1-yl)pyrazine 1-oxide3-(3-carboxy-4,5,5a,6,7,7a-hexahydro-1H-cyclobuta[g]indazol-1-yl)pyrazine 1-oxide
将化合物6l(0.18g,0.66mmol)溶解在甲酸(10mL)中，室温下向其中加入双氧水(35％,1mL)。室温下反应两个小时。加入15ml水，二氯甲烷(50mL×3)萃取并合并有机相，旋干得到化合物6m，无需纯化，备用。Compound 6l (0.18 g, 0.66 mmol) was dissolved in formic acid (10 mL), and hydrogen peroxide (35%, 1 mL) was added thereto at room temperature. React at room temperature for two hours. Add 15ml of water, extract with dichloromethane (50mL×3) and combine the organic phases, spin dry to obtain compound 6m, without purification, for use.
LC-MS(ESI)：m/z＝287.2[M+H] +。 LC-MS (ESI): m/z=287.2 [M+H] + .
第十三步：3-(3-((((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl))-4,5,5a,6,7,7a-六氢-1H-环丁 [g]吲唑-1-基)吡嗪1-氧化物(化合物6)The thirteenth step: 3-(3-((((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl))-4,5,5a,6,7,7a-hexahydro- 1H-cyclobutane[g]indazol-1-yl)pyrazine 1-oxide (compound 6)
3-(3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-4,5,5a,6,7,7a-hexahydro-1H-cyclobuta[g]indazol-1-yl)pyrazine 1-oxide3-(3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-4,5,5a,6,7,7a-hexahydro-1H-cyclobuta[g]indazol- 1-yl)pyrazine 1-oxide
将化合物6m(0.14g,0.53mmol)溶解在二氯甲烷(5mL)中，室温下向其中加入S-叔亮氨醇(68mg，0.58mmol)，HATU(262mg,0.69mmol)，DIPEA(137mg,1.06mmol)。室温下反应两个小时。加入30ml水淬灭反应，二氯甲烷(50mL×3)萃取并合并有机相，有机相浓缩后的粗品用高效液相制备分离得到化合物6(60mg,41.6％)。Compound 6m (0.14g, 0.53mmol) was dissolved in dichloromethane (5mL), S-tert-leucine alcohol (68mg, 0.58mmol), HATU (262mg, 0.69mmol), DIPEA (137mg, 1.06mmol). React at room temperature for two hours. The reaction was quenched by adding 30 ml of water, and the organic phases were extracted and combined with dichloromethane (50 mL×3). The crude product after the concentrated organic phase was prepared and separated by HPLC to obtain compound 6 (60 mg, 41.6%).
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：11.3min。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 0.45μm 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: 11.3min.
LC-MS(ESI)：m/z＝386.4[M+H] +。 LC-MS (ESI): m/z=386.4 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ9.20(dd,1H),8.40(d,1H),8.24(dd,1H),7.81(dd,1H),4.49(t,2H),3.99–3.78(m,2H),3.74–3.62(m,1H),3.52(t,1H),2.95–2.69(m,4H),1.97(s,1H),1.90–1.49(m,2H),0.94(d,9H)。 1 H NMR(400MHz,DMSO-d 6 )δ9.20(dd,1H), 8.40(d,1H), 8.24(dd,1H), 7.81(dd,1H), 4.49(t,2H), 3.99-- 3.78(m,2H),3.74-3.62(m,1H),3.52(t,1H),2.95-2.69(m,4H),1.97(s,1H),1.90-1.49(m,2H),0.94( d, 9H).
实施例7Example 7
3-(((5aS,6aR)-3-((1-(羟甲基)环戊基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲哒唑-1(4H)-基)吡嗪1-氧化物3-(((5aS,6aR)-3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1 (4H)-yl)pyrazine 1-oxide
3-((5aS,6aR)-3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aS,6aR)-3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
3-(((5aR,6aS)-3-((1-(羟甲基)环戊基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物3-(((5aR,6aS)-3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1( 4H)-yl)pyrazine 1-oxide
3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000078
Figure PCTCN2020114451-appb-000078
将化合物4(8g,21.7mmol)采用手性制备分离得到化合物7a(出峰时间约为4.31min,3.49g, 43.6％)和化合物7b(出峰时间约为4.84min,3.49g,43.6％)。Compound 4 (8g, 21.7mmol) was separated by chiral preparation to obtain compound 7a (peak time is about 4.31min, 3.49g, 43.6%) and compound 7b (peak time is about 4.84min, 3.49g, 43.6%) .
制备色谱条件：色谱柱ChiralCel OJ,300×50mm I.D.,10μm，流动相体系：二氧化碳/甲醇＝70/30(v)，流量200mL/min。得到化合物7a(3.49g)，化合物7b(3.49g)。Preparative chromatographic conditions: chromatographic column ChiralCel OJ, 300×50mm I.D., 10μm, mobile phase system: carbon dioxide/methanol=70/30(v), flow 200mL/min. Compound 7a (3.49g) and compound 7b (3.49g) were obtained.
化合物7aCompound 7a
1H NMR(400MHz,CDCl 3)δ8.83-8.84(m,1H),8.27-8.28(m,1H),7.99-8.01(m,1H)7.06(s,1H),3.72-3.78(m,2H),3.21-3.26(m,1H),3.03-3.09(m,1H),1.71-1.98(m,12H),1.13-1.18(m,1H),0.83-0.87(m,1H)。 1H NMR (400MHz, CDCl 3 ) δ8.83-8.84 (m, 1H), 8.27-8.28 (m, 1H), 7.99-8.01 (m, 1H) 7.06 (s, 1H), 3.72-3.78 (m, 2H) ), 3.21-3.26 (m, 1H), 3.03-3.09 (m, 1H), 1.71-1.98 (m, 12H), 1.13-1.18 (m, 1H), 0.83-0.87 (m, 1H).
化合物7bCompound 7b
1H NMR(400MHz,CDCl 3)δ8.83-8.84(m,1H),8.37-8.38(m,1H),7.92-8.03(m,1H)7.06(s,1H),3.72-3.78(m,2H),3.24-3.28(m,1H),3.03-3.12(m,1H),1.70-1.96(m,12H),1.14-1.20(m,1H),0.84-0.89(m,1H)。 1H NMR (400MHz, CDCl 3 ) δ8.83-8.84 (m, 1H), 8.37-8.38 (m, 1H), 7.92-8.03 (m, 1H) 7.06 (s, 1H), 3.72-3.78 (m, 2H) ), 3.24-3.28 (m, 1H), 3.03-3.12 (m, 1H), 1.70 to 1.96 (m, 12H), 1.14-1.20 (m, 1H), 0.84-0.89 (m, 1H).
实施例8Example 8
3-(((5aR,6aS)-3-((1-(三氟甲基)环丙基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物8)3-(((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1 (4H)-yl)pyrazine 1-oxide (Compound 8)
3-((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000079
Figure PCTCN2020114451-appb-000079
第一步:(5aR,6aS)-乙基-1-(吡嗪-2-基)-1,4,5,5a,6,6a-六氢环丙烷[g]吲唑-3-羧酸酯(8b)The first step: (5aR,6aS)-ethyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropane[g]indazole-3-carboxylic acid Ester (8b)
(5aR,6aS)-ethyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylate(5aR,6aS)-ethyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylate
将化合物8a(10g,0.09mol)溶解于200ml的乙醇溶液中，然后搅拌下加入草酸二乙酯(13g,0.09mol)以及叔丁醇钾(10g,0.09mol)，然后升温至40℃搅拌反应2小时，然后缓慢加入6M的盐酸溶液(50ml)，搅拌5分钟以后加入吡嗪肼(10g,0.09mol)，然后将反应液升至50℃继续反应2小时，TLC检测反应完全以后，反应液冷却至室温以后，加入饱和碳酸氢钠溶液调节pH至9左右，将反应液加入500ml的水中，用乙酸乙酯(500mL×3)萃取三次，有机相用无水硫酸钠干燥，旋干以后，柱层析纯化(洗脱剂PE/EA＝1/1)得到黄色油状物13g(8b)，收率50.4％。Dissolve compound 8a (10g, 0.09mol) in 200ml of ethanol solution, then add diethyl oxalate (13g, 0.09mol) and potassium tert-butoxide (10g, 0.09mol) with stirring, then heat to 40℃ and stir to react After 2 hours, slowly add 6M hydrochloric acid solution (50ml), stir for 5 minutes, add pyrazine hydrazine (10g, 0.09mol), then raise the reaction solution to 50°C and continue the reaction for 2 hours. TLC detects that the reaction is complete. After cooling to room temperature, add saturated sodium bicarbonate solution to adjust the pH to about 9, add the reaction solution to 500ml of water, extract three times with ethyl acetate (500mL×3), dry the organic phase with anhydrous sodium sulfate and spin dry, Purification by column chromatography (eluent PE/EA=1/1) gave 13 g (8b) of yellow oil with a yield of 50.4%.
LC-MS(ESI)：m/z＝285.31[M+H] +。 LC-MS (ESI): m/z=285.31 [M+H] + .
第二步：(5aR,6aS)-1-(吡嗪-2-基)-1,4,5,5a,6,6a-六氢环丙烷[g]吲唑-3-羧酸(8c)(5aR,6aS)-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylic acidThe second step: (5aR,6aS)-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropane[g]indazole-3-carboxylic acid (8c) (5aR,6aS)-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylic acid
将化合物8b(13g,0.05mol)，溶解于100ml甲醇与100ml的四氢呋喃的混合溶剂中，然后缓慢 加入氢氧化钠(1.5g,0.04mol)的水溶液，滴加完毕以后室温搅拌过夜，加入2M的稀盐酸调节反应液的pH至3左右，然后加入300ml的水，用二氯甲烷(500mL×3)萃取三次以后，有机相用无水硫酸钠干燥并旋干，得到黄色粉末固体10g(8c)，收率85.5％。Compound 8b (13g, 0.05mol) was dissolved in a mixed solvent of 100ml of methanol and 100ml of tetrahydrofuran, and then slowly added an aqueous solution of sodium hydroxide (1.5g, 0.04mol), after the addition was complete, stirred at room temperature overnight, and added 2M Adjust the pH of the reaction solution to about 3 with dilute hydrochloric acid, then add 300ml of water, extract three times with dichloromethane (500mL×3), dry the organic phase with anhydrous sodium sulfate and spin dry to obtain 10g of yellow powder solid (8c) , The yield is 85.5%.
LC-MS(ESI)：m/z＝257.3[M+H] +。 LC-MS (ESI): m/z=257.3 [M+H] + .
第三步：3-(((5aR,6aS)-3-羧基-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(8d)The third step: 3-(((5aR,6aS)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1(4H)-yl)pyrazine 1-oxide( 8d)
((5aR,6aS)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide((5aR,6aS)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
将原料8c(10g,0.04mol)溶解于100ml的甲酸溶液中，然后加入30％的双氧水溶液(10ml)，升温至64℃搅拌反应3小时以后，加入550ml的水，用乙酸乙酯(500mL×3)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直接进行下一步反应。The raw material 8c (10g, 0.04mol) was dissolved in 100ml of formic acid solution, and then 30% hydrogen peroxide solution (10ml) was added. The temperature was raised to 64℃ and the reaction was stirred for 3 hours. Then 550ml of water was added, and ethyl acetate (500mL× 3) Extract three times, combine the organic phases, dry with anhydrous sodium sulfate, and spin-dry the resulting brown oil directly for the next step.
