WO2024120505A1 - Fused ring derivative, preparation method therefor, intermediates thereof, and use thereof - Google Patents

Fused ring derivative, preparation method therefor, intermediates thereof, and use thereof Download PDF

Info

Publication number
WO2024120505A1
WO2024120505A1 PCT/CN2023/137329 CN2023137329W WO2024120505A1 WO 2024120505 A1 WO2024120505 A1 WO 2024120505A1 CN 2023137329 W CN2023137329 W CN 2023137329W WO 2024120505 A1 WO2024120505 A1 WO 2024120505A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
mmol
deuterium
group
Prior art date
Application number
PCT/CN2023/137329
Other languages
French (fr)
Chinese (zh)
Inventor
秦俊
吴永奇
翁扬扬
蔡津
张乐
谢兴昆
万泽红
Original Assignee
上海枢境生物科技有限公司
江苏恩华药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海枢境生物科技有限公司, 江苏恩华药业股份有限公司 filed Critical 上海枢境生物科技有限公司
Publication of WO2024120505A1 publication Critical patent/WO2024120505A1/en

Links

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a paracyclic derivative, a preparation method, an intermediate and an application thereof. More specifically, the present invention relates to a paracyclic derivative, a preparation method, an intermediate, a pharmaceutical composition comprising the paracyclic derivative, and an application of the paracyclic derivative or a pharmaceutical composition thereof in the preparation of a drug for preventing and/or treating central nervous system diseases associated with mammalian trace amine-related receptors and/or 5-hydroxytryptamine receptors and/or dopamine receptors.
  • Schizophrenia is a psychopathological disorder of unknown origin that usually first appears in early adulthood and is characterized by psychotic symptoms, stage progression and development, and/or deterioration in social behavior and professional abilities.
  • the symptoms of schizophrenia are generally manifested in three major categories: positive symptoms, negative symptoms, and cognitive symptoms.
  • Positive symptoms are symptoms that represent an "excess" of normal experience, such as hallucinations and delusions.
  • Negative symptoms are symptoms that the patient lacks normal experience, such as anhedonia and lack of social interaction.
  • Cognitive symptoms are related to cognitive impairment in schizophrenia, such as lack of sustained attention and poor decision-making. Current antipsychotic drugs can successfully treat positive symptoms, but are far from ideal for negative and cognitive symptoms.
  • Biogenic amines play an important role as neurotransmitters in the central and peripheral nervous systems.
  • the synthesis and storage of biogenic amines as well as their degradation and reabsorption after release are tightly controlled. Imbalance in the levels of biogenic amines is known to be the main cause of altered brain function in many pathological conditions. Serotonin, norepinephrine, epinephrine, dopamine, and histamine have been extensively studied as classic biogenic amines.
  • the 5-hydroxytryptamine system plays an important role in regulating the functions of the prefrontal cortex PFC, including emotional control, cognitive behavior, and working memory.
  • the pyramidal neurons and GABA interneurons of the PFC contain several 5-hydroxytryptamine receptor subtypes 5-HT 1A and 5-HT 2A with particularly high densities.
  • 5-HT 1A 5-hydroxytryptamine receptor subtypes
  • 5-HT 2A 5-hydroxytryptamine receptor subtypes
  • 5-HT 1AR 5-hydroxytryptamine receptor subtypes
  • various preclinical data suggest that 5-HT 1AR may be a new target for the development of antipsychotic drugs.
  • the high affinity of atypical antipsychotics e.g., olanzapine, aripiprazole, etc.
  • 5-HT 1AR may be a new target for the development of antipsychotic drugs.
  • the high affinity of atypical antipsychotics e.g., olanzapine, aripiprazole, etc.
  • 5-HT 1AR and their low EPS side effects indicate that the serotonin system plays an important role in regulating the functions of the PFC, including emotional control, cognitive behavior, and
  • the pyramidal neurons and GABA interneurons of the PFC contain several serotonin receptor subtypes 5-HT 1A and 5-HT 2A with particularly high densities. Recent studies have shown that 5-HT 1A agonists are associated with atypical antipsychotic treatment and can improve negative symptoms and cognitive impairment.
  • trace amines TA endogenous amine compounds
  • trace amines TA endogenous amine compounds
  • p-tyramine p-tyramine
  • ⁇ -phenylethylamine tryptamine
  • octopamine a second type of endogenous amine compounds
  • Their content levels in the mammalian nervous system are usually lower than those of classical biogenic amines, but they have similar characteristics to classical biogenic amines in terms of structure, metabolism and subcellular localization.
  • the trace amine-associated receptor TAAR has a similar structure and pharmacological data to the in-depth GPCR pharmacophore.
  • the phylogenetic relationship of the receptor gene shows that these receptors
  • the TAAR1 is the first of four genes (TAAR1-4) that are highly conserved between humans and rodents. TAARs activate TAAR1 through G ⁇ s and exert their effects.
  • TAARs activate TAAR1 through G ⁇ s and exert their effects.
  • Existing studies have shown that the dysregulation of trace amine-related receptors, especially TAAR1, is closely related to many psychiatric diseases such as schizophrenia and depression, as well as other conditions such as attention deficit hyperactivity disorder, migraine, Parkinson's disease, substance abuse and eating disorders. Therefore, TAAR ligands have a high potential for the treatment of these diseases.
  • anti-refractory schizophrenia treatment drugs have always been a difficult problem in current clinical drug research and a direction that needs to be overcome.
  • the technical problem to be solved by the present invention is to provide a type of cyclopentane derivatives with a novel structure, a preparation method, an intermediate and an application thereof.
  • the compound As a TAAR1 receptor agonist, the compound has anti-neuropsychiatric activity, that is, it has the effect of treating or preventing neuropsychiatric diseases.
  • the object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • Ring A is an aryl group or a heteroaryl group
  • Ra is hydrogen, deuterium, halogen, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl or -( CH2 ) n1C (O) NRARB ;
  • any two R a are linked to the ring atoms to form a cycloalkyl or heterocyclyl group
  • RA and RB are each independently hydrogen, deuterium, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • R b and R c are each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n 2 C(O)NR C R D or -(CH 2 ) n 2 R E ;
  • any two R b are linked to the ring atoms to which they are attached to form a cycloalkyl or heterocyclyl group;
  • any two R c are linked to the ring atoms to which they are attached to form a cycloalkyl or heterocyclyl group;
  • R C , R D and RE are each independently hydrogen, deuterium, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • R1 is hydrogen, deuterium, hydroxyl, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino;
  • x is an integer from 0 to 5;
  • y is an integer from 0 to 5;
  • z is an integer from 0 to 5;
  • n is an integer from 0 to 3;
  • n is an integer from 0 to 3;
  • n1 is an integer from 0 to 3;
  • n2 is an integer from 0 to 3.
  • ring A is an aryl group or a heteroaryl group
  • Ra is hydrogen, deuterium, halogen, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino or - ( CH2 ) n1C (O) NRARB ;
  • any two R a are linked to the ring atoms to form a cycloalkyl or heterocyclyl group
  • RA and RB are each independently hydrogen, deuterium, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino;
  • R b and R c are each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino;
  • R1 is hydrogen, deuterium, hydroxyl, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino;
  • x is an integer from 0 to 5;
  • y is an integer from 0 to 5;
  • z is an integer from 0 to 5;
  • n is an integer from 0 to 3;
  • n is an integer from 0 to 3;
  • n1 is an integer from 0 to 3.
  • Ring A is C 6-14 aryl or 5-14 membered heteroaryl, preferably C 6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and C 6-10 aryl or C 6-10 aryl and 5-6 membered heteroaryl, more preferably phenyl, naphthyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and phenyl or phenyl and 5-6 membered heteroaryl, and the following groups are further preferred:
  • Ra is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl or -( CH2 ) n1C (O)NR A R B , preferably hydrogen, deuterium, halogen or C1-6 alkyl, more preferably hydrogen, deuterium, halogen or C1-3 alkyl, further preferably hydrogen, deuterium, fluorine, chlorine, bromine or methyl;
  • any two Ra are linked to the ring atoms to which they are connected to form a C3-8 cycloalkyl or a 3-8 membered heterocyclyl, preferably a C3-6 cycloalkyl or a 3-6 membered heterocyclyl, more preferably a C3-5 cycloalkyl or a 3-5 membered heterocyclyl, further preferably a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxacyclopentyl, azetidinyl or azopentyl.
  • RA and RB are each independently hydrogen, deuterium, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, preferably hydrogen, C1-6 alkyl or C3-8 cycloalkyl, more preferably hydrogen, C1-3 alkyl or C3-6 cycloalkyl, further preferably hydrogen, methyl or cyclopropyl.
  • x is an integer of 0-4, preferably 0, 1 or 2.
  • n1 is an integer of 0-2, preferably 0 or 1.
  • R b is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)NR C R D or -(CH 2 ) n2 R E , preferably hydrogen, deuterium, halogen, oxo, C 1-6 alkyl or C 3-8 cycloalkyl, more preferably hydrogen, deuterium, halogen, oxo, C 1-3 alkyl or C 3-6 cycloalkyl, further preferably hydrogen, deuterium, fluorine, chlorine, bromine, oxo, methyl
  • any two R b are linked to the ring atoms to which they are connected to form a C 3-8 cycloalkyl or a 3-8 membered heterocyclyl, preferably a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, more preferably a C 3-5 cycloalkyl or a 3-5 membered heterocyclyl, further preferably a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxacyclopentyl, azetidinyl or azopentyl.
  • y is an integer of 0-4, preferably 0, 1 or 2.
  • R c is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)NR C R D or -(CH 2 ) n2 R E , preferably hydrogen, deuterium, halogen, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)
  • any two R c are linked to the ring atoms to which they are connected to form a C 3-8 cycloalkyl or a 3-8 membered heterocyclyl, preferably a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, more preferably a C 3-5 cycloalkyl or a 3-5 membered heterocyclyl, further preferably a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxacyclopentyl, azetidinyl or azopentyl.
  • R C , R D and R E are each independently hydrogen, deuterium, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl, more preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl, further preferably hydrogen, methyl, trifluoromethyl, trifluoroethyl or cyclopropyl.
  • z is an integer of 0-4, preferably 0, 1 or 2.
  • n2 is an integer of 0-2, preferably 0 or 1.
  • R1 is hydrogen, deuterium, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio or C1-6 alkylamino, preferably hydrogen or C1-6 alkyl, more preferably hydrogen or C1-3 alkyl, further preferably hydrogen or methyl.
  • m is an integer of 0-2, preferably 0 or 1.
  • n is an integer of 0-2, preferably 1 or 2.
  • the compound represented by general formula (I) is selected from:
  • R2 and R3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino or -( CH2 ) n1C (O) NRARB , preferably hydrogen, deuterium, halogen or C1-6 alkyl, more preferably hydrogen, deuterium, halogen or C1-3 alkyl, further preferably hydrogen, deuterium, fluorine, chlorine or methyl;
  • R 2 and R 3 are linked to the carbon atom to which they are attached to form a phenyl group or a 5-6 membered heteroaryl group, preferably a phenyl group or a pyridyl group;
  • RA , RB , R1 , Rb , Rc , y, z, m, n and n1 are as defined above.
  • R2 and R3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-8 cycloalkyl , 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl or -( CH2 ) n1C (O) NRARB , preferably hydrogen, deuterium, halogen or C1-6 alkyl, more preferably hydrogen, deuterium, halogen or C1-3 alkyl, further preferably hydrogen, deuterium, fluorine, chlorine or methyl;
  • R 2 and R 3 are linked to the carbon atom to which they are attached to form a phenyl group or a 5-6 membered heteroaryl group, preferably a phenyl group or a pyridyl group;
  • R 4a , R 4b , R 5a , R 5b , R 6a , R 6b and R 7 are each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)NR C R D or -(CH 2 ) n2 R E , preferably hydrogen, deuterium, halogen, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 membered aryl, 5
  • R 4a and R 4b , R 4a and R 5a or R 6a and R 7 are linked to the ring atom to which they are connected to form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclyl group, preferably a C 3-6 cycloalkyl group or a 3-6 membered heterocyclyl group, more preferably a C 3-5 cycloalkyl group or a 3-5 membered heterocyclyl group, further preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an oxetanyl group, an oxacyclopentyl group, an azetidinyl group or an azoxycyclopentyl group;
  • R C , R D and R E are each independently hydrogen, deuterium, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl, more preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl, further preferably hydrogen , methyl, trifluoromethyl, trifluoroethyl or cyclopropyl;
  • RA , RB , R1 , Rb , y, m, n1 and n2 are as described above.
  • the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are selected from the following compounds:
  • the salt is hydrochloride.
  • the hydrochloride is in crystalline form.
  • the present invention also provides a 4,7,8,9,10,10a-hexahydro-5H-thiophene [2',3':3,4] pyrido [1,2-a] pyrazine hydrochloride crystal form A, whose X-ray powder diffraction spectrum comprises diffraction peaks located at 2 ⁇ of 11.64 ⁇ 0.2°, 25.61 ⁇ 0.2°, and 26.29 ⁇ 0.2°; preferably, the X-ray powder diffraction spectrum comprises diffraction peaks located at 2 ⁇ of 11.64 ⁇ 0.2°, 17.33 ⁇ 0.2°, 22.06 ⁇ 0.2°, 25.61 ⁇ 0.2°, and 26.29 ⁇ 0.2°; preferably, the X-ray powder diffraction spectrum comprises diffraction peaks located at 2 ⁇ of 11.64 ⁇ 0.2°, 17.33 ⁇ 0.2°, 22.06 ⁇ 0.2°, 25.61 ⁇ 0.2°, and 26.29 ⁇ 0.2°.
  • the present invention also provides a (S)-4,7,8,9,10,10a-hexahydro-5H-thiophene [2',3':3,4] pyrido [1,2-a] pyrazine hydrochloride crystal form A, wherein the X-ray powder diffraction pattern thereof comprises diffraction peaks located at 2 ⁇ of 11.70 ⁇ 0.2°, 25.43 ⁇ 0.2°, and 28.06 ⁇ 0.2°; preferably, the X-ray powder diffraction pattern thereof comprises diffraction peaks located at 2 ⁇ of 11.70 ⁇ 0.2°, 16.49 ⁇ 0.2°, 25.43 ⁇ 0.2°, 26.81 ⁇ 0.2°, and 28.06 ⁇ 0.2°; preferably, the X-ray powder diffraction pattern thereof comprises diffraction peaks located at 2 ⁇ of 11.70 ⁇ 0.2°, 16.49 ⁇ 0.2°, 25.43 ⁇ 0.2°, 26.81 ⁇ 0.2°, and 28
  • the X-ray powder diffraction pattern comprises diffraction peaks at 2 ⁇ of 11.70 ⁇ 0.2°, 15.15 ⁇ 0.2°, 16.49 ⁇ 0.2°, 17.25 ⁇ 0.2°, 17.54 ⁇ 0.2°, 21.20 ⁇ 0.2°, 21.63 ⁇ 0.2°, 22.21 ⁇ 0.2°, 24.87 ⁇ 0.2°, 25.43 ⁇ 0.2°, 26.81 ⁇ 0.2°, 28.06 ⁇ 0.2°, 31.01 ⁇ 0.2°, 33.21 ⁇ 0.2°, and 34.03 ⁇ 0.2°; preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 2.
  • the present invention also provides a (R)-4,7,8,9,10,10a-hexahydro-5H-thiophene [2',3':3,4] pyrido [1,2-a] pyrazine hydrochloride crystal form A, whose X-ray powder diffraction spectrum includes diffraction peaks located at 2 ⁇ of 11.74 ⁇ 0.2°, 25.47 ⁇ 0.2°, and 28.12 ⁇ 0.2°; preferably, the X-ray powder diffraction spectrum includes diffraction peaks located at 2 ⁇ of 11.74 ⁇ 0.2°, 1 6.52 ⁇ 0.2°, 25.47 ⁇ 0.2°, 26.87 ⁇ 0.2°, 28.12 ⁇ 0.2°; preferably, its X-ray powder diffraction pattern comprises diffraction peaks at 2 ⁇ of 11.74 ⁇ 0.2°, 15.19 ⁇ 0.2°, 16.52 ⁇ 0.2°, 17.37 ⁇ 0.2°, 21.19 ⁇ 0.2°, 21.66 ⁇ 0.2°, 22.22 ⁇ 0.2°, 24.91 ⁇
  • the present invention also provides a compound represented by general formula (I-1), a stereoisomer thereof or a salt thereof:
  • Ring A, R1 , Ra , RA , RB, Rb , Rc , x , y, z, m, n and n1 are as defined above.
  • the present invention also provides a compound represented by general formula (I-2), a stereoisomer thereof or a salt thereof:
  • Ring A, R1 , Ra , RA , RB , Rb , Rc , x, y, z, m, n and n1 are defined as above.
  • the present invention further provides a method for preparing the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof.
  • the preparation method can be synthesized by known methods using commercially available raw materials.
  • the preparation method preferably comprises the following steps: in a solvent, the compound represented by the general formula (I-1), its stereoisomer or its salt is subjected to a carbonyl reduction reaction to a methylene group in the presence of a reducing reaction reagent to obtain the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt;
  • Ring A, R1 , Ra , RA , RB, Rb , Rc , x , y, z, m, n and n1 are as defined above.
  • reaction conditions for reducing the carbonyl group to the methylene group may be conventional conditions for such reactions in the art.
  • the solvent may be a conventional solvent for such reactions in the art, such as an organic solvent, preferably tetrahydrofuran.
  • the reduction reaction reagent may be a conventional reduction reaction reagent for such reactions in the art, such as a hydroboration and reducing agent, preferably borane tetrahydrofuran.
  • the preparation method preferably comprises the following steps: in a solvent, the compound represented by the general formula (I-2), its stereoisomer or its salt is subjected to reduction reaction and amine protection reaction to obtain the compound represented by the general formula (I-3), its stereoisomer or its salt, and then deprotected to obtain the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt;
  • PG is an amine protecting group, preferably selected from trifluoroacetyl, benzyloxycarbonyl, allyloxycarbonyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, phthaloyl, nitrobenzenesulfonyl, p-toluenesulfonyl, trityl, tert-butoxycarbonyl, methoxycarbonyl, (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl or allyl, preferably tert-butoxycarbonyl;
  • Ring A, R1 , Ra , RA, RB , Rb , Rc , x, y , z, m, n and n1 are as described above.
  • the solvent may be a conventional solvent for such reactions in the art, such as an organic solvent, preferably tetrahydrofuran.
  • the reducing agent used in the reduction reaction may be a conventional reducing agent for such reactions in the art, such as lithium aluminum tetrahydride.
  • reaction conditions for the amine protection and deprotection may be conventional conditions for such reactions in the art.
  • the present invention further provides a method for preparing a compound represented by general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
  • the preparation method can be synthesized using commercially available raw materials by known methods.
  • the preparation method preferably comprises the following steps: in a solvent, The compound represented by the compound, its stereoisomer or its salt is subjected to a carbonyl reduction reaction to a methylene group in the presence of a reducing agent to obtain a compound represented by the general formula (II), its stereoisomer or its salt;
  • R 1 , R 2 , R 3 , RA , RB , R b , R c , y, z, m, n and n1 are as defined above.
  • reaction conditions for reducing the carbonyl group to the methylene group may be conventional conditions for such reactions in the art.
  • the solvent may be a conventional solvent for such reactions in the art, such as an organic solvent, preferably tetrahydrofuran.
  • the reduction reaction reagent may be a conventional reduction reaction reagent for such reactions in the art, such as a hydroboration and reducing agent, preferably borane tetrahydrofuran.
  • the preparation method preferably comprises the following steps: in a solvent, the compound represented by the general formula (II-2), its stereoisomer or its salt is subjected to reduction reaction and amine protection reaction to obtain the compound represented by the general formula (II-3), its stereoisomer or its salt, and then deprotected to obtain the compound represented by the general formula (II), its stereoisomer or its pharmaceutically acceptable salt;
  • PG 1 is an amine protecting group, preferably selected from trifluoroacetyl, benzyloxycarbonyl, allyloxycarbonyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, phthaloyl, nitrobenzenesulfonyl, p-toluenesulfonyl, trityl, tert-butoxycarbonyl, methoxycarbonyl, (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl or allyl, preferably tert-butoxycarbonyl;
  • R1 , R2 , R3 , RA , RB , Rb , Rc , y, z, m, n and n1 are as defined above.
  • the solvent may be a conventional solvent for such reactions in the art, such as an organic solvent, preferably tetrahydrofuran.
  • the reducing agent used in the reduction reaction may be a conventional reducing agent for such reactions in the art, such as lithium aluminum tetrahydride.
  • reaction conditions for the amine protection and deprotection may be conventional conditions for such reactions in the art.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds shown, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients.
  • the present invention further relates to the use of any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs, preferably in the preparation of drugs for preventing and/or treating neuropsychiatric diseases in mammals, wherein the neuropsychiatric diseases are preferably central nervous system diseases related to 5-hydroxytryptamine receptors and/or trace amine-related receptors and/or dopamine receptors.
  • the present invention further relates to a method for preparing a drug for preventing and/or treating central nervous system diseases associated with mammalian trace amine-related receptors and/or 5-hydroxytryptamine receptors and/or dopamine receptors by using any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts, or their pharmaceutical compositions.
  • the present invention also relates to a method for preventing and/or treating central nervous system diseases associated with mammalian trace amine-related receptors and/or 5-hydroxytryptamine receptors and/or dopamine receptors, which comprises administering to the mammal a therapeutically effective dose of any of the compounds shown, its stereoisomers or pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof, or a pharmaceutical composition thereof.
  • the trace amine-related receptor involved in the present invention is preferably TAAR1 receptor.
  • the neuropsychiatric diseases involved in the present invention are schizophrenia, schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizophreniform personality disorder, schizotypal personality disorder, delusional disorder, psychosis, mental disorder, short-term mental disorder, shared mental disorder, mental disorder caused by physical illness, drug-induced psychosis, psychological affective disorder, aggression, psychosis, Parkinson's psychosis, irritant psychosis, Tourette syndrome, organic or NOS psychosis, epilepsy, agitation, post-traumatic stress disorder, behavioral disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, movement disorder, Huntington's disease, dementia, affective disorder, anxiety disorder, affective disorder One or more of psychosis, depression, major depressive disorder, dysthymia, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive compulsive disorder, vertigo, epilepsy, pain, neuropathic pain, neuropathic pain-
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond.
  • Alkyl can have 1-8 carbon atoms, i.e., "C 1 -C 8 alkyl", such as C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 3 alkyl, C 4 alkyl, C 1-6 alkyl, C 3-6 alkyl.
  • alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3- Dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like, or isomers thereof.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl group comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, further preferably 3 to 6 carbon atoms, most preferably 3 to 5 carbon atoms, or 5 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include cycloalkyl groups of spirocyclic, condensed and bridged rings.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • a spiral atom a carbon atom
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl or a double spiral cycloalkyl, more preferably 3 yuan/6 yuan, 3 yuan/5 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan of single spiral cycloalkyl. It also includes a spiral heterocycloalkyl that shares a spiral atom with a heterocycloalkyl.
  • condensed cycloalkyl refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • it is 6 to 14 members, more preferably 7 to 10 members.
  • the number of constituent rings it is divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic condensed cycloalkyl, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • bridged cycloalkyl refers to a 5-20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, wherein the group contains one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system. It is preferably 6-14 members, and more preferably 7-10 members. It is classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, and is preferably a bicyclic, tricyclic or tetracyclic bridged cycloalkyl group, and more preferably a bicyclic or tricyclic bridged cycloalkyl group.
  • heterocyclyl refers to a saturated or unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and S(O) m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • it contains 3 to 12 ring atoms, wherein 1 to 4 heteroatoms are contained; more preferably, it is a 3-8 membered heterocyclyl containing 1 to 4 or 1 to 2 atoms selected from N, O and S; further preferably, it is a 3-6 membered heterocyclyl containing 1 to 4 or 1 to 2 atoms selected from N, O and S; most preferably, it is a 5-6 membered heterocyclyl containing 1 to 4 or 1 to 2 atoms of N, O or S.
  • the "hetero" in the heterocyclyl means 1 to 4 heteroatoms selected from N, O and S(O) m , wherein m is an integer from 0 to 2.
  • Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolanyl, 2,2-difluoro-1,3-dioxolanyl, cyclopentanone, 2,2-difluorocyclopentanone, azepanyl, oxolanyl, azetidinyl or azocyclopentanyl, etc.
  • Non-limiting examples of polycyclic heterocyclic groups include spirocyclic, condensed and bridged heterocyclic groups, wherein the spirocyclic, condensed and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms on the ring.
  • spiro heterocyclic group refers to a polycyclic heterocyclic group in which one atom (called a spiral atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer of 0-2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group or a double spiral heterocyclic group, more preferably a 3 yuan/6 yuan, 3 yuan/5 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiral heterocyclic group.
  • the "miscellaneous" in the spiral heterocyclic group represents 1-4 heteroatoms selected from N, O and S(O) m , wherein m is an integer of 0-2.
  • fused heterocyclic group refers to a polycyclic heterocyclic group of 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer of 0-2) heteroatoms, and the remaining ring atoms are carbon, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the number of constituent rings it is divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic fused heterocyclic group.
  • the "miscellaneous" in the fused heterocyclic group represents 1-4 heteroatoms selected from N, O and S (O) m , wherein m is an integer of 0-2.
  • bridged heterocyclic group refers to a polyheterocyclic group of 5 to 20 members, in which any two rings share two atoms that are not directly connected, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer of 0-2), and the remaining ring atoms are carbon, wherein one or more double bonds are contained, but none of the rings has a completely conjugated ⁇ electron system.
  • it is 6 to 14 members, more preferably 7 to 10 members.
  • the number of constituent rings it is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, more preferably a bicyclic or tricyclic bridged heterocyclic group.
  • the "hetero" in the bridged heterocyclic group represents 1-4 heteroatoms selected from N, O and S(O) m , wherein m is an integer of 0-2.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or condensed polycyclic group having a conjugated ⁇ electron system, preferably a C 6-12 aryl group, more preferably a C 6-10 aryl group, further preferably a phenyl group or a naphthyl group, and particularly preferably a phenyl group.
  • heteroaryl refers to a monocyclic or fused polycyclic heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen and the like.
  • the heteroaryl group is preferably a 5-14-membered heteroaryl group, more preferably a 5-6-membered heteroaryl group, a 5-6-membered heteroaryl and a 5-6-membered heteroaryl group, a 5-6-membered heteroaryl and a C 6-10 aryl group, or a C 6-10 aryl and a 5-6-membered heteroaryl group, further preferably a 5-6-membered heteroaryl group, a 5-6-membered heteroaryl and a 5-6-membered heteroaryl group, a 5-6-membered heteroaryl and a phenyl group, or a phenyl and a 5-6-membered heteroaryl group, for example, a pyrrolyl group, an imidazolyl group, a furanyl group, a pyranyl group, a thienyl group, a thiazolyl group, a thiadiazolyl group, a
  • the heteroaryl group may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • the "hetero" in the heteroaryl group represents 1 to 4 heteroatoms selected from N, O and S, preferably 1 to 3 heteroatoms selected from N, O and S.
  • alkoxy refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • alkylthio refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), where alkyl and cycloalkyl are as defined above.
  • alkylthio groups include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
  • alkylamino refers to -NH-(alkyl or non-substituted cycloalkyl), or -N-(alkyl or non-substituted cycloalkyl)(alkyl or non-substituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • alkylamino include methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.
  • halo or "halogen” or “halo” is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • alkenyl refers to a chain alkenyl group, also known as an alkene group, wherein the alkene may be further substituted with other related groups.
  • alkynyl refers to (CH ⁇ C-), wherein the alkynyl may be further substituted with other related groups.
  • Hydroxyl refers to -OH.
  • Hydrophill refers to -OH.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Carboxy refers to -C(O)OH.
  • DMSO dimethyl sulfoxide.
  • LAH lithium aluminum hydride.
  • THF tetrahydrofuran.
  • Boc tert-butyloxycarbonyl.
  • DCM dichloromethane.
  • DCE dichloroethane.
  • THF trifluoroacetic acid.
  • EA ethyl acetate.
  • DMF N,N-dimethylformamide.
  • TBAI refers to tetrabutylammonium iodide.
  • DPPA diphenylphosphoryl azide.
  • DIBAL-H refers to diisobutylaluminum hydride.
  • tol refers to toluene.
  • ACN refers to acetonitrile.
  • DMF refers to N,N-dimethylformamide.
  • NCS N-chlorosuccinimide.
  • TMSCN trimethylsilyl cyanide.
  • TBAF tetrabutylammonium fluoride.
  • microwave refers to microwave.
  • TsCl refers to p-toluenesulfonic chloride.
  • DMAP refers to 4-dimethylaminopyridine.
  • DIEA refers to N,N-diisopropylethylamine.
  • DIPEA refers to N,N-diisopropylethylamine.
  • mn used herein refers to the range of m to n and the sub-ranges consisting of the individual point values therein and the individual point values.
  • C2 - C8 " or " C2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any sub-ranges and each point value therein, such as C2 - C5 , C3 - C4 , C2 - C6 , C3 - C6 , C4 - C6 , C4 - C7 , C4 - C8 , etc., as well as C2 , C3 , C4 , C5 , C6 , C7 , C8 , etc.
  • C3 - C10 or " C3-10 " should also be understood in a similar manner, e.g., may encompass any sub-ranges and point values contained therein, such as C3 - C9 , C6 - C9 , C6 - C8 , C6 - C7 , C7 - C10 , C7 - C9 , C7 - C8 , C8- C9 , etc., as well as C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , etc.
  • C 1 -C 6 or "C 1-6” encompasses a range of 1-6 carbon atoms and should be understood to also encompass any subranges and individual point values therein, such as C 2 -C 5 , C 3 -C 4 , C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , C 1 -C 6 , etc., as well as C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , etc.
  • the expression "three yuan to ten yuan” should be understood to include any sub-ranges therein and each point value, such as three yuan to five yuan, three yuan to six yuan, three yuan to seven yuan, three yuan to eight yuan, four yuan to five yuan, four yuan to six yuan, four yuan to seven yuan, four yuan to eight yuan, five yuan to seven yuan, five yuan to eight yuan, six yuan to seven yuan, six yuan to eight yuan, nine yuan to ten yuan, etc., as well as three, four, five, six, seven, eight, nine, ten yuan, etc.
  • Other similar expressions in this document should also be understood in a similar manner.
  • cycloalkyl optionally substituted with alkyl means that alkyl can but does not have to be present, and the description includes the situation that cycloalkyl is substituted with alkyl and the situation that cycloalkyl is not substituted with alkyl.
  • substituted and “substituted” refer to one or more (e.g., one, two, three, or four) hydrogens on the designated atom being replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only when such combinations form stable compounds.
  • substituent can be one or more hydrogen atoms, provided that the structure enables the compound to reach a stable state.
  • each carbon atom in a group can be optionally replaced by a heteroatom, the condition is that the normal valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed.
  • variable e.g., R
  • variables with labels e.g., R1 , R2 , R3 , R4 , R5 , R6 , R7 , etc.
  • substituted means that one or more hydrogen atoms on a compound or group are replaced by other atoms or groups. The condition is that a stable valence state or compound is formed.
  • non-substituted can also be understood as “not substituted”. It should be understood that when the substituent is hydrogen, this can also mean that the corresponding group is “non-substituted” or “not substituted”.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that show better biological activity.
  • Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures are also included within the scope of the present invention.
  • the purification and separation of such substances can be achieved by standard techniques known in the art.
  • the hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.
  • pharmaceutically acceptable refers to a substance that is, within the scope of normal medical judgment, suitable for contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.
  • pharmaceutically acceptable salt refers to salts of the compounds of the present invention which are safe and effective when used in mammals and have the desired biological activity.
  • composition refers to a composition containing one or more compounds of the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically/pharmaceutically acceptable carriers or excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • pharmaceutically acceptable carrier refers to those substances that have no significant irritation to organisms and do not impair the biological activity and performance of the active compound.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.
  • administration refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.
  • the term "treat” includes alleviating, reducing or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing metabolic factors underlying a symptom, inhibiting a disease or symptom, e.g., stopping the disease or symptom from developing, alleviating the disease or symptom, promoting remission of the disease or symptom, or causing cessation of symptoms of the disease or symptom, and extends to include prevention.
  • Treatment also includes achieving a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the condition being treated.
  • a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and although the patient may still suffer from the underlying disease, an improvement in the patient's disease is observed.
  • a prophylactic benefit refers to the fact that a patient receives treatment to prevent the risk of a certain disease. The composition is used while the patient is experiencing one or more physiological symptoms of a disease, even though the disease has not yet been diagnosed.
  • active ingredient refers to a chemical entity that is effective in treating or preventing a target disorder, disease or condition.
  • neuropsychiatric disease refers to a general term for neurological diseases and psychiatric diseases, including neurological diseases and/or psychiatric diseases.
  • the term "effective amount”, “therapeutically effective amount” or “prophylactically effective amount” refers to a sufficient amount of the drug or pharmaceutical agent that can achieve the desired effect with acceptable side effects.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the individual and on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.
  • “individual” includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • XRPD may produce certain displacement and intensity deviations due to the detection method, conditions and instruments.
  • the same sample of the same crystal form usually has the same main XRPD characteristic peak, but there may be certain operating errors.
  • the characteristic peak error is usually within ⁇ 0.2°, but different technicians using different instruments may occasionally have a few characteristic peaks with errors exceeding this range. For example, the error within ⁇ 0.5° or ⁇ 0.3° should be considered to belong to the XRPD characteristic peak of the same crystal form.
  • the present invention relates to a class of novel structural compounds, which, as a TAAR1 receptor agonist, have anti-neuropsychiatric activity, that is, have the effect of treating or preventing neuropsychiatric diseases.
  • the compounds of the present invention have a good agonist effect on the TAAR1 receptor.
  • the compounds of the present invention have good pharmacokinetic properties (such as suitable half-life and duration of action, good blood concentration, area under the drug-time curve and/or bioavailability).
  • the compounds of the present invention have improved in vivo pharmacodynamic effects, and/or improved safety (lower toxicity and/or fewer side effects), and/or good patient compliance, and/or Or better drug-making properties such as being less likely to develop tolerance.
  • the results of the agonist activity of the present disclosure on the TAAR1 receptor show that the compounds of the present invention are effective TAAR1 receptor agonists and have good agonist effects on the TAAR1 receptor.
  • the results of the mouse pharmacokinetic experiment show that the compounds of the present invention exhibit good drug metabolism properties, have excellent half-life t 1/2 and fast peak time T max , and the maximum blood drug concentration C max , the area under the drug-time curve AUC (0-t) and the oral bioavailability F and other metabolic parameters are all good.
  • Compounds with good oral bioavailability are of great significance in reducing the dosage of medication, reducing side effects and improving the efficacy of drugs.
  • Figure 1 is an XRPD diagram of Example 1 4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride.
  • FIG. 2 is an XRPD diagram of Example 1A (S)-4,7,8,9,10,10a-hexahydro-5H-thiophene[2′,3′:3,4]pyrido[1,2-a]pyrazine hydrochloride.
  • Example 3 is an XRPD diagram of Example 1B (R)-4,7,8,9,10,10a-hexahydro-5H-thiophene[2′,3′:3,4]pyrido[1,2-a]pyrazine hydrochloride.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shifts are given in parts per million (ppm). NMR measurements were performed using an AVANCE III 600 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ) as the solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS tetramethylsilane
  • LC-MS Liquid chromatography-mass spectrometry
  • HPLC determination was performed using Shimadzu LC20A liquid chromatograph.
  • the thin layer chromatography silica gel plate used was Yantai Jiangyou silica gel plate, the specification used for TLC was 0.2mm ⁇ 0.03mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm.
  • X-ray powder diffraction was measured using a German Bruker D2 phaser X-ray powder diffractometer, radiation source: copper target, voltage/current: 30 kV/10 mA, scanning range: 4°-40° (2 ⁇ value), scanning rate: 1 s/step.
  • the melting point was determined using a Swiss Mettler Toledo MP70 melting point apparatus with a heating rate of 3°C/min.
  • Step b Synthesis of 2-(1,3-dioxoisoindole-2-yl)-N-(2-(thiophen-3-yl)ethyl)acetamide
  • Step c 2-((4,5-dihydrothieno[2,3-c]pyridin-7-yl)methyl)isoindole-1,3-dione
  • the obtained organic phase was washed with water (50 mL x 2) and saturated brine (50 mL x 1), and the separated organic phase was dried over anhydrous sodium sulfate. Then the target compound (1.1 g, yield 82%) was obtained by filtration and concentration.
  • Step d 2-((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindole-1,3-dione
  • Step f tert-Butyl ((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate
  • Step g tert-Butyl (6-(2-chloroacetyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate
  • reaction solution was then washed with water (3 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target product (150 mg, yield 39%).
  • Step h 1-(7-(Aminomethyl)-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl)-2-chloroethanone
  • Step j 4,7,8,9,10,10a-Hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine
  • Step a Synthesis of tert-butyl (2-(thiophen-3-yl)-ethyl)carbamate
  • Step b Synthesis of 2-((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindole-1,3-dione
  • Step c Synthesis of ethyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)acetate
  • Step d Synthesis of 4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
  • Step e Synthesis of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
  • the mixture was filtered and di-tert-butyl dicarbonate (15.2 g, 69.7 mmol) was added to the filtrate and stirred for 0.5 hours.
  • the reaction mixture was concentrated and purified by column chromatography to obtain the target compound (17.0 g, yield 83%).
  • Step f Synthesis of 4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • Step a Synthesis of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
  • the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated.
  • the crude product was purified by The target product (135 mg, yield 85%) was obtained by separation and purification by column chromatography (dichloromethane/methanol).
  • Step b Chiral separation of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
  • Liquid phase analysis method chromatographic column: DAICEL CHIRALPAK IF column; mobile phase: acetonitrile; detection wavelength: 214nm; flow rate: 1.0mL/min; column temperature: 35°C.
  • the retention times of enantiomer 1 and enantiomer 2 are 4.49min and 5.26min, respectively.
  • Step c Preparation of enantiomers of 4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • Step a Synthesis of methyl 2-(7-(((tert-butoxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)yl)propanoate
  • reaction solution was poured into water (50 mL), extracted with dichloromethane three times (10 mL x 3), and the organic phase was washed with water three times (10 mL x 3), washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target compound (0.45 g, yield 35%).
  • Step b Synthesis of 7-methyl-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
  • the crude product was separated and purified by column chromatography (dichloromethane/methanol) to obtain a pair of diastereoisomers, namely isomer 1 (0.12 g, yield 43%) and isomer 2 (0.12 g, yield 43%).
  • Step a Synthesis of tert-butyl ((6-(2-chloropropionyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate
  • Step b Synthesis of 1-(7-(aminomethyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-2-chloropropane-1-one
  • tert-butyl ((6-(2-chloropropionyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate (0.70 g, 1.95 mmol) in a solution of hydrogen chloride in ethyl acetate (3M, 15 mL) and stir at room temperature for 1 h. Neutralize the reaction solution with saturated aqueous sodium bicarbonate solution until neutral. Extract three times with dichloromethane (15 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain the target product (0.4 g, yield 78%).
  • Step c Synthesis of 8-methyl-4,5,8,9,10,10a-hexahydro-7H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-7-one
  • the obtained organic phase was washed with water (50mL x3) and saturated brine (50mL x1), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by column chromatography (dichloromethane/methanol) to obtain the target compound.
  • the synthetic route of compound 4 refers to the synthetic route of Example 1.
  • the synthetic route of compound 5 refers to the synthetic route of Example 1.
  • Step b Synthesis of 2-(1,3-dioxoisoindolin-2-yl)-N-(2-(thiophene-3-ethyl)ethyl)propionamide
  • Step c Synthesis of 2-(1-(4,5-dihydrothieno[2,3-c]pyridin-7-yl)ethyl)isoindoline-1,3-dione
  • Step d Synthesis of tert-butyl 7-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
  • Step e Synthesis of tert-butyl 7-(1-aminoethyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
  • Step f Synthesis of tert-butyl 7-(1-(2-chloroacetylamino)ethyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
  • tert-butyl 7-(1-aminoethyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (1.2g, 4.3mmol) and triethylamine (860mg, 8.5mmol) were dissolved in dichloromethane (20mL), cooled to 0°C, 2-chloroacetyl chloride (572mg, 5.1mmol) was added dropwise, and stirred for 1h. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic phase was dried, filtered, and concentrated. The obtained crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target product (1.35g, yield 89%).
  • Step g Synthesis of 2-chloro-N-(1-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)ethyl)acetamide hydrochloride
  • Step h Synthesis of 10-methyl-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
  • Step i Synthesis of tert-butyl 10-methyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
  • lithium aluminum tetrahydride (351 mg, 9.2 mmol) was added to tetrahydrofuran (20 mL), cooled to 0°C, and a solution of 10-methyl-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one isomer 1 (410 mg, 1.8 mmol) in tetrahydrofuran (10 mL) was slowly added and refluxed for 4 hours.
  • Step j Synthesis of 10-methyl-4,7,8,9,10,10,10a-hexahydrothieno[2,3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • Isomer 2 (320 mg) of 10-methyl-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-8(7H)-one was used by a similar synthesis method to obtain isomer 2 (250 mg, 71%) of the target product.
  • Step a Synthesis of tert-butyl 7-methyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
  • Dissolve isomer 1 (0.12 g, 0.54 mmol) of 7-methyl-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one in tetrahydrofuran (15 mL), add lithium aluminum tetrahydride (0.08 g, 2.16 mmol), and reflux in an oil bath at 80°C under nitrogen protection for 2 h. After the reaction solution was cooled to room temperature, sodium sulfate decahydrate (0.21 g, 0.65 mmol) was slowly added and stirred for 10 min.
  • reaction solution was filtered, and water (5 mL), sodium bicarbonate (0.09 g, 1.08 mmol) and di-tert-butyl dicarbonate (0.17 g, 0.81 mmol) were added to the filtrate in sequence, and stirred at room temperature for 1 h after the addition.
  • the reaction solution was poured into water (30 mL), extracted three times with dichloromethane (50 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target crude product isomer 1 (100 mg, yield 60%).
  • Step b Synthesis of 7-methyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • Step a Synthesis of tert-butyl 8-methyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
  • reaction solution was poured into water (30 mL), extracted three times with dichloromethane (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target compound (200 mg, yield 72%).
  • Step b Synthesis of 8-methyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • the synthetic route of Example 9 refers to the synthetic route of step a to step i in Example 1.
  • Step a Preparation of methyl 3-(7-(((tert-butoxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)propanoate synthesis
  • Step b Synthesis of methyl 3-(7-(aminomethyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)propanoate hydrochloride
  • Step c Synthesis of 4,7,8,10,11,11a-hexahydrothiophene[2',3':3,4]pyrido[1,2-a][1,4]diazepine-9(5H)-one
  • Step d Synthesis of tert-butyl 4,5,8,9,11,11a-hexahydrothiophene[2',3':3,4]pyrido[1,2-a][1,4]diazepine-10(7H)-carboxylate
  • reaction was quenched with sodium sulfate, the reaction solution was filtered, the filtrate was concentrated and redissolved in tetrahydrofuran (4 mL), di-tert-butyl dicarbonate (56 mg, 0.26 mmol) was added, and the mixture was reacted at room temperature for about 2 hours. After the reaction was completed, the reaction solution was dried, and the crude product was separated and purified by column chromatography (dichloromethane/methanol) to obtain the target product (53 mg, yield 100%).
  • Step e Synthesis of 4,5,7,8,9,10,11,11a-octahydrothieno[2',3':3,4]pyrido[1,2-a][1,4]diazepine hydrochloride
  • the synthetic route of compound 11 refers to the synthetic route of Example 1.
  • the synthetic route of compound 12 refers to the synthetic route of Example 1.
  • reaction solution was poured into a sodium bicarbonate aqueous solution (30 mL), the organic phase was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain a crude product (80 mg). Subsequently, ethyl acetate (2 mL) was added, and a hydrochloric acid ethyl acetate solution (4.0 M, 10 mL) was slowly added dropwise at 0°C until a white solid precipitated, which was filtered and dried to obtain the target compound (50 mg, yield 48%).
  • the synthetic route of compound 14 refers to the synthetic route of Example 1.
  • Step a Synthesis of methyl (E)-3-(3-(benzyloxy)-3-oxopropyl-1-en-1-yl)picolinate
  • Step b Synthesis of 3-(2-(methoxycarbonyl)pyridin-3-yl)propionic acid
  • Step c Synthesis of methyl 3-(2-((tert-butyloxycarbonylamino)ethyl)picolinate
  • Step d Synthesis of tert-butyl (2-(2-formylpyridin-3-yl)ethyl)carbamate
  • Step f Synthesis of tert-butyl 8-nitromethyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate
  • Step g Synthesis of tert-butyl 8-aminomethyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate
  • Step h Synthesis of tert-butyl 8-(2-chloroacetylaminomethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate
  • Step i Synthesis of 2-chloro-N-(5,6,7,8-tetrahydro-1,7-naphthyridine-8-methyl)acetamide hydrochloride
  • Step j Synthesis of 5,10,11,11a-tetrahydro-6H-pyrazino[1,2-h][1,7]naphthyridine-9(8H)one
  • Step k Synthesis of 5,8,9,10,11,11a-hexahydropyrazino[1,2-h][1,7]naphthyridine hydrochloride
  • the liquid is added to a solution of hydrogen chloride in ethyl acetate (5 mL) and stirred for 1 hour.
  • the reaction solution is concentrated to obtain the target product (60 mg, yield 68%).
  • Step b Synthesis of ethyl 2-(3-cyanopyridin-4-yl)acetate
  • 1,4-Dihydro-2,7-naphthyridin-3(H)one (3.2 g, 21.6 mmol) was dissolved in tetrahydrofuran (40 mL) and slowly added under nitrogen.
  • Add a solution of borane in dimethyl sulfide (10M, 10.8 mL, 108.1 mmol) and stir at 60°C for 12 hours. After cooling to 0°C, slowly add the reaction solution into methanol to quench, then continue stirring at 60°C for 1 hour, cool to room temperature, and concentrate to obtain the target product (350 mg, yield 12%) as a yellow liquid.
  • Step f Synthesis of tert-butyl 1-nitromethyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate
  • Step g Synthesis of tert-butyl 1-aminomethyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate
  • Step h Synthesis of tert-butyl 1-(2-chloroacetylaminomethyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate
  • Step i Synthesis of 1,6,7,11b-tetrahydro-2H-pyrazino[2,1-a][2,7]naphthyridine-3(4H)one
  • Step j Synthesis of 1,3,4,6,7,11b-hexahydropyrazino[2,1-a][2,7]naphthyridine hydrochloride
  • the reaction solution is concentrated to obtain the target product (14 mg, yield 63%).
  • the synthetic route of compound 17 refers to the synthetic route of Example 15.
  • the synthetic route of compound 18 refers to the synthetic route of Example 15.
  • the synthetic route of compound 19 refers to the synthetic route of Example 1.
  • the synthetic route of compound 20 refers to the synthetic route of Example 1.
  • the synthetic route of compound 21 refers to the synthetic route of Example 1.
  • the synthetic route of compound 22 refers to the synthetic route of Example 1.
  • the synthetic route of compound 23 refers to the synthetic route of Example 1.
  • the synthetic route of compound 24 refers to the synthetic route of Example 1.
  • the synthetic route of compound 25 refers to the synthetic route of Example 1.
  • the synthetic route of compound 26 refers to the synthetic route of Example 1.
  • the synthetic route of compound 27 refers to the synthetic route of Example 1.
  • the synthetic route of compound 28 refers to the synthetic route of Example 1.
  • the synthetic route of compound 29 refers to the synthetic route of Example 1.
  • the synthetic route of compound 30 refers to the synthetic route of Example 1.
  • the synthetic route of compound 31 refers to the synthetic route of Example 1.
  • the synthetic route of compound 32 refers to the synthetic route of Example 1.
  • the synthetic route of compound 33 refers to the synthetic route of Example 1.
  • the synthetic route of compound 34 refers to the synthetic route of Example 1.
  • the synthetic route of compound 35 refers to the synthetic route of Example 1.
  • the synthetic route of compound 36 refers to the synthetic route of Example 1.
  • the synthetic route of compound 37 refers to the synthetic route of Example 1.
  • the synthetic route of compound 38 refers to the synthetic route of Example 1.
  • Step a Synthesis of tert-butyl 2-chloro-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
  • n-butyl lithium (0.60 mL, 2.5 mol/L, 1.5 mmol) was slowly added dropwise to a solution of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate (295 mg, 1.0 mmol) in tetrahydrofuran (10 mL), and the mixture was reacted at this temperature for 1 hour.
  • the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and spin-dried for the next reaction.
  • Step b Synthesis of 2-chloro-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • Step a Synthesis of tert-butyl 2-methyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
  • n-butyl lithium (0.60 mL, 2.5 mol/L, 1.5 mmol) was slowly added dropwise to a solution of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate (295 mg, 1.0 mmol) in tetrahydrofuran (10 mL), and the mixture was reacted at this temperature for 1 hour.
  • Step b Synthesis of 2-methyl-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • the synthetic route of compound 41 refers to the synthetic route of Example 40.
  • Step e Synthesis of 2-((-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione
  • Step f Synthesis of ethyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-3-methyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)yl)acetate
  • the reaction solution was stirred at 70 ° C for 3 hours, poured into water (30 mL), extracted with ethyl acetate (10 mL x 3), and the organic phase was washed with water (10 mL x 3), dried with sodium sulfate, and then purified by column chromatography to obtain the target product (0.38 g, yield 85%).
  • Step g Synthesis of 3-methyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
  • Step h Synthesis of tert-butyl 3-methyl-4,5,7,8,10,10-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
  • Step i Synthesis of 3-methyl-4,7,8,9,10,10-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • the synthetic route of compound 43 refers to the synthetic route of Example 42.
  • Step b Synthesis of 2-((3-chloro-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione
  • Step c Synthesis of ethyl 2-(3-chloro-7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)acetate
  • Step d Synthesis of 3-chloro-4,9,10,10-tetrahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
  • Step e Synthesis of tert-butyl 3-chloro-4,5,7,8,10,10-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
  • Step f Synthesis of 3-chloro-4,7,8,9,10,10-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • the synthetic route of compound 46 refers to the synthetic route of Example 7.
  • Step a Synthesis of tert-butyl ((6-(1,1,1-trifluoro-3-hydroxypropyl-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate
  • Step b Synthesis of 2-(7-(((tert-butyloxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-3,3,3-trifluoropropyl 4-methylbenzenesulfonate
  • Step c Synthesis of 2-(7-(aminomethyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-3,3,3-trifluoropropyl 4-methylbenzenesulfonate
  • Step d Synthesis of 7-(trifluoromethyl)-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine
  • reaction was quenched with saturated ammonium chloride, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained product was directly used in the next reaction without purification.
  • Step e Synthesis of tert-butyl 7-(trifluoromethyl)-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
  • Step f Synthesis of 7-(trifluoromethyl)-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • the synthetic route of compound 48 refers to the synthetic route of Example 7.
  • Step a Synthesis of methyl 2-methyl-2-(2-(thiophene-3-ethyl)ethylamino)propanoate
  • Step b Synthesis of methyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)yl)-2-methylpropanoate
  • Step c Synthesis of 7,7-dimethyl-4,9,10,10a-tetrahydrothieno[2,3":3,4]pyrido[1,2-a]pyrazine-8(7H)-one
  • Step d Synthesis of 7,7-dimethyl-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • the liquid was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1 mL) was added and stirred for 2 hours.
  • the reaction solution was concentrated to obtain the target product (110 mg, yield 72%).
  • the synthetic route of compound 50 refers to the synthetic route of Example 49.
  • the synthetic route of compound 51 refers to the synthetic route of Example 49.
  • Step a Synthesis of methyl 2-(7-(((tert-butyloxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-2-cyclopropylacetate
  • Step b Synthesis of 7-cyclopropyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
  • Step c Synthesis of tert-butyl 7-cyclopropyl-4,5,7,8,10,10-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
  • Step d Synthesis of 7-cyclopropyl-4,7,8,9,10,10-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • the synthetic route of compound 53 refers to the synthetic route of Example 52.
  • the synthetic route of compound 54 refers to the synthetic route of Example 52.
  • the synthetic route of compound 55 refers to the synthetic route of Example 52.
  • Step a Synthesis of tert-butyl 7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
  • Step b Synthesis of tert-butyl 7-(aminomethyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
  • Step c 7-(((tert-butyloxycarbonyl)(3-ethoxy-2-hydroxy-3-oxopropyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyrrolidone Synthesis of tert-butyl pyridine-6(5H)-carboxylate
  • Step d Synthesis of tert-butyl 7-(((tert-butyloxycarbonyl)(3-ethoxy-2-((ethylsulfonyl)oxy)-3-oxopropyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
  • Step e Synthesis of 9-tert-butyl-7-ethyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-7,9-dicarboxylate
  • the crude product was dissolved in acetonitrile (10 mL), followed by the addition of N,N-diisopropylethylamine (694 mg, 5.34 mmol) and stirred at 80°C for 1 hour. The reaction mixture was then cooled to room temperature, and di-tert-butyl dicarbonate (370 mg, 1.71 mmol) was added and reacted at room temperature for 30 minutes. The reaction solution was concentrated and column chromatography was performed to obtain the target compound (365 mg, yield 70%).
  • Step f 7-(Methylcarbamoyl)-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylic acid Synthesis of tert-butyl ester
  • the crude product was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (241 mg, 1.85 mmol), O-(7-nitrobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (282 mg, 0.74 mmol) and methylamine hydrochloride (126 mg, 1.85 mmol) were added in sequence, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, saturated brine (20 mL) was added to the reaction system, extracted with ethyl acetate, and the organic phase was concentrated. The crude product was then purified by thin layer chromatography to obtain the target compound (100 mg, yield 70%).
  • Step g Synthesis of N-methyl-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride
  • the synthetic route of compound 57 refers to the synthetic route of Example 52.
  • the synthetic route of compound 58 refers to the synthetic route of Example 52.
  • the synthetic route of compound 59 refers to the synthetic route of Example 52.
  • the synthetic route of compound 60 refers to the synthetic route of Example 52.
  • Step a Synthesis of 2-((5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione
  • Step b Synthesis of ethyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-5-methyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)yl)acetate
  • Step c Synthesis of 5-methyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
  • Step d Synthesis of 5-methyl-4,7,8,9,10,10-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • the filtrate was concentrated and hydrochloric acid ethyl acetate solution (4M, 2 mL) was added.
  • the reaction solution was extracted with water (5 mL x 3) and the aqueous phase was freeze-dried to obtain the target product (75 mg, yield 80%).
  • Step c Synthesis of 2-((4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione
  • Step d Synthesis of ethyl 2-(7-((1,3-dioxoisoindolin-2-yl(methyl)-4-methyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)yl)acetate
  • Step e Synthesis of 4-methyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-8(7H)-one
  • Step f Synthesis of 4-methyl-4,7,8,9,10,10-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • the filtrate was concentrated and added with hydrochloric acid ethyl acetate solution (4M, 2 mL), extracted with water (5 mL x 3), and the aqueous phase was freeze-dried to obtain the target product (47 mg, yield 51%).
  • the synthetic route of compound 63 refers to the synthetic route of Example 61.
  • Step c Synthesis of 2-(6,7-dihydro-5-H-spirocyclopropane-1,4-thieno[2,3-c]pyridin]-7-yl)methyl)isoindoline-1,3-dione
  • Step d Synthesis of ethyl 2-(7'-((1,3-dioxoisoindolin-2-yl)methyl)-5'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyridine]-6'(7'H)-yl)acetate
  • Step e Synthesis of 10,10a-dihydro-5,7-spirocyclopropane-1,4-thieno[2,3]:3,4]pyridopyrazino[1,2-a]pyrazin]-8(9'H)one
  • Step f Synthesis of 8,9,10,10a-tetrahydro-5H,7H-spiro[cyclopropane-1,4-thieno[2,3]:3,4]pyridopyrazine]
  • the synthetic route of compound 65 refers to the synthetic route of Example 61.
  • the synthetic route of compound 66 refers to the synthetic route of Example 61.
  • Step b Synthesis of 2-((7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione
  • Step c Synthesis of ethyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-7-methyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)acetate
  • Step d Synthesis of 10a-methyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
  • Step e Synthesis of 10a-methyl-4,7,8,9,10,10-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
  • the synthetic route of compound 68 refers to the synthetic route of Example 67.
  • the synthetic route of compound 69 refers to the synthetic route of Example 67.
  • the synthetic route of compound 70 refers to the synthetic route of Example 67.
  • the synthetic route of compound 71 refers to the synthetic route of Example 67.
  • the synthetic route of compound 72 refers to the synthetic route of Example 67.
  • the synthetic route of compound 73 refers to the synthetic route of Example 61.
  • the synthetic route of compound 74 refers to the synthetic route of Example 61.
  • the synthetic route of compound 75 refers to the synthetic route of Example 1.
  • the synthetic route of compound 76 refers to the synthetic route of Example 1.
  • the synthetic route of compound 77 refers to the synthetic route of Example 1.
  • the synthetic route of compound 78 refers to the synthetic route of Example 1.
  • the synthetic route of compound 79 refers to the synthetic route of Example 1.
  • the synthetic route of compound 80 refers to the synthetic route of Example 1.
  • Step a Synthesis of methyl 2-(7-(((tert-butyloxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)propanoate-2,3,3,3-d4
  • Step b Synthesis of methyl 2-(7-(aminomethyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)propanoate-2,3,3,3-d4
  • Step c Synthesis of 7-(methyl-d3)-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyridin[1,2-a]pyrazine-8(7H)-one-7-d
  • Step d Synthesis of 7-(methyl-d3)-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-7-d
  • Step e Synthesis of tert-butyl 7-(methyl-d3)-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate-7-d
  • Step f Synthesis of 7-(methyl-d3)-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-7-d hydrochloride
  • the synthetic route of compound 82 refers to steps ad of the synthetic route of Example 1a .
  • Step b Synthesis of tert-butyl (2-(thiophen-3-yl)ethyl-1,1,2,2-d4)carbamate
  • lithium aluminum hydride (336 mg, 8 mmol) was slowly added to a solution of aluminum chloride (1.6 g, 12 mmol) in tetrahydrofuran (30 mL), followed by a solution of 2-(thiophene-3-yl)acetonitrile-d2 (500 mg, 4 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise.
  • the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with sodium sulfate decahydrate, and the reaction solution was filtered and concentrated to obtain a crude product.
  • Step c Synthesis of 2-((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl-4,4,5,5-d4)methyl)isoindoline-1,3-dione
  • Step d Synthesis of 2-((6-(2-bromoethyl-1,1,2,2-d4)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl-4,4,5,5-d4)methyl)isoindoline-1,3-dione
  • Step e Synthesis of 2-((6-(2-chloroethyl-1,1,2,2-d4)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl-4,4,5,5-d4)methyl)isoindoline-1,3-dione
  • reaction was quenched with water, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was directly used in the next reaction without purification.
  • Step f Synthesis of 4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-4,4,5,5,7,7,8,8-d8
  • Step g Synthesis of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate-4,4,5,5,7,7,8,8-d8
  • Step h Synthesis of 4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-4,4,5,5,7,7,8,8-d 8 hydrochloride
  • Embodiment 84 is a diagrammatic representation of Embodiment 84.

