TWI768464B - Tricyclic pyrazole derivatives and their preparation - Google Patents

Abstract

The present invention discloses a tricyclic pyrazole compound represented by formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides, prodrugs and pharmaceutical compositions, preparations thereof Methods, and use in the prevention and treatment of diseases mediated by cannabinoid CB2 receptors.

Description

Tricyclic pyrazole derivatives and their preparation

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, as well as in the preparation of cannabis Use in the prevention and treatment of CB2 receptor-mediated diseases.

Neuropathic pain results from damage to peripheral or central nerve pathways, resulting in persistent spontaneous pain and hypersensitivity to pain and innocuous stimuli. The underlying etiologies of neuropathic pain vary widely but generally 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 increasing and is expected to increase further in the aging population. In addition to personal distress, increased treatment costs due to unemployment and social incapacity are 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, and recurrent anal fistulas or other extraintestinal manifestations. Drug therapy includes aminosalicylic acid preparations, glucocorticoids, immunosuppressants, antibiotics and anti-TNF-α monoclonal antibodies. There are currently no medications to manage abdominal pain associated with Crohn's disease.

Pain is one of the most common clinical symptoms and one of the main factors for patients to seek medical services. Currently, the widely used analgesics on the market can cause harmful side effects and unsatisfactory treatment effects. The development of new painkillers is urgent.

Cannabis extracts have been used for pain relief for centuries. In addition to Delta-9-THC, cannabidiol (CBD), there are a variety of endogenous ligand substances, as well as chemically synthesized cannabinoids, It exerts analgesic and euphoric effects by binding to cannabinoid receptors. And cannabinoids are a class of extracellular signaling molecules found in both plants and animals. Signaling from these molecules is mediated in animals through two G protein-coupled receptors, cannabinoid receptor 1 (CBl) and cannabinoid receptor 2 (CB2). CB1 is most abundantly expressed in neural members of the CNS, but is also present at lower concentrations in various peripheral tissues and cells (Matsuda, L.A. et al. (1990) Nature 346:561-564). In contrast, CB2 is predominantly, but not exclusively, 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. et al. (2006) Pharmacol. Rev. 58(3): 389-462). Central CB1 is distributed in the cerebral cortex and limbic system and is responsible for exerting analgesic effects and causing behavioral changes after cannabinoid priming. Although CB1 can mediate potent analgesic effects, it can cause psychotic symptoms such as euphoria, ataxia, and dizziness, and 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 inflammatory signaling. In addition, CB2 is also distributed in peripheral nerve fibers and nociceptive nerve endings. After CB2 activation, it exerts analgesic effect by inhibiting the production of toxins and inflammatory mediators by neutrophils and macrophages, and can also block the excitation conduction of injured nerves. CB2 is expressed in the brainstem, cerebral cortex and cerebellum of mice, but the expression is very low, about 3.4% of the spleen.

Currently, there are CN10259613, CN101014605, WO2006129178, US20090081123 on the research on acting on CB2 receptors.

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 were discontinued in the analgesic field due to insufficient analgesic efficacy in clinical trials, including JBT-101, LY2828360, etc. The reasons may be as follows: Although it exhibits a certain selectivity, it still has an agonistic effect on CB1, so it may lead to adverse events at effective doses, and the drug effect is insufficient at a safe dose; the agonistic effect on CB1 may lead to significant drug effects in animal models. Insufficient drug effect after transformation. CB2 agonists will have functional selectivity. The downstream of CB1/2 includes adenosyl cyclase synthesis, ERK signaling pathway activation, ion current changes, internalization, β-arrestin, etc. Different drugs have functional biases for downstream activation. .

The purpose of the present invention is to introduce a class of cannabinoid CB2 agonists with novel structure, efficacy, safety, high selectivity and good pharmacokinetic characteristics.

The present invention relates to a tricyclic pyrazole compound represented by formula (I) and its stereoisomer, pharmaceutically acceptable salt, solvate, hydrate, N-oxide or prodrug:

Wherein, 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 group, C _3-6 heterocyclic group, C _6-10 arylene group, C _5-10 heteroarylene group, C _4-12 bridged ring, C _4-12 parallel ring, C _5-10 spiro rings or absent, the alkylene, cycloalkenylene, cycloalkylene, unsaturated cycloalkylene, heterocyclylene, arylene, heteroarylene, bridged ring, and The ring and spiro ring are each independently optionally substituted by 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 cycloalkyl; 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 absent, the alkylene, cycloalkylene, hetero The cyclic group and the heteroarylene group 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 , amine group, ureido group, cyano group, C _1-6 alkyl group, C _3-7 cycloalkyl group, C _1-6 alkoxy group, C _3-6 heterocyclic group, C _2-6 alkynyl group, 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 cyclic ring or C _5-10 Spiro, the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkynyl, bridged, spiro, and parallel are optionally substituted by the following substituents: Halogen, cyano, hydroxyl, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkyl-OH, C _6-10 aryl or C _1-6 alkoxy; X is CR ^2' R ² , NR ³ or O; R ² , R ^2' are selected from H, halogen, cyano, hydroxyl, 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 is optionally further substituted by the following substituents: halogen, cyano, Hydroxy, C _1-6 alkyl, C _1-6 haloalkane base, C _1-6 haloalkoxy or C _1-6 alkoxy; R ³ is selected from H or C _1-6 alkyl; C ring is a 3- to 6-membered ring, and the ring 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 , 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 form a 3- to 6-membered ring, and 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 heterocyclyl, said aryl, heterocyclyl or heteroaryl is optionally substituted by the following substituents: F, Cl, hydroxyl, cyano, amino, C _1-6 alkyl or C _1-6 alkoxy, the heteroaryl group contains 1-3 heteroatoms selected from N, O, S and their oxidation states; m is selected from 0, 1, 2, 3, 4 or 5; the condition is : C ring is not substituted or unsubstituted heteroaryl.

In certain embodiments, the C ring is a 3- to 6-membered ring optionally substituted with 0 to 3 ^R7 .

In certain embodiments, R ¹ is selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl, C _4-12 bridged ring, C _4-12 parallel ring, C _5-10 spiro ring, the said Alkyl, cycloalkyl, bridged, paracyclic or spiro rings are optionally substituted with the following substituents: F, Cl, _C1-6 alkyl, hydroxy, hydroxy-substituted _C1-6 alkyl, halogenated _{C1 -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, Hydroxy or hydroxy-substituted C _1-6 alkyl; the definitions of other groups are the same as above.

In certain embodiments of the compounds of the present invention, R ¹ is selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _3-6 unsaturated cyclic hydrocarbon, C _6-10 Aryl, C _5-10 heteroaryl, C _4-12 bridged ring, C _{4-12 unbroken} ring, C _5-10 spiro ring, said alkyl group, cycloalkyl group, unsaturated cyclic hydrocarbon group, heterocyclic group , aryl, heteroaryl, bridged ring, paracyclic or spiro ring optionally substituted with 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 the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl, C _4-12 bridged ring, C _{4-12 unbroken} ring, C _5-10 spiro ring, said Alkyl, cycloalkyl, bridged, paracyclic or spirocyclic 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 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 heterocyclic group, hydroxy group or hydroxy substituted C _1-6 alkyl group; the definitions of other groups are the same as above.

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, 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, said Alkyl, 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, hydroxyl, halogenated C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl; in certain embodiments, R ¹ is selected from C _1-6 alkyl optionally substituted with the following substituents: F, Cl, hydroxy, halogenated C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, phenyl; in certain embodiments, R ¹ is selected from C _1-6 alkyl, and said alkyl is any is optionally substituted with 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 certain embodiments, R ¹ is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, and said alkyl and cycloalkyl are optionally substituted by the following Base substitution: F, Cl, hydroxy, halogenated C _1-6 alkyl, hydroxy substituted C _1-6 alkyl; in certain embodiments, R ¹ is selected from 3-membered cycloalkyl, 5-membered cycloalkyl , the cycloalkyl group is optionally substituted by 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 3-membered cycloalkyl and 5-membered cycloalkyl, the cycloalkyl is optionally substituted by the following substituents: hydroxyl, halogenated C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl; in a certain In some embodiments, R ¹ is selected from a 3-membered cycloalkyl group 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 5-membered cycloalkyl group optionally substituted with the following substituents: F, Cl, hydroxy, halogenated C _1-4 alkyl, Hydroxy-substituted C _1-4 alkyl; other groups are as defined above.

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, which groups are optionally Methylol, hydroxyl, methyl, tert-butyl, fluorine atom, trifluoromethoxymethyl, fluoromethyl, cyclopropylethynyl, trifluoromethyl, trifluoro-substituted tert-butyl substitution. In certain embodiments, R ¹ is selected from ethyl, propyl, isopropyl, butyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally hydroxymethyl, hydroxy, methyl, tert-butyl Substituted; other groups are as defined above.

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, these groups The group is optionally substituted by hydroxymethyl, hydroxy, methyl, tert-butyl, fluorine, trifluoromethoxymethyl, fluoromethyl, cyclopropylethynyl, trifluoromethyl, trifluoro-substituted tert-butyl replace. In certain embodiments, R ¹ is selected from ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally hydroxymethyl, hydroxy, trifluoro Methyl, methyl and tert-butyl substitution; other groups are the same as above.

取代。在某些實施方案中，R¹選自乙基、丙基、異丙基、丁基、環丙基、環丁基、環戊基、環己基，任選被羥甲基、羥基、三氟甲基、甲基、叔丁基、

取代；其他基團定義與前文一致。 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, these groups The group is optionally substituted by hydroxymethyl, hydroxy, methyl, tert-butyl, fluorine, trifluoromethoxymethyl, fluoromethyl, cyclopropylethynyl, trifluoromethyl, trifluoro-substituted tert-butyl ,

replace. In certain embodiments, R ¹ is selected from ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally hydroxymethyl, hydroxy, trifluoro Methyl, methyl, tert-butyl,

Substituted; other groups are as defined above.

In certain embodiments, R ¹ is selected from adamantane optionally substituted with hydroxy, cyano, halo, hydroxymethyl; other group definitions are the same as above.

、

、

、吲哚基、吡咯基、吡啶基、呱啶基、苯基、環己基、環戊基、吡嗪、金剛烷基、呱嗪、嗎啉基、

、

、

、

、

、

或

。在某些實施方案中，R¹選自

、

、

、金剛烷基、

、

、

、

、

、

、

、

；在某些實施方案中，R¹選自

、

、

、金剛烷基、

、

、

。以上實施方案中，其他基團與前文一致。 Compounds of the present invention, in certain embodiments, R ¹ is selected from

,

,

, indolyl, pyrrolyl, pyridyl, oxidyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, adamantyl, oxazine, morpholinyl,

,

,

,

,

,

or

. In certain embodiments, R ¹ is selected from

,

,

, adamantyl,

,

,

,

,

,

,

,

; In certain embodiments, R ¹ is selected from

,

,

, adamantyl,

,

,

. In the above embodiment, other groups are the same as the above.

