Spiro ring-containing derivatives, their preparation and use

Abstract

Spiro ring-containing derivatives, their preparation methods and uses are provided, in particular compounds of general formula (I), their preparation methods and pharmaceutical compositions containing said compounds, and their use in the preparation of medicaments for preventing and / or treating central nervous system disorders associated with 5-hydroxytryptamine receptors and / or trace amine associated receptors and / or dopamine receptors in mammals. JPEG2024511828000114.jpg4230

Description

[Technical field]

[0001] This application claims the priority of Chinese patent application No. 2021103384291, filed on March 29, 2021, the priority of Chinese patent application No. 2021111517346, filed on September 29, 2021, and the priority of Chinese patent application No. 2021114966347, filed on December 9, 2021. This application cites the above Chinese patent applications in full.

[0002] The present invention belongs to the field of medicinal chemistry, and in particular relates to spiro ring-containing derivatives, their preparation methods and uses. More specifically, the present invention relates to spiro ring-containing derivatives, their preparation methods, pharmaceutical compositions containing spiro ring-containing derivatives, and the use of spiro ring-containing derivatives or pharmaceutical compositions thereof in the preparation of medicaments for preventing and / or treating neuropsychiatric disorders in mammals. [Background technology]

[0003] Diseases related to the central nervous system affect many people to varying degrees. In general, the main features of such diseases include prominent impairments in cognition or memory, which show a significant decline compared to the original level of functioning. Schizophrenia is a psychopathological disorder of unknown etiology that usually first appears in early adulthood and is characterized by psychotic symptoms, gradual progression and development, and / or regression of social behavior and professional skills. Symptoms of schizophrenia are generally categorized into three categories: positive symptoms, negative symptoms, and cognitive symptoms. Positive symptoms are symptoms that represent an "excess" of normal experiences, such as hallucinations and delusions. Negative symptoms are symptoms in which the patient loses normal experiences, such as anhedonia and lack of social interaction. Cognitive symptoms are associated with the cognitive impairments of schizophrenia, such as lack of sustained attention and impaired decision-making. Current antipsychotic medications are successful in treating positive symptoms, but are still not ideal for negative and cognitive symptoms.

[0004] Biogenic amines play important roles 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. Imbalances in biogenic amine levels are known to be the main cause of altered brain function in many pathological conditions. Serotonin, norepinephrine, epinephrine, dopamine, and histamine have been widely studied as traditional biogenic amines. Among them, the 5-hydroxytryptamine system plays a key role in regulating the functions of the prefrontal cortex PFC, including emotion control, cognitive behavior, and working memory. PFC pyramidal neurons and GABA interneurons contain several highly dense 5-hydroxytryptamine receptor subtypes, 5-HT1A and 5-HT2A. PFC and NMDA receptor channels have recently been proven to be targets of 5-HT1AR, and these two receptors regulate excitatory neurons in the cerebral cortex, thereby affecting cognitive functions. Indeed, various preclinical data suggest that 5-HT1AR may be a new target for antipsychotic drug development. The high affinity of atypical antipsychotics (e.g., olanzapine, aripiprazole) for 5-HT1AR and low EPS side effects indicate that the 5-hydroxytryptamine system plays a key role in regulating PFC functions, including emotion regulation, cognitive behavior, and working memory. PFC pyramidal neurons and GABA interneurons contain several highly dense 5-hydroxytryptamine receptor subtypes, 5-HT1A and 5-HT2A. Recent studies have shown that 5-HT1A agonists are related to atypical antipsychotics and can improve negative symptoms and cognitive impairment.

[0005] In recent years, as research on traditional biogenic amines has gradually deepened, people have discovered a second class of endogenous amine compounds, namely trace amines TA, including p-tyramine, β-phenylethylamine, tryptamine, and octopamine. Although their content levels in the mammalian nervous system are generally lower than traditional biogenic amines, they all have similar characteristics to traditional biogenic amines in terms of structure, metabolism, and intracellular localization. As a new member of the GPCR family of G protein-coupled receptors, the trace amine-associated receptor TAAR has a similar structure to the deep GPCR pharmacophore, and the pharmacological data are also consistent. The phylogenetic development relationship of this receptor gene showed that these receptors form three different subfamilies, of which TAAR1 is the first subfamily of four genes (TAAR1-4) highly conserved between humans and rodents. TA activates TAAR1 through Gαs and plays a role. Existing studies clearly show that dysregulation of trace amine-associated receptors, especially TAAR1, is closely associated with many psychiatric disorders such as schizophrenia and depression, as well as conditions such as attention deficit hyperactivity disorder, migraine, Parkinson's disease, substance abuse, and eating disorders, so TAAR ligands have a high potential for use in treating these diseases.

[0006] Although there are many antischizophrenia drugs, the schizophrenia drugs used in clinical practice still have various side effects. In addition, although the current antischizophrenia negative symptom drugs have been clinically applied and the negative symptoms of some patients have been improved, the overall effect is limited, and there are still many patients who cannot recover or repair normal social functions due to negative symptoms, making it difficult to resume normal social activities. In addition, currently, the treatment of cognitive dysfunction is also an important point in the treatment of schizophrenia, which affects the verbal memory, language processing ability, and attention function of most schizophrenia patients, while the antischizophrenia drugs currently under investigation 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 kinds of antipsychotics with different active ingredients, but even if they receive a sufficient course of treatment with sufficient doses, they still do not respond well to treatment, cannot tolerate the side effects of antipsychotics, or the disease still recurs or worsens despite appropriate maintenance or preventive treatment. Therefore, anti-refractory schizophrenia treatment drugs have always been a difficult problem in current clinical drug research and are also a direction that must be overcome as soon as possible.

[0007] Sunovion's SEP-363856, currently in Phase III clinical research as a 5-hydroxytryptamine and / or trace amine-associated receptor agonist, has shown remarkable effects on 5-HT1A and TAAR1 receptors and has shown good activity in existing clinical studies. Therefore, it is urgent to develop a good and long-lasting effective treatment for negative symptoms, improve patients' cognitive function, and effectively treat refractory schizophrenia, and there is a need for a schizophrenia treatment with fewer side effects and multiple targets to meet the huge market demand. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide a spiro ring-containing derivative, its preparation method and use, which can be used as a new drug for neuropsychiatric disorders acting on 5-hydroxytryptamine receptors and / or trace amine-related receptors and / or dopamine receptors, and in particular has good agonistic effect on 5-HT1A receptors and / or TAAR1 receptors, and can effectively prevent and / or treat neuropsychiatric disorders in mammals.

[0009] The object of the present invention is to provide spiro ring-containing derivatives for preventing and / or treating neuropsychiatric disorders in mammals, their preparation methods, pharmaceutical compositions and their use in the medical field.

[0010] The present invention provides a compound represented by general formula (I), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof,

[0011] [ka]

[0012] During the ceremony, M1 and M2 each independently represent -(CR A R B ) n -, O or S; M3 is a CR a , N or S; M4 is a CR b , N or S; M5 is CR c , N or S; R A , R B , R a , R b , and R c are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6alkylamino, preferably hydrogen, halogen or C 1~6 alkyl, more preferably hydrogen, fluorine, chlorine, bromine or C 1~3 alkyl, more preferably selected from hydrogen, fluorine, chlorine, bromine or methyl; R1 and R2, together with the carbon atom to which they are attached, form 3~8 Forms a cycloalkyl group or a 3- to 8-membered heterocyclic group, preferably C 3~6 Forms a cycloalkyl group or a 3- to 6-membered heterocyclic group, more preferably C 3~4 forming a cycloalkyl group or a 3- to 4-membered heterocyclic group, more preferably forming a cyclopropyl, cyclobutyl or oxetanyl group; R3 and R4 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl or C 1~6 haloalkyl, preferably hydrogen, C 1~6 Alkyl, C 1~6 Deuterated alkyl or C 1~6 Haloalkyl, more preferably hydrogen, C 1~3 Alkyl, C 1~3 Deuterated alkyl or C 1~3 haloalkyl, more preferably selected from hydrogen, methyl, ethyl, isopropyl, -CD3 or -CH2CF3; or R3 and R4 taken together with the nitrogen atom to which they are attached form a 3-8 membered nitrogen-containing heterocyclic group, preferably a 4-6 membered nitrogen-containing heterocyclic group, more preferably azetidinyl; R5 and R6 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl or C 1~6 haloalkyl, preferably hydrogen or C 1~6 alkyl, more preferably hydrogen or C 1~3 alkyl, more preferably hydrogen or methyl; Alternatively, R5 and R6, together with the carbon atom to which they are attached, form C 3~8 Forms a cycloalkyl group or a 3- to 8-membered heterocyclic group, preferably C 3~5 forms a cycloalkyl or 3- to 5-membered heterocyclic group, more preferably cyclopropyl; Alternatively, R5 or R6 combine with R3 or R4 to form a 3-8 membered nitrogen-containing heterocyclic group, preferably a 4-6 membered nitrogen-containing heterocyclic group, more preferably tetrahydropyrrolyl; R7 is hydrogen, deuterium, halogen, hydroxyl, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl or C 1~6 haloalkyl, preferably hydrogen or C 1~6 Alkyl, more preferably hydrogen or C 1~3 alkyl, more preferably hydrogen or methyl; Alternatively, R7 combines with R3 or R4 to form a 4-8 membered nitrogen-containing heterocyclic group, preferably a 5-6 membered nitrogen-containing heterocyclic group, more preferably tetrahydropyrrolyl; Alternatively, R7 may be linked to R5 or R6 to form C 3~8 Forms a cycloalkyl group or a 3- to 8-membered heterocyclic group, preferably C 4~6 It forms a cycloalkyl group or a 4- to 6-membered heterocyclic group, more preferably a cyclobutyl group; The cycloalkyl or heterocyclic group formed by R1 and R2 linked to the carbon atom to which they are bonded, the nitrogen-containing heterocyclic group formed by R3 and R4 linked to the nitrogen atom to which they are bonded, the cycloalkyl or heterocyclic group formed by R5 and R6 linked to the carbon atom to which they are bonded, the nitrogen-containing heterocyclic group formed by R5 or R6 linked to R3 or R4, the nitrogen-containing heterocyclic group formed by R7 linked to R3 or R4, or the cycloalkyl or heterocyclic group formed by R7 linked to R5 or R6 may optionally be selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C 1~6 Alkyl, C 1~6 Alkoxy, -(CH2) n1 ORaa , -(CH2) n1 S.R. aa , -(CH2) n1 NR aa R bb , -(CH2) n1 NR aa C(O)R bb , -(CH2) n1 C(O)NR aa R bb , -(CH2) n1 C(O)R aa , -(CH2) n1 C(O)OR aa , -(CH2) n1 S(O)2R aa , -(CH2) n1 NR aa S(O)2R bb and (CH2) n1 S(O)2NR aa R bb may be further substituted by one or more of the following substituents: R aa and R bb are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl or C 1~6 haloalkyl, preferably hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C 1~3 Alkyl, C 1~3 Deuterated alkyl or C 1~3 haloalkyl; n is an integer from 0 to 2, and n1 is an integer from 0 to 2.