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a fused ring derivative, a preparation method therefor, intermediates thereof, and use thereof. Particularly, the present invention relates to a compound represented by general formula (I), a preparation method therefor, intermediates thereof, a pharmaceutical composition comprising the fused ring derivative, and use of the fused ring derivative or the pharmaceutical composition thereof in the preparation of drugs for preventing and/or treating central nervous system diseases associated with trace amine-associated receptors and/or 5-hydroxytryptamine receptors and/or dopamine receptors in mammals.

Description

并环类衍生物、其制备方法、中间体和应用Cyclic derivatives, preparation methods, intermediates and applications thereof
本申请要求申请日为2022/12/9的中国专利申请2022115782608的优先权，要求申请日为2023/3/14的中国专利申请2023102409801的优先权，要求申请日为2023/11/28的中国专利申请202311605281.9的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application No. 2022115782608 with a filing date of 2022/12/9, the priority of Chinese patent application No. 2023102409801 with a filing date of 2023/3/14, and the priority of Chinese patent application No. 202311605281.9 with a filing date of 2023/11/28. This application cites the full text of the above Chinese patent application.
技术领域Technical Field
本发明属于药物化学领域，特别涉及一种并环类衍生物、其制备方法、中间体和应用。更具体地，本发明涉及并环类衍生物、其制备方法、中间体、包含该并环类衍生物的药物组合物，以及该并环类衍生物或其药物组合物在制备预防和/或治疗与哺乳动物痕量胺相关受体和/或5-羟色胺受体和/或多巴胺受体相关的中枢神经系统疾病药物中的应用。The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a paracyclic derivative, a preparation method, an intermediate and an application thereof. More specifically, the present invention relates to a paracyclic derivative, a preparation method, an intermediate, a pharmaceutical composition comprising the paracyclic derivative, and an application of the paracyclic derivative or a pharmaceutical composition thereof in the preparation of a drug for preventing and/or treating central nervous system diseases associated with mammalian trace amine-related receptors and/or 5-hydroxytryptamine receptors and/or dopamine receptors.
背景技术Background technique
中枢神经系统的相关疾病不同程度地影响着广大人群。一般而言，这类疾病的主要特征包括认知或记忆的明显损伤，且表现出相对原始的功能水平的明显恶化。精神分裂症是一种来源不明的精神病理障碍，通常首次出现在成年阶段初期，具有精神病症状、阶段前进和发展和/或社会行为和专业能力上的退化等特征。精神分裂症的症状通常体现为三大类：阳性症状、阴性症状和认知症状。阳性症状是表现了“过量”正常体验的症状，如幻觉和妄想。阴性症状是患者缺失了正常体验的症状，如快感缺乏和社会相互作用的缺乏。认知症状与精神分裂症的认知损伤有关，如缺乏持续的注意力和决策力不足。目前的抗精神病药物可成功治疗阳性症状，但对于阴性和认知症状则远远不够理想。Diseases of the central nervous system affect a wide range of people to varying degrees. In general, the main features of these diseases include significant impairment of cognition or memory, and a marked deterioration from the original level of functioning. Schizophrenia is a psychopathological disorder of unknown origin that usually first appears in early adulthood and is characterized by psychotic symptoms, stage progression and development, and/or deterioration in social behavior and professional abilities. The symptoms of schizophrenia are generally manifested in three major categories: positive symptoms, negative symptoms, and cognitive symptoms. Positive symptoms are symptoms that represent an "excess" of normal experience, such as hallucinations and delusions. Negative symptoms are symptoms that the patient lacks normal experience, such as anhedonia and lack of social interaction. Cognitive symptoms are related to cognitive impairment in schizophrenia, such as lack of sustained attention and poor decision-making. Current antipsychotic drugs can successfully treat positive symptoms, but are far from ideal for negative and cognitive symptoms.
生物胺可作为神经递质在中枢和外周神经系统中发挥重要作用。生物胺的合成和储存以及其在释放后的降解和重吸收被紧密控制。已知生物胺水平失衡是许多病理学情况中脑功能改变的主要原因。血清素、去甲肾上腺素、肾上腺素、多巴胺、组胺作为经典的生物胺已被广泛进行研究。其中，5-羟色胺系统在调节前额叶皮层PFC的功能中起着重要作用，包括情绪控制，认知行为和工作记忆。PFC的锥体神经元和GABA中间神经元包含了几个具有特别高密度的5-羟色胺受体亚型5-HT1A和5-HT2A。最近得到证明PFC和NMDA受体通道是5-HT1AR的目标，这两个受体调节大脑皮层兴奋性神经元，从而影响认知功能。实际上，各种临床前数据表明5-HT1AR可能是抗精神病药发展药物的新目标。非典型抗精神药物(如olanzapine、aripiprazole等)对5-HT1AR的高亲和力及其低的EPS副作用均说明5-羟色胺系统在调节PFC的功能中起着重要作用，包括情绪控制、认知行为和工作记忆。PFC的锥体神经元和GABA中间神经元包含了几个具有特别高密度5-羟色胺受体亚型5-HT1A和5-HT2A。最近研究表明5-HT1A激动剂与非典型抗精神病药物治疗相关，能改善阴性症状和认知障碍。Biogenic amines play an important role as neurotransmitters in the central and peripheral nervous systems. The synthesis and storage of biogenic amines as well as their degradation and reabsorption after release are tightly controlled. Imbalance in the levels of biogenic amines is known to be the main cause of altered brain function in many pathological conditions. Serotonin, norepinephrine, epinephrine, dopamine, and histamine have been extensively studied as classic biogenic amines. Among them, the 5-hydroxytryptamine system plays an important role in regulating the functions of the prefrontal cortex PFC, including emotional control, cognitive behavior, and working memory. The pyramidal neurons and GABA interneurons of the PFC contain several 5-hydroxytryptamine receptor subtypes 5-HT 1A and 5-HT 2A with particularly high densities. Recently, it has been demonstrated that the PFC and NMDA receptor channels are targets of 5-HT 1AR , which regulate excitatory neurons in the cerebral cortex and thus affect cognitive function. In fact, various preclinical data suggest that 5-HT 1AR may be a new target for the development of antipsychotic drugs. The high affinity of atypical antipsychotics (e.g., olanzapine, aripiprazole, etc.) for 5-HT 1AR and their low EPS side effects indicate that the serotonin system plays an important role in regulating the functions of the PFC, including emotional control, cognitive behavior, and working memory. The pyramidal neurons and GABA interneurons of the PFC contain several serotonin receptor subtypes 5-HT 1A and 5-HT 2A with particularly high densities. Recent studies have shown that 5-HT 1A agonists are associated with atypical antipsychotic treatment and can improve negative symptoms and cognitive impairment.
近年来，随着经典生物胺的研究逐渐深入，人们又发现了第二类内源性胺化合物，即痕量胺TA，包括p-酪胺、β-苯乙胺、色胺和酚乙醇胺，它们在哺乳动物神经系统中的含量水平通常低于经典生物胺，但是它们在结构、代谢和亚细胞定位等方面均与经典生物胺具有类似特征。痕量胺相关受体TAAR作为G蛋白偶联受体GPCR族的新成员，与深入GPCR药效团具有相似的结构且药理学数据一致，该受体基因的系统发育关系表明这些受 体形成了三种不同的亚科，其中TAAR1是在人和啮齿动物间高保守的四个基因(TAAR1-4)中的第一个亚科。TA通过Gαs激活TAAR1并发挥作用。现有研究表明痕量胺相关受体，特别是TAAR1的失调与许多精神病学疾病如精神分裂症和抑郁以及其它一些情况如注意缺陷多动障碍、偏头痛、帕金森病、物质滥用和进食障碍存在密切联系，因此TAAR配体具有用于治疗这些疾病的高潜能。In recent years, as the study of classical biogenic amines has gradually deepened, a second type of endogenous amine compounds, namely trace amines TA, has been discovered, including p-tyramine, β-phenylethylamine, tryptamine and octopamine. Their content levels in the mammalian nervous system are usually lower than those of classical biogenic amines, but they have similar characteristics to classical biogenic amines in terms of structure, metabolism and subcellular localization. As a new member of the G protein-coupled receptor GPCR family, the trace amine-associated receptor TAAR has a similar structure and pharmacological data to the in-depth GPCR pharmacophore. The phylogenetic relationship of the receptor gene shows that these receptors The TAAR1 is the first of four genes (TAAR1-4) that are highly conserved between humans and rodents. TAARs activate TAAR1 through Gαs and exert their effects. Existing studies have shown that the dysregulation of trace amine-related receptors, especially TAAR1, is closely related to many psychiatric diseases such as schizophrenia and depression, as well as other conditions such as attention deficit hyperactivity disorder, migraine, Parkinson's disease, substance abuse and eating disorders. Therefore, TAAR ligands have a high potential for the treatment of these diseases.
尽管用于抗精神分裂症的治疗药物较多，但目前临床应用的精神分裂症药物依然存在着多种多样的不良反应。此外，虽然目前的抗精神分裂症阴性症状药物已经应用于临床，使部分患者的阴性症状得到改善，但总体而言效果有限，仍然有许多患者因阴性症状而无法痊愈和修复正常的社交功能，导致难以恢复正常的社会劳动。另外，认知障碍治疗也是目前精神分裂症治疗的一个重点，影响大多数精神分裂症患者的言语记忆、语义处理能力和注意力功能，而目前在研或上市的抗精神分裂症药物对认知功能的改善也非常有限。此外，难治性精神分裂症的治疗依然处于困境之中，该类患者已经经过了三种不同活性成分的抗精神病药物治疗，足量足疗程但治疗反应不佳或者无法耐受抗精神病药物的不良反应，或者即便得到充分的维持或预防治疗依然病情反复或恶化，因此抗难治性精神分裂症治疗药物一直是当下临床药物研究的难题，也是一直亟需攻克的方向。Although there are many drugs for treating schizophrenia, the current clinically used schizophrenia drugs still have a variety of adverse reactions. In addition, although the current anti-schizophrenia negative symptom drugs have been used in clinical practice and have improved the negative symptoms of some patients, the overall effect is limited. There are still many patients who cannot recover and restore normal social functions due to negative symptoms, which makes it difficult to resume normal social work. In addition, the treatment of cognitive impairment is also a focus of schizophrenia treatment at present, affecting the verbal memory, semantic processing ability and attention function of most schizophrenia patients, and the anti-schizophrenia drugs currently under development or on the market have very limited improvement in cognitive function. In addition, the treatment of refractory schizophrenia is still in a dilemma. Such patients have been treated with three different active ingredients of antipsychotic drugs, with sufficient doses and courses, but the treatment response is poor or they cannot tolerate the adverse reactions of antipsychotic drugs, or even if they receive adequate maintenance or preventive treatment, their condition still recurs or worsens. Therefore, anti-refractory schizophrenia treatment drugs have always been a difficult problem in current clinical drug research and a direction that needs to be overcome.
目前，处在临床III期研究中的Sunovion的SEP-363856，作为一种痕量胺相关受体激动剂，对TAAR1受体具有显著作用，在现有临床研究中表现出较好的活性。此外，PCT/CN2022/083485公开了一系列含螺环类衍生物，对TAAR1受体和5-HT1A受体具有良好的激动作用，和/或具有良好的体内药效作用，具有抗神经精神类疾病活性，也即具有治疗或预防神经精神类疾病作用。因此，迫切需要开发出具备良好且持续有效的阴性症状治疗效果，改善患者认知功能，能够有效治疗难治性精神分裂症，此外还需具备较低的药物不良反应，且作用于多靶点的抗精神分裂症药物，以满足巨大的市场需求。Currently, Sunovion's SEP-363856, which is in Phase III clinical research, is a trace amine-related receptor agonist that has a significant effect on the TAAR1 receptor and shows good activity in existing clinical studies. In addition, PCT/CN2022/083485 discloses a series of spirocyclic derivatives that have good agonist effects on TAAR1 receptors and 5-HT1A receptors, and/or have good in vivo pharmacodynamic effects, and have anti-neuropsychiatric activity, that is, they have the effect of treating or preventing neuropsychiatric diseases. Therefore, there is an urgent need to develop anti-schizophrenia drugs that have good and sustained effective negative symptom treatment effects, improve patients' cognitive functions, and can effectively treat refractory schizophrenia. In addition, they must have lower adverse drug reactions and act on multiple targets to meet the huge market demand.
发明内容Summary of the invention
本发明所要解决的技术问题是提供一类新型结构的并环类衍生物、其制备方法、中间体和应用。该类化合物作为一种TAAR1受体激动剂，具有抗神经精神类疾病活性，也即具有治疗或预防神经精神类疾病作用。The technical problem to be solved by the present invention is to provide a type of cyclopentane derivatives with a novel structure, a preparation method, an intermediate and an application thereof. As a TAAR1 receptor agonist, the compound has anti-neuropsychiatric activity, that is, it has the effect of treating or preventing neuropsychiatric diseases.
本发明的目的在于提供一种通式(I)所示的化合物、其立体异构体或其药学上可接受的盐：
The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
其中：in:
环A为芳基或杂芳基； Ring A is an aryl group or a heteroaryl group;
Ra为氢、氘、卤素、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基、烷胺基、环烷基、杂环基、芳基、杂芳基或-(CH2)n1C(O)NRARB； Ra is hydrogen, deuterium, halogen, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl or -( CH2 ) n1C (O) NRARB ;
或者，任意两个Ra与其连接的环原子链接形成环烷基或杂环基；Alternatively, any two R a are linked to the ring atoms to form a cycloalkyl or heterocyclyl group;
RA和RB各自独立地为氢、氘、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基、烷胺基、环烷基、杂环基、芳基或杂芳基； RA and RB are each independently hydrogen, deuterium, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl;
Rb和Rc各自独立地为氢、氘、卤素、羟基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基、烷胺基、环烷基、杂环基、芳基、杂芳基、-(CH2)n2C(O)NRCRD或-(CH2)n2RE；R b and R c are each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n 2 C(O)NR C R D or -(CH 2 ) n 2 R E ;
或者，任意两个Rb与其连接的环原子链接形成环烷基或杂环基；Alternatively, any two R b are linked to the ring atoms to which they are attached to form a cycloalkyl or heterocyclyl group;
或者，任意两个Rc与其连接的环原子链接形成环烷基或杂环基；Alternatively, any two R c are linked to the ring atoms to which they are attached to form a cycloalkyl or heterocyclyl group;
RC、RD和RE各自独立地为氢、氘、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基、烷胺基、环烷基、杂环基、芳基或杂芳基；R C , R D and RE are each independently hydrogen, deuterium, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl;
R1为氢、氘、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基或烷胺基； R1 is hydrogen, deuterium, hydroxyl, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino;
x为0-5的整数；x is an integer from 0 to 5;
y为0-5的整数；y is an integer from 0 to 5;
z为0-5的整数；z is an integer from 0 to 5;
m为0-3的整数；m is an integer from 0 to 3;
n为0-3的整数；n is an integer from 0 to 3;
n1为0-3的整数；且n1 is an integer from 0 to 3; and
n2为0-3的整数。n2 is an integer from 0 to 3.
在本发明进一步优选的实施例中，环A为芳基或杂芳基；In a further preferred embodiment of the present invention, ring A is an aryl group or a heteroaryl group;
Ra为氢、氘、卤素、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基、烷胺基或-(CH2)n1C(O)NRARB； Ra is hydrogen, deuterium, halogen, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino or - ( CH2 ) n1C (O) NRARB ;
或者，任意两个Ra与其连接的环原子链接形成环烷基或杂环基；Alternatively, any two R a are linked to the ring atoms to form a cycloalkyl or heterocyclyl group;
RA和RB各自独立地为氢、氘、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基或烷胺基； RA and RB are each independently hydrogen, deuterium, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino;
Rb和Rc各自独立地为氢、氘、卤素、羟基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基或烷胺基；R b and R c are each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino;
R1为氢、氘、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基或烷胺基； R1 is hydrogen, deuterium, hydroxyl, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino;
x为0-5的整数；x is an integer from 0 to 5;
y为0-5的整数；y is an integer from 0 to 5;
z为0-5的整数；z is an integer from 0 to 5;
m为0-3的整数；m is an integer from 0 to 3;
n为0-3的整数；且 n is an integer from 0 to 3; and
n1为0-3的整数。n1 is an integer from 0 to 3.
在本发明进一步优选的实施例中，环A为C6-14芳基或5-14元杂芳基，优选C6-10芳基、5-6元杂芳基、5-6元杂芳基并5-6元杂芳基、5-6元杂芳基并C6-10芳基或C6-10芳基并5-6元杂芳基，更优选苯基、萘基、5-6元杂芳基、5-6元杂芳基并5-6元杂芳基、5-6元杂芳基并苯基或苯基并5-6元杂芳基，进一步优选如下基团：
In a further preferred embodiment of the present invention, Ring A is C 6-14 aryl or 5-14 membered heteroaryl, preferably C 6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and C 6-10 aryl or C 6-10 aryl and 5-6 membered heteroaryl, more preferably phenyl, naphthyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and phenyl or phenyl and 5-6 membered heteroaryl, and the following groups are further preferred:
在本发明进一步优选的实施例中，Ra为氢、氘、卤素、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基或-(CH2)n1C(O)NRARB，优选氢、氘、卤素或C1-6烷基，更优选氢、氘、卤素或C1-3烷基，进一步优选氢、氘、氟、氯、溴或甲基；In a further preferred embodiment of the present invention, Ra is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl or -( CH2 ) n1C (O)NR A R B , preferably hydrogen, deuterium, halogen or C1-6 alkyl, more preferably hydrogen, deuterium, halogen or C1-3 alkyl, further preferably hydrogen, deuterium, fluorine, chlorine, bromine or methyl;
或者，任意两个Ra与其连接的环原子链接形成C3-8环烷基或3-8元杂环基，优选C3-6环烷基或3-6元杂环基，更优选C3-5环烷基或3-5元杂环基，进一步优选环丙基、环丁基、环戊基、氧杂环丁基、氧杂环戊基、氮杂环丁基或氮杂环戊基。Alternatively, any two Ra are linked to the ring atoms to which they are connected to form a C3-8 cycloalkyl or a 3-8 membered heterocyclyl, preferably a C3-6 cycloalkyl or a 3-6 membered heterocyclyl, more preferably a C3-5 cycloalkyl or a 3-5 membered heterocyclyl, further preferably a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxacyclopentyl, azetidinyl or azopentyl.
在本发明进一步优选的实施例中，RA和RB各自独立地为氢、氘、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，优选氢、C1-6烷基或C3-8环烷基，更优选氢、C1-3烷基或C3-6环烷基，进一步优选氢、甲基或环丙基。In a further preferred embodiment of the present invention, RA and RB are each independently hydrogen, deuterium, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, preferably hydrogen, C1-6 alkyl or C3-8 cycloalkyl, more preferably hydrogen, C1-3 alkyl or C3-6 cycloalkyl, further preferably hydrogen, methyl or cyclopropyl.
在本发明进一步优选的实施例中，x为0-4的整数，优选0、1或2。In a further preferred embodiment of the present invention, x is an integer of 0-4, preferably 0, 1 or 2.
在本发明进一步优选的实施例中，n1为0-2的整数，优选0或1。 In a further preferred embodiment of the present invention, n1 is an integer of 0-2, preferably 0 or 1.
在本发明进一步优选的实施例中，Rb为氢、氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n2C(O)NRCRD或-(CH2)n2RE，优选氢、氘、卤素、氧代基、C1-6烷基或C3-8环烷基，更优选氢、氘、卤素、氧代基、C1-3烷基或C3-6环烷基，进一步优选氢、氘、氟、氯、溴、氧代基、甲基或环丙基；In a further preferred embodiment of the present invention, R b is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)NR C R D or -(CH 2 ) n2 R E , preferably hydrogen, deuterium, halogen, oxo, C 1-6 alkyl or C 3-8 cycloalkyl, more preferably hydrogen, deuterium, halogen, oxo, C 1-3 alkyl or C 3-6 cycloalkyl, further preferably hydrogen, deuterium, fluorine, chlorine, bromine, oxo, methyl or cyclopropyl;
或者，任意两个Rb与其连接的环原子链接形成C3-8环烷基或3-8元杂环基，优选C3-6环烷基或3-6元杂环基，更优选C3-5环烷基或3-5元杂环基，进一步优选环丙基、环丁基、环戊基、氧杂环丁基、氧杂环戊基、氮杂环丁基或氮杂环戊基。Alternatively, any two R b are linked to the ring atoms to which they are connected to form a C 3-8 cycloalkyl or a 3-8 membered heterocyclyl, preferably a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, more preferably a C 3-5 cycloalkyl or a 3-5 membered heterocyclyl, further preferably a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxacyclopentyl, azetidinyl or azopentyl.
在本发明进一步优选的实施例中，y为0-4的整数，优选0、1或2。In a further preferred embodiment of the present invention, y is an integer of 0-4, preferably 0, 1 or 2.
在本发明进一步优选的实施例中，Rc为氢、氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n2C(O)NRCRD或-(CH2)n2RE，优选氢、氘、卤素、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n2C(O)NRCRD或-(CH2)n2RE，更优选氢、氘、卤素、氧代基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C3-6环烷基、3-6元杂环基、苯基、5-6元杂芳基、-C(O)NRCRD或-(CH2)RE，进一步优选氢、氘、氟、氯、溴、氧代基、甲基、乙基、二氟甲基、三氟甲基、三氟乙基、环丙基、苯基、噻唑基、异噁唑基、噁二唑基、-CD3、-C(O)NHCH3、-C(O)NHCH2CF3或 In a further preferred embodiment of the present invention, R c is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)NR C R D or -(CH 2 ) n2 R E , preferably hydrogen, deuterium, halogen, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)NR C R D or -(CH 2 ) n2 R E , more preferably hydrogen, deuterium, halogen, oxo, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -C(O)NR C R D or -(CH 2 ) R E , further preferably hydrogen, deuterium, fluorine, chlorine, bromine, oxo, methyl, ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, phenyl, thiazolyl, isoxazolyl, oxadiazolyl, -CD 3 , -C(O)NHCH 3 , -C(O)NHCH 2 CF 3 or
或者，任意两个Rc与其连接的环原子链接形成C3-8环烷基或3-8元杂环基，优选C3-6环烷基或3-6元杂环基，更优选C3-5环烷基或3-5元杂环基，进一步优选环丙基、环丁基、环戊基、氧杂环丁基、氧杂环戊基、氮杂环丁基或氮杂环戊基。Alternatively, any two R c are linked to the ring atoms to which they are connected to form a C 3-8 cycloalkyl or a 3-8 membered heterocyclyl, preferably a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, more preferably a C 3-5 cycloalkyl or a 3-5 membered heterocyclyl, further preferably a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxacyclopentyl, azetidinyl or azopentyl.
在本发明进一步优选的实施例中，RC、RD和RE各自独立地为氢、氘、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，优选氢、C1-6烷基、C1-6卤代烷基或C3-8环烷基，更优选氢、C1-3烷基、C1-3卤代烷基或C3-6环烷基，进一步优选氢、甲基、三氟甲基、三氟乙基或环丙基。In a further preferred embodiment of the present invention, R C , R D and R E are each independently hydrogen, deuterium, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl, more preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl, further preferably hydrogen, methyl, trifluoromethyl, trifluoroethyl or cyclopropyl.
在本发明进一步优选的实施例中，z为0-4的整数，优选0、1或2。In a further preferred embodiment of the present invention, z is an integer of 0-4, preferably 0, 1 or 2.
在本发明进一步优选的实施例中，n2为0-2的整数，优选0或1。In a further preferred embodiment of the present invention, n2 is an integer of 0-2, preferably 0 or 1.
在本发明进一步优选的实施例中，R1为氢、氘、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C1-6烷胺基，优选氢或C1-6烷基，更优选氢或C1-3烷基，进一步优选氢或甲基。In a further preferred embodiment of the present invention, R1 is hydrogen, deuterium, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio or C1-6 alkylamino, preferably hydrogen or C1-6 alkyl, more preferably hydrogen or C1-3 alkyl, further preferably hydrogen or methyl.
在本发明进一步优选的实施例中，m为0-2的整数，优选0或1。In a further preferred embodiment of the present invention, m is an integer of 0-2, preferably 0 or 1.
在本发明进一步优选的实施例中，n为0-2的整数，优选1或2。In a further preferred embodiment of the present invention, n is an integer of 0-2, preferably 1 or 2.
在本发明进一步优选的实施例中，通式(I)所示的化合物选自： In a further preferred embodiment of the present invention, the compound represented by general formula (I) is selected from:
或其混合物。 or a mixture thereof.
在本发明进一步优选的实施例中，通式(I)进一步如通式(II)所示：
In a further preferred embodiment of the present invention, the general formula (I) is further shown as the general formula (II):
其中：in:
R2和R3各自独立地为氢、氘、卤素、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基或-(CH2)n1C(O)NRARB，优选氢、氘、卤素或C1-6烷基，更优选氢、氘、卤素或C1-3烷基，进一步优选氢、氘、氟、氯或甲基； R2 and R3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino or -( CH2 ) n1C (O) NRARB , preferably hydrogen, deuterium, halogen or C1-6 alkyl, more preferably hydrogen, deuterium, halogen or C1-3 alkyl, further preferably hydrogen, deuterium, fluorine, chlorine or methyl;
或者，R2和R3与其连接的碳原子链接形成苯基或5-6元杂芳基，优选苯基或吡啶基；Alternatively, R 2 and R 3 are linked to the carbon atom to which they are attached to form a phenyl group or a 5-6 membered heteroaryl group, preferably a phenyl group or a pyridyl group;
RA、RB、R1、Rb、Rc、y、z、m、n和n1的定义均如上所述。 RA , RB , R1 , Rb , Rc , y, z, m, n and n1 are as defined above.
在本发明进一步优选的实施例中，通式(I)进一步如通式(III)所示：
In a further preferred embodiment of the present invention, the general formula (I) is further shown as the general formula (III):
其中：in:
R2和R3各自独立地为氢、氘、卤素、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基或-(CH2)n1C(O)NRARB，优选氢、氘、卤素或C1-6烷基，更优选氢、氘、卤素或C1-3烷基，进一步优选氢、氘、氟、氯或甲基； R2 and R3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-8 cycloalkyl , 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl or -( CH2 ) n1C (O) NRARB , preferably hydrogen, deuterium, halogen or C1-6 alkyl, more preferably hydrogen, deuterium, halogen or C1-3 alkyl, further preferably hydrogen, deuterium, fluorine, chlorine or methyl;
或者，R2和R3与其连接的碳原子链接形成苯基或5-6元杂芳基，优选苯基或吡啶基；Alternatively, R 2 and R 3 are linked to the carbon atom to which they are attached to form a phenyl group or a 5-6 membered heteroaryl group, preferably a phenyl group or a pyridyl group;
R4a、R4b、R5a、R5b、R6a、R6b和R7各自独立地为氢、氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n2C(O)NRCRD或-(CH2)n2RE，优选氢、氘、卤素、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n2C(O)NRCRD或-(CH2)n2RE，更优选氢、氘、 卤素、氧代基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C3-6环烷基、3-6元杂环基、苯基、5-6元杂芳基、-C(O)NRCRD或-(CH2)RE，进一步优选氢、氘、氟、氯、溴、氧代基、甲基、乙基、二氟甲基、三氟甲基、三氟乙基、环丙基、苯基、噻唑基、异噁唑基、噁二唑基、-CD3、-C(O)NHCH3、-C(O)NHCH2CF3或 R 4a , R 4b , R 5a , R 5b , R 6a , R 6b and R 7 are each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)NR C R D or -(CH 2 ) n2 R E , preferably hydrogen, deuterium, halogen, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 membered aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)NR C R D or -(CH 2 ) n2 R E , more preferably hydrogen, deuterium, halogen, oxo, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -C(O)NR C R D or -(CH 2 ) R E , further preferably hydrogen, deuterium, fluorine, chlorine, bromine, oxo, methyl, ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, phenyl, thiazolyl, isoxazolyl, oxadiazolyl, -CD 3 , -C(O)NHCH 3 , -C(O)NHCH 2 CF 3 or
或者，R4a和R4b，R4a和R5a或R6a和R7与其连接的环原子链接形成C3-8环烷基或3-8元杂环基，优选C3-6环烷基或3-6元杂环基，更优选C3-5环烷基或3-5元杂环基，进一步优选环丙基、环丁基、环戊基、氧杂环丁基、氧杂环戊基、氮杂环丁基或氮杂环戊基；Alternatively, R 4a and R 4b , R 4a and R 5a or R 6a and R 7 are linked to the ring atom to which they are connected to form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclyl group, preferably a C 3-6 cycloalkyl group or a 3-6 membered heterocyclyl group, more preferably a C 3-5 cycloalkyl group or a 3-5 membered heterocyclyl group, further preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an oxetanyl group, an oxacyclopentyl group, an azetidinyl group or an azoxycyclopentyl group;
RC、RD和RE各自独立地为氢、氘、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，优选氢、C1-6烷基、C1-6卤代烷基或C3-8环烷基，更优选氢、C1-3烷基、C1-3卤代烷基或C3-6环烷基，进一步优选氢、甲基、三氟甲基、三氟乙基或环丙基；R C , R D and R E are each independently hydrogen, deuterium, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl, more preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl, further preferably hydrogen , methyl, trifluoromethyl, trifluoroethyl or cyclopropyl;
RA、RB、R1、Rb、y、m、n1和n2如上所述。 RA , RB , R1 , Rb , y, m, n1 and n2 are as described above.
在本发明进一步优选的实施例中，通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，选自如下化合物：







In a further preferred embodiment of the present invention, the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are selected from the following compounds:







在本发明进一步优选的实施例中，所述盐为盐酸盐。In a further preferred embodiment of the present invention, the salt is hydrochloride.
在本发明进一步优选的实施例中，所述盐酸盐为晶型。In a further preferred embodiment of the present invention, the hydrochloride is in crystalline form.
本发明还提供了一种4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐晶型A，其X-射线粉末衍射图谱包含位于2θ为11.64±0.2°、25.61±0.2°、26.29±0.2°处的衍射峰；优选其X-射线粉末衍射图谱包含位于2θ为11.64±0.2°、17.33±0.2°、22.06±0.2°、25.61±0.2°、26.29±0.2°处的衍射峰；优选其X-射线粉末衍射图谱包含位于2θ为11.64±0.2°、15.12±0.2°、16.58±0.2°、17.33±0.2°、21.06±0.2°、21.55±0.2°、22.06±0.2°、24.55±0.2°、24.94±0.2°、25.61±0.2°、26.29±0.2°、26.81±0.2°、27.92±0.2°、28.55±0.2°、31.23±0.2°、33.24±0.2°、33.84±0.2°、34.61±0.2°处的衍射峰；优选其X-射线粉末衍射图谱基本如图1所示。The present invention also provides a 4,7,8,9,10,10a-hexahydro-5H-thiophene [2',3':3,4] pyrido [1,2-a] pyrazine hydrochloride crystal form A, whose X-ray powder diffraction spectrum comprises diffraction peaks located at 2θ of 11.64 ± 0.2°, 25.61 ± 0.2°, and 26.29 ± 0.2°; preferably, the X-ray powder diffraction spectrum comprises diffraction peaks located at 2θ of 11.64 ± 0.2°, 17.33 ± 0.2°, 22.06 ± 0.2°, 25.61 ± 0.2°, and 26.29 ± 0.2°; preferably, the X-ray powder diffraction spectrum comprises diffraction peaks located at 2θ of 11.64 ± 0.2°, 17.33 ± 0.2°, 22.06 ± 0.2°, 25.61 ± 0.2°, and 26.29 ± 0.2°. diffraction peaks at 64±0.2°, 15.12±0.2°, 16.58±0.2°, 17.33±0.2°, 21.06±0.2°, 21.55±0.2°, 22.06±0.2°, 24.55±0.2°, 24.94±0.2°, 25.61±0.2°, 26.29±0.2°, 26.81±0.2°, 27.92±0.2°, 28.55±0.2°, 31.23±0.2°, 33.24±0.2°, 33.84±0.2°, and 34.61±0.2°; preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 1.
本发明还提供了一种(S)-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐晶型A，其X-射线粉末衍射图谱均包含位于2θ为11.70±0.2°、25.43±0.2°、28.06±0.2°处的衍射峰；优选其X-射线粉末衍射图谱包含位于2θ为11.70±0.2°、16.49±0.2°、25.43±0.2°、26.81±0.2°、28.06±0.2°处的衍射峰；优选其X-射线粉末衍射图谱包含位于2θ为11.70±0.2°、15.15±0.2°、16.49±0.2°、17.25±0.2°、17.54±0.2°、21.20±0.2°、21.63±0.2°、22.21±0.2°、24.87±0.2°、25.43±0.2°、26.81±0.2°、28.06±0.2°、31.01±0.2°、33.21±0.2°、34.03±0.2°处的衍射峰；优选其X-射线粉末衍射图谱基本如图2所示。The present invention also provides a (S)-4,7,8,9,10,10a-hexahydro-5H-thiophene [2',3':3,4] pyrido [1,2-a] pyrazine hydrochloride crystal form A, wherein the X-ray powder diffraction pattern thereof comprises diffraction peaks located at 2θ of 11.70 ± 0.2°, 25.43 ± 0.2°, and 28.06 ± 0.2°; preferably, the X-ray powder diffraction pattern thereof comprises diffraction peaks located at 2θ of 11.70 ± 0.2°, 16.49 ± 0.2°, 25.43 ± 0.2°, 26.81 ± 0.2°, and 28.06 ± 0.2°; preferably, the X-ray powder diffraction pattern thereof comprises diffraction peaks located at 2θ of 11.70 ± 0.2°, 16.49 ± 0.2°, 25.43 ± 0.2°, 26.81 ± 0.2°, and 28.06 ± 0.2°. The X-ray powder diffraction pattern comprises diffraction peaks at 2θ of 11.70±0.2°, 15.15±0.2°, 16.49±0.2°, 17.25±0.2°, 17.54±0.2°, 21.20±0.2°, 21.63±0.2°, 22.21±0.2°, 24.87±0.2°, 25.43±0.2°, 26.81±0.2°, 28.06±0.2°, 31.01±0.2°, 33.21±0.2°, and 34.03±0.2°; preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 2.
本发明还提供了一种(R)-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐晶型A，其X-射线粉末衍射图谱均包含位于2θ为11.74±0.2°、25.47±0.2°、28.12±0.2°处的衍射峰；优选其X-射线粉末衍射图谱包含位于2θ为11.74±0.2°、16.52±0.2°、25.47±0.2°、26.87±0.2°、28.12±0.2°处的衍射峰；优选其X-射线粉末衍射图谱包含位于2θ为11.74±0.2°、15.19±0.2°、16.52±0.2°、17.37±0.2°、21.19±0.2°、21.66±0.2°、22.22±0.2°、24.91±0.2°、 25.47±0.2°、26.87±0.2°、28.12±0.2°、31.00±0.2°、33.25±0.2°、34.22±0.2°处的衍射峰；优选其X-射线粉末衍射图谱基本如图3所示。The present invention also provides a (R)-4,7,8,9,10,10a-hexahydro-5H-thiophene [2',3':3,4] pyrido [1,2-a] pyrazine hydrochloride crystal form A, whose X-ray powder diffraction spectrum includes diffraction peaks located at 2θ of 11.74 ± 0.2°, 25.47 ± 0.2°, and 28.12 ± 0.2°; preferably, the X-ray powder diffraction spectrum includes diffraction peaks located at 2θ of 11.74 ± 0.2°, 1 6.52±0.2°, 25.47±0.2°, 26.87±0.2°, 28.12±0.2°; preferably, its X-ray powder diffraction pattern comprises diffraction peaks at 2θ of 11.74±0.2°, 15.19±0.2°, 16.52±0.2°, 17.37±0.2°, 21.19±0.2°, 21.66±0.2°, 22.22±0.2°, 24.91±0.2°, Diffraction peaks at 25.47±0.2°, 26.87±0.2°, 28.12±0.2°, 31.00±0.2°, 33.25±0.2°, and 34.22±0.2°; preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 3.
本发明还提供了一种通式(I-1)所示的化合物、其立体异构体或其盐：
The present invention also provides a compound represented by general formula (I-1), a stereoisomer thereof or a salt thereof:
优选为通式(II-1)所示的化合物、其立体异构体或其盐：
Preferred are compounds represented by general formula (II-1), stereoisomers thereof or salts thereof:
其中，环A、R1、Ra、RA、RB、Rb、Rc、x、y、z、m、n和n1的定义均如上所述。wherein Ring A, R1 , Ra , RA , RB, Rb , Rc , x , y, z, m, n and n1 are as defined above.
本发明还提供了一种通式(I-2)所示的化合物、其立体异构体或其盐：
The present invention also provides a compound represented by general formula (I-2), a stereoisomer thereof or a salt thereof:
优选为通式(II-2)所示的化合物、其立体异构体或其盐：
Preferred are compounds represented by general formula (II-2), stereoisomers thereof or salts thereof:
其中，环A、R1、Ra、RA、RB、Rb、Rc、x、y、z、m、n和n1的定义均如上所述。本发明还进一步提供了一种通式(I)所示的化合物、其立体异构体或其药学上可接受的盐的制备方法。所述的制备方法可以用商业上可获得的原料，通过已知的方法合成得到。Wherein, Ring A, R1 , Ra , RA , RB , Rb , Rc , x, y, z, m, n and n1 are defined as above. The present invention further provides a method for preparing the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof. The preparation method can be synthesized by known methods using commercially available raw materials.
在某一实施方案中，所述的制备方法优选包括以下步骤：溶剂中，通式(I-1)所示的化合物、其立体异构体或其盐在还原反应试剂的存在下进行羰基还原为亚甲基反应，即得通式(I)所示的化合物、其立体异构体或其药学上可接受的盐；
In a certain embodiment, the preparation method preferably comprises the following steps: in a solvent, the compound represented by the general formula (I-1), its stereoisomer or its salt is subjected to a carbonyl reduction reaction to a methylene group in the presence of a reducing reaction reagent to obtain the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt;
其中，环A、R1、Ra、RA、RB、Rb、Rc、x、y、z、m、n和n1的定义均如上所述。wherein Ring A, R1 , Ra , RA , RB, Rb , Rc , x , y, z, m, n and n1 are as defined above.
在某一实施方案中，所述的羰基还原为亚甲基的反应条件可为本领域此类反应常规的条件。In one embodiment, the reaction conditions for reducing the carbonyl group to the methylene group may be conventional conditions for such reactions in the art.
在某一实施方案中，所述的溶剂可为本领域此类反应常规的溶剂，例如为有机溶剂，优选为四氢呋喃。In one embodiment, the solvent may be a conventional solvent for such reactions in the art, such as an organic solvent, preferably tetrahydrofuran.
在某一实施方案中，所述的还原反应试剂可为本领域此类反应常规的还原反应试剂，例如为硼氢化和还原性试剂，优选为硼烷四氢呋喃。In one embodiment, the reduction reaction reagent may be a conventional reduction reaction reagent for such reactions in the art, such as a hydroboration and reducing agent, preferably borane tetrahydrofuran.
在某一实施方案中，所述的制备方法优选包括以下步骤：溶剂中，通式(I-2)所示化合物、其立体异构体或其盐经还原反应和胺保护反应得到通式(I-3)所示化合物、其立体异构体或其盐，经脱保护，即得通式(I)所示的化合物、其立体异构体或其药学上可接受的盐；
In a certain embodiment, the preparation method preferably comprises the following steps: in a solvent, the compound represented by the general formula (I-2), its stereoisomer or its salt is subjected to reduction reaction and amine protection reaction to obtain the compound represented by the general formula (I-3), its stereoisomer or its salt, and then deprotected to obtain the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt;
其中，PG为胺保护基，优选选自三氟乙酰基、苄氧羰基、烯丙氧羰基、对甲氧基苄基、2,4-二甲氧基苄基、苄基、邻苯二甲酰基、硝基苯磺酰基、对甲苯磺酰基、三苯甲基、叔丁氧羰基、笏甲氧羰基、(三甲基硅)乙氧基甲基、四氢吡喃基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、乙酰基或烯丙基，优选叔丁氧羰基；wherein PG is an amine protecting group, preferably selected from trifluoroacetyl, benzyloxycarbonyl, allyloxycarbonyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, phthaloyl, nitrobenzenesulfonyl, p-toluenesulfonyl, trityl, tert-butoxycarbonyl, methoxycarbonyl, (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl or allyl, preferably tert-butoxycarbonyl;
环A、R1、Ra、RA、RB、Rb、Rc、x、y、z、m、n和n1如上所述。Ring A, R1 , Ra , RA, RB , Rb , Rc , x, y , z, m, n and n1 are as described above.
在某一实施方案中，所述的溶剂可为本领域此类反应常规的溶剂，例如为有机溶剂，优选为四氢呋喃。In one embodiment, the solvent may be a conventional solvent for such reactions in the art, such as an organic solvent, preferably tetrahydrofuran.
在某一实施方案中，所述还原反应所用的还原试剂可为本领域此类反应常规的还原反应试剂，例如为四氢锂铝。In one embodiment, the reducing agent used in the reduction reaction may be a conventional reducing agent for such reactions in the art, such as lithium aluminum tetrahydride.
在某一实施方案中，所述胺保护和脱保护的反应条件可为本领域此类反应常规的条件。In a certain embodiment, the reaction conditions for the amine protection and deprotection may be conventional conditions for such reactions in the art.
本发明还进一步提供了一种通式(II)所示的化合物、其立体异构体或其药学上可接受的盐的制备方法。所述的制备方法可以用商业上可获得的原料，通过已知的方法合成得到。The present invention further provides a method for preparing a compound represented by general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The preparation method can be synthesized using commercially available raw materials by known methods.
在某一实施方案中，所述的制备方法优选包括以下步骤：溶剂中，通式(II-1)所示 化合物、其立体异构体或其盐所示的化合物在还原反应试剂的存在下进行羰基还原为亚甲基反应，即得通式(II)所示的化合物、其立体异构体或其盐；
In one embodiment, the preparation method preferably comprises the following steps: in a solvent, The compound represented by the compound, its stereoisomer or its salt is subjected to a carbonyl reduction reaction to a methylene group in the presence of a reducing agent to obtain a compound represented by the general formula (II), its stereoisomer or its salt;
其中，R1、R2、R3、RA、RB、Rb、Rc、y、z、m、n和n1的定义均如上所述。wherein R 1 , R 2 , R 3 , RA , RB , R b , R c , y, z, m, n and n1 are as defined above.
在某一实施方案中，所述的羰基还原为亚甲基的反应条件可为本领域此类反应常规的条件。In one embodiment, the reaction conditions for reducing the carbonyl group to the methylene group may be conventional conditions for such reactions in the art.
在某一实施方案中，所述的溶剂可为本领域此类反应常规的溶剂，例如为有机溶剂，优选为四氢呋喃。In one embodiment, the solvent may be a conventional solvent for such reactions in the art, such as an organic solvent, preferably tetrahydrofuran.
在某一实施方案中，所述的还原反应试剂可为本领域此类反应常规的还原反应试剂，例如为硼氢化和还原性试剂，优选为硼烷四氢呋喃。In one embodiment, the reduction reaction reagent may be a conventional reduction reaction reagent for such reactions in the art, such as a hydroboration and reducing agent, preferably borane tetrahydrofuran.
在某一实施方案中，所述的制备方法优选包括以下步骤：溶剂中，通式(II-2)所示化合物、其立体异构体或其盐经还原反应和胺保护反应得到通式(II-3)所示化合物、其立体异构体或其盐，经脱保护，即得通式(II)所示的化合物、其立体异构体或其药学上可接受的盐；
In a certain embodiment, the preparation method preferably comprises the following steps: in a solvent, the compound represented by the general formula (II-2), its stereoisomer or its salt is subjected to reduction reaction and amine protection reaction to obtain the compound represented by the general formula (II-3), its stereoisomer or its salt, and then deprotected to obtain the compound represented by the general formula (II), its stereoisomer or its pharmaceutically acceptable salt;
其中，PG1为胺保护基，优选选自三氟乙酰基、苄氧羰基、烯丙氧羰基、对甲氧基苄基、2,4-二甲氧基苄基、苄基、邻苯二甲酰基、硝基苯磺酰基、对甲苯磺酰基、三苯甲基、叔丁氧羰基、笏甲氧羰基、(三甲基硅)乙氧基甲基、四氢吡喃基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、乙酰基或烯丙基，优选叔丁氧羰基；wherein PG 1 is an amine protecting group, preferably selected from trifluoroacetyl, benzyloxycarbonyl, allyloxycarbonyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, phthaloyl, nitrobenzenesulfonyl, p-toluenesulfonyl, trityl, tert-butoxycarbonyl, methoxycarbonyl, (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl or allyl, preferably tert-butoxycarbonyl;
R1、R2、R3、RA、RB、Rb、Rc、y、z、m、n和n1的定义均如上所述。 R1 , R2 , R3 , RA , RB , Rb , Rc , y, z, m, n and n1 are as defined above.
在某一实施方案中，所述的溶剂可为本领域此类反应常规的溶剂，例如为有机溶剂，优选为四氢呋喃。In one embodiment, the solvent may be a conventional solvent for such reactions in the art, such as an organic solvent, preferably tetrahydrofuran.
在某一实施方案中，所述还原反应所用的还原试剂可为本领域此类反应常规的还原反应试剂，例如为四氢锂铝。In one embodiment, the reducing agent used in the reduction reaction may be a conventional reducing agent for such reactions in the art, such as lithium aluminum tetrahydride.
在某一实施方案中，所述胺保护和脱保护的反应条件可为本领域此类反应常规的条件。In a certain embodiment, the reaction conditions for the amine protection and deprotection may be conventional conditions for such reactions in the art.
本发明进一步涉及一种药物组合物，其包含治疗有效剂量的任一所示的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。 The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds shown, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients.
本发明进一步涉及任一所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备药物中的应用，优选在制备预防和/或治疗哺乳动物神经精神类疾病药物中的应用，所述神经精神类疾病优选为5-羟色胺受体和/或痕量胺相关受体和/或多巴胺受体相关的中枢神经系统疾病。The present invention further relates to the use of any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs, preferably in the preparation of drugs for preventing and/or treating neuropsychiatric diseases in mammals, wherein the neuropsychiatric diseases are preferably central nervous system diseases related to 5-hydroxytryptamine receptors and/or trace amine-related receptors and/or dopamine receptors.
本发明进一步涉及任一所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备预防和/或治疗与哺乳动物痕量胺相关受体和/或5-羟色胺受体和/或多巴胺受体相关的中枢神经系统疾病药物的方法。The present invention further relates to a method for preparing a drug for preventing and/or treating central nervous system diseases associated with mammalian trace amine-related receptors and/or 5-hydroxytryptamine receptors and/or dopamine receptors by using any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts, or their pharmaceutical compositions.
本发明还涉及一种预防和/或治疗与哺乳动物痕量胺相关受体和/或5-羟色胺受体和/或多巴胺受体相关的中枢神经系统疾病的方法，其包括向所述哺乳动物施用治疗有效剂量的任一所示的化合物、其立体异构体或其药学上可接受的盐、酯、前药、溶剂化物、水合物或衍生物，或其药物组合物。The present invention also relates to a method for preventing and/or treating central nervous system diseases associated with mammalian trace amine-related receptors and/or 5-hydroxytryptamine receptors and/or dopamine receptors, which comprises administering to the mammal a therapeutically effective dose of any of the compounds shown, its stereoisomers or pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof, or a pharmaceutical composition thereof.
本发明涉及的痕量胺相关受体优选TAAR1受体。The trace amine-related receptor involved in the present invention is preferably TAAR1 receptor.
在一些实施方案中，本发明涉及的神经精神类疾病为精神分裂症、精神分裂症谱群疾病、急性精神分裂症、慢性精神分裂症、NOS精神分裂症、精神分裂样人格障碍、分裂型人格障碍、妄想性精神障碍、精神病、精神障碍、短时精神障碍、分享性精神障碍、躯体疾病所致精神障碍、药物诱发精神病、心理情感障碍、侵犯性、精神错乱、帕金森精神病、刺激性精神病、图雷特综合症、器官或NOS精神病、癫痫、精神激动、创伤后精神紧张性障碍、行为错乱、神经变性疾病、阿尔茨海默氏病、帕金森氏病、运动障碍、亨廷顿病、痴呆、情感障碍、焦虑症、情感性精神病、抑郁症、严重抑郁性障碍、情绪不良、双相性精神障碍、躁狂症、季节性情感性精神病、注意力缺陷障碍、注意力不足过动症、强迫性神经失调、眩晕、癫痫、疼痛、神经性疼痛、神经性疼痛易感状态、炎性疼痛、纤维肌痛、偏头痛、认知损伤、运动障碍、下肢不宁综合症、多发性硬化症、睡眠障碍、睡眠呼吸暂停、嗜眠发作、白天睡眠过多、时差反应、药物的嗜睡副作用、失眠、物质滥用依赖性、成瘾、进食障碍、性功能障碍、高血压、呕吐、Lesche-Nyhane病、Wilson病、自闭症、亨廷顿舞蹈病和经前焦虑中的一种或多种。In some embodiments, the neuropsychiatric diseases involved in the present invention are schizophrenia, schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizophreniform personality disorder, schizotypal personality disorder, delusional disorder, psychosis, mental disorder, short-term mental disorder, shared mental disorder, mental disorder caused by physical illness, drug-induced psychosis, psychological affective disorder, aggression, psychosis, Parkinson's psychosis, irritant psychosis, Tourette syndrome, organic or NOS psychosis, epilepsy, agitation, post-traumatic stress disorder, behavioral disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, movement disorder, Huntington's disease, dementia, affective disorder, anxiety disorder, affective disorder One or more of psychosis, depression, major depressive disorder, dysthymia, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive compulsive disorder, vertigo, epilepsy, pain, neuropathic pain, neuropathic pain-prone states, inflammatory pain, fibromyalgia, migraine, cognitive impairment, movement disorders, restless legs syndrome, multiple sclerosis, sleep disorders, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, somnolence side effects of medications, insomnia, substance abuse dependence, addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesche-Nyhane disease, Wilson disease, autism, Huntington's disease, and premenstrual dysphoria.
发明的详细说明Detailed description of the invention
除非另有定义，本文所用所有技术和科学术语与本发明所属领域的普通技术人员通常理解的含义相同。若存在矛盾，则以本申请提供的定义为准。当本文中出现商品名时，意在指代其对应的商品或其活性成分。本文引用的所有专利、已经公开的专利申请和出版物均通过引用并入到本文中。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. If there is a conflict, the definition provided in the application shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团，其通过单键与分子的其余部分连接。“烷基”可以具有1-8个碳原子，即“C1-C8烷基”，例如C1-4烷基、C1-3烷基、C1-2烷基、C3烷基、C4烷基、C1-6烷基、C3-6烷基。烷基的非限制性实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3- 二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等，或者它们的异构体。The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. "Alkyl" can have 1-8 carbon atoms, i.e., "C 1 -C 8 alkyl", such as C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 3 alkyl, C 4 alkyl, C 1-6 alkyl, C 3-6 alkyl. Non-limiting examples of alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3- Dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like, or isomers thereof.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基包含3至20个碳原子，优选包含3至12个碳原子，更优选3至8个碳原子，进一步优选包含3至6个碳原子，最优选包含3至5个碳原子，或者，包含5至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl group comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, further preferably 3 to 6 carbon atoms, most preferably 3 to 5 carbon atoms, or 5 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include cycloalkyl groups of spirocyclic, condensed and bridged rings.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选7至10元。根据环与环之间共用的螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基或双螺环烷基，更优选为3元/6元、3元/5元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。也包含单螺环烷基与杂环烷基共用螺原子的螺杂环烷基。The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl or a double spiral cycloalkyl, more preferably 3 yuan/6 yuan, 3 yuan/5 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan of single spiral cycloalkyl. It also includes a spiral heterocycloalkyl that shares a spiral atom with a heterocycloalkyl.
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选7至10元。根据组成环的数目分为双环、三环、四环或多环稠环烷基，优选为双环或三环稠环烷基，更优选为5元/5元或5元/6元双环烷基。The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it is divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic condensed cycloalkyl, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其中含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选7至10元。根据组成环的数目分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环桥环烷基，更优选为双环或三环桥环烷基。The term "bridged cycloalkyl" refers to a 5-20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, wherein the group contains one or more double bonds, but none of the rings has a completely conjugated π electron system. It is preferably 6-14 members, and more preferably 7-10 members. It is classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, and is preferably a bicyclic, tricyclic or tetracyclic bridged cycloalkyl group, and more preferably a bicyclic or tricyclic bridged cycloalkyl group.
术语“杂环基”指饱和或不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧和S(O)m(其中m是0-2的整数)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中含1-4个杂原子；更优选含1-4个或1-2个选自N、O和S原子的3-8元杂环基；进一步优选含1-4个或1-2个选自N、O和S原子的3-6元杂环基；最优选包含1-4或1-2个N、O或S原子的5-6元杂环基。所述杂环基中的“杂”表示1-4个选自N、O和S(O)m的杂原子，其中m是0-2的整数。The term "heterocyclyl" refers to a saturated or unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and S(O) m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, wherein 1 to 4 heteroatoms are contained; more preferably, it is a 3-8 membered heterocyclyl containing 1 to 4 or 1 to 2 atoms selected from N, O and S; further preferably, it is a 3-6 membered heterocyclyl containing 1 to 4 or 1 to 2 atoms selected from N, O and S; most preferably, it is a 5-6 membered heterocyclyl containing 1 to 4 or 1 to 2 atoms of N, O or S. The "hetero" in the heterocyclyl means 1 to 4 heteroatoms selected from N, O and S(O) m , wherein m is an integer from 0 to 2.
单环杂环基的非限制性实例包括氧杂环丁基、硫杂环丁基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、二氢咪唑基、二氢呋喃基、二氢吡唑基、哌啶基、哌嗪基、吗啉基、1,3-二氧环戊基、2,2-二氟-1,3-二氧环戊基、环戊酮基、2,2-二氟环戊酮基、吖庚基、氧杂环戊基、氮杂环丁基或氮杂环戊基等。多环杂环基的非限制性实例包括螺环、稠环和桥环的杂环基，其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。 Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolanyl, 2,2-difluoro-1,3-dioxolanyl, cyclopentanone, 2,2-difluorocyclopentanone, azepanyl, oxolanyl, azetidinyl or azocyclopentanyl, etc. Non-limiting examples of polycyclic heterocyclic groups include spirocyclic, condensed and bridged heterocyclic groups, wherein the spirocyclic, condensed and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms on the ring.
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是0-2的整数)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选7至10元。根据环与环之间共用的螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基或双螺杂环基，更优选为3元/6元、3元/5元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。所述螺杂环基中的“杂”表示1-4个选自N、O和S(O)m的杂原子，其中m是0-2的整数。The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiral atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer of 0-2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group or a double spiral heterocyclic group, more preferably a 3 yuan/6 yuan, 3 yuan/5 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiral heterocyclic group. The "miscellaneous" in the spiral heterocyclic group represents 1-4 heteroatoms selected from N, O and S(O) m , wherein m is an integer of 0-2.
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是0-2的整数)的杂原子，其余环原子为碳，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选7至10元。根据组成环的数目分为双环、三环、四环或多环稠杂环基，优选为双环或三环稠杂环基，更优选为5元/5元或5元/6元双环稠杂环基。所述稠杂环基中的“杂”表示1-4个选自N、O和S(O)m的杂原子，其中m是0-2的整数。The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer of 0-2) heteroatoms, and the remaining ring atoms are carbon, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it is divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic fused heterocyclic group. The "miscellaneous" in the fused heterocyclic group represents 1-4 heteroatoms selected from N, O and S (O) m , wherein m is an integer of 0-2.
术语“桥杂环基”指5至20元，任意两个环共用两个不直接连接的原子的多杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是0-2的整数)的杂原子，其余环原子为碳，其中含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选7至10元。根据组成环的数目分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环桥杂环基，更优选为双环或三环桥杂环基。所述桥杂环基中的“杂”表示1-4个选自N、O和S(O)m的杂原子，其中m是0-2的整数。The term "bridged heterocyclic group" refers to a polyheterocyclic group of 5 to 20 members, in which any two rings share two atoms that are not directly connected, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer of 0-2), and the remaining ring atoms are carbon, wherein one or more double bonds are contained, but none of the rings has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, more preferably a bicyclic or tricyclic bridged heterocyclic group. The "hetero" in the bridged heterocyclic group represents 1-4 heteroatoms selected from N, O and S(O) m , wherein m is an integer of 0-2.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环基团，优选为C6-12芳基，更优选C6-10芳基，进一步优选苯基或萘基，特别优选苯基。The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or condensed polycyclic group having a conjugated π electron system, preferably a C 6-12 aryl group, more preferably a C 6-10 aryl group, further preferably a phenyl group or a naphthyl group, and particularly preferably a phenyl group.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的单环或稠合多环杂芳族体系，其中杂原子选自氧、硫和氮等。杂芳基优选5-14元杂芳基，更优选5-6元杂芳基、5-6元杂芳基并5-6元杂芳基、5-6元杂芳基并C6-10芳基或C6-10芳基并5-6元杂芳基，进一步优选5-6元杂芳基、5-6元杂芳基并5-6元杂芳基、5-6元杂芳基并苯基或苯基并5-6元杂芳基，例如吡咯基、咪唑基、呋喃基、吡喃基、噻吩基、噻唑基、噻二唑基、吡唑基、噁唑基、异噁唑基、噁二唑基、三唑基、四唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻吩并苯基、噻吩并吡啶基、吡啶并噻吩基、吡啶并吡咯基、苯并噻吩基或吲哚基等。The term "heteroaryl" refers to a monocyclic or fused polycyclic heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen and the like. The heteroaryl group is preferably a 5-14-membered heteroaryl group, more preferably a 5-6-membered heteroaryl group, a 5-6-membered heteroaryl and a 5-6-membered heteroaryl group, a 5-6-membered heteroaryl and a C 6-10 aryl group, or a C 6-10 aryl and a 5-6-membered heteroaryl group, further preferably a 5-6-membered heteroaryl group, a 5-6-membered heteroaryl and a 5-6-membered heteroaryl group, a 5-6-membered heteroaryl and a phenyl group, or a phenyl and a 5-6-membered heteroaryl group, for example, a pyrrolyl group, an imidazolyl group, a furanyl group, a pyranyl group, a thienyl group, a thiazolyl group, a thiadiazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienophenyl group, a thienopyridinyl group, a pyridothiphenyl group, a pyridopyrrolyl group, a benzothienyl group, or an indolyl group.
所述的杂芳基可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。所述杂芳基中的“杂”表示1-4个选自N、O和S的杂原子，优选1-3个选自N、O和S的杂原子。The heteroaryl group may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The "hetero" in the heteroaryl group represents 1 to 4 heteroatoms selected from N, O and S, preferably 1 to 3 heteroatoms selected from N, O and S.
术语“烷氧基”指-O-(烷基)或-O-(非取代的环烷基)，其中烷基、环烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
术语“烷硫基”指-S-(烷基)或-S-(非取代的环烷基)，其中烷基、环烷基的定义如上 所述。烷硫基的非限制性实例包括：甲硫基、乙硫基、丙硫基、丁硫基、环丙硫基、环丁硫基、环戊硫基、环己硫基等。The term "alkylthio" refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), where alkyl and cycloalkyl are as defined above. Non-limiting examples of alkylthio groups include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
术语“烷胺基”指-NH-(烷基或非取代的环烷基)，或-N-(烷基或非取代的环烷基)(烷基或非取代的环烷基)，其中烷基、环烷基的定义如上所述。烷胺基的非限制性实例包括：甲胺基、乙胺基、丙胺基、丁胺基、环丙胺基、环丁胺基、环戊胺基、环己胺基等。The term "alkylamino" refers to -NH-(alkyl or non-substituted cycloalkyl), or -N-(alkyl or non-substituted cycloalkyl)(alkyl or non-substituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkylamino include methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.
术语“卤”或“卤素”或“卤代”应理解为表示氟(F)、氯(Cl)、溴(Br)或碘(I)原子，优选氟、氯、溴原子。The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.
术语“氘代烷基”指被一个或多个氘取代的烷基，其中烷基如上所定义。The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium, wherein alkyl is as defined above.
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
术语“烯基”指链烯基，又称烯烃基，其中所述的烯烃可以进一步被其他相关基团取代。The term "alkenyl" refers to a chain alkenyl group, also known as an alkene group, wherein the alkene may be further substituted with other related groups.
术语“炔基”指(CH≡C-)，其中所述的炔基可以进一步被其他相关基团取代。“羟基”指-OH。The term "alkynyl" refers to (CH≡C-), wherein the alkynyl may be further substituted with other related groups. "Hydroxy" refers to -OH.
“羟基”指-OH。"Hydroxyl" refers to -OH.
“氨基”指-NH2。"Amino" refers to -NH2 .
“氰基”指-CN。"Cyano" refers to -CN.
“硝基”指-NO2。"Nitro" refers to -NO2 .
“巯基”指-SH。"Mercapto" refers to -SH.
“羧基”指-C(O)OH。"Carboxy" refers to -C(O)OH.
“氧代基”指＝O。"Oxo" refers to =0.
“DMSO”指二甲基亚砜。“LAH”指氢化锂铝。“THF”指四氢呋喃。“Boc”指叔丁氧羰基。“DCM”指二氯甲烷。“DCE”指二氯乙烷。“TFA”指三氟乙酸。“EA”指乙酸乙酯。“DMF”指N,N-二甲基甲酰胺。“TBAI”指四丁基碘化铵。“TEA”指三乙胺。“DPPA”指叠氮磷酸二苯酯。“DIBAL-H”指二异丁基氢化铝。“tol”指甲苯。“ACN”指乙腈。“DMF”指N,N-二甲基甲酰胺。“NCS”指N-氯代丁二酰亚胺。“TMSCN”指三甲基硅氰。“TBAF”指四丁基氟化铵。“microwave”指微波。“TsCl”指对甲苯磺氯。“DMAP”指4-二甲胺基吡啶。“DIEA”指N,N-二异丙基乙胺。“DIPEA”指N,N-二异丙基乙胺。“DMSO” refers to dimethyl sulfoxide. “LAH” refers to lithium aluminum hydride. “THF” refers to tetrahydrofuran. “Boc” refers to tert-butyloxycarbonyl. “DCM” refers to dichloromethane. “DCE” refers to dichloroethane. “TFA” refers to trifluoroacetic acid. “EA” refers to ethyl acetate. “DMF” refers to N,N-dimethylformamide. “TBAI” refers to tetrabutylammonium iodide. “TEA” refers to triethylamine. “DPPA” refers to diphenylphosphoryl azide. “DIBAL-H” refers to diisobutylaluminum hydride. “tol” refers to toluene. “ACN” refers to acetonitrile. “DMF” refers to N,N-dimethylformamide. “NCS” refers to N-chlorosuccinimide. “TMSCN” refers to trimethylsilyl cyanide. “TBAF” refers to tetrabutylammonium fluoride. “microwave” refers to microwave. “TsCl” refers to p-toluenesulfonic chloride. “DMAP” refers to 4-dimethylaminopyridine. "DIEA" refers to N,N-diisopropylethylamine. "DIPEA" refers to N,N-diisopropylethylamine.
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的或开放式的，且不排除其它未列举的元素或方法步骤。本领域技术人员应当理解，上述术语如“包括”涵盖“由…组成”的含义。The terms "include", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will appreciate that the above terms such as "comprising" encompass the meaning of "consisting of".
术语“一个(种)或多个(种)”或者类似的表述“至少一个(种)”可以表示例如1、2、3、4、5、6、7、8、9、10个(种)或更多个(种)。The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.
当公开了数值范围的下限和上限时，落入该范围中的任何数值和任何包括的范围都被具体公开。特别地，本文公开的值的每个取值范围应理解为表示涵盖于较宽范围中的每个数值和范围。When the lower and upper limits of a numerical range are disclosed, any value and any included range falling within the range is specifically disclosed. In particular, each range of values disclosed herein should be understood to mean each value and range encompassed within the broader range.
在本文中，“Z”和“-Z-”均表示为同一特定的基团，其可以互换使用。 Herein, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.
本文所用的表述m-n指m至n的范围以及由其中的各个点值组成的亚范围以及各个点值。例如，表述“C2-C8”或“C2-8”涵盖2-8个碳原子的范围，并应理解为还涵盖其中的任意亚范围以及每个点值，例如C2-C5、C3-C4、C2-C6、C3-C6、C4-C6、C4-C7、C4-C8等，以及C2、C3、C4、C5、C6、C7、C8等。例如，表述“C3-C10”或“C3-10”也应当以类似的方式理解，例如可以涵盖包含于其中的任意亚范围和点值，例如C3-C9、C6-C9、C6-C8、C6-C7、C7-C10、C7-C9、C7-C8、C8-C9等以及C3、C4、C5、C6、C7、C8、C9、C10等。又例如，表述“C1-C6”或“C1-6”涵盖1-6个碳原子的范围，并应理解为还涵盖其中的任意亚范围以及每个点值，例如C2-C5、C3-C4、C1-C2、C1-C3、C1-C4、C1-C5、C1-C6等，以及C1、C2、C3、C4、C5、C6等。又例如，表述“三元至十元”应理解为涵盖其中的任意亚范围以及每个点值，例如三元至五元、三元至六元、三元至七元、三元至八元、四元至五元、四元至六元、四元至七元、四元至八元、五元至七元、五元至八元、六元至七元、六元至八元、九元至十元，等，以及三、四、五、六、七、八、九、十元，等。本文中其他类似的表述也应当以类似的方式理解。The expression mn used herein refers to the range of m to n and the sub-ranges consisting of the individual point values therein and the individual point values. For example, the expression " C2 - C8 " or " C2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any sub-ranges and each point value therein, such as C2 - C5 , C3 - C4 , C2 - C6 , C3 - C6 , C4 - C6 , C4 - C7 , C4 - C8 , etc., as well as C2 , C3 , C4 , C5 , C6 , C7 , C8 , etc. For example, the expression " C3 - C10 " or " C3-10 " should also be understood in a similar manner, e.g., may encompass any sub-ranges and point values contained therein, such as C3 - C9 , C6 - C9 , C6 - C8 , C6 - C7 , C7 - C10 , C7 - C9 , C7 - C8 , C8- C9 , etc., as well as C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , etc. For another example, the expression "C 1 -C 6 " or "C 1-6 " encompasses a range of 1-6 carbon atoms and should be understood to also encompass any subranges and individual point values therein, such as C 2 -C 5 , C 3 -C 4 , C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , C 1 -C 6 , etc., as well as C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , etc. For another example, the expression "three yuan to ten yuan" should be understood to include any sub-ranges therein and each point value, such as three yuan to five yuan, three yuan to six yuan, three yuan to seven yuan, three yuan to eight yuan, four yuan to five yuan, four yuan to six yuan, four yuan to seven yuan, four yuan to eight yuan, five yuan to seven yuan, five yuan to eight yuan, six yuan to seven yuan, six yuan to eight yuan, nine yuan to ten yuan, etc., as well as three, four, five, six, seven, eight, nine, ten yuan, etc. Other similar expressions in this document should also be understood in a similar manner.
本文所用的表述“X选自A、B或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。The expressions "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like used herein all express the same meaning, that is, X can be any one or more of A, B and C.
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，“任选(地)被烷基取代的环烷基”意味着烷基可以但不必须存在，该说明包括环烷基被烷基取代的情形和环烷基不被烷基取代的情形。The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl can but does not have to be present, and the description includes the situation that cycloalkyl is substituted with alkyl and the situation that cycloalkyl is not substituted with alkyl.
术语“取代”和“取代的”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。当描述某取代基不存在时，应当理解该取代基可以为一个或多个氢原子，前提是所述结构能使化合物达到稳定的状态。当描述基团中的每个碳原子可以任选地被杂原子代替时，条件是未超过基团中的所有原子在当前情况下的正常原子价，并且形成稳定的化合物。The terms "substituted" and "substituted" refer to one or more (e.g., one, two, three, or four) hydrogens on the designated atom being replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only when such combinations form stable compounds. When describing that a substituent does not exist, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure enables the compound to reach a stable state. When describing that each carbon atom in a group can be optionally replaced by a heteroatom, the condition is that the normal valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed.
如果取代基被描述为“任选地…被取代”，则取代基可以是未被取代的，或者可以是被取代的。如果某个原子或基团被描述为任选地被取代基列表中的一个或多个取代，则该原子或基团上的一个或多个氢可被独立地选择的、任选的取代基替代。当取代基为氧代(即＝O)时，意味着两个氢原子被替代。除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。If a substituent is described as "optionally substituted with", the substituent may be unsubstituted or substituted. If an atom or group is described as optionally substituted with one or more of the substituent list, one or more hydrogens on the atom or group may be replaced with independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代环中的任一成环原子。When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.
当任何变量(例如R)，以及带有标记的变量(例如R1、R2、R3、R4、R5、R6、R7等)在化合物的组成或结构中出现一次以上时，其在每次出现时在每一种情况下的定义都是独 立的。例如，如果一个基团被0、1、2、3或4个R取代基所取代，则所述基团可以任选地至多被四个R取代基所取代，并且每种情况下的每个R取代基的选项都是相互独立的。When any variable (e.g., R), as well as variables with labels (e.g., R1 , R2 , R3 , R4 , R5 , R6 , R7 , etc.) occurs more than once in a compound's composition or structure, its definition at each occurrence is unique. For example, if a group is substituted with 0, 1, 2, 3 or 4 R substituents, the group may optionally be substituted with up to four R substituents, and the options for each R substituent in each case are independent of each other.
术语“取代”表示化合物或基团上的一个或多个氢原子被其他原子或基团代替。条件是形成稳定的价态或化合物。表述“非取代”又可以理解为“未被取代”的。应当理解，取代基为氢时，这也可以表示对应的基团为“非取代”或者“未被取代”的。The term "substituted" means that one or more hydrogen atoms on a compound or group are replaced by other atoms or groups. The condition is that a stable valence state or compound is formed. The expression "non-substituted" can also be understood as "not substituted". It should be understood that when the substituent is hydrogen, this can also mean that the corresponding group is "non-substituted" or "not substituted".
本发明的化合物可以存在特定的几何或立体异构体形式。本发明所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。在某些实施方案中，优选化合物为那些显示更优生物活性的异构体化合物。本发明化合物已纯化的或部分纯化的异构体和立体异构体、或者外消旋混合物或非对映异构体混合物也均包括于本发明范围内。此类物质的纯化和分离可通过本领域已知的标准技术实现。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that show better biological activity. Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures are also included within the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.
术语“药学上可接受”的物质指这样的物质，其在正常的医学判断范围内适用于与患者的组织接触而不会有不适当毒性、刺激性、过敏反应等，具有合理的利弊比，且能有效用于其目的用途。The term "pharmaceutically acceptable" refers to a substance that is, within the scope of normal medical judgment, suitable for contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.
术语“药学上可接受盐”指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention which are safe and effective when used in mammals and have the desired biological activity.
术语“药物组合物”指含有一种或多种本发明所述的化合物或其生理学上/可药用的盐或前体药物，以及其他组分例如生理学上/可药用的载体或赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。The term "pharmaceutical composition" refers to a composition containing one or more compounds of the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically/pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些物质。“药学上可接受的载体”包括但不限于助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、崩解剂、稳定剂、溶剂或乳化剂。The term "pharmaceutically acceptable carrier" refers to those substances that have no significant irritation to organisms and do not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.
术语“给药”或“给予”等指可以使化合物或组合物能够递送至期望的生物作用位点的方法。这些方法包括但不限于口服或肠胃外(包括脑室内、静脉内、皮下、腹膜内、肌内、血管内注射或输注)、局部、直肠给药等。特别是注射或口服。The term "administration" or "administering" refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.
如本文所用，术语“治疗”包括缓解、减轻或改善疾病或症状，预防其他症状，改善或预防症状的潜在代谢因素，抑制疾病或症状，例如，阻止疾病或症状发展，减轻疾病或症状，促进疾病或症状缓解，或使疾病或症状的病征停止，和延伸至包括预防。“治疗”还包括实现治疗性获益和/或预防性获益。治疗性获益是指根除或改善所治疗的病症。此外，治疗性获益通过根除或改善一个或多个与潜在疾病相关的生理病征达到，尽管患者可能仍患有潜在疾病，但可观察到患者疾病的改善。预防性获益是指，患者为预防某种疾病风险 而使用组合物，或患者出现一个或多个疾病生理病症时服用，尽管尚未诊断此疾病。As used herein, the term "treat" includes alleviating, reducing or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing metabolic factors underlying a symptom, inhibiting a disease or symptom, e.g., stopping the disease or symptom from developing, alleviating the disease or symptom, promoting remission of the disease or symptom, or causing cessation of symptoms of the disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and although the patient may still suffer from the underlying disease, an improvement in the patient's disease is observed. A prophylactic benefit refers to the fact that a patient receives treatment to prevent the risk of a certain disease. The composition is used while the patient is experiencing one or more physiological symptoms of a disease, even though the disease has not yet been diagnosed.
术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，其可以有效地治疗或预防目标紊乱、疾病或病症。术语“神经精神类疾病”是指神经类疾病与精神类疾病的总称，包含神经类疾病和/或精神类疾病。The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating or preventing a target disorder, disease or condition. The term "neuropsychiatric disease" refers to a general term for neurological diseases and psychiatric diseases, including neurological diseases and/or psychiatric diseases.
针对药物、药物单元或活性成分而言，术语“有效量”、“治疗有效量”或“预防有效量”是指副作用可接受的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于个体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。With respect to a drug, drug unit or active ingredient, the term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" refers to a sufficient amount of the drug or pharmaceutical agent that can achieve the desired effect with acceptable side effects. The determination of the effective amount varies from person to person, depending on the age and general condition of the individual and on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
本发明公开或要求保护的晶体结构对等的晶体结构可能根据试验条件、纯度、设备和本领域技术人员已知的其他常用变量在合理误差范围内表现出类似但不完全相同的分析特性。相应地，本领域技术人员显而易见的是，可以在不背离本发明的范围和精神的情况下在本发明内做出各种修改和变动。在考虑本文公开的本发明的说明书和实践的基础上，本发明的其它实施方案是本领域技术人员显而易见的。申请人期望该说明书和实施例被视为示例性的，而非限制其范围。The crystal structures equivalent to the crystal structures disclosed or claimed in the present invention may show similar but not identical analytical characteristics within a reasonable error range according to experimental conditions, purity, equipment and other common variables known to those skilled in the art. Accordingly, it will be apparent to those skilled in the art that various modifications and changes can be made within the present invention without departing from the scope and spirit of the present invention. On the basis of considering the specification and practice of the present invention disclosed herein, other embodiments of the present invention are apparent to those skilled in the art. Applicants expect that the specification and examples are considered exemplary, rather than limiting their scope.
本领域普通技术人员公知，XRPD可能会因检测方法、条件和仪器的原因产生一定的位移和强度偏差。同一晶型的相同样品通常具有同样的主要XRPD特征峰，但可能存在一定操作误差，当由本领域普通技术人员，采用相应方法得到的同晶型样品采用相同的仪器和检测方法进行检测时，特征峰误差通常在±0.2°以内，然而不同技术人员使用不同仪器可能偶尔出现少数特征峰的误差超出该范围，如误差在±0.5°或±0.3°内均应认为属于相同晶型的XRPD特征峰。因此，作为本发明晶型的一个具体示例，其XRPD如图谱X所示，但普通技术人员了解的是，当关键特征峰位移2θ偏差在±0.5°、±0.3°或±0.2°以内，尤其在±0.2°左右时，均可以被认定为同一晶型，都可被解释为本发明保护范围之内。It is well known to those skilled in the art that XRPD may produce certain displacement and intensity deviations due to the detection method, conditions and instruments. The same sample of the same crystal form usually has the same main XRPD characteristic peak, but there may be certain operating errors. When the same crystal form sample obtained by the same method by the ordinary technicians in the art is detected by the same instrument and detection method, the characteristic peak error is usually within ±0.2°, but different technicians using different instruments may occasionally have a few characteristic peaks with errors exceeding this range. For example, the error within ±0.5° or ±0.3° should be considered to belong to the XRPD characteristic peak of the same crystal form. Therefore, as a specific example of the crystal form of the present invention, its XRPD is shown in spectrum X, but the ordinary technicians understand that when the 2θ deviation of the key characteristic peak displacement is within ±0.5°, ±0.3° or ±0.2°, especially around ±0.2°, it can be identified as the same crystal form and can be interpreted as within the scope of protection of the present invention.
下述发明详述旨在举例说明非限制性实施方案，使本领域其它技术人员更充分地理解本发明的技术方案、其原理及其实际应用，以便本领域其它技术人员可以以许多形式修改和实施本发明，使其可最佳地适应特定用途的要求。The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses.
有益效果Beneficial Effects
本发明涉及一类新型结构化合物，该类化合物作为一种TAAR1受体激动剂，具有抗神经精神类疾病活性，也即具有治疗或预防神经精神类疾病作用。在一些实施方式中，本发明化合物对TAAR1受体具有良好的激动作用。在一些实施方式中，本发明化合物具有良好的药物代谢动力学性质(例如合适的半衰期和作用持续时间，良好的血药浓度、药时曲线下面积和/或生物利用度)。在一些实施方式中，本发明化合物具有改善的体内药效作用，和/或改善的安全性(较低的毒性和/或较少的副作用)，和/或良好的患者依从性，和/ 或较不易产生耐受性等更优异的成药性质。The present invention relates to a class of novel structural compounds, which, as a TAAR1 receptor agonist, have anti-neuropsychiatric activity, that is, have the effect of treating or preventing neuropsychiatric diseases. In some embodiments, the compounds of the present invention have a good agonist effect on the TAAR1 receptor. In some embodiments, the compounds of the present invention have good pharmacokinetic properties (such as suitable half-life and duration of action, good blood concentration, area under the drug-time curve and/or bioavailability). In some embodiments, the compounds of the present invention have improved in vivo pharmacodynamic effects, and/or improved safety (lower toxicity and/or fewer side effects), and/or good patient compliance, and/or Or better drug-making properties such as being less likely to develop tolerance.
具体地，本公开内容的对TAAR1受体的激动活性结果表明，本发明化合物是有效的TAAR1受体激动剂，对TAAR1受体具有良好的激动作用。小鼠药代实验结果表明，本发明化合物表现出良好的药物代谢性质，具有优良的半衰期t1/2和快速的达峰时间Tmax，且最大血药浓度Cmax、药时曲线下面积AUC(0-t)和口服生物利用度F等代谢参数均表现良好。口服生物利用度良好的化合物在减少用药剂量、减轻副作用以及提高药物的药效等方面都具有重要的意义。Specifically, the results of the agonist activity of the present disclosure on the TAAR1 receptor show that the compounds of the present invention are effective TAAR1 receptor agonists and have good agonist effects on the TAAR1 receptor. The results of the mouse pharmacokinetic experiment show that the compounds of the present invention exhibit good drug metabolism properties, have excellent half-life t 1/2 and fast peak time T max , and the maximum blood drug concentration C max , the area under the drug-time curve AUC (0-t) and the oral bioavailability F and other metabolic parameters are all good. Compounds with good oral bioavailability are of great significance in reducing the dosage of medication, reducing side effects and improving the efficacy of drugs.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1为实施例1 4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的XRPD图示。Figure 1 is an XRPD diagram of Example 1 4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride.
图2为实施例1A(S)-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的XRPD图示。FIG. 2 is an XRPD diagram of Example 1A (S)-4,7,8,9,10,10a-hexahydro-5H-thiophene[2′,3′:3,4]pyrido[1,2-a]pyrazine hydrochloride.
图3为实施例1B(R)-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的XRPD图示。3 is an XRPD diagram of Example 1B (R)-4,7,8,9,10,10a-hexahydro-5H-thiophene[2′,3′:3,4]pyrido[1,2-a]pyrazine hydrochloride.
具体实施方式Detailed ways
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall within the scope limited by the appended claims of the application equally.
实施例Example
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员会理解，下列实施例仅用于说明本发明，而不应视为限制本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。如无特别指明，本文所用的比例或百分比按重量计。The embodiments of the present invention will be described in detail below in conjunction with examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If specific conditions are not specified in the examples, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially. If not otherwise specified, the ratios or percentages used herein are by weight.
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS).
NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用AVANCE III600核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代甲醇(CD3OD)和氘代氯仿(CDCl3)，内标为四甲基硅烷(TMS)。NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using an AVANCE III 600 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ) as the solvent, and tetramethylsilane (TMS) as the internal standard.
液质联用色谱(LC-MS)的测定用日本岛津LCMS2020质谱仪。Liquid chromatography-mass spectrometry (LC-MS) was performed using a Shimadzu LCMS2020 mass spectrometer.
HPLC的测定使用日本岛津LC20A液相色谱仪。HPLC determination was performed using Shimadzu LC20A liquid chromatograph.
薄层层析硅胶板使用烟台江友硅胶板，TLC采用的规格为0.2mm±0.03mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。The thin layer chromatography silica gel plate used was Yantai Jiangyou silica gel plate, the specification used for TLC was 0.2mm±0.03mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm.
X射线粉末衍射(XRPD)的测定采用德国布鲁克D2 phaser X射线粉末衍射仪，辐射源：铜靶，电压/电流：30k V/10mA，扫描范围：4°-40°(2θ值)，扫描速率：1s/step。 X-ray powder diffraction (XRPD) was measured using a German Bruker D2 phaser X-ray powder diffractometer, radiation source: copper target, voltage/current: 30 kV/10 mA, scanning range: 4°-40° (2θ value), scanning rate: 1 s/step.
熔点的测定采用瑞士梅特勒托利多MP70熔点仪，升温速率3℃/分钟。The melting point was determined using a Swiss Mettler Toledo MP70 melting point apparatus with a heating rate of 3°C/min.
实施例1Example 1
4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪
4,7,8,9,10,10a-Hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine
合成路线：
synthetic route:
步骤a：2-(噻吩-3-基)乙胺盐酸盐的合成
Step a: Synthesis of 2-(thiophen-3-yl)ethylamine hydrochloride
将2-(噻吩-3-基)乙腈(5.0g,0.04mol)溶于四氢呋喃(70mL)中，在室温下加入硼烷的四氢呋喃溶液(80mL,0.08mmol,1.0M)，在氮气保护下回流过夜。次日，将反应液冷却至室温后缓慢滴入甲醇(5mL)，然后缓慢加入盐酸的乙酸乙酯溶液(20mL,4M)，之后搅拌30分钟。然后将反应液抽滤，收集滤饼获得目标化合物(4.3g,收率65％)。Dissolve 2-(Thiophene-3-yl)acetonitrile (5.0g, 0.04mol) in tetrahydrofuran (70mL), add borane tetrahydrofuran solution (80mL, 0.08mmol, 1.0M) at room temperature, and reflux overnight under nitrogen protection. The next day, after cooling the reaction solution to room temperature, slowly drop methanol (5mL), then slowly add hydrochloric acid ethyl acetate solution (20mL, 4M), and then stir for 30 minutes. Then filter the reaction solution, collect the filter cake to obtain the target compound (4.3g, yield 65%).
LC-MS[M+H]+:128.2。LC-MS [M+H] + : 128.2.
1H NMR(400MHz,DMSO-d6):δ8.18(brs,3H),7.51(dd,J＝5.6,3.2Hz,1H),7.32(s,1H),7.05(d,J＝6.8Hz,1H),3.09-2.85(m,4H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.18 (brs, 3H), 7.51 (dd, J=5.6, 3.2 Hz, 1H), 7.32 (s, 1H), 7.05 (d, J=6.8 Hz, 1H), 3.09-2.85 (m, 4H).
步骤b：2-(1,3-二氧异吲哚-2-基)-N-(2-(噻吩-3-基)乙基)乙酰胺的合成
Step b: Synthesis of 2-(1,3-dioxoisoindole-2-yl)-N-(2-(thiophen-3-yl)ethyl)acetamide
将2-(噻吩-3-基)乙胺盐酸盐(2.0g,12.2mmol)和三乙胺(7.9g,78.75mmol)溶于二氯甲烷中(20mL)，然后在氮气保护和冰盐浴下将2-(1,3-二氧异吲哚-2-基)乙酰氯(3.5g,15.75mmol)的二氧六环溶液(5mL)缓慢加入上述溶液中，在室温下搅拌过夜。次日，反应液依次用水(10mL x 2)和饱和食盐水(10mL x 1)洗涤，分离有机相后用无水硫酸钠干燥，过滤浓 缩得到粗品，经柱层析(二氯甲烷/甲醇)分离纯化得到目标化合物(3.0g,收率78％)。Dissolve 2-(Thiophen-3-yl)ethylamine hydrochloride (2.0 g, 12.2 mmol) and triethylamine (7.9 g, 78.75 mmol) in dichloromethane (20 mL), then slowly add 2-(1,3-dioxoisoindol-2-yl)acetyl chloride (3.5 g, 15.75 mmol) in dioxane (5 mL) to the above solution under nitrogen protection and ice-salt bath, and stir overnight at room temperature. The next day, the reaction solution was washed with water (10 mL x 2) and saturated brine (10 mL x 1) in turn, the organic phase was separated and dried over anhydrous sodium sulfate, and the concentrated The crude product was obtained by condensation and separated and purified by column chromatography (dichloromethane/methanol) to obtain the target compound (3.0 g, yield 78%).
LC-MS[M+H]+:315.2。LC-MS [M+H] + : 315.2.
1H NMR(400MHz,DMSO-d6):δ8.33(t,J＝5.6Hz,1H),7.95-7.83(m,4H),7.46(dd,J＝4.8,2.8Hz,1H),7.21(d,J＝2.0Hz,1H),7.01(dd,J＝4.8,1.6Hz,1H),4.18(s,2H),3.32-3.24(m,2H),2.73(t,J＝7.6Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.33 (t, J = 5.6 Hz, 1H), 7.95-7.83 (m, 4H), 7.46 (dd, J = 4.8, 2.8 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 4.8, 1.6 Hz, 1H), 4.18 (s, 2H), 3.32-3.24 (m, 2H), 2.73 (t, J = 7.6 Hz, 2H).
步骤c：2-((4,5-二氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚-1,3-二酮
Step c: 2-((4,5-dihydrothieno[2,3-c]pyridin-7-yl)methyl)isoindole-1,3-dione
将2-(1,3-二氧异吲哚-2-基)-N-(2-(噻吩-3-基)乙基)乙酰胺(1.4g,4.46mmol)溶于三氯氧磷(10mL)中，在室温下加入五氯化磷(1.3g,6.25mmol)。反应液于40℃下搅拌4小时后冷却至室温，然后将反应液倒入水(100mL)中，调节溶液pH＝8后，用乙酸乙酯(50mL x 3)萃取。所得有机相用水(50mL x2)和饱和食盐水(50mL x1)洗涤，分离有机相用无水硫酸钠干燥。然后过滤浓缩得到目标化合物(1.1g,收率82％)。2-(1,3-dioxoisoindole-2-yl)-N-(2-(thiophene-3-yl)ethyl)acetamide (1.4 g, 4.46 mmol) was dissolved in phosphorus oxychloride (10 mL), and phosphorus pentachloride (1.3 g, 6.25 mmol) was added at room temperature. The reaction solution was stirred at 40°C for 4 hours and then cooled to room temperature. The reaction solution was then poured into water (100 mL), and after adjusting the solution pH to 8, it was extracted with ethyl acetate (50 mL x 3). The obtained organic phase was washed with water (50 mL x 2) and saturated brine (50 mL x 1), and the separated organic phase was dried over anhydrous sodium sulfate. Then the target compound (1.1 g, yield 82%) was obtained by filtration and concentration.
LC-MS[M+H]+:297.2。LC-MS [M+H] + : 297.2.
1H NMR(400MHz,CDCl3):δ7.93-7.85(m,2H),7.77-7.69(m,2H),7.35(d,J＝2.4Hz,1H),6.94(d,J＝2.8Hz,1H),4.76(s,2H),3.70(t,J＝8.4Hz,2H),2.71(t,J＝8.4Hz,2H). 1 H NMR (400 MHz, CDCl 3 ): δ7.93-7.85 (m, 2H), 7.77-7.69 (m, 2H), 7.35 (d, J=2.4 Hz, 1H), 6.94 (d, J=2.8 Hz, 1H), 4.76 (s, 2H), 3.70 (t, J=8.4 Hz, 2H), 2.71 (t, J=8.4 Hz, 2H).
步骤d：2-((4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚-1,3-二酮
Step d: 2-((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindole-1,3-dione
将2-((4,5-二氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚-1,3-二酮(600mg,2.03mmol)溶于1,2-二氯乙烷(15mL)中，然后在室温下加入乙酰氧基硼氢化钠(1.29g,6.08mmol)。加毕在氮气保护下于50℃油浴中搅拌过夜，然后冷却至室温后加入饱和碳酸氢钠水溶液(5mL)，分液得到有机相用水(5mL x 2)和饱和食盐水(5mL x 1)洗涤，之后用无水硫酸钠干燥，过滤浓缩得到粗品，经柱层析(二氯甲烷/甲醇)分离纯化后得到目标产物(154mg,收率25％)。2-((4,5-dihydrothieno[2,3-c]pyridin-7-yl)methyl)isoindole-1,3-dione (600 mg, 2.03 mmol) was dissolved in 1,2-dichloroethane (15 mL), and then sodium acetoxyborohydride (1.29 g, 6.08 mmol) was added at room temperature. After the addition, the mixture was stirred in an oil bath at 50°C under nitrogen protection overnight, and then cooled to room temperature and saturated sodium bicarbonate aqueous solution (5 mL) was added. The organic phase was separated and washed with water (5 mL x 2) and saturated brine (5 mL x 1), and then dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by column chromatography (dichloromethane/methanol) to obtain the target product (154 mg, yield 25%).
LC-MS[M+H]+:299.3。LC-MS [M+H] + : 299.3.
1H NMR(400MHz,CDCl3):δ7.92-7.82(m,2H),7.78-7.67(m,2H),7.17(d,J＝6.4Hz,1H),6.82(d,J＝6.8Hz,1H),4.46(t,J＝9.6Hz,1H),3.97(d,J＝10.0Hz,2H),3.35-3.20(m,1H),3.01-2.87(m,1H),2.71-2.59(m,2H). 1 H NMR (400 MHz, CDCl 3 ): δ7.92-7.82 (m, 2H), 7.78-7.67 (m, 2H), 7.17 (d, J=6.4 Hz, 1H), 6.82 (d, J=6.8 Hz, 1H), 4.46 (t, J=9.6 Hz, 1H), 3.97 (d, J=10.0 Hz, 2H), 3.35-3.20 (m, 1H), 3.01-2.87 (m, 1H), 2.71-2.59 (m, 2H).
步骤e：(4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲胺
Step e: (4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methanamine
将2-((4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚-1,3-二酮(1.0g,3.36mmol)和水合肼(1g,20.13mmol)加入乙醇(20mL)中回流3小时后冷却至室温。然后过滤反应液，浓缩滤液后得到目标产物(563mg,收率100％)。 2-((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindole-1,3-dione (1.0 g, 3.36 mmol) and hydrazine hydrate (1 g, 20.13 mmol) were added to ethanol (20 mL) and refluxed for 3 hours and then cooled to room temperature. The reaction solution was then filtered and the filtrate was concentrated to obtain the target product (563 mg, yield 100%).
LC-MS[M+H]+:169.2。LC-MS [M+H] + : 169.2.
步骤f：((4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸叔丁酯
Step f: tert-Butyl ((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate
将(4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲胺(563mg,3.36mmol)溶于二氯甲烷(10mL)中，加入二碳酸二叔丁酯(580mg,2.66mmol)和三乙胺(680mg,6.71mmol)，在室温下搅拌过夜。次日反应液用水(3mL x 3)洗涤，有机相用无水硫酸钠干燥，过滤浓缩得到粗品，经柱层析(石油醚/乙酸乙酯)分离纯化后得到目标产物(290mg,收率33％)。Dissolve (4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methylamine (563 mg, 3.36 mmol) in dichloromethane (10 mL), add di-tert-butyl dicarbonate (580 mg, 2.66 mmol) and triethylamine (680 mg, 6.71 mmol), and stir at room temperature overnight. The next day, the reaction solution was washed with water (3 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target product (290 mg, yield 33%).
LC-MS[M+H]+:269.3。LC-MS [M+H] + : 269.3.
1H NMR(400MHz,CD3OD):δ7.25(d,J＝5.2Hz,1H),6.84(d,J＝5.2Hz,1H),4.16(t,J＝6.0Hz,1H),3.47(dd,J＝13.6,5.2Hz,1H),3.31-3.20(m,2H),3.01-2.92(m,1H),2.79-2.64(m,2H),1.49(s,9H). 1 H NMR (400 MHz, CD 3 OD): δ7.25 (d, J=5.2 Hz, 1H), 6.84 (d, J=5.2 Hz, 1H), 4.16 (t, J=6.0 Hz, 1H), 3.47 (dd, J=13.6, 5.2 Hz, 1H), 3.31-3.20 (m, 2H), 3.01-2.92 (m, 1H), 2.79-2.64 (m, 2H), 1.49 (s, 9H).
步骤g：(6-(2-氯乙酰基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸叔丁酯
Step g: tert-Butyl (6-(2-chloroacetyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate
将((4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸叔丁酯(290mg,1.08mmol)和N,N-二异丙基乙胺(419mg,3.25mmol)溶于二氯甲烷(10mL)中，向反应液加入2-氯乙酰氯(149mg,1.30mmol)的二氯甲烷(1mL)溶液，在室温下搅拌3小时。之后反应液用水(3mL x3)洗涤，用无水硫酸钠干燥，过滤浓缩得到粗品，经柱层析(石油醚/乙酸乙酯)分离纯化后得到目标产物(150mg,收率39％)。Tert-butyl ((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate (290 mg, 1.08 mmol) and N,N-diisopropylethylamine (419 mg, 3.25 mmol) were dissolved in dichloromethane (10 mL), and a solution of 2-chloroacetyl chloride (149 mg, 1.30 mmol) in dichloromethane (1 mL) was added to the reaction solution, and stirred at room temperature for 3 hours. The reaction solution was then washed with water (3 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target product (150 mg, yield 39%).
LC-MS[M+H-100]+:245.1。LC-MS [M+H-100] + : 245.1.
步骤h：1-(7-(氨基甲基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-基)-2-氯乙酮
Step h: 1-(7-(Aminomethyl)-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl)-2-chloroethanone
将(6-(2-氯乙酰基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸叔丁酯(150mg,0.43mmol)加入盐酸的乙酸乙酯溶液(5mL,4M)中，在室温下搅拌1小时。然后浓缩反应液得到目标粗产物(107mg,收率100％)。Tert-butyl (6-(2-chloroacetyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate (150 mg, 0.43 mmol) was added to a solution of hydrochloric acid in ethyl acetate (5 mL, 4 M) and stirred at room temperature for 1 hour. The reaction solution was then concentrated to obtain the target crude product (107 mg, yield 100%).
LC-MS[M+H]+:245.1。LC-MS [M+H] + : 245.1.
步骤i：4,5,8,9,10,10a-六氢-7H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7-酮
Step i: 4,5,8,9,10,10a-Hexahydro-7H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-7-one
将1-(7-(氨基甲基)-4,5-二氢噻吩并[2,3-c]吡啶-6(7H)-基)-2-氯乙酮(107mg,0.43mmol)溶于二甲基亚砜(5mL)中，加入碳酸钾(300mg,2.17mmol)和碘化钠(33mg,0.22mmol)，反 应液在70℃下搅拌过夜。次日将反应液冷却至室温后倒入水(15mL)中，用二氯甲烷(10mL x 3)萃取。合并有机相，依次用水(10mL x1)和饱和食盐水(10mL x1)洗涤，用无水硫酸钠干燥，然后过滤浓缩后经柱层析(二氯甲烷/甲醇)分离纯化得到目标产物(50mg,收率55％)。1-(7-(Aminomethyl)-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl)-2-chloroethanone (107 mg, 0.43 mmol) was dissolved in dimethyl sulfoxide (5 mL), potassium carbonate (300 mg, 2.17 mmol) and sodium iodide (33 mg, 0.22 mmol) were added, and the mixture was stirred for 2 h. The reaction mixture was stirred at 70°C overnight. The next day, the reaction mixture was cooled to room temperature and poured into water (15 mL), and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography (dichloromethane/methanol) to obtain the target product (50 mg, yield 55%).
LC-MS[M+H]+:209.1。LC-MS [M+H] + : 209.1.
步骤j：4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪
Step j: 4,7,8,9,10,10a-Hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine
将8,9,10,10a-四氢-4H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7(5H)-酮(50mg,0.24mmol)溶于四氢呋喃(5mL)中，然后加入硼烷的四氢呋喃溶液(1.2mL,1.2mmol,1.0M)，在室温下搅拌过夜后加入甲醇(1mL)淬灭。浓缩反应液后粗产物经制备液相(水-乙腈-乙酸铵体系)分离纯化得到目标产物(5.7mg,收率12％)。8,9,10,10a-tetrahydro-4H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-7(5H)-one (50 mg, 0.24 mmol) was dissolved in tetrahydrofuran (5 mL), and then a tetrahydrofuran solution of borane (1.2 mL, 1.2 mmol, 1.0 M) was added. After stirring at room temperature overnight, methanol (1 mL) was added to quench. After the reaction solution was concentrated, the crude product was separated and purified by preparative liquid phase (water-acetonitrile-ammonium acetate system) to obtain the target product (5.7 mg, yield 12%).
LC-MS[M+H]+:195.1。LC-MS [M+H] + : 195.1.
1H NMR(400MHz,CD3OD):δ7.25(dd,J＝5.2,1.2Hz,1H),6.83(d,J＝5.2Hz,1H),3.45(d,J＝11.2Hz,1H),3.35-3.32(m,1H),3.16-3.05(m,2H),3.00-2.87(m,2H),2.80-2.67(m,2H),2.63-2.47(m,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.25 (dd, J=5.2, 1.2 Hz, 1H), 6.83 (d, J=5.2 Hz, 1H), 3.45 (d, J=11.2 Hz, 1H), 3.35-3.32 (m, 1H), 3.16-3.05 (m, 2H), 3.00-2.87 (m, 2H), 2.80-2.67 (m, 2H), 2.63-2.47 (m, 3H).
4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的制备：Preparation of 4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride:
合成路线:
synthetic route:
步骤a:(2-(噻吩-3-基)-乙基)氨基甲酸叔丁基酯的合成
Step a: Synthesis of tert-butyl (2-(thiophen-3-yl)-ethyl)carbamate
将2-(噻吩-3-基)乙腈(18.0g,0.15mol)溶于四氢呋喃(300mL)中，在氮气保护下冷却到0℃，缓慢加入硼烷二甲硫醚(10M,44mL,0.44mol)溶液后，恢复到室温搅拌1小时。然后继续回流4小时。冷却到室温后，将反应液缓慢加入到冰水冷却的甲醇中淬灭，然后回流1小时。冷却到室温后，浓缩得到黄色油状物。将该油状物溶于四氢呋喃(200mL)中，加入二碳酸二叔丁酯(31.9g,0.14mol)并搅拌2小时。将反应液浓缩、柱层析得到目标产物(31.0g,收率93％)。 Dissolve 2-(Thiophene-3-yl)acetonitrile (18.0g, 0.15mol) in tetrahydrofuran (300mL), cool to 0°C under nitrogen protection, slowly add borane dimethyl sulfide (10M, 44mL, 0.44mol) solution, return to room temperature and stir for 1 hour. Then continue to reflux for 4 hours. After cooling to room temperature, slowly add the reaction solution to ice-cooled methanol to quench, and then reflux for 1 hour. After cooling to room temperature, concentrate to obtain a yellow oil. Dissolve the oil in tetrahydrofuran (200mL), add di-tert-butyl dicarbonate (31.9g, 0.14mol) and stir for 2 hours. Concentrate the reaction solution and column chromatography to obtain the target product (31.0g, yield 93%).
LC-MS[M+H-56]+:172.1.LC-MS [M+H-56] + : 172.1.
步骤b:2-((4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚-1,3-二酮的合成
Step b: Synthesis of 2-((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindole-1,3-dione
将(2-(噻吩-3-基)-乙基)氨基甲酸叔丁基酯(31.0g,0.14mol)溶于二氯甲烷(250mL)中，在氮气保护下冷却到0℃，加入三氟乙酸(77.8g,0.68mol)后，恢复到室温搅拌0.5小时。加入2-(1,3-二氧杂吲哚-2-基)乙醛(25.8g,0.14mol)并继续搅拌至反应完全。将反应液浓缩后，用饱和碳酸钠水溶液中和，二氯甲烷萃取。所得有机相经干燥、浓缩和柱层析得到目标产物(35.0g,收率86％)。Dissolve tert-butyl (2-(thiophene-3-yl)-ethyl)carbamate (31.0 g, 0.14 mol) in dichloromethane (250 mL), cool to 0 ° C under nitrogen protection, add trifluoroacetic acid (77.8 g, 0.68 mol), return to room temperature and stir for 0.5 hours. Add 2-(1,3-dioxaindol-2-yl)acetaldehyde (25.8 g, 0.14 mol) and continue stirring until the reaction is complete. After concentrating the reaction solution, neutralize it with saturated sodium carbonate aqueous solution and extract with dichloromethane. The obtained organic phase is dried, concentrated and column chromatographed to obtain the target product (35.0 g, yield 86%).
LC-MS[M+H]+:299.3.LC-MS [M+H] + : 299.3.
步骤c:2-(7-((1,3-二氧代异吲哚啉-2-基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)乙酸乙酯的合成
Step c: Synthesis of ethyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)acetate
将2-((4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚-1,3-二酮(35.0g,0.12mol)溶于乙腈(230mL)中，加入N,N-二异丙基乙胺(30.3g,0.23mol)和溴乙酸乙酯(29.4g,0.18mol)后，在80℃下搅拌4小时。冷却到室温后，反应液经浓缩，饱和氯化铵洗涤，乙酸乙酯萃取。所得有机相经干燥、浓缩和柱层析得到目标化合物(33.0g,收率73％)。2-((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindole-1,3-dione (35.0 g, 0.12 mol) was dissolved in acetonitrile (230 mL), and N,N-diisopropylethylamine (30.3 g, 0.23 mol) and ethyl bromoacetate (29.4 g, 0.18 mol) were added, and stirred at 80°C for 4 hours. After cooling to room temperature, the reaction solution was concentrated, washed with saturated ammonium chloride, and extracted with ethyl acetate. The obtained organic phase was dried, concentrated and column chromatographed to obtain the target compound (33.0 g, yield 73%).
LC-MS[M+H]+:385.3.LC-MS [M+H] + : 385.3.
步骤d:4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的合成
Step d: Synthesis of 4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
将2-(7-((1,3-二氧代异吲哚啉-2-基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)乙酸乙酯(33.0g,85.9mmol)溶于乙醇(850mL)中，加入水合肼(16.1g,0.26mol,80％)后，在80℃下搅拌6小时。冷却到室温后，过滤。所得滤液经浓缩、柱层析得到目标化合物(14.5g,收率82％)。Ethyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)acetate (33.0 g, 85.9 mmol) was dissolved in ethanol (850 mL), hydrazine hydrate (16.1 g, 0.26 mol, 80%) was added, and the mixture was stirred at 80°C for 6 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated and subjected to column chromatography to obtain the target compound (14.5 g, yield 82%).
LC-MS[M+H]+:209.3.LC-MS [M+H] + : 209.3.
步骤e:4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的合成
Step e: Synthesis of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
将4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮(14.5g,69.7mmol)溶于四氢呋喃(350mL)中，在氮气下冷却到0℃后，分批加入四氢锂铝(13.2g,0.35mol)， 升温至65℃继续搅拌4小时。冷却到0℃后，缓慢加入十水硫酸钠淬灭。过滤，向所得滤液中加入二碳酸二叔丁酯(15.2g,69.7mmol)并搅拌0.5小时。反应液经浓缩、柱层析得到目标化合物(17.0g,收率83％)。Dissolve 4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one (14.5 g, 69.7 mmol) in tetrahydrofuran (350 mL), cool to 0°C under nitrogen, and add lithium aluminum tetrahydride (13.2 g, 0.35 mol) in batches. The mixture was heated to 65°C and stirred for 4 hours. After cooling to 0°C, sodium sulfate decahydrate was slowly added to quench the mixture. The mixture was filtered and di-tert-butyl dicarbonate (15.2 g, 69.7 mmol) was added to the filtrate and stirred for 0.5 hours. The reaction mixture was concentrated and purified by column chromatography to obtain the target compound (17.0 g, yield 83%).
LC-MS[M+H]+:295.4.LC-MS [M+H] + : 295.4.
步骤f:4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step f: Synthesis of 4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯(17.0g,57.8mmol)溶于乙酸乙酯(100mL)中，在氮气下冷却到0℃后，加入氯化氢的乙酸乙酯(100mL)溶液，恢复到室温并继续搅拌至反应完全。过滤，所得滤饼经干燥得到目标化合物(14.4g,收率94％)。呈灰白色粉末，熔点为279±2℃，具有如图1所示的XRPD图。Dissolve tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate (17.0 g, 57.8 mmol) in ethyl acetate (100 mL), cool to 0°C under nitrogen, add a solution of hydrogen chloride in ethyl acetate (100 mL), return to room temperature and continue stirring until the reaction is complete. Filter, and the filter cake obtained is dried to obtain the target compound (14.4 g, yield 94%). It is an off-white powder with a melting point of 279±2°C and an XRPD pattern as shown in Figure 1.
LC-MS[M+H]+:195.3.LC-MS [M+H] + : 195.3.
1H NMR(400MHz,CD3OD):δ7.56(d,J＝5.2Hz,1H),7.03(d,J＝5.2Hz,1H),5.14(d,J＝10.8Hz,1H),4.15(dd,J＝14.0,2.8Hz,1H),3.97-3.57(m,7H),3.34-3.25(m,1H),3.13(dd,J＝17.2,5.2Hz,1H). 1 H NMR (400 MHz, CD 3 OD): δ7.56 (d, J=5.2 Hz, 1H), 7.03 (d, J=5.2 Hz, 1H), 5.14 (d, J=10.8 Hz, 1H), 4.15 (dd, J=14.0, 2.8 Hz, 1H), 3.97-3.57 (m, 7H), 3.34-3.25 (m, 1H), 3.13 (dd, J=17.2, 5.2 Hz, 1H).
实施例1AExample 1A
(S)-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
(S)-4,7,8,9,10,10a-Hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
实施例1BExample 1B
(R)-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
(R)-4,7,8,9,10,10a-Hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
步骤a：4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的合成Step a: Synthesis of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
将5,7,8,9,10,10a-六氢-4H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪(0.11g,0.54mmol)溶于水(2mL)和四氢呋喃(10mL)的混合溶剂中，依次向反应液中加入碳酸氢钠(0.09g,1.08mmol)和二碳酸二叔丁酯(0.17g,0.81mmol)，加毕后在室温下搅拌1h。将反应液倒入水中(30mL)，用二氯甲烷萃取三次(50mL x 3)，合并有机相后经无水硫酸钠干燥，过滤浓缩，粗产物经 柱层析(二氯甲烷/甲醇)分离纯化得到目标产物(135mg,收率85％)。5,7,8,9,10,10a-hexahydro-4H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine (0.11 g, 0.54 mmol) was dissolved in a mixed solvent of water (2 mL) and tetrahydrofuran (10 mL). Sodium bicarbonate (0.09 g, 1.08 mmol) and di-tert-butyl dicarbonate (0.17 g, 0.81 mmol) were added to the reaction solution in sequence. After the addition, the mixture was stirred at room temperature for 1 h. The reaction solution was poured into water (30 mL) and extracted with dichloromethane three times (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by The target product (135 mg, yield 85%) was obtained by separation and purification by column chromatography (dichloromethane/methanol).
步骤b:4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的手性拆分Step b: Chiral separation of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
将4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯通过手性色谱柱拆分得到对映异构体1和对映异构体2。4,5,7,8,10,10a-Hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylic acid tert-butyl ester was separated by chiral chromatography to give enantiomer 1 and enantiomer 2.
液相分析方法：色谱柱：DAICEL CHIRALPAK IF column；流动相：乙腈；检测波长：214nm；流速：1.0mL/min；柱温：35℃。对映异构体1和对映异构体2的保留时间依次为4.49min和5.26min。Liquid phase analysis method: chromatographic column: DAICEL CHIRALPAK IF column; mobile phase: acetonitrile; detection wavelength: 214nm; flow rate: 1.0mL/min; column temperature: 35℃. The retention times of enantiomer 1 and enantiomer 2 are 4.49min and 5.26min, respectively.
步骤c:4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的对映异构体的制备Step c: Preparation of enantiomers of 4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将上述拆分得到的4,5,7,8,10,10a-六氢-9H-噻吩并[2'，3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的对映异构体1(0.65g,2.2mmol)溶于氯化氢的乙酸乙酯(3M,10mL)溶液中，室温搅拌3h后抽滤，并用乙酸乙酯洗涤滤饼，干燥后得到目标产物对映异构体P1(化合物1A，450mg,收率88％，[α]D29＝-63.3(c 0.12，H2O))。呈灰白色粉末，熔点为279±2℃，具有如图2所示的XRPD图。The enantiomer 1 (0.65 g, 2.2 mmol) of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate obtained by the above separation was dissolved in a solution of hydrogen chloride in ethyl acetate (3M, 10 mL), stirred at room temperature for 3 h, and then filtered, and the filter cake was washed with ethyl acetate and dried to obtain the target product enantiomer P1 (compound 1A, 450 mg, yield 88%, [α]D 29 =-63.3 (c 0.12, H 2 O)). It is an off-white powder with a melting point of 279±2°C and an XRPD pattern as shown in FIG2 .
LC-MS[M+H]+:195.1。LC-MS [M+H] + : 195.1.
1H NMR(400MHz,CD3OD):δ7.55(d,J＝4.8Hz,1H),7.01(d,J＝4.8Hz,1H),5.04(d,J＝11.2Hz,1H),4.11(dd,J＝14.0,2.8Hz,1H),3.89-3.53(m,7H),3.29-3.22(m,1H),3.10(dd,J＝17.6,5.2Hz,1H). 1 H NMR (400 MHz, CD 3 OD): δ7.55 (d, J=4.8 Hz, 1H), 7.01 (d, J=4.8 Hz, 1H), 5.04 (d, J=11.2 Hz, 1H), 4.11 (dd, J=14.0, 2.8 Hz, 1H), 3.89-3.53 (m, 7H), 3.29-3.22 (m, 1H), 3.10 (dd, J=17.6, 5.2 Hz, 1H).
将上述拆分得到的4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的对映异构体2(620mg)通过类似的合成方法得到目标产物的对映异构体P2(化合物1B，413mg,收率85％，[α]D29＝54.6(c 0.11，H2O))。呈灰白色粉末，熔点为281±2℃，具有如图3所示的XRPD图。The enantiomer 2 (620 mg) of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate obtained by the above separation was used to obtain the enantiomer P2 of the target product (compound 1B, 413 mg, yield 85%, [α]D 29 =54.6 (c 0.11, H 2 O)) by a similar synthesis method. It is an off-white powder with a melting point of 281±2° C. and an XRPD pattern as shown in FIG3 .
LC-MS[M+H]+:195.2。LC-MS [M+H] + : 195.2.
1H NMR(400MHz,CD3OD):δ7.54(d,J＝4.8Hz,1H),7.01(d,J＝5.2Hz,1H),4.99(d,J＝10.8Hz,1H),4.10(dd,J＝13.6,2.0Hz,1H),3.88-3.50(m,7H),3.29-3.21(m,1H),3.09(dd,J＝17.6,5.2Hz,1H). 1 H NMR (400 MHz, CD 3 OD): δ7.54 (d, J=4.8 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 4.99 (d, J=10.8 Hz, 1H), 4.10 (dd, J=13.6, 2.0 Hz, 1H), 3.88-3.50 (m, 7H), 3.29-3.21 (m, 1H), 3.09 (dd, J=17.6, 5.2 Hz, 1H).
实施例2Example 2
7-甲基-4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮
7-Methyl-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-8(7H)-one
合成路线：
synthetic route:
步骤a:2-(7-(((叔丁氧基羰基)氨基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)基)丙酸甲酯的合成
Step a: Synthesis of methyl 2-(7-(((tert-butoxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)yl)propanoate
将叔丁基((4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸酯(1.1g,4.10mmol)，碳酸钾(2.83g,20.5mmol)，碘化钠(0.31g,2.05mmol)和2-溴丙酸甲酯(1.03g,6.15mmol)加入至二甲基亚砜(15mL)中，于80℃油浴中搅拌2h。将反应液倒入水(50mL)中，用二氯甲烷萃取三次(10mL x 3)后，有机相依次用水洗涤三次(10mL x 3)，饱和食盐水洗涤一次(10mL)，用无水硫酸钠干燥后过滤浓缩，粗产物经柱层析(石油醚/乙酸乙酯)分离纯化得到目标化合物(0.45g,收率35％)。Tert-butyl ((4,5,6,7-tetrahydrothieno [2,3-c] pyridin-7-yl) methyl) carbamate (1.1 g, 4.10 mmol), potassium carbonate (2.83 g, 20.5 mmol), sodium iodide (0.31 g, 2.05 mmol) and methyl 2-bromopropionate (1.03 g, 6.15 mmol) were added to dimethyl sulfoxide (15 mL) and stirred in an oil bath at 80 ° C for 2 h. The reaction solution was poured into water (50 mL), extracted with dichloromethane three times (10 mL x 3), and the organic phase was washed with water three times (10 mL x 3), washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target compound (0.45 g, yield 35%).
LC-MS[M+H]+:355.4。LC-MS [M+H] + : 355.4.
步骤b:7-甲基-4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的合成
Step b: Synthesis of 7-methyl-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
将2-(7-(((叔丁氧基羰基)氨基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)基)丙酸甲酯(0.45g,1.27mmol)溶于氯化氢的乙酸乙酯溶液(3M,10mL)中，室温搅拌1h后直接浓缩反应液去除溶剂，之后加入乙醇(20mL)和碳酸钾(0.88g,6.35mmol)，反应液置于80℃油浴中搅拌3h后抽滤，浓缩滤液得粗品，经柱层析(二氯甲烷/甲醇)分离纯化得到一对非对映异构体，分别为异构体1(0.12g,收率43％)和异构体2(0.12g,收率43％)。Methyl 2-(7-(((tert-butoxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)yl)propanoate (0.45 g, 1.27 mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (3M, 10 mL). After stirring at room temperature for 1 h, the reaction solution was directly concentrated to remove the solvent. Ethanol (20 mL) and potassium carbonate (0.88 g, 6.35 mmol) were then added. The reaction solution was placed in an 80°C oil bath and stirred for 3 h. The mixture was filtered and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (dichloromethane/methanol) to obtain a pair of diastereoisomers, namely isomer 1 (0.12 g, yield 43%) and isomer 2 (0.12 g, yield 43%).
异构体1:Isomer 1:
LC-MS[M+H]+:223.0。LC-MS [M+H] + : 223.0.
1H NMR(400MHz,CDCl3):δ7.16(d,J＝5.2Hz,1H),6.82(d,J＝5.2Hz,1H),6.15(s,1H),3.80(d,J＝10.8Hz,1H),3.61-3.52(m,1H),3.41-3.31(m,2H),3.13(q,J＝6.8Hz,1H),2.95-2.82(m,1H),2.76-2.67(m,1H),2.39(td,J＝11.6,3.6Hz,1H),1.55(d,J＝6.8Hz,3H). 1 H NMR (400 MHz, CDCl 3 ): δ7.16 (d, J=5.2 Hz, 1H), 6.82 (d, J=5.2 Hz, 1H), 6.15 (s, 1H), 3.80 (d, J=10.8 Hz, 1H), 3.61-3.52 (m, 1H), 3.41-3.31 (m, 2H), 3.13 (q, J=6.8 Hz, 1H), 2.95-2.82 (m, 1H), 2.76-2.67 (m, 1H), 2.39 (td, J=11.6, 3.6 Hz, 1H), 1.55 (d, J=6.8 Hz, 3H).
异构体2:Isomer 2:
LC-MS[M+H]+:223.0。LC-MS [M+H] + : 223.0.
1H NMR(400MHz,CDCl3):δ7.16(d,J＝5.2Hz,1H),6.81(d,J＝5.2Hz,1H),6.11(s,1H),4.31(d,J＝9.6Hz,1H),3.77(q,J＝7.2Hz,1H),3.54(d,J＝10.8Hz,1H),3.35(t,J＝10.4Hz,1H),3.05-2.65(m,4H),1.43(d,J＝7.2Hz,3H). 1 H NMR (400 MHz, CDCl 3 ): δ7.16 (d, J=5.2 Hz, 1H), 6.81 (d, J=5.2 Hz, 1H), 6.11 (s, 1H), 4.31 (d, J=9.6 Hz, 1H), 3.77 (q, J=7.2 Hz, 1H), 3.54 (d, J=10.8 Hz, 1H), 3.35 (t, J=10.4 Hz, 1H), 3.05-2.65 (m, 4H), 1.43 (d, J=7.2 Hz, 3H).
实施例3Example 3
8-甲基-4,5,8,9,10,10a-六氢-7H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7-酮
8-Methyl-4,5,8,9,10,10a-hexahydro-7H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-7-one
合成路线：
synthetic route:
步骤a：叔丁基((6-(2-氯丙酰基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸酯的合成
Step a: Synthesis of tert-butyl ((6-(2-chloropropionyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate
将叔丁基((4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸酯(0.54g,2.01mol)溶于二氯甲烷(10mL)中，加入N,N-二异丙基乙胺(0.78g,6.03mmol)和2-氯丙酰氯(0.38g,3.01mmol)，在室温下搅拌2h。之后将反应液用水洗涤三次(10mL x 3)，无水硫酸钠干燥后浓缩得到目标化合物(0.7g,收率99％)。Tert-butyl ((4,5,6,7-tetrahydrothieno [2,3-c] pyridin-7-yl) methyl) carbamate (0.54 g, 2.01 mol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (0.78 g, 6.03 mmol) and 2-chloropropionyl chloride (0.38 g, 3.01 mmol) were added, and stirred at room temperature for 2 h. The reaction solution was then washed with water three times (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (0.7 g, yield 99%).
LC-MS[M+H]+:358.9。LC-MS [M+H] + : 358.9.
步骤b：1-(7-(氨基甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-2-氯丙烷-1-酮的合成
Step b: Synthesis of 1-(7-(aminomethyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-2-chloropropane-1-one
将叔丁基((6-(2-氯丙酰基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸酯(0.70g,1.95mmol)溶于氯化氢的乙酸乙酯溶液(3M,15mL)中，室温搅拌1h，将反应液用饱和碳酸氢钠水溶液中和至中性，用二氯甲烷萃取三次(15mL x 3)后合并有机相，经无水硫酸钠干燥后浓缩得到目标产物(0.4g,收率78％)。Dissolve tert-butyl ((6-(2-chloropropionyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate (0.70 g, 1.95 mmol) in a solution of hydrogen chloride in ethyl acetate (3M, 15 mL) and stir at room temperature for 1 h. Neutralize the reaction solution with saturated aqueous sodium bicarbonate solution until neutral. Extract three times with dichloromethane (15 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain the target product (0.4 g, yield 78%).
LC-MS[M+H]+:259.0。LC-MS [M+H] + : 259.0.
步骤c：8-甲基-4,5,8,9,10,10a-六氢-7H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7-酮的合成
Step c: Synthesis of 8-methyl-4,5,8,9,10,10a-hexahydro-7H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-7-one
将1-(7-(氨基甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-2-氯丙烷-1-酮(0.4g,1.55mmol)溶于二甲基亚砜(10mL)中，在室温下加入碘化钠(0.12g,0.78mmol)和碳酸钾(1.07g,7.75mmol)。反应液于80℃下搅拌3小时后冷却至室温，然后将反应液倒入水(50mL)中，用二氯甲烷(20mL x 3)萃取三次。所得有机相用水(50mL x3)和饱和食盐水(50mL x1)洗涤后，用无水硫酸钠干燥，过滤浓缩得到粗品，经柱层析(二氯甲烷/甲醇)分离纯化后得到目 标产物(235mg,收率68％,d.r.＝5.5:1)。1-(7-(Aminomethyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-2-chloropropane-1-one (0.4g, 1.55mmol) was dissolved in dimethyl sulfoxide (10mL), and sodium iodide (0.12g, 0.78mmol) and potassium carbonate (1.07g, 7.75mmol) were added at room temperature. The reaction solution was stirred at 80°C for 3 hours and then cooled to room temperature. The reaction solution was then poured into water (50mL) and extracted three times with dichloromethane (20mL x 3). The obtained organic phase was washed with water (50mL x3) and saturated brine (50mL x1), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by column chromatography (dichloromethane/methanol) to obtain the target compound. The target product (235 mg, yield 68%, dr = 5.5:1).
主要异构体：Main isomers:
LC-MS[M+H]+:223.0。LC-MS [M+H] + : 223.0.
1H NMR(400MHz,CDCl3):δ7.20(d,J＝5.2Hz,1H),6.83(d,J＝4.8Hz,1H),4.82-4.74(m,1H),3.67(q,J＝7.2Hz,1H),3.43(dd,J＝13.6,4.8Hz,1H),3.17(dd,J＝13.2,8.0Hz,1H),2.90-2.62(m,4H),1.38(d,J＝7.2Hz,3H). 1 H NMR (400 MHz, CDCl 3 ): δ7.20 (d, J=5.2 Hz, 1H), 6.83 (d, J=4.8 Hz, 1H), 4.82-4.74 (m, 1H), 3.67 (q, J=7.2 Hz, 1H), 3.43 (dd, J=13.6, 4.8 Hz, 1H), 3.17 (dd, J=13.2, 8.0 Hz, 1H), 2.90-2.62 (m, 4H), 1.38 (d, J=7.2 Hz, 3H).
实施例4Example 4
7,7-二氟-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
7,7-Difluoro-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物4的合成路线参考实施例1的合成路线。The synthetic route of compound 4 refers to the synthetic route of Example 1.
LC-MS[M+H]+:231.1。LC-MS [M+H] + : 231.1.
实施例5Example 5
8,8-二氟-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
8,8-Difluoro-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物5的合成路线参考实施例1的合成路线。The synthetic route of compound 5 refers to the synthetic route of Example 1.
LC-MS[M+H]+:231.1。LC-MS [M+H] + : 231.1.
实施例6Example 6
10-甲基-4,7,8,9,10,10,10a-六氢噻吩并[2,3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
10-Methyl-4,7,8,9,10,10,10a-hexahydrothieno[2,3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
步骤a:2-氯-N-(2-(噻吩-3-基)乙基)丙酰胺的合成
Step a: Synthesis of 2-chloro-N-(2-(thiophen-3-yl)ethyl)propionamide
在氮气保护下，将2-(噻吩-3-基)乙烷-1-胺(4.0g,31.5mmol)和三乙胺(6.4g,63.0mmol)溶于二氯甲烷(30mL)中，冷却到0℃，滴加2-氯丙酰氯(4.8g,37.8mmol)，搅拌1h。将反应液倒入饱和氯化铵水溶液中，用乙酸乙酯萃取，所得有机相经干燥浓缩，粗产物经柱层析(石油醚/乙酸乙酯)分离纯化得到目标产物(5.4g,收率79％)。Under nitrogen protection, 2-(thiophen-3-yl)ethane-1-amine (4.0 g, 31.5 mmol) and triethylamine (6.4 g, 63.0 mmol) were dissolved in dichloromethane (30 mL), cooled to 0°C, 2-chloropropionyl chloride (4.8 g, 37.8 mmol) was added dropwise, and stirred for 1 h. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic phase was dried and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target product (5.4 g, yield 79%).
步骤b:2-(1,3-二氧代异吲哚啉-2-基)-N-(2-(噻吩-3-乙基)乙基)丙酰胺的合成
Step b: Synthesis of 2-(1,3-dioxoisoindolin-2-yl)-N-(2-(thiophene-3-ethyl)ethyl)propionamide
在氮气保护下，将2-氯-N-(2-(噻吩-3-基)乙基)丙酰胺(5.4g,24.9mmol)溶于N,N-二甲基甲酰胺(50mL)溶液中，依次加入邻苯二甲酰亚胺钾盐(9.2g,49.8mmol)和四丁基碘化铵(1.8g,5.0mmol)，在120℃下搅拌4h。冷却到室温后，将反应液倒入饱和氯化铵水溶液中，用乙酸乙酯萃取，所得有机相经干燥后过滤浓缩，所得粗产物经柱层析(石油醚/乙酸乙酯)分离纯化得到目标产物(4.0g,收率49％)。Under nitrogen protection, 2-chloro-N-(2-(thiophen-3-yl)ethyl)propionamide (5.4 g, 24.9 mmol) was dissolved in N,N-dimethylformamide (50 mL) solution, and potassium phthalimide (9.2 g, 49.8 mmol) and tetrabutylammonium iodide (1.8 g, 5.0 mmol) were added in sequence, and stirred at 120°C for 4 h. After cooling to room temperature, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic phase was dried, filtered and concentrated, and the obtained crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target product (4.0 g, yield 49%).
步骤c:2-(1-(4,5-二氢噻吩并[2,3-c]吡啶-7-基)乙基)异吲哚啉-1,3-二酮的合成
Step c: Synthesis of 2-(1-(4,5-dihydrothieno[2,3-c]pyridin-7-yl)ethyl)isoindoline-1,3-dione
在氮气保护下，将2-(1,3-二氧代异吲哚啉-2-基)-N-(2-(噻吩-3-乙基)乙基)丙酰胺(4.0g,12.2mmol)溶于三氯氧磷(25mL)中，加入五氯化磷(3.8g,18.3mmol)，在55℃下搅拌4h。 冷却到室温后，将反应液浓缩，用乙酸乙酯溶解粗产物，缓慢加入到饱和碳酸钠水溶液中，用乙酸乙酯萃取，所得有机相经干燥后过滤浓缩，粗产物经柱层析(石油醚/乙酸乙酯)分离纯化得到目标产物(2.0g,收率53％)。Under nitrogen protection, 2-(1,3-dioxoisoindolin-2-yl)-N-(2-(thiophene-3-ethyl)ethyl)propionamide (4.0 g, 12.2 mmol) was dissolved in phosphorus oxychloride (25 mL), phosphorus pentachloride (3.8 g, 18.3 mmol) was added, and the mixture was stirred at 55 °C for 4 h. After cooling to room temperature, the reaction solution was concentrated, the crude product was dissolved with ethyl acetate, slowly added to a saturated aqueous sodium carbonate solution, extracted with ethyl acetate, and the obtained organic phase was dried, filtered, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target product (2.0 g, yield 53%).
步骤d:7-(1-(1,3-二氧代异吲哚啉-2-基)乙基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-甲酸叔丁酯的合成
Step d: Synthesis of tert-butyl 7-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
将2-(1-(4,5-二氢噻吩并[2,3-c]吡啶-7-基)乙基)异吲哚啉-1,3-二酮(2.0g,6.5mmol)溶于1,2-二氯乙烷(30mL)中，加入三乙酰氧基硼氢化钠(4.1g,19.4mmol)和二碳酸二叔丁酯(2.8g,12.9mmol)，在室温下搅拌12h。将反应液倒入饱和碳酸钠水溶液中，用乙酸乙酯萃取，所得有机相经干燥后过滤浓缩，粗产物经柱层析(石油醚/乙酸乙酯)分离纯化得到目标产物(2.0g,收率76％)。2-(1-(4,5-dihydrothieno[2,3-c]pyridin-7-yl)ethyl)isoindoline-1,3-dione (2.0 g, 6.5 mmol) was dissolved in 1,2-dichloroethane (30 mL), sodium triacetoxyborohydride (4.1 g, 19.4 mmol) and di-tert-butyl dicarbonate (2.8 g, 12.9 mmol) were added, and stirred at room temperature for 12 h. The reaction solution was poured into a saturated sodium carbonate aqueous solution and extracted with ethyl acetate. The obtained organic phase was dried, filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target product (2.0 g, yield 76%).