LC-MS(ESI)：m/z＝273.3[M+H] +。 LC-MS (ESI): m/z=273.3 [M+H] + .
第四步：3-(((5aR,6aS)-3-((1-(三氟甲基)环丙基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物8)The fourth step: 3-(((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane [g] Indazole-1(4H)-yl)pyrazine 1-oxide (Compound 8)
3-((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
将原料8d(300mg,1.1mmol)溶解于10ml的DMF溶液中，然后加入1-(三氟甲基)环丙胺(0.14g,1.1mmol)以及HATU(0.42g,1.1mmol)，三乙胺(0.36g,3.3mmol)，常温搅拌过夜，TLC监测反应完全，然后加入100ml的水至反应液中，用乙酸乙酯(100mL×3)萃取三次，合并有机相，无水硫酸钠干燥并旋干，柱层析纯化(流动相MeOH/DCM＝1/10)，得到类白色固体80mg(化合物8)，收率19.1％。The raw material 8d (300mg, 1.1mmol) was dissolved in 10ml of DMF solution, and then 1-(trifluoromethyl)cyclopropylamine (0.14g, 1.1mmol) and HATU (0.42g, 1.1mmol), triethylamine ( 0.36g, 3.3mmol), stirred overnight at room temperature, TLC monitored the reaction to be complete, then added 100ml of water to the reaction solution, extracted three times with ethyl acetate (100mL×3), combined the organic phases, dried with anhydrous sodium sulfate and spin-dried Column chromatography purification (mobile phase MeOH/DCM=1/10) to obtain 80 mg of off-white solid (compound 8), with a yield of 19.1%.
LC-MS(ESI)：m/z＝380.1[M+H] +。 LC-MS (ESI): m/z=380.1 [M+H] + .
1H NMR(400MHz,CDCl 3)δ8.85(s,1H),8.27(d,1H),7.02(d,1H),7.31(d,1H),3.21-3.27(m,1H),3.03-3.07(m,1H),2.14-2.29(m,2H),1.62-1.78(m,2H),1.40-1.56(m,2H),1.24-1.56(m,2H),1.14-1.17(m,1H),0.82-0.88(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 8.85 (s, 1H), 8.27 (d, 1H), 7.02 (d, 1H), 7.31 (d, 1H), 3.21-3.27 (m, 1H), 3.03- 3.07(m,1H),2.14-2.29(m,2H),1.62-1.78(m,2H),1.40-1.56(m,2H),1.24-1.56(m,2H),1.14-1.17(m,1H) ), 0.82-0.88 (m, 1H).
实施例9：Example 9:
3((5aR,6aS)-3-((S)-2-羟基-1-苯基乙基)氨基甲酰基)-5,5a,6,6a--四氢环丙基[g]吲唑-1(4H)-基吡嗪1-氧化物(化合物9)3((5aR,6aS)-3-((S)-2-hydroxy-1-phenylethyl)carbamoyl)-5,5a,6,6a--tetrahydrocyclopropyl(g)indazole -1(4H)-ylpyrazine 1-oxide (Compound 9)
3-((5aR,6aS)-3-(((S)-2-hydroxy-1-phenylethyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-(((S)-2-hydroxy-1-phenylethyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000080
Figure PCTCN2020114451-appb-000080
第一步:3((5aR,6aS)-3-((S)-2-羟基-1-苯基乙基)氨基甲酰基)-5,5a,6,6a--四氢环丙基[g]吲唑-1(4H)-基吡嗪1-氧化物(化合物9)The first step: 3((5aR,6aS)-3-((S)-2-hydroxy-1-phenylethyl)carbamoyl)-5,5a,6,6a--tetrahydrocyclopropyl[ g)Indazole-1(4H)-ylpyrazine 1-oxide (Compound 9)
((5aR,6aS)-3-(((S)-2-hydroxy-1-phenylethyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide((5aR,6aS)-3-(((S)-2-hydroxy-1-phenylethyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1- oxide
将原料8d(0.27g,1mmol)溶解于10ml的DMF溶液中，然后加入(S)-2-氨基-2-苯乙醇(0.14g,1mmol)以及HATU(0.57g,1.5mmol)，三乙胺(0.3g,3mmol)，常温搅拌过夜，加入50ml的水至反应液中，然后用乙酸乙酯(50mL×3)萃取三次，合并有机相，无水硫酸钠干燥并旋干，柱层析(洗脱剂MeOH/DCM＝1/10)分离纯化，得到白色固体137mg(化合物9)，收率35.03％。Dissolve raw material 8d (0.27g, 1mmol) in 10ml of DMF solution, then add (S)-2-amino-2-phenylethanol (0.14g, 1mmol) and HATU (0.57g, 1.5mmol), triethylamine (0.3g, 3mmol), stir overnight at room temperature, add 50ml of water to the reaction solution, then extract three times with ethyl acetate (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate and spin dry, column chromatography ( The eluent MeOH/DCM=1/10) was separated and purified to obtain 137 mg of a white solid (compound 9) with a yield of 35.03%.
LC-MS(ESI)：m/z＝392.4[M+H] +。 LC-MS (ESI): m/z=392.4 [M+H] + .
1H NMR(400MHz,CDCl 3)δ8.82-8.83(m,1H),8.25-8.26(s,1H),8.03-8.05(m,1H),7.52-7.54(m,1H),7.47-7.49(m,4H),7.35-7.37(m,1H),5.25-5.35(m,1H),4.01-4.04(m,2H),3.25-3.27(m,1H),3.05-3.07(m,1H),2.10-2.28(m,2H),1.55-1.77(m,2H),1.12-1.15(m,1H),0.81-0.85(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ8.82-8.83 (m, 1H), 8.25-8.26 (s, 1H), 8.03-8.05 (m, 1H), 7.52-7.54 (m, 1H), 7.47-7.49 (m,4H),7.35-7.37(m,1H),5.25-5.35(m,1H),4.01-4.04(m,2H),3.25-3.27(m,1H),3.05-3.07(m,1H) , 2.10-2.28 (m, 2H), 1.55-1.77 (m, 2H), 1.12-1.15 (m, 1H), 0.81-0.85 (m, 1H).
实施例10：Example 10:
3-((5aR,6aS)-3-((2-苯基丙烷-2-基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物10)3-((5aR,6aS)-3-((2-phenylpropan-2-yl)carbamyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1(4H) -Yl)pyrazine 1-oxide (compound 10)
3-((5aR,6aS)-3-((2-phenylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((2-phenylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000081
Figure PCTCN2020114451-appb-000081
第一步：3-((5aR，6aS)-3-((2-苯基丙烷-2-基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物10)The first step: 3-((5aR,6aS)-3-((2-phenylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole- 1(4H)-yl)pyrazine 1-oxide (Compound 10)
3-((5aR,6aS)-3-((2-phenylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((2-phenylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
将原料8d(0.27g,1mmol)溶解于10ml的DMF溶液中，然后加入2-苯丙-2-胺(0.14g,1mmol)以及HATU(0.57g,1.5mmol)，三乙胺(0.3g,3mmol)，常温搅拌过夜，加入50ml的水至反应液中，然后用乙酸乙酯(50mL×3)萃取三次，合并有机相，无水硫酸钠干燥旋干，柱层析(洗脱剂MeOH/DCM＝1/10)分离纯化，得到白色固体65mg(化合物10)，收率16.8％。The raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, and then 2-phenylpropan-2-amine (0.14g, 1mmol) and HATU (0.57g, 1.5mmol), triethylamine (0.3g, 3mmol), stir overnight at room temperature, add 50ml of water to the reaction solution, then extract three times with ethyl acetate (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate and spin dry, and column chromatography (eluent MeOH/ DCM=1/10) was separated and purified to obtain 65 mg of white solid (compound 10) with a yield of 16.8%.
LC-MS(ESI)：m/z＝390.45[M+H] +。 LC-MS (ESI): m/z=390.45 [M+H] + .
1H NMR(400MHz,CDCl 3)δ8.79-8.84(m,1H),8.25-8.27(s,1H),8.05-8.07(m,1H),7.45-7.48(m,1H),7.42-7.43(m,4H),7.36-7.39(m,1H),5.26-5.37(m,1H),4.02-4.11(m,2H),3.27-3.28(m,1H),3.05-3.11(m,2H),1.47-1.49(m,6H),1.11-1.19(m,1H),0.82-0.89(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 8.79-8.84 (m, 1H), 8.25-8.27 (s, 1H), 8.05-8.07 (m, 1H), 7.45-7.48 (m, 1H), 7.42-7.43 (m,4H),7.36-7.39(m,1H),5.26-5.37(m,1H),4.02-4.11(m,2H),3.27-3.28(m,1H),3.05-3.11(m,2H) , 1.47-1.49 (m, 6H), 1.11-1.19 (m, 1H), 0.82-0.89 (m, 1H).
实施例11：Example 11:
3-((5aR,6aS)-3-((2-甲基-1-吗啉代丙烷-2-基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物11)3-((5aR,6aS)-3-((2-Methyl-1-morpholinopropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]in Azol-1(4H)-yl)pyrazine 1-oxide (Compound 11)
3-((5aR,6aS)-3-((2-methyl-1-morpholinopropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((2-methyl-1-morpholinopropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000082
Figure PCTCN2020114451-appb-000082
将化合物8d(220mg,0.81mmol)溶解在DMF(10mL)中，室温下向其中加入HATU(400mg，1.1mmol)，DIPEA(2.0mL)，2-甲基-1-吗啉代丙烷-2-胺(256mg,1.62mmol)。室温下反应两个小时。稀盐酸调节至中性，二氯甲烷(50mL×3)萃取并合并有机相，无水硫酸钠干燥，减压除去溶剂，柱层析(洗脱剂MeOH/DCM＝1/10)分离纯化。得到化合物11(60mg,14.6％)。Compound 8d (220mg, 0.81mmol) was dissolved in DMF (10mL), HATU (400mg, 1.1mmol), DIPEA (2.0mL), 2-methyl-1-morpholinopropane-2- was added thereto at room temperature Amine (256 mg, 1.62 mmol). React at room temperature for two hours. Adjust the dilute hydrochloric acid to neutrality, extract with dichloromethane (50 mL×3) and combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and separate and purify by column chromatography (eluent MeOH/DCM=1/10). Compound 11 (60 mg, 14.6%) was obtained.
LC-MS(ESI)：m/z＝413.2[M+H] +。 LC-MS (ESI): m/z=413.2 [M+H] + .