、

、

、吲哚基、吡咯基、吡啶基、呱啶基、苯基、環己基、環戊基、吡嗪、金剛烷基、呱嗪、嗎啉基、

、

、

、

、

、

或者

。在某些實施方案中，R¹選自

、

、

、金剛烷基、

、

、

、

、

、

、

、

、

；在某些實施方案中，R¹選自

、

、

、金剛烷基、

、

、

、

。以上實施方案中，其他基團與前文一致。 Compounds of the present invention, in certain embodiments, R ¹ is selected from

,

,

, indolyl, pyrrolyl, pyridyl, oxidyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, adamantyl, oxazine, morpholinyl,

,

,

,

,

,

or

. In certain embodiments, R ¹ is selected from

,

,

, adamantyl,

,

,

,

,

,

,

,

,

; In certain embodiments, R ¹ is selected from

,

,

, adamantyl,

,

,

,

. In the above embodiment, other groups are the same as the above.

、

、

、

、

、

。在某些實施方案中，R¹選自

、

、

、

、

、

。在某些實施方案中，R¹選自

、

、

、

或者

。在某些實施方案中，R¹選自

、

或者

。在某些實施方案中，R¹選自

或者

。在某些實施方案中，R¹選自

。在某些實施方案中，R¹選自

。在某些實施方案中，R¹選自

。在某些實施方案中，R¹選自

、

、

、

、

或者

。在某些實施方案中，R¹選自

、

、

、

、

、

、

；在某些實施方案中，R¹選自

、

、

、

。在某些實施方案中，R¹選自

、

或者

；在某些實施方案中，R¹選自

；在某些實施方案中，R¹選自

。以上實施方案中，其他基團定義與前文一致。 Compounds of the Invention 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

,

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

. In the above embodiment, the definitions of other groups are the same as those described above.

In certain embodiments of the compounds of the present invention, X is CR ² 'R ² or O; R ² , R ^2' are selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Halogenated alkoxy or C _1-6 alkoxy.

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' are selected from H, F, Cl, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl base, fluoroethyl, trifluoroethyl.

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 ^{CR2'R2 ;} R2, R2 ^' are selected from H, F, Cl, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, Fluoroethyl, trifluoroethyl. ^In certain embodiments, X is ^{CR2'R2 ;} R2, R2 ^' are selected from H, F, methyl, fluoromethyl. ^In certain embodiments, X is ^{CR2'R2 ;} R2 is selected from H, F, methyl, fluoromethyl, and R2 ^' is selected from H or F. ^In certain embodiments, X is ^{CR2'R2 ;} R2 is selected from H, and R2 ^' is selected from H. In the above embodiment, the definitions of other groups are the same as those described above.

In certain embodiments of the compounds 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 heterocycle, and the cycloalkane, cycloalkene, and heterocycle are optionally substituted by 0 to 3 substituted with R ⁷ . Other group definitions are the same as above.

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-cyclohexene Dihexene, ethylene oxide, aziridine, azetidine, oxetane, pyrrolidine, pyrroline, pyrazolidine, tetrahydrofuran, oxidine, tetrahydropyran, oxazine 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; the above rings are optionally substituted with 0 to 3 R ⁷ ; each R ⁷ is independently selected from F, Cl, hydroxy, C _1-6 alkyl, cyano group, 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 In the scheme, R ⁷ is selected from F, Cl, methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl or trifluoroethyl ; In certain embodiments, R ⁷ is selected from F, Cl, methyl; in certain embodiments, R ⁷ is selected from F. Other group definitions are the same as above.

Compounds of the Invention In certain embodiments, the C ring is cyclopropane, cyclobutane, or cyclopentane, which is optionally substituted with 0 to 2 R ⁷ ; each R ⁷ Independently selected from F. Other group definitions are the same as above.

In certain embodiments of the compounds of the present invention, R ⁴ , R ⁵ , R ⁶ , R ⁹ are each independently selected from H or C _1-6 alkyl; or R ⁵ , R ⁶ form cyclopropane, and the C ring is absent. Other group definitions are the same as above.

In certain embodiments, R ⁴ , R ⁵ , R ⁹ are each independently selected from H; R ⁶ is selected from H or methyl; or R ⁵ , R ⁶ form cyclopropane, and the C ring is absent. Other group definitions are the same as above.

In the compounds 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 a C _1-6 alkyl group, the heteroaryl group contains 1-3 heteroatoms selected from N, O, S and their oxidation states. Other group definitions are the same as above.

)、吡咯基、咪唑基、吡唑基、呋喃基、噻吩基、噁唑、噻唑、1,2,3-三唑、1,2,4-三唑；以上基團任選被以下取代基取代：F、Cl或者甲基，在某些實施方案中，以上基團任選被F取代。其他基團定義與前文一致。 In certain embodiments, R ¹¹ is selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrazinyl oxynitride (

), pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole; the above groups are optionally substituted by the following groups Substitution: F, Cl or methyl, in certain embodiments, the above groups are optionally substituted with F. Other group definitions are the same as above.

、

或者

。在某些實施方案中，R¹¹選自

或

。在某些實施方案中，R¹¹選自

。在某些實施方案中，R¹¹選自

。在某些實施方案中，R¹¹選自

。其他基團定義與前文一致。 Compounds of the Invention In certain embodiments, R ¹¹ is selected from

,

or

. In certain embodiments, 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

. Other group definitions are the same as above.

、

或者

，在某些實施方案中，R¹¹選自

、

，在某些實施方案中，R¹¹選自

，在某些實施方案中，R¹¹選自

，在某些實施方案中，R¹¹選自

。 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 hydroxyl; compounds 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, difluoromethyl Fluoromethyl or hydroxy; or compounds of the present invention, in certain embodiments, R ¹ is selected from C _1-6 alkyl or C _3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally selected by the following Substituent substitution: 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, and the alkyl is any 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 _1-6 alkyl, the Alkyl 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 Said 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, optionally substituted with 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 is optionally substituted with the following substituents: hydroxy substituted C _1-6 alkyl; in certain embodiments, R ¹ is selected from C _3-6 cycloalkyl optionally substituted with group substitution: hydroxymethyl; or compounds 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 with the following substituents: F, Cl, _C1-6 alkyl, halo- _C1-6 alkyl, hydroxy-substituted _C1-6 alkyl, hydroxy; compounds of the present invention, in certain embodiments, R ¹ Selected from C _1-6 alkyl or C _3-6 cycloalkyl, the alkyl or cycloalkyl is optionally substituted by the following substituents: F, Cl, methyl, ethyl, isopropyl, methylol group, trifluoromethyl, difluoromethyl, hydroxyl; compounds of the present invention, in certain embodiments, R ¹ is selected from C _1-6 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered Cycloalkyl, optionally substituted with 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 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, and the cycloalkyl is optionally substituted by the following substituents: F, Cl, methyl, ethyl, isopropyl, hydroxymethyl , trifluoromethyl, difluoromethyl, hydroxyl; in certain embodiments, R ¹ is selected from C _1-6 alkyl optionally substituted with the following substituents: F, Cl, methyl , ethyl, isopropyl, hydroxymethyl, trifluoromethyl, difluoromethyl, hydroxy; X is CR ² 'R ² or O; in certain embodiments, X is CR ² 'R ² ; R ^2. R ^2' is selected from H, F, methyl or fluoromethyl; in certain embodiments, R ² and R ^2' are selected from H; C ring is cyclopropane, cyclobutane or cyclopentane In certain embodiments, the C ring is cyclopropane; In certain embodiments, the C ring is cyclobutane; In some embodiments, the C ring is cyclopentane; The cyclopropane, cyclobutane, or Cyclopentane is optionally substituted with R ^; in some embodiments, the C ring is cyclopropane; in some embodiments, the C ring is cyclopentane, and is optionally substituted with R ^; in some embodiments, C The ring is cyclopropane or cyclopentane; R ⁷ is 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; or R ⁵ and R ⁶ form cyclopropane, And 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

.

、

或者

；或者R¹選自

；在某些實施方案中，R¹選自

、

；在某些實施方案中，R¹選自R¹選自

、

；X為CR²’R²；R²、R^2’選自H；C環為環丙烷、環丁烷或者環戊烷；在某些實施方案中，C環為環丙烷；在某些實施方案中，C環為環丁烷；在有些實施方案中，C環為環戊烷；所述環丙烷、環丁烷或者環戊烷任選被R⁷取代；在有些實施方案中，C環為環丙烷、環戊烷；在有些實施方案中，C環為環丙烷；R⁷各自獨立選自F；R⁴、R⁵、R⁹各自獨立選自H；R⁶選自H或甲基；在某些實施方案中，R⁶選自H，在某些實施方案中，R⁶選自甲基；R¹⁰選自H； R¹¹選自

。 Compounds of the present invention, in certain embodiments, 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; C ring is cyclopropane, cyclobutane or cyclopentane; In certain embodiments, C ring is cyclopropane; In certain embodiments In the scheme, the C ring is cyclobutane; in some embodiments, the C ring is cyclopentane; the cyclopropane, cyclobutane, or cyclopentane is optionally substituted by R ⁷ ; in some embodiments, the C ring In some embodiments, C ring is cyclopropane; R ⁷ is each independently selected from F; R ⁴ , R ⁵ , 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, in certain embodiments, R ⁶ is selected from methyl; R ¹⁰ is selected from H; R ¹¹ is selected from

.

The tricyclic pyrazole compound described in the general formula (I) of the present invention and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, wherein the compound structure is as follows:

better,

The present invention also relates to a pharmaceutical composition comprising: an effective dose of Any of the compounds of the present invention and stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs thereof, or further comprising one or more other therapeutic agents and a pharmaceutically acceptable carrier 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 the compounds containing the present invention. Use of a composition in the manufacture of a medicament for the treatment of diseases mediated by CB2 receptors.

The present invention relates to tricyclic pyrazole compounds represented by the general formula (I) and stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs thereof, or combinations containing the compounds of the present invention Use of a substance in the preparation of a medicament for the treatment of pain.

Pain may be selected from the group consisting of: bone pain, arthralgia, muscle pain, dental pain, migraine, headache, inflammatory pain, neuropathic pain, abdominal pain associated with Crohn's disease, pain due to adverse effects of a therapeutic agent, and pain associated with the group selected from the group consisting of: Pain associated with the following diseases: osteoarthritis, cancer, multiple sclerosis, allergic response, nephritic 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 the compounds containing the present invention. Use of the composition in the preparation of a medicament for the treatment of 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 the compounds containing the present invention. Use of the composition in preparing a medicament for treating abdominal pain associated with Crohn's disease.

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 the compounds containing the present invention. The compositions are used in methods 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 the compounds containing the present invention. The composition is used in a method of treating pain.

Pain may be selected from the group consisting of: bone pain, arthralgia, muscle pain, dental pain, migraine, headache, inflammatory pain, neuropathic pain, Crohn's disease-related abdominal pain pain due to adverse effects of a therapeutic agent, and pain associated with the group consisting of: Pain associated with the diseases mentioned: osteoarthritis, cancer, multiple sclerosis, allergic response, nephritic syndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia, HIV-related neuropathy, sciatica and Autoimmune disease.

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 the compounds containing the present invention. Compositions A method of treating 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 the compounds containing the present invention. Compositions for methods of treating abdominal pain associated with Crohn's disease.

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopes, and carbon, hydrogen, oxygen, sulfur, The nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include12C, ^{13C and14C} , and isotopes of hydrogen include ^protium (H), deuterium (D, also known as deuterium) , tritium (T, also known as super heavy hydrogen), the isotopes of oxygen include ¹⁶ O, ¹⁷ O and ¹⁸ O, the isotopes of sulfur include ³² S, ³³ S, ³⁴ S and ³⁶ S, and the isotopes of nitrogen 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.