[0013] In a more preferred embodiment of the present invention, M1 and M2 each independently represent -(CR A R B ) n -, O or S; M3 is a CR a , N or S; M4 is a CR b Selected from; M5 is CR c , N or S; R A , R B , R a , R b , and R c are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 alkylamino, preferably hydrogen, halogen or C 1~6 alkyl, more preferably hydrogen, fluorine, chlorine, bromine or C 1~3 alkyl, more preferably selected from hydrogen, fluorine, chlorine or methyl; R1 and R2, together with the carbon atom to which they are attached, form 3~8 Forms a cycloalkyl group or a 3- to 8-membered heterocyclic group, preferably C 3~6 Forms a cycloalkyl group or a 3- to 6-membered heterocyclic group, more preferably C 3~4 forming a cycloalkyl group or a 3- to 4-membered heterocyclic group, more preferably forming a cyclopropyl, cyclobutyl or oxetanyl group; R3 and R4 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl or C 1~6 haloalkyl, preferably hydrogen, C 1~6 Alkyl, C 1~6 Deuterated alkyl or C 1~6 Haloalkyl, more preferably hydrogen, C 1~3 Alkyl, C 1~3 Deuterated alkyl or C 1~3 haloalkyl, more preferably selected from hydrogen, methyl, ethyl, isopropyl, -CD3 or -CH2CF3; or R3 and R4 taken together with the nitrogen atom to which they are attached form a 3-8 membered nitrogen-containing heterocyclic group, preferably a 4-6 membered nitrogen-containing heterocyclic group, more preferably azetidinyl; R5 and R6 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl or C 1~6 haloalkyl, preferably hydrogen or C 1~6 alkyl, more preferably hydrogen or C 1~3 alkyl, more preferably hydrogen or methyl; Alternatively, R5 and R6, together with the carbon atom to which they are attached, form C 3~8 Forms a cycloalkyl group or a 3- to 8-membered heterocyclic group, preferably C 3~5 forms a cycloalkyl or 3- to 5-membered heterocyclic group, more preferably cyclopropyl; Alternatively, R5 or R6 combine with R3 or R4 to form a 3-8 membered nitrogen-containing heterocyclic group, preferably a 4-6 membered nitrogen-containing heterocyclic group, more preferably tetrahydropyrrolyl; R7 is hydrogen, deuterium, halogen, hydroxyl, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl or C 1~6 haloalkyl, preferably hydrogen or C 1~6 Alkyl, more preferably hydrogen or C 1~3 alkyl, and more preferably hydrogen; Alternatively, R7 combines with R3 or R4 to form a 4-8 membered nitrogen-containing heterocyclic group, preferably a 5-6 membered nitrogen-containing heterocyclic group, more preferably tetrahydropyrrolyl; Alternatively, R7 may be linked to R5 or R6 to form C 3~8 Forms a cycloalkyl group or a 3- to 8-membered heterocyclic group, preferably C 4~6 It forms a cycloalkyl group or a 4- to 6-membered heterocyclic group, more preferably a cyclobutyl group; The cycloalkyl or heterocyclic group formed by R1 and R2 linked to the carbon atom to which they are bonded, the nitrogen-containing heterocyclic group formed by R3 and R4 linked to the nitrogen atom to which they are bonded, the cycloalkyl or heterocyclic group formed by R5 and R6 linked to the carbon atom to which they are bonded, the nitrogen-containing heterocyclic group formed by R5 or R6 linked to R3 or R4, the nitrogen-containing heterocyclic group formed by R7 linked to R3 or R4, or the cycloalkyl or heterocyclic group formed by R7 linked to R5 or R6 may optionally be selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C 1~6 Alkyl, C 1~6 Alkoxy, -(CH2) n1 OR aa , -(CH2) n1 S.R. aa , -(CH2) n1 NR aa R bb , -(CH2) n1 NR aa C(O)R bb , -(CH2) n1 C(O)NR aa R bb , -(CH2) n1 C(O)R aa , -(CH2) n1 C(O)OR aa , -(CH2) n1 S(O)2R aa , -(CH2) n1 NR aa S(O)2R bb and (CH2) n1 S(O)2NR aa R bb may be further substituted by one or more of the following substituents: R aa and R bb are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl or C 1~6 haloalkyl, preferably hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C1~3 Alkyl, C 1~3 Deuterated alkyl or C 1~3 haloalkyl; n is an integer from 0 to 2, and n1 is an integer from 0 to 2.

[0014] In a more preferred embodiment of the present invention, the compound represented by the general formula (I) is

[0015] [ka]

[0016] may be also possible.

[0017] In a more preferred embodiment of the present invention, the following compounds are not included:

[0018] [ka]

[0019] In a more preferred embodiment of the invention, M3 is selected from S and M4 is CR b or N, and M5 is CR c Or N.

[0020] In a more preferred embodiment of the present invention, M3 is CR a Or N is selected, M4 is selected from S, and M5 is CR c Or N.

[0021] In a more preferred embodiment of the invention, M3 is CR a or N, and M4 is CR b Or N, and M5 is selected from S.

[0022] In a more preferred embodiment of the present invention,

[0023] [ka]

[0024] However, the following group:

[0025] [ka]

[0026] is selected from Preferably

[0027] [ka]

[0028] is selected from Where: R a , R b and R c are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 alkylamino, preferably hydrogen, halogen or C 1~6 is preferably hydrogen, fluorine, chlorine, bromine or C 1~3 It is preferably an alkyl group, more preferably hydrogen, fluorine, chlorine, bromine or methyl.

[0029] In a more preferred embodiment of the present invention,

[0030] [ka]

[0031] However, the following group:

[0032] [ka]

[0033] is selected from Preferably

[0034] [ka]

[0035] is selected from Where: R a , R b and R c are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 alkylamino, preferably hydrogen, halogen or C 1~6 is preferably hydrogen, fluorine, chlorine, bromine or C 1~3 It is preferably an alkyl group, more preferably hydrogen, fluorine, chlorine or methyl.

[0036] In a more preferred embodiment of the present invention, general formula (I) is further represented by general formula (II-A):

[0037] [ka]

[0038] During the ceremony, R3 and R4 are each independently hydrogen, C 1~6 Alkyl, C 1~6 Deuterated alkyl or C 1~6 haloalkyl, preferably hydrogen, C 1~3 Alkyl, C 1~3 Deuterated alkyl or C 1~3 haloalkyl, more preferably hydrogen, methyl, ethyl, isopropyl, -CD3 or -CH2CF3; or R3 and R4 taken together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic group, preferably azetidinyl; R5 and R6 are each independently hydrogen or C 1~6 alkyl, preferably hydrogen or C 1~3 alkyl, more preferably hydrogen or methyl; Alternatively, R5 and R6, together with the carbon atom to which they are attached, form C 3~5 Forms a cycloalkyl group or a 3- to 5-membered heterocyclic group, preferably a cyclopropyl group; Alternatively, R5 or R6 combines with R3 or R4 to form a 4-6 membered nitrogen-containing heterocyclic group, preferably tetrahydropyrrolyl; R7 is hydrogen or C 1~6 Alkyl, preferably hydrogen or C 1~3 alkyl, more preferably hydrogen or methyl; Alternatively, R7 combines with R3 or R4 to form a 5-6 membered nitrogen-containing heterocyclic group, preferably tetrahydropyrrolyl; Alternatively, R7 may be linked to R5 or R6 to form C 4~6 Forms a cycloalkyl group or a 4- to 6-membered heterocyclic group, preferably a cyclobutyl group; R b and R c are each independently hydrogen, halogen or C 1~6 alkyl, preferably hydrogen, fluorine, chlorine, bromine or C 1~3 alkyl, more preferably hydrogen, fluorine, chlorine, bromine or methyl; and m is 0 or 1.

[0039] In a more preferred embodiment of the present invention, the general formula (I) is

[0040] [ka]

[0041] With (II-Aa) being preferred.

[0042] In a more preferred embodiment of the present invention, general formula (I) is further represented by general formula (II):

[0043] [ka]

[0044] During the ceremony, R b , R c , R3, R4, R5, R6 and R7 are as defined above.

[0045] In a more preferred embodiment of the present invention, the general formula (I) is

[0046] [ka]

[0047] With (IIa) being preferred.

[0048] In a more preferred embodiment of the present invention, general formula (I) is further represented by general formula (III):

[0049] [ka]

[0050] During the ceremony, R a , R b , R3, R4, R5, R6 and R7 are as defined above; For example, R and R are each independently hydrogen, C 1~6 Alkyl, C 1~6 Deuterated alkyl or C 1~6 haloalkyl, preferably hydrogen, C 1~3 Alkyl, C 1~3 Deuterated alkyl or C 1~3haloalkyl, more preferably hydrogen, methyl, ethyl, isopropyl, -CD3 or -CH2CF3; R5, R6 and R7 are each independently hydrogen or C 1~6 alkyl, preferably hydrogen or C 1~3 alkyl, more preferably hydrogen; R a and R b are each independently hydrogen, halogen or C 1~6 alkyl, preferably hydrogen or C 1~3 More preferably, it is selected from alkyl, and more preferably hydrogen.

[0051] In a more preferred embodiment of the present invention, the general formula (I) is

[0052] [ka]

[0053] With (IIIa) being preferred.

[0054] In a more preferred embodiment of the present invention, R3 and R4 in general formula (I) are not hydrogen at the same time.

[0055] In a more preferred embodiment of the present invention, R3 in the general formula (I) is hydrogen and R4 is C 1~3 Alkyl, C 1~3 Deuterated alkyl or C 1~3 haloalkyl.

[0056] In a more preferred embodiment of the present invention, R3 in general formula (I) is hydrogen and R4 is selected from methyl, ethyl, isopropyl, -CD3 or -CH2CF3.

[0057] In a more preferred embodiment of the present invention, R3 in general formula (I) is hydrogen and R4 is methyl or -CD3.

[0058] In a more preferred embodiment of the present invention, the compound represented by general formula (I), its stereoisomer or a pharma- ceutically acceptable salt thereof is selected from the group consisting of the following compounds:

[0059] [ka]

[0060] [ka]

[0061] [ka]

[0062] is selected from.

[0063] The present invention further provides a method for preparing a compound represented by general formula (II-A), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, the method comprising the steps of:

[0064] [ka]

[0065] The method comprises reacting a compound of general formula (II-A1) with a compound of general formula (II-2) to obtain a compound represented by general formula (II-A), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, During the ceremony, R b , R c , m, R3, R4, R5, R6 and R7 are as defined above.

[0066] The present invention further provides a method for preparing a compound represented by general formula (II), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, the method comprising the steps of:

[0067] [ka]

[0068] The method comprises reacting a compound of general formula (II-1) with a compound of general formula (II-2) to obtain a compound represented by general formula (II), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, During the ceremony, R b , R c , R3, R4, R5, R6 and R7 are as defined above.

[0069] The present invention further provides a method for preparing a compound represented by general formula (III), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, the method comprising the steps of:

[0070] [ka]

[0071] The method comprises reacting a compound of general formula (III-1) with a compound of general formula (II-2) to obtain a compound represented by general formula (III), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, During the ceremony, R a , R b , R3, R4, R5, R6 and R7 are as defined above.

[0072] The present invention further relates to pharmaceutical compositions comprising a therapeutically effective dose of any of the compounds set forth above, their stereoisomers or pharma- ceutically acceptable salts thereof, and one or more pharma- ceutically acceptable carriers (or excipients).

[0073] In a further preferred embodiment of the present invention, pharmaceutical compositions can be formulated in a conventional manner using one or more pharma-ceutically acceptable carriers.Accordingly, the active compound of the present invention can be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration, or can be suitable for administration by inhalation or insufflation.The compound of the present invention or its pharma-ceutically acceptable salt can also be formulated as sustained release dosage form.

[0074] In a further preferred embodiment of the present invention, for oral administration, the active compounds of the present invention can be formulated, for example, into tablets or capsules by conventional means using pharma- ceutically acceptable excipients such as binders, fillers, lubricants, disintegrants or wetting agents. Tablets can be coated by methods well known in the art. Liquid preparations for oral administration can be, for example, solutions, syrups or suspensions, or they can be evaporated to dry products and reconstituted with water or other suitable vehicles before use. Such liquid preparations can be prepared by conventional means using pharma- ceutically acceptable excipients such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives.

[0075] In a further preferred embodiment of the present invention, when the active compounds of the present invention are used for parenteral administration, the compounds provided by the present invention can be combined with sterile water or an organic medium to form an injectable solution or suspension.

[0076] In a further preferred embodiment of the invention, the active compounds of the invention can be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0077] The present invention further relates to the use of any of the compounds as set out above, their stereoisomers or pharma- ceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation of a medicament for the prevention and / or treatment of a neuropsychiatric disorder in a mammal, said neuropsychiatric disorder being preferably a central nervous system disorder associated with 5-hydroxytryptamine receptors and / or trace amine associated receptors and / or dopamine receptors.

[0078] The present invention further relates to a method for preparing a medicament for preventing and / or treating a central nervous system disease associated with 5-hydroxytryptamine receptors and / or trace amine associated receptors and / or dopamine receptors in a mammal, using any of the compounds, stereoisomers thereof or pharma- ceutically acceptable salts thereof as set forth above, or a pharmaceutical composition thereof.

[0079] The present invention also relates to a method for preventing and / or treating a central nervous system disorder associated with 5-hydroxytryptamine receptors and / or trace amine associated receptors and / or dopamine receptors in a mammal, comprising administering to the mammal a therapeutically effective amount of any of the compounds set forth above, their stereoisomers or their pharma- ceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives, or a pharmaceutical composition thereof.

[0080] The 5-hydroxytryptamine receptor of the present invention is preferably 5-HT 1A It is a receptor.

[0081] The trace amine associated receptor according to the present invention is preferably the TAAR1 receptor.

[0082] In some embodiments, the neuropsychiatric disorder of the present invention is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, transient psychotic disorder, shared psychotic disorder, psychotic disorder due to physical illness, drug-induced psychosis, psychoemotional disorder, aggression, delirium, Parkinson's psychosis, irritable psychosis, Tourette's 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, The condition is one or more of: movement disorder, anxiety disorder, affective psychosis, depression, major depressive disorder, dysthymia, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, dizziness, epilepsy, pain, neuropathic pain, neuropathic pain predisposition, inflammatory pain, fibromyalgia, migraine, cognitive impairment, movement disorder, restless legs syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, side effect of sleepiness caused by medication, insomnia, substance abuse dependency, addiction, eating disorder, sexual dysfunction, high blood pressure, vomiting, Lesch-Nyharn disease, Wilson's disease, autism, Huntington's chorea and premenstrual dysphoria. DISCLOSURE OF THEINVENTION

[0083] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of conflict, the definitions provided in this application shall prevail. When a trade name appears in this specification, it is intended to refer to the corresponding product or its active ingredient. All patents, published patent applications and publications cited in this specification are incorporated herein by reference.

