CN117069720A - 5-HT 2A Receptor agonist, preparation method and application thereof - Google Patents

5-HT 2A Receptor agonist, preparation method and application thereof Download PDF

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CN117069720A
CN117069720A CN202310548498.4A CN202310548498A CN117069720A CN 117069720 A CN117069720 A CN 117069720A CN 202310548498 A CN202310548498 A CN 202310548498A CN 117069720 A CN117069720 A CN 117069720A
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membered
compound
methylene
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宋云龙
付一伟
穆永钊
汪笛莎
寇红艳
王峰
张辰
董卫兵
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Shanghai Yishi Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings

Abstract

The invention provides a compound with a brand new structure as a 5-HT2A receptor agonist, a preparation method of the compound and application of the compound in the aspect of treating diseases related to a 5-HT2A receptor. Experiments prove that the compounds have stronger affinity to the 5-HT2A receptor and can be used as the prospect compounds for treating the diseases related to the 5-HT2A receptor.

Description

5-HT 2A Receptor agonist, preparation method and application thereof
Technical Field
The present invention relates to a class of 5-hydroxytryptamine 2A (5-HT) 2A ) Compounds of receptor agonists, methods for their preparation and their use in 5-HT 2A Research in the field of receptor-related diseases.
Background
Depression is a group of mental disorders characterized by significant and persistent mood swings as the primary clinical feature, and is also the most common suicidal-related mental disorder, caused by a variety of causes. World health organization data indicate that: global depression patients in 2015 exceeded 3.2 million people. The time-point incidence rate of Chinese depression is 3.02%, and currently, more than 4000 ten thousand depressed patients exist.
5-hydroxytryptamine receptors, also known as serotonin receptors or 5-HT receptors, are a group of G-protein coupled receptors and ligand-gated ion channels that occur centrally in the central nervous system and peripherally in the peripheral nervous system, and which regulate the delivery of both excitatory and inhibitory neurotransmission substances.
5-HT 2A Receptors, belonging to the 5-HT receptor family, are widely expressed throughout the Central Nervous System (CNS), and are expressed near most serotonergic terminal rich regions, including neocortex (mainly frontal lobe, parietal lobe and somatosensory cortex) and olfactory tuberosities.
Known 5-HT 2A The receptor is coupled primarily to the gαq signaling pathway. Upon stimulation of the receptor with an agonist, the gαq and β - γ subunits dissociate to initiate downstream effector pathways. Gαq stimulates phospholipase C (PLC) activity, followed by promotion of release of Diglyceride (DAG) and inositol triphosphate (IP 3), which in turn stimulates Protein Kinase C (PKC) activity and Ca 2+ Releasing.
In addition to the classical G protein signaling pathway, the currently accepted signaling pathway of GPCRs also has a β -arestin-dependent signaling pathway. Upon activation of the GPCR, a family of protein kinases called G protein coupled receptor kinases (GRKs) phosphorylate the intracellular domain upon G protein release. The phosphorylated GPCRs will recruit β -arestin proteins, which mediate desensitization of GPCR signaling and endocytosis of GPCRs, and thus serve to "turn off" signaling, leading to negative feedback of G-protein dependent GPCR signaling.
Antidepressant drugs currently being clinically recommended are selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), selective 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and specific 5-hydroxytryptamine reuptake inhibitors (NaSSAs), norepinephrine and dopamine reuptake inhibitors (ndis), and the like.
SSRIs: representative drugs are fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram and the like. Common adverse reactions are nausea, vomiting, diarrhea, restlessness, hyposexuality, headache, etc.
SNRIs: representative drugs are venlafaxine, duloxetine, etc. Common adverse reactions are nausea, vomiting, shock symptoms and sexual dysfunction.
NaSSAs: the representative drug is mirtazapine. Common adverse reactions are dry mouth, sedation and weight gain.
NDRIs: the representative drug is bupropion. Common adverse reactions are headache, tremors, convulsions, lassitude, insomnia, gastrointestinal discomfort, etc.
Drugs for treating depression are classified into two major classes, and "typical" antipsychotics have been rarely used in clinic due to side effects of motor functions (extrapyramidal side effects, parkinsonism-like symptoms, etc.) caused to the human body; current drugs are more focused on "atypical" antipsychotics. However, second generation antipsychotics, e.g. 5-HT 2A Receptor agonists (xylosibin, dimemol, ergoline) all have illusive side effects.
Recent studies have shown that shaking head 5-HT is produced in mice 2A Receptor agonists and 5-HT without pan-head production 2A There is a potential signal difference between receptor agonists within the somatosensory cortex, as these drugs are active 5-HT in spite of their activity 2A Receptor agonists, but also have no illusive effect on humans. A known example of a difference in signal transduction is two 5-HT 2A The difference between the receptor agonists serotonin and DOI, which involves differential recruitment of intracellular proteins known as β -arrestin (β -arestin), more specifically arrestin 2. It is therefore desirable to be able to modify 5-HT 2A The receptor agonist realizes the bias to beta-arestin, thereby reducing the fantasy side effect of antidepressants.
Disclosure of Invention
The present invention provides a pharmaceutical composition having 5-HT 2A Compounds having receptor agonistic activity, particularly beta-arestin-biased 5-HT2A receptor agonists, pharmaceutical compositions for treating central nervous system disorders comprising the same, and methods of treating central nervous system disorders are further provided.
In a first aspect of the present invention, there is provided a compound represented by the following formula (I), a stereoisomer, a tautomer, or a mixture thereof, which is a pharmaceutically acceptable salt of:
wherein,
ring A is selected from
L is selected from-C 1-6 Alkylene-, -C 1-6 Alkyloxy-, -C 1-6 Alkylthio-, -C 1-6 alkylene-NH-, -C 1-6 Alkylene-3-8 membered heterocyclyl-, -3-8 membered heterocyclyl-C 1-6 Alkylene-, -3-8 membered heterocyclyl-, said alkylene, alkyleneoxy, alkylenethio, heterocyclyl optionally being substituted with one or more groups each independently selected from deuterium, halogen, oxo (=o), -CN, -OH, -NH 2 、C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituted by substituents of haloalkoxy, formyl, acetyl, carboxamido, acetamido, or two substituents on the same C atom taken together to form C 3-8 Cycloalkyl, 4-8 membered heterocyclyl; the hetero atoms in the heterocyclic group are independently selected from O, N or S, and the number of the hetero atoms is 1 or 2; the left side of the L group is connected with a ring A, and the right side of the L group is connected with a ring B;
ring B is selected from C 6-12 Aryl, 5-12 membered heteroaryl or 5-12 membered heterocyclyl; the hetero atom in the heterocyclic group or the heteroaryl group is independently selected from O, N or S, and the number of the hetero atom is 1, 2 or 3;
each R A Independently selected from H, deuterium, halogen, -OH, -CN, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups;
each R B Independently selected from H, deuterium, halogen, -OH, -CN, oxo, -OC 1-6 Alkyl, C 1-6 Alkyl group，-C 1-6 alkylene-OC 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, carboxyl;
m is selected from 0,1,2,3,4;
n is selected from 0,1,2,3;
unless otherwise indicated, the heteroatoms in the heterocyclyl, heteroaryl groups described above are independently selected from O, N or S, the number of heteroatoms being 1,2,3 or 4.
In a preferred embodiment of the invention, L is-C 1-3 Alkylene-, -C 1-3 Alkyloxy-, -C 1-3 alkylene-NH-, -C 1-3 Alkylene-3-6 membered heterocyclyl-, -3-6 membered heterocyclyl-C 1-3 Alkylene-, -3-6 membered heterocyclyl-, said alkylene, alkyleneoxy, heterocyclyl optionally being substituted with one or more groups each independently selected from deuterium, halogen, oxo, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituted by substituents of haloalkoxy, formyl, acetyl, carboxamido, acetamido, or two substituents on the same C atom taken together to form C 3-8 Cycloalkyl, 4-8 membered heterocyclyl; the left side of the L group is connected with a ring A, and the right side of the L group is connected with a ring B;
in a preferred embodiment of the invention, L is-C 1-3 Alkylene-, -C 1-3 Alkyloxy-, -C 1-3 alkylene-NH-, -C 1-3 Alkylene-4-6 membered heterocyclyl-, -4-6 membered heterocyclyl-C 1-3 Alkylene-, -4-6 membered heterocyclyl-, said alkylene, alkyleneoxy, heterocyclyl optionally being substituted with one or more groups each independently selected from deuterium, halogen, oxo, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclyl, C 1-6 Alkoxy, C 1-3 Substituted by substituents of haloalkyl, acetyl, acetamido, or the same C-atomThe two substituents on the sub-groups being joined together to form C 3-8 Cycloalkyl, 4-8 membered heterocyclyl; the left side of the L group is connected with a ring A, and the right side of the L group is connected with a ring B;
in a preferred embodiment of the invention, L is-C 1-3 Alkylene-, -C 1-3 Alkyloxy-, -C 1-3 alkylene-NH-, -C 1-3 Alkylene-4-6 membered heterocyclyl-, -4-6 membered heterocyclyl-C 1-3 Alkylene-, -4-6 membered heterocyclyl-, said alkylene, alkyleneoxy, heterocyclyl optionally being substituted with one or more groups each independently selected from deuterium, halogen, oxo, -OH, C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclyl, C 1-3 Alkoxy, C 1-3 Substituted by substituent groups of haloalkyl, acetyl and acetamido; the left side of the L group is connected with a ring A, and the right side of the L group is connected with a ring B;
in a preferred embodiment of the present invention, L is-methylene-, -ethylene-, -propylene-, -C 1-3 Alkyloxy-, -C 1-3 alkylene-NH-, -methylene-azetidinyl-, -methylene-tetrahydropyrrolyl-, -methylene-imidazolinyl-, -methylene-pyrazolidinyl-, -methylene-piperidyl-, -methylene-piperazinyl-, -methylene-hexahydropyrimidinyl-, -methylene-oxazolidinyl-, -methylene-thiazolidinyl-, -methylene-isoxazolidinyl-, -methylene-morpholinyl-, -methylene-1, 3-oxazinyl-, -ethylene-azetidinyl-, -ethylene-tetrahydropyrrolyl-, -ethylene-imidazolinyl-, -ethylene-pyrazolidinyl-, -ethylene-piperidinyl-, -ethylene-piperazinyl-, -ethylene-hexahydropyrimidinyl-, -ethylene-oxazolidinyl-, -ethylene-isoxazolidinyl-, -ethylene-morpholinyl-, -ethylene-1, 3-oxazinyl-, -propylene-azetidinyl-, -ethylene-tetrahydropyrrolyl-, -propylene-imidazolinyl-, -propylene-pyrazolinyl-, -pyrazolidinyl-, -piperidinyl ethylene-piperidinyl, -propylene-piperazinyl-, -propylene-hexahydropyrimidinyl-, -propylene-oxazolidinyl-, -propylene-thiazolidine-, -propylene-isoxazolidinyl-, -propylene-morpholinyl-, -propylene-1, 3-oxazinylalkyl-, -azetidinyl-, -tetrahydropyrrolyl-, -imidazolinyl-, -a- -pyrazolidinyl-, -piperidinyl-, -piperazinyl-, -hexahydropyrimidinyl-, -oxazolidinyl-, -thiazolidine-, -isoxazolidinyl-, -morpholinyl-, -1, 3-oxazinyl-, -azetidinyl-methylene-, -tetrahydropyrrolyl-methylene-, -imidazolinyl-methylene-, -pyrazolidinyl-methylene-, -piperidinyl-methylene-, -piperazinyl-methylene-, -hexahydropyrimidinyl-methylene-, -oxazolidinyl-methylene-, -thiazolidine-methylene-, -isoxazolidinyl-methylene-, -morpholino-methylene-, -1, 3-oxazinoalkyl-methylene-, -azetidinyl-tetrahydropyridinyl-, -azetidinyl-imidazolinyl-, -azetidinyl-pyrazolidinyl-, -azetidinyl-piperidinyl-, -azetidinyl-piperazinyl-, -azetidinyl-hexahydropyrimidinyl-, -azetidinyl-oxazolidinyl-, -azetidinyl-thiazolidine-, -azetidinyl-isoxazolidinyl-, -azetidinyl-morpholinyl-, -azetidinyl-1, 3-oxazinyl-, -tetrahydropyrrolyl-imidazolinyl-, -tetrahydropyrrolyl-pyrazolidinyl-, -tetrahydropyrrolyl-piperidinyl-, -tetrahydropyrrolyl-piperazinyl-, -tetrahydropyrrolyl-hexahydropyrimidinyl-, -tetrahydropyrrolyl-oxazolidinyl-, -tetrahydropyrrolyl-thiazolidine-, -tetrahydropyrrolyl-isoxazolidinyl-, -tetrahydropyrrolyl-morpholinyl-, -tetrahydropyrrolyl-1, 3-oxazinyl-, -imidazolinyl-pyrazolidinyl-, -imidazolinyl-piperidinyl-, -imidazolinyl-piperazinyl-, -imidazolinyl-hexahydropyrimidinyl-, -imidazolinyl-oxazolidinyl-, -imidazolinyl-thiazolidine-, -imidazolinyl-isoxazolidinyl-, -imidazolinyl-morpholinyl-, -imidazolinyl-1, 3-oxazinyl-, -pyrazolidinyl-piperidinyl-, -pyrazolidinyl-piperazinyl-, -pyrazolidinyl-hexahydropyrimidinyl-, -pyrazolidinyl-oxazolidinyl-, -pyrazolidinyl-thiazolidine-, -pyrazolidinyl-isoxazolidinyl-, -pyrazolidinyl-morpholinyl-, -pyrazolidinyl-1, 3-oxazinyl-, -piperidinyl-piperazinyl-, -piperidinyl-hexahydropyrimidinyl-, -piperidinyl-oxazolidinyl-, -piperidinyl-thiazolidine-, -piperidinyl-isoxazolidinyl-, -piperidinyl-morpholinyl-, -piperidinyl-1, 3-oxazinylalkyl-, -piperazinyl-hexahydropyrimidinyl-, -piperazinyl-oxazolidinyl-, -piperazinyl-thiazolidine-, -piperazinyl-isoxazolidinyl-, -piperazinyl-morpholinyl-, -piperazine The group-1, 3-oxazinylalkyl-, -hexahydropyrimidinyl-oxazolidinyl-, -hexahydropyrimidinyl-thiazolidine-, -hexahydropyrimidinyl-isoxazolidinyl-, -hexahydropyrimidinyl-morpholinyl-, -hexahydropyrimidinyl-1, 3-oxazinylalkyl-, -oxazolidinyl-thiazolidine-, -oxazolidinyl-isoxazolidinyl-, -oxazolidinyl-morpholinyl-, -oxazolidinyl-1, 3-oxazinylalkyl-, -thiazolidine-isoxazolidinyl-, -thiazolidine-morpholinyl-, -thiazolidine 1, 3-oxazinylalkyl-, -isoxazolidinyl-morpholinyl-, -isoxazolidinyl-1, 3-oxazinylalkyl-, -morpholinyl-1, 3-oxazinylalkyl-; the methylene, ethylene, propylene, alkyleneoxy, alkylene, azetidinyl, tetrahydropyrrolyl, imidazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl, 1, 3-oxazinyl are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, -OH, C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, C 1-3 Alkoxy, C 1-3 Substituted by substituents of haloalkyl, acetyl, acetamido, or two substituents on the same C atom taken together to form C 3-8 Cycloalkyl, 4-8 membered heterocyclyl; the left side of the L group is connected with a ring A, and the right side of the L group is connected with a ring B;
In a preferred embodiment of the invention, L is
Wherein is the a-ring attachment site and is the B-ring attachment site;
in a preferred embodiment of the invention, ring B is C 6-10 Aryl, 6 membered monocyclic heterocyclyl, 7 membered monocyclic heterocyclyl, 5 membered mono-heteroaryl, 6 membered mono-heteroaryl, 5 membered/5 membered fused heterocyclyl, 5 membered/6 membered fused heterocyclyl, 6 membered/5 membered fused heterocyclyl, 4 membered/6 membered fused heterocyclyl, 6 membered/4 membered fused heterocyclylA group, a 6-membered/6-membered fused heterocyclic group, a 5-membered/5-membered fused heteroaryl group, a 5-membered/6-membered fused heteroaryl group, a 6-membered/5-membered fused heteroaryl group, a 6-membered/6-membered fused heteroaryl group, wherein the heteroatoms in the heterocyclic group, heteroaryl group, fused heterocyclic group, fused heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is 1,2 or 3;
in a preferred embodiment of the invention, ring B is phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, 1, 3-dihydroisobenzofuranyl, 2, 3-benzofuranyl, 1, 2-benzisoxazolyl, indolyl, indazolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzisothiazolyl, benzothiophenyl, benzopyranyl, tetrahydroisoquinolyl, tetrahydroquinolinyl, benzopiperazinyl, 7, 8-dihydro-5H-pyran [4,3-B ] pyridinyl, 5, 8-dihydro-6H-pyran [3,4-B ] pyridinyl, 7, 8-dihydro-5H-thiopyran [4,3-B ] pyridinyl, 5,6,7, 8-tetrahydro-1, 7-naphthyridinyl, 7, 8-dihydro-5H-pyran [4,3-B ] pyridinyl, 7, 3-dihydro-5H-pyran [4,3-B ] pyridinyl, 7, 8-dihydro-1, 3-B ] pyridinyl, 7, 3-dihydro-5H-thiopyran [4,3-B ] pyridinyl, 7, 8-tetrahydro-1, 7-naphthyridinyl, 7, 8-dihydro-3-H-pyran [4,3-B ] pyridinyl, 3-B ] pyridinyl;
In a preferred embodiment of the invention, ring B is
In a preferred embodiment of the invention, each R A Independently selected from H, deuterium, halogen, -OH, -CN, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-12 Aryl, 5-12 membered heteroaryl;
in a preferred embodiment of the inventionIn each R A Independently selected from H, deuterium, halogen, -OH, -CN, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, phenyl;
in a preferred embodiment of the invention, each R A Independently selected from H, deuterium, -F, -Cl, -Br, -OH, -CN, -OCH 3 Oxo, methyl, phenyl;
in a preferred embodiment of the invention, each R B Independently selected from H, deuterium, halogen, -OH, -CN, oxo, -OC 1-6 Alkyl, C 1-6 Alkyl, -C 1-6 alkyl-OC 1-6 A carboxyl group;
in a preferred embodiment of the invention, each R B Independently selected from deuterium, halogen, -OH, -CN, oxo, -OC 1-6 Alkyl, C 1-6 Alkyl, -C 1-6 alkyl-OC 1-6 ；
In a preferred embodiment of the invention, each R B Independently selected from H, deuterium, oxo, halogen, -OH, -CN, -OC 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Alkoxy or-C 1-3 alkyl-OC 1-3 A carboxyl group;
in a preferred embodiment of the invention, each R B Independently selected from deuterium, oxo, halogen, -OH, -CN, -OC 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Alkoxy or-C 1-3 alkyl-OC 1-3 ；
In a preferred embodiment of the invention, each R B Independently selected from H, deuterium, oxo, -F, -Cl, -Br, -OH, -CN, -OCH 3 Methyl, carboxyl;
in a preferred embodiment of the invention, each R B Independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -CN, -OCH 3 Methyl group;
in a preferred embodiment of the invention, m is selected from 0,1,2,3;
in a preferred embodiment of the invention, m is selected from 1 and 2;
in a preferred embodiment of the invention, m is 1;
in a preferred embodiment of the invention, n is selected from 0,1 and 2;
in a preferred embodiment of the invention, n is selected from 0 and 1;
the invention also provides a compound shown in the following formula (II), wherein the stereoisomer, tautomer or mixture thereof of the compound is pharmaceutically acceptable salt:
wherein L, ring B, R A 、R B M and n are as described for compounds of formula (I):
in a preferred embodiment of the present invention,is->
In a preferred embodiment of the invention, L is selected from:
in a preferred embodiment of the invention, L is selected from: Wherein × and->Connection to ring B;
in a preferred embodiment of the inventionIn the schemeSelected from->
In a preferred embodiment of the inventionSelected from->
In a preferred embodiment of the present invention,the method comprises the following steps: />
/>
In a preferred embodiment of the present invention,the method comprises the following steps: />
/>
In a preferred embodiment of the present invention, the compound of formula (II) according to the present invention is selected from:
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/>
/>
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the invention also provides a compound represented by the following formula (IV), a stereoisomer, a tautomer, or a mixture thereof, and a pharmaceutically acceptable salt of the compound:
wherein L, ring B, R A ，R B M and n are as described for the compounds of formula (I);
in a preferred embodiment of the present invention,the method comprises the following steps: />In a preferred embodiment of the invention, L is selected from: />Wherein × and->Connection to ring B;
in a preferred embodiment of the present invention,the method comprises the following steps: />
In a preferred embodiment of the invention, the compounds of formula (IV) according to the invention are selected from:
the invention also provides a compound represented by the following formula (V), a stereoisomer, a tautomer or a mixture thereof, and a pharmaceutically acceptable salt of the compound:
Wherein L, ring B, R A ，R B M and n are as described for the compounds of formula (I);
in a preferred embodiment of the present invention,the method comprises the following steps: />
In a preferred embodiment of the invention, L is selected from:wherein is equal toConnection to ring B;
in a preferred embodiment of the inventionSelected from: />
In a preferred embodiment of the present invention, the compounds of formula (V) according to the invention are selected from:
the invention also provides a compound represented by the following formula (VI), a stereoisomer, a tautomer, or a mixture thereof, which is a pharmaceutically acceptable salt:
wherein L, ring B, R A ，R B M and n are as described for the compounds of formula (I);
in a preferred embodiment of the present invention,the method comprises the following steps: />
In a preferred embodiment of the invention, L is selected from: wherein × and->Connection to ring B;
in a preferred embodiment of the present invention,selected from: />
In a preferred embodiment of the present invention, the compounds of formula (VI) of the present invention are selected from:
the object of the present invention is also to provide a process for preparing compounds of formulae (II) to (VI), stereoisomers, tautomers or mixtures thereof, which are pharmaceutically acceptable salts of the compounds.
Including but not limited to the following methods:
the general preparation method is as follows:
the general preparation method is as follows:
and the general preparation method is as follows:
the general preparation method is four:
wherein, in the above preparation method, each substituent in the compound is defined as above, wherein L' is-C 1-3 Alkylene-, -3-8 membered heterocyclyl-, said alkylene, heterocyclyl optionally being substituted with one or more groups each independently selected from oxo, -OH, -NH 2 、C 1-3 Substituted by alkyl; r' is OBn or H; x is halogen, preferably Cl, br;
the present invention also provides a pharmaceutical composition comprising a compound of formula (I), (ii), (iv), (v) or (vi) of the present invention, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof.
The invention also provides a pharmaceutical composition, which comprises the compound shown in the formula (I), (II), (IV), (V) or (VI), or a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliary materials.
The object of the present invention is also the provision of a compound of formula (I), (II), (IV), (V) or (VI) according to the invention, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, for the preparation of a 5-HT2A receptor agonist, in particular a 5-HT2A receptor agonist biased by β -arestin, for use in the treatment of a central nervous system disorder.
Definition of the definition
Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1-10 Alkyl groups), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl groups), more preferably containing 1 to 6 carbon atoms (i.e. C 1-6 Alkyl), e.g. "C 1-6 Alkyl "means that the group is alkyl and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1,2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.
Unless otherwise specified, the term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon atoms and hydrogen atoms. Alkenyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkenyl groups), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkenyl groups), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkenyl), 2 to 5 carbon atoms (i.e. C 2-5 Alkenyl), 2 to 4 carbon atoms (i.e. C 2-4 Alkenyl), 2 to 3 carbon atoms (i.e. C 2-3 Alkenyl), 2 carbon atoms (i.e. C 2 Alkenyl), e.g. "C 2-6 Alkenyl "means that the group is alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.
The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, having at least one triple bond, unless otherwise specified. Alkynyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl groups), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkynyl groups), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkynyl), 2 to 5 carbon atoms (i.e. C 2-5 Alkynyl), 2 to 4 carbon atoms (i.e. C 2-4 Alkynyl), 2 to 3 carbon atoms (i.e. C 2-3 Alkynyl), 2 carbon atoms (i.e. C 2 Alkynyl groups), e.g. "C 2-6 Alkynyl "means that the group is alkynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.
Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic radical having a specified number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C 3-12 Cycloalkyl), more preferably containing 3 to 10 carbon atoms (C 3-10 Cycloalkyl), more preferably 3 to 6 carbon atoms (C 3-6 Cycloalkyl), 4-6 carbon atoms (C 4-6 Cycloalkyl), 5-6 carbon atoms (C 5-6 Cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
The term "alkoxy", unless otherwise specified, refers to an-O-alkyl group, which is as defined above, i.e. comprising 1 to 20 carbon atoms, preferably comprising 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (in particular 1,2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-dimethylpropoxy, 1-ethylpropoxy, and the like.
The term "alkylthio" refers to the replacement of oxygen in an "alkoxy" group described above with sulfur, unless otherwise specified.
The term "halogen" or "halo" refers to F, cl, br, I unless otherwise specified. The term "haloalkyl" means that one, two or more hydrogen atoms or all hydrogen atoms in an alkyl group as defined above are replaced by halogen. Representative examples of haloalkyl groups include CCl 3 、CF 3 、CHCl 2 、CH 2 Cl、CH 2 Br、CH 2 I、CH 2 CF 3 、CF 2 CF 3 Etc.
Unless otherwise specified, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure, containing 3 to 20 ring atoms, wherein 1,2,3 or more ring atoms are selected from N, O or S and the remaining ring atoms are C. Preferably 3 to 12 ring atoms, more preferably 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 5 to 6 ring atoms. The heteroatoms are preferably 1 to 4, more preferably 1 to 3 (i.e., 1,2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl and the like. Bicyclic or polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclyl groups.