1H NMR(400MHz,Chloroform-d)δ8.84(s,1H),8.25(dd,1H),7.98(dd,1H),3.75(s,4H),3.23(dd,1H),3.06(t,1H),2.67(s,6H),2.26(dd,1H),2.16(dd,1H),1.83–1.70(m,1H),1.66(d,2H),1.50(s,6H),1.13(t,1H),0.84(t,1H)。 1 H NMR (400MHz, Chloroform-d) δ 8.84 (s, 1H), 8.25 (dd, 1H), 7.98 (dd, 1H), 3.75 (s, 4H), 3.23 (dd, 1H), 3.06 (t ,1H),2.67(s,6H),2.26(dd,1H),2.16(dd,1H),1.83-1.70(m,1H),1.66(d,2H),1.50(s,6H),1.13( t,1H),0.84(t,1H).
中间体合成8d和4a-1：Intermediate synthesis 8d and 4a-1:
中间体化合物8d 3-(((5aR,6aS)-3-羧基-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物((5aR,6aS)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxideIntermediate compound 8d 3-(((5aR,6aS)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1(4H)-yl)pyrazine 1-oxide( (5aR,6aS)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
中间体化合物4a-1 3-(((5aS,6aR)-3-羧基-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物Intermediate compound 4a-1 3-(((5aS,6aR)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1(4H)-yl)pyrazine 1-oxidation Things
3-((5aS,6aR)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aS,6aR)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000083
Figure PCTCN2020114451-appb-000083
化合物4a(2g,7.35mmol)，手型制备分离得到化合物8d(0.56g,28％)，化合物4a-1(0.62g,31％)，制备色谱条件：色谱柱ChiralPak AD,250×30mm I.D.,10μm，流动相体系：二氧化碳/乙醇＝45/55(v)，流量80mL/min，得到化合物8d(出峰时间约为2.746min)，化合物4a-1(出峰时间约为3.790min)。Compound 4a (2g, 7.35mmol), prepared and separated by hand to obtain compound 8d (0.56g, 28%), compound 4a-1 (0.62g, 31%), preparative chromatographic conditions: column ChiralPak AD, 250×30mm ID, 10μm, mobile phase system: carbon dioxide/ethanol=45/55(v), flow rate 80mL/min, compound 8d (peak time is about 2.746min), compound 4a-1 (peak time is about 3.790min).
化合物8dCompound 8d
1H NMR(400MHz,CDCl 3)δ8.63-8.64(m,1H),8.32-8.41(m,1H),8.21-8.31(m,1H),2.95-3.03(m,2H),2.10-2.21(m,2H),1.664-1.68(m,2H),1.10-1.13(m,1H),0.83-0.87(m,1H)。 1H NMR (400MHz, CDCl 3 ) δ8.63-8.64 (m, 1H), 8.32-8.41 (m, 1H), 8.21-8.31 (m, 1H), 2.95-3.03 (m, 2H), 2.10-2.21 ( m, 2H), 1.664-1.68 (m, 2H), 1.10-1.13 (m, 1H), 0.83-0.87 (m, 1H).
化合物4a-1Compound 4a-1
1H NMR(400MHz,CDCl 3)δ8.73-8.62(m,1H),8.33-8.42(m,1H),8.23-8.32(m,1H),2.96-3.01(m,2H),2.11-2.23(m,2H),1.64-1.69(m,2H),1.11-1.12(m,1H),0.84-0.89(m,1H)。 1H NMR (400MHz, CDCl 3 ) δ 8.73-8.62 (m, 1H), 8.33-8.42 (m, 1H), 8.23-8.32 (m, 1H), 2.96-3.01 (m, 2H), 2.11-2.23 ( m, 2H), 1.64-1.69 (m, 2H), 1.11-1.12 (m, 1H), 0.84-0.89 (m, 1H).
实施例12：Example 12:
3-((5aR,6aS)-3-((1-甲氧基-2-甲基-1-氧丙烷-2-基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物12)3-((5aR,6aS)-3-((1-methoxy-2-methyl-1-oxopropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane [g]Indazole-1(4H)-yl)pyrazine 1-oxide (Compound 12)
3-((5aR,6aS)-3-((1-methoxy-2-methyl-1-oxopropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((1-methoxy-2-methyl-1-oxopropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H) -yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000084
Figure PCTCN2020114451-appb-000084
第一步:3-((5aR,6aS)-3-((1-甲氧基-2-甲基-1-氧丙烷-2-基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物The first step: 3-((5aR,6aS)-3-((1-methoxy-2-methyl-1-oxopropan-2-yl)carbamyl)-5,5a,6,6a- Tetrahydrocyclopropane[g]indazole-1(4H)-yl)pyrazine-1-oxide
3-((5aR,6aS)-3-((1-methoxy-2-methyl-1-oxopropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((1-methoxy-2-methyl-1-oxopropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H) -yl)pyrazine 1-oxide
将原料8d(0.27g，1mmol)溶解于10ml的DMF溶液中，然后加入2-氨基-2-甲基丙酸甲酯(0.17g,1mmol)以及HATU(0.57g,1.5mmol)，三乙胺(0.3g,3mmol)，常温搅拌过夜，加入50ml的水至反应 液中，然后用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，减压除去溶剂，柱层析(洗脱剂MeOH/DCM＝1/10)分离纯化，得到白色固体62mg(化合物12)，收率16.7％。Dissolve raw material 8d (0.27g, 1mmol) in 10ml of DMF solution, then add methyl 2-amino-2-methylpropionate (0.17g, 1mmol) and HATU (0.57g, 1.5mmol), triethylamine (0.3g, 3mmol), stir overnight at room temperature, add 50ml of water to the reaction solution, then extract with ethyl acetate (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and column chromatography (Eluent MeOH/DCM=1/10) separation and purification, 62 mg of white solid (compound 12) was obtained, with a yield of 16.7%.
LC-MS(ESI)：m/z＝372.4[M+H] +。 LC-MS (ESI): m/z=372.4 [M+H] + .
1H NMR(400MHz,CDCl 3)δ9.24-9.26(m,1H),8.41-8.44(m,2H),8.32-8.35(m,1H),3.6(s,3H),3.02-3.05(m,2H),2.05-2.16(m,2H),1.64-1.81(m,2H),1.48-1.63(m,6H),1.11-1.12(m,1H),0.883-0.86(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ9.24-9.26 (m, 1H), 8.41-8.44 (m, 2H), 8.32-8.35 (m, 1H), 3.6 (s, 3H), 3.02-3.05 (m , 2H), 2.05-2.16 (m, 2H), 1.64-1.81 (m, 2H), 1.48-1.63 (m, 6H), 1.11-1.12 (m, 1H), 0.883-0.86 (m, 1H).
实施例13：Example 13:
3-((5aR,6aS)-3-((2-氰基丙烷-2-基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物13)3-((5aR,6aS)-3-((2-cyanopropane-2-yl)carbamyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1(4H) -Yl)pyrazine 1-oxide (Compound 13)
3-((5aR,6aS)-3-((2-cyanopropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((2-cyanopropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000085
Figure PCTCN2020114451-appb-000085
第一步：3-((5aR，6aS)-3-((2-氰基丙烷-2-基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物The first step: 3-((5aR,6aS)-3-((2-cyanopropane-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole- 1(4H)-yl)pyrazine 1-oxide
3-((5aR,6aS)-3-((2-cyanopropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((2-cyanopropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
将原料8d(0.27g，1mmol)溶解于10ml的DMF溶液中，然后加入2-氨基-2-甲基丙腈(0.084g,1mmol)以及HATU(0.57g,1.5mmol)，三乙胺(0.3g,3mmol)，常温搅拌过夜，加入50ml的水至反应液中，然后用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，减压除去溶剂，柱层析(洗脱剂MeOH/DCM＝1/10)分离纯化，得到白色固体65mg(化合物13)，收率19.2％。The raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, and then 2-amino-2-methylpropionitrile (0.084g, 1mmol) and HATU (0.57g, 1.5mmol), triethylamine (0.3 g, 3mmol), stir overnight at room temperature, add 50ml of water to the reaction solution, then extract with ethyl acetate (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and column chromatography (wash (MeOH/DCM=1/10) was separated and purified to obtain 65 mg of white solid (Compound 13) with a yield of 19.2%.
LC-MS(ESI)：m/z＝339.36[M+H] +。 LC-MS (ESI): m/z=339.36 [M+H] + .
1H NMR(400MHz,CDCl 3)δ9.21-9.23(m,1H),8.42-8.45(m,1H),8.32-8.36(m,1H),8.30-8.31(m,1H),3.04-3.09(m,2H),2.50-2.51(m,2H),1.65-1.72(m,7H),1.10-1.13(m,1H),0.84-0.87(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ9.21-9.23 (m, 1H), 8.42-8.45 (m, 1H), 8.32-8.36 (m, 1H), 8.30-8.31 (m, 1H), 3.04-3.09 (m, 2H), 2.50-2.51 (m, 2H), 1.65-1.72 (m, 7H), 1.10-1.13 (m, 1H), 0.84-0.87 (m, 1H).
实施例14：Example 14:
((5aR,6aS)-3-((四氢-2H-吡喃-4-基)甲基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物14)((5aR,6aS)-3-((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1 (4H)-yl)pyrazine 1-oxide (Compound 14)
3-((5aR,6aS)-3-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl) pyrazine 1-oxide
Figure PCTCN2020114451-appb-000086
Figure PCTCN2020114451-appb-000086
第一步:3-((5aR,6aS)-3-((四氢-2H-吡喃-4-基)甲基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物The first step: 3-((5aR,6aS)-3-((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[ g)Indazole-1(4H)-yl)pyrazine 1-oxide
3-((5aR,6aS)-3-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl) pyrazine 1-oxide
将原料8d(0.27g,1mmol)溶解于10ml的DMF溶液中，然后加入(四氢-2H-吡喃-4-基)甲酰胺(0.115g,1mmol)以及HATU(0.57g,1.5mmol)，三乙胺(0.3g,3mmol)，常温搅拌过夜，加入50ml的水至反应液中，然后用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，减压除去溶剂，柱层析(洗脱剂MeOH/DCM＝1/10)分离纯化，得到白色固体75mg(化合物14)，收率20.3％。Dissolve the raw material 8d (0.27g, 1mmol) in 10ml of DMF solution, then add (tetrahydro-2H-pyran-4-yl)formamide (0.115g, 1mmol) and HATU (0.57g, 1.5mmol), Triethylamine (0.3g, 3mmol), stir overnight at room temperature, add 50ml of water to the reaction solution, then extract with ethyl acetate (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure. Column chromatography (eluent MeOH/DCM=1/10) was separated and purified to obtain 75 mg of white solid (Compound 14) with a yield of 20.3%.
LC-MS(ESI)：m/z＝370.42[M+H] +。 LC-MS (ESI): m/z=370.42 [M+H] + .