[0084] The term "hydrocarbon chain" refers to a chain-like group composed of C and H. The hydrocarbon chain may be saturated or unsaturated, and in a preferred embodiment, the hydrocarbon chain is saturated. The hydrocarbon chain may be linear or branched, and in a preferred embodiment, the hydrocarbon chain is linear. The hydrocarbon chain may optionally include one or more heteroatoms, such as N, O, and S. If a heteroatom is included, the heteroatom may be located on the main chain. In a preferred embodiment, the hydrocarbon chain may be linear or branched, the hydrocarbon chain may be saturated, and the hydrocarbon chain may optionally include one or more heteroatoms, such as N, O, and S, in the main chain. When describing a hydrocarbon chain, whether or not it includes a heteroatom, it can be described by the number of C atoms without counting the number of heteroatoms. For example, C2-C8 or C2-C6 refers to a hydrocarbon chain containing 2-8 or 2-6 carbon atoms, and may optionally include additional heteroatoms.

[0085] The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms attached to the remainder of the molecule by a single bond. An "alkyl" can have 1 to 8 carbon atoms, i.e., "C1-C8 alkyl", e.g., C 1~4 Alkyl, C 1~3 Alkyl, C 1~2 Alkyl, C3 alkyl, C4 alkyl, C 1~6 Alkyl, C 3~6Non-limiting examples of alkyl groups include 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, etc., or isomers thereof. Alkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0086] The term "divalent radical" refers to a group obtained by removing an additional hydrogen atom from a carbon atom containing a free valence electron and having two bonding sites to the remainder of the molecule. For example, an "alkylene" or "alkyl divalent radical" refers to a saturated straight or branched chain divalent hydrocarbon radical.

[0087] The term "alkylene" as used herein alone or in combination with other groups refers to a linear or branched saturated divalent hydrocarbon radical. For example, "C 1~8The term "alkylene" refers to an alkylene group having 1 to 8 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, 1-methanoethylene, 2-methylethylene, methylpropylene, or ethylpropylene. The alkylene group may be optionally substituted or unsubstituted, and if substituted, the substituents may be substituted at any available point of attachment, preferably said substituents being independently one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0088] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where cycloalkyl contains 3 to 20 carbon atoms, i.e., "C3-C 20 Cycloalkyl", e.g., C 3~18 Cycloalkyl, C 3~16 Cycloalkyl, C 3~12 Cycloalkyl, C 3~8 Cycloalkyl, C 3~6 Cycloalkyl, C 3~5 Cycloalkyl, C 3~4 Cycloalkyl, C 4~8 Cycloalkyl, C 4~6 Cycloalkyl, C 5~6 Cycloalkyl is preferred, and C 3~8 Cycloalkyl, C 3~6 Cycloalkyl, C 3~5 Cycloalkyl, C 3~4 Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, and polycyclic cycloalkyls include spiro, fused, and bridged ring cycloalkyls.

[0089] The term "spirocycloalkyl" refers to a polycyclic group in which 5-20 membered monocyclic rings share one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into monospirocycloalkyl, dispirocycloalkyl or polyspirocycloalkyl, with monospirocycloalkyl or dispirocycloalkyl being preferred, and 3-membered / 7-membered, 3-membered / 6-membered, 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospirocycloalkyl being more preferred. Also included are spiroheterocycloalkyls, in which the monospirocycloalkyl shares a spiro atom with the heterocycloalkyl.

[0090] The term "fused ring alkyl" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring of the system shares adjacent pairs of carbon atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, preferably bicyclic or tricyclic fused ring alkyl groups, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups.

[0091] The term "bridged-ring alkyl" refers to a 5- to 20-membered all-carbon polycyclic group, in which any two rings share two carbon atoms that are not directly bonded and contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6-14-membered, more preferably 7-10-membered. Depending on the number of constituent rings, it is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged-ring alkyl groups, preferably bicyclic, tricyclic or tetracyclic bridged-ring alkyl groups, more preferably bicyclic or tricyclic bridged-ring alkyl groups.

[0092] All of the above ring alkyl groups can be fused to an aryl, heteroaryl or heterocycloalkyl ring, with the ring attached to the parent structure being the ring alkyl group. The ring alkyl group can be optionally substituted or unsubstituted, and if substituted, the substituents can be substituted at any available point of attachment, and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0093] The term "heterocyclic group" refers to a saturated or unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which may be nitrogen, oxygen or S(O). m (wherein m is an integer from 0 to 2), but does not include the ring moieties -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. That is, the heterocyclic group is a "3-20-membered heterocyclic group" such as a 3-18-membered heterocyclic group, a 3-16-membered heterocyclic group, a 3-12-membered heterocyclic group, a 3-8-membered heterocyclic group, a 3-6-membered heterocyclic group, a 3-5-membered heterocyclic group, a 3-4-membered heterocyclic group, a 4-8-membered heterocyclic group, a 4-6-membered heterocyclic group, or a 5-6-membered heterocyclic group, and is preferably a 3-8-membered heterocyclic group, a 3-6-membered heterocyclic group, a 3-5-membered heterocyclic group, a 3-4-membered heterocyclic group, a 4-8-membered heterocyclic group, a 4-6-membered heterocyclic group, or a 5-6-membered heterocyclic group, and optionally contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms, and the heteroatom is optionally an N, O, or S atom.

[0094] Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolyl, 2,2-difluoro-1,3-dioxolyl, or azepanyl, etc. Non-limiting examples of polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls, which are optionally linked to other groups via a single bond or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups via any two or more atoms on the ring.

[0095] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between the 5- to 20-membered monocyclic rings, where one or more of the ring atoms is nitrogen, oxygen, or S(O). m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. According to the number of spiro atoms shared between the rings, spiroheterocyclyl is divided into monospiroheterocyclyl, dispiroheterocyclyl or polyspiroheterocyclyl, preferably monospiroheterocyclyl or dispiroheterocyclyl, more preferably 3-membered / 6-membered, 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl.

[0096] The term "fused heterocyclic group" refers to a ring in which each ring of the system shares adjacent pairs of atoms with another ring in the system and one or more of the ring atoms is nitrogen, oxygen, or S(O). m(wherein m is an integer from 0 to 2), the remaining ring atoms are carbon, and one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, and is preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group.

[0097] The term "bridged heterocyclic group" refers to a heterocyclic group in which any two rings share two atoms that are not directly bonded together and one or more ring atoms is a nitrogen, oxygen, or S(O) atom. m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon, and may contain one or more double bonds, but no ring has a completely conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, and is preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, more preferably a bicyclic or tricyclic bridged heterocyclic group.

[0098] All of the above heterocyclic groups can be fused to an aryl, heteroaryl or cycloalkyl ring, with the ring attached to the parent structure being the heterocyclic group. The heterocyclic group can be optionally substituted or unsubstituted, and if substituted, the substituents can be substituted at any available point of attachment, and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0099] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic group having a conjugated π-electron system, preferably 6-14 members, such as phenyl or naphthyl, more preferably phenyl. The aryl group may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered heterocyclic groups, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heterocyclic groups. The aryl group may be optionally substituted or unsubstituted, and if substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0100] The term "heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, the heteroatoms being selected from oxygen, sulfur, nitrogen, and the like. Heteroaryls are preferably 5-12 membered, more preferably 5-6 membered, and include, for example, pyrrolyl, imidazolyl, furyl, pyrryl, thienyl, thiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, and the like. The heteroaryl group may be fused to an aryl, cycloalkyl, or heterocyclyl ring, where the ring attached to the parent structure is a heteroaryl ring. Heteroaryl may be optionally substituted or unsubstituted, and if substituted, the substituents may be substituted at any available point of attachment and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0101] The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), where alkyl and cycloalkyl are defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy may be optionally substituted or unsubstituted, and if substituted, the substituents may be substituted at any available point of attachment, and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0102] The term "alkylthio" refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), where alkyl and cycloalkyl are defined above. Non-limiting examples of alkylthio include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like. Alkylthio may be optionally substituted or unsubstituted, and if substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0103] The term "alkylamino" refers to -NH-(alkyl or unsubstituted cycloalkyl), or -N-(alkane or unsubstituted cycloalkyl)(alkyl or unsubstituted cycloalkyl), where alkyl and cycloalkyl groups are as defined above. Non-limiting examples of alkylamino include methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, and the like. Alkylamino may be optionally substituted or unsubstituted, and if substituted, the substituents may be substituted at any available point of attachment and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0104] The term "halo" or "halogen" or "halogenated" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine, bromine atom.

[0105] The term "deuterated hydrocarbon chain" refers to a hydrocarbon chain substituted with one or more deuterium atoms, where the hydrocarbon chain is as defined above.

[0106] The term "deuteroalkyl" refers to an alkyl group substituted with one or more deuterium atoms, where alkyl is defined above.

[0107] The term "halogenated hydrocarbon chain" refers to a hydrocarbon chain substituted with one or more halogens, where the hydrocarbon chain is as defined above.

[0108] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is defined above.

[0109] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where the alkoxy group is as defined above.

[0110] The term "alkenyl" refers to an alkenyl group, also known as an alkene group, where said alkenyl may be further substituted with other related groups.

[0111] The term "alkynyl" refers to (CH≡C-), wherein said alkynyl groups may be further substituted by other related groups.

[0112] "Hydroxy" refers to --OH.

[0113] "Amino" refers to -NH2.

[0114] "Cyano" refers to -CN.

[0115] "Nitro" refers to -NO2.

[0116] "Mercapto" refers to -SH.

[0117] "Carbonyl" refers to -C(O)-.

[0118] "Carboxy" refers to -C(O)OH.

[0119] "Oxo" refers to =O.

[0120] The terms "comprise," "include," "have," "contain," or "related to," and other variations thereof, herein are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art should understand that the above terms such as "comprise" encompass the meaning of "consisting of."

[0121] The term "one or more" or similar expressions "at least one" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0122] When a lower and upper limit of a numerical range is disclosed, every value and every encompassed range within that range is specifically disclosed. In particular, every range of values ​​disclosed herein should be understood to cover every value and range encompassed within the broader range.

[0123] As used herein, "Z" and "-Z-" both represent the same specific group and may be used interchangeably.

[0124] As used herein, the expression m to n refers to the range from m to n, as well as subranges and individual point values ​​therein. For example, "C2 to C8" or "C 2~8 " should be understood to cover the range of 2 to 8 carbon atoms, and further to cover any subranges and individual point values ​​therein, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C5, etc., and C2, C3, C4, C5, C6, C7, C8, etc. 10 " or "C 3~10 " should be understood in the same way, for example, C3-C9, C6-C9, C6-C8, C6-C7, C7-C 10 , C7~C9, C7~C8, C8~C9, etc., and C3, C4, C5, C6, C7, C8, C9, C 10 For example, "C1-C6" or "C 1~6" should be understood to cover the range of 1 to 6 carbon atoms, such as C2 to C5, C3 to C4, C1 to C2, C1 to C3, C1 to C4, C1 to C5, C1 to C6, etc., and any subranges and individual point values ​​therein, such as C1, C2, C3, C4, C5, C6, etc. As another example, the phrase "3-membered to 10-membered" should be understood to cover any subranges and individual point values ​​therein, such as 3-membered to 5-membered, 3-membered to 6-membered, 3-membered to 7-membered, 3-membered to 8-membered, 4-membered to 5-membered, 4-membered to 6-membered, 4-membered to 7-membered, 4-membered to 8-membered, 5-membered to 7-membered, 5-membered to 8-membered, 6-membered to 7-membered, 6-membered to 8-membered, 9-membered to 10-membered, etc., and any subranges and individual point values ​​therein, such as 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, etc. Other similar phrases throughout this specification should be understood in a similar manner.

[0125] As used herein, different expressions such as "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 represent the same meaning, i.e., X may be any one or more of A, B and C.

[0126] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the phrase includes both the occurrence and non-occurrence of the event or circumstance. For example, "cycloalkyl optionally substituted with alkyl" means that the alkyl group may be present, but does not have to be present, and the description includes cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0127] The terms "substituted" and "substituted" mean that one or more (e.g., one, two, three, or four) hydrogens on the specified atom are selectively replaced with the indicated group, provided that the specified atom does not exceed its normal valence under the circumstances and the replacement results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. When the absence of a substituent is described, it should be understood that the substituent may be one or more hydrogen atoms, provided that the structure is such that the compound is in a stable state. When it is described that each carbon atom in a group may be optionally replaced with a heteroatom, provided that the normal valence of all atoms in the group is not exceeded under the circumstances and a stable compound is obtained.

[0128] When a substituent is described as being "optionally substituted", the substituent may be unsubstituted or substituted. When an atom or group is described as being optionally substituted with one or more of a list of substituents, one or more hydrogens on the atom or group may be independently selected and replaced with any of the substituents. When a substituent is oxo (i.e. =O), it means that two hydrogen atoms are replaced. As used herein, unless otherwise specified, the attachment point of a substituent may be from any suitable position of the substituent.

[0129] When attachment of a substituent is indicated as being via a bond connecting two atoms in a ring, then such substituent may be attached to any ring-forming atom in the substitutable ring.

[0130] When any variable (e.g., R) and labeled variable (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) occurs more than one time in a composition or structure of a compound, its definition is independent at each occurrence. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, said group may optionally be substituted with up to 4 R substituents, and each R substituent option at each occurrence is independent of the others.