The term "fused heterocyclyl" or "fused heterocyclyl" refers, unless otherwise specified, to a 5-to 20-membered polycyclic heterocyclic group wherein each ring in the system shares an adjacent pair of atoms (carbon and carbon atoms or carbon and nitrogen atoms) with the other ring, containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the remaining ring members being carbon. One or more rings of the fused heterocyclic group may contain one or more double bonds. Preferably, the fused heterocyclyl is 6 to 14 membered, preferably 7 to 12 membered and more preferably 7 to 10 membered. The condensed heterocyclic group is classified into a bicyclic, tricyclic, tetracyclic, or polycyclic condensed heterocyclic group according to the number of member rings, preferably refers to a bicyclic or tricyclic condensed heterocyclic group, and more preferably a 5-membered/5-membered, 5-membered/6-membered, 6-membered/5-membered, 4-membered/6-membered, 6-membered/4-membered, or 6-membered/6-membered bicyclic condensed heterocyclic group. Representative examples of fused heterocycles include, but are not limited to, the following groups: octahydrocyclopenta [ c ] pyrrole (e.g., octahydrocyclopenta [ c ] pyrrol-2-yl), octahydropyrrolo [3,4-c ] pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindolin-2-yl or isoindolin-5-yl), octahydro-benzo [ b ] [1,4] dioxin, dihydropyridooxazinyl (e.g., 2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazinyl), or dihydrobenzoxazepinyl (e.g., 5-oxo-3, 4-dihydrobenzo [ f ] [1,4] oxaazepinyl), benzoazepinyl (e.g., 2,3,4, 5-tetrahydro-1-oxo-2-benzoazepin-6-yl), benzooxazepin-yl (e.g., 5-oxo-2, 3,4, 5-tetrahydro-1, 4-benzooxazepin-8-yl), dihydroisoquinolyl (e.g., 1-oxo-2-methyl-3, 4-dihydroisoquinolin-6-yl), tetrahydroisoquinolyl (e.g., 2-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-yl), dihydrobenzoxazine (e.g., 3, 4-dihydro-2H-1, 4-benzooxazin-6-yl), benzopiperazinyl, 7, 8-dihydro-5H-pyran [4,3-b ] pyridinyl, 5, 8-dihydro-6H-pyran [3,4-b ] pyridinyl, 7, 8-dihydro-5H-thiopyran [4,3-b ] pyridinyl, 5,6,7, 8-tetrahydro-1, 6-naphthyridinyl, 5,6,7, 8-tetrahydro-1, 7-naphthyridinyl, 7, 8-dihydro-5H-pyran [4,3-d ] pyridine, 3, 4-dihydro-1H-pyran [4,3-c ] pyridine, 2H-1-benzopyranyl or 4H-1-benzopyranyl, wherein the site of attachment to L is not on an aromatic or heteroaromatic ring.
Unless otherwise specified, the term "aryl" refers to monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems containing from 6 to 16 carbon atoms, or from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms, or from 6 to 10 carbon atoms, preferably from 6 to 10 carbon atoms, and the term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, and the like.
Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic, bicyclic or polycyclic ring system containing a 5-16 membered structure, or a 5-14 membered structure, a 5-12 membered structure, a 5-10 membered structure, a 5-8 membered structure, or a 5-6 membered structure, wherein 1,2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, the number of heteroatoms preferably being 1,2 or 3. Examples of heteroaryl groups may include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo [2,3-b ] pyridyl, imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,5-a ] triazolo [1,5-a ] pyridyl, and the like.
The term "fused heteroaryl", unless otherwise specified, refers to an unsaturated aromatic fused ring structure containing 5 to 14 ring atoms (at least one heteroatom contained therein) formed by two or more ring structures joined together by two adjacent atoms, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, the number of heteroatoms preferably being 1, 2 or 3. Preferably a 5-12 membered fused heteroaryl, 7-12 membered fused heteroaryl, 9-12 membered fused heteroaryl, etc., more preferably a 5-membered/5-membered fused heteroaryl, 5-membered/6-membered fused heteroaryl, 6-membered/5-membered fused heteroaryl, 6-membered/6-membered bicyclic fused heteroaryl. Examples of fused heteroaryl groups may include, but are not limited to, benzofuranyl, benzisothiofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazole, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, phenazine, phenothiazine, and the like, for example.
In the present invention, And/or +.>Wherein R is A May be attached to any ring of the fused ring system or the spiro ring system.
The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts, such as the pharmaceutically acceptable salts of amines, carboxylic acids and other types of compounds, which are, unless otherwise specified, suitable for use in contact with the tissues of mammals, especially humans, without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and are well known in the art. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the free base or the free acid with a suitable reagent alone.
The term "isotopically-derived" means that the compound of the present invention may be present in isotopically-labelled or enriched form, and contains one or more atoms having an atomic mass or mass number different from the maximum atomic mass or mass number found in nature, unless otherwise specified. The isotope may be a radioactive or non-radioactive isotope. Isotopes commonly used as isotopic labels are: the hydrogen isotope is selected from the group consisting of, 2 H and 3 h is formed; carbon isotopes: 13 c and C 14 C, performing operation; chlorine isotopes: 35 cl and Cl 37 Cl; fluorine isotopes: 18 f, performing the process; iodine isotopes: 123 i and 125 i, a step of I; nitrogen isotopes: 13 n and 15 n; oxygen isotopes: 15 O, 17 o and 18 isotopes of O and sulfur 35 S, S. These isotopically-labeled compounds can be used to study the distribution of a pharmaceutical molecule in a tissue. In particular, the method comprises 3 H and 13 c, because they are easily labeled and conveniently detected, the application is wider. Some of the weightsIsotopes such as heavy hydrogen @ 2 H) The substitution can enhance the metabolic stability and prolong the half-life period, thereby achieving the purpose of reducing the dosage and providing curative effect advantages. Isotopically-labeled compounds generally begin with a starting material that has been labeled, and are synthesized using known synthetic techniques like synthesizing non-isotopically-labeled compounds.
The term "solvate" or "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic), unless otherwise specified. The physical association includes hydrogen bonding. In some cases, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may be present in a regular arrangement and/or in a disordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric solvent molecule. "solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, ethanoates, methanoates, and isopropanolamates. Solvation methods are well known in the art.
The term "stereoisomer" refers to compounds having the same chemical structure, but spatially different arrangements of atoms or groups, unless otherwise specified. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers and the like. The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
Unless otherwise specified, the term "tautomer" refers to structural isomers having different energies that can be converted to each other by a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers include interconversions by recombination of some of the bond-forming electrons.
Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) thereof, are all within the scope of the invention.
The compounds of the invention also include co-crystals thereof, the term "co-crystal" being used to describe such situations, unless otherwise indicated: wherein the neutral molecular component is present in a defined stoichiometric ratio within the crystalline compound. The preparation of pharmaceutical co-crystals enables changes to be made to the crystalline form of the active pharmaceutical ingredient, which in turn can change its physicochemical properties without compromising its desired biological activity (see Pharmaceutical Salts and Co-crystals, J.Wobutes and L.Quere et al, RSC Publishing, 2012).
The compounds of the present invention also include polymorphs thereof, where the term "polymorph" refers to a different arrangement of chemical drug molecules, unless otherwise specified, typically expressed as the presence of a drug substance in a solid state. A drug may exist in a variety of crystalline forms, and different crystalline forms of the same drug may be differently dissolved and absorbed in the body, thereby affecting dissolution and release of the formulation.
The compounds of the present invention also include metabolites thereof, and the term "metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo, unless otherwise specified. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
The compounds of the present invention also include prodrugs thereof, and the term "prodrug" refers to a drug that is converted in vivo to the parent drug, unless otherwise specified. Prodrugs are often useful, which may improve some defined, undesirable physical or biological properties. Physical properties are often associated with solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too fast metabolism or poor bioavailability, which may itself be associated with physicochemical properties. For example, they may be bioavailable orally, whereas the parent is not. The solubility of the prodrug in the pharmaceutical composition is also improved compared to the parent drug. An example of a prodrug, but not limited thereto, may be any compound of the invention that is administered as an ester ("prodrug") to facilitate transport across the cell membrane, where water solubility is detrimental to mobility, but which is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, wherein the peptide is metabolized to reveal an active moiety.
The term "optionally substituted" means, unless otherwise specified, that the hydrogen of the substitutable site of the group is unsubstituted or substituted with one or more substituents, preferably selected from the group consisting of: halogen, hydroxy, mercapto, cyano, nitro, amino, azido, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl sulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-10 membered heteroaryl ring group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl sulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-to 10-membered heteroaryl ring groups may optionally be selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 Substituted by one or more substituents in an alkoxy group, the oxo group means that two H's at the same substitution position are replaced by the same O to form a double bond.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials are presented herein for illustrative purposes only.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS) or/and liquid chromatography (HPLC). The NMR measurements were performed using either Bruker 400MHz or/and Varian 400MHz; the LC-MS uses an instrument of Agilent,1260 Infinicity II-6120/6125MSD; the instrument used for HPLC is Waters Acquity UPLC _2 or/and Shimadzu LC2030 or/and Agilent,1260 Infinicity II.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
The invention provides a preparation method of the compound. The compounds can be prepared by the following steps.
Example 1
Preparation of (6 bR,10 aS) -8- (3- (2-methoxyphenyl) butyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxaline:
the first step: preparation of ethyl 3- (2-methoxyphenyl) but-2-enoate:
compound 2- (diethoxyphosphoryl) ethyl acetate (17.91 g,1.2 eq) was dissolved in tetrahydrofuran (100 mL), a tetrahydrofuran solution (100 mL) of sodium hydride (1.92 g,1.2 eq) was added under ice-bath conditions, stirred at room temperature for 2 hours, a tetrahydrofuran (100 mL) solution of compound 1- (2-methoxyphenyl) ethan-1-one (10 g,66.59mmol,1 eq) was added dropwise to the reaction solution, stirred at room temperature for 1 hour, refluxed at 70℃overnight, and the TLC detection reaction was complete. To the reaction solution was added saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography to give the objective compound (P1: 7.5g; P2:4.5 g). (P1 and P2 are E/Z isomers), and P1 and P2 are mixed for the next reaction.
P1: 1 H NMR(400MHz,CDCl 3 )δ7.29(td,J＝8.1,1.7Hz,1H),7.14(dd,J＝7.5,1.7Hz,1H),6.97-
6.87(m,2H),5.89(d,J＝1.3Hz,1H),4.20(q,J＝7.1Hz,2H),3.82(s,3H),2.49(d,J＝1.3Hz,3H),1.30(t,J＝7.1Hz,3H).
P2: 1 H NMR(400MHz,CDCl 3 )δ7.31-7.24(m,1H),7.02(d,J＝7.3Hz,1H),6.97 -6.87(m,2H),
5.95(s,1H),3.96(q,J＝7.1Hz,2H),3.80(s,3H),2.15(s,3H),1.05(t,J＝7.1Hz,3H).
And a second step of: preparation of ethyl 3- (2-methoxyphenyl) butyrate:
the compound 3- (2-methoxyphenyl) but-2-enoic acid ethyl ester (12 g,54.48mmol,1 eq) was dissolved in methanol (100 mL), 10% palladium on carbon (2.9 g,0.5 eq) was added, and the reaction solution was stirred under a hydrogen atmosphere at room temperature for 3 hours. LCMS detected complete reaction. The mixture was filtered through celite and washed with methanol, and the filtrate was concentrated to remove the solvent to give the crude target compound (10 g), which was used directly in the next step without further purification.
LCMS(ESI)[M+H] + ＝223.1。
And a third step of: preparation of 3- (2-methoxyphenyl) butanol:
compound 3- (2-methoxyphenyl) butanoic acid ethyl ester (3.5 g) was dissolved in tetrahydrofuran (35 mL), lithium borohydride (1.03 g,3 eq) was added, and the reaction mixture was stirred at room temperature for 16 hours, and LCMS showed completion of the reaction. Saturated ammonium chloride solution was slowly added in ice bath, dichloromethane (30 ml x 2) was extracted, the organic phases were combined, washed with saturated brine (100 ml x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography to give the title compound (2.6 g, yield 92%).
LCMS(ESI)[M+H+ACN] + ＝222.2。
Fourth step: preparation of 3- (2-methoxyphenyl) butanal:
compound 3- (2-methoxyphenyl) butanol (2.5 g,13.87mmol,1 eq) was dissolved in dichloromethane (30 mL), and dessert-Martin reagent (8.83 g,1.5 eq) was added at 0deg.C and the reaction was stirred at room temperature for 5 hours and the reaction was complete by TLC. Saturated sodium bicarbonate solution was added, the solution was separated, and the aqueous phase was extracted with dichloromethane (20 ml x 2). The organic phases were combined, washed with saturated brine (50 ml x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give a crude product, which was purified by column chromatography to give the title compound (1.8 g, yield 73%).
1 H NMR(400MHz,DMSO-d 6 )δ9.61(t,J＝1.9Hz,1H),7.19(t,J＝7.0Hz,2H),6.96(d,J＝8.6Hz,1H),6.91(t,J＝7.3Hz,1H),3.79(s,3H),3.66(dd,J＝14.1,7.1Hz,1H),2.66(dd,J＝5.5,3.6Hz,2H),1.18(d,J＝7.0Hz,3H).
Fifth step: preparation of (6 bR,10 aS) -8- (3- (2-methoxyphenyl) butyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxaline:
3- (2-methoxyphenyl) butanal (140 mg,1.5 eq) was added to a solution of (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-dehydroquinoline (120 mg,0.52mmol,1 eq) in tetrahydrofuran (10 mL), stirred for 1 hour, sodium triacetoxyborohydride (111 mg,2 eq) was added to the reaction solution, stirred at room temperature for 2 hours, LCMS was monitored to complete the reaction, the reaction solution was quenched with water (10 mL), extracted with dichloromethane (10 mL. Times.3), the organic phases were combined, dried over sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the title compound (37.14 mg, yield 18%).
LCMS(ESI)[M+H] + ＝392.3； 1 H NMR(400MHz,DMSO-d 6 )δ8.17(s,1H),7.19-7.13(m,2H),
6.95-6.87(m,2H),6.53-6.48(m,1H),6.43-6.38(m,1H),6.34-6.30(m,1H),3.77(d,J＝5.7Hz,3H),3.42(s,1H),3.31-3.26(m,2H),3.16-3.09(m,2H),3.04-2.99(m,1H),2.77(s,4H),2.69-2.61(m,2H),2.29-2.13(m,3H),1.92-1.87(m,1H),1.82-1.73(m,3H),1.67-1.59(m,1H),1.13(d,J＝6.9Hz,3H).
Example 2
Preparation of (6 br,10 as) -8 ((R) -3- (2-methoxyphenyl) butyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxaline:
with reference to the preparation method of example 1, the target compound 2 was obtained by resolution.
LCMS(ESI)[M+H] + ＝392.3； 1 H NMR(400MHz,DMSO)δ7.19(dd,J＝11.5,7.7Hz,2H),6.98–
6.87(m,2H),6.59(t,J＝7.6Hz,1H),6.50(d,J＝7.2Hz,1H),6.42(d,J＝7.9Hz,1H),3.77(s,3H),3.37–3.30(m,4H),3.21(s,1H),3.14–3.06(m,1H),3.05–2.93(m,2H),2.77(d,J＝24.9Hz,5H),2.71(dd,J＝11.8,9.1Hz,1H),2.45(s,1H),2.18(t,J＝15.6Hz,2H),2.11–1.83(m,3H),1.16(d,J＝6.9Hz,3H).
Example 3
Preparation of (6 br,10 as) -8 ((S) -3- (2-methoxyphenyl) butyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxaline:
With reference to the preparation method of example 1, the target compound 3 was obtained by resolution.
LCMS(ESI)[M+H] + ＝392.3； 1 H NMR(400MHz,CDCl 3 )δ8.55(s,1H),7.19–7.10(m,2H),6.91(t,
J＝7.1Hz,1H),6.82(d,J＝8.1Hz,1H),6.68(t,J＝7.7Hz,1H),6.51(d,J＝7.3Hz,1H),6.42(d,J＝7.9Hz,1H),3.78(s,3H),3.61–3.51(m,2H),3.34(dd,J＝11.8,6.6Hz,1H),3.31–3.23(m,4H),3.19(dd,J＝14.6,7.1Hz,1H),2.86(s,3H),2.82(ddd,J＝9.2,8.5,3.3Hz,2H),2.77–2.71(m,1H),2.66–2.56(m,1H),2.39(dt,J＝23.8,8.0Hz,2H),2.01(ddd,J＝18.4,11.5,4.8Hz,3H),1.23(d,J＝7.0Hz,3H).
Examples 4 to 12
Reference to the procedure for the preparation of example 1, the compounds of examples 4-12 were prepared
Example 13
Preparation of (6 bR,10 aS) -8- (3, 3-difluoro-3- (2-methoxyphenyl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deaggregation ] quinoxaline:
the first step: preparation of ethyl 3- (2-methoxyphenyl) -3-oxopropionate:
1- (2-methoxyphenyl) ethan-1-one (10 g,1 eq) was dissolved in tetrahydrofuran (80 mL), tetrahydrofuran (20 mL) of sodium hydride (4.79 g,3 eq) was added under ice-bath conditions, stirred under ice-bath for 1 hour, diethyl carbonate (31.47 g,4 eq) was added, slowly warmed to room temperature, stirred at room temperature overnight, and LCMS detection was complete. The reaction was quenched slowly with water in ice bath, extracted with ethyl acetate (100 ml x 3), washed with saturated brine (100 ml x 2), dried over anhydrous sodium sulfate, and concentrated to dryness to give the crude product which was purified by reverse phase flash chromatography (C18, 0.05%FA in water,MeCN) to give the title compound (4 g, yield 27.0%).
LCMS(ESI)[M+H] + ＝223.1； 1 H NMR(400MHz,CDCl 3 )δ7.88(dd,J＝7.8,1.7Hz,1H),7.54–
7.47(m,1H),7.03(t,J＝7.5Hz,1H),6.97(d,J＝8.4Hz,1H),4.18(q,J＝7.1Hz,2H),3.97(s,2H),3.90(d,J＝2.5Hz,3H),1.23(t,J＝7.1Hz,3H).
And a second step of: preparation of 3-hydroxy-1- (2-methoxyphenyl) propan-1-one:
ethyl 3- (2-methoxyphenyl) -3-oxopropionate (500 mg,1 eq) was dissolved in tetrahydrofuran (5 mL), lithium aluminum hydride (171 mg,2 eq) was slowly added at 0 ℃, the reaction system was stirred at room temperature for 5 hours, TLC showed the end of the reaction, water (0.2 mL), 15% sodium hydroxide (0.2 mL) and water (0.6 mL) were added to the reaction solution, anhydrous sodium sulfate was added and stirred for 5 minutes, filtration and concentration were carried out to obtain a crude product, which was separated and purified by flash chromatography (Silica gel, PE: ea=100:0 to 90:10) to obtain the objective compound (200 mg, 49.3%).
1 H NMR(400MHz,CDCl 3 )δ7.77(dd,J＝7.7,1.6Hz,1H),7.56–7.42(m,1H),7.04–6.93(m,2H),3.97(t,J＝4.9Hz,2H),3.92(s,3H),3.26(t,J＝5.3Hz,2H),2.70(s,1H).
And a third step of: preparation of 3- (2-methoxyphenyl) -3-oxopropyl acetate:
3-hydroxy-1- (2-methoxyphenyl) propan-1-one (1.5 g,1 eq) was dissolved in methylene chloride (15 mL), triethylamine (1263 mg,1.5 eq) was added dropwise acetyl chloride (784 mg,1.2 eq) at 0℃and the reaction system was stirred at 0℃for 1 hour, TLC showed the end of the reaction, the reaction solution was concentrated to give a crude product, which was purified by flash chromatography (Silica gel, PE: EA=100:0 to 92:8) to give the objective compound (1.4 g, 75.7%).
1 H NMR(400MHz,CDCl 3 )δ7.75(dd,J＝5.0,2.6Hz,1H),7.48(td,J＝7.3,1.7Hz,1H),7.07–6.92(m,2H),4.47(ddd,J＝8.9,6.1,3.0Hz,2H),3.92(t,J＝2.8Hz,3H),3.33(ddd,J＝8.9,6.1,3.1Hz,2H),2.07–1.97(m,3H).
Fourth step: preparation of ethyl 2- (2- (2-methoxyphenyl) -1, 3-dithien-2-yl) acetate:
3- (2-methoxyphenyl) -3-oxopropyl acetate (100 mg,1 eq) was dissolved in dichloromethane (2 mL), ethane-1, 2-dithiol (85 mg,2 eq), boron trifluoride diethyl ether (32 mg,0.5 eq) were added in sequence, the reaction system was stirred at room temperature for 16 hours, TLC showed the reaction was completed, the reaction system was adjusted to pH 7 with sodium hydrogencarbonate solution, then extracted with dichloromethane (10 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product, which was purified by flash chromatography (Silica gel, PE: ea=100:0 to 93:7) to give the objective compound (60 mg, 44.7%).
1 H NMR(400MHz,CDCl 3 )δ7.81(dd,J＝8.1,1.6Hz,1H),7.26–7.21(m,1H),6.93–6.87(m,2H),3.97(d,J＝6.9Hz,2H),3.90(s,3H),3.31(ddd,J＝7.1,6.1,3.9Hz,2H),3.19(ddd,J＝8.1,6.1,3.9Hz,2H),2.85(t,J＝6.9Hz,2H),1.88(s,3H).
Fifth step: preparation of 3- (5-bromo-2-methoxyphenyl) -3, 3-difluoropropan-1-ol:
1, 3-dibromo-5, 5-dimethylimidazoline-2, 4-dione (575 mg,4 eq) was dissolved in dichloromethane (2 mL), -60% aqueous pyridine fluoride (0.9 mL,18.08 eq) was added dropwise at 78 ℃, then a solution of ethyl 2- (2- (2-methoxyphenyl) -1, 3-dithiophene-2-yl) acetate (150 mg,1 eq) in dichloromethane (3 mL) was added dropwise, the reaction system was stirred at-78 ℃ for 1 hour, then slowly warmed to room temperature for more than 1 hour, the reaction solution was stirred at room temperature for 1 hour again, TLC showed the end of the reaction, pH was adjusted to 9 with sodium bicarbonate solution, extracted with dichloromethane (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product, which was purified by flash chromatography (sia gel, PE: ea=100:0 to 88:12) to obtain the objective compound (50 mg, yield 40.7%).
1 H NMR(400MHz,CDCl 3 )δ7.61(d,J＝2.4Hz,1H),7.50(dd,J＝8.8,2.4Hz,1H),6.84(d,J＝8.8Hz,1H),3.85(s,3H),3.81(t,J＝6.3Hz,2H),2.58(ddd,J＝17.3,11.8,6.3Hz,2H).
Sixth step: preparation of 3, 3-difluoro-3- (2-methoxyphenyl) propanol:
3- (5-bromo-2-methoxyphenyl) -3, 3-difluoropropan-1-ol (350 mg,1 eq) was dissolved in methanol (5 mL), palladium on charcoal (66 mg,0.5 eq) was added under hydrogen atmosphere, the reaction system was stirred for 1 hour at room temperature, TLC showed the reaction ended, the reaction solution was filtered, concentrated to give crude product, which was purified by flash chromatography (Silica gel, PE: ea=100:0 to 96:4) to give the target compound (200 mg, yield 79.4%).
1 H NMR(400MHz,CDCl 3 )δ7.50(dd,J＝7.7,1.4Hz,1H),7.40(dd,J＝8.2,0.8Hz,1H),6.99(dd,J＝17.8,8.1Hz,2H),3.87(s,3H),3.81(t,J＝6.2Hz,2H),2.62(tt,J＝17.2,6.2Hz,2H).
Seventh step: preparation of propyl 3, 3-difluoro-3- (2-methoxyphenyl) methanesulfonate:
3, 3-difluoro-3- (2-methoxyphenyl) propanol (50 mg,1 eq) was dissolved in dichloromethane (0.5 mL), triethylamine (25 mg,1 eq) was added, methanesulfonyl chloride (34 mg,1.2 eq) was slowly added dropwise under ice bath, the reaction was stirred under ice bath for 4 hours, TLC showed complete reaction, water (5 mL) was added, extracted with dichloromethane (5 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated to give crude product (40 mg, crude product).
1 H NMR(400MHz,DMSO-d 6 )δ7.58–7.37(m,2H),7.17(d,J＝8.3Hz,1H),7.05(t,J＝7.5Hz,1H),4.26(t,J＝6.2Hz,2H),3.84(s,3H),3.07(s,3H),2.88–2.68(m,2H).
Eighth step: preparation of (6 bR,10 aS) -8- (3, 3-difluoro-3- (2-methoxyphenyl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deaggregation ] quinoxaline:
3, 3-difluoro-3- (2-methoxyphenyl) methanesulfonate (123 mg,1 eq) and (6 br,10 as) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (100 mg,1 eq) were dissolved in N, N-dimethylformamide (5 mL), reacted for 16 hours at 70 ℃ with potassium carbonate (15 mg,0.11mmol,1.2 eq) added, water (20 mL) was added, extracted with ethyl acetate (15 mL x 3), the combined organic phases were dried with anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the title compound (11.51 mg, yield 6.3%).
LCMS(ESI)[M+H] + ＝414.2； 1 H NMR(400MHz,CDCl 3 )δ8.48(s,1H),7.45(d,J＝7.6Hz,1H),
7.38(t,J＝7.8Hz,1H),6.96(dd,J＝16.0,8.0Hz,2H),6.66(t,J＝7.7Hz,1H),6.49(d,J＝7.3Hz,1H),6.41(d,J＝7.9Hz,1H),3.86(s,3H),3.64–3.53(m,1H),3.33–3.19(m,4H),3.04–2.96(m,1H),2.85(d,J＝6.4Hz,4H),2.80(dd,J＝10.5,3.3Hz,1H),2.73–2.62(m,4H),2.52–2.45(m,1H),2.12(t,J＝11.3Hz,2H),1.97(d,J＝13.1Hz,1H).
Example 14
Preparation of (6 bR,10 aS) -8- (3- (2-methoxyphenyl) -3-methylbutyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deazating ] quinoxaline:
the first step: preparation of phenyl 3-methyl-2-enoic acid:
to a 250mL three-necked flask, sodium hydride (4.02 g,1.05 eq) and ultra-dry tetrahydrofuran (100 mL) were added, the mixture was replaced with nitrogen 3 times, phenol (15 g,1 eq) and tetrahydrofuran (20 mL) were slowly added under ice-bath conditions, the mixture was stirred for 10 minutes under ice-bath conditions, 3-methyl-2-enoyl chloride (20.79 g,1.1 eq) was added, and the reaction mixture was stirred under ice-bath for 4 hours, and the completion of the reaction was detected by LCMS. The reaction was quenched with water slowly in an ice bath, extracted with ethyl acetate (30 ml x 3), washed with saturated brine (100 ml x 2), dried over anhydrous sodium sulfate, and concentrated to dryness to give the crude product which was purified by flash chromatography (Silica gel, PE: ea=100:0 to 95:5) to give the desired product (18 g, yield 64%).