1H NMR(400MHz,CDCl 3)δ9.18-9.19(m,1H),8.47-8.62(m,2H),7.28-8.29(m,2H),3.75-3.81(m,2H),3.13-3.28(m,5H),2.06-2.17(m,2H),1.62-1.65(m,5H),1.08-1.11(m,3H),0.69-0.83(m,1H) 1 H NMR (400MHz, CDCl 3 ) δ 9.18-9.19 (m, 1H), 8.47-8.62 (m, 2H), 7.28-8.29 (m, 2H), 3.75-3.81 (m, 2H), 3.13-3.28 (m,5H),2.06-2.17(m,2H),1.62-1.65(m,5H),1.08-1.11(m,3H),0.69-0.83(m,1H)
实施例15：Example 15:
3-((5aR,6aS)-3-((四氢-2H-吡喃-4-基)氨苄基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物15)3-((5aR,6aS)-3-((tetrahydro-2H-pyran-4-yl)aminobenzyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1(4H )-Yl)pyrazine 1-oxide (Compound 15)
3-((5aR,6aS)-3-((tetrahydro-2H-pyran-4-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((tetrahydro-2H-pyran-4-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1- oxide
Figure PCTCN2020114451-appb-000087
Figure PCTCN2020114451-appb-000087
第一步：3-((5aR,6aS)-3-((四氢-2H-吡喃-4-基)氨苄基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物The first step: 3-((5aR,6aS)-3-((tetrahydro-2H-pyran-4-yl)aminobenzyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole -1(4H)-yl)pyrazine 1-oxide
3-((5aR,6aS)-3-((tetrahydro-2H-pyran-4-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((tetrahydro-2H-pyran-4-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1- oxide
将原料8d(0.27g,1mmol)溶解于10ml的DMF溶液中，然后加入四氢吡喃-4-胺(0.10g,1mmol)以及HATU(0.57g,1.5mmol)，三乙胺(0.3g,3mmol)，常温搅拌过夜，加入50ml的水至反应液中，然后用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，减压除去溶剂，柱层析(洗脱剂MeOH/DCM＝1/10)分离纯化，得到白色固体62mg(化合物15)，收率17.5％。The raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, and then tetrahydropyran-4-amine (0.10g, 1mmol) and HATU (0.57g, 1.5mmol), triethylamine (0.3g, 3mmol), stir overnight at room temperature, add 50ml of water to the reaction solution, then extract with ethyl acetate (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, column chromatography (eluent MeOH/DCM=1/10) was separated and purified to obtain 62 mg of a white solid (Compound 15) with a yield of 17.5%.
LC-MS(ESI)：m/z＝356.39[M+H] +。 LC-MS (ESI): m/z=356.39 [M+H] + .
1H NMR(400MHz,CDCl 3)δ9.12-9.19(m,1H),8.47-8.62(m,2H),7.28-8.29(m,2H),3.75-3.81(m,2H),3.13-3.28(m,5H),2.06-2.17(m,2H),1.62-1.67(m,5H),1.08-1.11(m,1H),0.69-0.83(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 9.12-9.19 (m, 1H), 8.47-8.62 (m, 2H), 7.28-8.29 (m, 2H), 3.75-3.81 (m, 2H), 3.13-3.28 (m, 5H), 2.06-2.17 (m, 2H), 1.62-1.67 (m, 5H), 1.08-1.11 (m, 1H), 0.69-0.83 (m, 1H).
实施例16：Example 16:
3-((5aR,6aS)-3-((1-(羟甲基)环丙基)氨甲酰)-5,5a,6,6a-四氢环丙基[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物16)3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropyl[g]indazole-1( 4H)-yl)pyrazine 1-oxide (Compound 16)
3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000088
Figure PCTCN2020114451-appb-000088
第一步：3-((5aR,6aS)-3-((1-(羟甲基)环丙基)氨甲酰)-5,5a,6,6a-四氢环丙基[g]吲唑-1(4H)-基)吡嗪1-氧化物The first step: 3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropyl[g]indole Azole-1(4H)-yl)pyrazine 1-oxide
3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
将原料8d(0.27g,1mmol)溶解于10ml的DMF溶液中，然后加入(1-氨基环丙基)甲醇(0.087g,1mmol)以及HATU(0.57g,1.5mmol)，三乙胺(0.3g,3mmol)，常温搅拌过夜，加入50ml的水至反应液中，然后用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，减压除去溶剂，柱层析(洗脱剂MeOH/DCM＝1/10)分离纯化，得到白色固体73mg(化合物16)，收率19.7％。Dissolve raw material 8d (0.27g, 1mmol) in 10ml of DMF solution, then add (1-aminocyclopropyl) methanol (0.087g, 1mmol) and HATU (0.57g, 1.5mmol), triethylamine (0.3g , 3mmol), stir overnight at room temperature, add 50ml of water to the reaction solution, and then extract with ethyl acetate (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, column chromatography (elution (MeOH/DCM=1/10) was separated and purified to obtain 73 mg of white solid (Compound 16) with a yield of 19.7%.
LC-MS(ESI)：m/z＝342.46[M+H] +。 LC-MS (ESI): m/z=342.46 [M+H] + .
1H NMR(400MHz,CDCl 3)δ9.18-9.19(m,1H),8.47-8.62(m,1H),8.28-8.29(m,1H),8.23-8.25(m,1H),4.67-4.70(m,1H),3.5-3.51(m,1H),3.03-3.08(m,2H),2.06-2.17(m,2H),1.62-1.65(m,2H),1.08-1.11(m,2H),0.69-0.83(m,5H)。 1 H NMR (400MHz, CDCl 3 ) δ 9.18-9.19 (m, 1H), 8.47-8.62 (m, 1H), 8.28-8.29 (m, 1H), 8.23-8.25 (m, 1H), 4.67-4.70 (m,1H),3.5-3.51(m,1H),3.03-3.08(m,2H),2.06-2.17(m,2H),1.62-1.65(m,2H),1.08-1.11(m,2H) ,0.69-0.83(m,5H).
实施例17：Example 17:
3-((5aR,6aS)-3-((2-(羟甲基)氧杂环丁-2-基)氨苄基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物17)3-((5aR,6aS)-3-((2-(hydroxymethyl)oxetan-2-yl)aminobenzyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole -1(4H)-yl)pyrazine 1-oxide (Compound 17)
3-((5aR,6aS)-3-((2-(hydroxymethyl)oxetan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((2-(hydroxymethyl)oxetan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1 -oxide
Figure PCTCN2020114451-appb-000089
Figure PCTCN2020114451-appb-000089
第一步：3-((5aR,6aS)-3-((2-(羟甲基)氧杂环丁-2-基)氨苄基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物The first step: 3-((5aR,6aS)-3-((2-(hydroxymethyl)oxetan-2-yl)aminobenzyl)-5,5a,6,6a-tetrahydrocyclopropane[ g)Indazole-1(4H)-yl)pyrazine 1-oxide
3-((5aR,6aS)-3-((2-(hydroxymethyl)oxetan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((2-(hydroxymethyl)oxetan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1 -oxide
将原料8d(0.27g，1mmol)溶解于10ml的DMF溶液中，然后加入(2-氨基氧杂环丁-2-基)甲醇(0.10g,1mmol)以及HATU(0.57g,1.5mmol)，三乙胺(0.3g,3mmol)，常温搅拌过夜，加入50ml的水至反应液中，然后用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，减压除去溶剂，柱层析(洗脱剂MeOH/DCM＝1/10)分离纯化，得到白色固体61mg(化合物17)，收率17.1％。The raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, and then (2-aminooxetan-2-yl)methanol (0.10g, 1mmol) and HATU (0.57g, 1.5mmol) were added. Ethylamine (0.3g, 3mmol), stir overnight at room temperature, add 50ml of water to the reaction solution, then extract with ethyl acetate (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure. Separation and purification by chromatography (eluent MeOH/DCM=1/10) yielded 61 mg of white solid (Compound 17) with a yield of 17.1%.
LC-MS(ESI)：m/z＝358.36[M+H] +。 LC-MS (ESI): m/z=358.36 [M+H] + .
1H NMR(400MHz,CDCl 3)δ0.85-0.87(m,1H),8.03-8.26(m,1H),8.00-8.02(m,1H),7.26-7.45(m,1H),4.68-4.84(m,2H),4.17(s,1H),3.04-3.27(m,2H),2.09-2.27(m,2H),1.68-1.76(m,5H),1.12-1.25(m,1H),0.85-0.86(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 0.85-0.87 (m, 1H), 8.03-8.26 (m, 1H), 8.00-8.02 (m, 1H), 7.26-7.45 (m, 1H), 4.68-4.84 (m,2H),4.17(s,1H),3.04-3.27(m,2H),2.09-2.27(m,2H),1.68-1.76(m,5H),1.12-1.25(m,1H),0.85 -0.86(m,1H).
实施例18：Example 18:
3-((5aR,6aS)-3-((1-苯基环丙基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物18)3-((5aR,6aS)-3-((1-phenylcyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1(4H)-yl ) Pyrazine 1-oxide (Compound 18)
3-((5aR,6aS)-3-((1-phenylcyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((1-phenylcyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000090
Figure PCTCN2020114451-appb-000090
第一步：3-((5aR,6aS)-3-((1-苯基环丙基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物The first step: 3-((5aR,6aS)-3-((1-phenylcyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1( 4H)-yl)pyrazine 1-oxide
3-((5aR,6aS)-3-((1-phenylcyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((1-phenylcyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
将原料8d(0.27g,1mmol)溶解于10ml的DMF溶液中，然后加入1-苯基环丙烷胺(0.13g,1mmol)以及HATU(0.57g,1.5mmol)，三乙胺(0.3g,3mmol)，常温搅拌过夜，加入50ml的水至反应液中，然后用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，减压除去溶剂，柱层析(洗脱剂MeOH/DCM＝1/10)分离纯化，得到白色固体66mg(化合物18)，收率17.0％。The raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, and then added 1-phenylcyclopropaneamine (0.13g, 1mmol) and HATU (0.57g, 1.5mmol), triethylamine (0.3g, 3mmol) ), stir overnight at room temperature, add 50ml of water to the reaction solution, then extract with ethyl acetate (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, column chromatography (eluent MeOH /DCM=1/10) was separated and purified to obtain 66 mg of white solid (Compound 18) with a yield of 17.0%.
LC-MS(ESI)：m/z＝388.43[M+H] +。 LC-MS (ESI): m/z=388.43 [M+H] + .
1H NMR(400MHz,CDCl 3)δ8.79-8.84(m,1H),8.25-8.27(m,1H),8.05-8.07(m,1H),8.56(s,1H),7.17-7.36(m,5H),3.22-3.28(m,1H),3.02-3.07(m,1H),2.00-2.28(m,2H),1.58-1.66(m,3H),1.36-1.38(m,3H),1.12-1.18(m,1H),0.82-0.89(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 8.79-8.84 (m, 1H), 8.25-8.27 (m, 1H), 8.05-8.07 (m, 1H), 8.56 (s, 1H), 7.17-7.36 (m ,5H),3.22-3.28(m,1H),3.02-3.07(m,1H),2.00-2.28(m,2H),1.58-1.66(m,3H),1.36-1.38(m,3H),1.12 -1.18 (m, 1H), 0.82-0.89 (m, 1H).