[0131] The term "substituted" means that one or more hydrogen atoms on a compound or group are replaced by another atom or group. The condition is that a stable valence state or compound is formed. The expression "unsubstituted" can be understood as "not substituted". It should be understood that if the substituent is hydrogen, this can also mean that the corresponding group is "unsubstituted" or "not substituted".

[0132] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomeric isomers, (D)-isomers, (L)-isomers, and other mixtures thereof, such as racemic mixtures and enantiomeric or diastereomeric enriched mixtures. All of these mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers and mixtures thereof are included within the scope of the present invention. In certain embodiments, preferred compounds are isomeric compounds that exhibit greater biological activity. Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic or diastereomeric mixtures, are also included within the scope of the present invention. Purification and isolation of such materials can be accomplished by standard techniques known in the art.

[0133] The hydrogen atoms described in the present invention can be substituted with their isotope, deuterium, and the content of the deuterium isotope is at least greater than the natural deuterium isotope content, and any hydrogen atom in the compound according to the embodiment of the present invention may be substituted with a deuterium atom.

[0134] The term "pharmacologically acceptable" means a substance that, within the bounds of ordinary medical judgment, is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, or allergic reaction, has a reasonable benefit / disadvantage ratio, and can be effectively used for its intended use.

[0135] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe and effective when used in a mammalian body and possesses the appropriate biological activity.

[0136] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutical acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism and promote absorption of the active ingredient, thereby exerting biological activity.

[0137] The term "pharmaceutically acceptable carrier" refers to a substance that has no obvious irritating effect on an organism and does not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, a flow agent, a sweetener, a diluent, a preservative, a dye / colorant, a flavoring agent, a surfactant, a wetting agent, a dispersant, a disintegrant, a stabilizer, a solvent or an emulsifier.

[0138] Terms such as "dosing" or "administering" refer to methods that allow for the delivery of a compound or composition to a desired site of biological 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, and the like, particularly injection and oral.

[0139] As used herein, the term "treating" includes ameliorating, reducing or improving a disease or condition, preventing other symptoms, improving or preventing metabolic factors underlying a condition, inhibiting a disease or condition, e.g., preventing the onset of a disease or condition, reducing a disease or condition, promoting remission of a disease or condition, or halting the pathology of a disease or condition, and even preventing it. "Treatment" also includes achieving therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to the eradication or improvement of the condition being treated. Additionally, therapeutic benefit is achieved by eradicating or improving one or more physical symptoms (physiological symptoms) associated with an underlying disease. This allows an improvement in the patient's disease to be observed, although the patient may still have the underlying disease. Prophylactic benefit refers to the use of the composition to prevent the patient's risk of a particular disease, or taking the composition when the disease has not yet been diagnosed, but the patient has one or more physiological symptoms of the disease.

[0140] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical compound that is effective in the treatment or prevention of a disorder, disease, or condition of a subject. The term "neuropsychiatric disorder" refers collectively to neurological and psychiatric disorders, including neurological and / or psychiatric disorders.

[0141] The term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" of a drug, drug unit or active ingredient refers to a sufficient amount of a drug or agent that can achieve the desired effect while having acceptable side effects. Determination of an effective amount varies from person to person, depending on the age and general condition of the individual, and also on the specific active agent. The appropriate effective amount in each case can be determined by one skilled in the art through routine experimentation.

[0142] As used herein, an "individual" includes a human or non-human animal. Exemplary human individuals include human subjects (referred to as patients) suffering from a disease (e.g., a disease described herein) or normal subjects. In the present invention, a "non-human animal" includes all vertebrates, such as non-mammals (birds, amphibians, reptiles, etc.) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0143] The following detailed description of the present invention is intended to describe non-limiting embodiments to enable other persons skilled in the art to more fully understand the technical solutions, principles, and practical applications of the present invention, so as to enable them to modify and implement the present invention in many forms that are best suited to the requirements of a particular application.

[0144] Beneficial effects The compounds of the present invention bind to the TAAR1 receptor and 5-HT 1A They have good agonistic activity on the receptor and / or good pharmacodynamic effect in vivo, and have anti-neuropsychiatric activity, i.e., have the effect of treating or preventing neuropsychiatric disorders. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0145] The present invention will be further described below in combination with specific examples. It should be understood that these examples are only used to explain the present invention and are not intended to limit the scope of the present invention. In addition, after reading the contents taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and it should be understood that these equivalent forms are also within the scope limited by the claims attached to this application.

[0146] Working Example The embodiments of the present invention are described in detail below in conjunction with examples, but those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be considered as limiting the scope of the present invention. In the examples, no specific conditions are shown, and the examples are carried out according to conventional conditions or conditions suggested by the manufacturer. For reagents and equipment used, if the manufacturer is not specified, conventional products available on the market were used. Unless otherwise specified, ratios or percentages used herein are by weight.

[0147] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS).

[0148] NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using an AVANCE III600 nuclear magnetics instrument, with the solvents being deuterated dimethylsulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3) and the internal standard being tetramethylsilane (TMS).

[0149] Liquid chromatography-mass spectrometry (LC-MS) was measured using a Japan Shimadzu LCMS2020 mass spectrometer.

[0150] The HPLC measurements were performed using a Shimadzu LC20A liquid chromatograph from Japan.

[0151] The thin-layer chromatography silica gel plate used was Yantai Jiangyou silica gel plate, the specification used in TLC was 0.2mm±0.03mm, and the specification used in thin-layer chromatography separation and purification products was 0.4mm~0.5mm.

[0152] Example 1 1-(5'H,7'H-spiro[oxetane-3,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine

[0153] [ka]

[0154] [ka]

[0155] LC-MS [M+H] + : 226.1.

[0156] Example 2 1-(5'H,7'H-spiro[cyclobutane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine

[0157] [ka]

[0158] [ka]

[0159] Step a: Synthesis of 1-(thiophen-3-yl)cyclobutyronitrile Under ice bath and nitrogen protection, sodium hydride (60%, 1.6 g, 40.59 mmol) was added to a solution of 2-(thiophen-3-yl)acetonitrile (2.0 g, 16.24 mmol) in N,N-dimethylformamide (30 mL) and reacted for 1 hour, then 1,3-dibromopropane (4.0 g, 19.8 mmol) was slowly added, the reaction solution was slowly warmed to room temperature, and stirred overnight. After the reaction was completed, the reaction solution was poured into ice water (300 mL), extracted with ethyl acetate (300 mL x 3), the extracted phase was washed with water (200 mL x 3) and saturated saline (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.5 g, yield 56.6%). 1H NMR (300 MHz, CDCl3) δ 7.39 - 7.33 (m, 1 H),7.30 - 7.23 (m, 1 H), 7.15 (dd, J = 5.1, 1.5 Hz, 1 H), 2.89 - 2.75 (m, 2 H), 2.68 - 2.49 (m, 2 H), 2.44 - 2.26 (m, 1 H), 2.19 - 2.00 (m, 1 H). Step b: Synthesis of 1-(thiophen-3-yl)cyclobutanal Under ice bath and nitrogen protection, 1-(thiophen-3-yl)cyclobutyronitrile (1.4g, 8.58mmol) in tetrahydrofuran (100mL) was slowly added with n-hexane solution of diisobutylaluminum hydride (1M in hexane, 19.0mL, 19.0mmol) and stirred at room temperature for 3 hours. After the reaction was completed, water (300mL) was added in an ice bath to quench the reaction, and the mixture was extracted with ethyl acetate (300mL x 3). The extracted phase was washed with water (300mL x 3) and saturated saline (300mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the target product (632.0mg, yield 44.3%). 1 H NMR (400 MHz, CDCl3) δ 9.57 (s, 1 H), 7.35 (dd, J = 4.8, 2.8 Hz, 1 H), 7.10-7.07 (m, 1 H), 6.93 (dd, J = 5.2, 1.2 Hz, 1 H), 2.76 - 2.65 (m, 2 H), 2.39 - 2.28 (m, 2 H), 2.04 - 1.92 (m, 2 H). Step c: Synthesis of (1-(thiophen-3-yl)cyclobutyl)methanol Under ice bath and nitrogen protection, a solution of lithium aluminum hydride in tetrahydrofuran (20 mL) (2.5 M in THF, 3.3 mL, 8.30 mmol) was slowly added to a solution of 1-(thiophen-3-yl)cyclobutanal (632.0 mg, 3.8 mmol) in tetrahydrofuran (20 mL), and the temperature was slowly raised to room temperature, followed by stirring for 2 hours. After the reaction was completed, water (200 mL) was added in an ice bath to quench the reaction, and the mixture was extracted with ethyl acetate (300 mL x 3). The extracted phase was washed with water (300 mL x 3) and saturated saline (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the target product (570.0 mg, yield 89.02%). 1 H NMR (300 MHz, CDCl3) δ 7.34 - 7.28 (m, 1 H), 7.04 - 7.00 (m, 1 H), 6.95 (d, J = 4.8 Hz, 1 H), 3.75 (s, 2 H), 2.40 - 1.83 (m, 6 H). Step d: Synthesis of 1-(5'H,7'H-spiro[cyclobutane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine 2,2-Dimethoxy-N-methylethylamine (170.0 mg, 1.43 mmol) and trifluoromethanesulfonic acid (0.4 mL) were added to a solution of (1-(thiophen-3-yl)cyclobutyl)methanol (200.0 mg, 1.19 mmol) in 2-methyltetrahydrofuran (4 mL), and the mixture was stirred at 80° C. for 20 minutes. After the reaction was completed, the pH of the reaction solution was adjusted to 13 with a 15% aqueous sodium hydroxide solution at room temperature, and the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL×3). The extract phases were combined and concentrated to obtain a crude product, which was separated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the desired final product (37.3 mg, yield 11.7%). 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1 H), 7.22 (d, J = 4.8 Hz, 1 H), 7.15 (d, J = 5.2 Hz, 1 H), 5.12 (dd, J = 9.6, 2.8 Hz, 1 H), 4.11 (d, J = 11.2 Hz, 1 H), 3.68 (d, J = 11.6 Hz, 1 H), 3.22 (dd, J = 12.8, 3.2 Hz, 1 H), 3.05 (dd, J = 12.8, 9.6 Hz, 1 H), 2.68 (s, 3 H), 2.39 - 2.28 (m, 1) H), 2.23 - 2.14 (m, 2 H), 2.05 - 1.88 (m, 3H). LC-MS [M+H] + : 224.2.

[0160] Example 3 1-(2'-Fluoro-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine

[0161] [ka]

[0162] [ka]

[0163] Step a: Synthesis of N-(2,2-dimethoxyethyl)-2,2,2-trifluoroacetamide Under ice bath and nitrogen protection, triethylamine (1.8g, 17.8mmol) was added to a solution of 2,2-dimethoxyethylamine (500.0mg, 4.75mmol) in dichloromethane (10mL) and stirred for 30 minutes, then trifluoroacetic anhydride (1.19g, 5.7mmol) was slowly added and stirring was continued at room temperature for 2 hours. After the reaction was completed, the reaction solution was neutralized with saturated aqueous sodium bicarbonate solution (20mL) in an ice bath, extracted with dichloromethane (20mL x 3), the extracted phase was washed with water (20mL x 3) and saturated saline (20mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the desired crude product (800mg), which was used in the next reaction without purification. Step b: Synthesis of N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)-2,2,2-trifluoroacetamide A solution of (1-(thiophen-3-yl)cyclopropyl)methanol (500.0 mg, 3.24 mmol) in 2-methyltetrahydrofuran (15 mL) was stirred with N-(2,2-dimethoxyethyl)-2,2,2-trifluoroacetamide (800 mg crude product) and trifluoromethanesulfonic acid (389.6 mg, 2.6 mmol) at room temperature for 16 hours. After the reaction, the reaction solution was adjusted to pH 13 with 15% aqueous sodium hydroxide solution and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 3), and the crude product obtained by concentrating the extract phase was separated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the target product (800.0 mg, yield 84.7%). LC-MS [M+H] + : 292.0. Step c: Synthesis of 1-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine To a solution of N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)-2,2,2-trifluoroacetamide (800.0 mg, 2.75 mmol) in N,N-dimethylformamide (10 mL), sodium hydride (60%, 219.9 mg, 5.5 mmol) and iodomethane (429.1 mg, 3.02 mmol) were added and stirred at room temperature for 16 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The crude product obtained by concentrating the extract phase was separated and purified by column chromatography to obtain the target product (320.0 mg, yield 55.7%). LC-MS [M+H] + : 210.0. Step d: Synthesis of tert-butyl((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)(methyl)carbamate 1-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine (252.0mg, 1.20mmol) and sodium hydroxide (241.0mg, 6.00mmol) in dichloromethane (10mL) were added with di-tert-butyl dicarbonate (526.0mg, 2.40mmol) and stirred overnight. After the reaction was completed, the reaction solution was diluted with water (10mL), extracted with ethyl acetate (10mL x 3), and the crude product obtained by concentrating the extract phase was separated and purified by column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain the target product (211.0mg, yield 56.6%). LC-MS [M+H-100] + : 210.1. Step e: Synthesis of tert-butyl((2'-fluoro-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)(methyl)carbamate At -70°C, under nitrogen protection, n-butyllithium (2.5M in hexane, 0.9mL, 2.25mmol) was added to a solution of tert-butyl((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)(methyl)carbamate (337.0mg, 1.09mmol) in tetrahydrofuran (4mL), and the temperature was maintained and stirring was continued for 30 minutes. Next, a solution of N-fluorobisbenzenesulfonamide (412.0mg, 1.30mmol) in tetrahydrofuran (2mL) was added, and stirring was continued for 2 hours at -70°C, after which the reaction was quenched by adding a saturated aqueous ammonium chloride solution (10mL), extracted with ethyl acetate (100mL), and the extracted phase was washed with water (100mL) and concentrated, and the obtained crude product was purified by column chromatography to obtain the desired product (250.0mg, 70% yield). LC-MS [M+H-100] + : 228.1. Step f: Synthesis of 1-(2'-fluoro-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine Dioxane hydrochloride (1 mL) was added to a solution of tert-butyl ((2'-fluoro-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)(methyl)carbamate (250.0 mg, 0.76 mmol) in dichloromethane (3 mL), and the mixture was stirred for 3 hours. After completion of the reaction, the reaction solution was concentrated, and the obtained crude product was separated and purified by preparative liquid chromatography (water / formic acid / acetonitrile) to obtain the target product (36.2 mg, yield 17.3%). 1H NMR (400 MHz, CD3OD) δ 8.53 (s, 1 H), 6.17 (d, J = 2.0 Hz, 1 H), 5.13 - 5.05 (m, 1 H), 4.02 (d, J = 11.6 Hz, 1 H), 3.63 (d, J = 11.6 Hz, 1 H), 3.39 (dd, J = 12.8, 3.2 Hz, 1 H), 3.33 - 3.24 (m, 1 H), 2.75 (s, 3 H), 1.06 - 0.76 (m, 4 H). LC-MS [M+H] + : 228.1.