LCMS(ESI)[M+H] + ＝177.4； 1 H NMR(400MHz,CDCl 3 )δ7.40–7.33(m,2H),7.20(td,J＝7.2,
3.5Hz,1H),7.09(dt,J＝8.9,1.8Hz,2H),5.93–5.90(m,1H),2.23(d,J＝1.1Hz,3H),1.98(d,J＝1.1Hz,3H).
And a second step of: preparation of 4, 4-dimethyl-3, 4-dihydro-2H-1-benzopyran-2-one:
to a 250mL three-necked flask, ultra-dry dichloromethane (100 mL) of aluminum trichloride (37.84 g,5 eq) was added, the mixture was replaced with nitrogen for 3 times, a dichloromethane solution (20 mL) of phenyl 3-methyl-2-enoic acid (10 g,1 eq) was slowly added dropwise under ice bath, stirred under ice bath for 1 hour, the temperature was slowly raised to room temperature, stirred at room temperature overnight, and LCMS detection was completed. The reaction was slowly poured into ice water, separated, the aqueous phase extracted with dichloromethane (30 ml x 3), washed with saturated brine (100 ml x 2), dried over anhydrous sodium sulfate and concentrated to dryness to give the crude product which was isolated and purified by reverse phase flash chromatography (C18, 0.05%FA in water,MeCN) to give the title compound (4.9 g, 49% yield).
LCMS(ESI)[M+H] + ＝177.2； 1 H NMR(400MHz,CDCl 3 )δ7.32(dd,J＝7.6,1.5Hz,1H),7.15(td,J
＝7.5,1.2Hz,1H),7.06(dd,J＝8.0,0.9Hz,1H),2.63(s,2H),1.36(s,6H).
And a third step of: preparation of 2- (4-hydroxy-2-methylbutan-2-yl) phenol:
4, 4-dimethyl-3, 4-dihydro-2H-1-benzopyran-2-one (2.1 g,1 eq) was dissolved in ultra-dry tetrahydrofuran (10 mL), lithium aluminum hydride (452.27 mg,1 eq) was slowly added at 0deg.C and stirred at room temperature for 4 hours, and the completion of the reaction was detected by LCMS. The reaction was quenched slowly with water at 0 ℃, the mixture was filtered over celite and washed with ethyl acetate, the liquid was separated, the aqueous phase was extracted with ethyl acetate (10 ml x 3), washed with saturated brine (50 ml x 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by flash chromatography (Silica gel, PE: ea=5:1 to 0:1) to give the desired product (1.2 g, 56% yield).
LCMS(ESI)[M+H] + ＝181.2； 1 H NMR(400MHz,DMSO-d 6 )δ9.26(s,1H),7.06(dd,J＝7.8,1.5
Hz,1H),6.99(td,J＝7.9,1.6Hz,1H),6.77–6.66(m,2H),4.13(t,J＝4.9Hz,1H),3.17–3.09(m,2H),2.06–1.94(m,2H),1.31(s,6H).
Fourth step: preparation of 3- (2-methoxyphenyl) -3-methylbutan-1-ol:
the compound 2- (4-hydroxy-2-methylbutan-2-yl) phenol (1 g,1 eq) was dissolved in N, N-dimethylformamide (10 mL), potassium hydroxide (467.12 mg,1.5 eq) and methyl iodide (1.58 g,2 eq) were added, and stirred at room temperature for 4 hours, and the TLC detection of the completion of the reaction was performed. Water (20 mL), ethyl acetate (10 mL x 3) and saturated brine (30 mL x 2) were added, washed, dried and concentrated in organic phase to give crude product, which was purified by flash chromatography (Silica gel, PE: ea=1:0 to 5:1) to give the desired product (300 mg, yield 27.8%).
1 H NMR(400MHz,DMSO-d 6 )δ7.20–7.12(m,2H),6.96(d,J＝7.9Hz,1H),6.86(t,J＝7.5Hz,1H),4.17(t,J＝5.0Hz,1H),3.79(s,3H),3.15–3.06(m,2H),2.01–1.95(m,2H),1.31(s,6H).
Fifth step: preparation of 3- (2-methoxyphenyl) -3-methylbutyl mesylate:
3- (2-methoxyphenyl) -3-methylbutan-1-ol (140 mg,1 eq) was dissolved in dichloromethane (2 mL), methanesulfonyl chloride (99 mg,1.2 eq) was slowly added dropwise under ice bath while triethylamine (72.92 mg,1 eq) was added, the reaction system was stirred in ice bath for 4 hours, TLC showed complete reaction, water (10 mL) was added, the aqueous phase was extracted with dichloromethane (10 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give crude 3- (2-methoxyphenyl) -3-methylbutanesulfonate (200 mg, crude) as yellow oil, which was used directly in the next step.
1 H NMR(400MHz,DMSO-d 6 )δ7.27–7.15(m,2H),7.00(dd,J＝8.2,1.1Hz,1H),6.90(td,J＝7.6,1.2Hz,1H),3.89(t,J＝7.4Hz,2H),3.80(d,J＝8.1Hz,3H),2.98(s,3H),2.24(t,J＝7.4Hz,2H),1.35(s,6H).
Sixth step: preparation of (6 bR,10 aS) -8- (3- (2-methoxyphenyl) -3-methylbutyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deazating ] quinoxaline:
3- (2-methoxyphenyl) -3-methylbutyl methanesulfonate (118.77 mg,1 eq) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine (3 ',4':4, 5) pyrrole (1, 2, 3-deo) quinoline (100 mg,0.44mmol,1 eq) were dissolved in N, N-dimethylformamide (3 mL), potassium carbonate (72.32 mg,0.52mmol,1.2 eq) was added, reacted overnight at 70℃and LCMS was successfully detected, diluted with water (10 mL), ethyl acetate (20 mL. Times.3) was extracted, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give crude product, which was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the title compound (18.87 mg, yield 10.6%).
LCMS(ESI)[M+H] + ＝406.2； 1 H NMR(400MHz,CDCl 3 )δ8.56(s,1H),7.26(s,1H),7.22–7.09(m,2H),6.90–6.79(m,2H),6.68(t,J＝7.7Hz,1H),6.50(d,J＝7.4Hz,1H),6.41(d,J＝7.9Hz,1H),3.78(s,3H),3.63–3.46(m,2H),3.27(dt,J＝24.3,10.7Hz,5H),2.85(d,J＝8.6Hz,3H),2.84–2.67(m,2H),2.59–2.19(m,6H),2.00(d,J＝15.0Hz,1H),1.36(d,J＝3.2Hz,6H).
Examples 15 to 36
Reference to the preparation of examples 1, 13, 14, the compounds of examples 15-36 were prepared
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Example 37
Preparation of (6 br,10 as) -8- (2- (benzofuran-3-yl) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxaline:
the first step: preparation of ethyl 2- (1-benzofuran-3-yl) acetate:
1-benzofuran-3-one (5 g,1 eq) was dissolved in toluene (50 mL), ethoxyformylmethylene triphenylphosphine (19.48 g,1.5 eq) was added under nitrogen protection, the reaction system was stirred for 48 hours at 118℃and TLC showed complete reaction, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to give crude product, which was purified by column chromatography over silica gel to give the title compound (4.5 g, yield 59%).
1 H NMR(400MHz,CDCl 3 )δ7.63(s,1H),7.59-7.55(m,1H),7.50-7.46(m,1H),7.33-7.26(m,1H),7.25-7.23(m,1H),4.19(q,J＝7.1Hz,2H),3.70(d,J＝0.9Hz,2H),1.27(t,J＝7.1Hz,3H).
And a second step of: preparation of 2- (1-benzofuran-3-yl) ethan-1-ol:
a solution of the starting material 2- (1-benzofuran-3-yl) acetic acid ethyl ester (500 mg,1 eq) in tetrahydrofuran (5 mL) was added dropwise to a solution of lithium aluminum hydride (93 mg,1 eq) in tetrahydrofuran (5 mL) at 0deg.C under nitrogen protection, the dropwise addition was completed, the reaction system was stirred for 1 hour at 0deg.C, TLC showed the end of the reaction, saturated ammonium chloride solution was added to the reaction solution until no bubbles were generated, filtration was carried out, the filtrate was extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to obtain a crude product, and the crude product was separated and purified by silica gel column to obtain the target compound (350 mg, yield 88%).
1 H NMR(400MHz,CDCl 3 )δ7.57-7.54(m,1H),7.51-7.45(m,2H),7.32-7.27(m,1H),7.26-7.22(m,1H),3.90(t,J＝6.4Hz,2H),2.93(t,J＝6.4Hz,2H).
And a third step of: preparation of 2- (1-benzofuran-3-yl) acetaldehyde:
2- (1-benzofuran-3-yl) ethan-1-ol (1.2 g,1 eq) was dissolved in dichloromethane (12 mL), dessicant (3.14 g,1 eq) was slowly added at 0deg.C, stirring was continued for 16 hours at 0deg.C after the addition was completed, TLC showed completion of the reaction, 10% sodium bicarbonate solution was added to quench the reaction, extraction was performed with ethyl acetate (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product, which was isolated and purified by silica gel column to give the title compound (420 mg, yield 35%).
1 H NMR(400MHz,CDCl 3 )δ9.82(t,J＝2.0Hz,1H),7.65(s,1H),7.52-7.48(m,2H),7.36-7.31(m,1H),7.29-7.26(m,1H),3.78(dd,J＝1.9,1.0Hz,2H).
Fourth step: preparation of (6 br,10 as) -8- (2- (benzofuran-3-yl) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoxaline:
(6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-desquinoline (100 mg,1 eq) was dissolved in tetrahydrofuran (2 mL), 2- (1-benzofuran-3-yl) acetaldehyde (85 mg,1.2 eq) and acetic acid (5 drops) were added sequentially, the reaction system was stirred at room temperature for 0.5 hours, sodium triacetoxyborohydride (187 mg,2 eq) was added, the reaction solution was stirred at room temperature for 4 hours, LCMS showed complete reaction, water (15 mL) was added to the reaction solution, extracted with dichloromethane (15 mL. Times.3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to give crude product, and prep-HPLC (0.1%FA in water:ACN) was used to prepare the purified title compound (27.13 mg, 17% yield).
LCMS(ESI)[M+H] + ＝374.1； 1 H NMR(400MHz,CDCl 3 )δ8.54(s,1H),7.64-7.57(m,1H),7.51-
7.42(m,2H),7.32-7.26(m,2H),6.75-6.65(m,1H),6.58-6.52(m,1H),6.47-6.39(m,1H),3.66 -3.53(m,2H),3.47-3.39(m,1H),3.36-3.25(m,4H),3.22-3.01(m,4H),2.92-2.78(m,5H),2.43(t,J＝11.2Hz,2H),2.15-2.04(m,1H).
Examples 38 to 83
Reference to the procedure for the preparation of example 37 gave the compounds of examples 38-83
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Example 84
Preparation of (6 bR,10 aS) -8- (chrome-3-ylmethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline:
the first step: preparation of methyl 2- (4- (benzyloxy) -1H-indol-3-yl) -2-oxoacetate:
palladium on carbon (2416 mg,2 eq) was added to a solution of 2H-chromene-3-carboxylic acid (2 g,11.35mmol,1 eq) in methanol (20 mL) under hydrogen atmosphere, the reaction system was stirred at room temperature for 8 hours, LCMS showed the reaction to end, the reaction solution was filtered and concentrated to give the title compound (1.6 g, crude).
LCMS(ESI)(M-H) - ＝177.2.
And a second step of: preparation of (3, 4-dihydro-2H-1-benzopyran-3-yl) methanol:
the compound 3, 4-dihydro-2H-1-benzopyran-3-carboxylic acid (600 mg,1 eq) was dissolved in tetrahydrofuran (10 mL), a solution of lithium aluminum hydride in tetrahydrofuran (3.4 mL,1 m) was slowly added under ice bath, stirring was continued overnight in ice bath, and TLC plates monitored for reaction completion. The reaction was quenched slowly with water in ice bath, diluted with ethyl acetate (20 mL), the mixture was filtered over celite, the filtrate was partitioned, extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated to dryness to give the crude product which was purified by flash chromatography (Silica gel, PE: ea=100:0 to 70:30) to give the title compound (500 mg, yield 90.4%).
1 H NMR(400MHz,DMSO-d6)δ9.74(s,1H),7.12(d,J＝7.5Hz,1H),7.05(t,J＝7.7Hz,1H),6.84(td,J＝7.4,1.0Hz,1H),6.72(d,J＝8.2Hz,1H),4.42(m,1H),4.30(dd,J＝11.1,3.0Hz,1H),3.33(s,2H),3.07(m,1H),3.05–2.90(m,2H).
And a third step of: preparation of methyl (3, 4-dihydro-2H-1-benzopyran-3-yl) methylsulfonate:
(3, 4-dihydro-2H-1-benzopyran-3-yl) methanol (250 mg,1 eq) was dissolved in methylene chloride (5 mL), triethylamine (154 mg,1 eq) was added, methanesulfonyl chloride (209 mg,1.2 eq) was slowly added dropwise under ice bath, and the reaction solution was stirred under ice bath conditions for 3 hours, and the reaction was completed by TLC. The reaction was quenched with water, separated, the aqueous phase extracted with dichloromethane (15 ml x 3), washed with saturated brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated to dryness to give the crude product (220 mg, 59.7% yield).
1 H NMR(400MHz,DMSO-d 6 )δ7.08(t,J＝7.8Hz,2H),6.84(t,J＝7.0Hz,1H),6.77(d,J＝8.0Hz,1H),4.23(dd,J＝11.0,5.0Hz,3H),3.92(dd,J＝10.7,8.0Hz,1H),3.21(s,3H),2.88(dd,J＝16.5,5.4Hz,1H),2.61(dd,J＝16.5,8.2Hz,1H),2.42(dd,J＝14.1,7.7Hz,1H).
Fourth step: preparation of (6 bR,10 aS) -8- (chrome-3-ylmethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline:
the compound (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine [3',4:4,5] pyrrole [1,2, 3-norquinoline (100 mg,1 eq) was dissolved in N, N-dimethylformamide (5 mL), methyl (3, 4-dihydro-2H-1-benzopyran-3-yl) methylsulfonate (121 mg,1.2 eq) and potassium carbonate (121 mg,2 eq) were added, the reaction solution was stirred overnight at 80℃and the LCMS detection was successful. Diluting with water (10 mL), extracting with ethyl acetate (10 mL. 3), washing the organic phase with saturated brine (20 mL. 2), drying the organic phase, concentrating to give the crude product, and purifying the crude product by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the title compound (43.31 mg, yield 27%).
LCMS(ESI)(M+H) + ＝376.2； 1 H NMR(400MHz,CDCl 3 )δ8.42(s,1H),7.12–7.02(m,2H),6.88
–6.77(m,2H),6.68(t,J＝7.7Hz,1H),6.52(d,J＝7.4Hz,1H),6.42(d,J＝7.9Hz,1H),4.29(dd,J＝10.9,3.1Hz,1H),4.06–3.93(m,1H),3.64–3.56(m,1H),3.46(dd,J＝11.3,6.0Hz,1H),3.34–3.25(m,3H),3.20(dd,J＝17.0,10.9Hz,1H),3.09–2.94(m,3H),2.87(s,3H),2.83(dd,J＝10.5,3.3Hz,1H),2.72–2.67(m,1H),2.63(dd,J＝12.0,7.4Hz,2H),2.54(dd,J＝22.7,11.3Hz,2H),2.35–2.23(m,2H),2.02(d,J＝14.6Hz,1H).
Examples 85 to 90
Reference to the procedure for the preparation of example 84 gave the compounds of examples 85-90
Example 91
Preparation of (6 bR,10 aS) -8- (2, 3-dihydrobenzofuran-3-yl) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deazate ] quinoxaline:
the first step: preparation of ethyl 2- (2, 3-dihydro-1-benzofuran-3-yl) acetate:
ethyl 2- (1-benzofuran-3-yl) acetate (1 g,1 eq) was dissolved in methanol (10 mL), palladium on carbon (261 mg,0.5 eq) was added, hydrogen was replaced 3 times, and stirred overnight at room temperature under a hydrogen atmosphere, and LCMS detection was complete. Filtration and concentration of the filtrate gave a crude product which was purified by flash chromatography to give the desired product (500 mg, yield 49.5%).
LCMS(ESI)[M+H] + ＝207.1.
And a second step of: preparation of 2- (2, 3-dihydro-1-benzofuran-3-yl) acetaldehyde:
ethyl 2- (2, 3-dihydro-1-benzofuran-3-yl) acetate (250 mg,1 eq) was dissolved in dichloromethane (5 mL), diisobutylaluminum hydride (0.43 mL,2.5eq,1 m) was added dropwise at-78 ℃, stirring was performed for half an hour at-78 ℃ after the addition, TLC showed the reaction was completed, water (3 mL) was added to the reaction solution, anhydrous sodium sulfate was stirred, filtration and concentration were performed to obtain a crude product, which was isolated and purified by flash chromatography (Silica gel, PE: ea=100:0 to 92:8) to obtain the objective compound (180 mg, yield 91.7%).
1 H NMR(400MHz,CDCl 3 )δ9.86(s,1H),7.15(dt,J＝7.1,3.5Hz,2H),6.87(t,J＝7.4Hz,1H),6.80(d,J＝8.3Hz,1H),4.79(t,J＝9.1Hz,1H),4.13(dd,J＝9.2,6.4Hz,1H),4.01–3.86(m,1H),3.02(dd,J＝18.6,5.0Hz,1H),2.78(dd,J＝18.6,8.8Hz,1H).
And a third step of: preparation of (6 bR,10 aS) -8- (2, 3-dihydrobenzofuran-3-yl) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deazate ] quinoxaline:
(6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-off ] quinoxaline (100 mg,1 eq) and 2- (2, 3-dihydro-1-benzofuran-3-yl) acetaldehyde (71 mg,1 eq) were dissolved in tetrahydrofuran (5 mL), acetic acid 5 drops were added, the reaction system was stirred at room temperature for 0.5H, sodium borohydride (185 mg,2 eq) was added, the reaction solution was stirred at room temperature for 1.5H, LCMS showed the end of the reaction, water (15 mL) was added, ethyl acetate (20 mL. Times.3) was used for extraction, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the target compound (44.84 mg, yield 27.1%).
LCMS(ESI)[M+H] + ＝376.2； 1 H NMR(400MHz,DMSO-d 6 )δ8.17(s,1H),7.24(d,J＝7.3Hz,1H),
7.08(t,J＝7.6Hz,1H),6.83(t,J＝7.4Hz,1H),6.74(d,J＝7.9Hz,1H),6.51(t,J＝7.6Hz,1H),6.43(d,J＝7.2Hz,1H),6.33(d,J＝7.8Hz,1H),4.60(t,J＝8.9Hz,1H),4.21–4.14(m,1H),3.33–3.25(m,4H),3.12(s,1H),3.03(dd,J＝10.7,5.8Hz,1H),2.85–2.77(m,4H),2.71–2.62(m,2H),2.34(dd,J＝17.0,9.6Hz,2H),2.20–2.10(m,1H),1.91(dd,J＝13.8,2.6Hz,2H),1.85–1.74(m,2H),1.72–1.62(m,1H).
Example 92
Preparation of (6 bR,10 aS) -8- (1- (2-methoxyphenyl) azetidin-3-yl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] carbostyril:
the first step: preparation of 1- (2-methoxyphenyl) azetidin-3-ol:
pyrrolidine-2-carboxylic acid (148 mg,0.3 eq), cuprous iodide (122 mg,0.15 eq), potassium carbonate (1.89 g,3.2 eq), nitrogen mustard-3-ol (250 mg,0.8 eq) were added to dimethyl sulfoxide (10 mL) of 1-iodo-2-methoxybenzene (1 g,1 eq) under nitrogen atmosphere, stirring was carried out at 90 ℃ for 16 hours, LCMS was detected to be complete, water (15 mL) was added to the reaction solution, ethyl acetate (15 mL x 3) was added to extract, the organic phases were combined, washed with water (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated and purified by column chromatography to give the title compound (420 mg, yield 55%).
LCMS(ESI)[M+H] + ＝180.0； 1 H NMR(400MHz,DMSO-d 6 )δ6.80(d,J＝10.1Hz,2H),6.70(d,
J＝5.8Hz,1H),6.38(s,1H),5.51(s,1H),4.45(s,1H),4.07(s,2H),3.70(s,3H),3.45(s,2H).
And a second step of: preparation of 1- (2-methoxyphenyl) azetidin-3-one:
dimethyl sulfoxide (1.73 g,3.3 eq) was slowly added to oxalyl chloride (1.44 g,1.7 eq) in dichloromethane (20 mL), stirred for 10 min, 1- (2-methoxyphenyl) azetidin-3-ol (1.2 g,1 eq) in dichloromethane (20 mL) was added to the reaction system, stirred for 1h, triethylamine (4.74 g,7 eq) was added to the system, stirred for 1h, and LCMS detected completion of the reaction. Quenched by addition of aqueous sodium bicarbonate (30 mL), extracted by addition of dichloromethane (20 mL x 3), the combined organic phases dried over anhydrous sodium sulfate, filtered, the filtrate concentrated and the residue isolated by column chromatography to give the title compound (450 mg, yield 38%).
LCMS(ESI)[M+H] + ＝178.4； 1 H NMR(400MHz,DMSO-d 6 )δ6.94(dd,J＝7.6,1.5Hz,1H),6.88
–6.82(m,2H),6.59(dd,J＝7.5,1.7Hz,1H),4.67(s,4H),3.76(s,3H).
And a third step of: preparation of (6 bR,10 aS) -8- (1- (2-methoxyphenyl) azetidin-3-yl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] carbostyril:
1- (2-methoxyphenyl) azetidin-3-one (139 mg,1.5 eq) was added to tetrahydrofuran (3 mL) of (6 br,10 as) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinoline (120 mg,1 eq), stirred for 1 hour, sodium triacetoxyborohydride (222 mg,2 eq) was added to the system, stirred at room temperature for 2 hours, LCMS was monitored to complete the reaction, the reaction was quenched with water (10 mL), extracted with dichloromethane (10 mL x 3), the organic phases were combined, dried over sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by prep-HPLC (C18, 0.1%FA in water,MeCN) to give the title compound (75.8 mg, 37%).
LCMS(ESI)[M+H] + ＝391.2； 1 H NMR(400MHz,DMSO-d6)δ6.84-6.76(m,2H),6.69(td,J＝
7.7,1.6Hz,1H),6.51(t,J＝7.6Hz,1H),6.43(d,J＝6.9Hz,1H),6.38(dd,J＝7.7,1.5Hz,1H),6.34-6.31(m,1H),3.94(dt,J＝11.6,7.1Hz,2H),3.70(s,3H),3.53(td,J＝6.3,4.1Hz,2H),3.47–3.41(m,1H),3.30(ddt,J＝22.3,11.3,2.7Hz,2H),3.13-3.08(m,1H),3.07-2.97(m,2H),2.78(s,3H),2.69(dt,J＝10.0,4.1Hz,2H),2.51(s,1H),2.03(td,J＝11.6,2.5Hz,1H),1.91(dd,J＝14.2,2.2Hz,1H),1.80-1.65(m,2H).
Examples 93 to 108
Reference to the procedure for the preparation of example 92 gave the compounds of examples 93-108
Example 109
(6 bR,10 aS) -8- ((1- (2-methoxyphenyl) azetidin-3-yl) methyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine (3', 4): preparation of 4, 5) pyrrole (1, 2, 3-deoxoquinoxaline):
the first step: preparation of methyl 1- (2-methoxyphenyl) azetidine-3-carboxylate:
azetidine-3-carboxylic acid methyl ester (2 g,1 eq), 1-iodo-2-methoxybenzene (5.08 g,1.25 eq), pyrrolidine-2-carboxylic acid (0.68 g,0.34 eq), potassium carbonate (9.6 g,4 eq) and cuprous iodide (0.56 g,0.17 eq) were dissolved in dimethyl sulfoxide (20 mL), and the reaction solution was stirred at 90 ℃ for 16 hours. LCMS detects completion of the reaction. Water (20 mL), ethyl acetate (20 mL x 3) were added to extract, the organic phases were combined, washed with saturated brine (50 mL x 2), and the organic phases were concentrated by dryness to give a crude product, which was purified by column chromatography (PE: ea=1:0 to 5:1) to give the title compound (800 mg, yield 21%).
LCMS(ESI)[M+H] + ＝222.4； 1 H NMR(400MHz,CDCl 3 )δ6.90-6.85(m,1H),6.83-6.77(m,2H),6.49-6.45(m,1H),4.15(t,J＝8.1Hz,2H),4.05(t,J＝7.2Hz,2H),3.79(s,3H),3.73(s,3H),3.56-3.47(m,1H).
And a second step of: preparation of 1- (2-methoxyphenyl) azetidine-3-carboxylic acid:
to a mixed solution of compound 1- (2-methoxyphenyl) azetidine-3-carboxylic acid methyl ester (800 mg,1 eq) in methanol (2 mL), tetrahydrofuran (2 mL) and water (2 mL), lithium hydroxide (433 mg,5 eq) was added, and the reaction solution was stirred at room temperature for 5 hours, and LCMS detection of the completion of the reaction. To the reaction solution was added water, the pH was adjusted to 4 to 5 with 1M hydrochloric acid solution, extracted with ethyl acetate (10 mL. Times.4), the organic phases were combined, washed with saturated brine (20 mL. Times.2), and the organic phase was dried and concentrated to give a crude product, which was purified by reverse phase column chromatography (0.05% FA in water/MeCN 0-36%) to give the objective compound (495 mg, yield 66%).
LCMS(ESI)[M+H]+＝208.4。
And a third step of: preparation of (1- (2-methoxyphenyl) azetidin-3-yl) ((6 br,10 as) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyridine (3 ',4':4, 5) pyrrole (1, 2, 3-des) quinoxalin-8 (7H) -yl) methanone:
the compound 1- (2-methoxyphenyl) azetidine-3-carboxylic acid (150 mg,1 eq) was dissolved in N, N-dimethylformamide (4 mL), and (6 br,10 as) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine (3 ',4':4, 5) pyrrole (1, 2, 3-deo) quinoline (166 mg,1 eq), ((dimethylamino) ((3H- (1, 2, 3) triazolo (4, 5-b) pyridin-3-yloxy)) methylene) dimethylazahexafluoro- λ5-phosphorus (275.22 mg,1 eq) and N, N-diisopropylethylamine (187.1 mg,2 eq) were added, the reaction was stirred at room temperature for 5 hours, the s detection reaction was completed, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (30 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product, which was purified by column chromatography (PE: ea=1:0-0:1) to give the title compound (112 mg, yield 37%).