步骤e:7-(1-氨基乙基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-甲酸叔丁酯的合成
Step e: Synthesis of tert-butyl 7-(1-aminoethyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
将7-(1-(1,3-二氧代异吲哚啉-2-基)乙基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-甲酸叔丁酯(2.0g,4.9mmol)溶于乙醇(25mL)中，加入水合肼(1.2g,24.3mmol)，回流4h。反应液冷却到室温后，过滤反应液，所得滤液经浓缩得到目标产物(1.2g,收率88％)。Dissolve tert-butyl 7-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (2.0 g, 4.9 mmol) in ethanol (25 mL), add hydrazine hydrate (1.2 g, 24.3 mmol), and reflux for 4 h. After the reaction solution is cooled to room temperature, the reaction solution is filtered, and the filtrate is concentrated to obtain the target product (1.2 g, yield 88%).
步骤f:7-(1-(2-氯乙酰氨基)乙基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-甲酸叔丁酯的合成
Step f: Synthesis of tert-butyl 7-(1-(2-chloroacetylamino)ethyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
在氮气保护下，将7-(1-氨基乙基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-甲酸叔丁酯(1.2g,4.3mmol)和三乙胺(860mg,8.5mmol)溶于二氯甲烷(20mL)中，冷却到0℃，滴加2-氯乙酰氯(572mg,5.1mmol)，搅拌1h。将反应液倒入饱和氯化铵水溶液中，用乙酸乙酯萃取，所得有机相经干燥后过滤浓缩，所得粗产物经柱层析(石油醚/乙酸乙酯)分离纯化得到目标产物(1.35g,收率89％)。Under nitrogen protection, tert-butyl 7-(1-aminoethyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (1.2g, 4.3mmol) and triethylamine (860mg, 8.5mmol) were dissolved in dichloromethane (20mL), cooled to 0°C, 2-chloroacetyl chloride (572mg, 5.1mmol) was added dropwise, and stirred for 1h. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic phase was dried, filtered, and concentrated. The obtained crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target product (1.35g, yield 89%).
步骤g:2-氯-N-(1-(4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)乙基)乙酰胺的盐酸盐的合成
Step g: Synthesis of 2-chloro-N-(1-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)ethyl)acetamide hydrochloride
向7-(1-(2-氯乙酰氨基)乙基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-甲酸叔丁酯(1.35g,3.8mmol)中加入氯化氢的乙酸乙酯(3M,10mL)溶液，室温下搅拌12h。反应液经浓缩后得到 目标粗产物(1.1g,收率100％)，直接用于下一步反应中。To tert-butyl 7-(1-(2-chloroacetylamino)ethyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (1.35 g, 3.8 mmol) was added a solution of hydrogen chloride in ethyl acetate (3M, 10 mL) and stirred at room temperature for 12 h. The reaction solution was concentrated to obtain The target crude product (1.1 g, yield 100%) was directly used in the next reaction.
步骤h:10-甲基-4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的合成
Step h: Synthesis of 10-methyl-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
在氮气保护下，将2-氯-N-(1-(4,5,6,7-四氢噻吩并[2，3-c]吡啶-7-基)乙基)乙酰胺的盐酸盐(1.1g,3.7mmol)溶于乙腈(20mL)中，加入碳酸钾(1.0g,7.5mmol)和碘化钠(561mg,3.7mmol)，在80℃下搅拌4h。反应液冷却到室温后，过滤浓缩，粗产物经柱层析(二氯甲烷/甲醇)分离纯化得到一对非对映异构体，分别为异构体1(410mg,收率49％)和异构体2(320mg,收率39％)。Under nitrogen protection, 2-chloro-N-(1-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)ethyl)acetamide hydrochloride (1.1 g, 3.7 mmol) was dissolved in acetonitrile (20 mL), potassium carbonate (1.0 g, 7.5 mmol) and sodium iodide (561 mg, 3.7 mmol) were added, and stirred at 80°C for 4 h. After the reaction solution was cooled to room temperature, it was filtered and concentrated, and the crude product was separated and purified by column chromatography (dichloromethane/methanol) to obtain a pair of diastereomers, namely isomer 1 (410 mg, yield 49%) and isomer 2 (320 mg, yield 39%).
步骤i:10-甲基-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的合成
Step i: Synthesis of tert-butyl 10-methyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
在氮气保护下，将四氢锂铝(351mg,9.2mmol)加入到四氢呋喃(20mL)中，冷却到0℃，缓慢加入10-甲基-4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的异构体1(410mg,1.8mmol)的四氢呋喃(10mL)溶液，回流4小时。反应液冷却到0℃后，加入十水硫酸钠淬灭反应，过滤混合物，向滤液中加入二碳酸二叔丁酯(805mg,3.7mmol)，搅拌2小时。将反应液浓缩，粗产物经柱层析(二氯甲烷/甲醇)分离纯化得到目标产物的异构体1(380mg,收率67％)。Under nitrogen protection, lithium aluminum tetrahydride (351 mg, 9.2 mmol) was added to tetrahydrofuran (20 mL), cooled to 0°C, and a solution of 10-methyl-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one isomer 1 (410 mg, 1.8 mmol) in tetrahydrofuran (10 mL) was slowly added and refluxed for 4 hours. After the reaction solution was cooled to 0°C, sodium sulfate decahydrate was added to quench the reaction, the mixture was filtered, di-tert-butyl dicarbonate (805 mg, 3.7 mmol) was added to the filtrate, and stirred for 2 hours. The reaction solution was concentrated, and the crude product was separated and purified by column chromatography (dichloromethane/methanol) to obtain the target product isomer 1 (380 mg, yield 67%).
步骤j:10-甲基-4,7,8,9,10,10,10a-六氢噻吩并[2,3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step j: Synthesis of 10-methyl-4,7,8,9,10,10,10a-hexahydrothieno[2,3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将10-甲基-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的异构体1(380mg,1.23mmol)加入到氯化氢的乙酸乙酯(3M,10mL)溶液中，室温下搅拌12h。反应液经浓缩得到目标产物的异构体1(260mg,收率86％)。Isomer 1 of tert-butyl 10-methyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate (380 mg, 1.23 mmol) was added to a solution of hydrogen chloride in ethyl acetate (3M, 10 mL) and stirred at room temperature for 12 h. The reaction solution was concentrated to obtain isomer 1 of the target product (260 mg, yield 86%).
LC-MS[M+H]+:209.4。LC-MS [M+H] + : 209.4.
1H NMR(400MHz,CD3OD):δ7.55(d,J＝5.2Hz,1H),6.97(d,J＝5.2Hz,1H),5.01(s,1H),4.45-4.35(m,1H),3.78-3.43(m,6H),3.28-3.19(m,1H),2.99(dd,J＝16.8,3.6Hz,1H),1.53(d,J＝6.8Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.55 (d, J=5.2 Hz, 1H), 6.97 (d, J=5.2 Hz, 1H), 5.01 (s, 1H), 4.45-4.35 (m, 1H), 3.78-3.43 (m, 6H), 3.28-3.19 (m, 1H), 2.99 (dd, J=16.8, 3.6 Hz, 1H), 1.53 (d, J=6.8 Hz, 3H).
将10-甲基-4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的异构体2(320mg)通过类似的合成方法得到目标产物的异构体2(250mg,71％)。Isomer 2 (320 mg) of 10-methyl-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-8(7H)-one was used by a similar synthesis method to obtain isomer 2 (250 mg, 71%) of the target product.
LC-MS[M+H]+:209.1。LC-MS [M+H] + : 209.1.
1H NMR(400MHz,CD3OD):δ7.59(d,J＝5.2Hz,1H),7.04(d,J＝5.2Hz,1H),4.97(d, J＝10.4Hz,1H),4.09-3.95(m,2H),3.90-3.83(m,2H),3.77-3.71(m,2H),3.70-3.62(m,1H),3.31-3.12(m,2H),1.80(d,J＝6.4Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.59 (d, J＝5.2 Hz, 1H), 7.04 (d, J＝5.2 Hz, 1H), 4.97 (d, J＝10.4 Hz, 1H), 4.09-3.95 (m, 2H), 3.90-3.83 (m, 2H), 3.77-3.71 (m, 2H), 3.70-3.62 (m, 1H), 3.31-3.12 (m, 2H), 1.80 (d, J＝6.4 Hz, 3H).
实施例7Example 7
7-甲基-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
7-Methyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
步骤a：7-甲基-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的合成
Step a: Synthesis of tert-butyl 7-methyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
将7-甲基-4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的异构体1(0.12g,0.54mmol)溶于四氢呋喃(15mL)中，加入四氢铝锂(0.08g,2.16mmol)后在氮气保护下于80℃油浴中回流2h。将反应液冷却至室温后，缓慢加入十水硫酸钠(0.21g,0.65mmol)并搅拌10min。之后抽滤反应液，依次向滤液中加入水(5mL)，碳酸氢钠(0.09g,1.08mmol)和二碳酸二叔丁酯(0.17g,0.81mmol)，加毕后在室温下搅拌1h。将反应液倒入水中(30mL)，用二氯甲烷萃取三次(50mL x 3)，合并有机相后经无水硫酸钠干燥，过滤浓缩得到目标粗产物的异构体1(100mg,收率60％)。Dissolve isomer 1 (0.12 g, 0.54 mmol) of 7-methyl-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one in tetrahydrofuran (15 mL), add lithium aluminum tetrahydride (0.08 g, 2.16 mmol), and reflux in an oil bath at 80°C under nitrogen protection for 2 h. After the reaction solution was cooled to room temperature, sodium sulfate decahydrate (0.21 g, 0.65 mmol) was slowly added and stirred for 10 min. Then, the reaction solution was filtered, and water (5 mL), sodium bicarbonate (0.09 g, 1.08 mmol) and di-tert-butyl dicarbonate (0.17 g, 0.81 mmol) were added to the filtrate in sequence, and stirred at room temperature for 1 h after the addition. The reaction solution was poured into water (30 mL), extracted three times with dichloromethane (50 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target crude product isomer 1 (100 mg, yield 60%).
LC-MS[M+H]+:309.0。LC-MS [M+H] + : 309.0.
步骤b：7-甲基-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step b: Synthesis of 7-methyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将7-甲基-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的异构体1(100mg,0.32mmol)溶于氯化氢的乙酸乙酯溶液(3M,10mL)中，室温搅拌1h后抽滤，滤饼用乙酸乙酯洗涤后得到目标产物的异构体1(35mg,收率38％)。Isomer 1 of tert-butyl 7-methyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate (100 mg, 0.32 mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (3M, 10 mL), stirred at room temperature for 1 h and then filtered. The filter cake was washed with ethyl acetate to obtain the target product isomer 1 (35 mg, yield 38%).
LC-MS[M+H]+:209.4。LC-MS [M+H] + : 209.4.
1H NMR(400MHz,CD3OD):δ7.56(d,J＝4.8Hz,1H),7.02(d,J＝5.2Hz,1H),5.10(d, J＝12.0Hz,1H),4.19-4.07(m,2H),4.03-3.90(m,1H),3.76(d,J＝13.6Hz,1H),3.64(t,J＝12.8Hz,1H),3.56-3.41(m,2H),3.30-3.21(m,1H),3.18-3.08(m,1H),1.61(d,J＝6.4Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.56 (d, J＝4.8 Hz, 1H), 7.02 (d, J＝5.2 Hz, 1H), 5.10 (d, J＝12.0 Hz, 1H), 4.19-4.07 (m, 2H), 4.03-3.90 (m, 1H), 3.76 (d, J＝13.6 Hz, 1H), 3.64 (t, J＝12.8 Hz, 1H), 3.56-3.41 (m, 2H), 3.30-3.21 (m, 1H), 3.18-3.08 (m, 1H), 1.61 (d, J＝6.4 Hz, 3H).
以7-甲基-4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的异构体2(0.12g,0.54mmol)为原料采用类似的合成方法得到目标产物的异构体2(55mg，收率36％)。A similar synthesis method was used to obtain the target product isomer 2 (55 mg, yield 36%) using 7-methyl-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-8(7H)-one isomer 2 (0.12 g, 0.54 mmol) as raw material.
LC-MS[M+H]+:209.1。LC-MS [M+H] + : 209.1.
1H NMR(400MHz,CD3OD):δ7.60(d,J＝5.2Hz,1H),7.06(d,J＝4.8Hz,1H),5.32(s,1H),4.05-3.87(m,3H),3.86-3.74(m,1H),3.73-3.50(m,3H),3.28-3.16(m,1H),3.15-3.05(m,1H),1.64(d,J＝6.8Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.60 (d, J=5.2 Hz, 1H), 7.06 (d, J=4.8 Hz, 1H), 5.32 (s, 1H), 4.05-3.87 (m, 3H), 3.86-3.74 (m, 1H), 3.73-3.50 (m, 3H), 3.28-3.16 (m, 1H), 3.15-3.05 (m, 1H), 1.64 (d, J=6.8 Hz, 3H).
实施例8Example 8
8-甲基-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
8-Methyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线
synthetic route
步骤a：8-甲基-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的合成
Step a: Synthesis of tert-butyl 8-methyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
将8-甲基-4,5,8,9,10,10a-六氢-7H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7-酮(0.2g,0.90mmol)溶于四氢呋喃(15mL)中，加入四氢铝锂(0.14g,3.60mmol)，在氮气保护下于80℃油浴中回流2h。将反应液冷却至室温，缓慢加入十水硫酸钠(0.35g,1.08mmol)搅拌10min，抽滤，依次向滤液中加入水(5mL)，碳酸氢钠(0.15g,1.80mmol)和二碳酸二叔丁酯(0.29g,1.35mmol)，加毕后在室温下搅拌1h。将反应液倒入水中(30mL)，用二氯甲烷萃取三次(50mL x 3)，有机相经无水硫酸钠干燥，过滤浓缩后得到目标化合物(200mg,收率72％)。Dissolve 8-methyl-4,5,8,9,10,10a-hexahydro-7H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-7-one (0.2g, 0.90mmol) in tetrahydrofuran (15mL), add lithium aluminum tetrahydride (0.14g, 3.60mmol), and reflux in an oil bath at 80℃ for 2h under nitrogen protection. Cool the reaction solution to room temperature, slowly add sodium sulfate decahydrate (0.35g, 1.08mmol) and stir for 10min, filter with suction, add water (5mL), sodium bicarbonate (0.15g, 1.80mmol) and di-tert-butyl dicarbonate (0.29g, 1.35mmol) to the filtrate in sequence, and stir at room temperature for 1h after the addition. The reaction solution was poured into water (30 mL), extracted three times with dichloromethane (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target compound (200 mg, yield 72%).
LC-MS[M+H]+:309.0。LC-MS [M+H] + : 309.0.
步骤b：8-甲基-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step b: Synthesis of 8-methyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将8-甲基-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯(0.20g,0.65mmol)溶于氯化氢的乙酸乙酯溶液(3M,15mL)中，在室温下搅拌1h后抽滤，并用乙酸乙酯洗涤滤饼后得到目标化合物(100mg,收率55％,d.r.＝4:1)。Dissolve tert-butyl 8-methyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate (0.20 g, 0.65 mmol) in a solution of hydrogen chloride in ethyl acetate (3M, 15 mL). Stir at room temperature for 1 h and then filter. Wash the filter cake with ethyl acetate to obtain the target compound (100 mg, yield 55%, d.r. = 4:1).
主要异构体：Main isomers:
LC-MS[M+H]+:209.1。LC-MS [M+H] + : 209.1.
1H NMR(400MHz,CD3OD):δ7.58(d,J＝5.2Hz,1H),7.03(d,J＝5.2Hz,1H),5.09(brs,1H),4.02-3.85(m,3H),3.74-3.53(m,4H),3.24-3.10(m,1H),3.03(dd,J＝17.2,4.8Hz,1H),1.46(d,J＝6.8Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.58 (d, J=5.2 Hz, 1H), 7.03 (d, J=5.2 Hz, 1H), 5.09 (brs, 1H), 4.02-3.85 (m, 3H), 3.74-3.53 (m, 4H), 3.24-3.10 (m, 1H), 3.03 (dd, J=17.2, 4.8 Hz, 1H), 1.46 (d, J=6.8 Hz, 3H).
实施例9Example 9
8,9,10,10a-四氢-4H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7(5H)-酮
8,9,10,10a-Tetrahydro-4H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-7(5H)-one
实施例9的合成路线参考实施例1中的步骤a至步骤i的合成路线。The synthetic route of Example 9 refers to the synthetic route of step a to step i in Example 1.
LC-MS[M+H]+:209.1。LC-MS [M+H] + : 209.1.
实施例10Example 10
4,5,7,8,9,10,11,11a-八氢噻吩并[2',3':3,4]吡啶并[1,2-a][1,4]二氮卓盐酸盐
4,5,7,8,9,10,11,11a-Octahydrothieno[2',3':3,4]pyrido[1,2-a][1,4]diazepine hydrochloride
合成路线：
synthetic route:
步骤a：3-(7-(((叔丁氧基羰基)胺基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)丙酸甲酯的 合成
Step a: Preparation of methyl 3-(7-(((tert-butoxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)propanoate synthesis
向反应瓶中先后加入N-[(4H,5H,6H,7H-噻吩并[2,3-c]吡啶-7-基)甲基]胺基甲酸叔丁酯(100mg,0.37mmol)、3-溴丙酸甲酯(120mg,0.74mmol)、碳酸钾(100mg,0.74mmol)、碘化钠(28mg,0.18mmol)和乙腈(5mL)，混合液在90℃下搅拌12小时。反应结束后，用饱和氯化铵淬灭反应，反应液用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，粗产物经柱层析(石油醚/乙酸乙酯)分离纯化得到目标产物(60mg,收率46％)。To the reaction flask, tert-butyl N-[(4H,5H,6H,7H-thieno[2,3-c]pyridin-7-yl)methyl]carbamate (100 mg, 0.37 mmol), methyl 3-bromopropionate (120 mg, 0.74 mmol), potassium carbonate (100 mg, 0.74 mmol), sodium iodide (28 mg, 0.18 mmol) and acetonitrile (5 mL) were added successively, and the mixture was stirred at 90°C for 12 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target product (60 mg, yield 46%).
LC-MS[M+H]+:355.4。LC-MS [M+H] + : 355.4.
步骤b：3-(7-(胺基甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)丙酸甲酯盐酸盐的合成
Step b: Synthesis of methyl 3-(7-(aminomethyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)propanoate hydrochloride
将3-(7-(((叔丁氧基羰基)胺基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)丙酸甲酯(60mg,0.17mmol)溶于氯化氢的乙酸乙酯溶液(3M,2mL)中，并在室温下搅拌2小时。经浓缩得到的盐酸盐粗产物，无需纯化直接用于下一步反应。Methyl 3-(7-(((tert-butoxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)propanoate (60 mg, 0.17 mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (3M, 2 mL) and stirred at room temperature for 2 hours. The crude hydrochloride product obtained by concentration was used directly in the next step without purification.
LC-MS[M+H]+:255.4。LC-MS [M+H] + : 255.4.
步骤c:4,7,8,10,11,11a-六氢噻吩[2',3':3,4]吡啶并[1,2-a][1,4]二氮卓-9(5H)-酮的合成
Step c: Synthesis of 4,7,8,10,11,11a-hexahydrothiophene[2',3':3,4]pyrido[1,2-a][1,4]diazepine-9(5H)-one
向反应瓶中分别加入3-(7-(胺基甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)丙酸甲酯盐酸盐(43mg,0.17mmol)、甲醇钠(92mg,1.7mmol)和甲醇(3mL)，混合液在室温下反应12小时。反应结束后，旋干反应液，加入二氯甲烷后过滤反应液，所得滤液经浓缩得到粗产物，无需纯化直接用于下一步反应。3-(7-(aminomethyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)propanoic acid methyl ester hydrochloride (43 mg, 0.17 mmol), sodium methoxide (92 mg, 1.7 mmol) and methanol (3 mL) were added to the reaction bottle, and the mixture was reacted at room temperature for 12 hours. After the reaction was completed, the reaction solution was dried, and dichloromethane was added and the reaction solution was filtered. The filtrate was concentrated to obtain a crude product, which was directly used in the next step without purification.
LC-MS[M+H]+:223.4。LC-MS [M+H] + : 223.4.
步骤d：4,5,8,9,11,11a-六氢噻吩[2',3':3,4]吡啶并[1,2-a][1,4]二氮卓-10(7H)-羧酸叔丁酯的合成
Step d: Synthesis of tert-butyl 4,5,8,9,11,11a-hexahydrothiophene[2',3':3,4]pyrido[1,2-a][1,4]diazepine-10(7H)-carboxylate
在0℃下，向四氢铝锂(65mg,1.7mmol)的四氢呋喃(2mL)溶液中缓慢滴加4,7,8,10,11,11a-六氢噻吩[2',3':3,4]吡啶并[1,2-a][1,4]二氮卓-9(5H)-酮(38mg,0.17mmol)的四氢呋喃(2mL)溶液，随后将反应液升温至65℃，搅拌约30分钟。反应结束后，用十水硫 酸钠淬灭反应，过滤反应液，滤液经浓缩后重新溶于四氢呋喃(4mL)中，加入二碳酸二叔丁酯(56mg,0.26mmol)，混合液在室温下反应约2小时。反应结束后，旋干反应液，粗产物经柱层析(二氯甲烷/甲醇)分离纯化得到目标产物(53mg,收率100％)。At 0°C, slowly add a solution of 4,7,8,10,11,11a-hexahydrothiophene[2',3':3,4]pyrido[1,2-a][1,4]diazepine-9(5H)-one(38mg, 0.17mmol) in tetrahydrofuran(2mL) to a solution of lithium aluminum tetrahydride(65mg, 1.7mmol) in tetrahydrofuran(2mL), then heat the reaction solution to 65°C and stir for about 30 minutes. The reaction was quenched with sodium sulfate, the reaction solution was filtered, the filtrate was concentrated and redissolved in tetrahydrofuran (4 mL), di-tert-butyl dicarbonate (56 mg, 0.26 mmol) was added, and the mixture was reacted at room temperature for about 2 hours. After the reaction was completed, the reaction solution was dried, and the crude product was separated and purified by column chromatography (dichloromethane/methanol) to obtain the target product (53 mg, yield 100%).
LC-MS[M+H]+:309.4。LC-MS [M+H] + : 309.4.
步骤e:4,5,7,8,9,10,11,11a-八氢噻吩并[2',3':3,4]吡啶并[1,2-a][1,4]二氮卓盐酸盐的合成
Step e: Synthesis of 4,5,7,8,9,10,11,11a-octahydrothieno[2',3':3,4]pyrido[1,2-a][1,4]diazepine hydrochloride
将4,5,8,9,11,11a-六氢噻吩[2',3':3,4]吡啶并[1,2-a][1,4]二氮卓-10(7H)-羧酸叔丁酯(100mg,0.17mmol)溶于盐酸/乙酸乙酯溶液(4mL)中，并在室温下搅拌2小时。反应结束后，旋干反应液，干燥后得到目标产物(70mg,收率100％)。Dissolve tert-butyl 4,5,8,9,11,11a-hexahydrothiophene[2',3':3,4]pyrido[1,2-a][1,4]diazepine-10(7H)-carboxylate (100 mg, 0.17 mmol) in hydrochloric acid/ethyl acetate solution (4 mL) and stir at room temperature for 2 hours. After the reaction, the reaction solution was spin-dried and dried to obtain the target product (70 mg, yield 100%).
LC-MS[M+H]+:209.10。LC-MS [M+H] + : 209.10.
1H NMR(400MHz,CD3OD):δ7.58(d,J＝5.2Hz,1H),6.97(d,J＝4.8Hz,1H),5.39(d,J＝8.4Hz,1H),4.05(dd,J＝16.0,8.8Hz,1H),3.93(d,J＝15.6Hz,1H),3.85-3.68(m,3H),3.67-3.57(m,2H),3.50-3.39(m,1H),3.23-3.00(m,2H),2.51-2.35(m,2H). 1 H NMR (400 MHz, CD 3 OD): δ7.58 (d, J=5.2 Hz, 1H), 6.97 (d, J=4.8 Hz, 1H), 5.39 (d, J=8.4 Hz, 1H), 4.05 (dd, J=16.0, 8.8 Hz, 1H), 3.93 (d, J=15.6 Hz, 1H), 3.85-3.68 (m, 3H), 3.67-3.57 (m, 2H), 3.50-3.39 (m, 1H), 3.23-3.00 (m, 2H), 2.51-2.35 (m, 2H).
实施例11Embodiment 11
4,6,7,8,9,9a-六氢噻吩[2',3':3,4]吡咯并[1,2-a]吡嗪
4,6,7,8,9,9a-Hexahydrothiophene[2',3':3,4]pyrrolo[1,2-a]pyrazine
化合物11的合成路线参考实施例1的合成路线。The synthetic route of compound 11 refers to the synthetic route of Example 1.
LC-MS[M+H]+:181.1。LC-MS [M+H] + : 181.1.
实施例12Example 12
6,7,8,9,10,10a-六氢-4H-噻吩并[2',3':3,4]吡咯[1,2-a][1,4]二氮杂卓
6,7,8,9,10,10a-Hexahydro-4H-thieno[2',3':3,4]pyrrolo[1,2-a][1,4]diazepine
化合物12的合成路线参考实施例1的合成路线。The synthetic route of compound 12 refers to the synthetic route of Example 1.
LC-MS[M+H]+:195.1。LC-MS [M+H] + : 195.1.
实施例13Example 13
9-甲基-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
9-Methyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
9-甲基-4,7,8,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成Synthesis of 9-methyl-4,7,8,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将4,7,8,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪(100mg,0.52mmol)加入到含有甲醇(5mL)的三口瓶中，后加入甲醛水溶液(0.3mL)，室温下反应1小时。随后在0℃下，缓慢加入硼氢化钠(50mg,1.29mmol)，加毕，反应混合液在室温下继续搅拌1小时。反应结束后，将反应液倒入碳酸氢钠水溶液(30mL)中，有机相用二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，粗产物经柱层析(石油醚/乙酸乙酯)分离纯化得到粗品(80mg)。随后加入乙酸乙酯(2mL)，在0℃下缓慢滴加盐酸的乙酸乙酯溶液(4.0M,10mL)至析出白色固体，过滤干燥得到目标化合物(50mg,收率48％)。4,7,8,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine (100 mg, 0.52 mmol) was added to a three-necked flask containing methanol (5 mL), followed by a formaldehyde aqueous solution (0.3 mL) and reacted at room temperature for 1 hour. Subsequently, sodium borohydride (50 mg, 1.29 mmol) was slowly added at 0°C. After the addition was completed, the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into a sodium bicarbonate aqueous solution (30 mL), the organic phase was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain a crude product (80 mg). Subsequently, ethyl acetate (2 mL) was added, and a hydrochloric acid ethyl acetate solution (4.0 M, 10 mL) was slowly added dropwise at 0°C until a white solid precipitated, which was filtered and dried to obtain the target compound (50 mg, yield 48%).
LC-MS[M+H]+:209.1.LC-MS [M+H] + : 209.1.
1H NMR(400MHz,CD3OD):δ7.54(dd,J＝4.8,0.8Hz,1H),7.00(d,J＝5.2Hz,1H),4.98(d,J＝11.2Hz,1H),4.22(d,J＝12.4Hz,1H),3.88-3.76(m,3H),3.73-3.47(m,4H),3.28-3.17(m,1H),3.11-3.03(m,4H). 1 H NMR (400 MHz, CD 3 OD): δ7.54 (dd, J=4.8, 0.8 Hz, 1H), 7.00 (d, J=5.2 Hz, 1H), 4.98 (d, J=11.2 Hz, 1H), 4.22 (d, J=12.4 Hz, 1H), 3.88-3.76 (m, 3H), 3.73-3.47 (m, 4H), 3.28-3.17 (m, 1H), 3.11-3.03 (m, 4H).
实施例14Embodiment 14
1,3,4,6,7,10b-六氢-2H-噻吩并[3',4':3,4]吡啶并[1,2-a]吡嗪
1,3,4,6,7,10b-Hexahydro-2H-thieno[3',4':3,4]pyrido[1,2-a]pyrazine
化合物14的合成路线参考实施例1的合成路线。The synthetic route of compound 14 refers to the synthetic route of Example 1.
LC-MS[M+H]+:195.1。LC-MS [M+H] + : 195.1.
实施例15Embodiment 15
5,8,9,10,11,11a-六氢吡嗪并[1,2-h][1,7]萘啶盐酸盐
5,8,9,10,11,11a-Hexahydropyrazino[1,2-h][1,7]naphthyridine hydrochloride
合成路线：
synthetic route:
步骤a:甲基(E)-3-(3-(苄氧基)-3-氧代丙基-1-烯-1-基)吡啶甲酸甲酯的合成
Step a: Synthesis of methyl (E)-3-(3-(benzyloxy)-3-oxopropyl-1-en-1-yl)picolinate
将3-溴吡啶-2-羧酸甲酯(5.0g,23.1mmol)，2-丙烯酸苄酯(7.51g,46.3mmol)，醋酸钯(0.52g,2.3mmol)，三苯基膦(1.21g,4.6mmol)和三乙胺(4.7g,46.3mmol)加入到N,N-二甲基甲酰胺(50mL)溶液中，氮气下，在100℃下反应12小时。冷却到室温后，将反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取，所得有机相经干燥，浓缩，柱层析(石油醚/乙酸乙酯＝3:1)得到黄色固体目标产物(5.2g,收率76％)。3-Bromopyridine-2-carboxylic acid methyl ester (5.0 g, 23.1 mmol), 2-benzyl acrylate (7.51 g, 46.3 mmol), palladium acetate (0.52 g, 2.3 mmol), triphenylphosphine (1.21 g, 4.6 mmol) and triethylamine (4.7 g, 46.3 mmol) were added to N,N-dimethylformamide (50 mL) solution and reacted at 100 ° C for 12 hours under nitrogen. After cooling to room temperature, the reaction solution was poured into saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The obtained organic phase was dried, concentrated, and column chromatography (petroleum ether/ethyl acetate = 3:1) was used to obtain the target product as a yellow solid (5.2 g, yield 76%).
步骤b:3-(2-(甲氧基羰基)吡啶-3-基)丙酸的合成
Step b: Synthesis of 3-(2-(methoxycarbonyl)pyridin-3-yl)propionic acid
将甲基(E)-3-(3-(苄氧基)-3-氧代丙基-1-烯-1-基)吡啶甲酸甲酯(5.2g,17.5mmol)溶于四氢呋喃(50mL)中，加入钯碳(520mg)，氢气氛围下，60℃搅拌48小时。冷却到室温后，过滤，所得滤液经浓缩得到淡黄色液体目标产物(3.5g,收率96％)。Methyl (E)-3-(3-(benzyloxy)-3-oxopropyl-1-en-1-yl)picolinate (5.2 g, 17.5 mmol) was dissolved in tetrahydrofuran (50 mL), palladium carbon (520 mg) was added, and stirred at 60°C for 48 hours under a hydrogen atmosphere. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to obtain the target product (3.5 g, yield 96%) as a pale yellow liquid.
步骤c:3-(2-((叔丁氧羰基氨基)乙基)吡啶甲酸甲酯的合成
Step c: Synthesis of methyl 3-(2-((tert-butyloxycarbonylamino)ethyl)picolinate
将3-(2-(甲氧基羰基)吡啶-3-基)丙酸(3.5g,16.7mmol)溶于四氢呋喃(10mL)和叔丁醇(10mL)溶液中，加入叠氮磷酸二苯酯(5.5g,20.1mmol)和三乙胺(5.1g,50.2mmol)，氮气氛围下，80℃下搅拌12小时。冷却到室温后，反应液经浓缩、柱层析(石油醚/乙酸乙酯＝3:1)得到淡黄色液体目标产物(2.4g,收率51％)。3-(2-(Methoxycarbonyl)pyridin-3-yl)propionic acid (3.5 g, 16.7 mmol) was dissolved in tetrahydrofuran (10 mL) and tert-butyl alcohol (10 mL), diphenylphosphoryl azide (5.5 g, 20.1 mmol) and triethylamine (5.1 g, 50.2 mmol) were added, and stirred at 80°C for 12 hours under nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated and column chromatography (petroleum ether/ethyl acetate = 3:1) was performed to obtain the target product as a light yellow liquid (2.4 g, yield 51%).
步骤d:(2-(2-甲酰基吡啶-3-基)乙基)氨基甲酸叔丁酯的合成
Step d: Synthesis of tert-butyl (2-(2-formylpyridin-3-yl)ethyl)carbamate
将3-(2-((叔丁氧羰基氨基)乙基)吡啶甲酸甲酯(1.2g,4.3mmol)溶于无水甲苯(20mL)中，氮气下冷却到-78℃，缓慢滴加二异丁基氢化铝的己烷溶液(1M,4.5mL)，在此温度下搅拌4小时。升温到室温后，加入30％氢氧化钠水溶液淬灭，乙酸乙酯萃取，所得有机相经干燥，浓缩、柱层析(石油醚/乙酸乙酯＝3:1)得到黄色油状液体目标产物(400mg,收率37％)。Methyl 3-(2-((tert-butoxycarbonylamino)ethyl)picolinate (1.2 g, 4.3 mmol) was dissolved in anhydrous toluene (20 mL), cooled to -78 ° C under nitrogen, and a hexane solution of diisobutylaluminum hydride (1M, 4.5 mL) was slowly added dropwise, and stirred at this temperature for 4 hours. After warming to room temperature, 30% aqueous sodium hydroxide solution was added to quench, and extracted with ethyl acetate. The obtained organic phase was dried, concentrated, and column chromatographed (petroleum ether/ethyl acetate = 3:1) to obtain the target product as a yellow oily liquid (400 mg, yield 37%).
步骤e:5,6-二氢-1,7-萘啶的合成
Step e: Synthesis of 5,6-dihydro-1,7-naphthyridine
将(2-(2-甲酰基吡啶-3-基)乙基)氨基甲酸叔丁酯(400mg,1.6mmol)溶于二氯甲烷(3mL)中，加入三氟乙酸(0.3mL)，室温下搅拌12小时。反应液经浓缩得到棕色目标产物，直接用于下一步。Dissolve tert-butyl (2-(2-formylpyridin-3-yl)ethyl)carbamate (400 mg, 1.6 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (0.3 mL), and stir at room temperature for 12 hours. The reaction solution is concentrated to obtain the brown target product, which is used directly in the next step.
步骤f:8-硝基甲基-5,8-二氢-1,7-萘啶-7(6H)-羧酸叔丁酯的合成
Step f: Synthesis of tert-butyl 8-nitromethyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate
将5,6-二氢-1,7-萘啶(210mg,1.6mmol)溶于二氯甲烷(10mL)中，加入硝基甲烷(485mg,8.0mmol)和三乙胺(161mg,1.6mmol)，在35℃下反应12小时。加入二碳酸二叔丁酯(416mg,2.0mmol)，继续反应2小时。将反应液浓缩，经柱层析得到(石油醚/乙酸乙酯＝2:1)得到目标产物(240mg,收率52％)。Dissolve 5,6-dihydro-1,7-naphthyridine (210 mg, 1.6 mmol) in dichloromethane (10 mL), add nitromethane (485 mg, 8.0 mmol) and triethylamine (161 mg, 1.6 mmol), and react at 35°C for 12 hours. Add di-tert-butyl dicarbonate (416 mg, 2.0 mmol) and continue to react for 2 hours. Concentrate the reaction solution and obtain the target product (240 mg, yield 52%) by column chromatography (petroleum ether/ethyl acetate = 2:1).
步骤g:8-氨甲基-5,8-二氢-1,7-萘啶-7(6H)-羧酸叔丁酯的合成
Step g: Synthesis of tert-butyl 8-aminomethyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate
将8-硝基甲基-5,8-二氢-1,7-萘啶-7(6H)-羧酸叔丁酯(240mg,0.82mmol)溶于甲醇(5mL)中，加入钯碳(24mg)，氢气氛围下，60℃搅拌2小时。冷却到室温后，反应液经过滤、浓缩得到目标产物，直接用于下一步。Dissolve 8-nitromethyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylic acid tert-butyl ester (240 mg, 0.82 mmol) in methanol (5 mL), add palladium carbon (24 mg), and stir at 60°C for 2 hours under a hydrogen atmosphere. After cooling to room temperature, the reaction solution was filtered and concentrated to obtain the target product, which was used directly in the next step.
步骤h:8-(2-氯乙酰氨基甲基)-5,8-二氢-1,7-萘啶-7(6H)-羧酸叔丁酯的合成
Step h: Synthesis of tert-butyl 8-(2-chloroacetylaminomethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate
将8-氨甲基-5,8-二氢-1,7-萘啶-7(6H)-羧酸叔丁酯(220mg,0.84mmol)和三乙胺(170mg,1.68mmol)溶于二氯甲烷(10mL)中，氮气下冷却到0℃，缓慢加入2-氯乙酰氯(104mg,0.92mmol)，然后恢复至室温，继续反应2小时。将反应液浓缩，经柱层析得到目标产物(190mg,收率67％)。Dissolve 8-aminomethyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylic acid tert-butyl ester (220 mg, 0.84 mmol) and triethylamine (170 mg, 1.68 mmol) in dichloromethane (10 mL), cool to 0°C under nitrogen, slowly add 2-chloroacetyl chloride (104 mg, 0.92 mmol), then return to room temperature and continue to react for 2 hours. Concentrate the reaction solution and obtain the target product (190 mg, yield 67%) by column chromatography.
步骤i:2-氯-N-(5,6,7,8-四氢-1,7-萘啶-8-甲基)乙酰胺盐酸盐的合成
Step i: Synthesis of 2-chloro-N-(5,6,7,8-tetrahydro-1,7-naphthyridine-8-methyl)acetamide hydrochloride
将8-(2-氯乙酰氨基甲基)-5,8-二氢-1,7-萘啶-7(6H)-羧酸叔丁酯(190mg,0.56mmol)加入到氯化氢的乙酸乙酯溶液(5mL)中，室温下搅拌2小时。反应液经浓缩得到目标产物(130mg,收率84％)。8-(2-Chloroacetylaminomethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylic acid tert-butyl ester (190 mg, 0.56 mmol) was added to a solution of hydrogen chloride in ethyl acetate (5 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the target product (130 mg, yield 84%).
步骤j:5,10,11,11a-四氢-6H-吡嗪并[1,2-h][1,7]萘啶-9(8H)酮的合成
Step j: Synthesis of 5,10,11,11a-tetrahydro-6H-pyrazino[1,2-h][1,7]naphthyridine-9(8H)one
将2-氯-N-(5,6,7,8-四氢-1,7-萘啶-8-甲基)乙酰胺的盐酸盐(130mg,0.47mmol)，碳酸钾(196mg,1.62mmol)和碘化钠(71mg,0.47mmol)加入到乙腈(5mL)中，80℃下反应4小时。冷却到室温后，反应液经过滤、浓缩、柱层析(二氯甲烷/甲醇＝20:1)得到目标产物(80mg,收率93％)。2-Chloro-N-(5,6,7,8-tetrahydro-1,7-naphthyridine-8-methyl)acetamide hydrochloride (130 mg, 0.47 mmol), potassium carbonate (196 mg, 1.62 mmol) and sodium iodide (71 mg, 0.47 mmol) were added to acetonitrile (5 mL) and reacted at 80°C for 4 hours. After cooling to room temperature, the reaction solution was filtered, concentrated, and column chromatographed (dichloromethane/methanol = 20:1) to obtain the target product (80 mg, yield 93%).
步骤k:5,8,9,10,11,11a-六氢吡嗪并[1,2-h][1,7]萘啶盐酸盐的合成
Step k: Synthesis of 5,8,9,10,11,11a-hexahydropyrazino[1,2-h][1,7]naphthyridine hydrochloride
将四氢锂铝(74.8mg,1.97mmol)加入到四氢呋喃(10mL)中，氮气下冷却到0℃，缓慢加入5,10,11,11a-四氢-6H-吡嗪并[1,2-h][1,7]萘啶-9(8H)酮(80mg,0.39mmol)的四氢呋喃(2mL)，然后在65℃下搅拌4小时。冷却到0℃后，加入十水硫酸钠淬灭。过滤，向所得滤液中加入二碳酸二叔丁酯(103.1mg,0.47mmol)，搅拌过夜。反应液经浓缩、柱层析(二氯甲烷/甲醇＝20:1)得到淡黄色液体目标产物(90mg)。将该液体加入到氯化氢的乙酸乙酯溶液中(5mL)中，搅拌1小时。反应液经浓缩得到目标产物(60mg,收率68％)。Add lithium aluminum tetrahydride (74.8 mg, 1.97 mmol) to tetrahydrofuran (10 mL), cool to 0 ° C under nitrogen, slowly add 5,10,11,11a-tetrahydro-6H-pyrazino[1,2-h][1,7]naphthyridine-9(8H)one (80 mg, 0.39 mmol) in tetrahydrofuran (2 mL), and then stir at 65 ° C for 4 hours. After cooling to 0 ° C, add sodium sulfate decahydrate to quench. Filter, add di-tert-butyl dicarbonate (103.1 mg, 0.47 mmol) to the filtrate, and stir overnight. The reaction solution is concentrated and column chromatography (dichloromethane/methanol = 20:1) to obtain a light yellow liquid target product (90 mg). The liquid is added to a solution of hydrogen chloride in ethyl acetate (5 mL) and stirred for 1 hour. The reaction solution is concentrated to obtain the target product (60 mg, yield 68%).
LC-MS[M+H]+:190.4.LC-MS [M+H] + : 190.4.
1H NMR(400MHz,CD3OD):δ8.54(d,J＝4.4Hz,1H),7.85(d,J＝8.0Hz,1H),7.49(dd,J＝8.0,4.8Hz,1H),5.04(dd,J＝11.6,3.2Hz,1H),4.57(dd,J＝14.0,2.8Hz,1H),3.94-3.62(m,7H),3.58-3.47(m,1H),3.22(dd,J＝17.6,3.2Hz,1H). 1 H NMR (400 MHz, CD 3 OD): δ8.54 (d, J=4.4 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.49 (dd, J=8.0, 4.8 Hz, 1H), 5.04 (dd, J=11.6, 3.2 Hz, 1H), 4.57 (dd, J=14.0, 2.8 Hz, 1H), 3.94-3.62 (m, 7H), 3.58-3.47 (m, 1H), 3.22 (dd, J=17.6, 3.2 Hz, 1H).
实施例16Example 16
1,3,4,6,7,11b-六氢吡嗪并[2,1-a][2,7]萘啶盐酸盐
1,3,4,6,7,11b-Hexahydropyrazino[2,1-a][2,7]naphthyridine hydrochloride
合成路线：
synthetic route:
步骤a:2-(3-氰基吡啶-4-基)丙二酸二乙酯的合成
Step a: Synthesis of diethyl 2-(3-cyanopyridin-4-yl)malonate
将氢化钠(2.6g,65.6mmol,含量60％)加入到四氢呋喃(40mL)中，氮气下冷却到0℃，缓慢加入丙二酸二乙酯(10.5g,65.6mmol)的四氢呋喃(10mL)溶液，在此温度下搅拌30分钟，缓慢加入4-氟烟腈(4.0g,32.8mmol)的四氢呋喃(10mL)溶液。升温至50℃继续反应2小时。冷却到室温后，将反应液缓慢加入到冰水中淬灭，乙酸乙酯萃取，所得滤液经浓缩，柱层析(石油醚:乙酸乙酯＝4:1)得到黄色固体目标产物(6.2g,收率72％)。Sodium hydride (2.6 g, 65.6 mmol, content 60%) was added to tetrahydrofuran (40 mL), cooled to 0 ° C under nitrogen, and a solution of diethyl malonate (10.5 g, 65.6 mmol) in tetrahydrofuran (10 mL) was slowly added. Stir at this temperature for 30 minutes, and a solution of 4-fluoronicotinonitrile (4.0 g, 32.8 mmol) in tetrahydrofuran (10 mL) was slowly added. The temperature was raised to 50 ° C and the reaction was continued for 2 hours. After cooling to room temperature, the reaction solution was slowly added to ice water to quench, extracted with ethyl acetate, and the filtrate was concentrated and column chromatography (petroleum ether: ethyl acetate = 4:1) was performed to obtain the target product (6.2 g, yield 72%) as a yellow solid.
步骤b:2-(3-氰基吡啶-4-基)乙酸乙酯的合成
Step b: Synthesis of ethyl 2-(3-cyanopyridin-4-yl)acetate
将2-(3-氰基吡啶-4-基)丙二酸二乙酯(6.2g,23.7mmol)和氯化锂(5.01g,118.2mmol)加入到二甲基亚砜(20mL)和水(2mL)中，100℃下搅拌12小时。冷却到室温后，反应液加入到水中，乙酸乙酯萃取，所得滤液经浓缩，柱层析(石油醚:乙酸乙酯＝4:1)得到淡黄色液体目标产物(4.3g,收率96％)。Diethyl 2-(3-cyanopyridin-4-yl)malonate (6.2 g, 23.7 mmol) and lithium chloride (5.01 g, 118.2 mmol) were added to dimethyl sulfoxide (20 mL) and water (2 mL) and stirred at 100°C for 12 hours. After cooling to room temperature, the reaction solution was added to water and extracted with ethyl acetate. The filtrate was concentrated and subjected to column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain the target product as a light yellow liquid (4.3 g, yield 96%).
步骤c:1,4-二氢-2,7-萘啶-3(H)酮的合成
Step c: Synthesis of 1,4-dihydro-2,7-naphthyridin-3(H)one
将2-(3-氰基吡啶-4-基)乙酸乙酯(4.3g,22.6mmol)溶于甲醇(45mL)中，加入钯碳(430mg)，氢气氛围下，50℃搅拌12小时。冷却到室温后，反应液经过滤、浓缩得到黄色固体目标产物(3.2g,收率96％)。Ethyl 2-(3-cyanopyridin-4-yl)acetate (4.3 g, 22.6 mmol) was dissolved in methanol (45 mL), palladium carbon (430 mg) was added, and stirred at 50°C for 12 hours under a hydrogen atmosphere. After cooling to room temperature, the reaction solution was filtered and concentrated to obtain the target product as a yellow solid (3.2 g, yield 96%).
步骤d:1,2,3,4-四氢-2,7-萘啶的合成
Step d: Synthesis of 1,2,3,4-tetrahydro-2,7-naphthyridine
将1,4-二氢-2,7-萘啶-3(H)酮(3.2g,21.6mmol)溶于四氢呋喃(40mL)中，氮气下缓慢加 入硼烷的二甲硫醚(10M,10.8mL,108.1mmol)溶液，60℃搅拌12小时。冷却到0℃后，将反应液缓慢加入到甲醇中淬灭，然后60℃下继续搅拌1小时，冷却到室温后，经浓缩得到黄色液体目标产物(350mg,收率12％)。1,4-Dihydro-2,7-naphthyridin-3(H)one (3.2 g, 21.6 mmol) was dissolved in tetrahydrofuran (40 mL) and slowly added under nitrogen. Add a solution of borane in dimethyl sulfide (10M, 10.8 mL, 108.1 mmol) and stir at 60°C for 12 hours. After cooling to 0°C, slowly add the reaction solution into methanol to quench, then continue stirring at 60°C for 1 hour, cool to room temperature, and concentrate to obtain the target product (350 mg, yield 12%) as a yellow liquid.
步骤e:3,4-二氢-2,7-萘啶的合成
Step e: Synthesis of 3,4-dihydro-2,7-naphthyridine
将1,2,3,4-四氢-2,7-萘啶(350mg,2.61mmol)溶于二氯甲烷(15mL)中，加入二氧化锰(2.2g,26.1mmol)，室温下搅拌12小时。反应液经过滤、浓缩得到黄色液体目标产物(345mg)，直接用于下一步。Dissolve 1,2,3,4-tetrahydro-2,7-naphthyridine (350 mg, 2.61 mmol) in dichloromethane (15 mL), add manganese dioxide (2.2 g, 26.1 mmol), and stir at room temperature for 12 hours. The reaction solution was filtered and concentrated to obtain the yellow liquid target product (345 mg), which was used directly in the next step.
步骤f:1-硝基甲基-3,4-二氢-2,7-萘啶-2(1H)-羧酸叔丁酯的合成
Step f: Synthesis of tert-butyl 1-nitromethyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate
将3,4-二氢-2,7-萘啶(345mg,2.61mmol)溶于二氯甲烷(15mL)中，加入硝基甲烷(318mg,5.2mmol)和三乙胺(528mg,5.2mmol)，于35℃下搅拌12小时。加入二碳酸二叔丁酯(683mg,3.13mmol)，继续搅拌1小时。反应液经过滤、浓缩。柱层析(石油醚:乙酸乙酯＝5:1)得到淡黄色液体目标产物(70mg,收率9％)。Dissolve 3,4-dihydro-2,7-naphthyridine (345 mg, 2.61 mmol) in dichloromethane (15 mL), add nitromethane (318 mg, 5.2 mmol) and triethylamine (528 mg, 5.2 mmol), and stir at 35 ° C for 12 hours. Add di-tert-butyl dicarbonate (683 mg, 3.13 mmol) and continue stirring for 1 hour. The reaction solution is filtered and concentrated. Column chromatography (petroleum ether: ethyl acetate = 5:1) gives the target product as a light yellow liquid (70 mg, yield 9%).
步骤g:1-氨甲基-3,4-二氢-2,7-萘啶-2(1H)-羧酸叔丁酯的合成
Step g: Synthesis of tert-butyl 1-aminomethyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate
将1-硝基甲基-3,4-二氢-2,7-萘啶-2(1H)-羧酸叔丁酯(70mg,0.24mmol)溶于甲醇(5mL)中，加入钯碳(10mg),氢气氛围下，在50℃下搅拌2小时。反应液经过滤、浓缩得到黄色液体目标产物(63mg)，直接用于下一步。Dissolve tert-butyl 1-nitromethyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (70 mg, 0.24 mmol) in methanol (5 mL), add palladium carbon (10 mg), and stir at 50°C for 2 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated to obtain a yellow liquid target product (63 mg), which was used directly in the next step.
步骤h:1-(2-氯乙酰氨基甲基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸叔丁酯的合成
Step h: Synthesis of tert-butyl 1-(2-chloroacetylaminomethyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate
将1-氨甲基-3,4-二氢-2,7-萘啶-2(1H)-羧酸叔丁酯(63mg,0.24mmol)溶于二氯甲烷(5mL)中，加入三乙胺(48.57mg,0.48mmol),氮气下冷却到0℃，缓慢加入2-氯乙酰氯(32.5mg,0.29mmol)，恢复到室温后继续搅拌1小时。反应液经过滤、浓缩。柱层析(石油醚:乙酸乙酯＝5:1)得到淡黄色固体目标产物(40mg,收率49％)。Dissolve 1-aminomethyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylic acid tert-butyl ester (63 mg, 0.24 mmol) in dichloromethane (5 mL), add triethylamine (48.57 mg, 0.48 mmol), cool to 0°C under nitrogen, slowly add 2-chloroacetyl chloride (32.5 mg, 0.29 mmol), return to room temperature and continue stirring for 1 hour. The reaction solution was filtered and concentrated. Column chromatography (petroleum ether: ethyl acetate = 5:1) gave the target product as a light yellow solid (40 mg, yield 49%).
步骤i:1,6,7,11b-四氢-2H-吡嗪并[2,1-a][2,7]萘啶-3(4H)酮的合成
Step i: Synthesis of 1,6,7,11b-tetrahydro-2H-pyrazino[2,1-a][2,7]naphthyridine-3(4H)one
将1-(2-氯乙酰氨基甲基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸叔丁酯(40mg,0.12mmol)加入到氯化氢的乙酸乙酯溶液中(5mL)，室温下搅拌2小时。反应液浓缩至干得淡黄色固体。 将该固体加入到乙腈(5mL)中，加入碳酸钾(48.7mg,0.35mmol)和碘化钠(17.7mg,0.12mmol)，在85℃下搅拌4小时。冷却到室温后，反应液经过滤、浓缩、柱层析(二氯甲烷:甲醇＝20:1)得到淡黄色固体目标产物(20mg,收率84％)。1-(2-Chloroacetylaminomethyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylic acid tert-butyl ester (40 mg, 0.12 mmol) was added to a solution of hydrogen chloride in ethyl acetate (5 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness to obtain a light yellow solid. The solid was added to acetonitrile (5 mL), potassium carbonate (48.7 mg, 0.35 mmol) and sodium iodide (17.7 mg, 0.12 mmol), and stirred at 85°C for 4 hours. After cooling to room temperature, the reaction solution was filtered, concentrated, and column chromatographed (dichloromethane: methanol = 20: 1) to obtain the target product as a light yellow solid (20 mg, yield 84%).
步骤j:1,3,4,6,7,11b-六氢吡嗪并[2,1-a][2,7]萘啶盐酸盐的合成
Step j: Synthesis of 1,3,4,6,7,11b-hexahydropyrazino[2,1-a][2,7]naphthyridine hydrochloride
将四氢锂铝(18.6mg,0.49mmol)加入到四氢呋喃(5mL)中，氮气下冷却到0℃，缓慢加入1,6,7,11b-四氢-2H-吡嗪并[2,1-a][2,7]萘啶-3(4H)酮(20mg,0.098mmol)的四氢呋喃(1mL)溶液。然后在60℃小搅拌4小时。冷却到0℃后，加入十水硫酸钠淬灭，过滤，向所得滤液中加入二碳酸二叔丁酯(25.7mg,0.12mmol)，搅拌过夜。反应液经浓缩、柱层析(二氯甲烷:甲醇＝20:1)得到淡黄色液体目标产物(30mg)。加入到氯化氢的乙酸乙酯溶液(5mL)中，搅拌2小时。反应液浓缩得到目标产物(14mg,收率63％)。Add lithium aluminum tetrahydride (18.6 mg, 0.49 mmol) to tetrahydrofuran (5 mL), cool to 0 ° C under nitrogen, and slowly add a solution of 1,6,7,11b-tetrahydro-2H-pyrazino[2,1-a][2,7]naphthyridine-3(4H)one (20 mg, 0.098 mmol) in tetrahydrofuran (1 mL). Then stir at 60 ° C for 4 hours. After cooling to 0 ° C, add sodium sulfate decahydrate to quench, filter, add di-tert-butyl dicarbonate (25.7 mg, 0.12 mmol) to the filtrate, and stir overnight. The reaction solution is concentrated and column chromatography (dichloromethane: methanol = 20: 1) to obtain a light yellow liquid target product (30 mg). Add to a solution of hydrogen chloride in ethyl acetate (5 mL) and stir for 2 hours. The reaction solution is concentrated to obtain the target product (14 mg, yield 63%).
LC-MS[M+H]+:190.3.LC-MS [M+H] + : 190.3.
1H NMR(400MHz,CD3OD):δ8.84(d,J＝5.6Hz,1H),8.65(d,J＝8.0Hz,1H),8.04(dd,J＝8.0,5.6Hz,1H),4.78(d,J＝9.2Hz,1H),4.35(dd,J＝13.2,2.4Hz,1H),3.78-3.64(m,4H),3.62-3.39(m,5H). 1 H NMR (400 MHz, CD 3 OD): δ8.84 (d, J=5.6 Hz, 1H), 8.65 (d, J=8.0 Hz, 1H), 8.04 (dd, J=8.0, 5.6 Hz, 1H), 4.78 (d, J=9.2 Hz, 1H), 4.35 (dd, J=13.2, 2.4 Hz, 1H), 3.78-3.64 (m, 4H), 3.62-3.39 (m, 5H).
实施例17Embodiment 17
1,3,4,6,7,11b-六氢-2H-吡嗪并[2,1-a][2,6]萘啶
1,3,4,6,7,11b-Hexahydro-2H-pyrazino[2,1-a][2,6]naphthyridine
化合物17的合成路线参考实施例15的合成路线。The synthetic route of compound 17 refers to the synthetic route of Example 15.
LC-MS[M+H]+:190.1。LC-MS [M+H] + : 190.1.
实施例18Embodiment 18
1,3,4,6,7,11b-六氢-2H-吡嗪并[2,1-f][1,6]萘啶
1,3,4,6,7,11b-Hexahydro-2H-pyrazino[2,1-f][1,6]naphthyridine
化合物18的合成路线参考实施例15的合成路线。The synthetic route of compound 18 refers to the synthetic route of Example 15.
LC-MS[M+H]+:190.1。LC-MS [M+H] + : 190.1.
实施例19Embodiment 19
1,3,4,6,7,12b-六氢-2H-苯并[4',5']噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
1,3,4,6,7,12b-Hexahydro-2H-benzo[4',5']thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物19的合成路线参考实施例1的合成路线。The synthetic route of compound 19 refers to the synthetic route of Example 1.
LC-MS[M+H]+:245.1。LC-MS [M+H] + : 245.1.
实施例20Embodiment 20
1,3,4,6,7,12b-六氢-2H-吡啶并[3”,2”:4',5']噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
1,3,4,6,7,12b-Hexahydro-2H-pyrido[3”,2”:4',5']thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物20的合成路线参考实施例1的合成路线。The synthetic route of compound 20 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例21Embodiment 21
1,3,4,6,7,12b-六氢-2H-吡啶并[4”,3”:4',5']噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
1,3,4,6,7,12b-Hexahydro-2H-pyrido[4”,3”:4',5']thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物21的合成路线参考实施例1的合成路线。The synthetic route of compound 21 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例22Embodiment 22
1,3,4,6,7,12b-六氢-2H-吡啶并[3”,4”:4',5']噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
1,3,4,6,7,12b-Hexahydro-2H-pyrido[3”,4”:4',5']thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物22的合成路线参考实施例1的合成路线。The synthetic route of compound 22 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例23Embodiment 23
1,3,4,6,7,12b-六氢-2H-吡啶并[2”,3”:4',5']噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
1,3,4,6,7,12b-Hexahydro-2H-pyrido[2”,3”:4',5']thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物23的合成路线参考实施例1的合成路线。 The synthetic route of compound 23 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例24Embodiment 24
1,3,4,6,7,12b-六氢-2H-吡嗪并[1,2-h]噻吩并[2,3-b][1,7]萘啶
1,3,4,6,7,12b-Hexahydro-2H-pyrazino[1,2-h]thieno[2,3-b][1,7]naphthyridine
化合物24的合成路线参考实施例1的合成路线。The synthetic route of compound 24 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例25Embodiment 25
1,3,4,6,7,12b-六氢-2H-吡嗪并[1,2-h]噻吩并[3,4-b][1,7]萘吡啶
1,3,4,6,7,12b-Hexahydro-2H-pyrazino[1,2-h]thieno[3,4-b][1,7]naphthyridine
化合物25的合成路线参考实施例1的合成路线。The synthetic route of compound 25 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例26Embodiment 26
1,3,4,6,7,12b-六氢-2H-吡嗪并[1,2-h]噻吩并[3,2-b][1,7]萘啶
1,3,4,6,7,12b-Hexahydro-2H-pyrazino[1,2-h]thieno[3,2-b][1,7]naphthyridine
化合物26的合成路线参考实施例1的合成路线。The synthetic route of compound 26 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例27Embodiment 27
1,2,3,4,6,7,11,12b-八氢吡嗪并[1,2-h]吡咯并[2,3-b][1,7]萘啶
1,2,3,4,6,7,11,12b-Octahydropyrazino[1,2-h]pyrrolo[2,3-b][1,7]naphthyridine
化合物27的合成路线参考实施例1的合成路线。The synthetic route of compound 27 refers to the synthetic route of Example 1.
LC-MS[M+H]+:229.1。LC-MS [M+H] + : 229.1.
实施例28Embodiment 28
1,2,3,4,6,7,9,12b-八氢吡嗪并[1,2-h]吡咯并[3,2-b][1,7]萘啶
1,2,3,4,6,7,9,12b-Octahydropyrazino[1,2-h]pyrrolo[3,2-b][1,7]naphthyridine
化合物28的合成路线参考实施例1的合成路线。The synthetic route of compound 28 refers to the synthetic route of Example 1.
LC-MS[M+H]+:229.1。LC-MS [M+H] + : 229.1.
实施例29Embodiment 29
1,3,4,6,7,12b-六氢-2H-吡嗪并[2,1-f]噻吩并[3,2-b][1,6]萘吡啶
1,3,4,6,7,12b-Hexahydro-2H-pyrazino[2,1-f]thieno[3,2-b][1,6]naphthyridine
化合物29的合成路线参考实施例1的合成路线。The synthetic route of compound 29 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例30Embodiment 30
1,3,4,6,7,12b-六氢-2H-吡嗪并[2,1-f]噻吩并[3,4-b][1,6]萘啶
1,3,4,6,7,12b-Hexahydro-2H-pyrazino[2,1-f]thieno[3,4-b][1,6]naphthyridine
化合物30的合成路线参考实施例1的合成路线。The synthetic route of compound 30 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例31Embodiment 31
1,3,4,6,7,12b-六氢-2H-吡嗪并[2,1-f]噻吩并[2,3-b][1,6]萘啶
1,3,4,6,7,12b-Hexahydro-2H-pyrazino[2,1-f]thieno[2,3-b][1,6]naphthyridine
化合物31的合成路线参考实施例1的合成路线。The synthetic route of compound 31 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例32Embodiment 32
1,2,3,4,6,7,11,12b-八氢吡嗪并[2,1-f]吡咯并[3,2-b][1,6]萘啶
1,2,3,4,6,7,11,12b-Octahydropyrazino[2,1-f]pyrrolo[3,2-b][1,6]naphthyridine
化合物32的合成路线参考实施例1的合成路线。 The synthetic route of compound 32 refers to the synthetic route of Example 1.
LC-MS[M+H]+:229.1。LC-MS [M+H] + : 229.1.
实施例33Embodiment 33
1,2,3,4,6,7,9,12b-八氢吡嗪并[2,1-f]吡咯并[2,3-b][1,6]萘啶
1,2,3,4,6,7,9,12b-Octahydropyrazino[2,1-f]pyrrolo[2,3-b][1,6]naphthyridine
化合物33的合成路线参考实施例1的合成路线。The synthetic route of compound 33 refers to the synthetic route of Example 1.
LC-MS[M+H]+:229.1。LC-MS [M+H] + : 229.1.
实施例34Embodiment 34
1,3,4,6,7,12b-六氢-2H-吡嗪并[2,1-a]噻吩并[3,2-g]异喹啉
1,3,4,6,7,12b-Hexahydro-2H-pyrazino[2,1-a]thieno[3,2-g]isoquinoline
化合物34的合成路线参考实施例1的合成路线。The synthetic route of compound 34 refers to the synthetic route of Example 1.
LC-MS[M+H]+:245.1。LC-MS [M+H] + : 245.1.
实施例35Embodiment 35
1,3,4,6,7,12b-六氢-2H-吡嗪并[2,1-a]噻吩并[3,4-g]异喹啉
1,3,4,6,7,12b-Hexahydro-2H-pyrazino[2,1-a]thieno[3,4-g]isoquinoline
化合物35的合成路线参考实施例1的合成路线。The synthetic route of compound 35 refers to the synthetic route of Example 1.
LC-MS[M+H]+:245.1。LC-MS [M+H] + : 245.1.
实施例36Embodiment 36
1,3,4,6,7,12b-六氢-2H-吡嗪并[2,1-a]噻吩并[2,3-g]异喹啉
1,3,4,6,7,12b-Hexahydro-2H-pyrazino[2,1-a]thieno[2,3-g]isoquinoline
化合物36的合成路线参考实施例1的合成路线。The synthetic route of compound 36 refers to the synthetic route of Example 1.
LC-MS[M+H]+:245.1。LC-MS [M+H] + : 245.1.
实施例37Embodiment 37
1,2,3,4,6,7,11,12b-八氢吡嗪并[2,1-a]吡咯并[3,2-g]异喹啉
1,2,3,4,6,7,11,12b-Octahydropyrazino[2,1-a]pyrrolo[3,2-g]isoquinoline
化合物37的合成路线参考实施例1的合成路线。The synthetic route of compound 37 refers to the synthetic route of Example 1.
LC-MS[M+H]+:228.1。LC-MS [M+H] + : 228.1.
实施例38Embodiment 38
1,2,3,4,6,7,9,12b-八氢吡嗪并[2,1-a]吡咯并[2,3-g]异喹啉
1,2,3,4,6,7,9,12b-Octahydropyrazino[2,1-a]pyrrolo[2,3-g]isoquinoline
化合物38的合成路线参考实施例1的合成路线。The synthetic route of compound 38 refers to the synthetic route of Example 1.
LC-MS[M+H]+:228.1。LC-MS [M+H] + : 228.1.
实施例39Embodiment 39
2-氯-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
2-Chloro-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
步骤a:2-氯-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯的合成
Step a: Synthesis of tert-butyl 2-chloro-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
在-78℃下，向4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯(295mg,1.0mmol)的四氢呋喃(10mL)溶液中缓慢滴加正丁基锂(0.60mL,2.5mol/L,1.5mmol)，在此温度下反应1小时。随后缓慢滴加N-氯代丁二酰亚胺(400mg,3.0mmol)的四氢呋喃(2mL)溶液，加毕将反应混合液恢复至室温反应2小时。反应结束后，饱和氯化铵淬灭反应，反应液用乙酸乙酯萃取，有机相再用饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，粗产物经柱层析(石油醚:乙酸乙酯＝3:1)纯化得到淡黄色油状目标产物(250mg,76％产率)。随后产物又经反相柱(水:乙腈＝2:3)纯化得到其水和乙腈的混合溶液，乙酸乙酯萃取， 有机相再用饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，旋干直接用于下一步反应。At -78°C, n-butyl lithium (0.60 mL, 2.5 mol/L, 1.5 mmol) was slowly added dropwise to a solution of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate (295 mg, 1.0 mmol) in tetrahydrofuran (10 mL), and the mixture was reacted at this temperature for 1 hour. Then, a solution of N-chlorosuccinimide (400 mg, 3.0 mmol) in tetrahydrofuran (2 mL) was slowly added dropwise, and the reaction mixture was returned to room temperature and reacted for 2 hours. After the reaction was completed, saturated ammonium chloride was used to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product as a light yellow oil (250 mg, 76% yield). The product was then purified by reverse phase column (water: acetonitrile = 2:3) to obtain a mixed solution of water and acetonitrile, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and spin-dried for the next reaction.
LC-MS[M+H]+:329.1.LC-MS [M+H] + : 329.1.
步骤b:2-氯-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step b: Synthesis of 2-chloro-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将2-氯-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯(60mg,0.18mmol)溶于盐酸/乙酸乙酯溶液(2mL)中，并在室温下搅拌过夜。反应结束后，旋干反应液，干燥后得到目标产物(40mg,收率84％)。2-Chloro-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylic acid tert-butyl ester (60 mg, 0.18 mmol) was dissolved in hydrochloric acid/ethyl acetate solution (2 mL) and stirred at room temperature overnight. After the reaction was completed, the reaction solution was spin-dried and dried to obtain the target product (40 mg, yield 84%).
LC-MS[M+H]+:229.1.LC-MS [M+H] + : 229.1.
1H NMR(400MHz,CD3OD):δ6.91(s,1H),4.76(d,J＝11.6Hz,1H),3.96(dd,J＝13.2,2.4Hz,1H),3.76-3.66(m,3H),3.63-3.42(m,4H),3.23-3.08(m,1H),2.98-2.92(m,1H). 1 H NMR (400 MHz, CD 3 OD): δ 6.91 (s, 1H), 4.76 (d, J = 11.6 Hz, 1H), 3.96 (dd, J = 13.2, 2.4 Hz, 1H), 3.76-3.66 (m, 3H), 3.63-3.42 (m, 4H), 3.23-3.08 (m, 1H), 2.98-2.92 (m, 1H).
实施例40Embodiment 40
2-甲基-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
2-Methyl-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
步骤a:2-甲基-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯的合成
Step a: Synthesis of tert-butyl 2-methyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
在-78℃下，向4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯(295mg,1.0mmol)的四氢呋喃(10mL)溶液中缓慢滴加正丁基锂(0.60mL,2.5mol/L,1.5mmol)，在此温度下反应1小时。随后缓慢滴加碘甲烷(0.2mL,3.0mmol)的四氢呋喃(2mL)溶液，加毕将反应混合液恢复至室温反应2小时。反应结束后，饱和氯化铵淬灭反应，反应液用乙酸乙酯萃取，有机相再用饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，粗产物经柱层析(石油醚:乙酸乙酯＝3:1)纯化得到淡黄色油状目标产物(290mg,收率94％)。At -78°C, n-butyl lithium (0.60 mL, 2.5 mol/L, 1.5 mmol) was slowly added dropwise to a solution of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate (295 mg, 1.0 mmol) in tetrahydrofuran (10 mL), and the mixture was reacted at this temperature for 1 hour. Then, a solution of iodomethane (0.2 mL, 3.0 mmol) in tetrahydrofuran (2 mL) was slowly added dropwise, and the reaction mixture was returned to room temperature and reacted for 2 hours. After the reaction was completed, saturated ammonium chloride was used to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product (290 mg, yield 94%) as a light yellow oil.
LC-MS[M+H]+:309.6.LC-MS [M+H] + : 309.6.
步骤b:2-甲基-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step b: Synthesis of 2-methyl-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将2-甲基-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯(290mg,0.94mmol)溶于4M的盐酸/乙酸乙酯溶液(10mL)中，并在室温下搅拌过夜。反应结束后，旋干反应液，干燥后得到目标产物(220mg,收率96％)。2-Methyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylic acid tert-butyl ester (290 mg, 0.94 mmol) was dissolved in 4M hydrochloric acid/ethyl acetate solution (10 mL) and stirred at room temperature overnight. After the reaction was completed, the reaction solution was spin-dried and dried to obtain the target product (220 mg, yield 96%).
LC-MS[M+H]+:209.3.LC-MS [M+H] + : 209.3.
1H NMR(400MHz,CD3OD):δ6.68(s,1H),5.14(d,J＝11.2Hz,1H),4.07(dd,J＝14.8,2.4Hz,1H),3.93-3.84(m,2H),3.83-3.72(m,3H),3.71-3.56(m,2H),3.31-3.17(m,1H),3.02(dd,J＝17.2,4.4Hz,1H),2.46(s,3H). 1 H NMR (400 MHz, CD 3 OD): δ 6.68 (s, 1H), 5.14 (d, J = 11.2 Hz, 1H), 4.07 (dd, J = 14.8, 2.4 Hz, 1H), 3.93-3.84 (m, 2H), 3.83-3.72 (m, 3H), 3.71-3.56 (m, 2H), 3.31-3.17 (m, 1H), 3.02 (dd, J = 17.2, 4.4 Hz, 1H), 2.46 (s, 3H).
实施例41Embodiment 41
2-氟-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪
2-Fluoro-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine
化合物41的合成路线参考实施例40的合成路线。The synthetic route of compound 41 refers to the synthetic route of Example 40.
LC-MS[M+H]+:213.1。LC-MS [M+H] + : 213.1.
实施例42Embodiment 42
3-甲基-4,7,8,9,10,10-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
3-Methyl-4,7,8,9,10,10-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
步骤a:(4-甲基噻吩-3-基)甲醇的合成
Step a: Synthesis of (4-methylthiophen-3-yl)methanol
将4-甲基噻吩-3-甲醛(0.44g,3.5mmol)溶于甲醇(10mL)中加入硼氢化钠(0.13g,3.5mmol)后，室温搅拌2小时后，反应液直接浓缩去除溶剂后柱层析得到目标产物(0.25g,收率56％)。4-Methylthiophene-3-carboxaldehyde (0.44 g, 3.5 mmol) was dissolved in methanol (10 mL), sodium borohydride (0.13 g, 3.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated to remove the solvent and then subjected to column chromatography to obtain the target product (0.25 g, yield 56%).
步骤b:3-(溴甲基)-4-甲基噻吩的合成
Step b: Synthesis of 3-(bromomethyl)-4-methylthiophene
将(4-甲基噻吩-3-基)甲醇(0.25g,1.9mmol)溶于二氯甲烷(10mL)中，加入三溴化磷(1.58g,5.8mmol)溶后室温搅拌2小时后，反应液倒入水(10mL)中，分液后有机相用饱和碳酸氢钠水溶液洗涤(10mL x 2)，硫酸钠干燥后浓缩至干直接进行下一步投料。Dissolve (4-methylthiophen-3-yl)methanol (0.25 g, 1.9 mmol) in dichloromethane (10 mL), add phosphorus tribromide (1.58 g, 5.8 mmol) and stir at room temperature for 2 hours. Pour the reaction solution into water (10 mL). After separation, the organic phase is washed with saturated sodium bicarbonate aqueous solution (10 mL x 2), dried over sodium sulfate and concentrated to dryness to proceed directly to the next step.
步骤c:2-(4-甲基噻吩-3-基)乙腈的合成
Step c: Synthesis of 2-(4-methylthiophen-3-yl)acetonitrile
将TMSCN(0.57g,5.7mmol)溶于乙腈(10mL)中，加入TBAF(0.57g,5.7mmol)后室温搅拌15分钟后，将原料3-(溴甲基)-4-甲基噻吩(0.36g,1.9mmol)的乙腈(10mL)溶液加入至上述反应液中，搅拌过夜后，倒入水(20mL)中，混合液用DCM(10mL x 3)萃取后浓缩柱层析得到目标产物(0.18g,收率69％)。TMSCN (0.57 g, 5.7 mmol) was dissolved in acetonitrile (10 mL). TBAF (0.57 g, 5.7 mmol) was added and stirred at room temperature for 15 minutes. Then, a solution of 3-(bromomethyl)-4-methylthiophene (0.36 g, 1.9 mmol) in acetonitrile (10 mL) was added to the reaction mixture. After stirring overnight, the mixture was poured into water (20 mL). The mixture was extracted with DCM (10 mL x 3) and concentrated by column chromatography to obtain the target product (0.18 g, yield 69%).
步骤d:2-(4-甲基噻吩-3-基)乙烷-1-胺的合成
Step d: Synthesis of 2-(4-methylthiophen-3-yl)ethane-1-amine
将2-(4-甲基噻吩-3-基)乙腈(0.18g,1.3mmol)溶于THF(15mL)中，加入硼烷二甲硫 醚复合物的四氢呋喃(2M,2mL,4mmol)溶液后，回流3小时后，滴入甲醇至无气泡产生，反应液淬灭后直接浓缩至干直接进行下一步投料。Dissolve 2-(4-methylthiophen-3-yl)acetonitrile (0.18 g, 1.3 mmol) in THF (15 mL) and add borane dimethyl sulfide. After the ether complex was dissolved in tetrahydrofuran (2M, 2 mL, 4 mmol), it was refluxed for 3 hours, and then methanol was added dropwise until no bubbles were generated. After the reaction solution was quenched, it was directly concentrated to dryness and then directly fed to the next step.
LC-MS[M+H]+:142.2.LC-MS [M+H] + : 142.2.
步骤e:2-((-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚啉-1,3-二酮的合成
Step e: Synthesis of 2-((-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione
将上步所得到2-(4-甲基噻吩-3-基)乙烷-1-胺粗品(1.3mmol)直接溶于DCM(15mL)中，加入三氟乙酸(1mL)后，加入2-(1,3-二氧杂吲哚-2-基)乙醛(0.49g,2.6mmol)室温搅拌过夜。次日将反应液倒入饱和碳酸氢钠水溶液中，分液后水洗涤有机相后，浓缩干后柱层析得到目标产物(0.35g,收率86％)。The crude 2-(4-methylthiophen-3-yl)ethane-1-amine (1.3mmol) obtained in the previous step was directly dissolved in DCM (15mL), and after adding trifluoroacetic acid (1mL), 2-(1,3-dioxaindol-2-yl)acetaldehyde (0.49g, 2.6mmol) was added and stirred at room temperature overnight. The next day, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution, and the organic phase was washed with water after separation, concentrated to dryness, and then column chromatography was performed to obtain the target product (0.35g, yield 86%).
LC-MS[M+H]+:312.9.LC-MS [M+H] + : 312.9.
步骤f:2-(7-((1,3-二氧代异吲哚啉-2-基)甲基)-3-甲基-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)基)乙酸乙酯的合成
Step f: Synthesis of ethyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-3-methyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)yl)acetate
将原料2-((-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚啉-1,3-二酮(0.35g,1.1mmol)溶于DMSO(10mL)中，依次加入碳酸钾(0.46g,3.3mmol)，碘化钠(0.02g,0.1mmol)和溴乙酸乙酯(0.37g,2.2mmol)，反应液于70℃条件下搅拌3小时后，倒入水(30mL)中，乙酸乙酯(10mL x 3)萃取，有机相经水洗涤(10mL x 3)，硫酸钠干燥后柱层析得到目标产物(0.38g,收率85％)。The raw material 2-((-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione (0.35 g, 1.1 mmol) was dissolved in DMSO (10 mL), and potassium carbonate (0.46 g, 3.3 mmol), sodium iodide (0.02 g, 0.1 mmol) and ethyl bromoacetate (0.37 g, 2.2 mmol) were added in sequence. The reaction solution was stirred at 70 ° C for 3 hours, poured into water (30 mL), extracted with ethyl acetate (10 mL x 3), and the organic phase was washed with water (10 mL x 3), dried with sodium sulfate, and then purified by column chromatography to obtain the target product (0.38 g, yield 85%).
LC-MS[M+H]+:399.3.LC-MS [M+H] + : 399.3.
步骤g:3-甲基-4,9,10,10-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的合成
Step g: Synthesis of 3-methyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
将原料2-(7-((1,3-二氧代异吲哚啉-2-基)甲基)-3-甲基-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)基)乙酸乙酯(0.38g,0.9mmol)溶于无水乙醇(20mL)中，加入水合肼(0.24g,4.7mmol)后于70℃搅拌2小时后，反应液倒入水中，二氯甲烷(10mL x 3)萃取，有机相经硫酸钠干燥后柱层析得到目标产物(0.17g,收率80％)。The raw material ethyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-3-methyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)yl)acetate (0.38 g, 0.9 mmol) was dissolved in anhydrous ethanol (20 mL). After adding hydrazine hydrate (0.24 g, 4.7 mmol), the mixture was stirred at 70 °C for 2 hours. The reaction solution was poured into water and extracted with dichloromethane (10 mL x 3). The organic phase was dried over sodium sulfate and then purified by column chromatography to obtain the target product (0.17 g, yield 80%).
LC-MS[M+H]+:222.9.LC-MS [M+H] + : 222.9.
步骤h:3-甲基-4,5,7,8,10,10-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的合成
Step h: Synthesis of tert-butyl 3-methyl-4,5,7,8,10,10-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
将3-甲基-4,9,10,10-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮(0.17g,0.7mmol)溶于THF(20mL)中，加入四氢铝锂(0.06g,1.5mmol)后，氮气保护下回流4小时后，反应液冷却至室温后用十水硫酸钠淬灭后，抽滤，向滤液中加入二碳酸二叔丁酯(0.33g,1.5mmol)后，搅拌2小时。反应液直接浓缩至干柱层析得到目标产物(0.1g,收率43％)。3-Methyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one (0.17g, 0.7mmol) was dissolved in THF (20mL), and lithium aluminum tetrahydride (0.06g, 1.5mmol) was added. After reflux for 4 hours under nitrogen protection, the reaction solution was cooled to room temperature and quenched with sodium sulfate decahydrate, and then filtered. Di-tert-butyl dicarbonate (0.33g, 1.5mmol) was added to the filtrate and stirred for 2 hours. The reaction solution was directly concentrated to dryness and column chromatography to obtain the target product (0.1g, yield 43%).
LC-MS[M+H]+:309.1.LC-MS [M+H] + : 309.1.
步骤i:3-甲基-4,7,8,9,10,10-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step i: Synthesis of 3-methyl-4,7,8,9,10,10-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将3-甲基-4,5,7,8,10,10-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯(0.1g,0.3mmol)溶于浓度为4M的盐酸乙酸乙酯(5mL)中，室温条件下搅拌2小时后，抽滤得到目标产物(30mg,收率33％)。Dissolve tert-butyl 3-methyl-4,5,7,8,10,10-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate (0.1 g, 0.3 mmol) in 4 M ethyl acetate (5 mL) and stir at room temperature for 2 hours. Then, filter and obtain the target product (30 mg, yield 33%).
LC-MS[M+H]+:209.3.LC-MS [M+H] + : 209.3.
1H NMR(400MHz,CD3OD):δ7.18(s,1H),5.00(d,J＝11.2Hz,1H),4.08(d,J＝14.0Hz,1H),3.93-3.83(m,2H),3.82-3.48(m,5H),3.17-3.03(m,1H),2.96(dd,J＝17.6,5.6Hz,1H),2.18(s,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.18 (s, 1H), 5.00 (d, J=11.2 Hz, 1H), 4.08 (d, J=14.0 Hz, 1H), 3.93-3.83 (m, 2H), 3.82-3.48 (m, 5H), 3.17-3.03 (m, 1H), 2.96 (dd, J=17.6, 5.6 Hz, 1H), 2.18 (s, 3H).
实施例43Embodiment 43
3-氟-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪
3-Fluoro-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine
化合物43的合成路线参考实施例42的合成路线。The synthetic route of compound 43 refers to the synthetic route of Example 42.
LC-MS[M+H]+:213.1。LC-MS [M+H] + : 213.1.
实施例44Embodiment 44
3-氯-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
3-Chloro-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
步骤a:2-(4-氯噻吩-3-基)乙烷-1-胺的合成
Step a: Synthesis of 2-(4-chlorothiophen-3-yl)ethane-1-amine
将2-(4-氯噻吩-3-基)乙腈(0.4g,2.55mmol)溶于四氢呋喃(4mL)中，加入硼烷二甲硫醚络合物(10M的四氢呋喃溶液,0.76mL,7.62mmol)，氮气保护在70℃下搅拌2小时。反应结束后，待反应液冷却至0℃，缓慢滴加甲醇(50mL)后搅拌30分钟。浓缩后得到淡黄色油状目标产物(0.4g,粗品)，无需纯化直接用于下一步。Dissolve 2-(4-chlorothiophene-3-yl)acetonitrile (0.4 g, 2.55 mmol) in tetrahydrofuran (4 mL), add borane dimethyl sulfide complex (10 M tetrahydrofuran solution, 0.76 mL, 7.62 mmol), and stir at 70 ° C for 2 hours under nitrogen protection. After the reaction is completed, the reaction solution is cooled to 0 ° C, methanol (50 mL) is slowly added dropwise, and stirred for 30 minutes. After concentration, the target product (0.4 g, crude product) is obtained as a light yellow oil, which is directly used in the next step without purification.
LC-MS[M+H]+:161.9.LC-MS [M+H] + : 161.9.
步骤b:2-((3-氯-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚啉-1,3-二酮的合成
Step b: Synthesis of 2-((3-chloro-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione
将2-(4-氯噻吩-3-基)乙烷-1-胺(0.40g,粗品)溶于冰醋酸(4mL)中，加入N-丙酮基邻苯二甲酰亚胺(0.52g,2.73mmol)和三氟乙酸(1.41g,12.40mmol)，在80℃下搅拌12小时。反应结束后，向反应液中加入饱和的碳酸氢钠溶液(100mL),用乙酸乙酯(50mL x 3)萃取三次后，有机相依次用水洗涤三次(50mL x 3)，饱和食盐水洗涤一次(50mL)，无水硫酸钠干燥后经柱层析(石油醚/乙酸乙酯＝3:1)分离纯化得到黄色油状目标产物(0.40g,收率49％)。2-(4-Chlorothiophene-3-yl)ethane-1-amine (0.40 g, crude product) was dissolved in glacial acetic acid (4 mL), and N-acetonylphthalimide (0.52 g, 2.73 mmol) and trifluoroacetic acid (1.41 g, 12.40 mmol) were added, and stirred at 80 ° C for 12 hours. After the reaction was completed, a saturated sodium bicarbonate solution (100 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL x 3). The organic phase was washed with water three times (50 mL x 3), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and separated and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain the target product as a yellow oil (0.40 g, yield 49%).
LC-MS[M+H]+:333.8.LC-MS [M+H] + : 333.8.
步骤c:2-(3-氯-7-((1,3-二氧代异吲哚啉-2-基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)乙酸乙酯的合成
Step c: Synthesis of ethyl 2-(3-chloro-7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)acetate
将2-((3-氯-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚啉-1,3-二酮(0.40g,1.20 mmol)溶于乙腈(4mL)中，加入溴乙酸乙酯(1.19g,7.16mmol)和N,N-二异丙基乙胺(1.15g,8.95mmol)，氮气保护下90℃搅拌12小时。反应结束后，将反应液倒入水(50mL)中，用二氯甲烷萃取三次(50mL x 3)后，有机相依次用水洗涤三次(50mL x 3)，饱和食盐水洗涤一次(50mL)，无水硫酸钠干燥后经柱层析(石油醚/乙酸乙酯＝4:1)分离纯化得到无色油状目标产物(0.30g,收率58％)。2-((3-chloro-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione (0.40 g, 1.20 mmol) was dissolved in acetonitrile (4mL), ethyl bromoacetate (1.19g, 7.16mmol) and N,N-diisopropylethylamine (1.15g, 8.95mmol) were added, and stirred at 90°C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (50mL), extracted with dichloromethane three times (50mL x 3), and the organic phase was washed with water three times (50mL x 3) and saturated brine once (50mL), dried over anhydrous sodium sulfate, and separated and purified by column chromatography (petroleum ether/ethyl acetate = 4:1) to obtain the target product as a colorless oil (0.30g, yield 58%).
LC-MS[M+H]+:418.9.LC-MS [M+H] + : 418.9.
步骤d:3-氯-4,9,10,10-四氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的合成
Step d: Synthesis of 3-chloro-4,9,10,10-tetrahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
将2-(3-氯-7-((1,3-二氧代异吲哚啉-2-基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)乙酸乙酯(300mg,0.72mmol)溶于乙醇(6mL)中，加入80％水合肼(130mg,2.15mmol)，在70℃下搅拌3小时。反应结束后，将反应液倒入水(50mL)中，用乙酸乙酯萃取三次(30mL x 3)后，有机相依次用水洗涤三次(30mL x 3)，饱和食盐水洗涤一次(30mL)，无水硫酸钠干燥后经柱层析(二氯甲烷/甲醇＝25:1)分离纯化得到黄色油状目标产物(90mg,收率52％)。Ethyl 2-(3-chloro-7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)acetate (300 mg, 0.72 mmol) was dissolved in ethanol (6 mL), 80% hydrazine hydrate (130 mg, 2.15 mmol) was added, and the mixture was stirred at 70°C for 3 hours. After the reaction, the reaction solution was poured into water (50 mL), extracted with ethyl acetate three times (30 mL x 3), and the organic phase was washed with water three times (30 mL x 3), washed with saturated brine once (30 mL), dried over anhydrous sodium sulfate, and separated and purified by column chromatography (dichloromethane/methanol = 25:1) to obtain the target product as a yellow oil (90 mg, yield 52%).
LC-MS[M+H]+:242.9.LC-MS [M+H] + : 242.9.
步骤e:3-氯-4,5,7,8,10,10-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的合成
Step e: Synthesis of tert-butyl 3-chloro-4,5,7,8,10,10-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
将3-氯-4,9,10,10-四氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮(90mg,0.45mmol)溶于四氢呋喃(2mL)中，加入四氢铝锂(0.05g,1.35mmol)，在氮气保护下80℃搅拌2小时。将反应液冷却至室温后缓慢加入十水硫酸钠(0.13g,0.46mmol)搅拌10分钟，抽滤，得到的滤液浓缩得到混合物(90mg,粗品)为黄色油状物，然后加入四氢呋喃(1mL)、三乙胺(119mg,1.18mmol)和二碳酸二叔丁酯(129mg,0.59mmol)，在25℃下搅拌3小时。反应结束后，将反应液倒入水(10mL)中，用乙酸乙酯萃取三次(10mL x 3)后，有机相依次用水洗涤三次(10mL x 3)，饱和食盐水洗涤一次(10mL)，无水硫酸钠干燥后经柱层析(石油醚/乙酸乙酯＝10:1)分离纯化得到无色油状目标产物(90mg,收率70％)。3-Chloro-4,9,10,10-tetrahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one (90 mg, 0.45 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum tetrahydride (0.05 g, 1.35 mmol) was added, and stirred at 80°C for 2 hours under nitrogen protection. After the reaction solution was cooled to room temperature, sodium sulfate decahydrate (0.13 g, 0.46 mmol) was slowly added and stirred for 10 minutes, and then filtered, and the filtrate was concentrated to obtain a mixture (90 mg, crude product) as a yellow oil, and then tetrahydrofuran (1 mL), triethylamine (119 mg, 1.18 mmol) and di-tert-butyl dicarbonate (129 mg, 0.59 mmol) were added, and stirred at 25°C for 3 hours. After the reaction, the reaction solution was poured into water (10 mL), extracted with ethyl acetate three times (10 mL x 3), and the organic phase was washed with water three times (10 mL x 3), washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and separated and purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain the target product as a colorless oil (90 mg, yield 70%).
LC-MS[M+H]+:329.1.LC-MS [M+H] + : 329.1.
步骤f:3-氯-4,7,8,9,10,10-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step f: Synthesis of 3-chloro-4,7,8,9,10,10-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将3-氯-4,5,7,8,10,10-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯(90mg,0.27mmol)溶于氯化氢的1,4-二氧六环溶液(4M,3mL)中，室温搅拌5小时后抽滤，滤饼用 乙酸乙酯洗涤得到白色固体目标产物(35mg,收率57％)。3-Chloro-4,5,7,8,10,10-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylic acid tert-butyl ester (90 mg, 0.27 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (4 M, 3 mL), stirred at room temperature for 5 hours, and then filtered. The filter cake was The target product (35 mg, yield 57%) was obtained by washing with ethyl acetate as a white solid.
LC-MS[M+H]+:229.3.LC-MS [M+H] + : 229.3.
1H NMR(400MHz,CD3OD):δ7.53(s,1H),5.00(d,J＝9.2Hz,1H),4.09(dd,J＝14.0,3.2Hz,1H),3.91-3.82(m,2H),3.78-3.71(m,1H),3.70-3.54(m,4H),3.16-3.05(m,1H),3.02-2.94(m,1H). 1 H NMR (400 MHz, CD 3 OD): δ7.53 (s, 1H), 5.00 (d, J=9.2 Hz, 1H), 4.09 (dd, J=14.0, 3.2 Hz, 1H), 3.91-3.82 (m, 2H), 3.78-3.71 (m, 1H), 3.70-3.54 (m, 4H), 3.16-3.05 (m, 1H), 3.02-2.94 (m, 1H).
实施例45Embodiment 45
7-乙基-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
7-Ethyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
参考实施例10的合成路线。Refer to the synthetic route of Example 10.
异构体1：Isomer 1:
LC-MS[M+H]+:223.1.LC-MS [M+H] + : 223.1.
1H NMR(400MHz,CD3OD):δ7.56(d,J＝4.8Hz,1H),7.01(d,J＝5.2Hz,1H),5.21(d,J＝6.4Hz,1H),3.94-3.85(m,2H),3.77-3.58(m,5H),3.23-3.02(m,2H),2.16-1.94(m,2H),1.12(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.56 (d, J=4.8 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 5.21 (d, J=6.4 Hz, 1H), 3.94-3.85 (m, 2H), 3.77-3.58 (m, 5H), 3.23-3.02 (m, 2H), 2.16-1.94 (m, 2H), 1.12 (t, J=7.2 Hz, 3H).
异构体2：Isomer 2:
LC-MS[M+H]+:223.1.LC-MS [M+H] + : 223.1.
1H NMR(400MHz,CD3OD):δ7.56(d,J＝5.2Hz,1H),7.01(d,J＝5.2Hz,1H),5.19(d,J＝10.4Hz,1H),4.14-4.03(m,2H),3.96-3.77(m,2H),3.72-3.62(m,1H),3.61-3.45(m,2H),3.30-3.10(m,2H),2.24-2.10(m,1H),1.96-1.83(m,1H),1.14(t,J＝7.6Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.56 (d, J=5.2 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 5.19 (d, J=10.4 Hz, 1H), 4.14-4.03 (m, 2H), 3.96-3.77 (m, 2H), 3.72-3.62 (m, 1H), 3.61-3.45 (m, 2H), 3.30-3.10 (m, 2H), 2.24-2.10 (m, 1H), 1.96-1.83 (m, 1H), 1.14 (t, J=7.6 Hz, 3H).
实施例46Embodiment 46
7-(2,2,2-三氟乙基)-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪
7-(2,2,2-Trifluoroethyl)-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine
化合物46的合成路线参考实施例7的合成路线。The synthetic route of compound 46 refers to the synthetic route of Example 7.
LC-MS[M+H]+:277.1。LC-MS [M+H] + : 277.1.
实施例47Embodiment 47
7-三氟甲基-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
7-Trifluoromethyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
步骤a:((6-(1,1,1-三氟-3-羟基丙基-2-基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸叔丁酯的合成
Step a: Synthesis of tert-butyl ((6-(1,1,1-trifluoro-3-hydroxypropyl-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate
在反应瓶中分别加入N-((4H,5H,6H,7H-噻吩并[2,3-c]吡啶-7-基)甲基)胺基甲酸叔丁酯(500mg,1.86mmol)、2-溴-3,3,3-三氟-1-丙醇(0.29mL,2.79mmol)、碳酸钾(770mg,5.58mmol)、碘化钠(28mg,0.19mmol)和乙腈(18mL)，混合液在120℃下微波反应(microwave)6小时。反应结束后，饱和氯化铵淬灭反应，反应液用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，粗产物经柱层析(石油醚:乙酸乙酯＝3:1)纯化得到淡黄色油状目标产物(480mg,收率68％)。Tert-butyl N-((4H,5H,6H,7H-thieno[2,3-c]pyridin-7-yl)methyl)carbamate (500 mg, 1.86 mmol), 2-bromo-3,3,3-trifluoro-1-propanol (0.29 mL, 2.79 mmol), potassium carbonate (770 mg, 5.58 mmol), sodium iodide (28 mg, 0.19 mmol) and acetonitrile (18 mL) were added to the reaction bottle, and the mixture was subjected to microwave reaction at 120°C for 6 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product as a light yellow oil (480 mg, yield 68%).
LC-MS[M+H]+:381.5.LC-MS [M+H] + : 381.5.
步骤b:2-(7-(((叔丁氧羰基)氨基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-3,3,3-三氟丙基4-甲基苯磺酸酯的合成
Step b: Synthesis of 2-(7-(((tert-butyloxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-3,3,3-trifluoropropyl 4-methylbenzenesulfonate
在0℃下，向4((6-(1,1,1-三氟-3-羟基丙基-2-基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸叔丁酯(280mg,0.74mmol)、三乙胺(110mg,1.11mmol)和4-二甲胺基吡啶(9mg,0.074mmol)的二氯甲烷(8mL)溶液中缓慢加入对甲基苯磺酰氯(200mg,1.11mmol)，加毕将反应混合液恢复至室温搅拌过夜。反应结束后，饱和氯化铵淬灭反应，反应液用二 氯甲烷DCM萃取，有机相再用饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，粗产物经柱层析(石油醚:乙酸乙酯＝4:1)纯化得到淡黄色油状目标产物(170mg,收率43％).At 0°C, p-toluenesulfonyl chloride (200 mg, 1.11 mmol) was slowly added to a solution of tert-butyl 4((6-(1,1,1-trifluoro-3-hydroxypropyl-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate (280 mg, 0.74 mmol), triethylamine (110 mg, 1.11 mmol) and 4-dimethylaminopyridine (9 mg, 0.074 mmol) in dichloromethane (8 mL). After the addition, the reaction mixture was returned to room temperature and stirred overnight. After the reaction was completed, the reaction was quenched with saturated ammonium chloride and the reaction solution was washed with dichloromethane (8 mL). The mixture was extracted with chloromethane (DCM), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to give the desired product as a light yellow oil (170 mg, yield 43%).
LC-MS[M+H]+:535.2.LC-MS [M+H] + : 535.2.
步骤c:2-(7-(氨甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-3,3,3-三氟丙基4-甲基苯磺酸酯的合成
Step c: Synthesis of 2-(7-(aminomethyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-3,3,3-trifluoropropyl 4-methylbenzenesulfonate
在0℃下，向2-(7-(((叔丁氧羰基)氨基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-3,3,3-三氟丙基4-甲基苯磺酸酯(170mg,0.32mmol)的二氯甲烷(3mL)溶液中缓慢加入三氟乙酸(0.6mL,8.05mmol)，加毕将反应混合液恢复至室温搅拌1小时。反应结束后，旋干反应液，浓缩得到的产物无需纯化直接用于下一步反应.At 0°C, trifluoroacetic acid (0.6 mL, 8.05 mmol) was slowly added to a solution of 2-(7-(((tert-butyloxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-3,3,3-trifluoropropyl 4-methylbenzenesulfonate (170 mg, 0.32 mmol) in dichloromethane (3 mL). After the addition, the reaction mixture was returned to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was dried and concentrated to obtain a product that was directly used in the next step without purification.
LC-MS[M+H]+:436.0.LC-MS [M+H] + : 436.0.
步骤d:7-(三氟甲基)-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪的合成
Step d: Synthesis of 7-(trifluoromethyl)-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine
在反应瓶中分别加入2-(7-(氨甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-3,3,3-三氟丙基4-甲基苯磺酸酯三氟乙酸盐(139mg,0.32mmol)、N,N-二异丙基乙胺(0.11mL,0.64mmol)和乙腈(7mL)，混合液在120℃下微波反应2小时。反应结束后，饱和氯化铵淬灭反应，反应液用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，得到的产物无需纯化直接用于下一步反应.2-(7-(Aminomethyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-3,3,3-trifluoropropyl 4-methylbenzenesulfonate trifluoroacetate (139 mg, 0.32 mmol), N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) and acetonitrile (7 mL) were added to the reaction bottle, and the mixture was subjected to microwave reaction at 120°C for 2 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained product was directly used in the next reaction without purification.
LC-MS[M+H]+:263.5.LC-MS [M+H] + : 263.5.
步骤e:7-(三氟甲基)-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯的合成
Step e: Synthesis of tert-butyl 7-(trifluoromethyl)-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
在反应瓶中分别加入7-(三氟甲基)-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪(84mg,0.32mmol)、二碳酸二叔丁酯(0.37mL,1.60mmol)和甲醇(3mL)，混合液在室温下搅拌过夜。反应结束后，直接旋干反应液，粗产物经柱层析(石油醚:乙酸乙酯＝10:1)纯化得到淡黄色油状目标产物(35mg,收率30％).7-(Trifluoromethyl)-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine (84 mg, 0.32 mmol), di-tert-butyl dicarbonate (0.37 mL, 1.60 mmol) and methanol (3 mL) were added to the reaction flask, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was directly dried, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product (35 mg, yield 30%) as a light yellow oil.
LC-MS[M+H]+:363.1.LC-MS [M+H] + : 363.1.
步骤f:7-(三氟甲基)-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step f: Synthesis of 7-(trifluoromethyl)-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将7-(三氟甲基)-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯(35mg,0.10mmol)溶于盐酸/乙酸乙酯溶液(2mL)中，并在室温下搅拌2小时。反应结束后，旋干反应液，冻干后得到目标产物(15mg,收率50％)。7-(Trifluoromethyl)-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylic acid tert-butyl ester (35 mg, 0.10 mmol) was dissolved in hydrochloric acid/ethyl acetate solution (2 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was dried and freeze-dried to obtain the target product (15 mg, yield 50%).
LC-MS[M+H]+:263.5.LC-MS [M+H] + : 263.5.
1H NMR(400MHz,CD3OD):δ7.47(dd,J＝4.8,0.8Hz,1H),6.96(d,J＝5.2Hz,1H),4.59(d,J＝11.2Hz,1H),4.16-4.08(m,1H),3.84(dd,J＝12.4,3.2Hz,1H),3.78-3.69(m,2H),3.59-3.52(m,1H),3.38(t,J＝12.0Hz,1H),3.27-3.14(m,2H),3.05(ddt,J＝15.6,5.2,1.6Hz,1H). 1 H NMR (400 MHz, CD 3 OD): δ7.47 (dd, J=4.8, 0.8 Hz, 1H), 6.96 (d, J=5.2 Hz, 1H), 4.59 (d, J=11.2 Hz, 1H), 4.16-4.08 (m, 1H), 3.84 (dd, J=12.4, 3.2 Hz, 1H), 3.78-3.69 (m, 2H), 3.59-3.52 (m, 1H), 3.38 (t, J=12.0 Hz, 1H), 3.27-3.14 (m, 2H), 3.05 (ddt, J=15.6, 5.2, 1.6 Hz, 1H).
19F NMR(376MHz,CD3OD):δ-76.8(s,3F). 19 F NMR (376 MHz, CD 3 OD): δ-76.8 (s, 3F).
实施例48Embodiment 48
7-二氟甲基-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪
7-Difluoromethyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine
化合物48的合成路线参考实施例7的合成路线。The synthetic route of compound 48 refers to the synthetic route of Example 7.
LC-MS[M+H]+:245.1。LC-MS [M+H] + : 245.1.
实施例49Embodiment 49
7,7-二甲基-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
7,7-Dimethyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
步骤a:2-甲基-2-(2-(噻吩-3-乙基)乙基氨基)丙酸甲酯的合成
Step a: Synthesis of methyl 2-methyl-2-(2-(thiophene-3-ethyl)ethylamino)propanoate
将2-(噻吩-3-基)乙烷-1-胺(2.0g,15.7mmol)和2-溴-2-甲基丙酸甲酯(3.4g,18.9mmol)溶于乙腈(30mL)溶液中，加入碳酸钾(4.3g,31.5mmol)和碘化钠(2.4g,15.7mmol)，80℃下反应12小时。冷却到室温后，反应液经过滤，浓缩，柱层析(石油醚:乙酸乙酯＝4:1)得到黄色液体目标产物(2.4g,收率67％)。2-(Thiophen-3-yl)ethane-1-amine (2.0 g, 15.7 mmol) and methyl 2-bromo-2-methylpropanoate (3.4 g, 18.9 mmol) were dissolved in acetonitrile (30 mL) solution, potassium carbonate (4.3 g, 31.5 mmol) and sodium iodide (2.4 g, 15.7 mmol) were added, and the mixture was reacted at 80°C for 12 hours. After cooling to room temperature, the reaction solution was filtered, concentrated, and column chromatography (petroleum ether: ethyl acetate = 4:1) was performed to obtain the target product as a yellow liquid (2.4 g, yield 67%).
步骤b:2-(7-((1,3-二氧代异吲哚啉-2-基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)基)-2-甲基丙酸甲酯的合成
Step b: Synthesis of methyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)yl)-2-methylpropanoate
将2-甲基-2-(2-(噻吩-3-乙基)乙基氨基)丙酸甲酯(500mg,2.2mmol)溶于乙酸(10mL)溶液中，加入2-(1,3-二氧代异吲哚啉-2-基)乙醛(458mg,2.4mmol)，80℃下反应12小时。冷却到室温后，浓缩，柱层析(石油醚:乙酸乙酯＝5:1)得到黄色液体目标产物(440mg,收率50％)。Dissolve methyl 2-methyl-2-(2-(thiophene-3-ethyl)ethylamino)propanoate (500 mg, 2.2 mmol) in acetic acid (10 mL) solution, add 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (458 mg, 2.4 mmol), and react at 80°C for 12 hours. After cooling to room temperature, concentrate, and column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product (440 mg, yield 50%) as a yellow liquid.
步骤c:7,7-二甲基-4,9,10,10a-四氢噻吩并[2,3":3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的合成
Step c: Synthesis of 7,7-dimethyl-4,9,10,10a-tetrahydrothieno[2,3":3,4]pyrido[1,2-a]pyrazine-8(7H)-one
将2-(7-((1,3-二氧代异吲哚啉-2-基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)基)-2-甲基丙酸甲酯(440mg,1.1mmol)溶于乙醇(10mL)中，加入水合肼(345mg,5.5mmol,含量80％)，80℃下搅拌12小时。冷却到室温后，过滤，所得滤液经浓缩，柱层析(二氯甲烷:甲醇＝20:1)得到目标产物(140mg,收率54％)。Dissolve methyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)yl)-2-methylpropanoate (440 mg, 1.1 mmol) in ethanol (10 mL), add hydrazine hydrate (345 mg, 5.5 mmol, content 80%), and stir at 80°C for 12 hours. After cooling to room temperature, filter, concentrate the filtrate, and perform column chromatography (dichloromethane:methanol=20:1) to obtain the target product (140 mg, yield 54%).
步骤d:7,7-二甲基-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐合成
Step d: Synthesis of 7,7-dimethyl-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
氮气下，将四氢锂铝(112.7mg,2.97mmol)加入到四氢呋喃(5mL)中，冷却到0℃，滴加7,7-二甲基-4,9,10,10a-四氢噻吩并[2,3":3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮(140mg,0.59mmol)的四氢呋喃(5mL)溶液，回流4小时。冷却到0℃后，加入十水硫酸钠淬灭反应。反应液经过滤、浓缩得到淡黄色液体。将该液体溶于乙酸乙酯(5mL)中，加入氯化氢的乙酸乙酯(1mL)溶液，搅拌2小时。反应液经浓缩得到目标产物(110mg,收率72％)。Under nitrogen, lithium aluminum tetrahydride (112.7 mg, 2.97 mmol) was added to tetrahydrofuran (5 mL), cooled to 0°C, and a solution of 7,7-dimethyl-4,9,10,10a-tetrahydrothieno[2,3":3,4]pyrido[1,2-a]pyrazine-8(7H)-one (140 mg, 0.59 mmol) in tetrahydrofuran (5 mL) was added dropwise, and refluxed for 4 hours. After cooling to 0°C, sodium sulfate decahydrate was added to quench the reaction. The reaction solution was filtered and concentrated to obtain a light yellow liquid. The liquid was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (1 mL) was added and stirred for 2 hours. The reaction solution was concentrated to obtain the target product (110 mg, yield 72%).
LC-MS[M+H]+:223.2.LC-MS [M+H] + : 223.2.
1H NMR(400MHz,CD3OD):δ7.56(d,J＝5.2Hz,1H),7.01(d,J＝4.8Hz,1H),5.38(d,J＝11.6Hz,1H),4.12-4.04(m,2H),3.76-3.62(m,3H),3.55(td,J＝12.0,4.4Hz,1H),3.38-3.33(m,1H),3.14(dd,J＝17.2,4.4Hz,1H),1.73(s,3H),1.71(s,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.56 (d, J=5.2 Hz, 1H), 7.01 (d, J=4.8 Hz, 1H), 5.38 (d, J=11.6 Hz, 1H), 4.12-4.04 (m, 2H), 3.76-3.62 (m, 3H), 3.55 (td, J=12.0, 4.4 Hz, 1H), 3.38-3.33 (m, 1H), 3.14 (dd, J=17.2, 4.4 Hz, 1H), 1.73 (s, 3H), 1.71 (s, 3H).
实施例50Embodiment 50
4',5',8',9',10',10a'-六氢螺并[环丙烷-1,7'-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪]
4',5',8',9',10',10a'-Hexahydrospiro[cyclopropane-1,7'-thieno[2',3':3,4]pyrido[1,2-a]pyrazine]
化合物50的合成路线参考实施例49的合成路线。The synthetic route of compound 50 refers to the synthetic route of Example 49.
LC-MS[M+H]+:221.1。LC-MS [M+H] + : 221.1.
实施例51Embodiment 51
4',5',8',9',10',10a'-六氢螺并[环丁烷-1,7'-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪]
4',5',8',9',10',10a'-Hexahydrospiro[cyclobutane-1,7'-thieno[2',3':3,4]pyrido[1,2-a]pyrazine]
化合物51的合成路线参考实施例49的合成路线。The synthetic route of compound 51 refers to the synthetic route of Example 49.
LC-MS[M+H]+:235.1。LC-MS [M+H] + : 235.1.
实施例52Embodiment 52
7-环丙基-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
7-Cyclopropyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线:
synthetic route:
步骤a:2-(7-(((叔丁氧羰基)氨基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-2-环丙基乙酸甲酯的合成