[0164] Example 4 1-(2'-chloro-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine

[0165] [ka]

[0166] [ka]

[0167] Step a: Synthesis of tert-butyl ((2'-chloro-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)(methyl)carbamate Under the condition of 50 ° C, tert-butyl ((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl) (methyl) carbamate (211.0 mg, 0.68 mmol) in a mixed solvent of acetic acid and tetrahydrofuran (2 mL: 8 mL) was added with N-chlorosuccinimide (137.0 mg, 1.02 mmol) and stirred for 3 hours while maintaining the temperature. After the reaction was completed, the reaction solution was cooled to room temperature, quenched by adding water (30 mL), extracted with ethyl acetate (15 mL × 3), and the crude product obtained by concentrating the extract phase was separated and purified by column chromatography (ethyl acetate: petroleum ether = 1: 10) to obtain the target product (203.0 mg, yield 86.8%). LC-MS [M+H] + : 344.1. Step b: Synthesis of 1-(2'-chloro-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine At room temperature, trifluoroacetic acid (2 mL) was added to a solution of tert-butyl ((2'-chloro-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)(methyl)carbamate (203.0 mg, 0.59 mmol) in dichloromethane (5 mL) and stirred for 30 minutes. After completion of the reaction, the reaction solution was concentrated, and the crude product was separated and purified by preparative liquid chromatography (water / formic acid / acetonitrile) to obtain the target product (10.6 mg, yield 6.2%). 1 H NMR (400 MHz, CD3OD) δ 8.55 (s, 1 H), 6.58 (s, 1 H), 5.13 (dd, J = 8.4, 2.8 Hz, 1 H), 4.00 (dd, J = 11.6, 1.2 Hz, 1 H), 3.62 (d, J = 11.6 Hz, 1 H), 3.41 (dd, J = 12.8, 3.2 Hz, 1 H), 3.33 - 3.25 (m, 1 H), 2.74 (s, 3 H), 1.10 - 0.82 (m, 4 H). LC-MS [M+H] + : 244.1.

[0168] Example 5 1-(2'-methyl-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine

[0169] [ka]

[0170] [ka]

[0171] Step a: Synthesis of (5-methylthiophen-3-yl)methanol 5-Methylthiophene-3-carboxylic acid (7.4 g, 52.1 mmol) was dissolved in tetrahydrofuran (200 mL), and under nitrogen protection and ice bath conditions, a solution of lithium aluminum tetrahydride in tetrahydrofuran (2.5 M in THF, 31.0 mL, 78.0 mmol) was slowly added dropwise to the above solution, followed by stirring at room temperature for 12 hours. After completion of the reaction, ethyl acetate (200 mL) and dilute hydrochloric acid (1.0 M, 20 mL) were added successively under ice cooling to quench the reaction, and stirring was continued for 1 hour. The above mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography to obtain the target product (6.7 g, yield 99%). 1 H NMR (400 MHz, CDCl3): δ 6.96 (s, 1 H), 6.75 (s, 1 H), 4.59 (s, 2 H), 2.47 (s, 3 H) 1.75 (brs, 1 H). Step b: Synthesis of 4-(bromomethyl)-2-methylthiophene Under ice bath and nitrogen protection, phosphorus tribromide (4.2 g, 15.6 mmol) was added to a solution of (5-methylthiophen-3-yl)methanol (4.0 g, 31.3 mmol) in ethyl ether (100 mL), stirred for 30 minutes, ethyl acetate (200 mL) was added, the mixture was washed with water (100 mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography to obtain the target product (4.2 g, yield 70.2%). 1 H NMR (400 MHz, CDCl3): δ 7.10 (s, 1H), 6.80 (s, 1H), 4.12 (s, 2H), 2.45 (s, 3H). Step c: Synthesis of 2-(5-methylthiophen-3-yl)acetonitrile Under nitrogen protection, trimethylsilylnitrile (6.2 g, 63 mmol) and tetrabutylammonium fluoride (1M in THF, 63 mL, 63 mmol) were slowly added to a solution of 4-(bromomethyl)-2-methylthiophene (4.0 g, 21 mmol) in acetonitrile (70 mL), and the mixture was stirred at room temperature for 14 hours. The reaction solution was then diluted with ethyl acetate (400 mL) and washed with dilute hydrochloric acid (0.5 M, 200 mL x 2), water (200 mL), and saturated saline (200 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain the desired product (2.6 g, yield 90.2%). 1 H NMR (400 MHz, CDCl3): δ 6.97 (s, 1 H), 6.69 (s, 1 H), 3.64 (s, 2 H), 2.47 (s, 3 H). Step d: Synthesis of 1-(5-methylthiophen-3-yl)cyclopropanenitrile To a solution of sodium hydride (60%, 1.89 g, 47.0 mmol) in dimethyl sulfoxide (20 mL), (5-methylthiophen-3-yl)acetonitrile (2.6 g, 19.0 mmol) was added, followed by 1-bromo-2-chloroethane (6.89 g, 47.0 mmol). After stirring at room temperature for 14 hours, the reaction solution was poured into water (100 mL) to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL). The extract was washed with water (300 mL x 2) and saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 20: 1 to 10: 1) to obtain the target product (2.9 g, yield 93.5%). 1 H NMR (400 MHz, CDCl3): δ 6.91 (d, J = 1.6 Hz, 1 H), 6.57 (s, 1 H), 2.45 (s, 3 H), 1.68 - 1.58 (m, 2 H), 1.36 - 1.26 (m, 2 H). Step e: Synthesis of 1-(5-methylthiophen-3-yl)cyclopropanal In an ice bath under nitrogen protection, diisobutylaluminum hydride (1M in hexane, 7.5mL, 7.5mmol) was slowly added dropwise to a solution of 1-(5-methylthiophen-3-yl)cyclopropanenitrile (815mg, 5.0mmol) in tetrahydrofuran (20mL) and stirred at room temperature for 3 hours. After the reaction was completed, water (0.5mL) was added to quench the reaction, diluted with ethyl acetate (100mL), washed with water (100mL x 3) and saturated saline (50mL), separated the organic phase and dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by column chromatography to obtain the target product (800.0mg, yield 96.2%). 1 H NMR (400 MHz, CDCl3): δ 9.22 (s, 1 H), 6.94 (d, J = 1.6 Hz, 1 H), 6.71 (s, 1 H), 2.47 (d, J = 1.2 Hz, 3 H), 1.56 - 1.48 (m, 2 H), 1.42 - 1.32 (m, 2H). Step f: Synthesis of (1-(5-methylthiophen-3-yl)cyclopropyl)methanol Under ice bath conditions, sodium borohydride (201.0 mg, 5.3 mmol) was slowly added to a solution of 1-(5-methylthiophen-3-yl)cyclopropanal (800.0 mg, 4.8 mmol) in methanol (20 mL) and stirred at room temperature for 1 hour. After completion of the reaction, the reaction was quenched with dilute hydrochloric acid (1.0 M, 2 mL), diluted with ethyl acetate (50 mL), washed with water (50 mL x 2) and saturated saline (30 mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain the target product (697.0 mg, yield 86.3%). 1 H NMR (400 MHz, CDCl3): δ 6.84 (d, J = 1.2 Hz, 1 H), 6.65 (s, 1 H), 3.67 (s, 2 H), 2.45 (s, 3 H), 0.90 - 0.75 (m, 4 H). Step g: Synthesis of 1-(2'-methyl-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine A solution of trifluoromethanesulfonic acid (900.0 mg, 6.0 mmol) in 2-methyltetrahydrofuran (3 mL) was slowly added dropwise to a solution of (1-(5-methylthiophen-3-yl)cyclopropyl)methanol (168.0 mg, 1.0 mmol) and methylaminoacetaldehyde dimethyl acetal (120.0 mg, 1.0 mmol) in tetrahydrofuran (3 mL), and stirred at room temperature overnight. After the reaction was completed, the mixture was diluted with dichloromethane (50 mL), washed with 5% aqueous sodium hydroxide solution (100 mL), water (100 mL), and saturated saline (50 mL) in that order, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) and preparative liquid chromatography to obtain the target product (11.6 mg, yield 5.2%). 1H NMR (400 MHz, CD3OD): δ 6.23 (s, 1 H), 4.97 - 4.88 (m, 1 H), 3.90 (d, J = 15.6 Hz, 1 H), 3.52 (d, J = 15.2 Hz, 1 H), 2.92 - 2.84 (m, 2 H), 2.46 (s, 3H), 2.40 (s, 3H), 1.05 - 0.67 (m, 4H). LC-MS [M+H]+: 224.1.

[0172] Example 6 1-(3'-Fluoro-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine

[0173] [ka]

[0174] [ka]

[0175] LC-MS [M+H] + : 228.1.

[0176] Example 7 1-(3'-methyl-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine

[0177] [ka]

[0178] [ka]