LCMS(ESI)[M+H] + ＝419.3。
Fourth step: (6 bR,10 aS) -8- ((1- (2-methoxyphenyl) azetidin-3-yl) methyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine (3', 4): preparation of 4, 5) pyrrole (1, 2, 3-deoxoquinoxaline):
The compound (1- (2-methoxyphenyl) azetidin-3-yl) ((6 br,10 as) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyridine (3 ',4':4, 5) pyrrole (1, 2, 3-decaquinoxalin-8 (7H) -yl) methanone (100 mg,1 eq) was dissolved in tetrahydrofuran (2 mL), a solution of lithium aluminum hydride in tetrahydrofuran (0.24 mL 1.5 m) was slowly added dropwise at 0 ℃, the reaction mixture was stirred continuously at 0 ℃ for 10 minutes, LCMS detection was completed, water (1 mL) was slowly added dropwise to the reaction mixture in an ice bath, followed by quenching with 10% sodium hydroxide solution, filtration, the cake was further washed with tetrahydrofuran (2 mL x 4), the filtrate was dried by spin-drying to give a crude product, which was purified by prep-HPLC (0.05% in water/MeCN) to give the target compound (11.63 mg, 12%).
LCMS(ESI)[M+H] + ＝405.5； 1 H NMR(400MHz,MeOD-d 4 )δ8.51(s,1H),6.86-6.77(m,3H),6.64(s,1H),6.57 -6.38(m,3H),4.08(dd,J＝12.2,7.1Hz,2H),3.77(s,3H),3.54(dt,J＝20.9,6.5Hz,3H),3.37(dd,J＝12.8,7.1Hz,2H),3.27-3.11(m,3H),3.03(s,4H),2.94-2.66(m,5H),2.36(t,J＝11.0Hz,1H),2.18(d,J＝14.6Hz,1H),2.06(dd,J＝15.9,7.8Hz,1H).
Examples 110 to 117
Reference to the procedure for the preparation of example 109 gave the compounds of examples 110-117
Example 118
Preparation of (6 bR,10 aS) -8- (3- (2-methoxypyridin-3-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido (3 ',4':4, 5) pyrrolo (1, 2, 3-deoxoquinoxaline):
the first step: preparation of ethyl 3- (2-methoxypyridin-3-yl) prop-2-enoate:
ethyl-2- (diethoxyphosphoryl) acetate (7.36 g,1 eq) was added to tetrahydrofuran (50 mL) of sodium hydride (0.79 g,1 eq) under nitrogen atmosphere at 0 ℃ and stirred for 5 minutes, the resulting mixture was added dropwise to tetrahydrofuran (50 mL) of 2-methoxypyridine-3-carbaldehyde (4.5 g,1 eq) at 0 ℃, heated to 70 ℃ and refluxed overnight, LCMS detected the reaction. The reaction was added to water (50 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was isolated and purified by flash chromatography (Silica gel, PE: ea=6:1) to give the title compound (2.7 g, 39.7% yield).
LCMS(ESI)[M+H] + ＝208.1； 1 H NMR(400MHz,DMSO-d 6 )δ8.23(dd,J＝4.9,1.8Hz,1H),8.13
(dd,J＝7.5,1.8Hz,1H),7.73(d,J＝16.2Hz,1H),7.07(dd,J＝7.5,4.9Hz,1H),6.72(d,J＝16.2Hz,1H),4.20(q,J＝7.1Hz,2H),3.97(s,3H),1.27(t,J＝7.1Hz,3H).
And a second step of: preparation of ethyl 3- (2-methoxypyridin-3-yl) propionate:
palladium on carbon (300 mg) was added to methanol (20 mL) of ethyl 3- (2-methoxypyridin-3-yl) prop-2-enoate (1.5 g,1 eq) at 25℃under hydrogen atmosphere, stirred for 3 hours, and after completion of the reaction by LCMS detection, filtration and concentration in vacuo, the objective compound (1.48 g, yield 97.7%) was obtained.
LCMS(ESI)[M+H] + ＝210.1； 1 H NMR(400MHz,DMSO-d 6 )8.02(dd,J＝5.0,1.8Hz,1H),7.53(dd,
J＝7.2,1.6Hz,1H),6.91(dd,J＝7.2,5.0Hz,1H),4.04(q,J＝7.1Hz,2H),3.87(d,J＝4.0Hz,3H),2.79(t,J＝7.6Hz,2H),2.58(t,J＝7.6Hz,2H),1.15(t,J＝7.1Hz,3H).
And a third step of: preparation of 3- (2-methoxypyridin-3-yl) propan-1-ol:
lithium aluminum hydride (537 mg,2 eq) was slowly added to tetrahydrofuran (20 mL) of ethyl 3- (2-methoxypyridin-3-yl) propionate (1.48 g,1 eq) at 0 ℃, the reaction was stirred for 3 hours at 25 ℃, LCMS detection was completed, water (0.5 mL), 15wt% aqueous sodium hydroxide solution (0.5 mL), water (1.5 mL) was added to quench, anhydrous sodium sulfate was added to stir for ten minutes, celite was filtered, and the filtrate was collected and concentrated in vacuo to give the title compound (1.07 g, yield 90.5%).
LCMS(ESI)[M+H] + ＝168.1； 1 H NMR(400MHz,DMSO-d 6 )δ7.36(td,J＝8.3,1.6Hz,1H),7.29
(dd,J＝7.7,1.5Hz,1H),7.14(d,J＝8.2Hz,1H),7.01(dd,J＝10.8,4.3Hz,1H),4.57(t,J＝5.5Hz,1H),3.82(s,3H),3.50–3.41(m,1H),3.40–3.31(m,2H),3.25–3.16(m,1H),1.62(s,3H).
Fourth step: preparation of 3- (2-methoxypyridin-3-yl) propanal:
dess-martin reagent (1.71 g,1.5 eq) was added to dichloromethane (10 mL) of 3- (2-methoxypyridin-3-yl) propan-1-ol (450 mg,1 eq) at 0 ℃ and allowed to stir at room temperature for 5 hours. After completion of LCMS detection, saturated sodium bicarbonate (20 mL) was added, extraction was performed with dichloromethane (10 mL x 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and the crude product was isolated and purified by flash chromatography (Silica gel, PE: ea=1:1) to give the title compound (340 mg, 76.5% yield).
LCMS(ESI)[M+H 2 O+H] + ＝184； 1 H NMR(400MHz,DMSO-d 6 )δ9.71(t,J＝1.2Hz,1H),8.02(dd,
J＝5.0,1.9Hz,1H),7.54(dd,J＝7.2,1.9Hz,1H),6.91(dd,J＝7.2,5.0Hz,1H),3.87(s,3H),2.78(d,J＝5.9Hz,2H),2.76(d,J＝1.1Hz,2H).
Fifth step: preparation of (6 bR,10 aS) -8- (3- (2-methoxypyridin-3-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido (3 ',4':4, 5) pyrrolo (1, 2, 3-deoxoquinoxaline):
3- (2-methoxypyridin-3-yl) propanal (108 mg,1.5 eq) was added to tetrahydrofuran (5 mL) of (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (100 mg,1 eq) at 25℃and stirred for 5 minutes, acetic acid (0.1 mL) and sodium triacetoxyborohydride (185 mg,2 eq) were added to the reaction system, stirred for 2 hours, after completion of LCMS detection reaction, water (15 mL), ethyl acetate (10 mL. Times.3) was added, and the combined organic phases were washed with saturated brine, filtered, and the crude product was concentrated in vacuo to give the title compound (29.04 mg, 17.4%) by prep-HPLC purification (C18, 0.1%FA in water,MeCN).
LCMS(ESI)[M+H] + ＝379.3； 1 H NMR(400MHz,DMSO-d 6 ),8.00(dd,J＝5.0,1.8Hz,1H),7.52
(dd,J＝7.2,1.8Hz,1H),6.91(dd,J＝7.1,5.0Hz,1H),6.52(t,J＝7.6Hz,1H),6.43(d,J＝7.1Hz,1H),6.34(d,J＝7.6Hz,1H),3.87(s,3H),3.46–3.40(m,1H),3.30(ddd,J＝19.4,10.9,2.8Hz,2H),3.12(d,J＝2.4Hz,1H),3.06(dd,J＝10.5,6.3Hz,1H),2.86(dd,J＝10.8,6.5Hz,1H),2.78(s,3H),2.72–2.65(m,2H),2.54(d,J＝7.5Hz,2H),2.36(td,J＝12.4,5.1Hz,2H),2.22(dd,J＝11.5,9.2Hz,1H),1.87(dt,J＝12.8,12.0Hz,3H),1.73(dd,J＝15.1,7.5Hz,2H).
Example 119
Preparation of (6 bR,10 aS) -8- (3- (5-fluoro-2-methoxyphenyl) -propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline
The first step: preparation of ethyl 3- (5-fluoro-2-methoxyphenyl) acrylate:
5-fluoro-2-methoxybenzaldehyde (1 g,1 eq) and [ (1E) -3-ethoxy-3-oxo-1-propen-1-yl ] triphenylphosphine (2.49 g,1.1 eq) were dissolved in dichloromethane (10 mL), stirred at room temperature under nitrogen for 12 hours, TLC showed the starting material was reacted, the reaction solution was concentrated to obtain a crude product, which was purified by flash chromatography (Silica gel, PE: EA=15:1) to give the objective compound (1.46 g, yield 99%).
1 H NMR(400MHz,DMSO-d 6 )δ7.83(dd,J＝16.2,1.2Hz,1H),7.64(dd,J＝9.6,3.1Hz,1H),7.30–7.22(m,1H),7.13–7.07(m,1H),6.69(d,J＝16.2Hz,1H),4.19(q,J＝7.1Hz,2H),3.86(s,3H),1.26(t,J＝7.1Hz,3H).
And a second step of: preparation of ethyl 3- (5-fluoro-2-methoxyphenyl) propionate:
ethyl 3- (5-fluoro-2-methoxyphenyl) acrylate (500 mg,1 eq) was dissolved in tetrahydrofuran (10 mL), 10% palladium on charcoal (22 mg,0.11 eq) was added, hydrogen was replaced, stirring was performed at room temperature for 15 hours, TLC showed complete reaction of the starting materials, and the reaction solution was suction filtered and concentrated to give the target compound (320 mg, yield 63.4%).
1 H NMR(400MHz,DMSO-d 6 )δ7.03–6.97(m,2H),6.94(dd,J＝9.8,4.8Hz,1H),4.04(q,J＝7.1Hz,2H),3.77(s,3H),2.80(t,J＝7.7Hz,2H),2.55(t,J＝7.7Hz,2H),1.16(t,J＝7.1Hz,3H).
And a third step of: preparation of 3- (5-fluoro-2-methoxyphenyl) propan-1-ol:
ethyl 3- (5-fluoro-2-methoxyphenyl) propionate (4 g,1 eq) was dissolved in tetrahydrofuran (10 mL), lithium aluminum hydride (1.01 g,1.5 eq) was added at 0deg.C, and stirred at room temperature for 4 hours, LCMS showed complete reaction of the starting materials. The reaction was quenched (100 mL) in water, extracted with ethyl acetate (50 mL x 3), the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by suction to give the title compound (2.8 g, 86% yield). LCMS (ESI) [ M+H ]] + ＝185.1.
Fourth step: preparation of propyl 3- (5-fluoro-2-methoxyphenyl) methanesulfonate:
3- (5-fluoro-2-methoxyphenyl) propan-1-ol (60 mg,1 eq) and triethylamine (66 mg,2 eq) were dissolved in dichloromethane (5 mL), methanesulfonyl chloride (56 mg,1.5 eq) was added at 0 ℃ and stirred for 1 hour at 0 ℃, LCMS showed the reaction was complete, water (5 mL) was added to the reaction solution, dichloromethane was extracted (15 mL x 3), the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by suction to give crude product which was purified by flash chromatography (Silica gel, PE: ea=20:1) to give the title compound (42 mg, yield 49%). LCMS (ESI) [ M+H ] ] + ＝262.9.
Fifth step: preparation of (6 bR,10 aS) -8- (3- (5-fluoro-2-methoxyphenyl) -propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline:
3- (5-fluoro-2-methoxyphenyl) propylmethanesulfonate (100 mg,1 eq) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (87 mg,1 eq) were dissolved in N, N-dimethylformamide (5 mL), potassium carbonate (53 mg,1 eq) was added, and stirred at 70℃for 16 hours, LCMS showed complete reaction of the starting materials. Water (50 mL), ethyl acetate extraction (50 mL. 3), combined organic phases, saturated brine, dry over anhydrous sodium sulfate, suction filtration and concentration to give crude product, which was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the title compound (24.96 mg, 15% yield).
LCMS(ESI)[M+H] + ＝396.2； 1 H NMR(400MHz,CDCl 3 )δ6.86(td,J＝8.5,3.1Hz,1H),6.79(dd,J
＝8.7,2.9Hz,1H),6.76–6.67(m,2H),6.51(d,J＝7.4Hz,1H),6.44(d,J＝8.0Hz,1H),3.77(s,3H),3.69–3.54(m,2H),3.45(dd,J＝32.3,11.6Hz,2H),3.27(dd,J＝13.3,6.8Hz,3H),2.95(dd,J＝17.4,9.2Hz,3H),2.87(s,3H),2.86–2.80(m,1H),2.64(dd,J＝12.0,7.0Hz,2H),2.49(dd,J＝25.3,13.5Hz,2H),2.14–2.03(m,4H).
Example 120
Preparation of N- (1- (2-methoxyphenyl) -3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) acetamide:
the first step: preparation of ethyl 3-amino-3- (2-methoxyphenyl) prop-2-enoate:
ethyl 3- (2-methoxyphenyl) -3-oxopropionate (10 g,1 eq) was dissolved in ethanol (10 mL), ammonium formate (17.03 g,6 eq) was added and the reaction system was stirred at 88 ℃ under nitrogen for 5 hours, LCMS showed the reaction to end, the reaction was concentrated, filtered and the filter cake was washed with ethyl acetate, the filtrate was added, water (100 mL), extracted with ethyl acetate (100 mL x 3), the combined organic phases dried over anhydrous sodium sulfate, filtered and concentrated to give crude (9.96 g, crude).
LCMS(ESI)[M+H] + ＝222.2； 1 H NMR(400MHz,CDCl 3 )δ7.43(dd,J＝7.6,1.7Hz,1H),7.39–
7.33(m,1H),7.01–6.92(m,2H),4.84(s,1H),4.16(q,J＝7.1Hz,2H),3.86(s,3H),1.29(t,J＝7.1Hz,3H).
And a second step of: preparation of ethyl 3-acetamido-3- (2-methoxyphenyl) acrylate:
ethyl 3-amino-3- (2-methoxyphenyl) prop-2-enoate (9 g,1 eq) was dissolved in tetrahydrofuran (100 mL), pyridine (0.32 g,0.1 eq), acetic anhydride (22.84 g,5.5 eq) were added under nitrogen protection, the reaction system was stirred at 90 ℃ for 20 hours, LCMS showed the reaction to end, the reaction solution was concentrated to crude product, and the crude product was isolated and purified by reverse phase flash chromatography (C18, 0.05%FA in water,MeCN) to give the target compound (6 g, yield 56.0%).
LCMS(ESI)[M+H] + ＝264.1.
And a third step of: preparation of ethyl 3-acetamido-3- (2-methoxyphenyl) propionate:
palladium on carbon (404 g,1 eq) was added to a solution of ethyl 3-acetamido-3- (2-methoxyphenyl) acrylate (1 g,1 eq) in methanol (10 mL) and acetic acid (1 mL) was further added under hydrogen atmosphere, the reaction system was reacted at 70℃in an autoclave for 16 hours, LCMS showed the reaction to be completed, the reaction solution was filtered, and concentrated to give a crude product (500 mg,1.88mmol, 49.6%).
LCMS(ESI)[M+H] + ＝264.1； 1 H NMR(400MHz,DMSO-d 6 )δ8.27(d,J＝8.6Hz,1H),7.29–7.19
(m,2H),7.03–6.87(m,2H),5.50(dd,J＝8.9,3.9Hz,1H),4.02(ddt,J＝10.6,7.1,3.5Hz,2H),3.80(s,3H),2.71–2.52(m,2H),1.82(s,3H),1.12(t,J＝7.1Hz,3H).
Fourth step: preparation of N- (3-hydroxy-1- (2-methoxyphenyl) propyl) acetamide:
ethyl 3-acetamido-3- (2-methoxyphenyl) propionate (500 mg,1 eq) was dissolved in tetrahydrofuran (5 mL), lithium borohydride (82 mg,2 eq), methanol (121 mg,2 eq) were added under ice bath and nitrogen protection, the reaction system was stirred at room temperature for 5 hours after the addition, LCMS showed the end of the reaction, water (20 mL) was added, extracted with ethyl acetate (30 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give crude, which was purified by reverse phase flash chromatography (C18, 0.05%FA in water,MeCN) to give the title compound (360 mg, 85.6% yield).
LCMS(ESI)[M+H] + ＝224.0； 1 H NMR(400MHz,CDCl 3 )δ7.30–7.21(m,2H),6.94(dd,J＝12.6,
4.8Hz,2H),6.82(d,J＝7.9Hz,1H),5.27(dd,J＝13.9,9.0Hz,1H),3.89(d,J＝1.2Hz,3H),3.64–3.58(m,2H),2.02(d,J＝1.2Hz,3H),1.95(ddd,J＝12.9,7.5,3.2Hz,2H).
Fifth step: preparation of N- (1- (2-methoxyphenyl) -3-carbonylpropyl) acetamide:
n- (3-hydroxy-1- (2-methoxyphenyl) propyl) acetamide (150 mg,1 eq) was dissolved in dichloromethane (5 mL), dessert-martin oxidant (570 mg,2 eq) was slowly added under ice bath, stirred at room temperature for 2 hours after the addition, LCMS showed the reaction was completed, sodium bicarbonate was added to quench the reaction, dichloromethane (20 mL. Times.3) was used to extract, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give crude product which was isolated and purified by reverse phase flash chromatography (C18, 0.05%FA in water,MeCN) to afford the title compound (120 mg, 81% yield).
LCMS(ESI)[M+H] + ＝222.1.
Sixth step: preparation of N- (1- (2-methoxyphenyl) -3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) acetamide:
(6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-desquinoxaline (100 mg,1 eq) and N- (1- (2-methoxyphenyl) -3-carbonylpropyl) acetamide (107 mg,1.1 eq) were dissolved in tetrahydrofuran (1 mL), acetic acid was added dropwise, stirring was performed at room temperature for 30 minutes, sodium bis (acetoxy) boronoyl acetate (187 mg,2 eq) was added, the reaction solution was stirred at room temperature for 2 hours, LCMS showed the end of the reaction, water (10 mL) was added to the reaction solution, ethyl acetate (20 mL. Times.3) was used for extraction, the combined organic phase was dried over anhydrous sodium sulfate, and the crude product was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the target compound (25.45 mg, yield 13.3%).
LCMS(ESI)[M+H] + ＝434.9； 1 H NMR(400MHz,DMSO-d 6 )δ11.09(s,1H),8.40(dd,J＝13.9,8.7
Hz,1H),7.31(d,J＝7.6Hz,1H),7.24(t,J＝7.6Hz,1H),6.99–6.91(m,2H),6.76(s,3H),5.12(d,J＝4.8Hz,1H),3.80(s,3H),3.53(d,J＝12.1Hz,5H),3.39(d,J＝13.1Hz,2H),3.15(s,1H),3.06–2.88(m,6H),2.65–2.53(m,1H),2.28(t,J＝18.0Hz,2H),2.08(d,J＝9.2Hz,2H),1.86(d,J＝4.5Hz,3H).
Example 121
Preparation of (6 bR,10 aS) -8- (2-fluoro-3- (2-methoxyphenyl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline:
the first step: preparation of 1-allyl-2-methoxybenzene:
2-allylphenol (9 g,1 eq) and methyl iodide (23.8 g,2.5 eq) were dissolved in acetone (90 mL), and anhydrous potassium carbonate (23.17 g,2.5 eq) was added and stirred at 30℃for 18 hours. LCMS detects completion of the reaction. The reaction mixture was diluted with ethyl acetate (180 mL), washed with water (180 mL), and extracted. The organic phase was washed with sodium bicarbonate (180 mL) and saturated brine (180 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by flash chromatography (Silica gel, PE: ea=10:1) to give the desired product (7 g, yield 70.4%).
LCMS(ESI)[M+H] + ＝149.2； 1 H NMR(400MHz,DMSO-d 6 )δ7.23–7.17(m,1H),7.10(dd,J＝
7.4,1.4Hz,1H),6.96(t,J＝10.3Hz,1H),6.88(td,J＝7.4,0.7Hz,1H),5.94(ddt,J＝16.8,10.1,6.6Hz,1H),5.19–4.89(m,2H),3.77(s,3H),3.32(t,J＝5.8Hz,2H).
And a second step of: preparation of 1- (2-fluoro-3-iodopropyl) -2-methoxybenzene:
1-allyl-2-methoxybenzene (128 mg,1 eq) and 1-fluoro-3, 3-dimethyl-1, 3-dihydro-1I 3-benzo [ d ] [1,2] iodooxazole (244 mg,1.01 eq) were dissolved in deuterated chloroform (5 mL), and palladium acetate (39 mg,0.2 eq) was added to the reaction mixture to react at 40℃for 12 hours. TLC detection showed no starting material remaining. The reaction solution was filtered, and the crude product was purified by flash chromatography (Silica gel, PE: ea=99:1) to give the objective product (80 mg, yield 31.5%).
1 H NMR(400MHz,CDCl 3 )δ7.18–7.12(m,2H),6.82(ddd,J＝21.8,10.9,4.6Hz,2H),4.72–4.52(m,1H),3.75(s,3H),3.34–3.11(m,2H),3.03–2.93(m,2H).
And a third step of: preparation of (6 bR,10 aS) -8- (2-fluoro-3- (2-methoxyphenyl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline:
1- (2-fluoro-3-iodopropyl) -2-methoxybenzene (104 mg,1.5 eq), (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (54 mg,1 eq) and anhydrous potassium carbonate (48.89 mg,1.5 eq) were added to N, N-dimethylformamide (5 mL), and reacted at 70℃for 16 hours. LCMS detected complete reaction. The reaction solution was cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was subjected to prep-HPLC (0.1% fa in water/MeCN) to give the title compound (13.47 mg, yield 12.7%).
LCMS(ESI)[M+H] + ＝395.9； 1 H NMR(400MHz,CDCl 3 )δ8.41(s,1H),7.21(d,J＝7.9Hz,1H),
7.15(d,J＝7.2Hz,1H),6.87(dd,J＝18.8,7.8Hz,2H),6.66(t,J＝7.7Hz,1H),6.50(d,J＝7.3Hz,1H),6.41(d,J＝7.9Hz,1H),5.28–5.04(m,1H),3.81(s,3H),3.59(t,J＝9.6Hz,1H),3.34(s,1H),3.31–3.25(m,2H),3.23(s,1H),3.18–3.04(m,2H),2.99(d,J＝6.1Hz,1H),2.94(d,J＝5.2Hz,1H),2.86(s,3H),2.85–2.71(m,3H),2.62(dd,J＝23.2,11.4Hz,1H),2.36–2.14(m,2H),1.98(d,J＝15.2Hz,1H).
Example 122
Preparation of (6 bR,10 aS) -8- (3- (4-methoxypyrimidin-5-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine (3 ',4':4, 5) pyrrole (1, 2, 3-deoxoquinoxaline):
the first step: preparation of 4-chloro-6-methoxypyrimidine-5-carbaldehyde:
4, 6-dichloropyrimidine-5-carbaldehyde (20 g,1 eq) was dissolved in methanol (1000 mL), sodium bicarbonate (10.44 g,1.1 eq) was added, stirred at room temperature for 16 hours, LCMS detection was completed, the methanol was dried by spin, extraction with water, ethyl acetate, the organic phase was collected, saturated brine was added, the organic phase was dried by spin, and the crude product was purified by flash chromatography (Silica gel, PE: ea=100:0 to 80:20) and isolated by reverse phase flash chromatography (C18, 0.05%FA in water,MeCN) to give the desired product (8 g, yield 41.0%).
LCMS(ESI)[M+H] + ＝173.1； 1 H NMR(400MHz,DMSO-d 6 )δ10.26(s,1H),8.82(s,1H),4.08(s,
3H).
And a second step of: preparation of 4-methoxypyrimidine-5-carbaldehyde:
4-chloro-6-methoxypyrimidine-5-carbaldehyde (6.2 g,1 eq) was dissolved in ethanol (240 mL), triethylamine (6 mL) and palladium on carbon (600 mg) were added and stirred at room temperature for 2 hours under a hydrogen atmosphere, LCMS detection was completed, and the filtrate was filtered and dried to give a crude product, which was purified by flash chromatography (Silica gel, PE: ea=5:1) to give the desired product (4 g, yield 80.6%).
LCMS(ESI)[M+H] + ＝139.1； 1 H NMR(400MHz,DMSO-d 6 )δ10.20(d,J＝2.1Hz,1H),9.02(d,J
＝2.2Hz,1H),8.90(d,J＝2.2Hz,1H),4.08(d,J＝2.0Hz,3H).
And a third step of: preparation of 3- (4-methoxypyrimidin-5-yl) prop-2-enoic acid ethyl ester:
sodium hydrogen (835.85 mg,1.3 eq) was dissolved in tetrahydrofuran (30 mL), a tetrahydrofuran solution of ethyl 2- (diethoxyphosphoryl) acetate (6.61 g,1.1 eq) was added dropwise at 0 ℃ and stirred at 0 ℃ for half an hour, then a tetrahydrofuran solution of 4-methoxypyrimidine-5-carbaldehyde (3.7 g,1 eq) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 hour, followed by LCMS detection. Water quenching, spin drying tetrahydrofuran, extraction with ethyl acetate (50 ml x 3), saturated brine, and drying over anhydrous sodium sulfate to give the desired product (5.2 g, crude).
LCMS(ESI)[M+H] + ＝209.2.
Fourth step: preparation of ethyl 3- (4-methoxypyrimidin-5-yl) propionate:
3- (4-Methoxypyrimidin-5-yl) prop-2-enoic acid ethyl ester (5.1 g, crude product) was dissolved in methanol (50 mL), palladium on carbon (1 g) was added, the reaction was carried out at room temperature under hydrogen atmosphere for 3 hours, LCMS detection was completed, filtration was carried out, and the filtrate was dried by spinning to obtain crude product, which was isolated and purified by flash chromatography (Silica gel, PE: EA=5:1) to obtain the objective product (4.1 g, yield 79.6%).