"Alkyl" refers to linear and branched monovalent saturated hydrocarbon groups, the main chain includes 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, more preferably Straight and branched chain groups of 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc.; the alkyl group can be further substituted by any substituent.

"Alkylene" refers to linear 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 Ethyl, propylene and butylene, etc.; the alkylene group may be optionally further substituted by any substituent. When the number of substituents in the alkylene group is 2 or more, the substituents can be fused together to form a cyclic structure.

"Alkoxy" refers to a monovalent group of O-alkyl (-O-alkyl), wherein 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-pentyloxy yl, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-1-butoxy and 2-methyl base-1-butoxy, etc.

"Alkenyl" refers to linear 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 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-butene base, 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-octenyl Alkenyl, 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 can be optionally further substituted by any group.

"Alkynyl" refers to linear and branched monovalent unsaturated hydrocarbon groups, which have 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, 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 can be any Optional is further substituted with optional substituents.

"Cycloalkyl" means a monovalent saturated carbocyclic hydrocarbon group, monocyclic, usually 3 to 10 carbons Atom, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and the like. The cycloalkyl group may be optionally further substituted with any substituent.

"Unsaturated cyclic hydrocarbon group" refers to a carbocyclic hydrocarbon group containing an unsaturated bond (such as a double bond) without aromaticity, non-limiting examples include cyclopropenyl, cyclobutenyl, 1,4-cyclohexanedi alkene, 1,3-cyclopentadiene, etc.

"Heterocyclyl" refers to a saturated or unsaturated cyclic hydrocarbon group containing at least one heteroatom, a single ring, the heteroatoms are N, O, S, P and their oxidized forms, non-limiting examples include aziridine base, oxetanyl, thietanyl, azetidine, oxetanyl, thietanyl, azetidine (aka azetidine), pyrrolyl, pyrroline base, 3-pyrrolinyl, 1-pyrrolinyl, pyrrolidinyl, pyrazolidinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, tetrahydrothienyl, 1,2,4 - Triazolyl, etc. Said 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, the heteroatom is N, O, S, P and its oxidized form, non-limiting examples include aziridine, oxirane, thiirane, azetidine, oxetane, thietane, azetane (aka azetidine), pyrrole, pyrroline, 3-pyrroline , 1-pyrroline, pyrrolidine, pyrazolidine, 2-pyrazoline, imidazole, pyrazole, tetrahydrofuran, tetrahydrothiophene, 1,2,4-triazole, etc. Said heterocycle may be optionally further substituted with any substituent.

和

。螺環可以被任意取代基進一步取代。 "Spirocycle" refers to a 5- to 20-membered polycyclic group of substituted or unsubstituted monocyclic rings sharing one atom (such as a carbon atom, referred to as a spiro atom), which may contain 0 to 5 double bonds, and may Contains 0 to 5 heteroatoms selected from N, O or S(=O)n. Preferably it is 6 to 14 members, more preferably 6 to 12 members, more preferably 6 to 10 members, non-limiting examples thereof include

and

. The spiro ring can be further substituted with any substituent.

和

。並環可以進一步被任意取代基取代。 "Paracyclic" 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, one or more of which may contain zero 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. Preferably it is 5 to 20 members, more preferably 5 to 14 members, more preferably 5 to 12 members, still more preferably 5 to 10 members. Non-limiting examples include

and

. The parallel ring may be further substituted with any substituent.

、

、

、

、

、

和金剛烷。橋環可以進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, may contain 0 or more double bonds, and may be substituted or unsubstituted, and the ring system Any ring in can contain 0 to 5 heteroatoms or groups selected from N, S(=O)n or O (wherein n is 1, 1, 2). The ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12 atoms, still more preferably 5 to 10 atoms. Non-limiting examples include

,

,

,

,

,

and adamantane. The bridged ring may be further substituted with any substituent.

、

、

和

。芳基可以進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 fused-ring aromatic groups. A 6- to 14-membered aromatic ring is preferable, and a 6- to 10-membered aromatic ring is further preferable, and non-limiting examples thereof include phenyl, naphthyl, anthracenyl, and phenanthryl, and the like. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include phenyl,

,

,

and

. The aryl group may be further substituted with any substituent.

、

、

、

、

、

、

和

。雜芳基可以進一步被任意取代基取代。 "Heteroaryl" refers to a substituted or unsubstituted 5- to 14-membered aromatic ring containing 1 to 5 heteroatoms or groups selected from N, O or S(=O)n, preferably a 5- to 10-membered heteroatom Aromatic ring, further 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, Ciridinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples include

,

,

,

,

,

,

and

. Heteroaryl groups may be further substituted with optional substituents.

"Pharmaceutically acceptable salt" means one that retains the biological availability and properties of a free acid or free base that has been treated with a non-toxic inorganic or organic base, or the free base that has been treated with a non-toxic Those salts obtained by the reaction of inorganic or organic acids.

"Carrier" refers to a carrier or diluent that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.

"Excipient" refers to an inert substance added to a pharmaceutical composition to further depend upon 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, granulation agents, lubricants, binders, disintegrants, etc.

"Prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound of the present invention. The prodrugs of the present invention are prepared by modifying the phenolic group in the compound, which modification can be removed by conventional procedures or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free hydroxyl groups, respectively. Examples of prodrugs include, but are not limited to, the phenolic hydroxyl and phosphate sodium derivatives of the compounds of the present invention.

"Effective dose" refers to the amount of a compound that elicits a physiological or medical response in a tissue, system, or subject for which it is sought, including one or more of which, when administered in a subject, is sufficient to prevent the condition or disorder being treated The amount of a compound at which symptoms occur or are alleviated to some extent.

"Solvates" refer to compounds of the present invention or salts thereof, which also include stoichiometric or non-stoichiometric amounts of solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

"Optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "alkyl optionally substituted by F" means that the alkyl group may but not necessarily 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 by R or not. When substituted, the number of R is not limited, as long as the principle of chemical bond is satisfied. When substituted by two or more Rs, R can be independently and freely selected, and can be the same or different, and are independent of each other.

The technical solutions of the present invention are described in detail below with reference to the embodiments, but the protection scope of the present invention includes but is not limited thereto.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).

NMR shifts ([delta]) are given in units of 10-6 (ppm).

NMR was measured with a (Bruker ADVANCE III 400) nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was Tetramethylsilane (TMS), ¹ HNMR information is listed in the following format: chemical shift (multiplet (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), number of protons).

For MS measurement (Agilent 6120B (ESI)).

The HPLC assay was performed using an 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 for thin layer chromatography (TLC) is 0.15mm~0.20mm, and the specification used for TLC separation and purification products is 0.4mm ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

There is no special description in the examples, and the solution refers to an aqueous solution.

There is no special description in the examples, and the temperature of the reaction is room temperature, which is 20°C to 30°C.

Short description: HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate; DMF: N,N-dimethylformamide; TEA: triethylamine; PE: petroleum ether; EA: ethyl acetate; DCM: dichloromethane; mCPBA: m-chloroperbenzoic acid; IBX: o-iodobenzoic acid; LHMDS: bis(trimethylsilyl)amine base lithium.

Intermediate 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-ol

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-trimethylpropanamide

Under nitrogen protection, at room temperature, to 3,3,3-trifluoro-2,2-dimethylpropionic acid (25 g, 0.16 mol), DMF (50 mL), TEA (32 mg, 0.25 mmol), HATU were added successively (77 mg, 0.2 mmol), N-methyl-N-methoxyamine hydrochloride (17.2 g, 0.176 mol), and stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution (200 mL) was added to the reaction to quench the reaction, extracted with 300 mL of ethyl acetate, left to stand for layers, and the aqueous phase was extracted three times with dichloromethane (200 mL×3) mL), and the combined organic phase was Dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a residue, that is, a crude product. The crude product was subjected to column chromatography (eluent PE:EA=10:1) to obtain Int-1-b (22 g, yield 69%), pale yellow Oily.

LC-MS (ESI): m/z=200.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.70 (s, 3H), 3.21 (s, 3H), 1.5 (s, 6H).

The second step: 3,3,3-trifluoro-2,2-dimethylpropanal ( Int-1-c )

3,3,3-trifluoro-2,2-dimethylpropanal

Under nitrogen protection, at room temperature, THF (50 mL) was added to a 250 mL single-neck flask, LiAlH ₄ (3.43 g, 90 mmol) was added at 0° C., and compound Int-1-b (15 g, 75.3 mmol) was slowly added dropwise, and stirred at room temperature. 2h. At 0 °C, water (3.5 mL), NaOH (15%, 3.5 mL), and water (3.5 mL) were sequentially added to the reaction to quench the reaction, and the reaction was stirred for 30 min. Then 200 mL of ether was added and vigorously stirred for 30 min, and filtered through celite. , and concentrated under reduced pressure to obtain crude Int-1-c (14 g), a colorless oily compound, which was used in the next reaction without purification.

LC-MS (ESI): m/z=141.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.69 (s, 1H), 1.30 (s, 6H).

The third step: 2-amino-4,4,4-trifluoro-3,3-dimethylbutyronitrile ( Int-1-d )

2-amino-4,4,4-trifluoro-3,3-dimethylbutanenitrile

Under nitrogen protection, at room temperature, sequentially add Int-1-c (4.5g), NH ₃ /MeOH (10 mL, 70 mmol), NH ₄ Cl (1.62 g, 30 mmol) to the single-necked flask, stir at room temperature for 30 min, and then KCN (1.95 g, 30 mmol) was added and the reaction continued to stir 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 was slowly added at 0 °C. 1,4-dioxane was dissolved and stirred to precipitate a white solid Int-1-d (1.65 g, yield 34.78%).

LC-MS (ESI): m/z=167.1 [M+H] ⁺ .

The fourth step: 2-amino-4,4,4-trifluoro-3,3-dimethylbutyric acid ( Int-1-e )

2-amino-4,4,4-trifluoro-3,3-dimethylbutanoic acid

Under nitrogen protection, at room temperature, Int-1-d (2.05 g, 10.14 mmol) and 6N HCl (20 mL) were successively added to the single-necked flask, and the mixture was stirred under reflux for 36 h. Cool to room temperature, add aqueous sodium hydroxide solution to the reaction to adjust pH to 8, the aqueous phase is washed with dichloromethane (20 mL) to recover 0.4 g of raw materials, the aqueous phase is adjusted to pH 7 again, and concentrated to solid under reduced pressure to obtain a crude white product Solid Int-1-e (1.3 g).

LC-MS (ESI): m/z=186.2 [M+H] ⁺ .

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-ol

Under nitrogen protection, THF (20 mL) was added to a 50 mL single-neck flask at room temperature, LiAlH ₄ (270 mg, 8.43 mmol) was added at 0° C., and compound Int-1-e (1.3 g, 7 mmol) was slowly added dropwise, and stirred for 3 h under reflux. The reaction is complete. At 0 °C, water (0.27 mL), NaOH (15%, 0.27 mL), and water (0.27 mL) were successively added to the reaction to quench the reaction, stirred for 30 min, and then THF (50 mL) was added to vigorously stir for 30 min, and dried over NaSO ₄ , filtered through celite, 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] ⁺ .