[0179] Step a: Synthesis of (4-methylthiophen-3-yl)methanol Under ice bath and nitrogen protection, lithium aluminum hydride (2.5M in THF, 60mL, 150mmol) was slowly added to a solution of 4-methylthiophene-3-carboxylic acid (10.0g, 70.4mmol) in tetrahydrofuran (100mL) and stirred at room temperature for 12 hours. After the reaction was completed, dilute hydrochloric acid (1.0M, 15mL) was added to the reaction solution in an ice bath to quench it, and then the mixture was extracted with ethyl acetate (400mL x 3). The combined extract was washed with water (400mL x 3) and saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain the desired product (4.0g, yield 44.3%). 1 H NMR (400 MHz, CDCl3): δ 7.20 (s, 1 H), 6.94 (s, 1 H), 4.63 (s, 2 H), 2.26 (s, 3 H). Step b: Synthesis of 3-(bromomethyl)-4-methylthiophene Under ice bath and nitrogen protection, phosphorus tribromide (2.85g, 10.5mmol) was slowly added to a solution of (4-methylthiophen-3-yl)methanol (2.7g, 21.1mmol) in ethyl ether (30mL), and the reaction was allowed to proceed for 30 minutes. Dilute hydrochloric acid (2.5M, 20mL) was then added to quench the reaction, followed by extraction with ethyl acetate (400mL×3). The combined extract was washed with water (400mL×3) and saturated saline (400mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the desired product (1.5g, yield 37.5%). 1 H NMR (400 MHz, CDCl3): δ 7.29 (s, 1 H), 6.95 (s, 1 H), 4.48 (s, 2 H), 2.29 (s, 3 H). Step c: Synthesis of 2-(4-methylthiophen-3-yl)acetonitrile Under nitrogen protection, trimethylsilylnitrile (2.3g, 23.7mmol) and tetrabutylammonium fluoride (5.8g, 23.7mmol) were added to a solution of 3-(bromomethyl)-4-methylthiophene (1.5g, 7.9mmol) in acetonitrile (30mL), and the mixture was stirred at room temperature for 14 hours. After the reaction was completed, water (200mL) was added under ice bath, and the mixture was extracted with ethyl acetate (300mL×3). The combined extract was washed with water (300mL×3) and saturated saline (300mL×3) in sequence, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the target product (1.0g, yield 92.6%). 1 H NMR (400 MHz, CDCl3): δ 7.25 (s, 1 H), 6.99 (s, 1 H), 3.59 (s, 2 H), 2.22 (s, 3 H). Step d: Synthesis of 1-(4-methylthiophen-3-yl)cyclopropanenitrile To a solution of sodium hydride (60%, 0.74 g, 18.3 mmol) in dimethyl sulfoxide (20 mL), 2-(4-methylthiophen-3-yl)acetonitrile (1.0 g, 7.3 mmol) and 1-bromo-2-chloroethane (2.6 g, 18.3 mmol) were slowly added, and the mixture was stirred at room temperature for 14 hours. The reaction was quenched by adding water (300 mL) in an ice bath, and the mixture was extracted with ethyl acetate (300 mL x 3). The extract was washed with water (200 mL x 3) and saturated saline (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography to obtain the target product (1.0 g, yield 83.9%). 1 H NMR (400 MHz, CDCl3): δ 7.09 (d, J = 3.2 Hz, 1 H), 6.96 - 6.92 (m, 1 H), 2.40 (s, 3 H), 1.65 - 1.57 (m, 2 H), 1.29 - 1.20 (m, 2 H). Step e: Synthesis of 1-(4-methylthiophen-3-yl)cyclopropanal Under ice bath and nitrogen protection, diisobutylaluminum hydride (1M in hexane, 12.2mL, 12.2mmol) was slowly added to a solution of 1-(4-methylthiophen-3-yl)cyclopropanenitrile (1.0g, 6.1mmol) in tetrahydrofuran (15mL) and stirred at room temperature for 16 hours. Then, water (300mL) was added under ice bath to quench the reaction, and the mixture was extracted with ethyl acetate (300mL x 3). The extract was washed with water (300mL x 3) and saturated saline (300mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the target product (450.0mg, yield 44.5%). 1 H NMR (400 MHz, CDCl3): δ 9.10 (s, 1 H), 7.06 (d, J = 3.2 Hz, 1 H), 6.98 - 6.93 (m, 1 H), 2.18 (s, 3 H), 1.66 - 1.50 (m, 2 H), 1.40 - 1.28 (m, 2H). Step f: Synthesis of (1-(4-methylthiophen-3-yl)cyclopropyl)methanol Under ice bath conditions, sodium borohydride (90.0 mg, 2.3 mmol) was slowly added to a solution of 1-(4-methylthiophen-3-yl)cyclopropanal (350 mg, 2.1 mmol) in methanol (7 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the extract was washed with water (50 mL x 3) and saturated saline (50 mL x 3) in sequence, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the target product (280.0 mg, yield 79.2%). 1 H NMR (400 MHz, CDCl3): δ 7.10 (d, J = 4.4 Hz, 1 H), 6.93 - 6.87 (m, 1 H), 3.54 (s, 2 H), 2.29 (s, 3 H), 0.89 - 0.76 (m, 4 H). Step g: Synthesis of 1-(3'-methyl-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine Under ice bath conditions, trifluoromethanesulfonic acid (900.0mg, 5.5mmol) was slowly added dropwise to a 2-methyltetrahydrofuran solution of (1-(4-methylthiophen-3-yl)cyclopropyl)methanol (170.0mg, 1.0mmol) and methylaminoacetaldehyde dimethyl acetal (120.0mg, 1mmol), and the mixture was stirred at room temperature for 19 hours. After that, dichloromethane (50mL) was added and diluted under ice bath, the mixture was washed with 5% aqueous sodium hydroxide solution (50mLx3) and saturated saline (50mLx3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the target product (58.9mg, yield 26.1%). 1 H NMR (400 MHz, CD3OD): δ 6.83 (s, 1 H), 5.02 - 4.92 (m, 1 H), 3.88 (dd, J = 15.6, 2.0 Hz, 1 H), 3.39 (d, J = 15.6 Hz, 1 H), 2.99 - 2.82 (m, 2 H), 2.46 (s, 3 H), 2.10 (s, 3 H), 1.61 - 1.47 (m, 1 H), 1.21-1.09 (m, 1 H), 0.89 - 0.77 (m, 1 H), 0.68 - 0.55 (m, 1 H). LC-MS [M+H] + : 224.2.

[0180] Example 8 1-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine

[0181] [ka]

[0182] [ka]

[0183] Step a: Synthesis of 1-(thiophen-3-yl)cyclopropanecarbonitrile 2-(thien-3-yl)acetonitrile (5g, 40.59mmol) was dissolved in N,N-dimethylformamide (130mL), then NaH (60%, 4.06g, 101.48mmol) was added little by little at 0°C, and the mixture was stirred for 0.5 hours. Then, a solution of 1-bromo-2-chloroethane (11.64g, 81.39mmol) dissolved in N,N-dimethylformamide (20mL) was slowly added dropwise to the reaction solution, and the mixture was reacted at room temperature for 15 hours. The reaction solution was then poured into 400mL of water, extracted twice with ethyl acetate (300mL x 2), and the combined organic phase was washed with saturated saline (300mL), 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 = 10:1) to obtain the target compound (4.2g, yield 69.3%). LC-MS [M+H] + : 150.1. 1 H NMR (CDCl3, 600 MHz): δ 7.33 - 7.29 (m, 1 H), 7.20 - 7.17 (m, 1 H), 6.91 (dd, J = 5.4, 1.2 Hz, 1 H), 1.71 - 1.67 (m, 2 H), 1.38 - 1.34 (m, 2H). Step b: Synthesis of 1-(thiophen-3-yl)cyclopropanecarbaldehyde 1-(thiophen-3-yl)cyclopropanecarbonitrile (4.2 g, 28.15 mmol) was dissolved in 100 mL of tetrahydrofuran, and a solution of diisobutylaluminum hydride (1 M in hexane, 56.30 mL, 56.30 mmol) was slowly added dropwise in an ice bath. After the dropwise addition was completed, the mixture was reacted at room temperature for 2 hours. Next, the reaction solution was slowly poured into 300 mL of an aqueous solution of ammonium chloride, and 300 mL of ethyl acetate was added for extraction. The organic phase was obtained by separation, and the aqueous phase was extracted with ethyl acetate (200 mL). The combined 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 = 10: 1) to obtain the target compound (3.0 g, yield 70.1%). LC-MS [M+H] + : 153.1. 1 H NMR (CDCl3, 600 MHz): δ 9.23 (s, 1 H), 7.34 - 7.31 (m, 1 H), 7.25 - 7.22 (m, 1 H), 7.05 (dd, J = 4.8, 1.2 Hz, 1 H), 1.60 - 1.55 (m, 2 H), 1.43 - 1.39 (m, 2H). Step c: Synthesis of 1-(thiophen-3-yl)cyclopropanemethanol 1-(Thiophen-3-yl)cyclopropanecarbaldehyde (1.0 g, 6.57 mmol) was dissolved in tetrahydrofuran (20 mL), lithium aluminum hydride (0.25 g, 6.57 mmol) was added in an ice bath, and the reaction was continued for 10 minutes. Ethyl acetate was slowly added dropwise to the reaction solution to stop the reaction, and the solvent was dried in an evaporator to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain the target compound (0.9 g, yield 89%). LC-MS [M+H] + : 155.1. 1H NMR (CDCl3, 600 MHz): δ 7.27 - 7.24 (m, 1 H), 7.12 - 7.09 (m, 1 H), 6.97 (dd, J = 4.8, 1.2 Hz, 1 H), 3.69 (d, J = 4.8 Hz, 2 H), 0.91 - 0.81 (m, 4H). Step d: Synthesis of 1-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine 1-(thiophen-3-yl)cyclopropanemethanol (450.0 mg, 2.92 mmol) and 2,2-dimethoxy-N-methylethylamine (417.5 mg, 3.50 mmol) were dissolved in 9 mL of dioxane, then trifluoromethanesulfonic acid (1314.7 mg, 8.76 mmol) was added dropwise in an ice bath and stirred at room temperature for 15 hours. The reaction solution was then poured into 30 mL of water, basified with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain the target product (90.0 mg, yield 14.7%). LC-MS [M+H] + : 210.1. 1 H NMR (CD3OD, 600 MHz): δ 7.29 (d, J = 4.8 Hz, 1 H), 6.58 (d, J = 5.4 Hz, 1 H), 5.21 (dd, J = 9.0, 3.0 Hz, 1 H), 3.93 (dd, J = 12.0, 1.2 Hz, 1 H), 3.59 (d, J = 11.4 Hz, 1 H), 3.49 (dd, J = 13.2, 3.0 Hz, 1 H), 3.30 -3.24 (m, 1 H), 2.73 (s, 3 H), 1.07 - 0.76 (m, 4 H).

[0184] Example 8-R and Example 8-S (R)-1-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine and (S)-1-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine

[0185] [ka]

[0186] Example 8 was resolved on a chiral chromatography column to give optical enantiomer 1 (Example 8-R) and optical enantiomer 2 (Example 8-S). Liquid chromatography method: Chromatography column: DAICEL CHIRALPAK IG column; Mobile phase A: supercritical CO2, Mobile phase B: methanol (containing 0.1% dimethylamine); Detection wavelength: 214 nm; Flow rate: 1.5 mL / min, Column temperature: 35° C.; Background column pressure: 1800 psi. Mobile phase gradient:

[0187] [Table 1]

[0188] Optical Enantiomer 1 (Example 8-R): RT: 3.29 min; [α]D 29 =81.9(c 0.177,MeOH);LC-MS [M+H] + : 210.1. 1 H NMR (CDCl3, 600 MHz): δ 7.12 (dd, J = 4.8, 0.6 Hz, 1 H), 6.48 (d, J = 5.4 Hz, 1 H), 4.99 (dd, J = 7.8, 4.8 Hz, 1 H), 3.99 (dd, J = 11.4, 1.2 Hz, 1 H), 3.50 (d, J = 11.4 Hz, 1 H), 3.01-2.94 (m, 2 H), 2.52 (s, 3 H), 1.04 - 0.75 (m, 4 H). Optical Enantiomer 2 (Example 8-S): RT: 3.67 min; [α]D 29 = -109.8 (c 0.186, MeOH); LC-MS [M+H] + : 210.1. 1 H NMR (CDCl3, 600 MHz): δ 7.12 (dd, J = 5.4, 1.2 Hz, 1 H), 6.48 (d, J = 4.8 Hz, 1 H), 4.99 (dd, J = 7.8, 4.2 Hz, 1 H), 3.99 (dd, J = 11.4, 1.2 Hz, 1 H), 3.50 (d, J = 11.4 Hz, 1 H), 3.02 - 2.93 (m, 2 H), 2.52 (s, 3 H), 1.05 - 0.74 (m, 4 H).

[0189] Example 9 1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine

[0190] [ka]

[0191] [ka]

[0192] Step a: Synthesis of 1-(thiophen-2-yl)cyclopropanenitrile Under ice bath and nitrogen protection, sodium hydride (60%, 1.6 g, 40.59 mmol) was added to a solution of 2-(thiophen-2-yl)acetonitrile (2.0 g, 16.24 mmol) in N,N-dimethylformamide (30 mL) and stirred for 1 hour to react. Then, 1,2-dibromoethane (4.0 g, 21.3 mmol) was slowly added, and the reaction solution was slowly warmed to room temperature and stirred overnight. After the reaction was completed, water (300 mL) was added in an ice bath to quench the reaction, and the mixture was extracted with ethyl acetate (300 mL x 3). The extracted phase was washed with water (200 mL x 3) and saturated saline (200 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.5 g, yield 61.9%). 1 H NMR (300 MHz, CDCl3) δ 7.17 (dd, J = 5.1, 0.6 Hz, 1 H), 7.07 - 7.02 (m, 1 H), 6.95 - 6.89 (m, 1 H), 1.78 - 1.67 (m, 2 H), 1.47 - 1.37 (m, 2 H). Step b: Synthesis of 1-(thiophen-2-yl)cyclopropanal Under ice bath and nitrogen protection, diisobutylaluminum hydride (1M in hexane, 18.8mL, 18.8mmol) was slowly added dropwise to a solution of 1-(thiophen-2-yl)cyclopropanenitrile (1.4g, 9.38mmol) in tetrahydrofuran (100mL), and stirring was continued at room temperature for 3 hours. After the reaction was completed, water (300mL) was added in an ice bath to quench the reaction, and the mixture was extracted with ethyl acetate (300mL x 3). The extracted phase was washed with water (300mL x 3) and saturated saline (300mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the target product (632.0mg, yield 44.3%). 1H NMR (300 MHz, CDCl3) δ 9.34 (s, 1 H), 7.27 - 7.20 (m, 1 H), 7.03 - 6.96 (m, 2 H), 1.73 - 1.64 (m, 2 H), 1.55 - 1.47 (m, 2 H). Step c: Synthesis of (1-(thiophen-2-yl)cyclopropyl)methanol Under ice bath and nitrogen protection, a solution of lithium aluminum hydride in tetrahydrofuran (20mL) (2.5M in THF, 3.3mL, 8.30mmol) was slowly added dropwise to a solution of 1-(thiophen-2-yl)cyclopropanal (632.0mg, 4.15mmol) in tetrahydrofuran (20mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (200mL) was added to quench the reaction in an ice bath, and the mixture was extracted with ethyl acetate (300mL x 3). The extracted phase was washed with water (300mL x 3) and saturated saline (300mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography to obtain the target product (570.0mg, yield 89.0%). 1 H NMR (300 MHz, CDCl3) δ 7.17- 7.11 (m, 1 H), 6.97 - 6.90 (m, 2 H), 3.68 (s, 2 H), 1.96 (s, 1 H), 1.06 - 0.89 (m, 4 H). Step d: Synthesis of 1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine 2,2-Dimethoxy-N-methylethanamine (386.0 mg, 3.24 mmol) and trifluoromethanesulfonic acid (0.8 mL) were added to a solution of (1-(thiophen-2-yl)cyclopropyl)methanol (250 mg, 1.62 mmol) in 2-methyltetrahydrofuran (5 mL), and the mixture was stirred at 80° C. for 20 minutes. After the reaction was completed, the pH of the reaction solution was adjusted to 13 with a 15% aqueous sodium hydroxide solution in an ice bath, and then the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL×3), and the crude product obtained by concentrating the extract phase was separated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the target product (7.3 mg, yield 2.2%). 1 H NMR (400 MHz, CD3OD) δ 7.21 (d, J = 5.2 Hz, 1 H), 6.89 (d, J = 5.2 Hz, 1 H), 5.11 (d, J = 8.8 Hz, 1 H), 3.99 (d, J = 11.6 Hz, 1 H), 3.68 (d, J = 11.2 Hz, 1 H), 3.60 (dd, J = 12.8, 2.4 Hz, 1 H), 3.32-3.25 (m, 1 H), 2.77 (s, 3 H), 1.16 - 0.85 (m, 4 H). LC-MS [M+H] + : 210.1.