实施例19：Example 19:
3-((5aR,6aS)-3-((S)-2,3-二羟基丙基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物19)3-((5aR,6aS)-3-((S)-2,3-dihydroxypropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1( 4H)-yl)pyrazine 1-oxide (Compound 19)
3-((5aR,6aS)-3-(((S)-2,3-dihydroxypropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-(((S)-2,3-dihydroxypropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1- oxide
Figure PCTCN2020114451-appb-000091
Figure PCTCN2020114451-appb-000091
第一步：3-((5aR,6aS)-3-((S)-2,3-二羟基丙基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物The first step: 3-((5aR,6aS)-3-((S)-2,3-dihydroxypropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indole Azole-1(4H)-yl)pyrazine 1-oxide
3-((5aR,6aS)-3-(((S)-2,3-dihydroxypropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-(((S)-2,3-dihydroxypropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1- oxide
将原料8d(0.27g,1mmol)溶解于10ml的DMF溶液中，然后加入(S)-3-氨基丙烷-1,2-二醇(0.09g,1mmol)以及HATU(0.57g,1.5mmol)，三乙胺(0.3g,3mmol)，常温搅拌过夜，加入50ml的水至反应液中，然后用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，减压除去溶剂，柱层析(洗脱剂MeOH/DCM＝1/10)分离纯化，得到白色固体105mg(化合物19)，收率30.4％。Dissolve raw material 8d (0.27g, 1mmol) in 10ml of DMF solution, then add (S)-3-aminopropane-1,2-diol (0.09g, 1mmol) and HATU (0.57g, 1.5mmol), Triethylamine (0.3g, 3mmol), stir overnight at room temperature, add 50ml of water to the reaction solution, then extract with ethyl acetate (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure. Column chromatography (eluent MeOH/DCM=1/10) was separated and purified to obtain 105 mg of white solid (Compound 19) with a yield of 30.4%.
LC-MS(ESI)：m/z＝346.35[M+H] +。 LC-MS (ESI): m/z=346.35 [M+H] + .
1H NMR(400MHz,CDCl 3)δ8.94(s,1H),8.21-8.22(m,1H),8.002-8.03(m,1H),7.45-7.48(m,1H), 3.87-3.91(m,1H),3.64-3.64(m,4H),3.004-3.23(m,2H),2.16-2.43(m,2H),1.67-1.76(m,2H),1.15-1.16(m,2H),0.82-0.89(m,1H)。 1 H NMR(400MHz, CDCl 3 )δ8.94(s,1H), 8.21-8.22(m,1H), 8.002-8.03(m,1H),7.45-7.48(m,1H), 3.87-3.91(m ,1H),3.64-3.64(m,4H),3.004-3.23(m,2H),2.16-2.43(m,2H),1.67-1.76(m,2H),1.15-1.16(m,2H),0.82 -0.89(m,1H).
实施例：20Example: 20
3-((5aR,6aS)-3-((R)-1-羟基-4-甲基戊烷-2-基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪-1-氧化物(化合物20)3-((5aR,6aS)-3-((R)-1-hydroxy-4-methylpentan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane(g ]Indazole-1(4H)-yl)pyrazine-1-oxide (Compound 20)
3-((5aR,6aS)-3-(((R)-1-hydroxy-4-methylpentan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-(((R)-1-hydroxy-4-methylpentan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H) -yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000092
Figure PCTCN2020114451-appb-000092
第一步：3-((5aR,6aS)-3-((R)-1-羟基-4-甲基戊烷-2-基)氨甲酰)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪-1-氧化物The first step: 3-((5aR,6aS)-3-((R)-1-hydroxy-4-methylpentan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydro Cyclopropane[g]indazole-1(4H)-yl)pyrazine-1-oxide
3-((5aR,6aS)-3-(((R)-1-hydroxy-4-methylpentan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-(((R)-1-hydroxy-4-methylpentan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H) -yl)pyrazine 1-oxide
将原料8d(0.27g,1mmol)溶解于10ml的DMF溶液中，然后加入(R)-2-氨基-4-甲基戊-1-醇(0.12g,1mmol)以及HATU(0.57g,1.5mmol)，三乙胺(0.3g,3mmol)，常温搅拌过夜，加入50ml的水至反应液中，然后用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，减压除去溶剂，柱层析(洗脱剂MeOH/DCM＝1/10)分离纯化，得到白色固体84mg(化合物20)，收率22.6％。The raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, and then (R)-2-amino-4-methylpentan-1-ol (0.12g, 1mmol) and HATU (0.57g, 1.5mmol) were added ), triethylamine (0.3g, 3mmol), stir overnight at room temperature, add 50ml of water to the reaction solution, then extract with ethyl acetate (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, and remove under reduced pressure Solvent, separation and purification by column chromatography (eluent MeOH/DCM=1/10) to obtain 84 mg of white solid (Compound 20) with a yield of 22.6%.
LC-MS(ESI)：m/z＝372.43[M+H] +。 LC-MS (ESI): m/z=372.43 [M+H] + .
1H NMR(400MHz,CDCl 3)δ8.81-8.84(m,1H),8.25-8.27(m,1H),8.05-8.07(m,1H),6.91-7.03(m,1H),4.18-4.20(m,2H),3.65-3.80(m,1H),3.05-3.29(m,2H),1.98-2.29(m,5H),1.46-1.98(m,2H),0.82-1.15(m,8H)。 1 H NMR (400MHz, CDCl 3 ) δ8.81-8.84 (m, 1H), 8.25-8.27 (m, 1H), 8.05-8.07 (m, 1H), 6.91-7.03 (m, 1H), 4.18-4.20 (m,2H),3.65-3.80(m,1H),3.05-3.29(m,2H),1.98-2.29(m,5H),1.46-1.98(m,2H),0.82-1.15(m,8H) .
实施例21：Example 21:
3-((5aS,6aR)-3-((1-(羟甲基)环丙基)氨甲酰)-5,5a,6,6a-四氢环丙基[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物21)3-((5aS,6aR)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropyl[g]indazole-1( 4H)-yl)pyrazine 1-oxide (Compound 21)
3-((5aS,6aR)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aS,6aR)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000093
Figure PCTCN2020114451-appb-000093
第一步：3-((5aR,6aS)-3-((1-(羟甲基)环丙基)氨甲酰)-5,5a,6,6a-四氢环丙基[g]吲唑-1(4H)-基)吡嗪1-氧化物The first step: 3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropyl[g]indole Azole-1(4H)-yl)pyrazine 1-oxide
3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
将原料4a-1(0.27g,1mmol)溶解于10ml的DMF溶液中，然后加入21a(0.087g,1mmol)以及HATU(0.57g,1.5mmol)，三乙胺(0.3g,3mmol)，常温搅拌过夜，加入50ml的水至反应液中，然后用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥并旋干，柱层析(洗脱剂MeOH/DCM＝1/10)分离纯化，得到白色固体70mg(化合物21)，收率20.5％。Dissolve raw material 4a-1 (0.27g, 1mmol) in 10ml of DMF solution, then add 21a (0.087g, 1mmol) and HATU (0.57g, 1.5mmol), triethylamine (0.3g, 3mmol), stir at room temperature Overnight, 50ml of water was added to the reaction solution, and then extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate and spin-dried, column chromatography (eluent MeOH/DCM=1/10 ) Isolation and purification to obtain 70 mg of white solid (Compound 21) with a yield of 20.5%.
LC-MS(ESI)：m/z＝342.2[M+H] +。 LC-MS (ESI): m/z=342.2 [M+H] + .
1H NMR(400MHz,CDCl 3)δ9.18-9.19(m,1H),8.62(s,1H),8.28-8.29(m,1H),8.23-8.25(m,1H),4.67-4.70(m,1H),3.5-3.51(m,1H),3.03-3.08(m,2H),2.06-2.17(m,2H),1.62-1.65(m,2H),1.08-1.11(m,2H),0.69-0.83(m,5H)。 1 H NMR (400MHz, CDCl 3 ) δ 9.18-9.19 (m, 1H), 8.62 (s, 1H), 8.28-8.29 (m, 1H), 8.23-8.25 (m, 1H), 4.67-4.70 (m ,1H),3.5-3.51(m,1H),3.03-3.08(m,2H),2.06-2.17(m,2H),1.62-1.65(m,2H),1.08-1.11(m,2H),0.69 -0.83(m,5H).
实施例22：Example 22:
3-(((5aS,6aR)-3-((1-(三氟甲基)环丙基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物22a)3-(((5aS,6aR)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1 (4H)-yl)pyrazine 1-oxide (Compound 22a)
((5aS,6aR)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide((5aS,6aR)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
3-(((5aR,6aS)-3-((1-(三氟甲基)环丙基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物22b)3-(((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1 (4H)-yl)pyrazine 1-oxide (Compound 22b)
3-((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
Figure PCTCN2020114451-appb-000094
Figure PCTCN2020114451-appb-000094
第一步：3-(3-((1-(三氟甲基)环丙基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物22)The first step: 3-(3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1(4H) -Yl)pyrazine 1-oxide (Compound 22)
3-(3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-(3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
将原料4a(400g,1.47mol)溶解于5L的DMF溶液中，然后加入1-三氟甲基环丙胺盐酸盐(183.8g,1.47mmol)以及HATU(670.3g,1.76mol)，三乙胺(445.41g,4.4mmol)，常温搅拌2小时，将反应液加入10L的冰水中，搅拌半小时，然后抽滤，得到的固体用水洗涤三次，烘干以后得到白色固体372g(化合物22)，收率66.8％。Dissolve raw material 4a (400g, 1.47mol) in 5L of DMF solution, then add 1-trifluoromethylcyclopropylamine hydrochloride (183.8g, 1.47mmol) and HATU (670.3g, 1.76mol), triethylamine (445.41g, 4.4mmol), stirred at room temperature for 2 hours, the reaction solution was added to 10L of ice water, stirred for half an hour, then suction filtered, the obtained solid was washed with water three times, after drying to obtain 372g of white solid (compound 22), yield The rate is 66.8%.
LC-MS(ESI)：m/z＝380.3[M+H] +。 LC-MS (ESI): m/z=380.3 [M+H] + .
1H NMR(400MHz,CDCl 3)δ8.83-8.91(m,1H),8.24-8.27(m,1H),8.01-8.03(m,1H),7.40(s,1H),3.22-3.27(m,1H),3.03-3.08(m,1H),1.67-1.76(m,2H),1.57-1.65(m,2H),1.42-1.47(m,2H),1.24-1.28(m,2H),1.23-1.26(m,1H),0.82-0.86(m,1H)。 1H NMR (400MHz, CDCl 3 ) δ8.83-8.91 (m, 1H), 8.24-8.27 (m, 1H), 8.01-8.03 (m, 1H), 7.40 (s, 1H), 3.22-3.27 (m, 1H),3.03-3.08(m,1H),1.67-1.76(m,2H),1.57-1.65(m,2H),1.42-1.47(m,2H),1.24-1.28(m,2H),1.23- 1.26 (m, 1H), 0.82-0.86 (m, 1H).