LCMS(ESI)[M+H] + ＝211.2； 1 H NMR(400MHz,CDCl 3 )δ8.66(s,1H),8.29(s,1H),4.13(q,J＝
7.1Hz,2H),4.01(s,3H),2.87(t,J＝7.5Hz,2H),2.62(t,J＝7.5Hz,2H),1.24(t,J＝7.1Hz,3H).
Fifth step: preparation of 3- (4-methoxypyrimidin-5-yl) propanal:
ethyl 3- (4-methoxypyrimidin-5-yl) propionate (1 g,1 eq) was dissolved in toluene (5 mL), the temperature was reduced to-78 ℃, diisobutylaluminum hydride (4.7 mL,1.5 eq) was slowly added dropwise, the reaction was carried out at-78 ℃ for 2 hours, LCMS was monitored to complete the reaction, water (4 mL) was added, quenched, filtered, and the filtrate was dried by spin to give a crude product, which was isolated and purified by flash chromatography (Silica gel, PE: ea=2:1) to give the objective product (450 mg, yield 56.9%).
LCMS(ESI)[M+H] + ＝169.2；
Sixth step: preparation of propyl 3- (4-methoxypyrimidin-5-yl) methanesulfonate:
3- (4-methoxypyrimidin-5-yl) propanol (300 mg,1 eq) was dissolved in dichloromethane (3 mL), triethylamine (452.23 mg,2.5 eq) was added dropwise methanesulfonyl chloride (306.48 mg,1.5 eq) under ice bath, stirred at room temperature for 1 hour, after completion of LCMS detection reaction, water was added, dichloromethane was extracted, and the organic phase was collected and dried by flash chromatography to give the crude product, which was isolated and purified by flash chromatography (Silica gel, PE: EA=1:5) to give the desired product (250 mg, yield 56.9%).
LCMS(ESI)[M+H] + ＝247.1； 1 H NMR(400MHz,CDCl 3 )δ8.67(s,1H),8.27(s,1H),4.26(t,J＝
6.2Hz,2H),4.02(s,3H),3.02(s,3H),2.78–2.57(m,2H),2.10–2.00(m,2H).
Seventh step: preparation of (6 bR,10 aS) -8- (3- (4-methoxypyrimidin-5-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine (3 ',4':4, 5) pyrrole (1, 2, 3-deoxoquinoxaline):
(6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyridine (3 ',4':4, 5) pyrrole (1, 2, 3-deoxoquinoxaline) (100 mg,1 eq) was dissolved in N, N-dimethylformamide (2 mL), 3- (4-methoxypyrimidin-5-yl) propanesulfonate (139.61 mg,1.3 eq) and potassium carbonate (180.81 mg,3 eq) were added, and reacted at 70℃for 4 hours, after LCMS detection, water (10 mL) and ethyl acetate (5 mL) were added to extract, the organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate to give a crude product, which was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the objective compound (74.1 mg, yield 47.7%).
LCMS(ESI)[M+H] + ＝380.4； 1 H NMR(400MHz,CDCl 3 )δ8.64(s,1H),8.54(s,1H),8.23(s,1H),
6.68(t,J＝7.7Hz,1H),6.52(d,J＝7.3Hz,1H),6.42(d,J＝8.0Hz,1H),4.00(s,3H),3.59(s,1H),3.40(dd,J＝11.3,5.8Hz,1H),3.28(d,J＝7.0Hz,3H),3.22–3.12(m,1H),3.04(d,J＝10.7Hz,1H),2.85(d,J＝14.3Hz,4H),2.76–2.52(m,5H),2.22(t,J＝11.3Hz,2H),2.05–1.92(m,3H).
Example 123
Preparation of (6 bR,10 aS) -8- (4- (2-methoxyphenyl) butan-2-yl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline:
the first step: preparation of 4- (2-methoxyphenyl) buten-2-one:
2-methoxybenzaldehyde (5 g,1 eq) was added to acetone (25 mL) and water (25 mL), 1% sodium hydroxide (5 mL) was slowly added, stirred at 65 ℃ for 1.5 hours, TLC plates were checked, the starting material disappeared, ethyl acetate (30 mL x 3) was added for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and the crude product was isolated and purified by flash chromatography (Silica gel, PE: ea=5:1) to give the title compound (5.4 g, yield 83.5%).
LCMS(ESI)[M+H] + ＝177.1； 1 H NMR(400MHz,DMSO-d 6 )δ7.79(d,J＝16.5Hz,1H),7.70(dd,
J＝7.7,1.6Hz,1H),7.47–7.39(m,1H),7.10(d,J＝8.3Hz,1H),7.00(t,J＝7.5Hz,1H),6.84(d,J＝16.4Hz,1H),3.88(s,3H),2.31(s,3H).
And a second step of: preparation of 4- (2-methoxyphenyl) butanone
Palladium on carbon (200 mg) was added to ethyl acetate (10 mL) of 4- (2-methoxyphenyl) buten-2-one (1 g,1 eq), stirred at room temperature under a hydrogen atmosphere (2 atm) for 2 hours, the reaction was detected by LCMS, the reaction solution was filtered, and the filtrate was collected and concentrated in vacuo to give the title compound (670 mg, yield 62.3%).
LCMS(ESI)[M+H] + ＝179.3； 1 H NMR(400MHz,MeOD-d 4 )δ7.19–7.12(m,1H),7.11–7.07(m,
1H),6.89(d,J＝8.2Hz,1H),6.82(t,J＝7.4Hz,1H),3.80(s,3H),2.87–2.78(m,2H),2.75–2.67(m,2H),2.11(s,3H).
And a third step of: preparation of (6 bR,10 aS) -8- (4- (2-methoxyphenyl) butan-2-yl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline:
(6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido (3 ',4':4, 5) pyrrolo (1, 2, 3-deoxoquinoxaline (100 mg,1 eq), 4- (2-methoxyphenyl) butanone-2-one (78 mg,1 eq) was added to tetrahydrofuran (5 mL), stirred at room temperature for 10 minutes, sodium triacetoxyborohydride (185 mg,2 eq) and acetic acid (0.1 mL) were added to the system, stirred at 70℃for 16 hours, the LCMS detection reaction was cooled to room temperature, quenched with saturated sodium bicarbonate solution (10 mL), dichloromethane (10 mL. Times.3) was extracted, the organic phases were combined, dried, concentrated in vacuo, and the crude product was purified by prep-HPLC (C18, 0.1%FA in water,MeCN) to give the title compound (29.77 mg, 17.3%).
LCMS(ESI)[M+H] + ＝392.3； 1 H NMR(400MHz,DMSO-d 6 )δ8.19(s,1H),7.14(dd,J＝13.0,7.2
Hz,2H),6.92(d,J＝8.0Hz,1H),6.85(t,J＝7.4Hz,1H),6.50(dd,J＝7.6,2.1Hz,1H),6.43(d,J＝7.2Hz,1H),6.32(d,J＝7.8Hz,1H),3.77(d,J＝2.9Hz,3H),3.43(d,J＝8.8Hz,2H),3.32(d,J＝10.1Hz,2H),3.26(d,J＝11.4Hz,2H),3.12(s,1H),3.04–2.95(m,1H),2.78(s,3H),2.67(s,2H),2.53(s,1H),2.34–2.12(m,2H),1.91(s,1H),1.79–1.63(m,2H),1.43(s,1H),0.88–0.83(m,3H).
Example 124
Preparation of 2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9, 10-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-d ] quinoxalin-8 (7H) -yl) propyl) benzonitrile:
the first step: preparation of ethyl 3- (2-cyanophenyl) acrylate:
ethyl 2- (diethoxyphosphoryl) acetate (20.52 g,1.2 eq) was dissolved in tetrahydrofuran (400 mL), sodium hydride (2.38 g,1.3 eq) was added in portions at 0 ℃ and stirred for 30 minutes at room temperature, 2-formylbenzonitrile (10 g,1 eq) was added and replaced with nitrogen and stirred for 16 hours at room temperature, LCMS showed that the starting material had reacted to completion, a large amount of the target compound had been formed, the reaction solution was added with water (400 mL), extracted with ethyl acetate (400 mL x 3), the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the mother liquor was concentrated to give the target compound (9.8 g, yield 63.9%).
LCMS(ESI)[M+MeCN+H] + ＝243.1； 1 H NMR(400MHz,CDCl 3 )δ7.97(d,J＝16.0Hz,1H),
7.76–7.69(m,2H),7.62(ddd,J＝7.6,4.4,1.0Hz,1H),7.48(td,J＝7.6,1.2Hz,1H),6.61(d,J＝16.0Hz,1H),4.30(q,J＝7.1Hz,2H),1.36(t,J＝7.1Hz,3H).
And a second step of: preparation of ethyl 2-cyanophenyl) propionate:
ethyl 3- (2-cyanophenyl) prop-2-enoate (10.2 g,1 eq) was dissolved in methanol (200 mL), glacial acetic acid (0.3 g,0.1 eq) and palladium on carbon (0.54 g,0.1 eq) were added to replace hydrogen, stirring was carried out at room temperature for 16 hours, LCMS showed complete reaction of starting materials, suction filtration of the reaction solution, and concentration of mother liquor to give the title compound (8.2 g, 79.6% yield).
LCMS(ESI)[M+H] + ＝204.1； 1 H NMR(400MHz,CDCl 3 )δ7.62(dd,J＝7.7,1.0Hz,1H),7.52(td,
J＝7.7,1.3Hz,1H),7.38(d,J＝7.8Hz,1H),7.31(dd,J＝14.5,6.9Hz,1H),4.13(q,J＝7.1Hz,2H),3.18(t,J＝7.6Hz,2H),2.71(t,J＝7.6Hz,2H),1.23(dd,J＝9.2,5.1Hz,3H).
And a third step of: preparation of 2- (3-hydroxypropyl) benzonitrile:
ethyl 3- (2-cyanophenyl) propionate (8.8 g,1 eq) was dissolved in tetrahydrofuran (200 mL), methanol (2.77 g,2 eq) and lithium borohydride (1.89 g,2 eq) were added for nitrogen substitution, stirring at room temperature for 16 hours, LCMS showed little starting material remaining, a large amount of the target compound was produced, the reaction solution was added with water (200 mL), extracted with ethyl acetate (200 mL x 5), the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, the mother liquor was concentrated to give the crude product, and the crude product was isolated and purified by flash chromatography (Silica gel, DCM: 20:1to 10:1) to give the target compound (4.5 g, yield 64.5%).
LCMS(ESI)[M+MeCN+H] + ＝203.2； 1 H NMR(400MHz,CDCl 3 )δ7.62(d,J＝7.7Hz,1H),
7.52(td,J＝7.7,0.8Hz,1H),7.36(d,J＝7.8Hz,1H),7.31–7.26(m,1H),3.71(t,J＝6.3Hz,2H),3.01–2.91(m,2H),1.95(dq,J＝9.2,6.3Hz,2H).
Fourth step: preparation of 2- (3-oxopropyl) benzonitrile:
2- (3-hydroxypropyl) benzonitrile (1.5 g,1 eq) was dissolved in dichloromethane (100 mL), dessert-martin reagent (7.9 g,2 eq) was added and stirred at room temperature for 2 hours, LCMS showed complete reaction of the starting material, the reaction solution was washed twice with saturated aqueous sodium bicarbonate, once with saturated brine, the separated solution was dried over anhydrous sodium sulfate, suction filtered, the mother liquor was concentrated to give crude product, which was isolated and purified by flash chromatography (Silica gel, PE: ea=15:1 to 10:1) to give the title compound (260 mg, yield 17.5%).
LCMS(ESI)[M+H] + ＝160.2； 1 H NMR(400MHz,CDCl 3 )δ9.83(s,1H),7.63(d,J＝7.7Hz,1H),
7.53(t,J＝7.7Hz,1H),7.35(dd,J＝13.9,7.7Hz,2H),3.18(t,J＝7.4Hz,2H),2.89(t,J＝7.4Hz,2H).
Fifth step: preparation of 2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9, 10-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-d ] quinoxalin-8 (7H) -yl) propyl) benzonitrile:
2- (3-oxopropyl) benzonitrile (260 mg,1 eq) was dissolved in dichloromethane (5 mL), added (6 br,10 as) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (374.56 mg,1 eq) and glacial acetic acid (9.81 mg,0.1 eq), stirred at room temperature for 30 min, sodium triacetoxyborohydride (692.35 mg,2 eq) was added, stirred at room temperature for 2H, LCMS showed the starting material was reacted to give a large amount of the target compound, the reaction solution was added to saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (20 mL x 3), the organic phase was combined, dried with saturated brine, and concentrated by suction HPLC to give crude product by prep-purification (C18, 0.05%FA in water,MeCN) to give the target compound (240 mg, 39%).
LCMS(ESI)[M+H] + ＝373.2； 1 H NMR(400MHz,CDCl 3 )δ8.50(s,1H),7.60(d,J＝7.7Hz,1H),
7.53(t,J＝7.2Hz,1H),7.38–7.28(m,2H),6.69(t,J＝7.7Hz,1H),6.53(d,J＝7.3Hz,1H),6.43(d,J＝7.9Hz,1H),3.59(dd,J＝15.6,6.9Hz,1H),3.53–3.44(m,1H),3.36(dd,J＝11.4,6.4Hz,1H),3.28(d,J＝8.1Hz,4H),2.94–2.76(m,9H),2.35(dd,J＝21.2,9.7Hz,2H),2.11(dt,J＝20.7,10.8Hz,3H).
Example 125
Preparation of 2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9, 10-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) benzoic acid:
the first step: preparation of 2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9, 10-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) benzoic acid:
Raw material 2- (3- ((6 br,10 as) -3-methyl-2, 3,6b,9, 10-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-d ] quinoxalin-8 (7H) -yl) propyl) benzonitrile (120 mg,1 eq) was dissolved in ethanol (5 mL), water (5 mL) and potassium hydroxide (500 mg,27.66 eq) were added, stirring at 110 ℃ for 16 hours, LCMS showed complete reaction of the raw material, a large amount of the target compound was produced, the reaction solution was adjusted to ph=7-8 with acetic acid, sufficient sodium chloride was added to saturate the reaction solution, tetrahydrofuran was extracted (10 mL, 3) was separated, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate, suction filtered, the mother liquor was concentrated to give crude product, which was purified (C18, 0.05%FA in water,MeCN) by prep-HPLC to give the target compound (17.05 mg, yield 13.6%).
LCMS(ESI)[M+H] + ＝391.1； 1 H NMR(400MHz,DMSO-d 6 )δ8.17(s,1H),7.80(s,1H),7.32(d,J
＝7.3Hz,3H),7.26(d,J＝7.1Hz,1H),7.21(t,J＝7.4Hz,1H),6.51(t,J＝7.6Hz,1H),6.42(d,J＝7.2Hz,1H),6.33(d,J＝7.8Hz,1H),3.46–3.40(m,1H),3.29(dd,J＝21.4,10.8Hz,2H),3.11(s,1H),3.05–2.99(m,1H),2.80(d,J＝14.1Hz,4H),2.75–2.70(m,2H),2.69–2.58(m,2H),2.36–2.22(m,2H),2.12(t,J＝11.0Hz,1H),1.90(d,J＝12.4Hz,1H),1.84–1.67(m,4H).
Example 126
Preparation of N- (2-methoxyphenyl) -N- (2- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido (3 ',4':4, 5) pyrrolo (1, 2, 3-deoxalin-8 (7H) -yl) ethyl) acetamide:
the first step: preparation of 2- ((2-methoxyphenyl) amino) ethan-1-ol:
1-iodo-2-methoxybenzene (12.97 g,1 eq) and 2-aminoethan-1-ol (16.93 g,5 eq) were added to cuprous chloride (549 mg,0.1 eq) and potassium hydroxide (6.22 g,2 eq) at 25 ℃ and stirred for 16 hours, LCMS showed the reaction was complete, water (50 mL), ethyl acetate (50 mL x 3) was added, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was isolated and purified by flash chromatography (Silica gel, PE: ea=5:1) to give the title compound (8.09 g, yield: 87.3%).
LCMS(ESI)(M+H) + ＝168.2； 1 H NMR(400MHz,DMSO-d 6 )δ6.78(dd,J＝13.9,7.4Hz,2H),6.55
(t,J＝7.2Hz,2H),4.76(t,J＝5.3Hz,2H),3.77(s,3H),3.59(q,J＝5.6Hz,2H),3.09(q,J＝5.7Hz,2H).
And a second step of: preparation of N- (2-hydroxyethyl) -N- (2-methoxyphenyl) acetamide:
acetyl acetate (5.93 g,1.2 eq) was added to methanol (100 mL) of 2- ((2-methoxyphenyl) amino) ethan-1-ol (8.09 g,1 eq) at 25 ℃ and stirred for 16 hours, and LCMS detected the reaction. Water (150 mL), ethyl acetate (100 mL x 3) were added, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and the crude product was isolated and purified by flash chromatography (Silica gel, meOH: dcm=1:10) to give the title compound (8.489 g, yield 83.8%).
LCMS(ESI)(M+H) + ＝210.2； 1 H NMR(400MHz,DMSO-d 6 )δ7.36(td,J＝8.3,1.6Hz,1H),7.29
(dd,J＝7.7,1.5Hz,1H),7.14(d,J＝8.2Hz,1H),7.01(dd,J＝10.8,4.3Hz,1H),4.57(t,J＝5.5Hz,1H),3.82(s,3H),3.50–3.41(m,1H),3.40–3.31(m,2H),3.25–3.16(m,1H),1.62(s,3H).
And a third step of: preparation of N- (2-methoxyphenyl) -N- (2-carbonylethyl) acetamide:
dess-martin reagent (1.52 g,1.5 eq) was added to dichloromethane (10 mL) of N- (2-hydroxyethyl) -N- (2-methoxyphenyl) acetamide (500 mg,1 eq) at 0 ℃, warmed to room temperature and stirred for 5 hours, LCMS detection was complete, saturated sodium bicarbonate (20 mL), dichloromethane (10 mL x 3) was added to extract, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and the crude product was isolated and purified by flash chromatography (Silica gel, meOH: dcm=1:19) to give the title compound (380 mg, 76.7% yield).
LCMS(ESI)(M+H) + ＝207.7； 1 H NMR(400MHz,CDCl 3 )δ9.68(t,J＝1.2Hz,1H),7.35(m,J＝9.3,
7.8,1.7Hz,1H),7.29–7.25(m,1H),7.00(dd,J＝11.9,4.5Hz,2H),4.30(dd,J＝17.8,1.2Hz,1H),4.15(d,J＝17.9Hz,1H),3.85(s,3H),1.92(s,3H).
Fourth step: preparation of N- (2-methoxyphenyl) -N- (2- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido (3 ',4':4, 5) pyrrolo (1, 2, 3-deoxalin-8 (7H) -yl) ethyl) acetamide:
N- (2-methoxyphenyl) -N- (2-carbonylethyl) acetamide (136 mg,1.5 eq) was added to tetrahydrofuran (10 mL) of (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (100 mg,1 eq) at room temperature, stirred for five minutes, acetic acid (1 mL) and sodium borohydride (277 mg,3 eq) were added, stirred for 1 hour, LCMS was assayed, water (15 mL) was added, dichloromethane (10 mL. Times.3) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and the crude product was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the title compound (63.98 mg, 34.9%).
LCMS(ESI)(M+H) + ＝421.2； 1 H NMR(400MHz,DMSO-d 6 )δ8.14(s,1H),7.36(td,J＝8.3,1.7Hz,
1H),7.28(ddd,J＝7.6,4.3,1.6Hz,1H),7.14(d,J＝7.5Hz,1H),7.00(tdd,J＝7.6,2.6,1.2Hz,1H),6.50(td,J＝7.6,2.9Hz,1H),6.41–6.35(m,1H),6.32(d,J＝7.8Hz,1H),3.92(dd,J＝13.8,6.8Hz,1H),3.82(s,3H),3.41(t,J＝9.6Hz,1H),3.30(dt,J＝20.4,9.5Hz,4H),3.07(s,1H),2.95(dd,J＝10.7,5.7Hz,1H),2.77(s,3H),2.70–2.57(m,2H),2.42–2.27(m,2H),2.19–2.11(m,1H),1.83(dd,J＝15.9,13.6Hz,2H),1.72(dd,J＝11.7,6.4Hz,1H),1.63(s,3H).
Example 127
Preparation of 6- (((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrroline [1,2, 3-des ] quinoxalin-8 (7H) -yl) methyl) -6, 7-dihydro-5H-pyrazolo [5,1-b ] [1,3] oxazine:
the first step: preparation of 6-methylene-5 h,6h,7 h-pyrazolo [3,2-b ] [1,3] oxazine:
2, 3-dihydro-1H-pyrazol-3-one (18.9 g,1 eq) was dissolved in N, N-dimethylformamide (500 mL), potassium carbonate (93.2 g,3 eq) was added, stirred at 100℃for 0.5 hour, 3-chloro-2- (chloromethyl) prop-1-ene (28.1 g,1 eq) was added, stirred at 100℃for 16 hours, LCMS showed no starting material remaining, the reaction solution was distilled off under reduced pressure at 60℃to remove N, N-dimethylformamide, water (300 mL) was added, extracted with ethyl acetate (300 mL. Times.3), the organic phases were combined, the organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, suction filtered, the mother liquor was concentrated to give a crude product, and the crude product was purified by flash chromatography (Silica gel, meOH=40:1) to give the target compound (4.5 g, yield 14.7%).
LCMS(ESI)[M+H] + ＝137.2； 1 H NMR(400MHz,CDCl 3 )δ8.01(s,1H),7.33(d,J＝1.9Hz,1H),
5.50(d,J＝2.0Hz,1H),5.38(d,J＝6.1Hz,2H),4.79(s,2H),4.62(s,2H).
And a second step of: preparation of 5h,6h,7 h-pyrazolo [3,2-b ] [1,3] oxazin-6-yl) methanol:
6-methylene-5H, 6H, 7H-pyrazolo [3,2-b ] [1,3] oxazine (4.5 g,1 eq) was dissolved in tetrahydrofuran (100 mL), borane dimethyl sulfide (66.1 mL,4 eq) was added dropwise at 0deg.C, stirring was done at room temperature for 16 hours, sodium hydroxide solution (110.17 mL,10 eq) was slowly added dropwise to the reaction solution, 30% aqueous hydrogen peroxide solution (14.99 g,4 eq) was added dropwise, the temperature was raised to 80deg.C for 2 hours, LCMS showed complete reaction of the starting material, the reaction solution was cooled to room temperature, 10% sodium thiosulfate solution (100 mL) was added, stirring was done at room temperature for 0.5 hours, the reaction solution was extracted with ethyl acetate (100 mL. 5), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, suction filtration was performed, the crude product was concentrated by flash chromatography and purified (Silica gel, DCM: =50:1:1) to give the target compound (1.3 g, 25%).
LCMS(ESI)[M+H] + ＝155.1； 1 H NMR(400MHz,CDCl 3 )δ7.30(d,J＝1.9Hz,1H),5.48(d,J＝
2.0Hz,1H),4.36(dd,J＝11.1,3.1Hz,1H),4.26–4.16(m,2H),4.03(dd,J＝12.3,6.9Hz,1H),3.76(d,J＝6.7Hz,2H),2.52(ddd,J＝12.8,6.8,3.1Hz,1H).
And a third step of: preparation of (5 h,6h,7 h-pyrazolo [3,2-b ] [1,3] oxazin-6-yl) methyltrifluoromethane sulfonate:
(5H, 6H,7H pyrazolo [3,2-b ] [1,3] oxazin-6-yl) methanol (200 mg,1 eq) was dissolved in dichloromethane (10 mL), triethylamine (196.91 mg,1.5 eq) was added, triflic anhydride (402.61 mg,1.1 eq) was added at 40℃and stirred for 1 hour at 40℃LCMS showed complete reaction of the starting material, saturated sodium bicarbonate solution (1 mL) was slowly added dropwise to the reaction solution at-40℃and warmed to room temperature after completion, water (10 mL) was added, extracted with dichloromethane (10 mL. X3), the organic phases were combined, washed with saturated salt, dried over anhydrous sodium sulfate, suction filtered, and the mother liquor was concentrated at low temperature to give a pale yellow oily liquid (190 mg, 51.2%) which was used directly in the next step.
LCMS(ESI)[M+H] + ＝287.1.
Fourth step: preparation of 6- (((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrroline [1,2, 3-des ] quinoxalin-8 (7H) -yl) methyl) -6, 7-dihydro-5H-pyrazolo [5,1-b ] [1,3] oxazine:
(5H, 6H, 7H-pyrazolo [3,2-b ] [1,3] oxazin-6-yl) methyltrifluoromethane sulfonate (70 mg,1 eq) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxaline (56.08 mg,1 eq) were dissolved in dichloromethane (5 mL), triethylamine (29.7 mg,1.2 eq) was added, LCMS showed the formation of the target compound, the reaction solution was added with water (10 mL), extracted with dichloromethane (10 mL. Times.3), the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, the mother liquor was concentrated to give the crude product, which was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the target compound (30.11 mg, 33.7%).
LCMS(ESI)[M+H] + ＝366.2； 1 H NMR(400MHz,CDCl 3 )δ8.20(s,1H),7.32(d,J＝1.9Hz,1H),
6.68(t,J＝7.6Hz,1H),6.52(d,J＝7.4Hz,1H),6.43(d,J＝7.9Hz,1H),5.49(s,1H),4.39–4.28(m,2H),4.23–4.14(m,1H),4.03–3.92(m,1H),3.64–3.55(m,1H),3.40–3.33(m,1H),3.32–3.24(m,3H),3.18(dd,J＝17.4,8.4Hz,1H),3.03(d,J＝9.0Hz,1H),2.87(s,3H),2.83(dd,J＝10.5,3.5Hz,2H),2.80–2.51(m,3H),2.29(t,J＝11.4Hz,1H),2.20(t,J＝13.8Hz,1H),2.03(d,J＝15.0Hz,1H).