[0193] Example 9-S and Example 9-R (S)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine and (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine

[0194] [ka]

[0195] Example 9 was resolved on a chiral chromatography column to give optical enantiomer 1 (Example 9-S) and optical enantiomer 2 (Example 9-R). Liquid chromatography method: Chromatography column: DAICEL CHIRALPAK IG column; Mobile phase A: supercritical CO2, Mobile phase B: methanol (containing 0.1% dimethylamine); Detection wavelength: 214 nm; Flow rate: 1.5 mL / min, Column temperature: 35° C.; Background column pressure: 1800 psi. Mobile phase gradient:

[0196] [Table 2]

[0197] Optical Enantiomer 1 (Example 9-S): RT: 3.23 min; [α]D 29 = 65.1 (c 0.175, MeOH); LC-MS [M+H] + : 210.1. 1 H NMR (CDCl3, 600 MHz): δ 7.00 (d, J = 5.4 Hz, 1 H), 6.75 (d, J = 4.8 Hz, 1 H), 4.98 (dd, J = 9.0, 2.4 Hz, 1 H), 3.92 (d, J = 11.4 Hz, 1 H), 3.57 (d, J = 11.4 Hz, 1 H), 3.07 (dd, J = 12.6, 2.4 Hz, 1 H), 2.95 (dd, J = 12.0, 9.0 Hz, 1H), 2.54 (s, 3 H), 1.08 - 0.90 (m, 4 H). Optical Enantiomer 1 (Example 9-R): RT: 3.62 min; [α]D 29 = -59.1 (c 0.163, MeOH); LC-MS [M+H] + : 210.1. 1H NMR (CDCl3, 600 MHz): δ 7.00 (d, J = 5.4 Hz, 1 H), 6.75 (d, J = 4.8 Hz, 1 H), 4.93 (dd, J = 9.0, 3.0 Hz, 1 H), 3.92 (dd, J = 11.4, 1.2 Hz, 1 H), 3.56 (d, J = 11.4 Hz, 1 H), 3.02 (dd, J = 12.6, 3.0 Hz, 1 H), 2.92 (dd, J = 12.6, 9 Hz, 1 H), 2.51 (s, 3 H), 1.05 - 0.90 (m, 4 H).

[0198] Example 10 1-(6',7'-dihydrospiro[cyclopropane-1,4'-thieno[3,2-c]pyran]-7'-yl)-N-methylmethylamine

[0199] [ka]

[0200] [ka]

[0201] LC-MS [M+H] + : 210.1.

[0202] Example 11 1-(6'H-spiro[cyclopropane-1,4'-thieno[2,3-c]furan]-6'-yl)-N-methylmethylamine

[0203] [ka]

[0204] [ka]

[0205] LC-MS [M+H] + : 196.1.

[0206] Example 12 1-(6,7-dihydro-5H-spiro[benzo[b]thiophene-4,1'-cyclopropane]-7-yl)-N-methylmethylamine

[0207] [ka]

[0208] [ka]

[0209] LC-MS [M+H] + : 208.1.

[0210] Example 13 1-(5,6-Dihydrospiro[cyclopentadieno[b]thiophene-4,1'-cyclopropane]-6-yl)-N-methylmethylamine

[0211] [ka]

[0212] [ka]

[0213] LC-MS [M+H] + : 194.1.

[0214] Example 15 N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)methan-d3-amine

[0215] [ka]

[0216] [ka]

[0217] Step a: Synthesis of tert-butyl ((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)carbamate To a solution of (5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methylamine (500.0 mg, 2.56 mmol) in dichloromethane (5 mL), sodium hydroxide (512.04 mg, 12.80 mmol) and di-tert-butyl dicarbonate (1.12 g, 5.12 mmol) were added and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched by adding water (10 mL), extracted with ethyl acetate (10 mL x 3), and the extract phase was concentrated to obtain a crude product, which was separated and purified by column chromatography to obtain the target product (430.0 mg, yield 56.9%). LC-MS [M+H-56] + : 240.1. Step b: Synthesis of tert-butyl((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)(base-d3)carbamate To a solution of tert-butyl ((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)carbamate (180.0 mg, 0.61 mmol) in N,N-dimethylformamide (6 mL), sodium hydride (60%, 48.8 mg, 1.22 mmol) and deuterated iodomethane (92.3 mg, 0.64 mmol) were added and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), and the extract phase was concentrated to obtain the desired crude product (600 mg). LC-MS [M+H-100] + : 213.0. Step c: Synthesis of N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)methane-d3-amine Dioxane hydrochloride (4M, 2mL) was added to a solution of tert-butyl ((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)(methyl-d3)carbamate (600mg crude product) in dioxane (6mL) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated, and the obtained crude product was separated and purified by preparative liquid chromatography to obtain the target product (21.2mg, yield 4.3%). 1 H NMR (600 MHz, CDCl3): δ 7.12 (d, J = 5.4 Hz, 1 H), 6.48 (d, J = 5.4 Hz, 1 H), 5.01 - 4.97 (m, 1 H), 3.98 (d, J = 11.4 Hz, 1 H), 3.49 (d, J = 11.4 Hz, 1 H), 3.01 - 2.93 (m, 2 H), 1.05 - 0.75 (m, 4 H). LC-MS [M+H] + : 213.1.

[0218] Example 16 N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)ethylamine

[0219] [ka]

[0220] [ka]

[0221] Step a: Synthesis of N-(2,2-dimethoxyethyl)acetamide In an ice bath and under nitrogen protection, triethylamine (288.6 mg, 2.85 mmol) was added to a solution of 2,2-dimethoxyethylamine (200.0 mg, 1.90 mmol) in dichloromethane (2 mL), and the mixture was stirred for 30 minutes. After that, acetic anhydride (233.0 mg, 2.28 mmol) was slowly added and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added in an ice bath, and the mixture was extracted with dichloromethane (10 mL x 3). The extract was washed with water (10 mL x 3) and saturated saline (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the target product (500 mg crude product), which was used in the next reaction without purification. Step b: Synthesis of N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)acetamide To a solution of (1-(thiophen-3-yl)cyclopropyl)methanol (200 mg, 1.3 mmol) in 2-methyltetrahydrofuran (9 mL), N-(2,2-dimethoxyethyl)acetamide (500 mg crude product) and trifluoromethanesulfonic acid (389.6 mg, 2.6 mmol) were added and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was adjusted to pH 13 with 15% aqueous sodium hydroxide solution, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), and the extract was purified by column chromatography to obtain the target product (250.0 mg, yield 81.0%). LC-MS [M+H] + : 238.1. Step c: Synthesis of N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)ethylamine Under ice bath and nitrogen protection, lithium aluminum hydride (2.5M in THF, 0.84mL, 2.1mmol) was slowly added to a solution of N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)acetamide (250mg, 1.05mmol) in tetrahydrofuran (2.5mL), and the reaction was carried out at 70°C for 2 hours. After the reaction was completed, water (10mL) was added in an ice bath to quench the reaction, and the mixture was extracted with ethyl acetate (10mL x 3). The extracted phase was washed with water (10mL x 3) and saturated saline (10mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by preparative liquid chromatography (water / formic acid / acetonitrile) to obtain the target product (87.0mg, 19.9%). 1 H NMR (400 MHz, CD3OD): δ 8.49 (s, 1 H), 7.31 (dd, J = 5.2, 0.8 Hz, 1 H), 6.61 (d, J = 5.2 Hz, 1 H), 5.22 (dd, J = 9.2, 2.8 Hz, 1 H), 3.96 (dd, J = 11.6, 1.2 Hz, 1 H), 3.62 (d, J = 11.6 Hz, 1 H), 3.51-3.44 (m, 1 H), 3.30 - 3.23 (m, 1 H), 3.17 - 3.09 (m, 2 H), 1.32 (t, J = 7.6 Hz, 3 H), 1.10 - 1.02 (m, 1 H), 1.00 - 0.78 (m, 3H). LC-MS [M+H] + : 224.1.

[0222] Example 17 N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)propan-2-amine

[0223] [ka]

[0224] [ka]

[0225] Step a: Synthesis of (5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methanamine 2,2-Dimethoxyethylamine (1.5g, 14.26mmol) and trifluoromethanesulfonic acid (3.89g, 25.94mmol) were added to a solution of (1-(thiophen-3-yl)cyclopropyl)methanol (2.0g, 12.97mmol) in 2-methyltetrahydrofuran (40mL), and the mixture was stirred at room temperature for 16 hours. Then, the reaction solution was adjusted to pH 13 with 15% aqueous sodium hydroxide solution, diluted with water (20mL), and the mixture was extracted with ethyl acetate (20mL x 3). The extract phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography to obtain the target product (500.0mg, yield 19.7%). LC-MS [M+H] + : 196.1. Step b: Synthesis of tert-butyl ((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)carbamate Sodium hydroxide (512.04g, 12.80mmol) and di-tert-butyl dicarbonate (1.12g, 5.12mmol) were added to a dichloromethane (5mL) solution of (5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methylamine (500.0mg, 2.56mmol) and stirred at room temperature for 16 hours. The reaction solution was then diluted with water (10mL) and extracted with ethyl acetate (10mL x 3). The extract phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography to obtain the target product (430mg, yield 56.9%). LC-MS [M+H-56] + : 240.1. Step c: Synthesis of tert-butyl((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)(isopropyl)carbamate To a solution of tert-butyl ((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)carbamate (250.0 mg, 0.85 mmol) in N,N-dimethylformamide (2.5 mL), sodium hydride (60%, 67.8 mg, 1.69 mmol) and 2-iodopropane (1.12 g, 1.69 mmol) were added and stirred at room temperature for 3 days. Then, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The crude product obtained by concentrating the extract phase was purified by column chromatography to obtain the desired product (120.0 mg, 41.8% yield). LC-MS [M+H-100] + : 238.1. Step d: Synthesis of N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)propan-2-amine To a solution of tert-butyl ((5',7'-dihydrospiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)(isopropyl)carbamate (120.0 mg, 0.36 mmol) in dioxane (2 mL), dioxane hydrochloride (4 M, 1 mL) was added, stirred at room temperature for 2 hours, and then directly concentrated. The resulting crude product was separated and purified by preparative liquid chromatography to obtain the desired product (6.1 mg, yield 7.2%). 1H NMR (400 MHz, CD3OD): δ 7.25 (d, J = 5.2 Hz, 1 H), 6.59 (d, J = 5.2 Hz, 1 H), 5.02 (dd, J = 9.2, 3.2 Hz, 1 H), 3.96 (d, J = 11.6 Hz, 1 H), 3.58 (d, J = 11.6 Hz, 1 H), 3.06 (dd, J = 12.4, 3.2 Hz, 1 H), 3.01 - 2.90 (m, 2 H), 1.16 (d, J = 6.4 Hz, 6 H), 1.09 - 0.77 (m, 4 H). LC-MS [M+H] + : 238.2.