第二步：3-(((5aS,6aR)-3-((1-(三氟甲基)环丙基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物22a)The second step: 3-(((5aS,6aR)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane [g] Indazole-1(4H)-yl)pyrazine 1-oxide (Compound 22a)
((5aS,6aR)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide((5aS,6aR)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
3-(((5aR,6aS)-3-((1-(三氟甲基)环丙基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪1-氧化物(化合物22b)3-(((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1 (4H)-yl)pyrazine 1-oxide (Compound 22b)
3-((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
化合物22(372g,0.98mol)，手型制备分离得到化合物22a(145g,39.4％)，化合物22b(150g,40.4％)，制备色谱条件：色谱柱ChiralCel OJ,300×50mm I.D.,10μm，流动相体系：二氧化碳/乙醇＝65/35(v)，流量200mL/min，得到化合物22a(出峰时间约为2.746min)，化合物22b(出峰时间约为3.790min，与化合物8相同)。Compound 22 (372g, 0.98mol), prepared and separated by hand to obtain compound 22a (145g, 39.4%), compound 22b (150g, 40.4%), preparative chromatographic conditions: column ChiralCel OJ, 300×50mm ID, 10μm, mobile phase System: carbon dioxide/ethanol=65/35(v), flow rate 200mL/min, compound 22a (peak time is about 2.746min), compound 22b (peak time is about 3.790min, same as compound 8).
化合物22aCompound 22a
1H NMR(400MHz,CDCl 3)δ8.90-8.92(m,1H),8.223-8.24(m,1H),8.01-8.03(m,1H),7.40(s,1H),3.22-3.27(m,1H),3.03-3.07(m,1H),1.67-1.76(m,2H),1.57-1.62(m,2H),1.42-1.43(m,2H),1.24-1.26(m,2H),1.23-1.24(m,1H),0.82-0.86(m,1H)。 1H NMR (400MHz, CDCl 3 ) δ 8.90-8.92 (m, 1H), 8.223-8.24 (m, 1H), 8.01-8.03 (m, 1H), 7.40 (s, 1H), 3.22-3.27 (m, 1H),3.03-3.07(m,1H),1.67-1.76(m,2H),1.57-1.62(m,2H),1.42-1.43(m,2H),1.24-1.26(m,2H),1.23- 1.24 (m, 1H), 0.82-0.86 (m, 1H).
化合物22bCompound 22b
1H NMR(400MHz,CDCl 3)δ8.90-8.91(m,1H),8.223-8.24(m,1H),8.01-8.03(m,1H)7.40(s,1H),3.22-3.27(m,1H),3.04-3.08(m,1H),1.67-1.77(m,2H),1.57-1.62(m,2H),1.42-1.43(m,2H),1.24-1.28(m,2H),1.23-1.25(m,1H),0.82-0.86(m,1H)。 1H NMR (400MHz, CDCl 3 ) δ 8.90-8.91 (m, 1H), 8.223-8.24 (m, 1H), 8.01-8.03 (m, 1H) 7.40 (s, 1H), 3.22-3.27 (m, 1H) ),3.04-3.08(m,1H),1.67-1.77(m,2H),1.57-1.62(m,2H),1.42-1.43(m,2H),1.24-1.28(m,2H),1.23-1.25 (m, 1H), 0.82-0.86 (m, 1H).
实施例23Example 23
3-((5aR,6aS)-3-((1-羟基-2-甲基丙-2-基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪-1-氧化物(化合物23a)3-((5aR,6aS)-3-((1-hydroxy-2-methylprop-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole- 1(4H)-yl)pyrazine-1-oxide (Compound 23a)
((5aR,6aS)-3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine-1-oxide((5aR,6aS)-3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine-1 -oxide
Figure PCTCN2020114451-appb-000095
Figure PCTCN2020114451-appb-000095
将原料8d(1g,3.7mmol)溶解于10ml的DMF溶液中，然后加入2-氨基-2-甲基丙烷-1-醇(0.33g,3.7mmol)以及HATU(1.7g,4.4mmol)，三乙胺(1.1g,11.1mmol)，常温搅拌过夜，加入100ml的水至反应液中，然后用乙酸乙酯(100mL×3)萃取，合并有机相，无水硫酸钠干燥并旋干，柱层析纯化(洗脱剂MeOH/DCM＝1/10)，得到淡黄色固体320mg(23a)，收率34.8％。The raw material 8d (1g, 3.7mmol) was dissolved in 10ml of DMF solution, and then 2-amino-2-methylpropane-1-ol (0.33g, 3.7mmol) and HATU (1.7g, 4.4mmol) were added. Ethylamine (1.1g, 11.1mmol), stir overnight at room temperature, add 100ml of water to the reaction solution, then extract with ethyl acetate (100mL×3), combine the organic phases, dry with anhydrous sodium sulfate and spin dry, column layer Analytical purification (eluent MeOH/DCM=1/10), 320 mg (23a) of pale yellow solid was obtained, with a yield of 34.8%.
LC-MS(ESI)：m/z＝344.3[M+H] +。 LC-MS (ESI): m/z=344.3 [M+H] + .
1H NMR(400MHz,CDCl 3)δ9.66-9.79(m,3H),8.03(s,1H),3.50-3.52(m,2H),2.75-2.85(m,2H),1.46-1.71(m,3H),1.38-1.40(m,6H),0.34-0.59(m,4H)。 1 H NMR (400MHz, CDCl 3 ) δ9.66-9.79 (m, 3H), 8.03 (s, 1H), 3.50-3.52 (m, 2H), 2.75-2.85 (m, 2H), 1.46-1.71 (m , 3H), 1.38-1.40 (m, 6H), 0.34-0.59 (m, 4H).
3-((5aS,6aR)-3-((1-羟基-2-甲基丙-2-基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪-1-氧化物(化合物23b)3-((5aS,6aR)-3-((1-hydroxy-2-methylprop-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazole- 1(4H)-yl)pyrazine-1-oxide (Compound 23b)
((5aS,6aR)-3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine-1-oxide((5aS,6aR)-3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine-1 -oxide
Figure PCTCN2020114451-appb-000096
Figure PCTCN2020114451-appb-000096
将原料4a-1(1g,3.7mmol)溶解于10ml的DMF溶液中，然后加入2-氨基-2-甲基丙烷-1-醇(0.33g,3.7mmol)以及HATU(1.7g,4.4mmol)，三乙胺(1.1g,11.1mmol)，常温搅拌过夜，加入100ml的水至反应液中，然后用乙酸乙酯(100mL×3)萃取，合并有机相，无水硫酸钠干燥并旋干，柱层析纯化(洗脱剂MeOH/DCM＝1/10)，得到淡黄色固体370mg(23b)，收率40.2％。Dissolve the raw material 4a-1 (1g, 3.7mmol) in 10ml of DMF solution, then add 2-amino-2-methylpropane-1-ol (0.33g, 3.7mmol) and HATU (1.7g, 4.4mmol) , Triethylamine (1.1g, 11.1mmol), stir overnight at room temperature, add 100ml of water to the reaction solution, then extract with ethyl acetate (100mL×3), combine the organic phases, dry with anhydrous sodium sulfate and spin dry. Purification by column chromatography (eluent MeOH/DCM=1/10) gave 370 mg (23b) of pale yellow solid with a yield of 40.2%.
LC-MS(ESI)：m/z＝344.3[M+H] +。 LC-MS (ESI): m/z=344.3 [M+H] + .
1H NMR(400MHz,CDCl 3)δ9.46-9.72(m,3H),8.07(s,1H),3.40-3.62(m,2H),2.65-2.75(m,2H),1.52-1.77(m,3H),1.39-1.42(m,6H),0.42-0.61(m,4H)。 1 H NMR (400MHz, CDCl 3 ) δ9.46-9.72 (m, 3H), 8.07 (s, 1H), 3.40-3.62 (m, 2H), 2.65-2.75 (m, 2H), 1.52-1.77 (m , 3H), 1.39-1.42 (m, 6H), 0.42-0.61 (m, 4H).
实施例24：Example 24:
3-((5aR,6aS)-3-(((R)-4,4,4-三氟-1-羟基-3,3-二甲基丁烷-2-基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪-1-氧代3-((5aR,6aS)-3-(((R)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5 ,5a,6,6a-Tetrahydrocyclopropane[g]indazole-1(4H)-yl)pyrazine-1-oxo
3-((5aR,6aS)-3-(((R)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-(((R)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a- tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
3-((5aR,6aS)-3-(((S)-4,4,4-三氟-1-羟基-3,3-二甲基丁烷-2-基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪-1-氧代3-((5aR,6aS)-3-(((S)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5 ,5a,6,6a-Tetrahydrocyclopropane[g]indazole-1(4H)-yl)pyrazine-1-oxo
3-((5aR,6aS)-3-(((S)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide(化合物24a和24b)3-((5aR,6aS)-3-(((S)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a- tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide (compounds 24a and 24b)
Figure PCTCN2020114451-appb-000097
Figure PCTCN2020114451-appb-000097
第一步：3-((5aR,6aS)-3-(((R)-4,4,4-三氟-1-羟基-3,3-二甲基丁烷-2-基)氨基甲酰基-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪-1-氧代The first step: 3-((5aR,6aS)-3-(((R)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)aminomethyl Acyl-5,5a,6,6a-tetrahydrocyclopropane[g]indazole-1(4H)-yl)pyrazine-1-oxo
3-((5aR,6aS)-3-(((R)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide3-((5aR,6aS)-3-(((R)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a- tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide
3-((5aR,6aS)-3-(((S)-4,4,4-三氟-1-羟基-3,3-二甲基丁烷-2-基)氨基甲酰基)-5,5a,6,6a-四氢环丙烷[g]吲唑-1(4H)-基)吡嗪-1-氧代3-((5aR,6aS)-3-(((S)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5 ,5a,6,6a-Tetrahydrocyclopropane[g]indazole-1(4H)-yl)pyrazine-1-oxo
3-((5aR,6aS)-3-(((S)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide(化合物24a和24b)3-((5aR,6aS)-3-(((S)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl)-5,5a,6,6a- tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide (compounds 24a and 24b)
氮气保护，室温下，向化合物8d(0.15g,0.55mmol)中依次加入DMF(3mL)，DIPEA(78mg,1.1mmol)，HATU(228mg,0.6mmol)，2-氨基-4,4,4-三氟-3,3-二甲丁烷-1-醇(int-1)(187mg,1.1mmol)，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(50mL×3)萃取，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，减压浓缩后得到残留物，即粗品，粗品经高效液相制备分离得到化合物24a，淡黄色固体(33mg,收率11.18％)和化合物24b，淡黄色固体(34mg,收率14.51％)。Under nitrogen protection, at room temperature, to compound 8d (0.15g, 0.55mmol) was added DMF (3mL), DIPEA (78mg, 1.1mmol), HATU (228mg, 0.6mmol), 2-amino-4,4,4- Trifluoro-3,3-dimethylbutan-1-ol (int-1) (187mg, 1.1mmol), stirred at room temperature for 3h. The reaction was quenched by adding saturated aqueous sodium bicarbonate (30 mL) to the reaction, extracted with ethyl acetate (50 mL×3), allowed to stand for separation, and the aqueous phase was extracted with dichloromethane (20 mL). After drying with sodium sulfate and concentrating under reduced pressure, the residue was obtained as the crude product. The crude product was prepared and separated by HPLC to obtain compound 24a, pale yellow solid (33mg, yield 11.18%) and compound 24b, pale yellow solid (34mg, yield 14.51%).