Step a: Synthesis of methyl 2-(7-(((tert-butyloxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-2-cyclopropylacetate
将叔丁基((4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸酯(2.5g,9.32mmol)，2-溴-2-环丙基乙酸甲酯(1.8g,9.32mmol)，碘化钠(0.7g,4.66mmol)和碳酸钾(6.4g,46.6mmol)溶于DMSO(10mL)中，在70℃条件下搅拌5小时。之后将反应液倒入水(50mL)中，用乙酸乙酯萃取(10mL x 3)，有机相经水洗涤(10mL x 3)后无水硫酸钠干燥，浓缩得到目标化合物粗品(1.0g,收率29％)。Tert-butyl ((4,5,6,7-tetrahydrothieno [2,3-c] pyridin-7-yl) methyl) carbamate (2.5 g, 9.32 mmol), methyl 2-bromo-2-cyclopropylacetate (1.8 g, 9.32 mmol), sodium iodide (0.7 g, 4.66 mmol) and potassium carbonate (6.4 g, 46.6 mmol) were dissolved in DMSO (10 mL) and stirred at 70 ° C for 5 hours. The reaction solution was then poured into water (50 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water (10 mL x 3) and dried over anhydrous sodium sulfate and concentrated to obtain the crude target compound (1.0 g, yield 29%).
LC-MS[M+H-100]+:281.1。LC-MS [M+H-100] + : 281.1.
步骤b:7-环丙基-4,9,10,10-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的合成
Step b: Synthesis of 7-cyclopropyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
将2-(7-(((叔丁氧羰基)氨基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-2-环丙基乙酸甲酯(1.0g,2.6mmol)溶于氯化氢的乙酸乙酯溶液(3M,15mL)中，室温搅拌1小时，将反应液直接浓缩至干后加入无水乙醇(15mL)和碳酸钾(1.82g,13.2mmol)。将反应液于80℃条件下搅拌5小时后过滤浓缩，粗品经柱层析得到一对非对映体异构体，分别为异构体1(150mg,0.6mmol)和异构体2(40mg,0.16mmol)。Dissolve methyl 2-(7-(((tert-butyloxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-2-cyclopropylacetate (1.0 g, 2.6 mmol) in a solution of hydrogen chloride in ethyl acetate (3M, 15 mL) and stir at room temperature for 1 hour. Concentrate the reaction solution to dryness and add anhydrous ethanol (15 mL) and potassium carbonate (1.82 g, 13.2 mmol). Stir the reaction solution at 80°C for 5 hours, filter and concentrate, and the crude product is subjected to column chromatography to obtain a pair of diastereoisomers, namely isomer 1 (150 mg, 0.6 mmol) and isomer 2 (40 mg, 0.16 mmol).
LC-MS[M+H]+:249.1(异构体1),249.2(异构体2).LC-MS [M+H] + : 249.1 (isomer 1), 249.2 (isomer 2).
步骤c:7-环丙基-4,5,7,8,10,10-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的合成
Step c: Synthesis of tert-butyl 7-cyclopropyl-4,5,7,8,10,10-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
将7-环丙基-4,9,10,10-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的异构体1(150mg,0.60mmol)溶于四氢呋喃(15mL)中，加入四氢铝锂(0.09g,2.4mmol)，在氮气保护和80℃油浴下回流2小时。将反应液冷却至室温，缓慢加入十水硫酸钠至无气泡产生继续搅拌10分钟，抽滤，依次向滤液中加入水(5mL)，碳酸氢钠(0.13g,1.50mmol)和二碳酸二叔丁酯(0.2g,0.9mmol)，加毕后在室温下搅拌1小时。将反应液倒入水中(30mL)，用二氯甲烷萃取三次(50mL x 3)，经无水硫酸钠干燥浓缩，得到目标化合物的异构体1(100mg,收率50％)。Dissolve the isomer 1 (150 mg, 0.60 mmol) of 7-cyclopropyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one in tetrahydrofuran (15 mL), add lithium aluminum tetrahydride (0.09 g, 2.4 mmol), and reflux for 2 hours under nitrogen protection and 80°C oil bath. Cool the reaction solution to room temperature, slowly add sodium sulfate decahydrate until no bubbles are generated, continue stirring for 10 minutes, filter, add water (5 mL), sodium bicarbonate (0.13 g, 1.50 mmol) and di-tert-butyl dicarbonate (0.2 g, 0.9 mmol) to the filtrate in turn, and stir at room temperature for 1 hour after the addition. The reaction solution was poured into water (30 mL), extracted three times with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain isomer 1 of the target compound (100 mg, yield 50%).
LC-MS[M+H]+:335.3.LC-MS [M+H] + : 335.3.
1H NMR(400MHz,CDCl3):δ7.15(d,J＝5.2Hz,1H),6.80(d,J＝4.8Hz,1H),4.29(d,J＝14.4Hz,1H),4.25(s,1H),3.71(dd,J＝13.6,3.6Hz,1H),3.34-3.17(m,3H),2.93(dd,J＝10.8,4.0Hz,1H),2.90-2.79(m,1H),2.64(d,J＝11.2Hz,1H),2.51(dd,J＝16.8,4.8Hz,1H),1.44(s,9H),0.93-0.83(m,1H),0.64-0.54(m,1H),0.52-0.43(m,2H),0.29-0.21(m,1H). 1 H NMR (400 MHz, CDCl 3 ): δ7.15 (d, J = 5.2 Hz, 1H), 6.80 (d, J = 4.8 Hz, 1H), 4.29 (d, J = 14.4 Hz, 1H), 4.25 (s, 1H), 3.71 (dd, J = 13.6, 3.6 Hz, 1H), 3.34-3.17 (m, 3H), 2.93 (dd, J = 10.8, 4.0 Hz, 1H), 2.90-2.79 (m, 1H), 2.64 (d, J = 11.2 Hz, 1H), 2.51 (dd, J = 16.8, 4.8 Hz, 1H), 1.44 (s, 9H), 0.93-0.83 (m, 1H), 0.64-0.54 (m, 1H), 0.52-0.43 (m, 2H), 0.29-0.21 (m, 1H).
步骤d:7-环丙基-4,7,8,9,10,10-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step d: Synthesis of 7-cyclopropyl-4,7,8,9,10,10-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将7-环丙基-4,5,7,8,10,10-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的异构体1(0.10g,0.30mmol)溶于氯化氢的乙酸乙酯溶液(3M,15mL)中，在室温下搅拌1小时后抽滤，并用乙酸乙酯洗涤滤饼后得到目标化合物的异构体1(30mg,收率33％)。Isomer 1 of tert-butyl 7-cyclopropyl-4,5,7,8,10,10-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate (0.10 g, 0.30 mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (3M, 15 mL). The mixture was stirred at room temperature for 1 hour and filtered. The filter cake was washed with ethyl acetate to obtain isomer 1 of the target compound (30 mg, yield 33%).
LC-MS[M+H]+:235.2.LC-MS [M+H] + : 235.2.
1H NMR(400MHz,CD3OD):δ7.53(d,J＝5.2Hz,1H),7.00(d,J＝5.2Hz,1H),4.10(dd,J＝13.6,3.2Hz,1H),3.95(dd,J＝13.2,3.2Hz,1H),3.81-3.71(m,1H),3.63-3.39(m,4H),3.28-3.16(m,1H),3.14-3.02(m,2H),1.20-1.07(m,1H),0.89-0.78(m,2H),0.73-0.65(m,1H),0.61-0.54(m,1H). 1 H NMR (400 MHz, CD 3 OD): δ7.53 (d, J=5.2 Hz, 1H), 7.00 (d, J=5.2 Hz, 1H), 4.10 (dd, J=13.6, 3.2 Hz, 1H), 3.95 (dd, J=13.2, 3.2 Hz, 1H), 3.81-3.71 (m, 1H), 3.63-3.39 (m, 4H), 3.28-3.16 (m, 1H), 3.14-3.02 (m, 2H), 1.20-1.07 (m, 1H), 0.89-0.78 (m, 2H), 0.73-0.65 (m, 1H), 0.61-0.54 (m, 1H).
将7-环丙基-4,5,7,8,10,10-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-甲酸叔丁酯的异构体2(40mg,0.16mmol)为原料采用类似的合成方法得到目标产物的异构体2(5mg,收率10％)。Isomer 2 of tert-butyl 7-cyclopropyl-4,5,7,8,10,10-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate (40 mg, 0.16 mmol) was used as raw material to obtain isomer 2 of the target product (5 mg, yield 10%) using a similar synthesis method.
LC-MS[M+H]+:235.3.LC-MS [M+H] + : 235.3.
1H NMR(400MHz,CD3OD):δ7.56(d,J＝4.4Hz,1H),7.02(d,J＝4.8Hz,1H),5.58-5.46(m,1H),4.15-3.93(m,2H),3.92-3.64(m,4H),3.30-3.06(m,3H),1.66-1.47(m,1H),1.09-0.98(m,1H),0.95-0.84(m,2H),0.56-0.45(m,1H). 1 H NMR (400 MHz, CD 3 OD): δ7.56 (d, J=4.4 Hz, 1H), 7.02 (d, J=4.8 Hz, 1H), 5.58-5.46 (m, 1H), 4.15-3.93 (m, 2H), 3.92-3.64 (m, 4H), 3.30-3.06 (m, 3H), 1.66-1.47 (m, 1H), 1.09-0.98 (m, 1H), 0.95-0.84 (m, 2H), 0.56-0.45 (m, 1H).
实施例53Embodiment 53
7-(环丙基甲基)-4,7,8,9,10-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪
7-(Cyclopropylmethyl)-4,7,8,9,10-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine
化合物53的合成路线参考实施例52的合成路线。The synthetic route of compound 53 refers to the synthetic route of Example 52.
LC-MS[M+H]+:249.1。LC-MS [M+H] + : 249.1.
实施例54Embodiment 54
1,1a,3,4,7b,8,9,9a-八氢环丙基[e]噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
1,1a,3,4,7b,8,9,9a-Octahydrocyclopropyl[e]thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物54的合成路线参考实施例52的合成路线。The synthetic route of compound 54 refers to the synthetic route of Example 52.
LC-MS[M+H]+:207.1。LC-MS [M+H] + : 207.1.
实施例55Embodiment 55
3b,4,5a,6,7,7a,9,10-八氢-5H-环丁基[e]噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
3b,4,5a,6,7,7a,9,10-Octahydro-5H-cyclobutyl[e]thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物55的合成路线参考实施例52的合成路线。The synthetic route of compound 55 refers to the synthetic route of Example 52.
LC-MS[M+H]+:221.1。LC-MS [M+H] + : 221.1.
实施例56Embodiment 56
N-甲基-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7-甲酰胺盐酸盐
N-Methyl-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride
合成路线:
synthetic route:
步骤a:7-((1,3-二氧代异吲哚啉-2-基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-羧酸叔丁酯的合成
Step a: Synthesis of tert-butyl 7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
将2-((4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚啉-1,3-二酮(1.5g,5.02mmol)、二碳酸二叔丁酯(1.3g,6.02mmol)和N,N-二异丙基乙胺(1.96g,15.06mmol)溶于二氯甲烷(30mL)中，在40℃下搅拌1小时。反应结束后，将反应液浓缩，加入石油醚(150mL)析出固体，过滤，收集白色固体得到目标化合物(1.8g,收率90％)。2-((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione (1.5 g, 5.02 mmol), di-tert-butyl dicarbonate (1.3 g, 6.02 mmol) and N,N-diisopropylethylamine (1.96 g, 15.06 mmol) were dissolved in dichloromethane (30 mL) and stirred at 40°C for 1 hour. After the reaction was completed, the reaction solution was concentrated, petroleum ether (150 mL) was added to precipitate solids, filtered, and the white solids were collected to obtain the target compound (1.8 g, yield 90%).
LC-MS[M+H]+:399.1.LC-MS [M+H] + : 399.1.
步骤b:7-(氨基甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-羧酸叔丁酯的合成
Step b: Synthesis of tert-butyl 7-(aminomethyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
将7-((1,3-二氧代异吲哚啉-2-基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-羧酸叔丁酯(1.8g,4.51mmol)溶于乙醇(20mL)中，随后加入水合肼(0.85g,13.53mmol)，60℃搅拌1小时，将反应液浓缩后加入二氯甲烷(30mL)，搅拌30分钟,随后过滤，收集滤液。将滤液浓缩得到目标化合物(1.3g,粗品)。Dissolve tert-butyl 7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (1.8 g, 4.51 mmol) in ethanol (20 mL), then add hydrazine hydrate (0.85 g, 13.53 mmol), stir at 60°C for 1 hour, concentrate the reaction solution, add dichloromethane (30 mL), stir for 30 minutes, then filter and collect the filtrate. Concentrate the filtrate to obtain the target compound (1.3 g, crude product).
LC-MS[M+H]+:269.1.LC-MS [M+H] + : 269.1.
步骤c:7-(((叔丁氧羰基)(3-乙氧基-2-羟基-3-氧代丙基)氨基)甲基)-4,7-二氢噻吩并[2,3-c]吡 啶-6(5H)-羧酸叔丁酯的合成
Step c: 7-(((tert-butyloxycarbonyl)(3-ethoxy-2-hydroxy-3-oxopropyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyrrolidone Synthesis of tert-butyl pyridine-6(5H)-carboxylate
将7-(氨基甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-羧酸叔丁酯(800mg,2.97mmol)溶于乙腈(10mL)中，随后加入N,N-二异丙基乙胺(1.16g,8.91mmol)，环氧乙烷-2-羧酸乙酯(517mg,4.46mmol)，在80℃油浴下回流4小时。反应结束后，将反应液冷却至室温，随后加入二碳酸二叔丁酯(645mg,2.97mmol)继续搅拌30分钟。将反应液浓缩柱层析得到目标产物(864mg,收率61％)。Dissolve tert-butyl 7-(aminomethyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (800 mg, 2.97 mmol) in acetonitrile (10 mL), then add N,N-diisopropylethylamine (1.16 g, 8.91 mmol) and ethyl oxirane-2-carboxylate (517 mg, 4.46 mmol), and reflux in an oil bath at 80°C for 4 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and then di-tert-butyl dicarbonate (645 mg, 2.97 mmol) is added and stirred for 30 minutes. The reaction solution is concentrated and column chromatography is performed to obtain the target product (864 mg, yield 61%).
LC-MS[M+H]+:485.2.LC-MS [M+H] + : 485.2.
步骤d:7-(((叔丁氧羰基)(3-乙氧基-2-((乙基磺酰基)氧基)-3-氧代丙基)氨基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-羧酸叔丁酯的合成
Step d: Synthesis of tert-butyl 7-(((tert-butyloxycarbonyl)(3-ethoxy-2-((ethylsulfonyl)oxy)-3-oxopropyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
将7-(((叔丁氧羰基)(3-乙氧基-2-羟基-3-氧代丙基)氨基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-羧酸叔丁酯(864mg,1.78mmol)溶于二氯甲烷(10mL)中，随后加入N,N-二异丙基乙胺(694mg,5.34mmol)和乙基磺酰氯(276mg,2.14mmol)。室温搅拌1小时，将反应液直接浓缩，粗品经柱层析得到目标产物(820mg,收率80％)。7-(((tert-Butyloxycarbonyl)(3-ethoxy-2-hydroxy-3-oxopropyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (864 mg, 1.78 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of N,N-diisopropylethylamine (694 mg, 5.34 mmol) and ethylsulfonyl chloride (276 mg, 2.14 mmol). The mixture was stirred at room temperature for 1 hour, and the reaction solution was directly concentrated. The crude product was purified by column chromatography to obtain the target product (820 mg, yield 80%).
LC-MS[M+H]+:577.2.LC-MS [M+H] + : 577.2.
步骤e:9-叔丁基-7-乙基-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7,9-二羧酸酯的合成
Step e: Synthesis of 9-tert-butyl-7-ethyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-7,9-dicarboxylate
将7-(((叔丁氧羰基)(3-乙氧基-2-((乙基磺酰基)氧基)-3-氧代丙基)氨基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-羧酸叔丁酯(820mg,1.42mmol)溶于氯化氢的1,4-二氧六环溶液(4M,10mL)中，在室温下搅拌1小时后直接浓缩。将粗品溶于乙腈(10mL)，随后加入N,N-二异丙基乙胺(694mg,5.34mmol)，80℃搅拌1小时。然后将反应降至室温，加入二碳酸二叔丁酯(370mg,1.71mmol)，室温反应30分钟。将反应液浓缩柱层析得到目标化合物(365mg,收率70％)。7-(((tert-Butyloxycarbonyl)(3-ethoxy-2-((ethylsulfonyl)oxy)-3-oxopropyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (820 mg, 1.42 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (4M, 10 mL), stirred at room temperature for 1 hour and then concentrated directly. The crude product was dissolved in acetonitrile (10 mL), followed by the addition of N,N-diisopropylethylamine (694 mg, 5.34 mmol) and stirred at 80°C for 1 hour. The reaction mixture was then cooled to room temperature, and di-tert-butyl dicarbonate (370 mg, 1.71 mmol) was added and reacted at room temperature for 30 minutes. The reaction solution was concentrated and column chromatography was performed to obtain the target compound (365 mg, yield 70%).
LC-MS[M+H]+:367.1.LC-MS [M+H] + : 367.1.
步骤f:7-(甲基氨基甲酰基)-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧 酸叔丁酯的合成
Step f: 7-(Methylcarbamoyl)-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylic acid Synthesis of tert-butyl ester
将9-叔丁基-7-乙基-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7,9-二羧酸酯(0.14g,0.37mmol)溶于乙醇和水的混合液(5mL,v/v＝4/1)中，随后加入氢氧化锂(78mg,1.85mmol)，在50℃下搅拌1小时后直接浓缩至干。将粗品溶于N,N-二甲基甲酰胺(5mL)，依次加入N,N-二异丙基乙胺(241mg,1.85mmol)、O-(7-氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(282mg,0.74mmol)和甲胺盐酸盐(126mg,1.85mmol)，室温反应1小时。反应结束后，向反应体系中加入饱和食盐水(20mL)，乙酸乙酯萃取，有机相浓缩。然后将粗品经薄层色谱板纯化得到目标化合物(100mg,收率70％)。9-tert-Butyl-7-ethyl-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-7,9-dicarboxylate (0.14 g, 0.37 mmol) was dissolved in a mixture of ethanol and water (5 mL, v/v = 4/1), followed by the addition of lithium hydroxide (78 mg, 1.85 mmol), and the mixture was stirred at 50°C for 1 hour and then concentrated to dryness. The crude product was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (241 mg, 1.85 mmol), O-(7-nitrobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (282 mg, 0.74 mmol) and methylamine hydrochloride (126 mg, 1.85 mmol) were added in sequence, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, saturated brine (20 mL) was added to the reaction system, extracted with ethyl acetate, and the organic phase was concentrated. The crude product was then purified by thin layer chromatography to obtain the target compound (100 mg, yield 70%).
LC-MS[M+H]+:352.2.LC-MS [M+H] + : 352.2.
步骤g:N-甲基-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7-甲酰胺盐酸盐的合成
Step g: Synthesis of N-methyl-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-7-carboxamide hydrochloride
将7-(甲基氨基甲酰基)-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯(0.10g,0.28mmol)溶于氯化氢的1,4-二氧六环溶液(5mL)中，室温搅拌0.5小时后过滤，固体用乙酸乙酯(3mL)淋洗，收集固体得到目标化合物(20mg,收率29％,d.r.＝1:1)。7-(Methylcarbamoyl)-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylic acid tert-butyl ester (0.10 g, 0.28 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (5 mL), stirred at room temperature for 0.5 hour and then filtered. The solid was rinsed with ethyl acetate (3 mL) and the solid was collected to give the title compound (20 mg, yield 29%, d.r. = 1:1).
LC-MS[M+H]+:252.1.LC-MS [M+H] + : 252.1.
1H NMR(400MHz,CD3OD):δ7.49(t,J＝5.4Hz,1H),7.38(t,J＝5.4Hz,1H),6.98(t,J＝4.4Hz,1H),6.89(t,J＝4.4Hz,1H),4.36-4.17(m,1H),4.12-3.94(m,2H),3.88-3.77(m,1H),3.71-3.23(m,9H),3.27-3.19(m,1H),3.18-2.87(m,6H),2.85(d,J＝1.4Hz,3H),2.83(d,J＝1.4Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.49 (t, J=5.4 Hz, 1H), 7.38 (t, J=5.4 Hz, 1H), 6.98 (t, J=4.4 Hz, 1H), 6.89 (t, J=4.4 Hz, 1H), 4.36-4.17 (m, 1H), 4.12-3.94 (m, 2H), 3.88-3.77 (m, 1H), 3.71-3.23 (m, 9H), 3.27-3.19 (m, 1H), 3.18-2.87 (m, 6H), 2.85 (d, J=1.4 Hz, 3H), 2.83 (d, J=1.4 Hz, 3H).
实施例57Embodiment 57
7-苯基-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
7-phenyl-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物57的合成路线参考实施例52的合成路线。The synthetic route of compound 57 refers to the synthetic route of Example 52.
LC-MS[M+H]+:271.1。LC-MS [M+H] + : 271.1.
实施例58Embodiment 58
3-(4,7,8,9,10-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7-基)异恶唑
3-(4,7,8,9,10-Hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-7-yl)isoxazole
化合物58的合成路线参考实施例52的合成路线。The synthetic route of compound 58 refers to the synthetic route of Example 52.
LC-MS[M+H]+:262.1。LC-MS [M+H] + : 262.1.
实施例59Embodiment 59
3-(4,7,8,9,10-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7-基)-1,2,4-恶二唑
3-(4,7,8,9,10-Hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-7-yl)-1,2,4-oxadiazole
化合物59的合成路线参考实施例52的合成路线。The synthetic route of compound 59 refers to the synthetic route of Example 52.
LC-MS[M+H]+:263.1。LC-MS [M+H] + : 263.1.
实施例60Embodiment 60
7-(噻唑-2-基)-4,7,8,9,10-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪
7-(Thiazol-2-yl)-4,7,8,9,10-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine
化合物60的合成路线参考实施例52的合成路线。The synthetic route of compound 60 refers to the synthetic route of Example 52.
LC-MS[M+H]+:278.1。LC-MS [M+H] + : 278.1.
实施例61Embodiment 61
5-甲基-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
5-Methyl-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
步骤a:2-((5-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚啉-1,3-二酮的合成
Step a: Synthesis of 2-((5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione
将1-(噻吩-3-基)丙-2-胺(1g,7.09mmol)溶于二氯甲烷(20mL)中，加入N-(2-乙醛基)邻苯二甲酰亚胺(1.47g,7.80mmol)和三氟乙酸(4.04g,35.46mmol)，在25℃下搅拌12小时。向反应液中加入饱和的碳酸氢钠溶液(100mL)，用乙酸乙酯(50mL x 3)萃取后，有机相依次用水洗涤(50mL x 3)，饱和食盐水洗涤(50mL)，无水硫酸钠干燥后经柱层析(石油醚:乙酸乙酯＝3:1)分离纯化得到目标化合物(1.4g,收率64％)。1-(Thiophen-3-yl)propan-2-amine (1 g, 7.09 mmol) was dissolved in dichloromethane (20 mL), and N-(2-acetaldehyde)phthalimide (1.47 g, 7.80 mmol) and trifluoroacetic acid (4.04 g, 35.46 mmol) were added, and stirred at 25°C for 12 hours. Saturated sodium bicarbonate solution (100 mL) was added to the reaction solution, and after extraction with ethyl acetate (50 mL x 3), the organic phase was washed with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target compound (1.4 g, yield 64%).
LC-MS[M+H]+:313.3.LC-MS [M+H] + : 313.3.
步骤b:2-(7-((1,3-二氧代异吲哚啉-2-基)甲基)-5-甲基-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)基)乙酸乙酯的合成
Step b: Synthesis of ethyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-5-methyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)yl)acetate
将2-((5-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚啉-1,3-二酮(1.2g,3.5mmol)溶于乙腈(12mL)中，加入溴乙酸乙酯(1.28g,7.69mmol)和N,N-二异丙基乙胺(1.354g,10.5mmol)，氮气保护下80℃搅拌12小时。将反应液倒入水(50mL)中，用二氯甲烷萃取(50mL x 3)后，有机相依次用水洗涤(50mL x 3)，饱和食盐水洗涤(50mL)，无水硫酸钠干燥后经柱层析(石油醚:乙酸乙酯＝4:1)分离纯化得到目标化合物(1.1g,收率85％)。2-((5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione (1.2 g, 3.5 mmol) was dissolved in acetonitrile (12 mL), ethyl bromoacetate (1.28 g, 7.69 mmol) and N,N-diisopropylethylamine (1.354 g, 10.5 mmol) were added, and stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL x 3), and the organic phase was washed with water (50 mL x 3) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, and separated and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain the target compound (1.1 g, yield 85%).
LC-MS[M+H]+:399.4.LC-MS [M+H] + : 399.4.
步骤c:5-甲基-4,9,10,10-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的合成
Step c: Synthesis of 5-methyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
将2-(7-((1,3-二氧代异吲哚啉-2-基)甲基)-5-甲基-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)基)乙酸乙酯(1.1g,2.75mmol)溶于乙醇(22mL)中，加入含量为80％水合肼(0.52g,8.28mmol)， 在70℃下搅拌3小时。将反应液倒入水(50mL)中，用乙酸乙酯萃取(30mL x 3)后，有机相依次用水(30mL x 3)、饱和食盐水(30mL)洗涤，无水硫酸钠干燥后经柱层析(二氯甲烷/甲醇)分离纯化得到目标化合物(0.4g,收率65％)。Dissolve ethyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-5-methyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)yl)acetate (1.1 g, 2.75 mmol) in ethanol (22 mL), add 80% hydrazine hydrate (0.52 g, 8.28 mmol), Stir at 70°C for 3 hours. Pour the reaction solution into water (50 mL), extract with ethyl acetate (30 mL x 3), wash the organic phase with water (30 mL x 3) and saturated brine (30 mL) in sequence, dry over anhydrous sodium sulfate, and separate and purify by column chromatography (dichloromethane/methanol) to obtain the target compound (0.4 g, yield 65%).
LC-MS[M+H]+:223.1.LC-MS [M+H] + : 223.1.
步骤d:5-甲基-4,7,8,9,10,10-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step d: Synthesis of 5-methyl-4,7,8,9,10,10-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将5-甲基-4,9,10,10-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮(100mg,0.45mmol)溶于四氢呋喃(2mL)中，加入四氢铝锂(0.05g,1.35mmol)，在氮气保护下80℃搅拌2小时。将反应液冷却至室温后缓慢加入十水硫酸钠(0.13g,0.46mmol)搅拌10分钟，抽滤，得到的滤液浓缩后加入盐酸乙酸乙酯溶液(4M,2mL),反应液用水(5mL x 3)萃取后将水相冻干得到目标产物(75mg,收率80％)。5-Methyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one (100 mg, 0.45 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum tetrahydride (0.05 g, 1.35 mmol) was added, and stirred at 80 ° C for 2 hours under nitrogen protection. After the reaction solution was cooled to room temperature, sodium sulfate decahydrate (0.13 g, 0.46 mmol) was slowly added and stirred for 10 minutes, and then filtered. The filtrate was concentrated and hydrochloric acid ethyl acetate solution (4M, 2 mL) was added. The reaction solution was extracted with water (5 mL x 3) and the aqueous phase was freeze-dried to obtain the target product (75 mg, yield 80%).
LC-MS[M+H]+:209.3.LC-MS [M+H] + : 209.3.
1H NMR(400MHz,CD3OD):δ7.44(d,J＝5.2Hz,1H),6.93(d,J＝5.2Hz,1H),4.56(s,1H),3.93(d,J＝12.4Hz,1H),3.81-3.59(m,2H),3.51-3.33(m,3H),3.20-3.08(m,1H),3.07-2.96(m,1H),2.88-2.76(m,1H),1.45(d,J＝6.4Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.44 (d, J=5.2 Hz, 1H), 6.93 (d, J=5.2 Hz, 1H), 4.56 (s, 1H), 3.93 (d, J=12.4 Hz, 1H), 3.81-3.59 (m, 2H), 3.51-3.33 (m, 3H), 3.20-3.08 (m, 1H), 3.07-2.96 (m, 1H), 2.88-2.76 (m, 1H), 1.45 (d, J=6.4 Hz, 3H).
实施例62Embodiment 62
4-甲基-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
4-Methyl-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
步骤a:2-(噻吩-3-基)丙腈的合成
Step a: Synthesis of 2-(thiophen-3-yl)propionitrile
将二异丙胺(7.8mL,54.8mmol)溶于四氢呋喃(100mL)中，氮气保护下-78℃缓慢滴加正丁基锂(20.0mL,2.5mol/L,50.0mmol)，搅拌30分钟后加入3-噻吩乙腈(5.6g,45.0mmol)，继续保持在-78℃下搅拌1小时，然后滴加碘甲烷(2.8mL,45.0mmol)，缓慢升温至25℃搅拌12小时。向反应中加入10％的氯化铵水溶液(50mL)，用乙酸乙酯(50mL x 3)萃取后，有机相依次用水洗涤(50mL x 3)，饱和食盐水洗涤(50mL)，无水硫酸钠干燥后经柱层析(石油醚:乙酸乙酯＝50:1)分离纯化得到无色油状目标化合物(4.0g,收率64％)。Dissolve diisopropylamine (7.8mL, 54.8mmol) in tetrahydrofuran (100mL), slowly add n-butyl lithium (20.0mL, 2.5mol/L, 50.0mmol) at -78℃ under nitrogen protection, add 3-thiopheneacetonitrile (5.6g, 45.0mmol) after stirring for 30 minutes, continue to stir at -78℃ for 1 hour, then add iodomethane (2.8mL, 45.0mmol), slowly warm to 25℃ and stir for 12 hours. Add 10% ammonium chloride aqueous solution (50mL) to the reaction, extract with ethyl acetate (50mL x 3), wash the organic phase with water (50mL x 3), wash with saturated brine (50mL), dry over anhydrous sodium sulfate, and separate and purify by column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain the target compound (4.0g, yield 64%) as a colorless oil.
1H NMR(400MHz,CD3Cl):δ7.38-7.34(m,1H),7.28-7.24(m,1H),7.07(d,J＝5.2Hz,1H),3.99(q,J＝7.2Hz,1H),1.66(d,J＝7.6Hz,3H). 1 H NMR (400 MHz, CD 3 Cl): δ 7.38-7.34 (m, 1H), 7.28-7.24 (m, 1H), 7.07 (d, J=5.2 Hz, 1H), 3.99 (q, J=7.2 Hz, 1H), 1.66 (d, J=7.6 Hz, 3H).
步骤b:2-(噻吩-3-基)丙-1-胺盐酸盐的合成
Step b: Synthesis of 2-(thiophen-3-yl)propan-1-amine hydrochloride
将2-(噻吩-3-基)丙腈(4.0g，29.19mmol)溶于四氢呋喃(40mL)中，加入浓度为10M硼烷二甲硫醚的四氢呋喃溶液(5.83mL,58.3mmol)，氮气保护在70℃下搅拌2小时。待反应液冷却至0℃，缓慢滴加甲醇(50mL)后搅拌30分钟。将反应液浓缩后加入盐酸乙酸乙酯溶液(4M,10mL)析出固体，固体用乙酸乙酯洗涤后得到目标化合物(2g,收率49％)。Dissolve 2-(Thiophene-3-yl)propionitrile (4.0g, 29.19mmol) in tetrahydrofuran (40mL), add 10M borane dimethyl sulfide tetrahydrofuran solution (5.83mL, 58.3mmol), and stir at 70°C for 2 hours under nitrogen protection. After the reaction solution is cooled to 0°C, methanol (50mL) is slowly added dropwise and stirred for 30 minutes. After the reaction solution is concentrated, hydrochloric acid ethyl acetate solution (4M, 10mL) is added to precipitate solids, and the solids are washed with ethyl acetate to obtain the target compound (2g, yield 49%).
LC-MS[M+H]+:142.0.LC-MS [M+H] + : 142.0.
步骤c:2-((4-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚啉-1,3-二酮的合成
Step c: Synthesis of 2-((4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione
将2-(噻吩-3-基)丙-1-胺溶于(2g,14.18mmol)二氯甲烷(20mL)中，加入N-(2-乙醛基)邻苯二甲酰亚胺(2.97g,15.9mmol)和三氟乙酸(8.086g,70.9mmol)，在25℃下搅拌12小时。向反应液中加入饱和的碳酸氢钠溶液(100mL)，用乙酸乙酯(50mL x 3)萃取后，有机相依次用水洗涤(50mL x 3)，饱和食盐水洗涤(50mL)，无水硫酸钠干燥后经柱层析(石油醚:乙酸乙酯＝3:1)分离纯化得到目标化合物(2.0g,收率50％)。2-(Thiophen-3-yl)propan-1-amine was dissolved in (2 g, 14.18 mmol) dichloromethane (20 mL), and N-(2-acetaldehyde)phthalimide (2.97 g, 15.9 mmol) and trifluoroacetic acid (8.086 g, 70.9 mmol) were added, and stirred at 25°C for 12 hours. Saturated sodium bicarbonate solution (100 mL) was added to the reaction solution, and after extraction with ethyl acetate (50 mL x 3), the organic phase was washed with water (50 mL x 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target compound (2.0 g, yield 50%).
LC-MS[M+H]+:313.3.LC-MS [M+H] + : 313.3.
步骤d:2-(7-((1,3-二氧代异吲哚啉-2-基(甲基)-4-甲基-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)基)乙酸乙酯的合成
Step d: Synthesis of ethyl 2-(7-((1,3-dioxoisoindolin-2-yl(methyl)-4-methyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)yl)acetate
将2-((4-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚啉-1,3-二酮(1.1g,3.5mmol)溶于乙腈(11mL)中，加入溴乙酸乙酯(1.17g,7.05mmol)和N,N-二异丙基乙胺(0.91g,10.05mmol)，氮气保护下80℃搅拌12小时。将反应液倒入水(50mL)中，用二氯甲烷萃取(50mL x 3)后，有机相依次用水洗涤(50mL x 3)，饱和食盐水洗涤(50mL)，无水硫酸钠 干燥后经柱层析(石油醚:乙酸乙酯＝4:1)分离纯化得到目标化合物(0.86g,收率66％)。Dissolve 2-((4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione (1.1 g, 3.5 mmol) in acetonitrile (11 mL), add ethyl bromoacetate (1.17 g, 7.05 mmol) and N,N-diisopropylethylamine (0.91 g, 10.05 mmol), and stir at 80 °C for 12 hours under nitrogen protection. Pour the reaction solution into water (50 mL), extract with dichloromethane (50 mL x 3), wash the organic phase with water (50 mL x 3), wash with saturated brine (50 mL), and wash with anhydrous sodium sulfate. After drying, the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate=4:1) to obtain the target compound (0.86 g, yield 66%).
LC-MS[M+H]+:399.3.LC-MS [M+H] + : 399.3.
步骤e:4-甲基-4,9,10,10-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的合成
Step e: Synthesis of 4-methyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-8(7H)-one
将2-(7-((1,3-二氧代异吲哚啉-2-基(甲基)-4-甲基-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)基)乙酸乙酯(0.860g,2.16mmol)溶于乙醇(16mL)中，加入含量为80％水合肼(0.41g,6.48mmol)，在70℃下搅拌3小时。将反应液倒入水(50mL)中，用乙酸乙酯萃取(30mL x 3)后，有机相依次用水洗涤(30mL x 3)，饱和食盐水洗涤(30mL)，无水硫酸钠干燥后经柱层析(二氯甲烷:甲醇＝20:1)分离纯化得到目标化合物(0.3g,收率63％)。Ethyl 2-(7-((1,3-dioxoisoindolin-2-yl(methyl)-4-methyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)yl)acetate (0.860 g, 2.16 mmol) was dissolved in ethanol (16 mL), 80% hydrazine hydrate (0.41 g, 6.48 mmol) was added, and the mixture was stirred at 70°C for 3 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with water (30 mL x 3), saturated brine (30 mL), dried over anhydrous sodium sulfate, and separated and purified by column chromatography (dichloromethane:methanol=20:1) to obtain the target compound (0.3 g, yield 63%).
LC-MS[M+H]+:223.3.LC-MS [M+H] + : 223.3.
步骤f:4-甲基-4,7,8,9,10,10-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step f: Synthesis of 4-methyl-4,7,8,9,10,10-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将4-甲基-4,9,10,10-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮(100mg,0.45mmol)溶于四氢呋喃(2mL)中，加入四氢铝锂(0.05g,1.35mmol)，在氮气保护下80℃搅拌2小时。将反应液冷却至室温后缓慢加入十水硫酸钠(0.13g,0.46mmol)搅拌10分钟，抽滤，得到的滤液浓缩后加入盐酸乙酸乙酯溶液(4M,2mL),用水(5mL x 3)萃取后将水相冻干得到目标产物(47mg,收率51％)。4-Methyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one (100 mg, 0.45 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum tetrahydride (0.05 g, 1.35 mmol) was added, and stirred at 80 ° C for 2 hours under nitrogen protection. After the reaction solution was cooled to room temperature, sodium sulfate decahydrate (0.13 g, 0.46 mmol) was slowly added and stirred for 10 minutes, and then filtered. The filtrate was concentrated and added with hydrochloric acid ethyl acetate solution (4M, 2 mL), extracted with water (5 mL x 3), and the aqueous phase was freeze-dried to obtain the target product (47 mg, yield 51%).
LC-MS[M+H]+:209.3.LC-MS [M+H] + : 209.3.
1H NMR(400MHz,CD3OD):δ7.57(d,J＝5.2Hz,1H),7.15(d,J＝5.2Hz,1H),5.10(d,J＝11.6Hz,1H),4.18-4.10(m,1H),3.94-3.85(m,1H),3.83-3.74(m,2H),3.73-3.64(m,2H),3.62-3.54(m,1H),3.53-3.45(m,1H),3.36(d,J＝12.0Hz,1H),1.37(d,J＝6.8Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.57 (d, J=5.2 Hz, 1H), 7.15 (d, J=5.2 Hz, 1H), 5.10 (d, J=11.6 Hz, 1H), 4.18-4.10 (m, 1H), 3.94-3.85 (m, 1H), 3.83-3.74 (m, 2H), 3.73-3.64 (m, 2H), 3.62-3.54 (m, 1H), 3.53-3.45 (m, 1H), 3.36 (d, J=12.0 Hz, 1H), 1.37 (d, J=6.8 Hz, 3H).
实施例63Embodiment 63
4',7',8',9',10',10a'-六氢螺环[环丙烷-1,5'-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪]
4',7',8',9',10',10a'-Hexahydrospiro[cyclopropane-1,5'-thieno[2',3':3,4]pyrido[1,2-a]pyrazine]
化合物63的合成路线参考实施例61的合成路线。The synthetic route of compound 63 refers to the synthetic route of Example 61.
LC-MS[M+H]+:221.1。LC-MS [M+H] + : 221.1.
实施例64Embodiment 64
8',9',10',10a'-四氢-5'H,7'H-吡啶并[环丙烷-1,4'-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪]
8',9',10',10a'-Tetrahydro-5'H,7'H-pyrido[cyclopropane-1,4'-thieno[2',3':3,4]pyrido[1,2-a]pyrazine]
合成路线：
synthetic route:
步骤a:1-(噻吩-3-基)环丙烷-1-甲腈的合成
Step a: Synthesis of 1-(thiophen-3-yl)cyclopropane-1-carbonitrile
将2-(噻吩-3-基)乙腈(1.0g,8.13mmol)溶于N,N-二甲基甲酰胺(10mL)中，随后加入氢化钠(0.49g,12.20mmol)，反应30分钟。然后将1,2-二溴乙烷(2.30g,12.20mmol)加入至反应体系室温搅拌2小时。将反应液倒入饱和食盐水(50mL)中，用二氯甲烷萃取三次(50mL x 3)后，有机相依次用水洗涤三次(50mL x 3)，饱和食盐水洗涤一次(50mL)，无水硫酸钠干燥后经柱层析(石油醚/乙酸乙酯)分离纯化得到目标化合物(0.75g,收率62％)。2-(Thiophene-3-yl)acetonitrile (1.0 g, 8.13 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of sodium hydride (0.49 g, 12.20 mmol) and the reaction mixture was allowed to react for 30 minutes. 1,2-Dibromoethane (2.30 g, 12.20 mmol) was then added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was poured into saturated brine (50 mL), extracted with dichloromethane three times (50 mL x 3), and the organic phase was washed with water three times (50 mL x 3), and then with saturated brine once (50 mL). After drying over anhydrous sodium sulfate, the mixture was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target compound (0.75 g, yield 62%).
LC-MS[M+H]+:150.0.LC-MS [M+H] + : 150.0.
步骤b:1-(噻吩-3-基)环丙基)甲胺的合成
Step b: Synthesis of 1-(thiophen-3-yl)cyclopropyl)methylamine
将1-(噻吩-3-基)环丙烷-1-甲腈(0.75g,5.04mmol)溶于四氢呋喃(10mL)中，然后将硼烷二甲硫醚(1.5mL,15.12mmol)加入反应体系。70℃搅拌1小时。待反应完毕，加入甲醇(20mL)淬灭反应，浓缩得到粗品，未分离纯化直接用于下一步反应(0.93g,粗品)。1-(Thiophen-3-yl)cyclopropane-1-carbonitrile (0.75 g, 5.04 mmol) was dissolved in tetrahydrofuran (10 mL), and then borane dimethyl sulfide (1.5 mL, 15.12 mmol) was added to the reaction system. Stir at 70 °C for 1 hour. After the reaction was completed, methanol (20 mL) was added to quench the reaction, and the crude product was concentrated to obtain a crude product, which was directly used in the next step without separation and purification (0.93 g, crude product).
LC-MS[M+H]+:154.0.LC-MS [M+H] + : 154.0.
步骤c:2-(6,7-二氢-5-H-螺环丙烷-1,4-噻吩并[2,3-c]吡啶]-7-基)甲基)异吲哚啉-1,3-二酮的合成
Step c: Synthesis of 2-(6,7-dihydro-5-H-spirocyclopropane-1,4-thieno[2,3-c]pyridin]-7-yl)methyl)isoindoline-1,3-dione
将1-(噻吩-3-基)环丙基)甲胺(0.93g,6.04mmol)，2-(1,3-二氧代异吲哚啉-2-基)乙醛(1.38g,7.24mmol)，三氟乙酸(3.44g,30.20mmol)加入至二氯甲烷(15mL)中，室温搅拌12小时。将三乙胺(3.05g,30.2mmol)加入至反应体系中淬灭反应，直接浓缩经柱层析(石油醚/乙酸乙酯)分离纯化得到目标化合物(1.28g,收率65％)。1-(Thien-3-yl)cyclopropyl)methylamine (0.93 g, 6.04 mmol), 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (1.38 g, 7.24 mmol), trifluoroacetic acid (3.44 g, 30.20 mmol) were added to dichloromethane (15 mL) and stirred at room temperature for 12 hours. Triethylamine (3.05 g, 30.2 mmol) was added to the reaction system to quench the reaction, and the mixture was directly concentrated and separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target compound (1.28 g, yield 65%).
LC-MS[M+H]+:325.0.LC-MS [M+H] + : 325.0.
步骤d:2-(7'-((1,3-二氧代异吲哚啉-2-基)甲基)-5'H-螺[环丙烷-1,4'-噻吩并[2,3-c]吡啶]-6'(7'H)-基)乙酸乙酯的合成
Step d: Synthesis of ethyl 2-(7'-((1,3-dioxoisoindolin-2-yl)methyl)-5'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyridine]-6'(7'H)-yl)acetate
将2-(6,7-二氢-5-H-螺环丙烷-1,4-噻吩并[2,3-c]吡啶]-7-基)甲基)异吲哚啉-1,3-二酮(0.5g,1.54mmol)，溴乙酸乙酯(0.77g,4.62mmol)，二异丙基乙胺(1.20g,9.24mmol)加入至乙腈(10ml)中，于80℃搅拌12小时，直接浓缩经柱层析(石油醚/乙酸乙酯)分离纯化得到目标化合物(0.32g,收率51％)。2-(6,7-Dihydro-5-H-spirocyclopropane-1,4-thieno[2,3-c]pyridin]-7-yl)methyl)isoindoline-1,3-dione (0.5 g, 1.54 mmol), ethyl bromoacetate (0.77 g, 4.62 mmol) and diisopropylethylamine (1.20 g, 9.24 mmol) were added to acetonitrile (10 ml), stirred at 80°C for 12 hours, directly concentrated and separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target compound (0.32 g, yield 51%).
LC-MS[M+H]+:411.1.LC-MS [M+H] + : 411.1.
步骤e:10,10a-二氢-5,7-螺环丙烷-1,4-噻吩并[2,3]:3,4]吡啶并吡嗪[1,2-a]吡嗪]-8(9'H)酮的合成
Step e: Synthesis of 10,10a-dihydro-5,7-spirocyclopropane-1,4-thieno[2,3]:3,4]pyridopyrazino[1,2-a]pyrazin]-8(9'H)one
将2-(7'-((1,3-二氧代异吲哚啉-2-基)甲基)-5'H-螺[环丙烷-1,4'-噻吩并[2,3-c]吡啶]-6'(7'H)-基)乙酸乙酯(0.32g,0.79mmol)加入至乙醇(10mL)中，随后加入水合肼(0.14g,2.37mmol)，60℃搅拌2小时。然后过滤，收集滤液。将滤液浓缩经柱层析(石油醚/乙酸乙酯)分离纯化得到目标化合物(0.12g,收率65％)。2-(7'-((1,3-dioxoisoindolin-2-yl)methyl)-5'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyridine]-6'(7'H)-yl)ethyl acetate (0.32 g, 0.79 mmol) was added to ethanol (10 mL), followed by hydrazine hydrate (0.14 g, 2.37 mmol), and stirred at 60°C for 2 hours. Then filtered and the filtrate was collected. The filtrate was concentrated and separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain the target compound (0.12 g, yield 65%).
LC-MS[M+H]+:235.0.LC-MS [M+H] + : 235.0.
步骤f:8,9,10,10a-四氢-5H,7H-螺[环丙烷-1,4-噻吩并[2,3]:3,4]吡啶并吡嗪]的合成
Step f: Synthesis of 8,9,10,10a-tetrahydro-5H,7H-spiro[cyclopropane-1,4-thieno[2,3]:3,4]pyridopyrazine]
将10,10a-二氢-5,7-螺环丙烷-1,4-噻吩并[2,3]:3,4]吡啶并吡嗪[1,2-a]吡嗪]-8(9'H)酮(0.06g,0.25mmol)加入至四氢呋喃(5mL)中，然后将四氢铝锂(0.048g,1.25mmol)加入其中，于70℃搅拌1小时。加入十水硫酸钠淬灭，过滤，收集滤液。将滤液浓缩经反相(水/乙腈) 分离纯化得到目标化合物(10mg,收率18％)。10,10a-dihydro-5,7-spirocyclopropane-1,4-thieno[2,3]:3,4]pyridopyrazine[1,2-a]pyrazine]-8(9'H)one (0.06 g, 0.25 mmol) was added to tetrahydrofuran (5 mL), and then lithium aluminum tetrahydride (0.048 g, 1.25 mmol) was added and stirred at 70°C for 1 hour. Sodium sulfate decahydrate was added to quench, filtered, and the filtrate was collected. The filtrate was concentrated and filtered through a reverse phase (water/acetonitrile). The target compound (10 mg, yield 18%) was obtained by separation and purification.
LC-MS[M+H]+:221.1.LC-MS [M+H] + : 221.1.
1H NMR(400MHz,CD3OD):δ8.52(brs,1H),7.22(d,J＝5.2Hz,1H),6.51(d,J＝5.2Hz,1H),3.77(d,J＝10.4Hz,1H),3.64(d,J＝11.2Hz,1H),3.36(d,J＝12.4Hz,1H),3.33-3.13(m,1H),3.12-2.95(m,3H),2.69(t,J＝11.6Hz,1H),2.35(d,J＝12.0Hz,1H),1.14-0.88(m,2H),0.86-0.75(m,2H). 1 H NMR (400 MHz, CD 3 OD): δ 8.52 (brs, 1H), 7.22 (d, J = 5.2 Hz, 1H), 6.51 (d, J = 5.2 Hz, 1H), 3.77 (d, J = 10.4 Hz, 1H), 3.64 (d, J = 11.2 Hz, 1H), 3.36 (d, J = 12.4 Hz, 1H), 3.33-3.13 (m, 1H), 3.12-2.95 (m, 3H), 2.69 (t, J = 11.6 Hz, 1H), 2.35 (d, J = 12.0 Hz, 1H), 1.14-0.88 (m, 2H), 0.86-0.75 (m, 2H).
实施例65Embodiment 65
4',7',8',9',10',10a'-六氢螺环[环丁烷-1,5'-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪]
4',7',8',9',10',10a'-Hexahydrospiro[cyclobutane-1,5'-thieno[2',3':3,4]pyrido[1,2-a]pyrazine]
化合物65的合成路线参考实施例61的合成路线。The synthetic route of compound 65 refers to the synthetic route of Example 61.
LC-MS[M+H]+:235.1。LC-MS [M+H] + : 235.1.
实施例66Embodiment 66
8',9',10',10a'-四氢-5'H,7'H-吡啶并[环丁烷-1,4'-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪]
8',9',10',10a'-Tetrahydro-5'H,7'H-pyrido[cyclobutane-1,4'-thieno[2',3':3,4]pyrido[1,2-a]pyrazine]
化合物66的合成路线参考实施例61的合成路线。The synthetic route of compound 66 refers to the synthetic route of Example 61.
LC-MS[M+H]+:235.1。LC-MS [M+H] + : 235.1.
实施例67Embodiment 67
10a-甲基-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
10a-Methyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线:
synthetic route:
步骤a:2-(噻吩-3-基)乙烷-1-胺的合成
Step a: Synthesis of 2-(thiophen-3-yl)ethane-1-amine
将3-噻吩乙腈(4.0g,32.47mmol)溶于四氢呋喃(40mL)中，加入硼烷二甲硫醚络合物(10M的四氢呋喃溶液,4.87mL,48.7mmol)，氮气保护在70℃下搅拌2小时。待反应液冷却至0℃，缓慢滴加甲醇(50mL)后搅拌30分钟。将反应液浓缩后加入盐酸乙酸乙酯溶液(4M,10mL)析出固体，固体用乙酸乙酯洗涤后得到白色固体目标产物(2g,收率50％)。Dissolve 3-thiopheneacetonitrile (4.0g, 32.47mmol) in tetrahydrofuran (40mL), add borane dimethyl sulfide complex (10M tetrahydrofuran solution, 4.87mL, 48.7mmol), and stir at 70℃ for 2 hours under nitrogen protection. After the reaction solution is cooled to 0℃, methanol (50mL) is slowly added dropwise and stirred for 30 minutes. After the reaction solution is concentrated, hydrochloric acid ethyl acetate solution (4M, 10mL) is added to precipitate solids, and the solids are washed with ethyl acetate to obtain the target product as a white solid (2g, yield 50%).
LC-MS[M+H]+:128.0.LC-MS [M+H] + : 128.0.
步骤b:2-((7-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚啉-1,3-二酮的合成
Step b: Synthesis of 2-((7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione
将2-(噻吩-3-基)乙烷-1-胺(0.80g,6.30mmol)溶于冰醋酸(20mL)中，加入N-丙酮基邻苯二甲酰亚胺(1.41g,6.93mmol)和三氟乙酸(3.59g,31.50mmol)，在100℃下搅拌12小时。向反应液中加入饱和的碳酸氢钠溶液(100mL)，用乙酸乙酯(50mL x 3)萃取三次后，有机相依次用水洗涤三次(50mL x 3)，饱和食盐水洗涤一次(50mL)，无水硫酸钠干燥后经柱层析(石油醚:乙酸乙酯＝3:1)分离纯化得到黄色油状目标产物(0.56g,收率28％)。2-(Thiophen-3-yl)ethane-1-amine (0.80 g, 6.30 mmol) was dissolved in glacial acetic acid (20 mL), and N-acetonylphthalimide (1.41 g, 6.93 mmol) and trifluoroacetic acid (3.59 g, 31.50 mmol) were added, and stirred at 100 ° C for 12 hours. Saturated sodium bicarbonate solution (100 mL) was added to the reaction solution, and after extraction with ethyl acetate (50 mL x 3) three times, the organic phase was washed with water three times (50 mL x 3), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product as a yellow oil (0.56 g, yield 28%).
LC-MS[M+H]+:313.3.LC-MS [M+H] + : 313.3.
步骤c:2-(7-((1,3-二氧代异吲哚啉-2-基)甲基)-7-甲基-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)乙酸乙酯的合成
Step c: Synthesis of ethyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-7-methyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)acetate
将2-((7-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚啉-1,3-二酮(0.56g,1.79mmol)溶于乙腈(11mL)中，加入溴乙酸乙酯(1.19g,7.16mmol)和N,N-二异丙基乙胺(1.15g,8.95mmol)，氮气保护下90℃搅拌12小时。将反应液倒入水(50mL)中，用二氯甲烷萃取三次(50mL x 3)后，有机相依次用水洗涤(50mL x 3)，饱和食盐水洗涤(50mL)，无水硫酸钠干燥后经柱层析(石油醚:乙酸乙酯＝4:1)分离纯化得到黄色固体目标产物(0.23g,收率32％)。2-((7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione (0.56 g, 1.79 mmol) was dissolved in acetonitrile (11 mL), ethyl bromoacetate (1.19 g, 7.16 mmol) and N,N-diisopropylethylamine (1.15 g, 8.95 mmol) were added, and stirred at 90 °C for 12 hours under nitrogen protection. The reaction solution was poured into water (50 mL), extracted with dichloromethane three times (50 mL x 3), and the organic phase was washed with water (50 mL x 3) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, and separated and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain the target product as a yellow solid (0.23 g, yield 32%).
LC-MS[M+H]+:399.4.LC-MS [M+H] + : 399.4.
步骤d:10a-甲基-4,9,10,10-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮的合成
Step d: Synthesis of 10a-methyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one
将2-(7-((1,3-二氧代异吲哚啉-2-基)甲基)-7-甲基-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)乙酸乙酯(0.23g,0.68mmol)溶于乙醇(6mL)中，加入80％水合肼(0.11g,1.74mmol)，在 70℃下搅拌3小时。将反应液倒入水(50mL)中，用乙酸乙酯萃取(30mL x 3)后，有机相依次用水洗涤(30mL x 3)，饱和食盐水洗涤(30mL)，无水硫酸钠干燥后经柱层析(二氯甲烷:甲醇＝20:1)分离纯化得到黄色油状目标产物(0.09g,收率60％)。2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-7-methyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)acetic acid ethyl ester (0.23 g, 0.68 mmol) was dissolved in ethanol (6 mL), 80% hydrazine hydrate (0.11 g, 1.74 mmol) was added, and the mixture was stirred for 2 hours. Stir at 70°C for 3 hours. Pour the reaction solution into water (50 mL), extract with ethyl acetate (30 mL x 3), wash the organic phase with water (30 mL x 3), wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, and separate and purify by column chromatography (dichloromethane: methanol = 20: 1) to obtain the target product (0.09 g, yield 60%) as a yellow oil.
LC-MS[M+H]+:223.3.LC-MS [M+H] + : 223.3.
步骤e:10a-甲基-4,7,8,9,10,10-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step e: Synthesis of 10a-methyl-4,7,8,9,10,10-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将10a-甲基-4,9,10,10-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮(90mg,0.45mmol)溶于四氢呋喃(2mL)中，加入四氢铝锂(0.05g,1.35mmol)，在氮气保护下80℃搅拌2小时。将反应液冷却至室温后缓慢加入十水硫酸钠(0.13g,0.46mmol)搅拌10分钟，抽滤，得到的滤液浓缩后加入盐酸乙酸乙酯溶液(4M,2mL)，用水(5mL x 3)萃取三次后将水相冻干得到目标产物(35mg,收率42％)。10a-Methyl-4,9,10,10-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one (90 mg, 0.45 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum tetrahydride (0.05 g, 1.35 mmol) was added, and stirred at 80 ° C for 2 hours under nitrogen protection. After the reaction solution was cooled to room temperature, sodium sulfate decahydrate (0.13 g, 0.46 mmol) was slowly added and stirred for 10 minutes, and then filtered. The filtrate was concentrated and then hydrochloric acid ethyl acetate solution (4M, 2 mL) was added. After extraction with water (5 mL x 3) three times, the aqueous phase was freeze-dried to obtain the target product (35 mg, yield 42%).
LC-MS[M+H]+:209.3.LC-MS [M+H] + : 209.3.
1H NMR(400MHz,CD3OD):δ7.60(d,J＝5.2Hz,1H),7.01(d,J＝5.2Hz,1H),4.10-3.93(m,2H),3.92-3.76(m,3H),3.75-3.60(m,3H),3.23-3.12(m,2H),1.99(s,3H). 1 H NMR (400 MHz, CD 3 OD): δ7.60 (d, J=5.2 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 4.10-3.93 (m, 2H), 3.92-3.76 (m, 3H), 3.75-3.60 (m, 3H), 3.23-3.12 (m, 2H), 1.99 (s, 3H).
实施例68Embodiment 68
10a-氟-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪
10a-Fluoro-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine
化合物68的合成路线参考实施例67的合成路线。The synthetic route of compound 68 refers to the synthetic route of Example 67.
LC-MS[M+H]+:213.1。LC-MS [M+H] + : 213.1.
实施例69Embodiment 69
10a-氯-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪
10a-Chloro-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine
化合物69的合成路线参考实施例67的合成路线。The synthetic route of compound 69 refers to the synthetic route of Example 67.
LC-MS[M+H]+:229.1。LC-MS [M+H] + : 229.1.
实施例70Embodiment 70
10a-环丙基-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪
10a-Cyclopropyl-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine
化合物70的合成路线参考实施例67的合成路线。The synthetic route of compound 70 refers to the synthetic route of Example 67.
LC-MS[M+H]+:235.1。LC-MS [M+H] + : 235.1.
实施例71Embodiment 71
2,3,5,6,10,10a-六氢-1H-环丙基[b]噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
2,3,5,6,10,10a-Hexahydro-1H-cyclopropyl[b]thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物71的合成路线参考实施例67的合成路线。The synthetic route of compound 71 refers to the synthetic route of Example 67.
LC-MS[M+H]+:207.1。LC-MS [M+H] + : 207.1.
实施例72Embodiment 72
1,2,3,5,6,10,11,11a-八氢环丁烷[b]噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
1,2,3,5,6,10,11,11a-Octahydrocyclobutane[b]thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物72的合成路线参考实施例67的合成路线。The synthetic route of compound 72 refers to the synthetic route of Example 67.
LC-MS[M+H]+:221.1。LC-MS [M+H] + : 221.1.
实施例73Embodiment 73
3b,4,4a,6,7,8,9,9a-八氢环丙基[5,6]噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
3b,4,4a,6,7,8,9,9a-Octahydrocyclopropyl[5,6]thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物73的合成路线参考实施例61的合成路线。The synthetic route of compound 73 refers to the synthetic route of Example 61.
LC-MS[M+H]+:207.1。LC-MS [M+H] + : 207.1.
实施例74Embodiment 74
3b,5,5a,7,8,9,10-八氢-4H-环丁烷[5,6]噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪
3b,5,5a,7,8,9,10-Octahydro-4H-cyclobutane[5,6]thieno[2',3':3,4]pyrido[1,2-a]pyrazine
化合物74的合成路线参考实施例61的合成路线。 The synthetic route of compound 74 refers to the synthetic route of Example 61.
LC-MS[M+H]+:221.1。LC-MS [M+H] + : 221.1.
实施例75Embodiment 75
1,3,4,6,7,10b-六氢-2H-噻吩并[3',2':3,4]吡啶并[1,2-a]吡嗪
1,3,4,6,7,10b-Hexahydro-2H-thieno[3',2':3,4]pyrido[1,2-a]pyrazine
化合物75的合成路线参考实施例1的合成路线。The synthetic route of compound 75 refers to the synthetic route of Example 1.
LC-MS[M+H]+:195.1。LC-MS [M+H] + : 195.1.
实施例76Embodiment 76
1,3,4,6,7,12c-六氢-2H-苯并[4',5']噻吩并[3',2':3,4]吡啶并[1,2-a]吡嗪
1,3,4,6,7,12c-Hexahydro-2H-benzo[4',5']thieno[3',2':3,4]pyrido[1,2-a]pyrazine
化合物76的合成路线参考实施例1的合成路线。The synthetic route of compound 76 refers to the synthetic route of Example 1.
LC-MS[M+H]+:245.1。LC-MS [M+H] + : 245.1.
实施例77Embodiment 77
1,3,4,6,7,12c-六氢-2H-吡啶并[2”,3”:4',5']噻吩并[3',2':3,4]吡啶并[1,2-a]吡嗪
1,3,4,6,7,12c-Hexahydro-2H-pyrido[2”,3”:4',5']thieno[3',2':3,4]pyrido[1,2-a]pyrazine
化合物77的合成路线参考实施例1的合成路线。The synthetic route of compound 77 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例78Embodiment 78
1,3,4,6,7,12c-六氢-2H-吡啶[3”,4”:4',5']噻吩并[3',2':3,4]吡啶并[1,2-a]吡嗪
1,3,4,6,7,12c-Hexahydro-2H-pyrido[3”,4”:4',5']thieno[3',2':3,4]pyrido[1,2-a]pyrazine
化合物78的合成路线参考实施例1的合成路线。The synthetic route of compound 78 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例79Embodiment 79
1,3,4,6,7,12c-六氢-2H-吡啶并[4”,3”:4',5']噻吩并[3',2':3,4]吡啶并[1,2-a]吡嗪
1,3,4,6,7,12c-Hexahydro-2H-pyrido[4”,3”:4',5']thieno[3',2':3,4]pyrido[1,2-a]pyrazine
化合物79的合成路线参考实施例1的合成路线。The synthetic route of compound 79 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例80Embodiment 80
1,3,4,6,7,12c-六氢-2H-吡啶并[3”,2”:4',5']噻吩并[3',2':3,4]吡啶并[1,2-a]吡嗪
1,3,4,6,7,12c-Hexahydro-2H-pyrido[3”,2”:4',5']thieno[3',2':3,4]pyrido[1,2-a]pyrazine
化合物80的合成路线参考实施例1的合成路线。The synthetic route of compound 80 refers to the synthetic route of Example 1.
LC-MS[M+H]+:246.1。LC-MS [M+H] + : 246.1.
实施例81Embodiment 81
7-(甲基-d3)-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7-d盐酸盐
7-(Methyl-d3)-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-7-d hydrochloride
合成路线：
synthetic route:
步骤a:2-(7-(((叔丁氧羰基)氨基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)丙酸甲酯-2,3,3,3-d4的合成
Step a: Synthesis of methyl 2-(7-(((tert-butyloxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)propanoate-2,3,3,3-d4
在反应瓶中分别加入N-[(4H,5H,6H,7H-噻吩并[2,3-c]吡啶-7-基)甲基]胺基甲酸叔丁酯(430mg,1.60mmol)、2-溴丙酸甲酯-2,3,3,3-d4(0.185mL,1.62mmol)、碳酸钾(666mg,4.80mmol)、碘化钠(238mg,1.60mmol)和乙腈(17mL)，混合液在80℃下反应2小时。反应结 束后，饱和氯化铵淬灭反应，反应液用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，粗产物经柱层析(石油醚:乙酸乙酯＝5:1)纯化得到一对非对映异构体，分别为异构体1(144mg,0.4mmol)和异构体2(108mg,0.3mmol)。In the reaction flask, tert-butyl N-[(4H,5H,6H,7H-thieno[2,3-c]pyridin-7-yl)methyl]carbamate (430 mg, 1.60 mmol), methyl 2-bromopropionate-2,3,3,3-d4 (0.185 mL, 1.62 mmol), potassium carbonate (666 mg, 4.80 mmol), sodium iodide (238 mg, 1.60 mmol) and acetonitrile (17 mL) were added respectively, and the mixture was reacted at 80°C for 2 hours. After the reaction was completed, saturated ammonium chloride was used to quench the reaction. The reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a pair of diastereomers, namely isomer 1 (144 mg, 0.4 mmol) and isomer 2 (108 mg, 0.3 mmol).
LC-MS[M+H]+:359.5(异构体1/异构体2).LC-MS [M+H] + : 359.5 (isomer 1/isomer 2).
步骤b:2-(7-(氨甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)丙酸甲酯-2,3,3,3-d4的合成
Step b: Synthesis of methyl 2-(7-(aminomethyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)propanoate-2,3,3,3-d4
将2-(7-(((叔丁氧羰基)氨基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)丙酸甲酯-2,3,3,3-d4的异构体1(144mg,0.40mmol)溶于盐酸/乙酸乙酯溶液(4mL)中，并在室温下搅拌2小时。经浓缩得到的盐酸盐无需纯化直接用于下一步反应。Isomer 1 of methyl 2-(7-(((tert-butyloxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)propanoate-2,3,3,3-d4 (144 mg, 0.40 mmol) was dissolved in hydrochloric acid/ethyl acetate solution (4 mL) and stirred at room temperature for 2 hours. The hydrochloride obtained by concentration was used directly in the next step without purification.
LC-MS[M+H]+:259.4.LC-MS [M+H] + : 259.4.
步骤c:7-(甲基-d3)-4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶[1,2-a]吡嗪-8(7H)-酮-7-d的合成
Step c: Synthesis of 7-(methyl-d3)-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyridin[1,2-a]pyrazine-8(7H)-one-7-d
在反应瓶中分别加入2-(7-(氨甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)丙酸甲酯盐酸盐-2,3,3,3-d4(118mg,0.40mmol)、甲醇钠(216mg,4.0mmol)和甲醇(4mL)，混合液在室温下反应12小时。反应结束后，旋干反应液，加入乙酸乙酯后过滤反应液，滤液经浓缩得到的产物无需纯化直接用于下一步反应。2-(7-(Aminomethyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)propanoic acid methyl ester hydrochloride-2,3,3,3-d4 (118 mg, 0.40 mmol), sodium methoxide (216 mg, 4.0 mmol) and methanol (4 mL) were added to the reaction bottle, and the mixture was reacted at room temperature for 12 hours. After the reaction was completed, the reaction solution was dried, ethyl acetate was added and the reaction solution was filtered, and the product obtained by concentrating the filtrate was directly used in the next step without purification.
LC-MS[M+H]+:227.5.LC-MS [M+H] + : 227.5.
步骤d:7-(甲基-d3)-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7-d的合成
Step d: Synthesis of 7-(methyl-d3)-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-7-d
在0℃下，向四氢铝锂(152mg,4mmol)的四氢呋喃(4mL)溶液中缓慢滴加7-(甲基-d3)-4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶[1,2-a]吡嗪-8(7H)-酮-7-d(90mg,0.4mmol的四氢呋喃(4mL)溶液，随后将反应升温至65℃反应约2小时。反应结束后，十水合硫酸钠淬灭反应，过滤后反应液经浓缩得到的产物无需纯化直接用于下一步反应。At 0°C, a solution of 7-(methyl-d3)-4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyridin[1,2-a]pyrazine-8(7H)-one-7-d (90 mg, 0.4 mmol) in tetrahydrofuran (4 mL) was slowly added dropwise to a solution of lithium aluminum tetrahydride (152 mg, 4 mmol) in tetrahydrofuran (4 mL), and then the reaction temperature was raised to 65°C for about 2 hours. After the reaction was completed, the reaction was quenched with sodium sulfate decahydrate, and the reaction solution was filtered and concentrated to obtain a product that was directly used in the next step without purification.
LC-MS[M+H]+:213.5.LC-MS [M+H] + : 213.5.
步骤e:7-(甲基-d3)-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯-7-d的合成
Step e: Synthesis of tert-butyl 7-(methyl-d3)-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate-7-d
在反应瓶中分别加入7-(甲基-d3)-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a] 吡嗪-7-d(85mg,0.4mmol)、二碳酸二叔丁酯(262mg,1.2mmol)和四氢呋喃(4mL)，混合液在室温下反应约2小时。反应结束后，旋干反应液，粗产物经柱层析(乙酸乙酯:石油醚＝3:1)纯化得到淡黄色油状目标产物(122mg,收率98％)。Add 7-(methyl-d3)-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a] Pyrazine-7-d (85 mg, 0.4 mmol), di-tert-butyl dicarbonate (262 mg, 1.2 mmol) and tetrahydrofuran (4 mL) were reacted at room temperature for about 2 hours. After the reaction, the reaction solution was dried and the crude product was purified by column chromatography (ethyl acetate: petroleum ether = 3:1) to obtain the target product (122 mg, yield 98%) as a light yellow oil.
LC-MS[M+H-56]+:257.1.LC-MS [M+H-56] + : 257.1.
步骤f:7-(甲基-d3)-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7-d盐酸盐的合成
Step f: Synthesis of 7-(methyl-d3)-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-7-d hydrochloride
将7-(甲基-d3)-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯-7-d(122mg,0.39mmol)溶于盐酸/乙酸乙酯溶液(4mL)中，并在室温下搅拌2小时。反应结束后，旋干反应液，干燥后得到目标产物异构体1(72mg,收率74％)。7-(Methyl-d3)-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylic acid tert-butyl ester-7-d (122 mg, 0.39 mmol) was dissolved in hydrochloric acid/ethyl acetate solution (4 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was spin-dried and dried to obtain the target product isomer 1 (72 mg, yield 74%).
LC-MS[M+H]+:213.2.LC-MS [M+H] + : 213.2.
1H NMR(400MHz,CD3OD):δ7.59(d,J＝5.2Hz,1H),7.03(d,J＝5.2Hz,1H),5.40(s,1H),4.03-3.84(m,3H),3.75-3.67(m,2H),3.58(d,J＝14.0Hz,1H),3.25-3.20(m,1H),3.11(d,J＝16.8Hz,1H). 1 H NMR (400 MHz, CD 3 OD): δ7.59 (d, J=5.2 Hz, 1H), 7.03 (d, J=5.2 Hz, 1H), 5.40 (s, 1H), 4.03-3.84 (m, 3H), 3.75-3.67 (m, 2H), 3.58 (d, J=14.0 Hz, 1H), 3.25-3.20 (m, 1H), 3.11 (d, J=16.8 Hz, 1H).
将2-(7-(((叔丁氧羰基)氨基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)丙酸甲酯-2,3,3,3-d4的异构体2(108mg,0.30mmol)为原料采用类似的合成方法得到目标产物的异构体2(44mg,收率81％)。Isomer 2 (108 mg, 0.30 mmol) of methyl 2-(7-(((tert-butoxycarbonyl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)propanoate-2,3,3,3-d4 was used as raw material to obtain isomer 2 of the target product (44 mg, yield 81%) using a similar synthesis method.
LC-MS[M+H]+:213.2.LC-MS [M+H] + : 213.2.
1H NMR(400MHz,CD3OD):δ7.56(d,J＝5.2Hz,1H),7.00(d,J＝5.2Hz,1H),5.21(d,J＝11.6Hz,1H),4.17-4.11(m,2H),3.62-3.80(m,2H),3.56(d,J＝14.0Hz,2H),3.33-3.25(m,1H),3.17-3.11(m,1H). 1 H NMR (400 MHz, CD 3 OD): δ7.56 (d, J=5.2 Hz, 1H), 7.00 (d, J=5.2 Hz, 1H), 5.21 (d, J=11.6 Hz, 1H), 4.17-4.11 (m, 2H), 3.62-3.80 (m, 2H), 3.56 (d, J=14.0 Hz, 2H), 3.33-3.25 (m, 1H), 3.17-3.11 (m, 1H).
实施例82Embodiment 82
4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮
4,9,10,10a-Tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-8(7H)-one
化合物82的合成路线参考实施例1a的合成路线步骤a-d。The synthetic route of compound 82 refers to steps ad of the synthetic route of Example 1a .
LC-MS[M+H]+:209.3.LC-MS [M+H] + : 209.3.
1H NMR(400MHz,CD3OD):δ7.28(d,J＝4.8Hz,1H),6.84(d,J＝5.2Hz,1H),3.72(d,J＝10.4Hz,1H),3.62(dd,J＝11.6,3.6Hz,1H),3.56(d,J＝16.8Hz,1H),3.25-3.14(m,2H),3.13-3.05(m,1H),2.94-2.83(m,1H),2.76-2.68(m,1H),2.62-2.52(m,1H). 1 H NMR (400 MHz, CD 3 OD): δ7.28 (d, J=4.8 Hz, 1H), 6.84 (d, J=5.2 Hz, 1H), 3.72 (d, J=10.4 Hz, 1H), 3.62 (dd, J=11.6, 3.6 Hz, 1H), 3.56 (d, J=16.8 Hz, 1H), 3.25-3.14 (m, 2H), 3.13-3.05 (m, 1H), 2.94-2.83 (m, 1H), 2.76-2.68 (m, 1H), 2.62-2.52 (m, 1H).
实施例83Embodiment 83
4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-4,4,5,5,7,7,8,8-d8盐酸盐
4,7,8,9,10,10a-Hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-4,4,5,5,7,7,8,8-d 8 hydrochloride
合成路线:
synthetic route:
步骤a:2-(噻吩-3-基)乙腈-d2的合成
Step a: Synthesis of 2-(thiophen-3-yl)acetonitrile-d2
将2-(噻吩-3-基)乙腈(3.0g,24.4mmol)溶于四氢呋喃(25mL)中，分别加入三乙胺(40.7mL,292.8mmol)和重水(53.0mL,2928mmol)，反应液在室温下搅拌过夜。反应结束后，水淬灭反应，反应液用乙酸乙酯萃取，有机相再用饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，粗产物经柱层析(石油醚:乙酸乙酯＝10:1)纯化得到无色油状目标产物(3.0g,收率98％)。2-(Thiophen-3-yl)acetonitrile (3.0 g, 24.4 mmol) was dissolved in tetrahydrofuran (25 mL), and triethylamine (40.7 mL, 292.8 mmol) and heavy water (53.0 mL, 2928 mmol) were added respectively, and the reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product (3.0 g, yield 98%) as a colorless oil.
步骤b:(2-(噻吩-3-基)乙基-1,1,2,2-d4)氨基甲酸叔丁酯的合成
Step b: Synthesis of tert-butyl (2-(thiophen-3-yl)ethyl-1,1,2,2-d4)carbamate
在0℃下，向三氯化铝(1.6g,12mmol)的四氢呋喃(30mL)溶液中缓慢加入氘代氢化铝锂(336mg,8mmol)，随后缓慢滴加2-(噻吩-3-基)乙腈-d2(500mg,4mmol)的四氢呋喃(10mL)溶液。反应液在室温下搅拌2小时。反应结束后，十水合硫酸钠淬灭反应，过滤后反应液经浓缩得到粗产物。随后将粗产物溶于四氢呋喃(10mL)中，加入二碳酸二叔丁酯(2.6g,12mmol)，室温下搅拌30分钟。反应结束后，旋干反应液，粗产物经柱层析(石油醚:乙酸乙酯＝10:1)纯化得到无色油状目标产物(550mg,收率59％)。At 0°C, lithium aluminum hydride (336 mg, 8 mmol) was slowly added to a solution of aluminum chloride (1.6 g, 12 mmol) in tetrahydrofuran (30 mL), followed by a solution of 2-(thiophene-3-yl)acetonitrile-d2 (500 mg, 4 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with sodium sulfate decahydrate, and the reaction solution was filtered and concentrated to obtain a crude product. The crude product was then dissolved in tetrahydrofuran (10 mL), di-tert-butyl dicarbonate (2.6 g, 12 mmol) was added, and stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was spin-dried, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a colorless oily target product (550 mg, yield 59%).
LC-MS[M-Me]+:216.9.LC-MS [M-Me] + : 216.9.
步骤c:2-((4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基-4,4,5,5-d4)甲基)异吲哚啉-1,3-二酮的合成
Step c: Synthesis of 2-((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl-4,4,5,5-d4)methyl)isoindoline-1,3-dione
将(2-(噻吩-3-基)乙基-1,1,2,2-d4)氨基甲酸叔丁酯(550mg,2.38mmol)溶于二氯甲烷(5mL)中，加入三氟乙酸(0.88mL,11.9mmol)，室温下搅拌30分钟后，缓慢加入N-(2-乙醛基)邻苯二甲酰亚胺(539.8mg,2.86mmol)。加毕反应液在室温下搅拌过夜。反应结束后，饱和碳酸氢钠淬灭反应，反应液用二氯甲烷萃取，有机相再用饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，粗产物经柱层析(石油醚:乙酸乙酯＝1:4)纯化得到淡黄色固体目标产物(668mg,收率93％)。Dissolve tert-butyl (2-(thiophen-3-yl)ethyl-1,1,2,2-d4)carbamate (550 mg, 2.38 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (0.88 mL, 11.9 mmol), stir at room temperature for 30 minutes, and then slowly add N-(2-acetaldehyde)phthalimide (539.8 mg, 2.86 mmol). After the addition, the reaction solution was stirred at room temperature overnight. After the reaction was completed, saturated sodium bicarbonate was used to quench the reaction, the reaction solution was extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:4) to obtain the target product (668 mg, yield 93%) as a light yellow solid.
LC-MS[M+H]+:303.0.LC-MS [M+H] + : 303.0.
步骤d:2-((6-(2-溴乙基-1,1,2,2-d4)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基-4,4,5,5-d4)甲基)异吲哚啉-1,3-二酮的合成
Step d: Synthesis of 2-((6-(2-bromoethyl-1,1,2,2-d4)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl-4,4,5,5-d4)methyl)isoindoline-1,3-dione
将2-((4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基-4,4,5,5-d4)甲基)异吲哚啉-1,3-二酮(450mg,1.49mmol)溶于N,N-二甲基甲酰胺(15mL)中，分别加入N,N-二异丙基乙胺(0.78mL,4.47mmol)和1,2-二溴乙烷-D4(0.64mL,7.45mmol)，反应液在100℃下反应2小时。反应结束后，饱和氯化铵淬灭反应，反应液用乙酸乙酯萃取，有机相再用饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，粗产物经柱层析(石油醚:乙酸乙酯＝4:1)纯化得到白色固体目标产物(133mg,收率22％)。2-((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl-4,4,5,5-d4)methyl)isoindoline-1,3-dione (450 mg, 1.49 mmol) was dissolved in N,N-dimethylformamide (15 mL), and N,N-diisopropylethylamine (0.78 mL, 4.47 mmol) and 1,2-dibromoethane-D4 (0.64 mL, 7.45 mmol) were added respectively, and the reaction solution was reacted at 100°C for 2 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain the target product as a white solid (133 mg, yield 22%).
LC-MS[M+H]+:414.9.LC-MS [M+H] + : 414.9.
步骤e:2-((6-(2-氯乙基-1,1,2,2-d4)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基-4,4,5,5-d4)甲基)异吲哚啉-1,3-二酮的合成
Step e: Synthesis of 2-((6-(2-chloroethyl-1,1,2,2-d4)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl-4,4,5,5-d4)methyl)isoindoline-1,3-dione
在反应瓶中分别加入2-((6-(2-溴乙基-1,1,2,2-d4)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基-4,4,5,5-d4)甲基)异吲哚啉-1,3-二酮(133mg,0.32mmol)、氯化锂(41mg,0.96mmol)和N,N-二甲基甲酰胺(2mL)，混合液在70℃下反应30分钟。反应结束后，水淬灭反应，反应液用乙酸乙酯萃取，有机相再用饱和食盐水洗涤，无水硫酸钠干燥后过滤，浓缩得到的粗产物无需纯化直接用于下一步反应。2-((6-(2-bromoethyl-1,1,2,2-d4)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl-4,4,5,5-d4)methyl)isoindoline-1,3-dione (133 mg, 0.32 mmol), lithium chloride (41 mg, 0.96 mmol) and N,N-dimethylformamide (2 mL) were added to the reaction bottle, and the mixture was reacted at 70°C for 30 minutes. After the reaction was completed, the reaction was quenched with water, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was directly used in the next reaction without purification.
LC-MS[M+H]+:369.3.LC-MS [M+H] + : 369.3.
步骤f:4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-4,4,5,5,7,7,8,8-d8的合成
Step f: Synthesis of 4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-4,4,5,5,7,7,8,8-d8
将2-((6-(2-氯乙基-1,1,2,2-d4)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基-4,4,5,5-d4)甲基)异吲哚啉-1,3-二酮(110mg,0.30mmol)溶于乙醇(3mL)中，加入水合肼(75mg,1.5mmol)，随后反应液在室温下搅拌过夜。反应结束后，过滤反应液，滤饼用乙酸乙酯洗涤，滤液旋干后得到的粗产物无需纯化直接用于下一步反应。2-((6-(2-chloroethyl-1,1,2,2-d4)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl-4,4,5,5-d4)methyl)isoindoline-1,3-dione (110 mg, 0.30 mmol) was dissolved in ethanol (3 mL), hydrazine hydrate (75 mg, 1.5 mmol) was added, and the reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, and the filtrate was dried to obtain a crude product that was directly used in the next step without purification.
LC-MS[M+H]+:202.5.LC-MS [M+H] + : 202.5.
步骤g:4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯-4,4,5,5,7,7,8,8-d8的合成
Step g: Synthesis of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate-4,4,5,5,7,7,8,8-d8
将4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-4,4,5,5,7,7,8,8-d8粗产物溶于四氢呋喃(3mL)中，加入二碳酸二叔丁酯(0.34mL,1.5mmol)，随后反应液在室温下搅拌30分钟。反应结束后，旋干反应液，粗产物经柱层析(石油醚:乙酸乙酯＝3:1)纯化得到无色油状目标产物(81mg,收率89％)The crude product of 4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-4,4,5,5,7,7,8,8-d8 was dissolved in tetrahydrofuran (3 mL), di-tert-butyl dicarbonate (0.34 mL, 1.5 mmol) was added, and the reaction solution was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was dried and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product as a colorless oil (81 mg, yield 89%)
LC-MS[M+H]+:303.0.LC-MS [M+H] + : 303.0.
步骤h:4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-4,4,5,5,7,7,8,8-d8盐酸盐的合成
Step h: Synthesis of 4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-4,4,5,5,7,7,8,8-d 8 hydrochloride
将4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯-4,4,5,5,7,7,8,8-d8(81mg,0.27mmol)溶于盐酸/乙酸乙酯溶液(3mL)中，并在室温下搅拌2小时。反应结束后，旋干反应液，加水冻干后得到目标产物(50mg,收率91％)。4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylic acid tert-butyl ester-4,4,5,5,7,7,8,8-d8 (81 mg, 0.27 mmol) was dissolved in hydrochloric acid/ethyl acetate solution (3 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was dried and freeze-dried with water to obtain the target product (50 mg, yield 91%).
LC-MS[M+H]+:202.9.LC-MS [M+H] + : 202.9.
1H NMR(400MHz,CD3OD):δ7.53(d,J＝5.2Hz,1H),7.01(d,J＝5.2Hz,1H),4.95(dd,J＝11.2,2.4Hz,1H),4.08(dd,J＝13.6,3.2Hz,1H),3.51(dd,J＝13.2,11.6Hz,1H). 1 H NMR (400 MHz, CD 3 OD): δ7.53 (d, J=5.2 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 4.95 (dd, J=11.2, 2.4 Hz, 1H), 4.08 (dd, J=13.6, 3.2 Hz, 1H), 3.51 (dd, J=13.2, 11.6 Hz, 1H).
实施例84Embodiment 84
4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-4,4,5,5-d4盐酸盐
4,7,8,9,10,10a-Hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-4,4,5,5-d 4 hydrochloride
合成路线:
synthetic route:
步骤a:2-(7-((1,3-二氧代异吲哚啉-2-基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基-4,4,5,5-D4)乙酸乙酯的合成
Step a: Synthesis of ethyl 2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl-4,4,5,5-D4)acetate
将2-((4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基-4,4,5,5-d4)甲基)异吲哚啉-1,3-二酮(100mg,0.33mmol)溶于N,N-二甲基甲酰胺(3mL)中，分别加入N,N-二异丙基乙胺(0.17mL,0.99mmol)和溴乙酸乙酯(0.11mL,0.99mmol)，反应液在80℃下反应2小时。反应结束后，饱和氯化铵淬灭反应，反应液用乙酸乙酯萃取，有机相再用饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，粗产物经柱层析(石油醚:乙酸乙酯＝4:1)纯化得到无色油状目标产物(110mg,收率86％)。2-((4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl-4,4,5,5-d4)methyl)isoindoline-1,3-dione (100 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (0.17 mL, 0.99 mmol) and ethyl bromoacetate (0.11 mL, 0.99 mmol) were added respectively, and the reaction solution was reacted at 80°C for 2 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain the target product as a colorless oil (110 mg, yield 86%).
LC-MS[M+H]+:389.3.LC-MS [M+H] + : 389.3.
步骤b:4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮-4,4,5,5-d4的合成
Step b: Synthesis of 4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one-4,4,5,5-d4
将2-(7-((1,3-二氧代异吲哚啉-2-基)甲基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基-4,4,5,5-D4)乙酸乙酯(110mg,0.28mmol)溶于乙醇(3mL)中，加入水合肼(70mg,1.4mmol)，随后反应液在70℃下搅拌6小时。反应结束后，过滤反应液，滤饼用乙酸乙酯洗涤，滤液旋干后得到的粗产物无需纯化直接用于下一步反应。2-(7-((1,3-dioxoisoindolin-2-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl-4,4,5,5-D4)ethyl acetate (110 mg, 0.28 mmol) was dissolved in ethanol (3 mL), hydrazine hydrate (70 mg, 1.4 mmol) was added, and the reaction solution was stirred at 70°C for 6 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, and the crude product obtained after the filtrate was dried was directly used in the next reaction without purification.
LC-MS[M+H]+:212.9.LC-MS [M+H] + : 212.9.
步骤c:4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-4,4,5,5-d4的合成
Step c: Synthesis of 4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-4,4,5,5-d4
在0℃下，向四氢铝锂(106.4mg,2.8mmol)的四氢呋喃(3mL)溶液中缓慢滴加4,9,10,10a-四氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-8(7H)-酮-4,4,5,5-d4(60mg,0.28mmol的四氢呋喃(3mL)溶液，随后将反应升温至65℃反应约2小时。反应结束后，十水合硫酸钠淬灭反应，过滤后反应液经浓缩得到的产物无需纯化直接用于下一步反应。At 0°C, a solution of 4,9,10,10a-tetrahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-8(7H)-one-4,4,5,5-d4(60 mg, 0.28 mmol) in tetrahydrofuran(3 mL) was slowly added dropwise to a solution of lithium aluminum tetrahydride(106.4 mg, 2.8 mmol) in tetrahydrofuran(3 mL), and then the reaction temperature was raised to 65°C for about 2 hours. After the reaction was completed, the reaction was quenched with sodium sulfate decahydrate, and the reaction solution was filtered and concentrated to obtain a product that was directly used in the next step without purification.
LC-MS[M+H]+:199.2.LC-MS [M+H] + : 199.2.
步骤d:4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯-4,4,5,5-D4的合成
Step d: Synthesis of tert-butyl 4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate-4,4,5,5-D4
在反应瓶中分别加入4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-4,4,5,5-d4(56mg,0.28mmol)、二碳酸二叔丁酯(0.32mL,1.4mmol)和四氢呋喃(3mL)，混合液在室温下反应约2小时。反应结束后，旋干反应液，粗产物经柱层析(乙酸乙酯:石油醚＝3:1)纯化得到无色油状目标产物(70mg,收率84％)。4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-4,4,5,5-d4 (56 mg, 0.28 mmol), di-tert-butyl dicarbonate (0.32 mL, 1.4 mmol) and tetrahydrofuran (3 mL) were added to the reaction bottle, and the mixture was reacted at room temperature for about 2 hours. After the reaction was completed, the reaction solution was dried, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether = 3:1) to obtain the target product (70 mg, yield 84%) as a colorless oil.
LC-MS[M+H]+:299.0.LC-MS [M+H] + : 299.0.
步骤e:4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-4,4,5,5-d4盐酸盐的合成
Step e: Synthesis of 4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-4,4,5,5-d 4 hydrochloride
将4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯-4,4,5,5-D4(70mg,0.23mmol)溶于盐酸/乙酸乙酯溶液(3mL)中，并在室温下搅拌2小时。反应结束后，旋干反应液，干燥后得到淡黄色固体目标产物(50mg,收率93％)。4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylic acid tert-butyl ester-4,4,5,5-D4 (70 mg, 0.23 mmol) was dissolved in hydrochloric acid/ethyl acetate solution (3 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was spin-dried and dried to obtain the target product as a light yellow solid (50 mg, yield 93%).
LC-MS[M+H]+:199.0.LC-MS [M+H] + : 199.0.
1H NMR(400MHz,CD3OD):δ7.54(dd,J＝5.2,0.8Hz,1H),7.01(d,J＝5.2Hz,1H),5.01(dd,J＝11.2,2.8Hz,1H),4.11(ddd,J＝13.6,3.2,1.6Hz,1H),3.89-3.85(m,1H),3.80-3.76(m,1H),3.74-3.67(m,1H),3.67-3.60(m,1H),3.54(dd,J＝13.6,11.6Hz,1H). 1 H NMR (400 MHz, CD 3 OD): δ7.54 (dd, J=5.2, 0.8 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 5.01 (dd, J=11.2, 2.8 Hz, 1H), 4.11 (ddd, J=13.6, 3.2, 1.6 Hz, 1H), 3.89-3.85 (m, 1H), 3.80-3.76 (m, 1H), 3.74-3.67 (m, 1H), 3.67-3.60 (m, 1H), 3.54 (dd, J=13.6, 11.6 Hz, 1H).
实施例85Embodiment 85
4,4-二氟-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐
4,4-Difluoro-4,7,8,9,10,10a-hexahydro-5H-thiophene[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
合成路线：
synthetic route:
步骤a:2-羟基-2-(噻吩-3-基)乙腈的合成
Step a: Synthesis of 2-hydroxy-2-(thiophen-3-yl)acetonitrile
将噻吩-3-甲醛(5.0g,44.64mmol)和碘化锌(1.4g,4.46mmol)溶于二氯甲烷(50mL)中，随后加入三甲基氰硅烷(4.5g,44.64mmol)，室温搅拌10小时。之后将反应液浓缩，柱层析得到目标产物(4.4g,收率71％)。Thiophene-3-carboxaldehyde (5.0 g, 44.64 mmol) and zinc iodide (1.4 g, 4.46 mmol) were dissolved in dichloromethane (50 mL), and trimethylsilyl cyanide (4.5 g, 44.64 mmol) was added and stirred at room temperature for 10 hours. The reaction solution was then concentrated and the target product (4.4 g, yield 71%) was obtained by column chromatography.
LC-MS[M+H]+:140.0.LC-MS [M+H] + : 140.0.
步骤b:2-氨基-1-(噻吩-3-基)乙-1-醇的合成
Step b: Synthesis of 2-amino-1-(thiophen-3-yl)ethan-1-ol
将2-羟基-2-(噻吩-3-基)乙腈(4.4g,31.23mmol)溶于四氢呋喃(50mL)中，随后加入硼烷二甲硫醚(15.6mL,156.15mmol)，反应液在70℃下搅拌1小时，反应结束后，甲醇(50mL)淬灭反应，浓缩得到目标产物(5.5g,粗品)。2-Hydroxy-2-(thiophen-3-yl)acetonitrile (4.4 g, 31.23 mmol) was dissolved in tetrahydrofuran (50 mL), and then borane dimethyl sulfide (15.6 mL, 156.15 mmol) was added. The reaction solution was stirred at 70 °C for 1 hour. After the reaction was completed, methanol (50 mL) was added to quench the reaction and the target product (5.5 g, crude product) was obtained by concentration.
LC-MS[M+H]+:144.1.LC-MS [M+H] + : 144.1.
步骤c:2-((4-羟基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚啉-1,3-二酮的合成
Step c: Synthesis of 2-((4-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione
将2-氨基-1-(噻吩-3-基)乙-1-醇(3.0g,20.84mmol)和2-(1,3-二氧代异吲哚啉-2-基)乙醛 (4.0g,20.84mmol)于二氯甲烷(100mL)中，随后加入三氟乙酸(11.98g,104.20mmol)，反应液在室温下搅拌10小时。反应结束后，三乙胺(20mL)淬灭反应，浓缩后经柱层析得到目标产物(4.0g,收率61％)。2-Amino-1-(thiophen-3-yl)ethan-1-ol (3.0 g, 20.84 mmol) and 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde were added. (4.0 g, 20.84 mmol) was dissolved in dichloromethane (100 mL), followed by the addition of trifluoroacetic acid (11.98 g, 104.20 mmol), and the reaction mixture was stirred at room temperature for 10 hours. After the reaction was completed, triethylamine (20 mL) was added to quench the reaction, and the target product (4.0 g, yield 61%) was obtained by column chromatography after concentration.
LC-MS[M+H]+:315.1.LC-MS [M+H] + : 315.1.
步骤d:7-((1,3-二氧代异吲哚啉-2-基)甲基)-4-羟基-4,7-二氢噻吩并[2,3-c]吡啶-6)5H)-羧酸叔丁酯的合成
Step d: Synthesis of tert-butyl 7-((1,3-dioxoisoindolin-2-yl)methyl)-4-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-6)5H)-carboxylate
将2-((4-羟基-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)异吲哚啉-1,3-二酮(2.0g,6.35mmol)和N,N-二异丙基乙胺(2.5g,19.05mmol)溶于乙醇(50mL)中，随后加入二碳酸二叔丁酯(2.1g,9.53mmol)，反应液在60℃下搅拌1小时，反应结束后，直接浓缩反应液，粗品经柱层析得到目标产物(2.1g,收率80％)。2-((4-Hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)isoindoline-1,3-dione (2.0 g, 6.35 mmol) and N,N-diisopropylethylamine (2.5 g, 19.05 mmol) were dissolved in ethanol (50 mL), and then di-tert-butyl dicarbonate (2.1 g, 9.53 mmol) was added. The reaction solution was stirred at 60 ° C for 1 hour. After the reaction was completed, the reaction solution was directly concentrated, and the crude product was purified by column chromatography to obtain the target product (2.1 g, yield 80%).
LC-MS[M+H]+:415.1.LC-MS [M+H] + : 415.1.
步骤e:7-((1,3-二氧代异吲哚啉-2-基)甲基)-4-氧代-4,7-二氢噻吩并[2,3-c]吡啶-6)5H)-羧酸叔丁酯的合成
Step e: Synthesis of tert-butyl 7-((1,3-dioxoisoindolin-2-yl)methyl)-4-oxo-4,7-dihydrothieno[2,3-c]pyridine-6)5H)-carboxylate
将7-((1,3-二氧代异吲哚啉-2-基)甲基)-4-羟基-4,7-二氢噻吩并[2,3-c]吡啶-6)5H)-羧酸叔丁酯(2.1g,5.06mmol)溶于1,2-二氯乙烷(50mL)中，随后加入二氧化锰(8.8g,101.21mmol)，反应液在45℃下搅拌2小时。反应结束后，直接过滤，收集滤液，将滤液浓缩得到目标化合物(1.6g,粗品)。Tert-butyl 7-((1,3-dioxoisoindolin-2-yl)methyl)-4-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-6)5H)-carboxylate (2.1 g, 5.06 mmol) was dissolved in 1,2-dichloroethane (50 mL), followed by the addition of manganese dioxide (8.8 g, 101.21 mmol), and the reaction solution was stirred at 45°C for 2 hours. After the reaction was completed, the reaction solution was directly filtered, the filtrate was collected, and the filtrate was concentrated to obtain the target compound (1.6 g, crude product).
LC-MS[M+H]+:413.1.LC-MS [M+H] + : 413.1.
步骤f:7-((1,3-二氧代异吲哚啉-2-基)甲基)-4,4-二氟-4,7-二氢噻吩并[2,3-c]吡啶-6)5H)-羧酸叔丁酯的合成
Step f: Synthesis of tert-butyl 7-((1,3-dioxoisoindolin-2-yl)methyl)-4,4-difluoro-4,7-dihydrothieno[2,3-c]pyridine-6)5H)-carboxylate
将7-((1,3-二氧代异吲哚啉-2-基)甲基)-4-氧代-4,7-二氢噻吩并[2,3-c]吡啶-6)5H)-羧酸叔丁酯(1.6g,3.88mmol)溶于二乙胺基三氟化硫(15mL)中，反应液在70℃下搅拌10小时。反应结束后，加入饱和碳酸氢钠水溶液(100mL)，水相用乙酸乙酯(150mL)萃取，有机相浓缩后得到的粗品经柱层析纯化得到目标产物(1.0g,收率60％)。 Tert-butyl 7-((1,3-dioxoisoindolin-2-yl)methyl)-4-oxo-4,7-dihydrothieno[2,3-c]pyridine-6)5H)-carboxylate (1.6 g, 3.88 mmol) was dissolved in diethylaminosulfur trifluoride (15 mL), and the reaction solution was stirred at 70°C for 10 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (100 mL) was added, the aqueous phase was extracted with ethyl acetate (150 mL), and the crude product obtained after the organic phase was concentrated was purified by column chromatography to obtain the target product (1.0 g, yield 60%).
LC-MS[M+H]+:435.1.LC-MS [M+H] + : 435.1.
步骤g:(4,4-二氟-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲胺的合成
Step g: Synthesis of (4,4-difluoro-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methanamine
将7-((1,3-二氧代异吲哚啉-2-基)甲基)-4,4-二氟-4,7-二氢噻吩并[2,3-c]吡啶-6)5H)-羧酸叔丁酯(1.0g,2.33mmol)溶于乙醇(10mL)中，随后加入水合肼(437mg,6.99mmol)，反应液在60℃下搅拌1小时后过滤，收集滤液，将滤液浓缩后溶于二氯甲烷(10mL)中，随后加入盐酸二氧六环溶液(20mL)，将反应液浓缩得到目标化合物(550mg,粗品)。Tert-butyl 7-((1,3-dioxoisoindolin-2-yl)methyl)-4,4-difluoro-4,7-dihydrothieno[2,3-c]pyridine-6)5H)-carboxylate (1.0 g, 2.33 mmol) was dissolved in ethanol (10 mL), followed by the addition of hydrazine hydrate (437 mg, 6.99 mmol). The reaction solution was stirred at 60°C for 1 hour and then filtered. The filtrate was collected and concentrated and dissolved in dichloromethane (10 mL). A dioxane hydrochloride solution (20 mL) was then added, and the reaction solution was concentrated to obtain the target compound (550 mg, crude product).
LC-MS[M+H]+:205.1.LC-MS [M+H] + : 205.1.
步骤h:((4,4-二氟-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸叔丁酯的合成
Step h: Synthesis of tert-butyl ((4,4-difluoro-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate
将(4,4-二氟-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲胺(550mg,2.68mmol)溶于四氢呋喃(10mL)中，随后加入二碳酸二叔丁酯(582mg g,2.68mmol)，反应液在40℃下搅拌1小时。之后将反应浓缩得到目标化合物(0.9g,粗品)。Dissolve (4,4-difluoro-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methanamine (550 mg, 2.68 mmol) in tetrahydrofuran (10 mL), then add di-tert-butyl dicarbonate (582 mg g, 2.68 mmol), and stir the reaction solution at 40°C for 1 hour. Then concentrate the reaction to obtain the target compound (0.9 g, crude product).
LC-MS[M+H]+:305.1.LC-MS [M+H] + : 305.1.
步骤i:((6-(2-溴乙酰基)-4,4-二氟-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸叔丁酯的合成
Step i: Synthesis of tert-butyl ((6-(2-bromoacetyl)-4,4-difluoro-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate
将((4,4-二氟-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸叔丁酯(0.9g,2.95mmol)和N,N-二异丙基乙胺(1.15g,8.85mmol)溶于四氢呋喃(10mL)中，随后加入溴乙酰氯(0.47g,2.95mmol)，加毕反应液在室温下搅拌1小时。反应结束后，直接浓缩反应液，得到的粗品经柱层析得到目标产物(0.6g,收率48％)。Tert-butyl ((4,4-difluoro-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate (0.9 g, 2.95 mmol) and N,N-diisopropylethylamine (1.15 g, 8.85 mmol) were dissolved in tetrahydrofuran (10 mL), and then bromoacetyl chloride (0.47 g, 2.95 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated, and the crude product was subjected to column chromatography to obtain the target product (0.6 g, yield 48%).
LC-MS[M+H]+:427.0.LC-MS [M+H] + : 427.0.
步骤j:1-(7-(氨基甲基)-4,4-二氟-4,7-二氢噻吩并[2,3-c]吡啶-6)5H)-基)-2-氯乙烷-1-酮的合成
Step j: Synthesis of 1-(7-(aminomethyl)-4,4-difluoro-4,7-dihydrothieno[2,3-c]pyridine-6)5H)-yl)-2-chloroethane-1-one
将((6-(2-溴乙酰基)-4,4-二氟-4,5,6,7-四氢噻吩并[2,3-c]吡啶-7-基)甲基)氨基甲酸叔丁酯的(0.6g,1.41mmol)溶于乙酸乙酯(5mL)中，随后加入盐酸二氧六环溶液(15mL)，反应液 在室温下搅拌1小时。反应结束后，浓缩反应液得到目标产物(0.6g,粗品)。Tert-butyl ((6-(2-bromoacetyl)-4,4-difluoro-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-7-yl)methyl)carbamate (0.6 g, 1.41 mmol) was dissolved in ethyl acetate (5 mL), and then a dioxane hydrochloride solution (15 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain the target product (0.6 g, crude product).
LC-MS[M+H]+:281.0.LC-MS [M+H] + : 281.0.
步骤k:4,4-二氟-4,5,8,9,10,10a-六氢-7H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7-酮的合成
Step k: Synthesis of 4,4-difluoro-4,5,8,9,10,10a-hexahydro-7H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-7-one
将1-(7-(氨基甲基)-4,4-二氟-4,7-二氢噻吩并[2,3-c]吡啶-6)5H)-基)-2-氯乙烷-1-酮(0.6g,2.14mmol)溶于乙腈(10mL)中，随后加入N,N-二异丙基乙胺(0.84g,6.42mmol)，反应液在80℃下搅拌1小时。反应结束后，将反应浓缩，得到的粗品经柱层析得到目标产物(0.3g,收率57％)。1-(7-(Aminomethyl)-4,4-difluoro-4,7-dihydrothieno[2,3-c]pyridine-6)5H)-yl)-2-chloroethane-1-one (0.6 g, 2.14 mmol) was dissolved in acetonitrile (10 mL), and then N,N-diisopropylethylamine (0.84 g, 6.42 mmol) was added, and the reaction solution was stirred at 80°C for 1 hour. After the reaction was completed, the reaction mixture was concentrated, and the crude product was subjected to column chromatography to obtain the target product (0.3 g, yield 57%).
LC-MS[M+H]+:245.0.LC-MS [M+H] + : 245.0.
步骤l:4,4-二氟-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯的合成
Step 1: Synthesis of tert-butyl 4,4-difluoro-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylate
将4,4-二氟-4,5,8,9,10,10a-六氢-7H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-7-酮(0.15g,0.62mmol)溶于四氢呋喃(5mL)中，随后加入硼烷四氢呋喃溶液(3.1mL,3.06mmol)，反应液在70℃下搅拌1小时。反应结束后，甲醇(5mL)淬灭反应，随后加入二碳酸二叔丁酯(202mg,0.93mmol)，室温下搅拌0.5小时。反应结束后，浓缩反应液，粗品经柱层析得到目标化合物(100mg,收率48％)。4,4-difluoro-4,5,8,9,10,10a-hexahydro-7H-thieno[2',3':3,4]pyrido[1,2-a]pyrazin-7-one (0.15 g, 0.62 mmol) was dissolved in tetrahydrofuran (5 mL), and then borane tetrahydrofuran solution (3.1 mL, 3.06 mmol) was added, and the reaction solution was stirred at 70 ° C for 1 hour. After the reaction was completed, methanol (5 mL) was quenched, and then di-tert-butyl dicarbonate (202 mg, 0.93 mmol) was added and stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was subjected to column chromatography to obtain the target compound (100 mg, yield 48%).
LC-MS[M+H]+:331.1.LC-MS [M+H] + : 331.1.
步骤m:4,4-二氟-4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐的合成
Step m: Synthesis of 4,4-difluoro-4,7,8,9,10,10a-hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine hydrochloride
将4,4-二氟-4,5,7,8,10,10a-六氢-9H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-9-羧酸叔丁酯(50mg,0.15mmol)溶于乙酸乙酯(0.5mL)中，随后加入盐酸二氧六环(3mL)，反应液在室温下搅拌1小时。反应结束后，浓缩反应液，加入纯水(2mL)，水相经乙酸乙酯(5mL)萃取后冻干得到目标化合物(12mg,收率35％)。4,4-difluoro-4,5,7,8,10,10a-hexahydro-9H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-9-carboxylic acid tert-butyl ester (50 mg, 0.15 mmol) was dissolved in ethyl acetate (0.5 mL), followed by addition of dioxane hydrochloride (3 mL), and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, pure water (2 mL) was added, and the aqueous phase was extracted with ethyl acetate (5 mL) and freeze-dried to obtain the target compound (12 mg, yield 35%).
LC-MS[M+H]+:231.1.LC-MS [M+H] + : 231.1.
1H NMR(400MHz,CD3OD)δ7.53(d,J＝5.2Hz,1H),7.23(d,J＝5.2Hz,1H),3.94-3.84(m,1H),3.83-3.76(m,1H),3.51-3.39(m,2H),3.29-2.25(m,1H),3.24-3.17(m,1H),3.14-2.99(m,2H),2.97-2.88(m,1H). 1 H NMR (400 MHz, CD 3 OD) δ7.53 (d, J=5.2 Hz, 1H), 7.23 (d, J=5.2 Hz, 1H), 3.94-3.84 (m, 1H), 3.83-3.76 (m, 1H), 3.51-3.39 (m, 2H), 3.29-2.25 (m, 1H), 3.24-3.17 (m, 1H), 3.14-2.99 (m, 2H), 2.97-2.88 (m, 1H).
19F NMR(376MHz,CD3OD):δ-84.6(d,J＝263.6Hz,1F),-102.0(d,J＝264.0Hz,1F). 19 F NMR (376 MHz, CD 3 OD): δ -84.6 (d, J = 263.6 Hz, 1F), -102.0 (d, J = 264.0 Hz, 1F).
实施例86 Embodiment 86
4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-2,3-d2
4,7,8,9,10,10a-Hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-2,3-d 2
化合物86的合成路线参考实施例83。The synthetic route of compound 86 can be found in Example 83.
LC-MS[M+H]+:197.1.LC-MS [M+H] + : 197.1.
实施例87Embodiment 87
4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-2,3,4,4,5,5-d6
4,7,8,9,10,10a-Hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-2,3,4,4,5,5-d 6
化合物87的合成路线参考实施例83。The synthetic route of compound 87 can be found in Example 83.
LC-MS[M+H]+:201.1.LC-MS [M+H] + : 201.1.
实施例88Embodiment 88
4,7,8,9,10,10a-六氢-5H-噻吩并[2',3':3,4]吡啶并[1,2-a]吡嗪-2,3,4,4,5,5,7,7,8,8-d10
4,7,8,9,10,10a-Hexahydro-5H-thieno[2',3':3,4]pyrido[1,2-a]pyrazine-2,3,4,4,5,5,7,7,8,8-d 10
化合物88的合成路线参考实施例83。The synthetic route of compound 88 can be found in Example 83.
LC-MS[M+H]+:205.1.LC-MS [M+H] + : 205.1.
实施例2-88的对映体合成路线具体如下表所示：

