Example 128
Preparation of 6- (((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) methyl) -1,5,6, 7-tetrahydropyrano [3,2-c ] pyrazole:
the first step: preparation of (1- ((2- (trimethylsilyl) ethoxy) methyl) -1,5,6, 7-tetrahydropyrano [3,2-c ] pyrazol-6-yl) methanol:
Methyl 1- (2- (trimethylsilyl) ethoxy) methyl-1, 5,6, 7-tetrahydropyran [3,2-c ] pyrazole-6-carboxylate (200 mg,1 eq) was dissolved in tetrahydrofuran (15 mL), the reaction solution was placed in a 0 ℃ brine bath, slowly added (48.58 mg,2 eq), replaced with nitrogen, kept at 0 ℃ for 2 hours with stirring, LCMS monitored the reaction was complete, added sodium sulfate decahydrate (200 mg) and ethyl acetate (20 mL) quenched, stirred continuously for 0.5 hours, filtered, and the filtrate was dried by spinning to give the title compound (180 mg, 98.9%).
LCMS(ESI)[M+H] + ＝285.1； 1 HNMR(400MHz,CDCl 3 )δ7.19(s,1H),5.33(d,J＝3.2Hz,2H),
4.23(dd,J＝10.8,2.6Hz,1H),4.01(dd,J＝10.8,7.4Hz,1H),3.73(dd,J＝4.8,2.4Hz,2H),3.61–3.51(m,2H),2.90(dd,J＝16.1,6.2Hz,1H),2.61(dd,J＝16.2,7.0Hz,1H),0.97–0.85(m,2H),0.03(s,1H),0.00(s,9H).
And a second step of: preparation of (1- ((2- (trimethylsilyl) ethoxy) methyl) -1,5,6, 7-tetrahydropyran [3,2-c ] pyrazol-6-yl) methyltrifluoromethanesulfonate:
compound (1- ((2- (trimethylsilyl) ethoxy) methyl) -1,5,6, 7-tetrahydropyrano [3,2-c ] pyrazol-6-yl) methanol (180 mg,1 eq) was dissolved in dichloromethane (15 mL) triethylamine (128.08 mg,2 eq) was added, the reaction solution was cooled to minus 65 ℃, trifluoromethanesulfonic anhydride (196.41 mg,1.1 eq) was slowly added dropwise, the reaction was kept at this temperature with stirring for 2 hours, LCMS was monitored for completion of the reaction, and the next reaction was directly fed without purification.
LCMS(ESI)[M+H] + ＝417.0.
And a third step of: preparation of 6- (((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrolo [1,2, 3-off ] quinoxalin-8 (7H) -yl) methyl) -1- ((2- (trimethylsilicon) ethoxy) methyl) -1,5,6, 7-tetrahydropyran [3,2-c ] pyrazole:
To the reaction solution of the previous step were added (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-dean ] quinoxaline (44.05 mg,1 eq) and triethylamine (38.45 mg,2 eq), the reaction was raised to 40℃and stirred for 1 hour, LCMS monitors disappearance of the starting material, and there was formation of a product, the reaction was completed, the organic phase was washed with water (10 mL), the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by reverse phase flash chromatography (C18, 0.05%FA in water,MeCN) to give the desired product (35 mg, yield: 37.2%).
LCMS(ESI)[M+H] + ＝496.3.
Fourth step: preparation of 6- (((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) methyl) -1,5,6, 7-tetrahydropyrano [3,2-c ] pyrazole:
the compound 6- (((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-off ] quinoxalin-8 (7H) -yl) methyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1,5,6, 7-tetrahydropyrano [3,2-C ] pyrazole (35 mg,1 eq) was dissolved in dichloromethane (8 mL) and trifluoroacetic acid (2 mL) was added, nitrogen displacement, stirred at room temperature for 2 hours, LCMS monitors the reaction completion, spin-dry solvent, and the crude product was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the title compound (18 mg, 69.8%).
LCMS(ESI)[M+H] + ＝366.2； 1 HNMR(400MHz,CDCl 3 )δ8.18(s,1H),7.13(s,1H),6.70(s,1H),
6.52(s,1H),6.45(s,1H),4.18–3.99(m,3H),3.62–3.48(m,3H),3.41(s,1H),3.30(s,2H),3.13–2.93(m,4H),2.88(s,4H),2.79(d,J＝18.7Hz,1H),2.72(s,2H),2.49(dd,J＝25.5,14.2Hz,2H),2.11(d,J＝16.9Hz,1H).
Example 129
Preparation of 4- (2- ((6 br,10 as) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyridine (3, 4':4, 5) pyrrolo (1, 2, 3-deoxo) quinoxalin-8 (7H) -yl) ethyl) -3, 4-dihydro-2H-benzo (b) (1, 4) oxazine:
the first step: preparation of ethyl 2- (3, 4-dihydro-2H-1, 4-benzoxazin-4-yl) acetate:
3, 4-dihydro-2H-1, 4-benzoxazine (2 g,1 eq) and ethyl 2-bromoacetate (2.47 g,1 eq) were dissolved in N, N-dimethylformamide (20 mL), potassium carbonate (4.09 mg,2 eq) and sodium iodide (3.33 g,1.5 eq) were added, reacted at 125℃for 2 hours, after completion of LCMS detection, water was added, ethyl acetate was extracted three times, the organic phase was added to saturated brine, and the organic phase was collected to give a crude product, which was purified by flash chromatography (Silica gel, PE: EA=4:1) to give the desired product (2.5 g, yield 76.4%).
LCMS(ESI)[M+H] + ＝222.1； 1 H NMR(400MHz,CDCl 3 )δ6.79(ddd,J＝6.3,3.8,1.3Hz,2H),
6.69–6.60(m,1H),6.55–6.44(m,1H),4.29–4.26(m,2H),4.18(d,J＝7.1Hz,2H),3.99(s,2H),3.51–3.46(m,2H),1.24(t,J＝7.1Hz,3H).
And a second step of: preparation of 2- (3, 4-dihydro-2H-1, 4-benzoxazin-4-yl) ethan-1-ol:
ethyl 2- (3, 4-dihydro-2H-1, 4-benzoxazin-4-yl) acetate (1 g,1 eq) was dissolved in toluene (10 mL), the temperature was reduced to-78 ℃, diisobutylaluminum hydride (9 mL,3 eq) was slowly added dropwise with heat preservation, reacted under ice bath for 1 hour, LCMS monitored the reaction was complete, quenched with water, and filtered. The filtrate was dried by spin to give a crude product which was purified by flash chromatography (Silica gel, PE: ea=5:1) to give the desired product (700 mg, 86.4% yield).
LCMS(ESI)[M+H] + ＝180.2； 1 H NMR(400MHz,CDCl 3 )δ6.90–6.59(m,4H),4.33–4.20(m,2H),
3.83(t,J＝5.5Hz,2H),3.48–3.30(m,4H).
And a third step of: preparation of ethyl 2- (3, 4-dihydro-2H-1, 4-benzoxazin-4-yl) methanesulfonate:
2- (3, 4-dihydro-2H-1, 4-benzoxazin-4-yl) ethan-1-ol (970 mg,1 eq) was dissolved in dichloromethane (10 mL), triethylamine (1.37 mL,2.5 eq) was added, methanesulfonyl chloride (0.93 mL,1.5 eq) was added under ice bath, and the mixture was allowed to react at room temperature for 0.5H, after completion of LCMS detection, quenched with water, extracted with dichloromethane, and the organic phase was collected and dried to give a crude product, which was purified by flash chromatography (Silica gel, PE: EA=1:1) to afford the desired product (600 mg, 43.1% yield).
LCMS(ESI)[M+H] + ＝258.1； 1 H NMR(400MHz,CDCl 3 -d)δ6.92–6.75(m,2H),6.66(td,J＝7.7,
1.6Hz,2H),4.41(t,J＝5.7Hz,2H),4.30–4.18(m,2H),3.65(t,J＝5.7Hz,2H),3.46(dd,J＝11.8,7.3Hz,2H),2.97(s,3H).
Fourth step: preparation of 4- (2- ((6 br,10 as) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyridine (3, 4':4, 5) pyrrolo (1, 2, 3-deoxo) quinoxalin-8 (7H) -yl) ethyl) -3, 4-dihydro-2H-benzo (b) (1, 4) oxazine:
ethyl 2- (3, 4-dihydro-2H-1, 4-benzoxazin-4-yl) methylsulfonate (145.87 mg,1.3 eq) and (6 br,10 as) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido (3 ',4':4, 5) pyrrolo (1, 2, 3-de) quinoxaline (100 mg,1 eq) were dissolved in N, N-dimethylformamide (5 mL), potassium carbonate (180.81 mg,3 eq) was added, the reaction was carried out at 60 ℃ for 3 hours, LCMS detection was completed, water and ethyl acetate were added for three times, the organic phases were combined, washed with saturated salt and dried over anhydrous sodium sulfate to obtain a crude product. The crude product was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the title compound (18.87 mg, 14.4% yield).
LCMS(ESI)[M+H] + ＝391.2； 1 H NMR(400MHz,CDCl 3 )δ8.31(s,1H),6.80(ddd,J＝10.9,9.4,4.5
Hz,2H),6.72(t,J＝7.7Hz,1H),6.68–6.60(m,2H),6.53(d,J＝7.3Hz,1H),6.45(d,J＝7.9Hz,1H),4.28–4.19(m,2H),3.90–3.77(m,2H),3.68–3.56(m,2H),3.54–3.49(m,1H),3.45–3.39(m,3H),3.30(dd,J＝8.5,3.0Hz,3H),3.11(s,1H),3.07–2.93(m,3H),2.88(s,3H),2.86(d,J＝3.2Hz,1H),2.53(s,1H),2.11(d,J＝15.2Hz,1H).
Example 130
Preparation of (6 bR,10 aS) -8- (2- (5-methoxy-1H-indol-1-yl) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline:
the first step: preparation of ethyl 2- (5-methoxy-1H-indol-1-yl) acetate:
the starting material 5-methoxy-1H-indole (2 g,1 eq) was dissolved in N, N-dimethylformamide (20 mL), followed by addition of potassium carbonate (3756 mg,2 eq), ethyl 2-bromoacetate (3404 mg,1.5 eq), stirring of the reaction system at 50℃for 4 hours, LCMS showed the reaction to end, the reaction solution was filtered, and the crude product was isolated and purified by reverse phase flash chromatography (C18, 0.05%FA in water,MeCN) to give the title compound (800 mg, yield 25.2%).
LCMS(ESI)[M+H] + ＝234.1.
And a second step of: preparation of 2- (5-methoxy-1H-indol-1-yl) acetaldehyde:
ethyl 2- (5-methoxy-1H-indol-1-yl) acetate (700 mg,1 eq) was dissolved in dichloromethane (10 mL), -1M diisobutylamine aluminum hydride (1.07 mL,2.5 eq) was added dropwise at 78 ℃ and stirred for half an hour at-78 ℃ after the addition, LCMS showed the reaction to be complete, water (2 mL) was added, anhydrous sodium sulfate was added and stirred thoroughly for 10 minutes, filtered, and the filtrate was concentrated to give the title compound (600 mg, crude).
LCMS(ESI)[M+H] + ＝190.1.
And a third step of: preparation of (6 bR,10 aS) -8- (2- (5-methoxy-1H-indol-1-yl) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline:
(6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxaline (100 mg) and 2- (5-methoxy-1H-indol-1-yl) acetaldehyde (124 mg,1.5 eq) were dissolved in tetrahydrofuran (5 mL), acetic acid 5 drops were added, stirring was continued for half an hour, sodium triacetoxyborohydride (187 mg,2 eq) was added, the reaction mixture was stirred for 1.5 hours, LCMS showed the end of the reaction, water (10 mL) was added, extracted with ethyl acetate (15 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the target compound (29.62 mg, 17%).
LCMS(ESI)[M+H] + ＝403.2； 1 H NMR(400MHz,CDCl 3 )δ7.27(s,1H),7.25–7.24(m,1H),7.17
(s,1H),7.08(d,J＝2.3Hz,1H),6.87(dd,J＝8.8,2.3Hz,1H),6.67(t,J＝7.6Hz,1H),6.50(d,J＝7.3Hz,1H),6.43–6.39(m,2H),3.84(s,3H),3.58(t,J＝9.2Hz,1H),3.27(d,J＝11.2Hz,4H),2.99–2.71(m,8H),1.96(d,J＝13.4Hz,1H),1.64(s,5H).
Example 131
Preparation of (6 bR,10 aS) -3-methyl-8- (3- (1-methyl-1H-pyrazol-4-yl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deaggregation ] quinoxaline:
the first step: preparation of ethyl 3- (1-methyl-1H-pyrazol-4-yl) prop-2-enoyl acid ester:
triethyl phosphorylacetate (36.65 g,2 eq) was dissolved in tetrahydrofuran (200 mL), and stirred in an ice-water bath. Sodium hydride (6.53 g,3.3 eq) was added to the reaction mixture in portions, and after stirring under nitrogen for 1 hour, 1-methyl-1H-pyrazole-4-carbaldehyde (9 g,1 eq) was added to the reaction mixture, and after the addition was completed, the ice-water bath was removed, and the mixture was reacted at 30℃for 16 hours. LCMS detects completion of the reaction. To the reaction solution was added 200mL of water, which was quenched, extracted with ethyl acetate (150 mL. Times.2), washed with saturated brine (100 m, L. Times.2), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by flash chromatography (Silica gel, PE: ea=5:1) to give the desired product (10 g, 33.9% yield).
LCMS(ESI)[M+H] + ＝181.2； 1 H NMR(400MHz,CDCl 3 )δ7.68(s,1H),7.61–7.49(m,2H),6.16
(d,J＝16.0Hz,1H),4.29–4.19(m,2H),4.16–4.06(m,1H),1.32(t,J＝7.1Hz,3H).
And a second step of: preparation of ethyl 3- (1-methyl-1H-pyrazol-4-yl) propionate:
ethyl 3- (1-methyl-1H-pyrazol-4-yl) prop-2-enoyl acid ester (2 g,1 eq) was dissolved in tetrahydrofuran (20 mL), and a palladium-carbon catalyst (0.24 g,2 eq) was added to the reaction solution to react for 12 hours under a hydrogen atmosphere. LCMS detects completion of the reaction. The reaction mixture was filtered, washed with tetrahydrofuran (50 mL. Times.2), and the filtrate was concentrated to give ethyl 3- (1-methyl-1H-pyrazol-4-yl) propionate (1.5 g, yield 74.2%) as a target product.
LCMS(ESI)[M+H] + ＝183.0； 1 H NMR(400MHz,CDCl 3 )δ7.31(s,1H),7.17(s,1H),4.13(q,J＝
7.1Hz,2H),3.84(s,3H),2.78(t,J＝7.4Hz,2H),2.59–2.35(m,2H),1.24(t,J＝7.1Hz,4H).
And a third step of: preparation of 3- (1-methyl-1H-pyrazol-4-yl) propanal:
ethyl 3- (1-methyl-1H-pyrazol-4-yl) propionate (1.18 g,1 eq) was dissolved in toluene (5 mL), stirred under nitrogen at-78 ℃, diisobutylaluminum hydride (5.6 mL,1.5m/L,1.3 eq) was slowly added to the reaction solution, the reaction was continued for 1H, and lcms detection reaction was complete with a small amount of over-reduced product. Methanol (2 mL) was slowly added dropwise to the reaction solution to quench it, and the reaction solution was then poured into water (20 mL). Extracted with ethyl acetate (20 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by flash chromatography (Silica gel, PE: ea=3:1) to give the desired product (500 mg, yield 55.8%).
LCMS(ESI)[M+H] + ＝139.2； 1 H NMR(400MHz,DMSO-d 6 )δ9.69(s,1H),7.44(s,1H),7.23(s,
1H),3.75(s,3H),2.67(s,5H).
Fourth step: preparation of (6 bR,10 aS) -3-methyl-8- (3- (1-methyl-1H-pyrazol-4-yl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deaggregation ] quinoxaline:
3- (1-methyl-1H-pyrazol-4-yl) propanal (72 mg,1.2 eq) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (100 mg,1 eq) were dissolved in tetrahydrofuran (10 mL) and stirred, 2 drops of acetic acid were added dropwise to the reaction mixture, and the mixture was reacted at 30℃for 0.5 hours. Sodium triacetyl borohydride (185 mg,2 eq) was added to the reaction solution, and the reaction was continued for 1 hour. LCMS detected complete reaction. The reaction was added to water (10 mL), extracted with ethyl acetate (50 ml×3), and the combined organic phases were washed with saturated brine (20 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the title compound (21.59 mg, yield 14%).
LCMS(ESI)[M+H] + ＝352.2； 1 H NMR(400MHz,DMSO-d 6 )δ8.15(s,1H),7.44(s,1H),7.21(s,
1H),6.51(t,J＝7.7Hz,1H),6.42(d,J＝7.1Hz,1H),6.33(d,J＝7.7Hz,1H),3.75(s,3H),3.43(s,5H),3.11(s,2H),3.02(d,J＝10.9Hz,2H),2.78(s,4H),2.69(d,J＝10.3Hz,1H),2.58(s,1H),2.36(dd,J＝17.6,9.8Hz,2H),2.26(d,J＝8.2Hz,2H),2.12(s,1H),1.90(d,J＝14.5Hz,1H),1.79(t,J＝10.7Hz,2H),1.69–1.60(m,2H).
Example 132
Preparation of 3, 5-dimethyl-4- (3- ((6 br,10 as) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) propyl) isoxazole:
the first step: (2E) Preparation of ethyl 3- (3, 5-dimethyl-1, 2-oxazol-4-yl) prop-2-enoate:
ethyl 2- (diethoxyphosphoryl) acetate (8.6 g,1.2 eq) was added to tetrahydrofuran (50 mL) of sodium hydride (1.53 g,1.2 eq) in portions at 0 ℃ and stirred for 30 min, the system was added to tetrahydrofuran (50 mL) of 3, 5-dimethyl-1, 2-oxazole-4-carbaldehyde (4 g,1 eq), stirred at 70 ℃ for 6 hours, LCMS monitored the reaction, the reaction solution quenched with water (100 mL), extracted with ethyl acetate (60 mL x 3), the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was isolated and purified by flash chromatography (Silica gel, PE: ea=10:1) to give the title compound (6.83 g, crude product).
LCMS(ESI)[M+H+41] + ＝237.2,t R ＝1.643min. 1 H NMR(400MHz,CDCl 3 )δ7.46(d,J＝16.3Hz,
1H),6.15(d,J＝16.3Hz,1H),4.26(q,J＝7.1Hz,2H),2.51(s,3H),2.39(s,3H),1.34(t,J＝7.1Hz,3H).
And a second step of: preparation of ethyl 3- (3, 5-dimethyl-1, 2-oxazol-4-yl) propionate:
palladium on carbon (2 g) was added to tetrahydrofuran (100 mL) of ethyl (2E) -3- (3, 5-dimethyl-1, 2-oxazol-4-yl) prop-2-enoate (7, 1g, crude) and stirred at room temperature under hydrogen atmosphere for 2 hours, LCMS monitored reaction, celite suction filtration, filtrate collection, vacuum concentration and purification of crude product by reverse phase flash chromatography (C18, 0.05%FA in water,MeCN) afforded the title compound (1.9 g, 26.5% yield).
LCMS(ESI)(M+H) + ＝198.0； 1 H NMR(400MHz,CDCl 3 )δ4.11(d,J＝7.1Hz,2H),2.63(t,J＝7.5
Hz,2H),2.46(t,J＝7.4Hz,2H),2.33(s,3H),2.23(s,3H),1.24(t,J＝7.1Hz,3H).
And a third step of: preparation of 3- (3, 5-dimethyl-1, 2-oxazol-4-yl) propanol:
lithium aluminum hydride (731 mg,2 eq) was added in portions to ethyl 3- (3, 5-dimethyl-1, 2-oxazol-4-yl) propionate (1.9 g,1 eq) in tetrahydrofuran (20 mL) at 0 ℃ and stirred for 3 hours at room temperature, LCMS monitored the reaction, water (1 mL), 15% sodium hydroxide (1 mL), quenched with water (3 mL), stirred for 15 minutes with anhydrous sodium sulfate, suction filtered, the filtrate collected and concentrated in vacuo to give the title compound (1.49 g, crude).
LCMS(ESI)[M+H] + ＝156.0； 1 H NMR(400MHz,CDCl 3 )δ3.63(t,J＝6.3Hz,2H),2.44–2.38(m,
2H),2.31(s,3H),2.21(s,3H),1.72(dd,J＝8.0,7.1Hz,2H).
Fourth step: preparation of 3- (3, 5-dimethyl-1, 2-oxazol-4-yl) propanal:
dessmartin reagent (6.72 g,1.5 eq) was added to dichloromethane (20 mL) of 3- (3, 5-dimethyl-1, 2-oxazol-4-yl) propanol-1-ol (1, 64g,1 eq), stirred at room temperature for 2 hours, LCMS monitored the reaction, quenched with saturated sodium bicarbonate (30 mL), extracted with ethyl acetate (20 mL x 3), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude was isolated and purified by reverse phase flash chromatography (C18, 0.05%FA in water,MeCN) to give the title compound (150 mg, 9.3% yield).
LCMS(ESI)(M+H) + ＝154.3.
Fifth step: preparation of 3, 5-dimethyl-4- (3- ((6 br,10 as) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) propyl) isoxazole:
(6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-off ] quinoxaline (100 mg,1 eq), 3- (3, 5-dimethyl-1, 2-oxazol-4-yl) propanal (100 mg,1.5 eq) was added to tetrahydrofuran (10 mL), stirred for 5 minutes, sodium triacetoxyborohydride (185 mg,2 eq) and acetic acid (0.1 mL) were added to the system, stirred at room temperature for 2 hours, LCMS was monitored for reaction, water (20 mL), ethyl acetate (20 mL. Times.3) was added, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the target compound (23.14 mg, yield 14.4%).
LCMS(ESI)[M+H] + ＝367.3； 1 H NMR(400MHz,DMSO-d 6 )δ8.16(s,1H),6.51(t,J＝7.6Hz,
1H),6.42(d,J＝7.0Hz,1H),6.33(d,J＝7.9Hz,1H),3.43(s,1H),3.32(dd,J＝10.1,2.9Hz,2H),3.27(dd,J＝11.3,2.8Hz,2H),3.12(s,1H),3.05–3.00(m,1H),2.78(s,3H),2.69(dd,J＝9.9,7.1Hz,1H),2.61(d,J＝11.1Hz,1H),2.31(s,2H),2.29(s,3H),2.24(dd,J＝14.2,7.0Hz,2H),2.14(s,3H),1.92(d,J＝14.4Hz,1H),1.81(t,J＝11.1Hz,2H),1.62–1.55(m,2H).
Example 133
Preparation of 2-methyl-4- (3- ((6 br,10 as) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido (3 ',4':4, 5) pyrrolo (1, 2, 3-deoxalin-8 (7H) -yl) propyl) oxazole:
the first step: preparation of 3- (2-methyl-1, 3-oxazol-4-yl) prop-2-enoic acid ethyl ester:
sodium hydrogen (266.79 mg,1.3 eq) was dissolved in tetrahydrofuran (20 mL), a solution of ethyl 2- (diethoxyphosphoryl) acetate (2.3 g,1.2 eq) in tetrahydrofuran (30 mL) was added dropwise at 0 ℃, stirred for half an hour at 0 ℃, then a solution of 2-methyl-oxazole-4-carbaldehyde (950 mg,1 eq) in tetrahydrofuran (10 mL) was added dropwise, reacted at room temperature for 2 hours, LCMS detection was completed, quenched with water, extracted three times with ethyl acetate, the organic phase was collected with saturated brine, and the organic phase was dried by spin to give a crude product, which was purified by flash chromatography (Silica gel, PE: ea=5:1) to give the objective product (980 mg, yield 63.3%).
LCMS(ESI)[M+H] + ＝182.1； 1 H NMR(400MHz,CDCl 3 )δ7.67(s,1H),7.46(d,J＝15.6Hz,1H),
6.58(d,J＝15.6Hz,1H),4.24(q,J＝7.1Hz,2H),2.48(s,3H),1.31(t,J＝7.1Hz,3H).
And a second step of: preparation of ethyl 3- (2-methyl-1, 3-oxazol-4-yl) propionate:
ethyl 3- (2-methyl-1, 3-oxazol-4-yl) prop-2-enoate (800 mg,1 eq) was dissolved in ethyl acetate (12 mL), palladium on carbon (60 mg) was added and stirred at room temperature for 3 hours under hydrogen atmosphere, TLC plate detected the reaction completion, and the filtrate was obtained by filtration through celite and dried to give the objective product (600 mg, yield 74.2%).
1 H NMR(400MHz,CDCl 3 )δ7.29(s,1H),4.13(t,J＝7.1Hz,2H),2.81(t,J＝7.4Hz,2H),2.63(t,J＝7.3Hz,2H),2.41(s,3H),1.24(t,J＝7.1Hz,3H).
And a third step of: preparation of 3- (2-methyl-1, 3-oxazol-4-yl) propanal:
ethyl 3- (2-methyl-1, 3-oxazol-4-yl) propionate (700 mg,1 eq) was dissolved in dichloromethane (15 mL), the temperature was reduced to-78 ℃, diisobutylaluminum hydride toluene solution (3.8 mL,1.5 eq) was slowly added dropwise with heat preservation, the reaction was continued at-78 ℃ for 1 hour, monitored by TLC plate, the reaction was shown to be complete by 2, 4-dinitrophenylhydrazine color development, water (2 mL) was added for quenching, anhydrous sodium sulfate was added, tetrahydrofuran solution was added for 5 minutes, filtration was carried out to obtain filtrate, and the crude product was isolated and purified by flash chromatography (Silica gel, PE: ea=1:1) to obtain the objective product (300 mg, yield 56.4%).
LCMS(ESI)[M+H] + ＝140.2； 1 H NMR(400MHz,CDCl 3 -d)δ9.82(d,J＝1.1Hz,1H),7.29(s,1H),
2.95–2.68(m,4H),2.41(s,3H).
Fourth step: preparation of 2-methyl-4- (3- ((6 br,10 as) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido (3 ',4':4, 5) pyrrolo (1, 2, 3-deoxalin-8 (7H) -yl) propyl) oxazole:
3- (2-methyl-1, 3-oxazol-4-yl) propanal (78.88 mg,1.3 eq) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido (3 ',4':4, 5) pyrrolo (1, 2, 3-deoxoquinoxaline) (100 mg,1 eq) were dissolved in tetrahydrofuran (3 mL), acetic acid (0.3 mL) and sodium triacetoxyborohydride (277.73 mg,3 eq) were added and stirred at room temperature for 1 hour, the LCMS detection reaction was completed, water (10 mL), ethyl acetate (5 mL) were added, the organic phases were combined, washed with saturated saline, and the crude product was dried over anhydrous sodium sulfate to give the title compound (29.96 mg, yield 19.5%) which was purified by prep-HPLC (C18, 0.05%FA in water,MeCN).