制备条件：Preparation conditions:
仪器：waters 2767制备液相；色谱柱：SunFire C18 5μm,19x250mm。样品用水溶解，用0.45μm滤头过滤，制成样品液。制备色谱条件：流动相A,B组成：流动相A：乙腈，流动相B：水(含1％TFA)。梯度洗脱，流动相A含量从5％-50％。流量12ml/min。洗脱时间15min。化合物24a：Rt＝8.46min，构型不确定；化合物24b：Rt＝9.05min，构型不确定。Instrument: waters 2767 preparation liquid phase; chromatographic column: SunFire C18 5μm, 19x250mm. The sample was dissolved in water and filtered with a 0.45μm filter to prepare a sample solution. Preparative chromatographic conditions: mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 1% TFA). Gradient elution, the content of mobile phase A ranges from 5% to 50%. The flow rate is 12ml/min. The elution time is 15min. Compound 24a: Rt=8.46min, the configuration is uncertain; Compound 24b: Rt=9.05min, the configuration is uncertain.
化合物24a：Compound 24a:
1H NMR(400MHz,CDCl 3)δ8.87(s,1H),8.30-8.29(m,1H),8.03-8.02(m,1H),7.24-7.21(m,1H),4.36-4.33(m,1H),4.02-3.98(m,1H),3.83-3.78(m,1H),3.26-3.20(m,1H),3.10-3.05(m,1H),2.33-2.15(m,3H),1.80-1.68(m,2H),1.30(s,3H),1.27(s,3H),1.18-1.13(m,1H),0.89-0.83(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ8.87 (s, 1H), 8.30-8.29 (m, 1H), 8.03-8.02 (m, 1H), 7.24-7.21 (m, 1H), 4.36-4.33 (m ,1H),4.02-3.98(m,1H),3.83-3.78(m,1H),3.26-3.20(m,1H),3.10-3.05(m,1H),2.33-2.15(m,3H),1.80 -1.68 (m, 2H), 1.30 (s, 3H), 1.27 (s, 3H), 1.18-1.13 (m, 1H), 0.89-0.83 (m, 1H).
LC-MS(ESI)：m/z＝426.2[M+H] +。 LC-MS (ESI): m/z=426.2 [M+H] + .
化合物24b：Compound 24b:
1H NMR(400MHz,CDCl 3)δ8.95(s,1H),8.33-8.32(m,1H),8.06-8.04(m,1H),7.27-7.25(m,1H),4.36-4.33(m,1H),4.03-3.99(m,1H),3.83-3.79(m,1H),3.26-3.21(m,1H),3.10-3.05(m,1H),2.31-2.15(m,3H),1.80-1.68(m,2H),1.30(s,3H),1.27(s,3H),1.18-1.13(m,1H),0.89-0.83(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ8.95 (s, 1H), 8.33-8.32 (m, 1H), 8.06-8.04 (m, 1H), 7.27-7.25 (m, 1H), 4.36-4.33 (m ,1H),4.03-3.99(m,1H),3.83-3.79(m,1H),3.26-3.21(m,1H),3.10-3.05(m,1H),2.31-2.15(m,3H),1.80 -1.68 (m, 2H), 1.30 (s, 3H), 1.27 (s, 3H), 1.18-1.13 (m, 1H), 0.89-0.83 (m, 1H).
LC-MS(ESI)：m/z＝426.2[M+H] +。 LC-MS (ESI): m/z=426.2 [M+H] + .
生物测试Biological test
1、CB2激动剂活性检测1. CB2 agonist activity detection
实验对象：本发明实施例化合物。Experimental object: Example compounds of the present invention.
实验方法：experimental method:
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WIN 55212-2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europium cryptate标记的cAMP抗体。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。 CHO cells expressing human CB2 were suspended in HBSS buffer (containing 20mM HEPES, pH=7.4), and 7.5×10 3 cells per well (cell density of 1.5×10 6 cells/mL) were seeded in the added sample (HBSS , The positive control WIN 55212-2 or different concentrations of the compound in the 384-well white board. Add the adenylate cyclase activator NKH 477 to the above 384-well plate at a final concentration of 3 μM. After incubating at 37°C for 10 minutes, the cells were lysed, and cAMP antibodies labeled with D2-labeled cAMP and europium cryptate were added. After incubating for 1 hour at room temperature, HTRF detection was performed with a microplate reader (Envison, Perkin Elmer) (λex=337nm, λem=620 and 665nm). Calculate the signal ratio Ratio (Signal 665/Signal 620*10 4 ), and the result is expressed as a percentage value relative to 100 nM WIN 55212-2, and the DoseResp function is used to fit the EC 50 value. The results are shown in Table 1.
表1 CB2受体活性Table 1 CB2 receptor activity
Figure PCTCN2020114451-appb-000098
Figure PCTCN2020114451-appb-000098
Figure PCTCN2020114451-appb-000099
Figure PCTCN2020114451-appb-000099
注：ND表示未测。Note: ND means not tested.
APD-371为专利文献WO2011025541化合物699。APD-371 is compound 699 in patent document WO2011025541.
结论：本发明化合物对于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3、4、8、22a对CB 2/CB 1受体显示了较高的选择性。 Conclusion: The compounds of the present invention show higher agonistic activity for CB 2 receptors. Some compounds, especially compounds 3, 4, 8, 22a, show higher selectivity for CB 2 /CB 1 receptors.
2、大鼠药代动力学测试2. Rat pharmacokinetic test
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。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.
实验对象：APD-371及本发明实施例化合物。Experimental subjects: APD-371 and the compounds of the examples of the present invention.
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。Test animals: Male SD rats, about 220 g, 6-8 weeks old, 6 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
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。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.
表2给药信息Table 2 Administration Information
Figure PCTCN2020114451-appb-000100
Figure PCTCN2020114451-appb-000100
Figure PCTCN2020114451-appb-000101
Figure PCTCN2020114451-appb-000101
*剂量以游离碱计。*Dose is based on free alkali.
取样sampling
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。Before and after the administration, 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.
G1组采集血浆时间点：0,2,5,15,30min,1,2,4,6,8,24h。Plasma collection time points in group G1: 0, 2, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h.
G2组采集血浆时间点：0,5,15,30min,1,2,4,6,8,24h。Plasma collection time points in group G2: 0,5,15,30min,1,2,4,6,8,24h.
分析检测前，所有样品存于-80℃。Before analysis and testing, all samples were stored at -80°C.
样品前处理Sample preparation
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。Take 30μL of plasma sample, standard curve and quality control sample, add 200μL of acetonitrile solution containing internal standard, vortex to mix, and centrifuge at 4℃, 12000rpm for 10min. Take 170 μL of the supernatant in a 96-well plate and analyze by LC-MS/MS. The injection volume is 5 μL.
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。The main pharmacokinetic parameters were analyzed with WinNonlin 8.0 software non-compartmental model. The experimental results are shown in Table 3.
表3化合物大鼠药代动力学Table 3 Compound rat pharmacokinetics
Figure PCTCN2020114451-appb-000102
Figure PCTCN2020114451-appb-000102
Figure PCTCN2020114451-appb-000103
Figure PCTCN2020114451-appb-000103
APD-371为专利文献WO2011025541化合物699。APD-371 is compound 699 in patent document WO2011025541.
结论：化合物4、7a、7b、8、22a、23a、23b，特别是化合物8、22a、23a，具有较好的生物利用度，具有良好的药代动力学特征。Conclusion: Compounds 4, 7a, 7b, 8, 22a, 23a, 23b, especially compounds 8, 22a, 23a, have good bioavailability and good pharmacokinetic characteristics.

Claims (23)

  1. 一种式(I)所示的三环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：A tricyclic pyrazole compound represented by formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs:
    Figure PCTCN2020114451-appb-100001
    Figure PCTCN2020114451-appb-100001
    其中，among them,
    R 1选自-L 1-L 2-L 3-L 4； R 1 is selected from -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 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 1-6 alkyl, benzene ring, -C 1-6 alkyl-O-haloalkyl, -C(O)OC 1-6 alkyl or C 3-6 cycloalkane base;
    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 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选自C 1-6亚烷基或者不存在； L 3 is selected from C 1-6 alkylene or absent;
    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、C 1-6烷基-OH、C 6-10芳基或者C 1-6烷氧基； 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, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkynyl, bridged ring, spiro ring, and double ring Optionally substituted by the following substituents: halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-OH, C 6-10 aryl or C 1- 6 alkoxy;
    X为CR 2’R 2、NR 3或者O； X is CR 2 'R 2, NR 3 or O;
    R 2、R 2’选自H、卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或者C 1-6烷氧基；或者 R 2 and R 2'are selected from H, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy; or
    R 2与R 4或者R 3与R 4形成3至6元环且C环不存在，所述的环任选进一步被以下取代基取代： 卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或者C 1-6烷氧基； R 2 and R 4 or R 3 and R 4 form a 3- to 6-membered ring and the C ring does not exist. The ring may be further substituted by the following substituents: halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy;
    R 3选自H或者C 1-6烷基； R 3 is selected from H or C 1-6 alkyl;
    C环为3至6元环，所述环任选被0至3个R 7取代； The C ring is a 3 to 6 membered ring, and the ring is optionally substituted with 0 to 3 R 7 ;
    R 7各自独立选自F、Cl、羟基、C 1-6烷基、氰基、C 1-6烷氧基或者C 1-6卤代烷基； R 7 is each independently selected from F, Cl, hydroxyl, C 1-6 alkyl, cyano, C 1-6 alkoxy or C 1-6 haloalkyl;
    R 4、R 5、R 6、R 9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；或者 R 4 , R 5 , R 6 , and R 9 are each independently selected from H, F, Cl, amino, cyano, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl; or
    R 5、R 6形成3至6元环，且C环不存在； R 5 and R 6 form a 3- to 6-membered ring, and the C ring does not exist;
    R 10选自H或者C 1-6烷基； R 10 is selected from H or C 1-6 alkyl;
    R 11选自-(CH 2) m-C 6-10芳基、-(CH 2) m-C 5-10杂芳基、-(CH 2) m-C 3-6杂环基，所述的芳基、杂环基或杂芳基任选被以下取代基取代：F、Cl、羟基、氰基、氨基、C 1-6烷基或者C 1-6烷氧基，所述的杂芳基包含1-3个选自N、O、S杂原子及其氧化态； R 11 is selected from -(CH 2 ) m -C 6-10 aryl, -(CH 2 ) m -C 5-10 heteroaryl, -(CH 2 ) m -C 3-6 heterocyclic group, said The aryl, heterocyclic or heteroaryl group is optionally substituted by the following substituents: F, Cl, hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy, the heteroaryl The base contains 1-3 heteroatoms selected from N, O, S and their oxidation states;
    m选自0、1、2、3、4或者5；m is selected from 0, 1, 2, 3, 4 or 5;
    条件是：C环不为取代或未取代杂芳基。The condition is that the C ring is not a substituted or unsubstituted heteroaryl group.