The enantiomeric synthesis routes of Example 2-88 are specifically shown in the following table:

























生物学测试评价Biological test evaluation
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.
测试例1、TAAR1受体cAMP激动剂测试方法Test Example 1: TAAR1 receptor cAMP agonist test method
1.1细胞信息1.1 Cell Information
稳定表达TAAR1受体的HEK293细胞株(HEK293/TAAR1#C9)由上海枢境生物科技有限公司构建。The HEK293 cell line stably expressing the TAAR1 receptor (HEK293/TAAR1#C9) was constructed by Shanghai Shujing Biotechnology Co., Ltd.
1.2实验试剂耗材
1.2 Experimental reagents and consumables
1.3仪器设备
1.3 Instruments and Equipment
1.4实验步骤 1.4 Experimental procedures
(1)实验缓冲液配置：用ddH2O将5×stimulation buffer稀释成1×，并加入终浓度为0.5mM的IBMX，混匀备用。(1) Experimental buffer preparation: Dilute 5× stimulation buffer to 1× with ddH 2 O, add IBMX to a final concentration of 0.5 mM, mix well and set aside.
(2)化合物准备：待测化合物使用stimulation buffer稀释成2×备用。(2) Compound preparation: Dilute the test compound to 2× using stimulation buffer for later use.
(3)使用bravo稀释和转移化合物：4倍稀释，10个浓度。(3) Use bravo to dilute and transfer compounds: 4-fold dilution, 10 concentrations.
(4)复苏冻存的细胞，用9mL预热的HBSS重悬细胞沉淀，离心，再加入1mL stimulation buffer重悬，取20μL进行细胞计数。(4) To thaw frozen cells, resuspend the cell pellet in 9 mL of preheated HBSS, centrifuge, add 1 mL of stimulation buffer to resuspend, and take 20 μL for cell counting.
(5)取适量的细胞悬液稀释到3×106/mL，细胞板中每孔加入5μL的细胞悬液(15000个/孔)，1000rpm离心1分钟。(5) Take an appropriate amount of cell suspension and dilute it to 3×10 6 /mL. Add 5 μL of cell suspension to each well of the cell plate (15,000 cells/well) and centrifuge at 1000 rpm for 1 minute.
(6)然后使用bravo将稀释好的化合物转移5μL至384白板中，1000rpm离心1分钟，室温孵育45分钟。(6) Then use a bravo to transfer 5 μL of the diluted compound to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 45 minutes.
(7)加5μL的cAMP-d2溶液(原液按照1：20用裂解缓冲液稀释)到实验板中，1000rpm离心1分钟。(7) Add 5 μL of cAMP- d2 solution (the stock solution was diluted with lysis buffer at a ratio of 1:20) to the experimental plate and centrifuge at 1000 rpm for 1 minute.
(8)然后再加5μL的Anti-cAMP-Cryptate溶液(原液按照1：20用裂解缓冲液稀释)到实验板中，1000rpm离心1分钟。(8) Then add 5 μL of Anti-cAMP-Cryptate solution (the stock solution was diluted with lysis buffer at a ratio of 1:20) to the experimental plate and centrifuge at 1000 rpm for 1 minute.
(9)实验板置于室温孵育45分钟，读数前1000rpm离心1分钟。(9) The test plate was incubated at room temperature for 45 minutes and centrifuged at 1000 rpm for 1 minute before reading.
(10)使用Envision进行读板。激发光320nm，发射光620nm和665nm。(10) The plate was read using Envision, with excitation at 320 nm and emission at 620 nm and 665 nm.
1.5数据分析1.5 Data Analysis
激动剂测试中化合物激活率计算公式：The formula for calculating compound activation rate in agonist test is:
激活率(Activity％)＝100-(Readout-LC)/(HC-LC)*100Activation rate (Activity%) = 100-(Readout-LC)/(HC-LC)*100
Readout:化合物读值Readout: Compound reading
HC(High Control):DMSO+Forskolin孔的读数的平均值HC (High Control): Average of the readings from the DMSO+Forskolin wells
LC(Low Control):高浓度激动剂化合物+Forskolin孔的读数的平均值LC (Low Control): Average of the readings from the high concentration agonist compound + Forskolin wells
采用GraphPad Prism中四参数拟合模型log(agonist)vs.response--Variable slope(four parameters)计算出化合物的EC50值。The EC50 values of the compounds were calculated using the four-parameter fitting model log(agonist) vs. response--Variable slope (four parameters) in GraphPad Prism.
1.6实验结果：1.6 Experimental results:
通过以上方案得出本发明的化合物在对TAAR1受体激动活性测试中的具体结果如表1所示。The specific results of the compounds of the present invention in the test of TAAR1 receptor agonist activity obtained through the above scheme are shown in Table 1.
表1本发明化合物对TAAR1受体的激动活性结果