Example 1

3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)aminocarbamide)-5,5a,6,6a-tetrahydro Cyclopropane[g]indazol-1(4H)-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-oxide

3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)aminocarboxy)-5,5a,6,6a-tetrahydro Cyclopropane[g]indazol-1(4H)-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-oxide

The first step: [4.1.0]heptan-2-one ( 1b )

bicyclo[4.1.0]heptan-2-one

In a 500mL three-necked flask, add 250mL of dimethylsulfite solution, slowly add sodium hydrogen (14.2g, 0.35mol) under ice bath conditions, add trimethylsulfite iodide (78.3g, 0.35mol) after stirring for 10 minutes, Then, after stirring for half an hour, slowly drop the solution of cyclohex-2-enone (30 ml) dissolved in 50 mL of dimethyl sulfite solution, the reaction solution was returned to room temperature and continued to stir for half an hour, and then the temperature was raised to 50 ° C and reacted for 2 hours , after the TLC detection reaction was complete, then cooled the reaction solution to room temperature, poured the reaction solution into 300 g of ice water, stirred for half an hour, filtered, and added 500 ml of water to the filtrate obtained, then used (600 mL × 3) of ethyl acetate The solution was extracted and the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried in a water bath at 35°C to obtain the desired compound 32g ( 1b ), which was directly carried out for the next step. The yield was 93.2%.

¹ H NMR (400MHz, CDCl ₃ )δ 2.33-2.23(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).

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-carboxylate

Compound 1b (20g, 0.18mol) was dissolved in 400ml of ethanol solution, then diethyl oxalate (26g, 0.18mol) and potassium tert-butoxide (20g, 0.18mol) were added under stirring, and then the temperature was raised to 40°C and stirred for reaction 2 hours, then slowly add 6M hydrochloric acid solution (100ml), add pyrazine hydrazine (20g, 0.18mol) after stirring for 5 minutes, then the reaction solution is raised to 50 ℃ and continue to react for 2 hours, after TLC detects that the reaction is complete, it is cooled to After room temperature, add saturated sodium bicarbonate solution to adjust the pH to about 9, add 500 ml of water, extract with ethyl acetate (500 mL × 3), dry with anhydrous sodium sulfate, spin dry, and perform column chromatography (eluent PE/ EA=5/1) was purified to obtain yellow oil 27g ( 1c ), yield 53%.

LC-MS (ESI): m/z=285.3 [M+H] ⁺ .

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 acid

Compound 1c (18g, 0.06mol) was dissolved in a mixed solvent of 200ml methanol and 200ml tetrahydrofuran, and then 20ml of an aqueous solution of sodium hydroxide (3g, 0.08mol) was slowly added. After the dropwise addition, the mixture was stirred at room temperature overnight, and 2M was added. The dilute hydrochloric acid was used to adjust the pH of the reaction solution to about 3, then 500ml of water was added, and after extraction with dichloromethane (800mL×3), dried over anhydrous sodium sulfate and spin-dried to obtain a yellow powder solid 15g ( 1d ) with a yield of 92.5 %.

LC-MS (ESI): m/z=257.3 [M+H] ⁺ .

The fourth step: N-((S)-1-hydroxy-3,3-dimethylbutan-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-carboxamide

Compound 1d (0.3g, 1.2mmol) was dissolved in 25ml of DMF solution, then S-tertiary leucinol (0.17g, 1.44mmol) and HATU (0.55g, 1.44mmol), triethylamine (0.36g, 1.44mmol) were added. 3.6 mmol), stirred at room temperature overnight, added 100 ml of water to the reaction solution, then extracted with ethyl acetate (100 mL×3), combined the organic phases, dried over anhydrous sodium sulfate and spin-dried, column chromatography (eluent MeOH/DCM) = 1/10) and purified to obtain 230 mg of pale yellow solid (1e) with a yield of 55.3%.

LC-MS (ESI): m/z=356.4 [M+H] ⁺ .

The fifth step: 3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)amine carboxamide)-5,5a,6, 6a-Tetrahydrocyclopropane[g]indazol-1(4H)-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-oxide

3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)aminocarboxy)-5,5a,6,6a-tetrahydro Cyclopropane[g]indazol-1(4H)-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-oxide

Compound 1e (0.13g, 0.37mmol) was dissolved in 5ml of formic acid solution, then 30% hydrogen peroxide solution (0.5ml) was added, the temperature was raised to 64°C and stirred for 3 hours, then 50ml of water was added, and dichloromethane ( 50mL × 3) extraction, combined organic phases, dried over anhydrous sodium sulfate, after spin drying, the obtained brown oil was dissolved in a mixed solvent of 3ml of methanol and 3ml of tetrahydrofuran, and then slowly added dropwise an aqueous solution of sodium hydroxide 2ml ( 0.015g, 0.4mmol), after stirring and reacting 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, silica gel After column chromatography (eluent MeOH/DCM=1/10), 10 mg of final product white powder ( compound 1-a ) was obtained, HPLC peak time (t=3.948); yield 7.35%, and 8 mg of white powder ( compound 1-a) 1-b ), HPLC peak time (t=4.272), yield 5.88%.

Compound 1-a:

LC-MS (ESI): m/z=372.4 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ 9.66-9.79(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).

Compound 1-b:

LC-MS (ESI): m/z=372.4 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ 9.62-9.79(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).

Example 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-carboxamide

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-carboxylate

Compound 1b (0.1 g, 0.9 mmol) was dissolved in 2 ml of ethanol solution, and then diethyl oxalate (0.13 g, 0.9 mmol) and potassium tert-butoxide (0.1 g, 0.9 mmol) were added with stirring, and the temperature was raised 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 for 2 After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature, and the pH of the reaction solution was adjusted to about 9 by adding saturated sodium bicarbonate solution, adding 50 ml of water, extracting with ethyl acetate (50 mL×3) and drying over anhydrous sodium sulfate. After spin-drying, column chromatography (eluent PE/EA=3/1) was used for purification to obtain 0.1 g of yellow oil ( 2a ) with a yield of 34.6%. .

LC-MS (ESI): m/z=317.3 [M+H] ⁺ .

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 acid

Compound 2a (0.3 g, 1 mmol) was dissolved in a mixed solvent of 3 ml of methanol and 3 ml of tetrahydrofuran, and then an aqueous solution of sodium hydroxide (0.048 g, 1.2 mmol) was slowly added. After the dropwise addition, the mixture was stirred at room temperature overnight, and 2M was added. The pH of the reaction solution was adjusted to about 3 with dilute hydrochloric acid, then 25ml of water was added, and after extraction with dichloromethane (30mL×3), the organic phase was dried with anhydrous sodium sulfate, and then spin-dried to obtain a yellow solid 250mg ( 2b ), The yield was 91.6%.

LC-MS (ESI): m/z=291.2 [M+H] ⁺ .

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-carboxylate

Raw material 2b (0.1g, 0.34mmol) was dissolved in 3ml of DMF solution, then S-tertiary leucinol (0.056g, 0.48mmol) and HATU (0.18g, 0.47mmol), triethylamine (0.12g, 0.48mmol) were added. 1.09 mmol), stirred at room temperature overnight, added 50 ml of water to the reaction solution, then extracted with ethyl acetate (100 mL×3), combined the organic phases, dried over anhydrous sodium sulfate and spin-dried, column chromatography (eluent MeOH/ DCM=1/10) was purified to obtain 230 mg of pale yellow solid (compound 2 ), yield 55.3%.

LC-MS (ESI): m/z=390.4 [M+H] ⁺ .

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).

Example 3

3-(3-((1-Hydroxy-2-methylpropan-2-yl)aminocarboxy)-5,5a,6,6a-tetrahydrocyclopropyl[g]indazole-1(4H )-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-oxide

The first step: N-(1-hydroxy-2-methylpropan-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

Raw material 1d (0.3g, 1.2mmol) was dissolved in 10ml of DMF solution, then 2-amino-2-methylpropan-1-ol (0.12g, 1.44mmol) and HATU (0.53g, 1.44mmol) were added , triethylamine (0.36g, 3.6mmol), stir at room temperature overnight, add 100ml of water to the reaction solution, then extract with ethyl acetate (100mL×3), combine the organic phases, dry over anhydrous sodium sulfate and spin dry, the column layer Purification by precipitation (eluent MeOH/DCM=1/10) to obtain 200 mg of pale yellow solid ( 3a ) with a yield of 52.2%.

LC-MS (ESI): m/z=328.3 [M+H] ⁺ .

The second step: 3-(3-((1-hydroxy-2-methylpropan-2-yl)aminocarboxyl)-5,5a,6,6a-tetrahydrocyclopropyl[g]indazole -1(4H)-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-oxide

The raw material 3a (0.2g, 0.61mmol) was dissolved in 25ml of formic acid solution, then 30% hydrogen peroxide solution (0.5ml) was added, the temperature was raised to 64°C and stirred for 3 hours, then 50ml of water was added, and ethyl acetate ( 50mL×3) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, the obtained brown oil was dissolved in a mixed solvent of 3ml of methanol and 3ml of tetrahydrofuran after being spin-dried, and then slowly added dropwise an aqueous solution of sodium hydroxide 2ml ( 0.03g, 0.8mmol), after 15 minutes of stirring reaction at room temperature, TLC detected, the reaction was complete, 50ml of water was added, extracted with ethyl acetate (50mL×3), the combined organic phases were dried over anhydrous sodium sulfate and spin-dried, column chromatography ( After separation and purification with eluent MeOH/DCM=1/5), 17 mg of the final product white powder ( compound 3 ) was obtained , with a yield of 7.7%.

LC-MS (ESI): m/z=344.3 [M+H] ⁺ .

¹ H NMR(400MHz, CDCl3)δ 9.66-9.79(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).

Example 4

3-(3-((1-(Hydroxymethyl)cyclopentyl)aminocarbamoyl)-5,5a,6,6a-tetrahydrocyclopropyl[g]indazol-1(4H)-yl ) pyrazine 1-oxide (compound 4)

3-(3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide

The first step: 3-(3-carboxy-5,5a,6,6a-tetrahydrochloropropane[g]indazol-1(4H)-yl)pyrazine 1-oxide ( 4a )

3-(3-carboxy-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide

The raw material 1d (2g, 7.8mmol) was dissolved in 25ml of formic acid solution, then 30% hydrogen peroxide solution (5ml) was added, the temperature was raised to 64°C and stirred for 3 hours, then 250ml of water was added, and ethyl acetate (50mL× 3) Extraction, combine the organic phases, dry over anhydrous sodium sulfate, and spin the obtained brown oily substance 4a for the next reaction directly.

LC-MS (ESI): m/z=273.2 [M+H] ⁺ .

The second step: 3-(3-((1-(hydroxymethyl)cyclopentyl)aminocarboxyl)-5,5a,6,6a-tetrahydrocyclopropyl[g]indazole-1( 4H)-yl)pyrazine 1-oxide ( compound 4 )

3-(3-((1-(hydroxymethyl)cyclopentyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide

Raw material 4a (0.7g, 2.57mmol) was dissolved in 25ml of DMF solution, then (1-aminocyclopentyl)methanol (0.35g, 3.08mmol) and HATU (1.17g, 3.08mmol), triethylamine were added (1.1g, 10.9mmol), stirred at room temperature overnight, added 200ml of water to the reaction solution, then extracted with ethyl acetate (70mL×3), combined the organic phases, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (Eluent MeOH/DCM=1/10) to obtain 350 mg of pale yellow solid ( compound 4 ), yield 36.9%.