  2. 根据权利要求1所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs thereof according to claim 1, wherein:
    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、C 1-6烷基、羟基取代的C 1-6烷基、卤代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；或者 R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 3-6 unsaturated cyclic hydrocarbon group, C 6-10 aryl, C 5-10 heteroaryl , C 4-12 bridged ring, C 4-12 parallel ring, C 5-10 spiro ring, the alkyl group, cycloalkyl group, unsaturated cyclic hydrocarbon group, heterocyclic group, aryl group, heteroaryl group, bridged ring , And ring or spiro ring is optionally substituted by the following substituents: F, Cl, hydroxy, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 Alkoxy, C 3-6 heterocyclyl, benzene ring, -C(O)OC 1-6 alkyl or C 3-6 cycloalkyl; or
    R 1选自C 1-6烷基、C 3-6环烷基，所述的烷基、环烷基任选被以下取代基取代：F、Cl、羟基、卤代C 1-6烷基、羟基取代的C 1-6烷基、苯基。 R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, said alkyl and cycloalkyl are optionally substituted by the following substituents: F, Cl, hydroxy, halogenated C 1-6 alkyl , Hydroxy substituted C 1-6 alkyl, phenyl.
  3. 根据权利要求2所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs thereof according to claim 2, wherein:
    R 1选自
    Figure PCTCN2020114451-appb-100002
    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 PCTCN2020114451-appb-100003
    Figure PCTCN2020114451-appb-100004
    Figure PCTCN2020114451-appb-100005
    或者     R 1 is selected from
    Figure PCTCN2020114451-appb-100002
    Indolyl, pyrrolyl, pyridyl, piperidinyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, adamantyl, piperazine, morpholinyl,
    Figure PCTCN2020114451-appb-100003
    Figure PCTCN2020114451-appb-100004
    Figure PCTCN2020114451-appb-100005
    or
    R 1选自
    Figure PCTCN2020114451-appb-100006
    或者R 1选自
    Figure PCTCN2020114451-appb-100007
    R 1 is selected from
    Figure PCTCN2020114451-appb-100006
    Or R 1 is selected from
    Figure PCTCN2020114451-appb-100007
  4. 根据权利要求1所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs according to claim 1, wherein:
    X为CR 2’R 2或者O； X is CR 2 'R 2 or O;
    R 2、R 2’选自H、卤素、C 1-6烷基或者C 1-6卤代烷基。 R 2 and R 2'are selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl.
  5. 根据权利要求4所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs thereof according to claim 4, wherein:
    X为CR 2’R 2； X is CR 2 'R 2;
    R 2、R 2’选自H、F、甲基、氟代甲基，优选H。 R 2 and R 2'are selected from H, F, methyl and fluoromethyl, preferably H.
  6. 根据权利要求1所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs according to claim 1, wherein:
    C环为3至6元环烷烃、3至6元环烯烃或者3至6元杂环，所述环烷烃、环烯烃、杂环任选被0至3个R 7取代； The C ring is a 3 to 6 membered cycloalkane, a 3 to 6 membered cycloalkene, or a 3 to 6 membered heterocycle, and the cycloalkane, cycloalkene, and heterocycle are optionally substituted with 0 to 3 R 7 ;
    R 7各自独立选自F、Cl、羟基、C 1-6烷基、氰基、C 1-6烷氧基或者C 1-6卤代烷基。 R 7 is each independently selected from F, Cl, hydroxyl, C 1-6 alkyl, cyano, C 1-6 alkoxy, or C 1-6 haloalkyl.
  7. 根据权利要求6所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs thereof according to claim 6, wherein:
    C环为环丙烷、环丁烷或者环戊烷，所述环丙烷、环丁烷或者环戊烷任选被0至2个R 7取代，优选C环为环丙基、环丁基； C ring is a cyclopropane, cyclobutane or cyclopentane, a cyclopropane, cyclobutane or cyclopentane is optionally substituted with 0-2 R, C ring is preferably cyclopropyl, cyclobutyl;
    R 7各自独立选自F。 Each R 7 is independently selected from F.
  8. 根据权利要求1所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs according to claim 1, wherein:
    R 4、R 5、R 6、R 9各自独立选自H或者C 1-6烷基；或者 R 4 , R 5 , R 6 , and R 9 are each independently selected from H or C 1-6 alkyl; or
    R 5、R 6形成环丙烷，且C环不存在。 R 5 and R 6 form cyclopropane, and the C ring does not exist.
  9. 根据权利要求1所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs according to claim 1, wherein:
    R 11选自C 5-10芳基或者C 5-10杂芳基，所述的芳基或杂芳基任选被以下取代基取代：F、Cl或者C 1-6烷基，所述的杂芳基包含1-3个选自N、O、S杂原子及其氧化态。 R 11 is selected from C 5-10 aryl or C 5-10 heteroaryl, said aryl or heteroaryl is optionally substituted by the following substituents: F, Cl or C 1-6 alkyl, said The heteroaryl group contains 1-3 heteroatoms selected from N, O, S and their oxidation states.
  10. 根据权利要求9所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs thereof according to claim 9, wherein:
    R 11选自
    Figure PCTCN2020114451-appb-100008
    或者
    Figure PCTCN2020114451-appb-100009
    优选R 11选自
    Figure PCTCN2020114451-appb-100010
    R 11 is selected from
    Figure PCTCN2020114451-appb-100008
    or
    Figure PCTCN2020114451-appb-100009
    Preferably R 11 is selected from
    Figure PCTCN2020114451-appb-100010
  11. 根据权利要求1所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs thereof according to claim 1, wherein:
    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、卤代C 1-6烷基、羟基取代的C 1-6烷基或者羟基； 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, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl or hydroxy;
    X为CR 2’R 2或者O； X is CR 2 'R 2 or O;
    R 2、R 2’选自H、F、甲基或者氟代甲基； R 2 and R 2'are selected from H, F, methyl or fluoromethyl;
    C环为环丙烷、环丁烷或者环戊烷，所述环丙烷、环丁烷或者环戊烷任选被0至2个R 7取代； Ring C is cyclopropane, cyclobutane or cyclopentane, and the cyclopropane, cyclobutane or cyclopentane is optionally substituted with 0 to 2 R 7 ;
    R 7各自独立选自F； R 7 is each independently selected from F;
    R 4、R 5、R 9各自独立选自H； R 4 , R 5 , and R 9 are each independently selected from H;
    R 6选自H或者甲基；或者 R 6 is selected from H or methyl; or
    R 5、R 6形成环丙烷，且C环不存在； R 5 and R 6 form cyclopropane, and the C ring does not exist;
    R 10选自H； R 10 is selected from H;
    R 11选自
    Figure PCTCN2020114451-appb-100011
    或者
    Figure PCTCN2020114451-appb-100012
    R 11 is selected from
    Figure PCTCN2020114451-appb-100011
    or
    Figure PCTCN2020114451-appb-100012
  12. 根据权利要求1所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs thereof according to claim 1, wherein:
    R 1选自
    Figure PCTCN2020114451-appb-100013
    或者
    Figure PCTCN2020114451-appb-100014
    R 1 is selected from
    Figure PCTCN2020114451-appb-100013
    or
    Figure PCTCN2020114451-appb-100014
    X为CR 2’R 2； X is CR 2 'R 2;
    R 2、R 2’选自H； R 2 and R 2'are selected from H;
    C环为环丙烷、环丁烷或者环戊烷，所述环丙烷、环丁烷或者环戊烷任选被0至2个R 7取代； Ring C is cyclopropane, cyclobutane or cyclopentane, and the cyclopropane, cyclobutane or cyclopentane is optionally substituted with 0 to 2 R 7 ;
    R 7各自独立选自F； R 7 is each independently selected from F;
    R 4、R 5、R 9各自独立选自H； R 4 , R 5 , and R 9 are each independently selected from H;
    R 6选自H或甲基； R 6 is selected from H or methyl;
    R 10选自H； R 10 is selected from H;
    R 11选自
    Figure PCTCN2020114451-appb-100015
    R 11 is selected from
    Figure PCTCN2020114451-appb-100015
  13. 根据权利要求1所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs according to claim 1, wherein the compound structure is as follows:
    Figure PCTCN2020114451-appb-100016
    Figure PCTCN2020114451-appb-100016
    Figure PCTCN2020114451-appb-100017
    Figure PCTCN2020114451-appb-100017
  14. 根据权利要求13所述的三环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：The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs according to claim 13, wherein the compound structure is as follows:
    Figure PCTCN2020114451-appb-100018
    Figure PCTCN2020114451-appb-100018
    Figure PCTCN2020114451-appb-100019
    Figure PCTCN2020114451-appb-100019
  15. 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14中任一项所述通式(I)所示的三环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。A pharmaceutical composition comprising: an effective dose of the tricyclic pyrazole compound represented by the general formula (I) according to any one of claims 1 to 14 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.
  16. 权利要求1至14中任一项所述通式(I)所示的三环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15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。The tricyclic pyrazole compound represented by the general formula (I) according to any one of claims 1 to 14 and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or pro- The use of the medicine or the composition of claim 15 in the preparation of a medicine for treating diseases mediated by CB2 receptors.
  17. 根据权利要求16所述的用途，由CB2受体介导的疾病为疼痛。The use according to claim 16, wherein the disease mediated by the CB2 receptor is pain.
  18. 根据权利要求17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。The use according to claim 17, wherein the pain is selected from the group consisting of: bone pain, arthralgia, muscle pain, toothache, migraine, headache, inflammatory pain, neuropathic pain, Crohn’s disease-related abdominal pain, and dysfunction due to therapeutic agents 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.
  19. 根据权利要求18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。The use according to claim 18, wherein the pain is selected from neuropathic pain and Crohn's disease-related abdominal pain.
  20. 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14中任一项所述通式(I)所示的三环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15所述的组合物。A method for treating CB2 receptor-mediated diseases, the method comprising administering the tricyclic pyrazole compound represented by the general formula (I) and its stereoisomers, A pharmaceutically acceptable salt, solvate, hydrate, N-oxide or prodrug or the composition of claim 15.
  21. 根据权利要求20所述的方法，其中由CB2受体介导的疾病为疼痛。The method according to claim 20, wherein the disease mediated by the CB2 receptor is pain.
  22. 根据权利要求21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。The method according to claim 21, wherein the pain is selected from the group consisting of: 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, HIV-related neuropathy, sciatica and autoimmune diseases.
  23. 根据权利要求22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。The method according to claim 22, wherein the pain is selected from the group consisting of neuropathic pain and Crohn's disease-related abdominal pain.
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