Table 1 Results of the agonist activity of the compounds of the present invention on TAAR1 receptor

1.7实验结论：1.7 Experimental conclusion:
体外实验结果表明本发明的化合物对TAAR1受体具有良好的激动作用。The results of in vitro experiments show that the compounds of the present invention have a good agonist effect on TAAR1 receptor.
测试例2、本发明化合物的小鼠药代动力学测试Test Example 2: Pharmacokinetics of the Compounds of the Invention in Mice
2.1试验目的：2.1 Test Purpose:
对雄性ICR小鼠进行口服灌胃和静脉给药，测定本发明化合物在小鼠中的血药浓度，计算PK参数，对本发明化合物进行药代动力学评价。The male ICR mice were given oral gavage and intravenous administration, the blood concentration of the compound of the present invention in the mice was measured, the PK parameters were calculated, and the pharmacokinetic evaluation of the compound of the present invention was performed.
2.2试验材料：2.2 Test materials:
(1)试验样品：本发明实施例化合物，自制。(1) Test sample: Compounds of the present invention, prepared in-house.
(2)试验动物：ICR小鼠，SPF级，雄性，上海灵畅生物科技有限公司。(2) Experimental animals: ICR mice, SPF grade, male, obtained from Shanghai Lingchang Biotechnology Co., Ltd.
(3)主要试验仪器：