LC-MS (ESI): m/z=370.4 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 8.83-8.84 (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).

Example 5

3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)aminocarbamoyl)-5amethyl-5,5a, 6,6a-Tetrahydrocyclopropane[g]indazol-1(4H)-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-oxide

3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)aminocarboxy)-5amethyl-5,5a, 6,6a-Tetrahydrocyclopropane[g]indazol-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-oxide

The first step: 6-methylbicyclo[4.1.0]heptan-2-one ( 5b )

6-methylbicyclo[4.1.0]heptan-2-one

In a 250mL three-necked flask, add 100mL of dimethylsulfite solution, slowly add sodium hydrogen (4.73g, 0.20mol) under ice bath conditions, add trimethylsulfite iodide (26.1g, 0.12mol) after stirring for 10 minutes, Then, after stirring for half an hour, 3-methylcyclohex-2-enone (10 ml) dissolved in 20 mL of dimethyl sulfoxide solution was slowly added dropwise, and stirring was continued for ten minutes, and then the reaction solution was returned to room temperature and continued to stir for half an hour. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature, poured into 100 g of ice water, stirred for half an hour, and then filtered. The obtained filtrate was added with 150 ml of water, and the Extract with ethyl ester (200 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, spin dry in a water bath at 35° C. to obtain the desired compound 10 g ( 5b ), and proceed directly to the next reaction. The yield was 89.3%.

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).

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-carboxylate

Compound 5b (1 g, 8 mmol) was dissolved in 20 ml of ethanol solution, and then diethyl oxalate (1.17 g, 8 mmol) and potassium tert-butoxide (0.9 g, 8 mmol) were added under stirring, and then the temperature was raised to 40 ° C and stirred for reaction 2 hour, then slowly add 6M hydrochloric acid solution (5ml), add pyrazine hydrazine (0.88g, 0.18mol) after stirring for 5 minutes, then the reaction solution is raised to 50 ℃ and continue to react for 2 hours, after TLC detects that the reaction is complete, it is cooled to After room temperature, saturated sodium bicarbonate solution was added to adjust the pH to about 9, the reaction solution was added to 100 ml of water, and then extracted with ethyl acetate (100 mL×3). Purification by precipitation (eluent EA/PE=1/5) to obtain 0.18g ( 5c ) of yellow oil, with a yield of 7.5%.

LC-MS (ESI): m/z=299.3 [M+H] ⁺ .

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 acid

Compound 5c (0.18 g, 0.6 mmol) was dissolved in a mixed solvent of 5 ml of methanol and 5 ml of tetrahydrofuran, and then an aqueous solution of sodium hydroxide (0.029 g, 0.72 mmol) was slowly added. 2M dilute hydrochloric acid was used to adjust the pH of the reaction solution to about 3, then 30ml of water was added, and after extraction with dichloromethane (50mL×3), the organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain a yellow oil 0.14g ( 5d ), yield 85.9%.

LC-MS (ESI): m/z=271.3 [M+H] ⁺ .

The fourth step: N-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-5a methyl-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-carboxamide

Raw material 5d (0.14g, 0.52mmol) was dissolved in 5ml of DMF solution, then S-tertiary leucinol (0.073g, 0.62mmol) and HATU (0.24g, 0.62mmol), triethylamine (0.16g, 0.62mmol) were added. 1.6 mmol), stirred at room temperature overnight, TLC monitored the reaction to complete, then added 20 ml of water to the reaction solution, then extracted with ethyl acetate (30 mL × 3), combined the organic phases, dried over anhydrous sodium sulfate and spin-dried, column chromatography (Eluent MeOH/DCM=1/10) was purified to obtain light yellow solid 130mg ( 5e ) , yield 68.4%.

LC-MS (ESI): m/z=370.4 [M+H] ⁺ .

The fifth step: 3-((5aR,6aS)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)aminocarboxy)-5amethyl- 5,5a,6,6a-Tetrahydrocyclopropane[g]indazol-1(4H)-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-oxide

3-((5aS,6aR)-3-(((S)-1-hydroxy-3,3-dimethylbutan-2-yl)aminocarboxy)-5amethyl-5,5a, 6,6a-Tetrahydrocyclopropane[g]indazol-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-oxide

The raw material 5e (0.13g, 0.35mmol) was dissolved in 5ml of formic acid solution, then 30% hydrogen peroxide solution (0.7ml) was added, the temperature was raised to 64°C and stirred for 3 hours, then 50ml of water was added, and ethyl acetate ( 50mL×3) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, the obtained brown oil was dissolved in a mixed solvent of 3ml of methanol and 3ml of tetrahydrofuran after being spin-dried, and then slowly added dropwise an aqueous solution of sodium hydroxide 2ml ( 0.015g, 0.4mmol), after stirring and reacting at room temperature for 15 minutes, TLC detection, the reaction is complete, add 50ml of water, extract with ethyl acetate (50mL × 3), combine the organic phases and dry with anhydrous sodium sulfate and spin dry, silica gel column After purification and separation by chromatography (eluent MeOH/DCM=1/10), the final product was obtained as white powder 10mg ( compound 5-a ), HPLC (retention time t=3.885), yield 7.4%, and white powder 8mg ( compound 5-a) 5-b ), HPLC (retention time t=4.042), yield 5.9%.

Compound 5-a:

LC-MS (ESI): m/z=386.4 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 9.66-9.89(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).

Compound 5-b :

LC-MS (ESI): m/z=386.4 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ 9.62-9.91(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).

Example 6

3-(3-(((S)-1-Hydroxy-3,3-dimethylbutan-2-yl)aminocarboxy)-4,5,5a,6,7,7a-hexahydro- 1Hydro-cyclobuta[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-oxide

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-one

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 the reaction was carried out at room temperature overnight. The zinc powder was removed by filtration, the solvent was spin-dried and the sample was mixed with silica gel, and the compound 6b (3.0 g, 66%) was isolated by column chromatography (eluent: petroleum ether/ethyl acetate=10:1~5:1).

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).

Step 2: Bicyclo[4.2.0]oct-2-en-7-one ( 6c )

bicyclo[4.2.0]oct-2-en-7-one

Compound 6b (1.0 g, 5.3 mmol) was dissolved in acetic acid (40 mL). Zinc dust (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, extracted with dichloromethane (50 mL×3) 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=10:1~5:1) gave compound 6c (0.5 g, 80%).

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).

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-ene

Compound 6c (450 mg, 3.68 mmol) was dissolved in toluene (1.5 mL), ethylene glycol (1.5 mL) and p-toluenesulfonic acid (633 mg, 3.68 mmol) were added thereto, the temperature was raised to 120°C and refluxed to separate four Hour. After the reaction solution was cooled to room temperature, the toluene was removed by rotary evaporation, and the compound 6d (0.65 g, 80%) was isolated by column chromatography (eluent: petroleum ether/ethyl acetate=10:1~5:1).

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).

Step 4: 3'-oxaspiro[[1,3]dioxolane 2,8'-tricyclo[ ^5.2.0.02,4 ]nonane] ( 6e )

mCPBA (85%, 136 mg, 0.67 mmol) was added to a solution of compound 6d (100 mg, 0.56 mmol) in dichloromethane (5 mL), and the reaction was stirred at room temperature for 5 hours. Add 5 ml of water to quench the reaction, extract with dichloromethane (20 mL×3) and combine the organic phases, wash the combined organic phases with saturated sodium bicarbonate solution, spin dry the solvent, and perform column chromatography (eluent: petroleum ether/ Ethyl acetate=10:1~5:1) was isolated to obtain compound 6e (86 mg, 78.6%).

¹ H 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).

Step 5: Spiro[bicyclo[4.2.0]octane 7,2'-[1,3]dioxolane]-2-ol ( 6f )

Compound 6e (450 mg, 3.68 mmol) was dissolved in tetrahydrofuran (1.5 mL), and the temperature was lowered to zero degrees Celsius. Lithium tetrahydroaluminum (450 mg, 3.68 mmol) was added thereto, and the temperature was raised to 65 degrees Celsius and reacted 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, respectively. The insolubles were removed by filtration, and then 20 ml of saturated sodium bicarbonate solution was added to quench the reaction, extracted with dichloromethane (50 mL×3) and the organic phases were combined. ether/ethyl acetate=8:1~3:1) was isolated to obtain compound 6f (420 mg, 77%).

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).

The sixth step: 2-hydroxybicyclo[4.2.0]octan-7-one ( 6g )

2-hydroxybicyclo[4.2.0]octan-7-one

Compound 6f (120 mg, 2.36 mmol) was dissolved in concentrated hydrochloric acid in methanol (1 M, 1.5 mL) 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 separate by column chromatography (eluent: petroleum ether/ethyl acetate=8:1~3:1) Compound 6g was obtained (89 mg, 79%).

¹ H NMR (400MHz, Chloroform-d) δ 4.15(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).

Step 7: Bicyclo[4.2.0]octan-2-ol ( 6h )

bicyclo[4.2.0]octan-2-ol

Compound 6g (320 mg, 3.56 mmol) was dissolved in ethylene glycol (1 M, 1.5 mL), hydrazine hydrate and potassium hydroxide (140 mg, 4.5 mmol) were sequentially added thereto, and the temperature was raised to 160° C. to react for one hour. Excess hydrazine hydrate and water were removed by rotary evaporation. Then the temperature was raised to 200 degrees Celsius and the reaction was carried out for two hours. A large amount of water was added to the reaction system, extracted with dichloromethane and the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound 6h (270 mg, 69%).

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).

Step 8: Bicyclo[4.2.0]octan-2-ol ( 6i )

bicyclo[4.2.0]octan-2-ol

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°C to react for one hour. The insoluble matter was removed by filtration, and silica gel was added to the filtrate, followed by column chromatography (eluent: petroleum ether/ethyl acetate=8:1~3:1) to obtain compound 6i (79 mg, 77%).

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).

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)acetate

Compound 6i (3.0 g, 21.4 mmol) was dissolved in tetrahydrofuran (30 mL), the temperature was lowered to minus 78 degrees Celsius, LHMDS (1 M, 23.5 mL) was added to it, and diethyl oxalate (3.4 mL) was added to it after half an hour. g, 23.5 mmol), warmed to room temperature and reacted overnight. The reaction was quenched with dilute hydrochloric acid (1M, 30mL), extracted with ethyl acetate (50mL×3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, and silica gel was added to the sample column chromatography (eluent: petroleum ether/acetic acid). Ethyl ester=5:1~2:1) was separated to obtain compound 6j (1.9 g, 37.0%).

LC-MS (ESI): m/z=225.2 [M+H] ⁺ .

The tenth step: 1-(pyrazin-2-yl)-4,5,5a,6,7,7a-hexahydro-1hydro-cyclobutyl[g]indazole-3-carboxylate ethyl ester ( 6k )

ethyl 1-(pyrazin-2-yl)-4,5,5a,6,7,7a-hexahydro-1H-cyclobuta[g]indazole-3-carboxylate

Compound 6j (2.1 g, 8.8 mmol) was dissolved in sulfuric acid ethanol solution (1:100 (v/v), 21 mL), and pyrazine-2-hydrazine (1.45 g, 13.2 mmol) was added thereto at room temperature, The temperature was raised and refluxed for half an hour. The reaction solution was spin-dried, and silica gel mixed sample column chromatography (eluent: petroleum ether/ethyl acetate=5:1~2:1) was added to separate to obtain compound 6k (1.85g, 73.4%).