LCMS(ESI)[M+H] + ＝353.2； 1 H NMR(400MHz,CDCl 3 )δ8.60(s,1H),7.30(s,1H),6.73–6.62(m,
1H),6.51(d,J＝7.1Hz,1H),6.42(d,J＝7.4Hz,1H),3.64–3.57(m,1H),3.43(s,1H),3.31–3.24(m,3H),3.18–3.10(m,1H),3.03–2.95(m,1H),2.87(d,J＝3.1Hz,3H),2.83(d,J＝3.1Hz,1H),2.70–2.57(m,3H),2.52(t,J＝7.2Hz,2H),2.40(s,3H),2.22(dd,J＝24.5,12.3Hz,2H),2.05–1.95(m,3H).
Example 134
Preparation of 4- (3- (6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinolin-8 (7H) -yl) propyl) thiazole:
the first step: preparation of ethyl 3- (1-methyl-1H-pyrazol-4-yl) prop-2-enoyl acid ester:
triethyl phosphonoacetate (11.88 g,2 eq) was dissolved in tetrahydrofuran (150 mL), sodium hydride (1.27 g,2 eq) was added to the reaction mixture in portions under an ice-water bath, and after stirring under nitrogen atmosphere for 1 hour, thiazole-4-carbonyl aldehyde (3 g,1 eq) was added to the reaction mixture, and after the addition was completed, the reaction was carried out at 30℃for 16 hours. LCMS detects completion of the reaction. To the reaction solution was added water (200 mL) and quenched, extracted with ethyl acetate (150 mL x 2), washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by flash chromatography (Silica gel, PE: ea=5:1) to give the objective product (3.5 g, yield 72.0%).
LCMS(ESI)[M+H] + ＝184.1； 1 H NMR(400MHz,CDCl 3 )δ8.83(dd,J＝1.9,0.5Hz,1H),7.68(d,J
＝15.6Hz,1H),7.48(d,J＝1.9Hz,1H),6.79(d,J＝15.5Hz,1H),4.27(q,J＝7.1Hz,2H),1.33(t,J＝7.1Hz,3H).
And a second step of: preparation of ethyl 3- (thiazol-4-yl) propionate:
ethyl 3- (thiazol-4-yl) acrylate (2 g,1 eq) was dissolved in methanol (20 mL), palladium on carbon (232.32 mg,0.2 eq) was added to the reaction solution, and the reaction was carried out at 50 ℃ for 8 hours under a hydrogen atmosphere. LCMS detects completion of the reaction. The reaction solution was filtered, the filter cake was washed with methanol (100 ml x 2), and the filtrate was concentrated to give the target product (1.8 g, yield 89.0%).
LCMS(ESI)[M+H] + ＝186.0； 1 H NMR(400MHz,CDCl 3 )δ8.75(d,J＝1.8Hz,1H),7.09–6.88(m,
1H),4.14(q,J＝7.1Hz,2H),3.16(t,J＝7.5Hz,2H),2.76(t,J＝7.5Hz,2H),1.24(t,J＝7.1Hz,3H).
And a third step of: preparation of 3- (thiazol-4-yl) propanal:
ethyl 3- (thiazol-4-yl) propionate (1.8 g,1 eq) was dissolved in toluene (20 mL), and diisobutylaluminum hydride (9.72 mL,1.5m,1.5 eq) was slowly added to the reaction solution under nitrogen atmosphere at-78 ℃ and the reaction was continued for 1 hour, and LCMS detection of the end of the reaction. Slowly dripping water (20 mL) into the reaction solution for quenching, adding anhydrous sodium sulfate into the reaction solution for stirring, filtering, washing with ethyl acetate (200 mL x 2), and concentrating to obtain a filtrate to obtain a crude product. The crude product was isolated and purified by flash chromatography (Silica gel, PE: ea=3:1) to give the desired product (300 mg, yield 21.9%).
LCMS(ESI)[M+H] + ＝142.0； 1 H NMR(400MHz,CDCl 3 )δ9.85(t,J＝1.2Hz,1H),8.75(d,J＝1.9
Hz,1H),7.02(dt,J＝1.8,0.8Hz,1H),3.17(t,J＝7.2Hz,3H),2.96–2.89(m,3H).
Fourth step: preparation of 4- (3- (6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyridine [3',4':4,5] pyrrole [1,2, 3-des ] quinolin-8 (7H) -yl) propyl) thiazole:
3- (thiazol-4-yl) propanal (73.88 mg,1.2 eq) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (100 mg,1 eq) were dissolved in tetrahydrofuran (10 mL) and stirred, acetic acid (2.62 mg,0.1 eq) was added dropwise to the reaction mixture, and the mixture was reacted at 30℃for 0.5 hours. Sodium triacetyl borohydride (184.84 mg,2 eq) was added to the reaction mixture, and the reaction was continued for 1 hour. LCMS detected complete reaction. The reaction was added with water (10 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the title compound (12.23 mg, yield 6.6%).
LCMS(ESI)[M+H] + ＝355.1； 1 H NMR(400MHz,MeOD-d 4 )δ8.92(d,J＝2.0Hz,1H),7.25(d,J＝
1.9Hz,1H),6.59(t,J＝7.6Hz,1H),6.48(d,J＝7.1Hz,1H),6.41(d,J＝7.8Hz,1H),3.51–3.47(m,1H),3.37(t,J＝3.0Hz,1H),3.27(d,J＝2.8Hz,1H),3.13(s,1H),3.10(dd,J＝11.8,5.5Hz,1H),2.90(d,J＝11.7Hz,1H),2.85–2.81(m,5H),2.75(dd,J＝10.0,7.2Hz,2H),2.42(d,J＝6.1Hz,2H),2.32(s,1H),1.97(dd,J＝16.0,7.6Hz,5H).
Example 135
Preparation of (6 bR,11 aS) -13- (3- (2-methoxyphenyl) propyl) -3-methyl-2, 3,6b,8,9,10,11 a-octahydro-1H, 7H-7, 10-oxirane [4,5] pyrrolo [1,2, 3-deaggregation ] quinoxaline:
the first step: preparation of 4-bromo-5, 6,7,8,9, 10-hexahydro-7, 10-oxirane [ b ] indole:
2-bromophenylhydrazine hydrochloride (25 g,1 eq) and nortropinone hydrochloride (21.7 g,1.3 eq) were dissolved in acetic acid (300 mL) and reacted at 100℃for 16 hours. LCMS detects completion of the reaction. Acetic acid in the reaction solution was removed by vacuum concentration, and the solution was slurried with water (300 mL) and filtered. Hydrochloric acid-ethyl acetate solution (100 ml,3 m) was added and the mixture was slurried again, filtered and lyophilized. The desired product (30 g, yield 66.6%) was obtained.
LCMS(ESI)[M+H] + ＝277.1； 1 H NMR(400MHz,DMSO-d 6 )δ11.38(s,1H),7.58(d,J＝7.9Hz,
1H),7.30(d,J＝7.5Hz,1H),6.98(t,J＝7.8Hz,1H),5.16(s,1H),4.42(s,1H),3.41(s,2H),2.89(d,J＝17.4Hz,1H),2.25(d,J＝7.6Hz,2H),2.07(s,1H),1.81(s,1H),1.24(s,1H).
And a second step of: preparation of 4-bromo-5, 5a,6,7,8,9, 10-octahydro-7, 10-oxirane [ b ] indole:
4-bromo-5, 6,7,8,9, 10-hexahydro-7, 10-oxirane [ b]Indole (30 g,1 eq) was dissolved in trifluoroacetic acid (400 mL) and triethylsilane (31.47 mL,2.5 eq) was added dropwise under nitrogen, and the reaction was completed at 50℃for 16 hours. LCMS detects completion of the reaction. The reaction mixture was concentrated to remove trifluoroacetic acid and triethylsilane to give a brown oil. Petroleum ether (200 mL) was added to the oil and poured out after stirring for 1 hour. Petroleum ether (200 mL) was added and the mixture was stirred for 1 hour and poured out. The oil was dissolved in dichloromethane (200 mL), the pH of the solution was adjusted to 12 using sodium hydroxide solution (2M/L), the organic phase was extracted and concentrated to give the crude product. The crude product was purified by flash chromatography (Silica gel, CH) 2 Cl 2 Meoh=10:1) to give the objective compound (20 g, yield 66.2%).
LCMS(ESI)[M+H] + ＝281.1； 1 H NMR(400MHz,DMSO-d 6 )δ7.12(d,J＝8.0Hz,1H),7.01(d,J＝
7.1Hz,1H),6.49(t,J＝7.6Hz,1H),5.61(d,J＝2.5Hz,1H),3.86(s,1H),3.59–3.45(m,2H),3.38–3.28(m,6H),3.17(s,1H),2.04–1.81(m,3H),1.66(qd,J＝12.0,7.6Hz,1H),1.30(td,J＝12.2,6.1Hz,1H),1.26–1.08(m,1H).
And a third step of: (5 aS,10 aR) -4-bromo-5, 5 a 6,7,8,9,10,10-octahydro-7, 10-epi-oxirane [ b ]]Preparation of indole-2-hydroxy-2-phenylacetate:
4-bromo-5, 5a,6,7,8,9, 10-octahydro-7, 10-oxirane [ b ] indole (20 g,1 eq) and (2S) -2-hydroxy-2-phenylacetic acid (13.08 g,1.2 eq) were dissolved in ethanol (250 mL), stirred at 50℃for 2 hours, then at 30℃for 2 hours, and finally at an ice-water bath for 2 hours. Ethanol was removed by concentration, methylene chloride (50 mL) was added thereto, and the mixture was stirred overnight to precipitate a large amount of a white solid, which was dried to give the objective product (10 g, yield 32.3%).
LCMS(ESI)[M+H] + ＝279.1； 1 H NMR(400MHz,DMSO-d 6 )δ7.36(d,J＝7.3Hz,2H),7.24(t,J＝
7.4Hz,2H),7.17(dd,J＝15.3,7.7Hz,2H),7.08(d,J＝7.2Hz,1H),6.58–6.52(m,1H),5.82(d,J＝2.8Hz,1H),4.56(s,1H),3.87(s,2H),3.72(s,1H),3.59(s,1H),2.12(s,1H),2.06(s,1H),2.02(s,1H),1.85(s,1H),1.50(s,1H),1.37–1.28(m,1H),1.23(s,1H).
Fourth step: preparation of (5 as,10 as) -4-bromo-5, 5a,6,7,8,9, 10-octahydro-7, 10-oxirane [ b ] indole-11-carboxylic acid ethyl ester:
(5 aS,10 aR) -4-bromo-5, 5a,6,7,8,9, 10-octahydro-7, 10-epi-oxirane [ b ] indol-2-hydroxy-2-phenylacetate (10 g,1 eq) and sodium carbonate (5.41 g,2.2 eq) were dissolved in tetrahydrofuran (50 mL) and stirred at 27 ℃. Ethyl chloroformate (3.02 g,1.2 eq) was dissolved in tetrahydrofuran (50 mL) and added dropwise to the reaction mixture, followed by reaction for 0.5 hour, and a white solid formed, followed by further reaction for 0.5 hour. LCMS detected complete reaction. The inorganic salts in the reaction solution were removed by suction filtration, and methanol (200 mL) was added after concentrating the filtrate, and the mixture was stirred at 50℃for 20 minutes and at 30℃for 1 hour, followed by suction filtration and concentration to give the objective compound (6 g, yield 73.7%).
LCMS(ESI)[M+H] + ＝351.0； 1 H NMR(400MHz,DMSO-d 6 )δ7.22(d,J＝8.0Hz,1H),7.12(d,J＝
7.1Hz,1H),6.59(t,J＝7.6Hz,1H),5.85(s,1H),4.26(s,1H),4.15(dd,J＝13.0,6.1Hz,2H),4.10–4.05(m,1H),3.99(s,1H),3.53(s,1H),2.02(t,J＝13.4Hz,3H),1.94(s,1H),1.56(s,1H),1.36(t,J＝9.0Hz,1H),1.28(t,J＝7.1Hz,3H).
Fifth step: preparation of ethyl (5 as,1a0 s) -4-bromo-5- (2-chloroacetyl) -5,5a,6,7,8,9,10 a-octahydro-7, 10-oxirane [ b ] indole-11-carboxylic acid ethyl ester:
ethyl (5 as,10 as) -4-bromo-5, 5a,6,7,8,9, 10-octahydro-7, 10-oxirane [ b ] indole-11-carboxylate (1 g,1 eq) was dissolved in toluene (10 mL), 2-chloroacetyl chloride (6437.58 mg,20 eq) was added, the reaction system was stirred for 1 hour at 125 ℃, LCMS showed the reaction was completed, the reaction solution was concentrated to give crude product, which was purified by flash chromatography (Silica gel, PE: ea=100:0 to 70:30) to give the target compound (1 g, yield 82.0%).
LCMS(ESI)[M+H] + ＝429.0； 1 H NMR(400MHz,DMSO-d 6 )δ7.45(d,J＝8.0Hz,1H),7.31(d,J＝
7.3Hz,1H),7.10(t,J＝7.7Hz,1H),4.63–4.49(m,3H),4.39(q,J＝8.2Hz,1H),4.31–4.22(m,2H),4.10(q,J＝7.1Hz,2H),2.71–2.60(m,1H),1.73(d,J＝8.3Hz,1H),1.63(dd,J＝11.5,5.7Hz,1H),1.53(s,1H),1.41(d,J＝9.9Hz,1H),1.29(d,J＝4.5Hz,1H),1.23(t,J＝7.1Hz,3H).
Sixth step: preparation of ethyl (6 bs,11 as) -3-methyl-1-oxo-2, 3,6b,8,9,10,11 a-octahydro-1 h,7h-7, 10-oxirane [4,5] pyrrolo [1,2, 3-deagglomeration ] quinoxaline-13-carboxylic acid ethyl ester:
ethyl (5 as,1 as) -4-bromo-5- (2-chloroacetyl) -5,5a,6,7,8,9,10 a-octahydro-7, 10-oxirane [ b ] indole-11-carboxylate (950 mg,1 eq) was dissolved in a solution of 2M methylamine in tetrahydrofuran (10 mL), the reaction was stirred for 16 h at 80 ℃, LCMS showed the end of the reaction, the reaction was concentrated to give crude product, which was isolated and purified by reverse phase flash chromatography (C18, 0.05%FA in water,MeCN) to give the title compound (600 mg, yield 79.2%).
LCMS(ESI)[M+H] + ＝342.1； 1 H NMR(400MHz,DMSO-d 6 )δ6.90(t,J＝7.7Hz,1H),6.64(d,J＝
7.4Hz,1H),6.56(d,J＝7.9Hz,1H),4.36(t,J＝7.6Hz,1H),4.19(d,J＝5.5Hz,1H),4.11(dt,J＝13.9,7.0Hz,4H),3.90(d,J＝15.7Hz,1H),3.67(s,1H),2.96(d,J＝5.7Hz,1H),2.76(s,3H),2.22–2.13(m,1H),1.85(s,1H),1.49(dd,J＝21.0,7.6Hz,2H),1.22(t,J＝7.0Hz,4H).
Seventh step: preparation of ethyl (6 bs,11 as) -3-methyl-2, 3,6b,8,9,10,11 a-octahydro-1 h,7h-7, 10-oxirane [4,5] pyrrolo [1,2, 3-dean ] quinoxaline-13-carboxylic acid ethyl ester:
ethyl (6 bs,11 as) -3-methyl-1-oxo-2, 3,6b,8,9,10,11 a-octahydro-1 h,7h-7, 10-oxirane [4,5] pyrrolo [1,2, 3-de ] quinoxaline-13-carboxylate (200 mg,1 eq) was dissolved in tetrahydrofuran (2 mL), borane-tetrahydrofuran complex (0.1 mL,2 eq) was added under nitrogen protection, the reaction was stirred at 80 ℃ for 1 hour, LCMS showed the end of the reaction, the reaction was cooled to room temperature, methanol was slowly added dropwise until no more bubbles were generated, stirred for 1 hour, the reaction was concentrated to give a crude product, water (15 mL) was added, the combined organic phase was dried over anhydrous sodium sulfate, and the crude product was isolated and purified by flash chromatography (Silica gel, PE: ea=3:1) to give the target compound (100 mg, 51.8%).
LCMS(ESI)[M+H] + ＝328.3； 1 H NMR(400MHz,DMSO-d 6 )δ6.54(s,1H),6.43(s,1H),6.36(d,J
＝7.7Hz,1H),4.18(s,1H),4.12–4.04(m,3H),3.32(d,J＝47.5Hz,5H),2.80(s,3H),2.59(s,1H),1.88(d,J＝28.6Hz,4H),1.51(s,2H),1.21(t,J＝7.1Hz,3H).
Eighth step: preparation of (6 bR,11 aS) -3-methyl-2, 3,6b,8,9,10,11 a-octahydro-1H, 7H-7, 10-oxirane [4,5] pyrrolo [1,2, 3-des ] quinoxaline:
ethyl (6 bs,11 as) -3-methyl-2, 3,6b,8,9,10,11 a-octahydro-1 h,7h-7, 10-oxirane [4,5] pyrrolo [1,2, 3-off ] quinoxaline-13-carboxylate (1 g,1 eq) was dissolved in 6N hydrochloric acid (1 mL), the reaction was stirred at 100 ℃ for 12 hours, LCMS showed the end of the reaction, the reaction was diluted with ethyl acetate, pH was adjusted to 10 with 1N sodium hydroxide, extracted with ethyl acetate (30 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give crude product, which was isolated and purified by reverse phase flash chromatography (C18, 0.1%FAin water,MeCN) to give the target compound (500 mg, 64.2%).
LCMS(ESI)[M+H] + ＝256.2.
Ninth step: preparation of (6 bR,11 aS) -13- (3- (2-methoxyphenyl) propyl) -3-methyl-2, 3,6b,8,9,10,11 a-octahydro-1H, 7H-7, 10-oxirane [4,5] pyrrolo [1,2, 3-deaggregation ] quinoxaline:
(6 bR,11 aS) -3-methyl-2, 3,6b,8,9,10,11 a-octahydro-1H, 7H-7, 10-oxirane [4,5] pyrrolo [1,2, 3-desquinoxaline (100 mg,1 eq) and 3- (2-methoxyphenyl) propanal (321.51 mg,5 eq) were dissolved in dichloromethane (4 mL) and methanol (0.4 mL), stirred for 5 minutes after the addition of acetic acid (0.3 mL), then stirred for 1 hour after the addition of sodium triacetoxyborohydride (414.98 mg,5 eq), LCMS showed the end of the reaction, water (15 mL) was added, extracted three times with dichloromethane and methanol (10:1), the combined organic phases were dried over anhydrous sodium sulfate, and the crude product was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the target compound (13.99 mg, yield 8.9%).
LCMS(ESI)[M+H] + ＝404.4； 1 H NMR(400MHz,DMSO-d 6 )δ9.35(s,1H),7.24–7.17(m,2H),
6.99(d,J＝8.1Hz,1H),6.91(t,J＝7.3Hz,1H),6.58(t,J＝7.6Hz,1H),6.49–6.45(m,1H),6.39(d,J＝7.8Hz,1H),3.98(dd,J＝18.3,11.4Hz,2H),3.81(d,J＝3.7Hz,3H),3.65(d,J＝5.2Hz,1H),3.42–3.37(m,3H),3.29(d,J＝9.1Hz,2H),3.04–2.93(m,2H),2.80(s,3H),2.68–2.57(m,3H),2.22(d,J＝8.4Hz,1H),2.14–2.04(m,2H),2.01–1.94(m,2H),1.79(td,J＝13.2,4.6Hz,1H),1.66(dd,J＝9.7,8.9Hz,1H).
Example 136
Preparation of 1- (1- (3- (2-methoxyphenyl) propyl) piperidin-4-yl) -2, 3-dihydro-1H-1, 3-benzodiazol-2-one:
the first step: preparation of 3- (2-methoxyphenyl) propanal:
raw material 3- (2-methoxyphenyl) propan-1-ol (800 mg,1 eq) was dissolved in dimethyl sulfoxide (10 mL), 2-iodoxybenzoic acid (2.7 g,2 eq) was slowly added at 0 ℃ and stirring was continued for 4 hours at 0 ℃ after the addition was completed, TLC showed the reaction was completed, water (10 mL) was added, extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with brine (50 mL x 2), the organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product, which was isolated and purified by flash chromatography (Silica gel, PE: ea=100:0 to 97:3) to obtain the target compound (600 mg, yield 76%).
1 H NMR(400MHz,CDCl3)δ9.81(d,J＝1.5Hz,1H),7.23–7.18(m,1H),7.14(d,J＝7.3Hz,1H),6.91–6.82(m,2H),3.82(s,3H),2.95(t,J＝7.5Hz,2H),2.72(td,J＝7.5,1.3Hz,2H).
And a second step of: preparation of 1- (1- (3- (2-methoxyphenyl) propyl) piperidin-4-yl) -2, 3-dihydro-1H-1, 3-benzodiazol-2-one:
the compound 1- (piperidin-4-yl) -2, 3-dihydro-1H-1, 3-benzodiazole-2-one (250 mg,1 eq) was dissolved in dichloromethane (4 mL), 3- (2-methoxyphenyl) propanal (189 mg,1 eq) and acetic acid (0.2 mL) were added and stirred at room temperature for 1 hour, sodium borohydride (488 mg,2 eq) was added and stirring was continued at room temperature for 1 hour, LCMS detection was complete, ammonium chloride (5 mL) was added, dichloromethane (6 mL x 3) was extracted, the combined organic phases were washed with brine (20 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by prep-HPLC (C18, 0.05%FA in water,MeCN) to give the title compound (75.67 mg, yield 18%).
LCMS(ESI)[M+H] + ＝366.3； 1 H NMR(400MHz,MeOD-d 4 )δ8.48(s,1H),7.33(s,1H),7.23–7.16
(m,2H),7.07(s,3H),6.95(d,J＝8.1Hz,1H),6.89(t,J＝7.4Hz,1H),4.55(d,J＝3.7Hz,1H),3.84(s,3H),3.67(d,J＝12.1Hz,2H),3.17–3.08(m,4H),2.82(d,J＝9.7Hz,2H),2.74(t,J＝7.3Hz,2H),2.20–1.95(m,5H).
Example 137
Preparation of ethyl 2- (1-benzofuran-3-yl) acetate:
1- (2-methoxyphenyl) azetidin-3-one (163 mg,1 eq), 1- (piperidin-4-yl) -2, 3-dihydro-1H-1, 3-benzodiazol-2-one (200 mg,1 eq) was dissolved in tetrahydrofuran (5 mL), acetic acid (2 drops) was added, the reaction system was stirred for 1 hour at room temperature, sodium triacetoxyborohydride (390 mg,2 eq) was added, the reaction was stirred for 2 hours, LCMS showed complete reaction, water (15 mL) was added to the reaction, extracted with dichloromethane (15 mL. 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give the crude product which was purified by prep-HPLC to give the title compound (26.88 mg, yield 8%).
LCMS(ESI)[M+H] + ＝379.1； 1 H NMR(400MHz,DMSO-d 6 )δ10.82(s,1H),7.23-7.18(m,1H),6.95
(t,J＝4.2Hz,3H),6.86-6.79(m,2H),6.71(t,J＝7.6Hz,1H),6.43-6.39(m,1H),4.17(s,1H),3.99(t,J＝7.1Hz,2H),3.72(s,3H),3.58(t,J＝6.8Hz,2H),3.22-3.16(m,1H),2.95-2.86(m,2H),2.38-2.29(m,2H),2.03-1.94(m,2H),1.70-1.63(m,2H).
Examples 135, 138-145
Reference to the procedure for the preparation of example 137 gave the compounds of examples 135, 136, 138-145
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Example 155
Preparation of 8- (3- (2-methoxyphenyl) propyl) -1-phenyl-1, 3, 8-triazaspiro (4.5) decan-4-one formate:
the first step: preparation of 1-benzyl-4- (phenylamino) piperidine-4-carbonitrile:
raw material 1-benzyl piperidine-4-ketone (5 g,1 eq) and aniline (2.46 g,1 eq) were dissolved in acetic acid (67 mL), trimethylcyanosilane (7.86 g,3 eq) was added under ice bath, stirred at normal temperature for 2.5 hours, LCMS detection reaction was completed, acetic acid was dried by spin-drying, 2mol sodium hydroxide solution was added until pH >10, dichloromethane (150 mL), water (150 mL x 3), saturated saline (100 mL) were added for washing, dried over anhydrous sodium sulfate, and organic phase was dried and concentrated to give crude product, which was slurried with methyl tert-butyl ether to give the title compound (6.8 g, 88.3% yield).
LCMS(ESI)(M+H) + ＝292.5； 1 H NMR(400MHz,DMSO-d 6 )δ7.37–7.28(m,4H),7.28–7.20(m,
1H),7.16(t,J＝7.9Hz,2H),6.83(d,J＝7.9Hz,2H),6.72(t,J＝7.3Hz,1H),3.56(d,J＝32.2Hz,2H),2.71(d,J＝34.6Hz,2H),2.29(d,J＝9.0Hz,4H),1.86(d,J＝27.8Hz,2H).
And a second step of: preparation of 1-benzyl-4- (phenylamino) piperidine-4-carboxamide:
the starting material 1-benzyl-4- (phenylamino) piperidine-4-carbonitrile (6 g,1 eq) was dissolved in concentrated sulfuric acid (33 mL) and stirred at room temperature for 16 hours, LCMS detection was complete, aqueous ammonia was added until pH >10, water (700 mL), dichloromethane (30 mL x 3) were added to extract the aqueous phase to give the organic phase which was washed with saturated brine (30 mL x 2) and the organic phase was dried by spinning to give the crude 1-benzyl-4- (phenylamino) piperidine-4-carboxamide (5 g, crude).
LCMS(ESI)[M+H] + ＝310.6.
And a third step of: preparation of 8-benzyl-1-phenyl-1, 3, 8-triazaspiro (4.5) dec-2-en-4-one:
1-benzyl-4- (phenylamino) piperidine-4-carboxamide (4 g, crude product) was dissolved in methanol (50 mL), added with (dimethoxymethyl) dimethylamine (4.62 g,3 eq) and reacted at 55℃for 16 hours, after which the reaction was detected by LCMS, the reaction solution was dried by spin-drying to give the crude product, and slurried with methyl tert-butyl ether to give the filter cake 8-benzyl-1-phenyl-1, 3, 8-triazaspiro (4.5) dec-2-en-4-one (2.98 g, yield 72.2%) as a white solid.