(3) Main test instruments:

2.3试验方案：2.3 Experimental plan:
(1)给药信息：(1) Dosage information:
药品配制：根据称量药物的重量，计算配制体积，先加入5％的DMSO，待药物充分溶解后，再加入95％的20％β-环糊精水溶液，充分混匀备用。Drug preparation: Calculate the preparation volume based on the weight of the drug, first add 5% DMSO, and after the drug is fully dissolved, add 95% of 20% β-cyclodextrin aqueous solution, mix thoroughly and set aside.
给药途径：经口灌胃和静脉注射给药，静脉注射给药剂量为2mg/kg，口服给药剂量为10mg/kg。Administration route: oral gavage and intravenous injection, the intravenous injection dose is 2 mg/kg, and the oral dose is 10 mg/kg.
给药频率及期限：单次给药。Frequency and duration of administration: Single administration.
(2)试验方法：(2) Test method:
将ICR小鼠按体重分层后随机分成两组，每组9只小鼠，试验前过夜禁食。两组分别尾静脉注射及经口灌胃给药，采用交叉采血的方式静脉给药组在0、0.083、0.25、0.5、1、2、4、6、8、12和24小时，经口灌胃给药组在0、0.167、0.333、0.5、1、2、4、6、8、12和24小时，于小鼠眼底静脉取血50μL至含有抗凝剂肝素钠的样品管并置于湿冰中，4000r·min-1离心10min，分离血浆，冷冻保存在-80℃冰箱中待测。ICR mice were randomly divided into two groups according to body weight, with 9 mice in each group, and fasted overnight before the experiment. The two groups were injected with tail vein and administered by oral gavage, respectively. Blood was collected by cross sampling at 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours for the intravenous administration group and 0, 0.167, 0.333, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours for the oral gavage administration group. 50 μL of blood was collected from the fundus vein of the mice into a sample tube containing the anticoagulant heparin sodium and placed in wet ice, centrifuged at 4000 r·min -1 for 10 minutes, and the plasma was separated and frozen and stored in a -80℃ refrigerator for testing.
2.4试验结果与分析：2.4 Test results and analysis:
采用高效液相色谱-串联质谱(LC-MS/MS)测定血浆样品的浓度。化合物和内标的保留时间、色谱采集和色谱的积分采用软件Analyst(AB SCIEX)进行处理，数据的统计采用软件Microsoft office进行处理。采用WinNonlinTM Version 6.3(Pharsight,Mountain View,CA)药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数。具体结果如表2所示。High performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the concentration of plasma samples. The retention time of the compound and the internal standard, the chromatographic acquisition and the integration of the chromatogram were processed using the software Analyst (AB SCIEX), and the statistics of the data were processed using the software Microsoft office. The non-compartmental model of WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process the plasma concentration, and the pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method. The specific results are shown in Table 2.
表2本发明化合物小鼠药代实验结果
Table 2 Results of pharmacokinetic experiments on the compounds of the present invention in mice
2.5试验结论：2.5 Test conclusion:
从表中小鼠药代实验结果可以看出，本发明化合物表现出良好的药物代谢性质，具有优良的半衰期t1/2和快速的达峰时间Tmax，且最大血药浓度Cmax、药时曲线下面积AUC(0-t)和口服生物利用度F等代谢参数均表现良好。口服生物利用度良好的化合物在减少用药剂量、减轻副作用以及提高药物的药效等方面都具有重要的意义。 From the results of the mouse pharmacokinetic experiment in the table, it can be seen that the compounds of the present invention exhibit good drug metabolism properties, have excellent half-life t 1/2 and fast peak time T max , and the maximum blood drug concentration C max , the area under the concentration-time curve AUC (0-t) and the oral bioavailability F and other metabolic parameters all show good performance. Compounds with good oral bioavailability are of great significance in reducing the dosage of drugs, reducing side effects and improving the efficacy of drugs.

Claims (15)

  1. 一种通式(I)所示的化合物、其立体异构体或其药学上可接受的盐：
    A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof:
    其中：in:
    环A为芳基或杂芳基；Ring A is an aryl group or a heteroaryl group;
    Ra为氢、氘、卤素、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基、烷胺基、环烷基、杂环基、芳基、杂芳基或-(CH2)n1C(O)NRARB； Ra is hydrogen, deuterium, halogen, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl or -( CH2 ) n1C (O) NRARB ;
    或者，任意两个Ra与其连接的环原子链接形成环烷基或杂环基；Alternatively, any two R a are linked to the ring atoms to form a cycloalkyl or heterocyclyl group;
    RA和RB各自独立地为氢、氘、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基、烷胺基、环烷基、杂环基、芳基或杂芳基； RA and RB are each independently hydrogen, deuterium, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl;
    Rb和Rc各自独立地为氢、氘、卤素、羟基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基、烷胺基、环烷基、杂环基、芳基、杂芳基、-(CH2)n2C(O)NRCRD或-(CH2)n2RE；R b and R c are each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n 2 C(O)NR C R D or -(CH 2 ) n 2 R E ;
    或者，任意两个Rb与其连接的环原子链接形成环烷基或杂环基；Alternatively, any two R b are linked to the ring atoms to which they are attached to form a cycloalkyl or heterocyclyl group;
    或者，任意两个Rc与其连接的环原子链接形成环烷基或杂环基；Alternatively, any two R c are linked to the ring atoms to which they are attached to form a cycloalkyl or heterocyclyl group;
    RC、RD和RE各自独立地为氢、氘、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基、烷胺基、环烷基、杂环基、芳基或杂芳基；R C , R D and RE are each independently hydrogen, deuterium, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl;
    R1为氢、氘、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基或烷胺基； R1 is hydrogen, deuterium, hydroxyl, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino;
    x为0-5的整数；x is an integer from 0 to 5;
    y为0-5的整数；y is an integer from 0 to 5;
    z为0-5的整数；z is an integer from 0 to 5;
    m为0-3的整数；m is an integer from 0 to 3;
    n为0-3的整数；n is an integer from 0 to 3;
    n1为0-3的整数；且n1 is an integer from 0 to 3; and
    n2为0-3的整数。n2 is an integer from 0 to 3.
  2. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，其中：The compound represented by general formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that:
    环A为芳基或杂芳基；Ring A is an aryl group or a heteroaryl group;
    Ra为氢、氘、卤素、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基、烷胺基或-(CH2)n1C(O)NRARB； Ra is hydrogen, deuterium, halogen, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, alkylamino or - ( CH2 ) n1C (O) NRARB ;
    或者，任意两个Ra与其连接的环原子链接形成环烷基或杂环基；Alternatively, any two R a are linked to the ring atoms to form a cycloalkyl or heterocyclyl group;
    RA和RB各自独立地为氢、氘、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基或烷胺基； RA and RB are each independently hydrogen, deuterium, hydroxy, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino;
    Rb和Rc各自独立地为氢、氘、卤素、羟基、氰基、氨基、氧代基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基或烷胺基；R b and R c are each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino;
    R1为氢、氘、羟基、氰基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、烷硫基或烷胺基； R1 is hydrogen, deuterium, hydroxyl, cyano, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino;
    x为0-5的整数；x is an integer from 0 to 5;
    y为0-5的整数；y is an integer from 0 to 5;
    z为0-5的整数；z is an integer from 0 to 5;
    m为0-3的整数；m is an integer from 0 to 3;
    n为0-3的整数；且n is an integer from 0 to 3; and
    n1为0-3的整数。n1 is an integer from 0 to 3.
  3. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，其满足如下条件中的一种或多种：The compound represented by the general formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:
    (1)环A为C6-14芳基或5-14元杂芳基，优选C6-10芳基、5-6元杂芳基、5-6元杂芳基并5-6元杂芳基、5-6元杂芳基并C6-10芳基或C6-10芳基并5-6元杂芳基，更优选为苯基、萘基、5-6元杂芳基、5-6元杂芳基并5-6元杂芳基、5-6元杂芳基并苯基或苯基并5-6元杂芳基，进一步优选如下基团：

    (1) Ring A is C 6-14 aryl or 5-14 membered heteroaryl, preferably C 6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and C 6-10 aryl, or C 6-10 aryl and 5-6 membered heteroaryl, more preferably phenyl, naphthyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and phenyl, or phenyl and 5-6 membered heteroaryl, and further preferably the following groups:

    (2)Ra为氢、氘、卤素、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基或-(CH2)n1C(O)NRARB，优选氢、氘、卤素或C1-6烷基，更优选氢、氘、卤素或C1-3烷基，进一步优选氢、氘、氟、氯、溴或甲基；(2) Ra is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, or -( CH2 ) n1C (O) NRARB , preferably hydrogen , deuterium, halogen, or C1-6 alkyl, more preferably hydrogen, deuterium, halogen, or C1-3 alkyl, further preferably hydrogen, deuterium, fluorine, chlorine, bromine, or methyl;
    或者，任意两个Ra与其连接的环原子链接形成C3-8环烷基或3-8元杂环基，优选C3-6环烷基或3-6元杂环基，更优选C3-5环烷基或3-5元杂环基，进一步优选环丙基、环丁基、环戊基、氧杂环丁基、氧杂环戊基、氮杂环丁基或氮杂环戊基；Alternatively, any two R a are linked to the ring atoms to form a C 3-8 cycloalkyl or a 3-8 membered heterocyclyl, preferably a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, more preferably a C 3-5 cycloalkyl or a 3-5 membered heterocyclyl, further preferably a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxacyclopentyl, azetidinyl or azacyclopentyl;
    (3)RA和RB各自独立地为氢、氘、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，优选氢、C1-6烷基或C3-8环烷基，更优选氢、C1-3烷基或C3-6环烷基，进一步优选氢、甲基或环丙基；(3) RA and RB are each independently hydrogen, deuterium, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, preferably hydrogen , C1-6 alkyl or C3-8 cycloalkyl, more preferably hydrogen, C1-3 alkyl or C3-6 cycloalkyl, further preferably hydrogen, methyl or cyclopropyl;
    (4)Rb为氢、氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n2C(O)NRCRD或-(CH2)n2RE，优选氢、氘、卤素、氧代基、C1-6烷基或C3-8环烷基，更优选氢、氘、卤素、氧代基、C1-3烷基或C3-6环烷基，进一步优选氢、氘、氟、氯、溴、氧代基、甲基或环丙基；(4) R b is hydrogen, deuterium, halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)NR C R D or -(CH 2 ) n2 R E , preferably hydrogen, deuterium, halogen, oxo, C 1-6 alkyl or C 3-8 cycloalkyl, more preferably hydrogen, deuterium, halogen, oxo, C 1-3 alkyl or C 3-6 cycloalkyl, further preferably hydrogen, deuterium, fluorine, chlorine, bromine, oxo, methyl or cyclopropyl;
    或者，任意两个Rb与其连接的环原子链接形成C3-8环烷基或3-8元杂环基，优选C3-6环烷基或3-6元杂环基，更优选C3-5环烷基或3-5元杂环基，进一步优选环丙基、环丁基、环戊基、氧杂环丁基、氧杂环戊基、氮杂环丁基或氮杂环戊基；Alternatively, any two R b are linked to the ring atoms to which they are connected to form a C 3-8 cycloalkyl or a 3-8 membered heterocyclyl, preferably a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, more preferably a C 3-5 cycloalkyl or a 3-5 membered heterocyclyl, further preferably a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxacyclopentyl, azetidinyl or azoxyl;
    (5)Rc为氢、氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n2C(O)NRCRD或-(CH2)n2RE，优选氢、氘、卤素、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n2C(O)NRCRD或-(CH2)n2RE，更优选氢、氘、卤素、氧代基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C3-6环烷基、3-6元杂环基、苯基、5-6元杂芳基、-C(O)NRCRD或-(CH2)RE，进一步优选氢、氘、氟、氯、溴、氧代基、甲基、乙基、二氟甲基、三氟甲基、三氟乙基、环丙基、苯基、噻唑基、异噁唑基、噁二唑基、-CD3、-C(O)NHCH3、-C(O)NHCH2CF3或 (5) R c is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)NR C R D or -(CH 2 ) n2 R E , preferably hydrogen, deuterium, halogen, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)NR C R D or -(CH 2 ) n2 R E , more preferably hydrogen, deuterium, halogen, oxo, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -C(O)NR C R D or -(CH 2 ) R E , further preferably hydrogen, deuterium, fluorine, chlorine, bromine, oxo, methyl, ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, phenyl, thiazolyl, isoxazolyl, oxadiazolyl, -CD 3 , -C(O)NHCH 3 , -C(O)NHCH 2 CF 3 or
    或者，任意两个Rc与其连接的环原子链接形成C3-8环烷基或3-8元杂环基，优选C3-6环烷基或3-6元杂环基，更优选C3-5环烷基或3-5元杂环基，进一步优选环丙基、环丁基、环戊基、氧杂环丁基、氧杂环戊基、氮杂环丁基或氮杂环戊基；Alternatively, any two R c are linked to the ring atoms to which they are connected to form a C 3-8 cycloalkyl or a 3-8 membered heterocyclyl, preferably a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, more preferably a C 3-5 cycloalkyl or a 3-5 membered heterocyclyl, further preferably a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxacyclopentyl, azetidinyl or azoxyl;
    (6)RC、RD和RE各自独立地为氢、氘、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷 基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，优选氢、C1-6烷基、C1-6卤代烷基或C3-8环烷基，更优选氢、C1-3烷基、C1-3卤代烷基或C3-6环烷基，进一步优选氢、甲基、三氟甲基、三氟乙基或环丙基；(6) RC , RD and RE are each independently hydrogen, deuterium, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkane alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl, more preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl, further preferably hydrogen, methyl, trifluoromethyl, trifluoroethyl or cyclopropyl;
    (7)R1为氢、氘、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基或C1-6烷胺基，优选氢或C1-6烷基，更优选氢或C1-3烷基，进一步优选氢或甲基；(7) R1 is hydrogen, deuterium, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio or C1-6 alkylamino, preferably hydrogen or C1-6 alkyl , more preferably hydrogen or C1-3 alkyl, further preferably hydrogen or methyl;
    (8)x为0-4的整数，优选0、1或2；(8) x is an integer from 0 to 4, preferably 0, 1 or 2;
    (9)y为0-4的整数，优选0、1或2；(9) y is an integer from 0 to 4, preferably 0, 1 or 2;
    (10)z为0-4的整数，优选0、1或2；(10) z is an integer from 0 to 4, preferably 0, 1 or 2;
    (11)m为0-2的整数，优选0或1；(11) m is an integer from 0 to 2, preferably 0 or 1;
    (12)n为0-2的整数，优选1或2；(12) n is an integer from 0 to 2, preferably 1 or 2;
    (13)n1为0-2的整数，优选0或1；(13) n1 is an integer from 0 to 2, preferably 0 or 1;
    (14)n2为0-2的整数，优选0或1；(14) n2 is an integer from 0 to 2, preferably 0 or 1;
    (15)通式(I)所示的化合物选自：
    或其混合物。    (15) The compound represented by the general formula (I) is selected from:
    or a mixture thereof.
  4. 根据权利要求1-3中任意一项所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，通式(I)进一步如通式(II)所示：
    The compound represented by the general formula (I) according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the general formula (I) is further represented by the general formula (II):
    其中：in:
    R2和R3各自独立地为氢、氘、卤素、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基或-(CH2)n1C(O)NRARB，优选氢、氘、卤素或C1-6烷基，更优选氢、氘、卤素或C1-3烷基，进一步优选氢、氘、氟、氯或甲基； R2 and R3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino or -( CH2 ) n1C (O) NRARB , preferably hydrogen, deuterium, halogen or C1-6 alkyl, more preferably hydrogen, deuterium, halogen or C1-3 alkyl, further preferably hydrogen, deuterium, fluorine, chlorine or methyl;
    或者，R2和R3与其连接的碳原子链接形成苯基或5-6元杂芳基，优选苯基或吡啶基；Alternatively, R 2 and R 3 are linked to the carbon atom to which they are attached to form a phenyl group or a 5-6 membered heteroaryl group, preferably a phenyl group or a pyridyl group;
    RA、RB、R1、Rb、Rc、y、z、m、n和n1如前述权利要求所述。 RA , RB , R1 , Rb , Rc , y, z, m, n and n1 are as described in the preceding claims.
  5. 根据权利要求1-3中任意一项所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，通式(I)进一步如通式(III)所示：
    The compound represented by the general formula (I) according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the general formula (I) is further represented by the general formula (III):
    其中：in:
    R2和R3各自独立地为氢、氘、卤素、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基或-(CH2)n1C(O)NRARB，优选氢、氘、卤素或C1-6烷基，更优选氢、氘、卤素或C1-3烷基，进一步优选氢、氘、氟、氯或甲基； R2 and R3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-8 cycloalkyl , 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl or -( CH2 ) n1C (O) NRARB , preferably hydrogen, deuterium, halogen or C1-6 alkyl, more preferably hydrogen, deuterium, halogen or C1-3 alkyl, further preferably hydrogen, deuterium, fluorine, chlorine or methyl;
    或者，R2和R3与其连接的碳原子链接形成苯基或5-6元杂芳基，优选苯基或吡啶基；Alternatively, R 2 and R 3 are linked to the carbon atom to which they are attached to form a phenyl group or a 5-6 membered heteroaryl group, preferably a phenyl group or a pyridyl group;
    R4a、R4b、R5a、R5b、R6a、R6b和R7各自独立地为氢、氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n2C(O)NRCRD或-(CH2)n2RE，优选氢、氘、卤素、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n2C(O)NRCRD或-(CH2)n2RE，更优选氢、氘、卤素、氧代基、C1-3烷基、C1-3卤代烷基、C1-3氘代烷基、C3-6环烷基、3-6元杂环基、苯基、5-6元杂芳基、-C(O)NRCRD或-(CH2)RE，进一步优选氢、氘、氟、氯、溴、氧代基、甲基、乙基、二氟甲基、三氟甲基、三氟乙基、环丙基、苯基、噻唑基、异噁唑基、噁二唑基、-CD3、-C(O)NHCH3、-C(O)NHCH2CF3或 R 4a , R 4b , R 5a , R 5b , R 6a , R 6b and R 7 are each independently hydrogen, deuterium, halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)NR C R D or -(CH 2 ) n2 R E , preferably hydrogen, deuterium, halogen, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 membered aryl, 5-10 membered heteroaryl, -(CH 2 ) n2 C(O)NR C R D or -(CH 2 ) n2 R E , more preferably hydrogen, deuterium, halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuterated alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -C(O)NR C R D or -(CH 2 ) R E , further preferably hydrogen, deuterium, fluorine, chlorine, bromine, oxo, methyl, ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, phenyl, thiazolyl, isoxazolyl, oxadiazolyl, -CD 3 , -C(O)NHCH 3 , -C(O)NHCH 2 CF 3 or
    或者，R4a和R4b，R4a和R5a或R6a和R7与其连接的环原子链接形成C3-8环烷基或3-8元杂环基，优选C3-6环烷基或3-6元杂环基，更优选C3-5环烷基或3-5元杂环基，进一步优选环丙基、环丁基、环戊基、氧杂环丁基、氧杂环戊基、氮杂环丁基或氮杂环戊基；Alternatively, R 4a and R 4b , R 4a and R 5a or R 6a and R 7 are linked to the ring atom to which they are connected to form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclyl group, preferably a C 3-6 cycloalkyl group or a 3-6 membered heterocyclyl group, more preferably a C 3-5 cycloalkyl group or a 3-5 membered heterocyclyl group, further preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an oxetanyl group, an oxacyclopentyl group, an azetidinyl group or an azoxycyclopentyl group;
    RC、RD和RE各自独立地为氢、氘、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，优选氢、C1-6烷基、C1-6卤代烷基或C3-8环烷基，更优选氢、C1-3烷基、C1-3卤代烷基或C3-6环烷基，进一步优选氢、甲基、三氟甲基、三氟乙基或环丙基；R C , R D and R E are each independently hydrogen, deuterium, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl, more preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl, further preferably hydrogen , methyl, trifluoromethyl, trifluoroethyl or cyclopropyl;
    RA、RB、R1、Rb、y、m、n1和n2如前述权利要求所述。 RA , RB , R1 , Rb , y, m, n1 and n2 are as described in the preceding claims.
  6. 根据权利要求1-5中任一项所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述的通式(I)所示的化合物选自如下所示具体化合物：






    The compound represented by the general formula (I) according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound represented by the general formula (I) is selected from the specific compounds shown below:






  7. 根据权利要求1-6中任一项所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述盐为盐酸盐。 The compound represented by the general formula (I) according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the salt is a hydrochloride.
  8. 根据权利要求7所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述盐酸盐为晶型，优选为4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐晶型A，其X-射线粉末衍射图谱基本如图1所示；(S)-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐晶型A，其X-射线粉末衍射图谱基本如图2所示；(R)-4,7,8,9,10,10a-六氢-5H-噻吩[2',3':3,4]吡啶并[1,2-a]吡嗪盐酸盐晶型A，其X-射线粉末衍射图谱基本如图3所示。The compound represented by the general formula (I) according to claim 7, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that the hydrochloride is a crystalline form, preferably 4,7,8,9,10,10a-hexahydro-5H-thiophene [2',3':3,4]pyrido [1,2-a]pyrazine hydrochloride crystalline form A, whose X-ray powder diffraction pattern is substantially as shown in Figure 1; (S)-4,7,8,9,10,10a-hexahydro-5H-thiophene [2',3':3,4]pyrido [1,2-a]pyrazine hydrochloride crystalline form A, whose X-ray powder diffraction pattern is substantially as shown in Figure 2; (R)-4,7,8,9,10,10a-hexahydro-5H-thiophene [2',3':3,4]pyrido [1,2-a]pyrazine hydrochloride crystalline form A, whose X-ray powder diffraction pattern is substantially as shown in Figure 3.
  9. 一种通式(I-1)所示的化合物、其立体异构体或其盐：
    A compound represented by general formula (I-1), a stereoisomer thereof or a salt thereof:
    其中，环A、R1、Ra、RA、RB、Rb、Rc、x、y、z、m、n和n1如权利要求1-8中任一项所述。wherein ring A, R1 , Ra , RA, RB , Rb , Rc , x , y, z, m, n and n1 are as described in any one of claims 1-8.
  10. 一种通式(I-2)所示的化合物、其立体异构体或其盐：
    A compound represented by general formula (I-2), a stereoisomer thereof or a salt thereof:
    其中，环A、R1、Ra、RA、RB、Rb、Rc、x、y、z、m、n和n1如权利要求1-8中任一项所述。wherein ring A, R1 , Ra , RA, RB , Rb , Rc , x , y, z, m, n and n1 are as described in any one of claims 1-8.
  11. 一种通式(I)所示的化合物、其立体异构体或其药学上可接受的盐的制备方法，其特征在于，包括以下步骤：溶剂中，通式(I-1)所示的化合物、其立体异构体或其盐在还原反应试剂的存在下进行羰基还原为亚甲基反应，即得通式(I)所示的化合物、其立体异构体或其药学上可接受的盐；
    A method for preparing a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps: in a solvent, the compound represented by general formula (I-1), a stereoisomer thereof or a salt thereof is subjected to a carbonyl reduction reaction to a methylene group in the presence of a reducing reaction reagent to obtain the compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
    其中，环A、R1、Ra、RA、RB、Rb、Rc、x、y、z、m、n和n1如权利要求1-9中任一项所述。wherein ring A, R1 , Ra , RA, RB , Rb , Rc , x , y, z, m, n and n1 are as described in any one of claims 1-9.
  12. 一种通式(I)所示的化合物、其立体异构体或其药学上可接受的盐的制备方法，其特征在于，包括以下步骤：溶剂中，通式(I-2)所示化合物、其立体异构体或其盐经还原反应和胺保护反应得到通式(I-3)所示化合物、其立体异构体或其盐，经脱保护，即得通式(I)所示的化合物、其立体异构体或其药学上可接受的盐；
    A method for preparing a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps: in a solvent, the compound represented by general formula (I-2), a stereoisomer thereof or a salt thereof is subjected to reduction reaction and amine protection reaction to obtain a compound represented by general formula (I-3), a stereoisomer thereof or a salt thereof, and then deprotected to obtain a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
    其中，PG为胺保护基，优选选自三氟乙酰基、苄氧羰基、烯丙氧羰基、对甲氧基苄基、2,4-二甲氧基苄基、苄基、邻苯二甲酰基、硝基苯磺酰基、对甲苯磺酰基、三苯甲基、叔丁氧羰基、笏甲氧羰基、(三甲基硅)乙氧基甲基、四氢吡喃基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、乙酰基或烯丙基，优选叔丁氧羰基；wherein PG is an amine protecting group, preferably selected from trifluoroacetyl, benzyloxycarbonyl, allyloxycarbonyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, phthaloyl, nitrobenzenesulfonyl, p-toluenesulfonyl, trityl, tert-butoxycarbonyl, methoxycarbonyl, (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl or allyl, preferably tert-butoxycarbonyl;
    环A、R1、Ra、RA、RB、Rb、Rc、x、y、z、m、n和n1如权利要求1-8或10中任一项所述。Ring A, R1 , Ra , RA, RB , Rb , Rc , x , y, z, m, n and n1 are as described in any one of claims 1 to 8 or 10.
  13. 一种药物组合物，其包含治疗有效剂量的权利要求1-8中任一项所示的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。A pharmaceutical composition comprising a therapeutically effective dose of the compound as claimed in any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
  14. 根据权利要求1-8中任一项所示的化合物、其立体异构体或其药学上可接受的盐，或权利要求13所述的药物组合物在制备药物中的用途，所述的药物可为预防和/或治疗哺乳动物神经精神类疾病的药物；所述神经精神类疾病优选为痕量胺相关受体和/或5-羟色胺受体和/或多巴胺受体相关的中枢神经系统疾病。Use of the compound according to any one of claims 1 to 8, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in the preparation of a drug, wherein the drug may be a drug for preventing and/or treating neuropsychiatric diseases in mammals; the neuropsychiatric diseases are preferably central nervous system diseases related to trace amine-related receptors and/or 5-hydroxytryptamine receptors and/or dopamine receptors.
  15. 根据权利要求14所述的用途，其特征在于，所述神经精神类疾病为精神分裂症、精神分裂症谱群疾病、急性精神分裂症、慢性精神分裂症、NOS精神分裂症、精神分裂样人格障碍、分裂型人格障碍、妄想性精神障碍、精神病、精神障碍、短时精神障碍、分享性精神障碍、躯体疾病所致精神障碍、药物诱发精神病、心理情感障碍、侵犯性、精神错 乱、帕金森精神病、刺激性精神病、图雷特综合症、器官或NOS精神病、癫痫、精神激动、创伤后精神紧张性障碍、行为错乱、神经变性疾病、阿尔茨海默氏病、帕金森氏病、运动障碍、亨廷顿病、痴呆、情感障碍、焦虑症、情感性精神病、抑郁症、严重抑郁性障碍、情绪不良、双相性精神障碍、躁狂症、季节性情感性精神病、注意力缺陷障碍、注意力不足过动症、强迫性神经失调、眩晕、癫痫、疼痛、神经性疼痛、神经性疼痛易感状态、炎性疼痛、纤维肌痛、偏头痛、认知损伤、运动障碍、下肢不宁综合症、多发性硬化症、睡眠障碍、睡眠呼吸暂停、嗜眠发作、白天睡眠过多、时差反应、药物的嗜睡副作用、失眠、物质滥用依赖性、成瘾、进食障碍、性功能障碍、高血压、呕吐、Lesche-Nyhane病、Wilson病、自闭症、亨廷顿舞蹈病和经前焦虑中的一种或多种。 The use according to claim 14, characterized in that the neuropsychiatric disease is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizophreniform personality disorder, schizotypal personality disorder, delusional mental disorder, psychosis, mental disorder, short-term mental disorder, shared mental disorder, mental disorder caused by physical disease, drug-induced psychosis, psychological affective disorder, aggression, mental disorder one or more of: dysphoria, Parkinson's disease, irritation disorder, Tourette's syndrome, organic or NOS psychosis, epilepsy, agitation, post-traumatic stress disorder, behavioral disturbances, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, movement disorders, Huntington's disease, dementia, affective disorders, anxiety disorders, affective disorders, depression, major depressive disorder, dysthymia, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive compulsive disorder, vertigo, epilepsy, pain, neuropathic pain, neuropathic pain-prone states, inflammatory pain, fibromyalgia, migraine, cognitive impairment, movement disorders, restless leg syndrome, multiple sclerosis, sleep disorders, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, somnolence side effects of medications, insomnia, substance abuse dependence, addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's disease, and premenstrual dysphoria.
PCT/CN2023/137329 2022-12-09 2023-12-08 Fused ring derivative, preparation method therefor, intermediates thereof, and use thereof WO2024120505A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202211578260.8 2022-12-09
CN202211578260 2022-12-09
CN202310240980.1 2023-03-14
CN202310240980 2023-03-14
CN202311605281.9 2023-11-28
CN202311605281 2023-11-28

Publications (1)

Publication Number Publication Date
WO2024120505A1 true WO2024120505A1 (en) 2024-06-13

Family

ID=91378617

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/137329 WO2024120505A1 (en) 2022-12-09 2023-12-08 Fused ring derivative, preparation method therefor, intermediates thereof, and use thereof

Country Status (1)

Country Link
WO (1) WO2024120505A1 (en)

Similar Documents

Publication Publication Date Title
TWI768557B (en) 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as hdac inhibitors
WO2021088945A1 (en) Compound as shp2 inhibitor and use thereof
TW201643139A (en) 3-spirocyclic-6-hydroxamic acid tetralins as HDAC inhibitors
WO2023001123A1 (en) New pyridopyrimidine derivative
CN112979655A (en) Triazolopyridazine derivative, preparation method, pharmaceutical composition and application thereof
CN115433205A (en) Polycyclic derivative receptor agonist, preparation method and application thereof
CN111108101A (en) Novel propylamine derivatives useful for treating pain and pain-related disorders
WO2024120505A1 (en) Fused ring derivative, preparation method therefor, intermediates thereof, and use thereof
TWI836390B (en) Spirocyclic derivatives, their preparation methods and applications
CN109790160A (en) Pyrido 5-membered aromatic cyclics, preparation method and the usage
AU2003295171A1 (en) Benzoxazocines and their use as monoamine-reuptake inhibitors
WO2023125935A1 (en) Benzopyridine derivative regulator, and preparation method therefor and use thereof
ES2256506T3 (en) TRICYCLE AGONISTS OF THE CRF RECEIVER.
CN105712952B (en) 2-substituted oxy-5-methylsulfonyl phenyl piperazine amide analogue and preparation method and application thereof
CN113773251A (en) Anilines useful as ROR gamma modulators
CN113666863A (en) Biaryl compounds useful as ROR gamma modulators
JP2023528281A (en) 3-((1H-pyrazol-4-yl)methyl)-6′-(phenyl)-2H-(1,2′-bipyridine)-2 as a GPR139 antagonist for use eg in methods of treating depression -one derivatives and related compounds
CN112839931A (en) 1,2,3, 4-tetrahydroquinoxaline derivative and preparation method and application thereof
TWI820847B (en) Regulators containing tricyclic derivatives, preparation methods and applications thereof
WO2016171181A1 (en) 2-substituted fused pyrazole derivatives
WO2024067819A1 (en) Piperidine-containing polycyclic derivative modulator, preparation method therefor, and use thereof
WO2024088307A1 (en) Novel peptidyl nitrile compound and use thereof
WO2023197984A1 (en) Fused ring compound, pharmaceutical composition containing same, and use of fused ring compound
JP5873612B2 (en) Tricyclic derivatives and their pharmaceutical uses and compositions
CN115667236A (en) 1,5-dihydro-2,4-benzodiazepine-3-one derivative and use thereof