LC-MS (ESI): m/z=299.4 [M+H] ⁺ .

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 acid

Compound 6k (0.15 g, 0.54 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL), and thereto was added sodium hydroxide solution (2M, 10 mL) at room temperature. The reaction was carried out at room temperature for two hours. The pH of the reaction solution was adjusted to 6, extracted with dichloromethane (50 mL×3), and the organic phases were combined, and the organic phases were spin-dried to obtain compound 61 , which was used for later use without purification.

LC-MS(ESI): m/z=271.2[M+H] ⁺

The twelfth step: 3-(3-carboxy-4,5,5a,6,7,7a-hexahydro-1hydro-cyclobutan[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-oxide

Compound 61 (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. The reaction was carried out at room temperature for two hours. Add 15 ml of water, extract with dichloromethane (50 mL×3), combine the organic phases, spin dry to obtain compound 6m , which is used for later use without purification.

LC-MS (ESI): m/z=287.2 [M+H] ⁺ .

Thirteenth Step: 3-(3-((((S)-1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl))-4,5,5a,6,7,7a-hexahydro- 1H-Cyclobutan[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-oxide

Compound 6m (0.14g, 0.53mmol) was dissolved in dichloromethane (5mL), S-tertiary leucinol (68mg, 0.58mmol), HATU (262mg, 0.69mmol), DIPEA (137mg) were added thereto at room temperature , 1.06 mmol). The reaction was carried out at room temperature for two hours. The reaction was quenched by adding 30 ml of water, extracted with dichloromethane (50 mL×3), and the organic phases were combined. The crude product after concentration of the organic phase was separated by high-performance liquid phase preparation to obtain compound 6 (60 mg, 41.6%).

Preparation method: 1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×250mm). 2. The sample was dissolved in DMF and filtered with a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatography 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. The flushing time is 20min. Peak time: 11.3min.

LC-MS (ESI): m/z=386.4 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ 9.20(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).

Example 7

3-(((5aS,6aR)-3-((1-(hydroxymethyl)cyclopentyl)aminocarboxy)-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-oxide

3-(((5aR,6aS)-3-((1-(hydroxymethyl)cyclopentyl)aminocarboxy)-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-oxide

Compound 4 (8 g, 21.7 mmol) was separated by chiral preparation to obtain compound 7a (approximately 4.31 min, 3.49 g, 43.6%) and 7b (approximately 4.84 min, 3.49 g, 43.6%) .

Preparative chromatography conditions: chromatographic column ChiralCel OJ, 300×50 mm I.D., 10 μm, mobile phase system: carbon dioxide/methanol=70/30(v), flow rate 200 mL/min. Compound 7a (3.49 g), compound 7b (3.49 g) were obtained.

Compound 7a

1H NMR (400MHz, CDCl ₃ )δ 8.83-8.84(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).

Compound 7b

1H NMR (400MHz, CDCl ₃ )δ 8.83-8.84(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).

Example 8

3-(((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)aminocarbamoyl)-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-oxide

The first step: (5aR,6aS)-ethyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropane[g]indazole-3-carboxylic acid Esters ( 8b )

(5aR,6aS)-ethyl-1-(pyrazin-2-yl)-1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-3-carboxylate

Compound 8a (10g, 0.09mol) was dissolved in 200ml of ethanol solution, then diethyl oxalate (13g, 0.09mol) and potassium tert-butoxide (10g, 0.09mol) were added under stirring, and then the temperature was raised to 40°C and stirred for reaction 2 hours, then slowly add 6M hydrochloric acid solution (50ml), add pyrazine hydrazine (10g, 0.09mol) after stirring for 5 minutes, then the reaction solution is raised to 50 ℃ and continue to react for 2 hours, after TLC detects that the reaction is complete, the reaction solution After cooling to room temperature, add saturated sodium bicarbonate solution to adjust 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, spin dry, Purified by column chromatography (eluent PE/EA=1/1) to obtain 13g ( 8b ) of yellow oil with a yield of 50.4%.

LC-MS (ESI): m/z=285.31 [M+H] ⁺ .

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

Compound 8b (13g, 0.05mol) was dissolved in a mixed solvent of 100ml methanol and 100ml tetrahydrofuran, and then an aqueous solution of sodium hydroxide (1.5g, 0.04mol) was slowly added. After the addition was completed, the mixture was stirred at room temperature overnight, and 2M was added. The pH of the reaction solution was adjusted to about 3 with dilute hydrochloric acid, then 300ml of water was added, and after extraction with dichloromethane (500mL×3) three times, the organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain 10g ( 8c ) of yellow powder solids , the yield is 85.5%.

LC-MS (ESI): m/z=257.3 [M+H] ⁺ .

The third step: 3-(((5aR,6aS)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropane[g]indazol-1(4H)-yl)pyrazine 1-oxide ( 8d )

((5aR,6aS)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide

The raw material 8c (10g, 0.04mol) was dissolved in 100ml of formic acid solution, then 30% hydrogen peroxide solution (10ml) was added, the temperature was raised to 64°C and 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-dried the obtained brown oily substance directly for the next step reaction.

LC-MS (ESI): m/z=273.3 [M+H] ⁺ .

The fourth step: 3-(((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)aminocarbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[ g]Indazol-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-oxide

The raw material 8d (300 mg, 1.1 mmol) was dissolved in 10 ml of DMF solution, and then 1-(trifluoromethyl)cyclopropylamine (0.14 g, 1.1 mmol) and HATU (0.42 g, 1.1 mmol), triethylamine ( 0.36g, 3.3mmol), stirred at room temperature overnight, TLC monitored the reaction to complete, then added 100ml of water to the reaction solution, extracted three times with ethyl acetate (100mL×3), combined the organic phases, dried over anhydrous sodium sulfate and spin-dried, Purified by column chromatography (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] ⁺ .

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).

Example 9:

3((5aR,6aS)-3-((S)-2-hydroxy-1-phenylethyl)aminocarboxy)-5,5a,6,6a--tetrahydrocyclopropyl[g] Indazol-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-oxide

The first step: 3((5aR,6aS)-3-((S)-2-hydroxy-1-phenylethyl)aminocarbamoyl)-5,5a,6,6a--tetrahydrocyclopropane yl[g]indazol-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

The raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, then (S)-2-amino-2-phenethyl alcohol (0.14g, 1mmol) and HATU (0.57g, 1.5mmol) were added, triethyl Amine (0.3g, 3mmol), stirred at room temperature overnight, added 50ml of water to the reaction solution, then extracted three times with ethyl acetate (50mL×3), combined the organic phases, dried over anhydrous sodium sulfate and spin-dried, column chromatography ( Eluent (MeOH/DCM=1/10) was separated and purified to obtain 137 mg of white solid ( compound 9 ) with a yield of 35.03%.

LC-MS (ESI): m/z=392.4 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ 8.82-8.83(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).

Example 10:

3-((5aR,6aS)-3-((2-phenylpropan-2-yl)aminocarboxy)-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-oxide

The first step: 3-((5aR,6aS)-3-((2-phenylpropan-2-yl)aminocarbamoyl)-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-oxide

Raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, then 2-phenylpropan-2-amine (0.14g, 1mmol) and HATU (0.57g, 1.5mmol), triethylamine (0.3g, 3 mmol), stirred at room temperature overnight, added 50 ml of water to the reaction solution, then extracted three times with ethyl acetate (50 mL×3), combined the organic phases, dried over anhydrous sodium sulfate and spin-dried, column chromatography (eluent MeOH/DCM) = 1/10) separation and purification to obtain 65 mg of white solid ( compound 10 ) with a yield of 16.8%.

LC-MS (ESI): m/z=390.45 [M+H] ⁺ .

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).

Example 11:

3-((5aR,6aS)-3-((2-methyl-1-morpholinopropan-2-yl)aminocarbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g ]Indazol-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-oxide

Compound 8d (220 mg, 0.81 mmol) was dissolved in DMF (10 mL), and thereto were added HATU (400 mg, 1.1 mmol), DIPEA (2.0 mL), 2-methyl-1-morpholinopropane-2 at room temperature - Amine (256 mg, 1.62 mmol). The reaction was carried out at room temperature for two hours. Dilute hydrochloric acid was adjusted to neutrality, extracted with dichloromethane (50 mL×3) and the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the mixture was separated and purified by column chromatography (eluent MeOH/DCM=1/10). Compound 11 was obtained (60 mg, 14.6%).

LC-MS (ESI): m/z=413.2 [M+H] ⁺ .

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).

Intermediate synthesis of 8d and 4a-1:

Intermediate compound 8d 3-(((5aR,6aS)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropane[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

Intermediate compound 4a-1 3-(((5aS,6aR)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropane[g]indazol-1(4H)-yl)pyrazine 1-oxidation thing

3-((5aS,6aR)-3-carboxy-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)pyrazine 1-oxide

Compound 4a (2g, 7.35mmol) was isolated by chiral preparation to obtain compound 8d (0.56g, 28%), compound 4a-1 (0.62g, 31%), preparative chromatography conditions: chromatographic column ChiralPak AD, 250×30mm ID, 10 μm, mobile phase system: carbon dioxide/ethanol=45/55(v), flow rate 80 mL/min, to obtain compound 8d (peak time is about 2.746min), compound 4a-1 (peak time is about 3.790min).

Compound 8d

1H NMR (400MHz, _CDCl3 )δ 8.63-8.64(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).

Compound 4a-1

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).

Example 12:

3-((5aR,6aS)-3-((1-Methoxy-2-methyl-1-oxopropan-2-yl)aminocarbamide)-5,5a,6,6a-tetrahydrocyclopropane [g]Indazol-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-oxide

The first step: 3-((5aR,6aS)-3-((1-methoxy-2-methyl-1-oxopropan-2-yl)amine methyl Acyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indazol-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-oxide

The raw material 8d (0.27 g, 1 mmol) was dissolved in 10 ml of DMF solution, and then 2-amino-2-methylpropionic acid methyl ester (0.17 g, 1 mmol) and HATU (0.57 g, 1.5 mmol) were added, triethyl Amine (0.3 g, 3 mmol), stirred at room temperature overnight, added 50 ml of water to the reaction solution, then extracted with ethyl acetate (50 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, removed the solvent under reduced pressure, and performed column chromatography (Eluent MeOH/DCM=1/10) was separated and purified to obtain 62 mg of white solid ( Compound 12 ) with a yield of 16.7%.

LC-MS (ESI): m/z=372.4 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ 9.24-9.26(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).

Example 13:

3-((5aR,6aS)-3-((2-cyanopropan-2-yl)aminocarboxamide)-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-oxide

The first step: 3-((5aR, 6aS)-3-((2-cyanopropan-2-yl)aminocarbamide)-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-oxide

Raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, then 2-amino-2-methylpropionitrile (0.084g, 1mmol) and HATU (0.57g, 1.5mmol), triethylamine ( 0.3 g, 3 mmol), stirred at room temperature overnight, added 50 ml of water to the reaction solution, then extracted with ethyl acetate (50 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, removed the solvent under reduced pressure, and chromatographed (washed) Extraction agent MeOH/DCM=1/10) was separated and purified to obtain 65 mg of white solid ( compound 13 ), the yield was 19.2%.