LCMS(ESI)[M+H] + ＝320.3； 1 H NMR(400MHz,CDCl 3 )δ8.23(s,1H),7.49–7.47(m,2H),7.27
(t,J＝3.9Hz,5H),7.23(dd,J＝8.9,4.7Hz,1H),7.18(dd,J＝5.9,3.5Hz,2H),3.57(s,2H),3.01(td,J＝11.8,2.5Hz,2H),2.67(d,J＝11.7Hz,2H),2.00(td,J＝12.6,4.4Hz,2H),1.80(d,J＝12.6Hz,2H).
Fourth step: preparation of 8-benzyl-1-phenyl-1, 3, 8-triazaspiro (4.5) decan-4-one:
8-benzyl-1-phenyl-1, 3, 8-triazacyclo (4.5) dec-2-en-4-one (3 g,1 eq) was dissolved in methanol (30 mL), sodium borohydride (445 mg,1.25 eq) was added, stirred at room temperature for 2 hours, LCMS detection was complete, water quenched, dried methanol was added, ethyl acetate (30 mL x 3) was added to extract, the organic phases were combined and washed with brine (15 mL), and the crude product obtained by drying with anhydrous sodium sulfate was slurried with methyl tert-butyl ether to give the title compound (2.87 g, yield 95.1%).
LCMS(ESI)[M+H] + ＝322.2.
Fifth step: preparation of 1-phenyl-1, 3, 8-triazaspiro (4.5) decan-4-one:
8-benzyl-1-phenyl-1, 3, 8-triazaspiro (4.5) decan-4-one (2.55 g,1 eq) was dissolved in methanol (230 mL), acetic acid (7 mL) was added, palladium on carbon (480 mg) was added, hydrogen was replaced 3 times, stirring was performed at room temperature under hydrogen atmosphere for 4 hours, LCMS detection was completed, the reaction solution was filtered through celite, the filtrate was dried by spin to give crude product, saturated sodium bicarbonate was added to adjust pH >10, dichloromethane: methanol=10:1 (20 ml x 6) to give an organic phase, which was washed with saturated brine, dried over anhydrous sodium sulfate, and slurried with methyl tert-butyl ether to give a filter cake as the objective product (1.5 g, yield 81.8%).
LCMS(ESI)[M+H] + ＝232.2. 1 H NMR(400MHz,DMSO-d 6 )δ8.59(s,1H),7.27–7.12(m,2H),
6.86(dd,J＝22.3,8.7Hz,2H),6.73(t,J＝7.3Hz,1H),4.57(s,2H),3.14(td,J＝12.4,3.1Hz,2H),2.82(dt,J＝47.3,23.7Hz,2H),2.39(tt,J＝16.3,8.1Hz,2H),1.47(d,J＝13.3Hz,2H),1.31–1.14(m,1H).
Sixth step: preparation of 8- (3- (2-methoxyphenyl) propyl) -1-phenyl-1, 3, 8-triazaspiro (4.5) decan-4-one formate:
1-phenyl-1, 3, 8-triazaspiro (4.5) decan-4-one (300 mg,1 eq) and 3- (2-methoxyphenyl) propanal (255.58 mg,1.2 eq) were dissolved in dichloromethane (5 mL), sodium triacetoxyborohydride (824.7 mg,3 eq) and acetic acid (0.5 mL) were added, stirred at room temperature for 1 hour, LCMS monitored for reaction, quenched with water, extracted with ethyl acetate (5 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate to give the crude product, which was purified by prep-HPLC (C18, 0.1%FA in water,MeCN) to give the title compound (279.5 mg, 57.5% yield).
LCMS(ESI)[M+H] + ＝380.2； 1 H NMR(400MHz,CDCl 3 )δ8.65(s,1H),7.29(dd,J＝8.7,7.5Hz,
2H),7.20(td,J＝8.0,1.7Hz,1H),7.11(dd,J＝7.4,1.5Hz,1H),6.94(d,J＝8.2Hz,2H),6.91–6.80(m,3H),6.70(s,1H),4.74(s,2H),3.81(s,3H),3.41(dd,J＝16.7,3.7Hz,4H),3.21–3.05(m,2H),2.90(dd,J＝10.0,6.5Hz,2H),2.68(t,J＝7.4Hz,2H),2.17–1.93(m,2H),1.79(d,J＝14.7Hz,2H).
Examples 146 to 154, 156 to 172
Reference to the preparation of examples 1, 37, 91, 118 137 or 155, the compounds of examples 146-154, 156-172 were prepared
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Example 173
Preparation of (5 as,10 as) -11- (3- (2-methoxyphenyl) propyl) -5,5a,6,7,8,9,10 a-octahydro-7, 10-oxirane [ b ] indole:
the first step: preparation of (5 as,10 ar) -4-bromo-5, 5a,6,7,8,9,10 a-octahydro-7, 10-oxirane [ b ] indole (S) -2-hydroxy-2-phenylacetate:
the compound (5 as,10 ar) -4-bromo-5, 5a,6,7,8,9,10 a-octahydro-7, 10-oxirane [ b ] indole (6 g,1 eq) and (2S) -2-hydroxy-2-phenylacetic acid (3.92 g,1.2 eq) were dissolved in a mixed solvent of ethanol (10 mL) and dichloromethane (50 mL), stirred at 50 ℃ for 2 hours, stirred at 30 ℃ for 2 hours, finally stirred under an ice water bath for 2 hours, a large amount of white solid precipitated, filtered, the filter cake was washed with dichloromethane (30 mL x 3), and the filter cake was dried to give the target product (3 g, yield 32.3%).
LCMS(ESI)[M+H] + ＝281.1； 1 H NMR(400MHz,DMSO-d 6 )δ7.45(s,2H),7.30(d,J＝7.7Hz,2H),7.24(dd,J＝15.5,7.7Hz,2H),7.15(d,J＝7.2Hz,1H),6.62(t,J＝7.6Hz,1H),5.87(d,J＝2.5Hz,1H),4.63(s,1H),3.93(s,2H),3.78(s,1H),3.67(d,J＝4.7Hz,1H),2.27–2.18(m,1H),2.10(d,J＝14.6Hz,2H),1.97–1.87(m,1H),1.62–1.51(m,1H),1.43–1.35(m,1H).
And a second step of: preparation of (5 as,10 ar) -5,5a,6,7,8,9,10 a-octahydro-7, 10-oxirane [ b ] indole:
palladium on carbon (30 mg) was added to a methanol solution (10 mL) of (5 aS,10 aR) -4-bromo-5, 5a,6,7,8,9,10 a-octahydro-7, 10-oxirane [ b ] indole (S) -2-hydroxy-2-phenylacetate (900 mg,1 eq) and stirred at 25℃for 1 hour under a hydrogen atmosphere. LCMS detected complete reaction. And (3) carrying out suction filtration on the reaction liquid, and concentrating the filtrate to obtain a crude product. The crude product was isolated and purified by flash chromatography (Silica gel, DCM: meoh=5:1) to give the desired product (300 mg, 71.8% yield).
LCMS(ESI)[M+H] + ＝201.2； 1 H NMR(400MHz,DMSO-d 6 )δ7.00(d,J＝7.2Hz,1H),6.92(t,J＝7.6Hz,1H),6.54(t,J＝7.3Hz,1H),6.49(d,J＝7.7Hz,1H),5.48(d,J＝3.3Hz,1H),3.80(t,J＝8.7Hz,1H),3.62(d,J＝8.4Hz,1H),3.36–3.31(m,1H),3.23(dd,J＝7.9,5.2Hz,1H),1.98(dt,J＝14.0,5.2Hz,1H),1.89(dd,J＝12.7,6.1Hz,1H),1.82–1.74(m,1H),1.67(dt,J＝11.1,7.6Hz,1H),1.29(dd,J＝9.6,5.5Hz,2H).
And a third step of: preparation of (5 as,10 as) -11- (3- (2-methoxyphenyl) propyl) -5,5a,6,7,8,9,10 a-octahydro-7, 10-oxirane [ b ] indole:
the compound (5 aS,10 aR) -5,5a,6,7,8,9,10 a-octahydro-7, 10-oxirane [ b ] indole (300 mg,1 eq) and propyl 3- (2-methoxyphenyl) methanesulfonate (439.14 mg,1.2 eq) were dissolved in N, N-dimethylformamide (15 mL), and potassium carbonate (310.54 mg,1.5 eq) was added to react at 70℃for 12 hours. LCMS checked the completion of the reaction, water (10 mL) was added to the reaction, extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash chromatography (Silica gel, DCM: meoh=10:1) to give the title compound (50.71 mg, yield 8.5%).
LCMS(ESI)[M+H] + ＝349.2； 1 H NMR(400MHz,CDCl 3 )δ7.21–7.14(m,2H),7.03(t,J＝7.4Hz,2H),6.91–6.83(m,2H),6.71(t,J＝7.4Hz,1H),6.60(d,J＝7.8Hz,1H),4.01(d,J＝5.9Hz,1H),3.83(s,3H),3.74(s,1H),3.42(s,1H),3.31(d,J＝11.9Hz,1H),2.67(dd,J＝23.3,15.6Hz,5H),1.98(d,J＝15.6Hz,4H),1.81(d,J＝13.8Hz,1H),1.62–1.41(m,2H).
Biological example
Experimental example 1:5-HT2A receptor isotope competition affinity assay
The radiolabeled ligand (agonist or antagonist) and the receptor protein may be incubated to form a receptor-ligand complex, and upon addition of the test compound, the radiolabeled ligand may compete with the isotopically-labeled ligand for binding to the receptor, ultimately forming a relative steady state equilibrium. The affinity of the test compound to the receptor is assessed by determining the dissociation of the isotopically labeled ligand from the receptor.
Experimental procedure
Compounds were prepared in DMSO at 100x serial dilutions, starting at 1mM, 4-fold serial dilutions, 10 concentration points. mu.L of the gradient concentration of the compound was transferred to a 96-well assay plate (starting at a final concentration of 10. Mu.M, 4-fold serial gradient dilutions, 10 concentration spots) using a pipette, and 49. Mu.L of 5-HT2AR receptor protein (final concentration 5. Mu.g/well) in 102. Mu.g/mL of assay buffer (50 mM Tris-HCl, pH 7.4) was added to each well. Then 50. Mu.L of 2nM isotopically labelled [ with assay buffer ] was added 3 H]Ketansertin (2X final concentration), shaking after sealing at room temperature for 1 hour. The reaction was filtered through a 0.3% PEI pretreated Unifilter-96GF/C filter plate, and the plate was rinsed with 4℃pre-chilled laboratory buffer and placed in a 50℃incubator to dry the plate. After addition of the scintillation fluid, the values were read using a MicroBeta2 instrument. The percentage inhibition rate is calculated by the formula: % inhibition = (Count High signal contrast -Count Sample well )/(Count High signal contrast -Count Low signal contrast ) 100, four parameter fitting calculation IC 50 Value, high signal control: compound-free DMSO group, low signal control: 1. Mu.M group of yang ginseng Ketanserin.
Results of 5-HT2A receptor isotope competition affinity test IC 50 Ki value
A：IC 50 ≤25nM；B：25＜IC 50 ≤50nM；C：50＜IC 50 ≤100nM
Experiments show that the compounds of the invention have good affinity with the 5-HT2A receptor.
Experimental example 2:5-HT2A beta-arestin recruitment experiment
Co-expression of ProLink in human osteosarcoma cells (U2 OS) TM (PK) -labeled GPCR receptors and enzyme receptor (EA) -labeled beta-Arretin. Activation of GPCR-PK induces β -arestin-EA recruitment, forcing complementation of the two enzyme fragments. The resulting functional enzyme hydrolyzes the substrate, producing a chemiluminescent signal. These cells have been modified with proprietary compounds that have no significant impact on detection performance to prevent their long-term proliferation and expansion.
Cell preparation: assayComplete Cell Plating Reagent was preheated in a 37 ℃ water bath for 15 minutes. 11.5mL of pre-warmed AssayComplete Cell Plating Reagent was transferred to a sterile new 15mL centrifuge tube. 5-HT2A U OS cells were removed from-80℃or liquid nitrogen and placed on dry ice prior to thawing. Immediately, 0.5mL of pre-warmed AssayComplete Cell Plating Reagent was added to the cell cryopreservation tube to thaw the cells. Transfer 0.6mL of thawed cell suspension to a pre-warmed AssayComplete Cell Plating Reagent centrifuge tube that had been added to 23.5mL, gently mix the cells, and transfer to a disposable sterile loading well. In 384 well plates, 20 μl of cell suspension was added per well. 384 well plates were placed in an incubator at 37℃with 5% CO 2 Culturing for 48 hours under the condition.
beta-Arrestin 2 experiment: prepare dilutions of molecules (agonists) with Cell Plating Reagent 0, 4-fold dilutions, 10 spots in one dilution plate. The concentration of each dilution should be 5 times the final concentration. mu.L of 5 Xagonist was added to each well of the well plate, and the well plate was incubated at 37℃for 90 minutes. 19 parts Cell Assay Buffer,5 parts Substrate Reagent 1, and 1 part Substrate Reagent 2 were added to a 15mL centrifuge tube; add 12.5. Mu.L of detection reagent per well in the detection plate; the well plate was placed in the dark and incubated at room temperature for 1 hour; reading (Envision).
Beta-arestin 2 test results
Compounds of formula (I) β-arrestin2/EC 50 (nM) Emax(％)
92 7163 39.5
Wherein Emax (%) >20% represents agonistic activity and <20% represents non-agonistic activity. Experiments show that the compound has agonistic activity.

Claims (12)

1. A compound of formula (I) a stereoisomer, tautomer, or mixture thereof, said compound being a pharmaceutically acceptable salt:
wherein,
ring A is selected from
L is selected from-C 1-6 Alkylene-, -C 1-6 Alkyloxy-, -C 1-6 Alkylthio-, -C 1-6 alkylene-NH-, -C 1-6 Alkylene-3-8 membered heterocyclyl-, -3-8 membered heterocyclyl-C 1-6 Alkylene-, -3-8 membered heterocyclyl-, said alkylene, alkyleneoxy, alkylenethio, heterocyclyl optionally being substituted with one or more groups each independently selected from deuterium, halogen, oxo (=o), -CN, -OH, -NH 2 、C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituted by substituents of haloalkoxy, formyl, acetyl, carboxamido, acetamido, or two substituents on the same C atom taken together to form C 3-8 Cycloalkyl, 4-8 membered heterocyclyl; the hetero atoms in the heterocyclic group are independently selected from O, N or S, and the number of the hetero atoms is 1 or 2; the left side of the L group is connected with a ring A, and the right side of the L group is connected with a ring B;
ring B is selected from C 6-12 Aryl, 5-12 membered heteroaryl or 5-12 membered heterocyclyl; the hetero atom in the heterocyclic group or the heteroaryl group is independently selected from O, N or S, and the number of the hetero atom is 1, 2 or 3;
each R A Independently selected from H, deuterium, halogen, -OH, -CN, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups;
each R B Independently selected from H, deuterium, halogen, -OH, -CN, oxo, -OC 1-6 Alkyl, C 1-6 Alkyl, -C 1-6 alkylene-OC 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, carboxyl;
m is selected from 0,1,2,3,4;
n is selected from 0,1,2,3;
unless otherwise indicated, the heteroatoms in the heterocyclyl, heteroaryl groups described above are independently selected from O, N or S, the number of heteroatoms being 1,2,3 or 4.
2. The compound of claim 1, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt of the compound, wherein: l is-methylene-, -ethylene-, -propylene-, -C 1-3 Alkyloxy-, -C 1-3 alkylene-NH-, -methylene-azetidinyl-, -methylene-tetrahydropyrrolyl-, -methylene-imidazolinyl-, -methylene-pyrazolidinyl-, -methylene-piperidyl-, -methylene-piperazinyl-, -methylene-hexahydropyrimidinyl-, -methylene-oxazolidinyl-, -methylene-thiazolidinyl-, -methylene-isoxazolidinyl-, -methylene-morpholinyl-, -methylene-1, 3-oxazinyl-, -ethylene-azetidinyl-, -ethylene-tetrahydropyrrolyl-, -ethylene-imidazolinyl-, -ethylene-pyrazolidinyl-, -ethylene-piperidinyl-, -ethylene-piperazinyl-, -ethylene-hexahydropyrimidinyl-, -ethylene-oxazolidinyl-, -ethylene-isoxazolidinyl-, -ethylene-morpholinyl-, -ethylene-1, 3-oxazinyl-, -propylene-azetidinyl-, -ethylene-tetrahydropyrrolyl-, -propylene-imidazolinyl-, -propylene-pyrazolinyl-, -pyrazolidinyl-, -piperidinyl ethylene-piperidinyl, -propylene-piperazinyl-, -propylene-hexahydropyrimidinyl-, -propylene-oxazolidinyl-, -propylene-thiazolidine-, -propylene-isoxazolidinyl-, -propylene-morpholinyl-, -propylene-1, 3-oxazinyl-, -azetidinyl-, -tetrahydropyrrolyl-, -imidazolinyl-, -pyrazolidinyl-, -piperidinyl-, -piperazinyl-, -hexahydropyrimidinyl-, -oxazolidinyl-, -thiazolidine-, -isoxazolidinyl-, -morpholinyl-, -1, 3-oxazinyl -, -azetidinyl-methylene-, -tetrahydropyrrolyl-methylene-, -imidazolinyl-methylene-, -pyrazolidinyl-methylene-, -piperidinyl-methylene-, -piperazinyl-methylene-, -hexahydropyrimidinyl-methylene-, -oxazolidinyl-methylene-, -thiazolidine-methylene-, -isoxazolidinyl-methylene-, -morpholinyl-methylene-, -1, 3-oxazinyl-methylene-, -azetidinyl-tetrahydropyrrolyl-, -azetidinyl-imidazolinyl-, -azetidinyl-pyrazolidinyl-, -azetidinyl-piperidinyl-, -azetidinyl-piperazinyl-, -azetidinyl-hexahydropyrimidinyl-, -azetidinyl-oxazolidinyl-, -azetidinyl-thiazolidine-, -azetidinyl-isoxazolidinyl-, -azetidinyl-morpholinyl-, -azetidinyl-1, 3-oxazinyl-, -tetrahydropyrrolyl-imidazolinyl-, -tetrahydropyrrolyl-pyrazolidinyl-, -tetrahydropyrrolyl-piperidinyl-, -tetrahydropyrrolyl-piperazinyl-, -tetrahydropyrrolyl-hexahydropyrimidinyl-, -tetrahydropyrrolyl-oxazolidinyl-, -tetrahydropyrrolyl-thiazolidine-, -tetrahydropyrrolyl-isoxazolidinyl-, -tetrahydropyrrolyl-morpholinyl-, -tetrahydropyrrolyl-1, 3-oxazinyl-, -imidazolinyl-pyrazolidinyl-, -imidazolinyl-piperidinyl-, -imidazolinyl-piperazinyl-, -imidazolinyl-hexahydropyrimidinyl-, -imidazolinyl-oxazolidinyl-, -imidazolinyl-thiazolidine-, -imidazolinyl-isoxazolidinyl-, -imidazolinyl-morpholinyl-, -imidazolinyl-1, 3-oxazinylalkyl-, -pyrazolidinyl-piperidinyl-, -pyrazolidinyl-piperazinyl-, -pyrazolidinyl-hexahydropyrimidinyl-, -pyrazolidinyl-oxazolidinyl-, -pyrazolidinyl-thiazolidine-, -pyrazolidinyl-isoxazolidinyl-, -pyrazolidinyl-morpholinyl-, -pyrazolidinyl-1, 3-oxazinylalkyl-, -piperidinyl-piperazinyl-, -piperidinyl-hexahydropyrimidinyl-, -piperidinyl-oxazolidinyl-, -piperidinyl isoxazolidinyl-, -piperidinyl-morpholinyl-, -piperidinyl-1, 3-oxazinylalkyl-, -piperazinyl-hexahydropyrimidinyl-, -piperazinyl-oxazolidinyl-, -piperazinyl-thiazolidinyl-, -piperazinyl-isoxazolidinyl-, -piperazinyl-morpholinyl-, -piperazinyl-1, 3-oxazinylalkyl-, -hexahydropyrimidinyl-oxazolidinyl-, -hexahydropyrimidinyl-thiazolidinyl-, -hexahydropyrimidinyl-isoxazolidinyl-, -hexahydropyrimidinyl-morpholinyl -, -hexahydropyrimidinyl-1, 3-oxazinylalkyl-, -oxazolidinyl-thiazolidine-, -oxazolidinyl-isoxazolidinyl-, -oxazolidinyl-morpholinyl-, -oxazolidinyl-1, 3-oxazinylalkyl-, -thiazolidine-isoxazolidinyl-, -thiazolidine-morpholinyl-, -thiazolidine-1, 3-oxazinylalkyl-, -isoxazolidinyl-morpholinyl-, -isoxazolidinyl-1, 3-oxazinylalkyl-, -morpholinyl-1, 3-oxazinylalkyl-; the methylene, ethylene, propylene, alkyleneoxy, alkylene, azetidinyl, tetrahydropyrrolyl, imidazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl, 1, 3-oxazinyl are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, -OH, C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, C 1-3 Alkoxy, C 1-3 Substituted by substituents of haloalkyl, acetyl, acetamido, or two substituents on the same C atom taken together to form C 3-8 Cycloalkyl, 4-8 membered heterocyclyl; the left side of the L group is connected with a ring A, and the right side of the L group is connected with a ring B;
preferably, the method comprises the steps of, wherein is the a-ring attachment site and is the B-ring attachment site.
3. The compound of any one of claims 1-2, a stereoisomer, a tautomer, or a mixture thereof, the compound being a pharmaceutically acceptable salt, wherein: ring B is C 6-10 Aryl, 6 membered monocyclic heterocyclyl, 7 membered monocyclic heterocyclyl, 5 membered monoheteroaryl, 6 membered monoheteroaryl, 5 membered/5 membered fused heterocyclyl, 5 membered/6 membered fused heterocyclyl, 6 membered/5 membered fused heterocyclyl, 4 membered/6 membered fused heterocyclyl, 6 membered/4 membered fused heterocyclyl, 6 membered/6 membered fused heterocyclylHeterocyclyl, 5-membered/5-membered fused heteroaryl, 5-membered/6-membered fused heteroaryl, 6-membered/5-membered fused heteroaryl, 6-membered/6-membered fused heteroaryl, wherein the heteroatoms in the heterocyclyl, heteroaryl, fused heterocyclyl, fused heteroaryl are independently selected from O, N or S, the number of heteroatoms being 1,2 or 3;
preferably, ring B is phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, 1, 3-dihydroisobenzofuran, 2, 3-benzofuranyl, 1, 2-benzisoxazolyl, indolyl, indazolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzisothiazolyl, benzitrahydrofuran, benzitrahydropyranyl, benzopyranyl, tetrahydroisoquinolyl, tetrahydroquinolinyl, benzopiperazinyl, 7, 8-dihydro-5H-pyran [4,3-B ] pyridinyl, 5, 8-dihydro-6H-pyran [3,4-B ] pyridinyl, 7, 8-dihydro-5H-thiopyran [4,3-B ] pyridinyl, 5,6,7, 8-tetrahydro-1, 7-naphthyridinyl, 7, 8-dihydro-5H-pyran [4,3-B ] pyridinyl, 5, 3-dihydro-6H-pyran [4,3-B ] pyridinyl, 7, 8-dihydro-1, 3-B ] pyridinyl, 7, 8-tetrahydro-1, 7-naphthyridinyl, 7, 3-dihydro-5H-pyran [4,3-B ] pyridinyl, 3-B ] pyridinyl, 7, 8-dihydro-1, 3-B ] pyridinyl;
More preferably, ring B is
4. A compound according to any one of claims 1-3, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt of said compound, wherein: each R A Independently selected from H, deuterium, halogen, -OH, -CN, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-12 Aryl, 5-12 membered heteroaryl;
preferably, each R A Independently selected from H, deuterium, halogen, -OH, -CN, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, phenyl;
preferably, each R A Independently selected from H, deuterium, -F, -Cl, -Br, -OH, -CN, -OCH 3 Oxo, methyl, phenyl.
5. The compound of any one of claims 1-4, a stereoisomer, a tautomer, or a mixture thereof, the compound being a pharmaceutically acceptable salt, wherein: each R B Independently selected from H, deuterium, halogen, -OH, -CN, oxo, -OC 1-6 Alkyl, C 1-6 Alkyl, -C 1-6 alkyl-OC 1-6 A carboxyl group;
preferably, each R B Independently selected from H, deuterium, oxo, halogen, -OH, -CN, -OC 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Alkoxy or-C 1-3 alkyl-OC 1-3 A carboxyl group;
more preferably, each R B Independently selected from H, deuterium, oxo, -F, -Cl, -Br, -OH, -CN, -OCH 3 Methyl, carboxyl.
6. The compound of any one of claims 1-5, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt of the compound, wherein: m is selected from 0,1,2,3; preferably, m is selected from 1 and 2; more preferably, m is 1; n is selected from 0,1 and 2; preferably, n is selected from 0 and 1.
7. A compound of formula (II) as shown below, a stereoisomer, tautomer, or mixture thereof, the compound being a pharmaceutically acceptable salt:
wherein L, ring B, R A 、R B M and n are as defined in claims 1 to 6.
8. A compound according to claim 7,a stereoisomer, tautomer, or mixture thereof, of a compound that is pharmaceutically acceptable salt, wherein:is->
9. A compound of formula (IV), (V) or (VI) as shown below, stereoisomers, tautomers or mixtures thereof, said compound being a pharmaceutically acceptable salt thereof:
wherein L, ring B, R A 、R B M and n are as defined in claims 1 to 6.
10. A compound selected from the group consisting of stereoisomers, tautomers, or mixtures thereof, which compound is a pharmaceutically acceptable salt:
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, a stereoisomer, a tautomer, or a mixture thereof, said compound being a pharmaceutically acceptable salt.
12. Use of a compound according to any one of claims 1 to 10, a stereoisomer, a tautomer of said compound or a mixture of same, a pharmaceutically acceptable salt of said compound or a pharmaceutical composition according to claim 11, as a 5-HT2A receptor agonist for the manufacture of a medicament for the treatment of a central nervous system disorder.
CN202310548498.4A 2022-05-17 2023-05-16 5-HT 2A Receptor agonist, preparation method and application thereof Pending CN117069720A (en)

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