LC-MS (ESI): m/z=339.36 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ 9.21-9.23(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).

Example 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-oxide

The first step: 3-((5aR,6aS)-3-((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[ g]Indazol-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-oxide

Raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, then (tetrahydro-2H-pyran-4-yl)formamide (0.115g, 1mmol) and HATU (0.57g, 1.5mmol) were added , triethylamine (0.3g, 3mmol), stirred at room temperature overnight, added 50ml of water to the reaction solution, then extracted with ethyl acetate (50mL×3), combined the organic phases, dried over anhydrous sodium sulfate, and removed the solvent under reduced pressure, Column chromatography (eluent MeOH/DCM=1/10) was used for separation and purification to obtain 75 mg of white solid ( compound 14 ), with a yield of 20.3%.

LC-MS (ESI): m/z=370.42 [M+H] ⁺ .

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)

Example 15:

3-((5aR,6aS)-3-((tetrahydro-2H-pyran-4-yl)aminocarboxyl)-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- oxide

The first step: 3-((5aR,6aS)-3-((tetrahydro-2H-pyran-4-yl)aminocarbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g ]Indazol-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- oxide

Raw material 8d (0.27 g, 1 mmol) was dissolved in 10 ml of DMF solution, then tetrahydropyran-4-amine (0.10 g, 1 mmol) and HATU (0.57 g, 1.5 mmol), triethylamine (0.3 g, 1.5 mmol) were added. 3 mmol), stirred at room temperature overnight, added 50 ml of water to the reaction solution, then extracted with ethyl acetate (50 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, removed the solvent under reduced pressure, and chromatographed (eluent MeOH). /DCM=1/10) was separated and purified to obtain 62 mg of white solid ( compound 15 ) with a yield of 17.5%.

LC-MS (ESI): m/z=356.39 [M+H] ⁺ .

¹ H NMR (400 MHz, 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).

Example 16:

3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)aminocarboxy)-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-oxide

The first step: 3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)amine carboxamide)-5,5a,6,6a-tetrahydrocyclopropyl[g]indium oxazol-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-oxide

The raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, then (1-aminocyclopropyl) methanol (0.087g, 1mmol) and HATU (0.57g, 1.5mmol), triethylamine (0.3 g, 3 mmol), stirred at room temperature overnight, added 50 ml of water to the reaction solution, then extracted with ethyl acetate (50 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, removed 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] ⁺ .

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).

Example 17:

3-((5aR,6aS)-3-((2-(hydroxymethyl)oxetan-2-yl)aminocarbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g ]Indazol-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 -oxide

The first step: 3-((5aR,6aS)-3-((2-(hydroxymethyl)oxetan-2-yl)aminocarbamoyl)-5,5a,6,6a-tetrahydro Cyclopropane[g]indazol-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 -oxide

Raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, then (2-aminooxetan-2-yl)methanol (0.10g, 1mmol) and HATU (0.57g, 1.5mmol) were added, Triethylamine (0.3 g, 3 mmol), stirred at room temperature overnight, added 50 ml of water to the reaction solution, then extracted with ethyl acetate (50 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, removed the solvent under reduced pressure, column Chromatography (eluent MeOH/DCM=1/10) was used for separation and purification to obtain 61 mg of white solid ( compound 17 ) with a yield of 17.1%.

LC-MS (ESI): m/z=358.36 [M+H] ⁺ .

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).

Example 18:

3-((5aR,6aS)-3-((1-phenylcyclopropyl)aminocarboxy)-5,5a,6,6a-tetrahydrocyclopropane[g]indazol-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-oxide

The first step: 3-((5aR,6aS)-3-((1-phenylcyclopropyl)amine carboxamide)-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-oxide

Raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, then 1-phenylcyclopropaneamine (0.13g, 1mmol) and HATU (0.57g, 1.5mmol), triethylamine (0.3g, 3mmol) were added ), stirred at room temperature overnight, added 50 ml of water to the reaction solution, then extracted with ethyl acetate (50 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, removed the solvent under reduced pressure, and chromatographed (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] ⁺ .

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).

Example 19:

3-((5aR,6aS)-3-((S)-2,3-dihydroxypropyl)aminocarboxamide)-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- oxide

The first step: 3-((5aR,6aS)-3-((S)-2,3-dihydroxypropyl)amine carboxamide)-5,5a,6,6a-tetrahydrocyclopropane[g]indium oxazol-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- oxide

Raw material 8d (0.27g, 1mmol) was dissolved in 10ml of DMF solution, then (S)-3-aminopropane-1,2-diol (0.09g, 1mmol) and HATU (0.57g, 1.5mmol) were added , triethylamine (0.3g, 3mmol), stirred at room temperature overnight, added 50ml of water to the reaction solution, then extracted with ethyl acetate (50mL×3), combined the organic phases, dried over anhydrous sodium sulfate, and removed the solvent under reduced pressure, Column chromatography (eluent MeOH/DCM=1/10) was used for separation and purification to obtain 105 mg of white solid ( compound 19 ), with a yield of 30.4%.

LC-MS (ESI): m/z=346.35 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ 8.94(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).

Example: 20

3-((5aR,6aS)-3-((R)-1-hydroxy-4-methylpentan-2-yl)aminocarbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g ]Indazol-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-oxide

The first step: 3-((5aR,6aS)-3-((R)-1-hydroxy-4-methylpentan-2-yl)aminoformamide)-5,5a,6,6a-tetrahydro Cyclopropane[g]indazol-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-oxide

Raw material 8d (0.27 g, 1 mmol) was dissolved in 10 ml of DMF solution, then (R)-2-amino-4-methylpentan-1-ol (0.12 g, 1 mmol) and HATU (0.57 g, 1.5 mmol), triethylamine (0.3g, 3mmol), stirred at room temperature overnight, added 50ml of water to the reaction solution, then extracted with ethyl acetate (50mL×3), combined the organic phases, dried over anhydrous sodium sulfate, and removed under reduced pressure The solvent was separated and purified 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] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ 8.81-8.84(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).

Example 21:

3-((5aS,6aR)-3-((1-(hydroxymethyl)cyclopropyl)aminocarboxy)-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-oxide

The first step: 3-((5aR,6aS)-3-((1-(hydroxymethyl)cyclopropyl)amine carboxamide)-5,5a,6,6a-tetrahydrocyclopropyl[g]indium oxazol-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-oxide

The raw material 4a-1 (0.27g, 1mmol) was dissolved in 10ml of DMF solution, then 21a (0.087g, 1mmol) and HATU (0.57g, 1.5mmol), triethylamine (0.3g, 3mmol) were added, and stirred at room temperature Overnight, 50 ml of water was added to the reaction solution, then extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate and spun to dryness, column chromatography (eluent MeOH/DCM=1/10) After separation and purification, 70 mg of white solid ( compound 21 ) was obtained with a yield of 20.5%.

LC-MS (ESI): m/z=342.2 [M+H] ⁺ .

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).

Example 22:

3-(((5aS,6aR)-3-((1-(trifluoromethyl)cyclopropyl)aminocarboxy)-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

3-(((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)aminocarbamoyl)-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-oxide

The first step: 3-(3-((1-(trifluoromethyl)cyclopropyl)aminocarboxyl)-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-oxide

Raw material 4a (400g, 1.47mol) was dissolved in 5L of DMF solution, then 1-trifluoromethylcyclopropylamine hydrochloride (183.8g, 1.47mmol) and HATU (670.3g, 1.76mol) were added, triethylamine (445.41g, 4.4mmol), stirring at room temperature for 2 hours, adding the reaction solution to 10L of ice water, stirring for half an hour, then suction filtration, the solid obtained was washed three times with water, and after drying, a white solid 372g ( compound 22 ) was obtained. The rate is 66.8%.

LC-MS (ESI): m/z=380.3 [M+H] ⁺ .

1H NMR (400MHz, CDCl ₃ )δ 8.83-8.91(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).

The second step: 3-(((5aS,6aR)-3-((1-(trifluoromethyl)cyclopropyl)aminocarbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[ g]Indazol-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

3-(((5aR,6aS)-3-((1-(trifluoromethyl)cyclopropyl)aminocarbamoyl)-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-oxide

Compound 22 (372g, 0.98mol) was isolated by chiral preparation to obtain compound 22a (145g, 39.4%), compound 22b (150g, 40.4%), preparative chromatography conditions: chromatographic column ChiralCel OJ, 300×50mm ID, 10μm, mobile phase System: carbon dioxide/ethanol=65/35(v), flow rate 200mL/min, to obtain compound 22a (peak time is about 2.746min), compound 22b (peak time is about 3.790min, same as compound 8).

Compound 22a

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).

Compound 22b

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).

Example 23

3-((5aR,6aS)-3-((1-Hydroxy-2-methylpropan-2-yl)aminocarbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indium oxazol-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

Raw material 8d (1 g, 3.7 mmol) was dissolved in 10 ml of DMF solution, then 2-amino-2-methylpropan-1-ol (0.33 g, 3.7 mmol) and HATU (1.7 g, 4.4 mmol) were added, Triethylamine (1.1 g, 11.1 mmol), stirred at room temperature overnight, added 100 ml of water to the reaction solution, then extracted with ethyl acetate (100 mL×3), combined the organic phases, dried over anhydrous sodium sulfate and spin-dried, the column layer Purification by analytical (eluent MeOH/DCM=1/10) gave 320 mg of pale yellow solid ( 23a ) with a yield of 34.8%.

LC-MS (ESI): m/z=344.3 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ 9.66-9.79(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-Hydroxy-2-methylpropan-2-yl)aminocarbamoyl)-5,5a,6,6a-tetrahydrocyclopropane[g]indium oxazol-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

Raw material 4a-1 (1 g, 3.7 mmol) was dissolved in 10 ml of DMF solution, then 2-amino-2-methylpropan-1-ol (0.33 g, 3.7 mmol) and HATU (1.7 g, 4.4 mmol) were added ), triethylamine (1.1g, 11.1mmol), stirred at room temperature overnight, added 100ml of water to the reaction solution, then extracted with ethyl acetate (100mL×3), combined the organic phases, dried over anhydrous sodium sulfate and spin-dried, Purified by column chromatography (eluent MeOH/DCM=1/10) to obtain 370 mg of pale yellow solid ( 23b ) with a yield of 40.2%.

LC-MS (ESI): m/z=344.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.46-9.72 (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).

Example 24:

3-((5aR,6aS)-3-(((R)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)aminocarboxy) -5,5a,6,6a-Tetrahydrocyclopropane[g]indazol-1(4H)-yl)pyrazine-1-oxide

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-oxide

3-((5aR,6aS)-3-(((S)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)aminocarboxy) -5,5a,6,6a-Tetrahydrocyclopropane[g]indazol-1(4H)-yl)pyrazine-1-oxide

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 )

The first step: 3-((5aR,6aS)-3-(((R)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)amino Carboxylo-5,5a,6,6a-tetrahydrocyclopropane[g]indazol-1(4H)-yl)pyrazine-1-oxide

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-oxide

3-((5aR,6aS)-3-(((S)-4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)aminocarboxy) -5,5a,6,6a-Tetrahydrocyclopropane[g]indazol-1(4H)-yl)pyrazine-1-oxide

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 )

Under nitrogen protection, DMF (3 mL), DIPEA (78 mg, 1.1 mmol), HATU (228 mg, 0.6 mmol), 2-amino-4,4, 2-amino-4,4 were added to compound 8d (0.15 g, 0.55 mmol) at room temperature. 4-Trifluoro-3,3-dimethylbutan-1-ol ( int-1 ) (187 mg, 1.1 mmol), stirred at room temperature for 3 h. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction to quench the reaction, extracted with ethyl acetate (50 mL×3), left to stand for layers, the aqueous phase was extracted with dichloromethane (20 mL), and the combined organic phases were washed with anhydrous It was dried over sodium sulfate and concentrated under reduced pressure to obtain the residue, namely the crude product. The crude product was separated by high performance liquid phase preparation to obtain compound 24a , pale yellow solid (33 mg, yield 11.18%) and compound 24b , pale yellow solid (34 mg, yield 14.51 %). %).

Preparation conditions:

Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire C18 5μm, 19x250mm. The sample was dissolved in water and filtered with a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water (containing 1% TFA). Gradient elution, mobile phase A content from 5% to 50%. Flow 12ml/min. The brewing time is 15min. Compound 24a : Rt=8.46min, the configuration is uncertain; Compound 24b : Rt=9.05min, the configuration is uncertain.

Compound 24a :

¹ H NMR (400MHz, CDCl ₃ )δ 8.87(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] ⁺ .

Compound 24b :

¹ H NMR (400MHz, CDCl ₃ )δ 8.95(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] ⁺ .

biological test

1. Detection of CB2 agonist activity

Experimental objects: compounds of the examples of the present invention.

experimental method:

CHO cells with high expression of human CB2 were suspended in HBSS buffer (containing 20mM HEPES, pH=7.4), and 7.5×10 ³ cells per well (cell density was 1.5×10 ⁶ cells/mL) were seeded on the added sample ( HBSS, positive control WIN 55212-2 or different concentrations of Example compounds) in 384-well white plates. A final concentration of 3 μM adenylate cyclase activator NKH 477 was added to the above 384-well plate. After 10 min incubation at 37°C, cells were lysed and D2-labeled cAMP and europium cryptate-labeled cAMP antibodies were added. After 1 hour incubation at room temperature, HTRF detection (λex=337 nm, λem=620 and 665 nm) was performed with a microplate reader (Envison, Perkin Elmer). The signal ratio Ratio (Signal 665/Signal 620*10 ⁴ ) was calculated, and the results were expressed as a percentage value relative to 100 nM WIN 55212-2, and the _EC50 value was fitted using the DoseResp function. The results are shown in Table 1.

Note: ND means not tested.

APD-371 is compound 699 of patent document WO2011025541.

Conclusion: The compounds of the present invention show higher agonistic activity for CB ₂ receptors, and some compounds, especially compounds 3, 4, 8, and 22a, show higher selectivity for CB ₂ /CB ₁ receptors.

2. Pharmacokinetic test in rats

Experimental purpose: The test substance was administered to SD rats through a single dose of intravenous and intragastric administration, the concentration of the test substance in the rat plasma was determined, and the pharmacokinetic characteristics and bioavailability of the test substance in rats were evaluated.

Experimental objects: APD-371 and the compounds of the examples of the present invention.

Test animals: male SD rats, about 220 g, 6-8 weeks old, 6 rats/compound. Purchased from Chengdu Dashuo Laboratory Animal Co., Ltd.

Test method: On the test day, 6 SD rats were randomly divided into groups according to their body weight. Fasting for 12-14 hours on the day before administration, and 4 hours after administration. Dosing according to Table 2.

*Dose is based on free base.

sampling

Before and after administration of isoflurane anesthesia, 0.1 ml of blood was collected from the orbit and placed in an EDTAK2 centrifuge tube. The plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min.

Time points of plasma collection in group G1: 0, 2, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h.

Time points of plasma collection in group G2: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h.

All samples were stored at -80°C prior to analysis.

sample preparation

Take 30 μL of plasma sample, standard curve and quality control sample, add 200 μL of acetonitrile solution containing internal standard, vortex and mix, and then centrifuge at 12000 rpm for 10 min at 4°C. 170 μL of supernatant was taken into a 96-well plate for LC-MS/MS analysis, and the injection volume was 5 μL.

The main pharmacokinetic parameters were analyzed using WinNonlin 8.0 software non-compartmental model. The experimental results are shown in Table 3.

APD-371 is compound 699 of patent document WO2011025541.

Conclusion: Compounds 4, 7a, 7b, 8, 22a, 23a, 23b, especially compounds 8, 22a, 23a, have good bioavailability and good pharmacokinetic characteristics.

Claims (21)

A tricyclic pyrazole compound represented by formula (I) and its stereoisomer, pharmaceutically acceptable salt, hydrate or N-oxide:

Wherein, 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 heterocyclic group or C _6-10 arylene group, said alkylene group, cycloalkenylene group, cycloalkylene group, heterocyclic group and arylene group are each independently optionally substituted by 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 alkane oxy, 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 cycloalkyl; L ₂ is selected from C _1-6 alkylene, C _3-6 heterocyclylene or absent, and said alkylene and cycloalkylene are each independently optionally substituted as follows Base substitution: C _1-6 alkyl or halogen; L ₃ is selected from C _1-6 alkylene or absent; L ₄ is selected from H or halogen X is CR ^2' R ² ; R ² and R ^2' are selected from H, halogen, cyano, hydroxyl or C _1-6 alkyl; C ring is a 3- to 6-membered cycloalkane optionally substituted by 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; R ⁴ , R ⁵ , R ⁶ , R ⁹ are each independently selected from H, F, Cl, amine R ¹⁰ _{is selected from H or C 1-6 alkyl ;} R ¹¹ is selected from -(CH ₂ ) _m -C _6-10 aryl group or -(CH ₂ ) _m -C _5-10 heteroaryl, the aryl or heteroaryl is optionally substituted by the following substituents: F, Cl, hydroxyl, cyano, amine, C _1-6 Alkyl or C _1-6 alkoxy, the heteroaryl group contains 1-3 heteroatoms selected from N, O, S and their oxidation states; m is selected from 0, 1, 2, 3, 4 or 5 . The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, hydrates or N-oxides according to claim 1, wherein: R ¹ is selected from C _1-6 alkyl, C _{3- 6} cycloalkyl, C _3-6 heterocyclyl or C _6-10 aryl, the alkyl, cycloalkyl heterocyclyl or aryl is optionally substituted by the following substituents: F, Cl, hydroxyl, C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl, halogenated 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 is selected from C _1-6 alkyl or C _3-6 cycloalkyl, and the alkyl and cycloalkyl are optionally substituted by the following substituents : F, Cl, hydroxyl, halogenated C _1-6 alkyl, hydroxyl substituted C _1-6 alkyl, phenyl. The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, hydrates or N-oxides according to claim 2, wherein: R ¹ is selected from

,

,

, pyrrolyl, pyridyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, morpholinyl,

,

,

,

,

,

,

,

,

,

or

; or R ¹ is selected from

,

,

,

,

,

,

; or R ¹ is selected from

,

,

,

. The tricyclic pyrazole compound and its stereoisomer, pharmaceutically acceptable salt, hydrate or N-oxide according to claim 1, wherein: X is CR ^2' R ² ; R ² , R ^2' Selected from H, halogen or C _1-6 alkyl. The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, hydrates or N-oxides according to claim 4, wherein: X is CR ^2' R ² ; R ² , R ^2' Selected from H, F, methyl, fluoromethyl. The tricyclic pyrazole compound and its stereoisomer, pharmaceutically acceptable salt, hydrate or N-oxide according to claim 5, wherein R ² and R ^2′ are H. The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, hydrates or N-oxides according to claim 1, wherein: the C ring is cyclopropane, cyclobutane or cyclopentane, The cyclopropane, cyclobutane or cyclopentane is optionally substituted with 0 to 2 R ⁷ ; each R ⁷ is independently selected from F. The tricyclic pyrazole compound and its stereoisomer, pharmaceutically acceptable salt, hydrate or N-oxide according to claim 7, wherein the C ring is cyclopropyl or cyclobutyl. The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, hydrates or N-oxides according to claim 1, wherein: R ⁴ , R ⁵ , R ⁶ , and R ⁹ are each independently selected From H or C _1-6 alkyl. The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, hydrates or N-oxides according to claim 1, wherein: R ¹¹ is selected from C _6-10 aryl or C _{5- 10} Heteroaryl, the aryl or heteroaryl is optionally substituted by the following substituents: F, Cl or C _1-6 alkyl, the heteroaryl contains 1-3 selected from N, O, S heteroatoms and their oxidation states. The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, hydrates or N-oxides according to claim 10, wherein: R ¹¹ is selected from

,

or

. The tricyclic pyrazole compound according to claim 11 and its stereoisomers, pharmaceutically acceptable salts, hydrates or N-oxides, wherein R ¹¹ is selected from

or

. The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, hydrates or N-oxides according to claim 1, wherein: 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 hydroxyl; X is CR ^2' R ² ; R ² and R ^2' are selected from H, F, methyl or fluoromethyl; C ring is cyclopropane, cyclobutane or cyclopentane, the ring Propane, cyclobutane or cyclopentane are optionally substituted by 0 to 2 R ⁷ ; R ⁷ is each independently selected from F; R ⁴ , R ⁵ , R ⁹ are each independently selected from H; R ⁶ is selected from H or methyl ; R ¹⁰ is selected from H; R ¹¹ is selected from

,

or

. The tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, hydrates or N-oxides according to claim 1, wherein: R ¹ is selected from

,

,

or

; X is CR ^2' R ² ; R ² and R ^2' are selected from H; 2 R ⁷ are substituted; R ⁷ is independently selected from F; R ⁴ , R ⁵ , R ⁹ are each independently selected from H; R ⁶ is selected from H or methyl; R ¹⁰ is selected from H; R ¹¹ is selected from

. The tricyclic pyrazole compound and its stereoisomer, pharmaceutically acceptable salt, hydrate or N-oxide according to claim 1, wherein the compound structure is as follows:

The tricyclic pyrazole compound and its stereoisomer, pharmaceutically acceptable salt, hydrate or N-oxide according to claim 15, wherein the compound structure is as follows:

A pharmaceutical composition comprising: an effective dose of the tricyclic pyrazole compound and its stereoisomers, pharmaceutically acceptable salts, hydrates or N-oxide, or further include one or more other therapeutic agents and a pharmaceutically acceptable carrier or excipient. A tricyclic pyrazole compound and its stereoisomer, pharmaceutically acceptable salt, hydrate or N-oxide according to any one of claims 1 to 16 or the composition of claim 17 in Use in the manufacture of a medicament for the treatment of diseases mediated by CB2 receptors. According to the use of claim 18, the disease mediated by CB2 receptors is pain. The use according to claim 19, wherein the pain is selected from the group consisting of: bone pain, arthralgia, muscle pain, dental pain, migraine, headache, inflammatory pain, neuropathic pain, abdominal pain associated with Crohn's disease, adverse effects due to therapeutic agents Pain due to action and pain associated with a disease selected from the group consisting of: Arthritis, cancer, multiple sclerosis, allergic response, nephritic syndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia, HIV-related neuropathy, sciatica, and autoimmune diseases. Use according to claim 20, wherein the pain is selected from neuropathic pain, abdominal pain associated with Crohn's disease.