[0226] Example 18 N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)-2,2,2-trifluoroethane-1-amine

[0227] [ka]

[0228] [ka]

[0229] Under ice bath and nitrogen protection, N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)-2,2,2-trifluoroacetamide (300.0 mg, 1.03 mmol) in tetrahydrofuran (10 mL) was added with borane in tetrahydrofuran (1M in THF, 3.09 mL, 3.09 mmol), and the mixture was stirred at 70 ° C for 2 hours. After the reaction was completed, methanol (10 mL) and hydrochloric acid (2 M, 10 mL) were added in an ice bath to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The extracted phase was washed with water (10 mL x 3) and saturated saline (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained crude product was separated and purified by preparative liquid chromatography to obtain the target product (76.6 mg, yield 26.8%). 1 H NMR (400 MHz, CD3OD): δ 7.23 (d, J = 5.2 Hz, 1 H), 6.58 (d, J = 5.2 Hz, 1 H), 4.97 (t, J = 5.6 Hz, 1 H), 3.96 (d, J = 11.2 Hz, 1 H), 3.56 (d, J = 11.6 Hz, 1 H), 3.44 - 3.26 (m, 2 H), 3.12 - 3.02 (m, 2 H), 1.10 - 0.77 (m, 4 H). LC-MS [M+H] + : 278.1.

[0230] Example 19 N-Methyl-1-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)ethan-1-amine

[0231] [ka]

[0232] [ka]

[0233] Step a: Synthesis of 1,1-dimethoxy-N-methylpropan-2-amine Under nitrogen protection at 10°C, titanium tetraisopropoxide (9.62g, 33.86mmol), methylamine (526.0mg, 33.86mmol) and triethylamine (3.42g, 33.86mmol) were added to a solution of 1,1-dimethoxypropan-2-one (2.0g, 16.93mmol) in ethanol (20mL) and stirred at room temperature for 16 hours. Then, sodium borohydride (1.28g, 33.86mmol) was added and stirred at room temperature for 6 hours. After the reaction was completed, the reaction was quenched by adding aqueous ammonia (2M, 60mL) in an ice bath, the reaction solution was filtered, the filtrate was extracted with dichloromethane (30mL x 3), the extract phase was washed with water (15mL x 3) and saturated saline (15mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the desired crude product (1.8g). Step b: Synthesis of N-(1,1-dimethoxypropan-2-yl)-2,2,2-trifluoro-N-methylacetamide In an ice bath and under nitrogen protection, triethylamine (341.7 mg, 3.37 mmol) was added to a solution of 1,1-dimethoxy-N-methylpropan-2-amine (300.0 mg, 2.25 mmol) in dichloromethane (10 mL), and after stirring for 30 minutes, trifluoroacetic anhydride (568.4 mg, 2.7 mmol) was added and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution (10 mL) in an ice bath, and then extracted with dichloromethane (10 mL x 3). The extracted phase was washed with water (10 mL x 3) and saturated saline (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the desired crude product (600 mg). Step c: Synthesis of N-methyl-1-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)ethan-1-amine

[0234] [ka]

[0235] To a solution of (1-(thiophen-3-yl)cyclopropyl)methanol (200.0 mg, 1.3 mmol) in 2-methyltetrahydrofuran (9 mL), N-(1,1-dimethoxypropan-2-yl)-2,2,2-trifluoro-N-methylacetamide (crude product 600 mg) and trifluoromethanesulfonic acid (584.4 mg, 3.9 mmol) were added and stirred at room temperature for 16 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 13 with a 15% aqueous sodium hydroxide solution, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), and the extracted phase was concentrated. The obtained crude product was separated and purified by preparative liquid chromatography (water / formic acid / acetonitrile) to obtain the target product (5.3 mg, yield 1.5%). 1 H NMR (400 MHz, CD3OD): δ 8.56 (s, 1 H), 7.38 (d, J = 5.2, 0.8 Hz, 1 H), 6.67 (d, J = 5.2 Hz, 1 H), 5.05 (d, J = 3.6 Hz, 1 H), 4.05 (d, J = 11.2, 1.6 Hz, 1 H), 3.60 (d, J = 11.6 Hz, 1 H), 3.57 - 3.48 (m, 1 H), 2.62 (s, 3 H), 1.56 (d, J = 6.4 Hz, 3 H), 1.18 - 1.08 (m, 1 H), 1.07 - 0.97 (m, 1 H), 0.96 - 0.82 (m, 2H). LC-MS [M+H] + : 224.1.

[0236] Example 20 N-Methyl-2-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)propan-2-amine

[0237] [ka]

[0238] [ka]

[0239] Step a: Synthesis of 2,2,2-trifluoro-N-(1-hydroxy-2-methylpropan-2-yl)acetamide Under ice bath and nitrogen protection, ethyl trifluoroacetate (8.5g, 60.0mmol) and triethylamine (7.6g, 75.0mmol) were added to a solution of 2-amino-2-methylpropan-1-ol (4.4g, 49.4mmol) in methanol (100mL), and the reaction solution was stirred overnight. After that, the reaction solution was directly concentrated to obtain a crude product, which was separated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain the target product (4.2g, yield 45.9%). 1 H NMR (400 MHz, CDCl3): δ 6.47 (brs, 1H), 3.63 (s, 2H), 1.39 (s, 6H). Step b: Synthesis of 2,2,2-trifluoro-N-(2-methyl-1-oxopropan-2-yl)acetamide Under ice bath and nitrogen protection, Dess-Martin reagent (14.4g, 34.0mmol) was added to a dichloromethane (140mL) solution of 2,2,2-trifluoro-N-(1-hydroxy-2-methylpropan-2-yl)acetamide (4.2g, 22.8mmol) and stirred for 12 hours while keeping warm. Then, saturated aqueous sodium thiosulfate solution (100mL) was added, followed by extraction with dichloromethane (100mL). The extracted phase was washed with saturated aqueous sodium bicarbonate solution (100mL x 2), water (100mL) and saturated saline (100mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the desired crude product (3.5g, yield 91.0%). Step c: Synthesis of N-(2-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)propan-2-yl)-2,2,2-trifluoroacetamide (1-(thiophen-3-yl)cyclopropyl)methanol (600.0 mg, 3.89 mmol) and 2,2,2-trifluoro-N-(2-methyl-1-oxopropan-2-yl)acetamide (1.4 g, 8.0 mmol) in 2-methyltetrahydrofuran (10 mL) were slowly added with trifluoromethanesulfonic acid (2.4 g, 16.0 mmol) in 2-methyltetrahydrofuran (2 mL) and stirred in an ice bath for 6 hours. After the reaction was completed, the reaction solution was adjusted to pH 13 with 15% aqueous sodium hydroxide solution, diluted with water (100 mL), extracted with ethyl acetate (100 mL x 2), and the crude product obtained by concentrating the extract phase was separated and purified by column chromatography (petroleum ether: ethyl acetate = 20: 1 to 10: 1) to obtain the target product (250.0 mg, yield 20.1%). 1 H NMR (400 MHz, CDCl3): δ 7.15 (d, J = 5.2 Hz, 1 H), 6.67 (brs, 1 H), 6.52 (d, J = 5.6 Hz, 1 H), 5.15 (s, 1 H), 4.04 (dd, J = 11.2, 1.2 Hz, 1 H), 3.39 (d, J = 11.2 Hz, 1 H), 1.54 (d, J = 4.4 Hz, 6 H), 1.11-1.03 (m, 1 H), 1.02 - 0.92 (m, 1 H), 0.90 - 0.73 (m, 2 H). Step d: Synthesis of N-methyl-2-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)propan-2-amine To a solution of N-(2-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)propan-2-yl)-2,2,2-trifluoroacetamide (245.0 mg, 0.77 mmol) in tetrahydrofuran (6 mL) was added sodium hydride (60%, 123.0 mg, 3.1 mmol) in an ice bath and stirred for 30 minutes, then iodomethane (219.0 mg, 1.54 mmol) was added and stirred at room temperature for 2 hours. The temperature was then raised to 55°C and stirring was continued for 3 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (100 mL), washed successively with saturated aqueous ammonium chloride solution (50 mL), water (50 mL), and saturated saline solution (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography (dichloromethane:methanol=20:1) and preparative liquid chromatography to obtain the desired product (14.6 mg, yield 6.7%). 1 H NMR (400 MHz, CD3OD): δ 8.53 (s, 1 H), 7.33 (d, J = 5.2 Hz, 1 H), 6.66 (d, J = 5.2 Hz, 1 H), 5.10 (s, 1 H), 4.07 (d, J = 11.2 Hz, 1 H), 3.49 (d, J = 11.6 Hz, 1 H), 2.66 (s, 3 H), 1.62 (s, 3 H), 1.23 (s, 3 H), 1.21-1.10 (m, 1 H), 1.05-0.95 (m, 1 H), 0.88-0.78 (m, 2 H). LC-MS [M+H] + : 238.1.

[0240] Example 21 N-Methyl-1-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)cyclopropan-1-amine

[0241] [ka]

[0242] [ka]

[0243] Step a: Synthesis of methyl 1-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)cyclopropanecarboxylate In an ice bath, sodium carbonate (4.77g, 45.0mmol), fluorenyl methoxycarbonyl chloride (11.6g, 45.0mmol), and triethylamine (7.6g, 75.0mmol) were added to a mixed solution (50mL:50mL) of 2-amino-2-methylpropan-1-ol (3.45g, 30.0mmol) in dioxane and water, and the reaction solution was slowly warmed to room temperature and stirred overnight. The mixture was then diluted with ethyl acetate (300mL), washed with water (300mL x 3) and saturated saline (50mL), and the organic phase was separated and concentrated to obtain a crude product, which was washed with a mixed solvent (petroleum ether:ethyl acetate:methanol = 10:2:1) and stirred to obtain the desired product (9.4g, yield 92.9%). Step b: Synthesis of (9H-fluoren-9-yl)methyl (1-(hydroxymethyl)cyclopropyl)carbamate In an ice bath and under nitrogen protection, lithium aluminum hydride (2.5M in THF, 14.2mL, 35.6mmol) was added to a solution of methyl 1-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)cyclopropanecarboxylate (8.0g, 23.7mmol) in tetrahydrofuran (100mL), and the mixture was stirred for 3 hours while keeping warm. After the reaction was completed, water (1mL), 10% aqueous sodium hydroxide solution (4mL), and ethyl acetate (100mL) were added sequentially to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, 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 (3.0g, yield 40.9%). Step c: Synthesis of (9H-fluoren-9-yl)methyl (1-formylcyclopropyl)carbamate At -70°C and under nitrogen protection, a solution of oxalyl chloride (1.9g, 15mmol) in dichloromethane (5mL) was slowly added dropwise to a solution of dimethylsulfoxide (1.17g, 15mmol) in dichloromethane (50mL), and the mixture was stirred for 30 minutes while keeping the temperature. Next, (9H-fluoren-9-yl)methyl (1-(hydroxymethyl)cyclopropyl)carbamate (3.0g, 9.7mmol) was dissolved in a mixed solvent of tetrahydrofuran and dichloromethane (20mL:20mL), slowly added dropwise to the above reaction solution, and reacted for 1 hour while keeping the temperature. Then, triethylamine (7mL, 50mmol) was added, and the reaction solution was slowly returned to room temperature. The reaction was then quenched by adding water (100 mL) and extracted with dichloromethane (100 mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give the desired product (900.0 mg, 30.2% yield). Step d: Synthesis of (9H-fluoren-9-yl)methyl (1-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)cyclopropyl)carbamate A solution of (1-(thiophen-3-yl)cyclopropyl)methanol (251.0 mg, 1.63 mmol) and (9H-fluoren-9-yl)methyl (1-formylcyclopropyl)carbamate (500.0 mg, 1.63 mmol) in 2-methyltetrahydrofuran (10 mL) was added with a solution of trifluoromethanesulfonic acid (978.0 mg, 6.52 mmol) in 2-methyltetrahydrofuran (2 mL) and stirred in an ice bath for 30 minutes. After the reaction was completed, the pH of the reaction solution was adjusted to 13 with a 15% aqueous sodium hydroxide solution, diluted with water (100 mL), extracted with ethyl acetate (100 mL x 2), and the extract phase was concentrated to obtain a crude product, which was separated and purified by column chromatography to obtain the target product (170.0 mg, yield 23.5%). LC-MS [M+H] + : 444.2. Step e: Synthesis of 1-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)cyclopropanamine Under ice bath and nitrogen protection, piperidine (161.0 mg, 1.9 mmol) was added to a dichloromethane (3 mL) solution of (9H-fluoren-9-yl)methyl (1-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c])pyran]-7'-yl)cyclopropyl)carbamate (170.0 mg, 0.38 mmol) and stirred at room temperature for 5 hours. The reaction solution was then poured into water (50 mL), extracted with dichloromethane (50 mL), and the extracted phase was washed with saturated aqueous sodium bicarbonate solution (100 mL x 2), water (100 mL) and saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the target product (80 mg, yield 95.1%). LC-MS [M+H] + : 222.1. Step f: Synthesis of N-methyl-1-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)cyclopropan-1-amine Under ice bath conditions, 1-(5',7'-dihydrospiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)cyclopropanamine (44.0 mg, 0.2 mmol) in hexafluoroisopropanol (6 mL) was added with methyl trifluoromethanesulfonate (50.0 mg, 0.3 mmol) and stirred at room temperature for 3 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (10 mL), water (50 mL), and saturated saline (50 mL) in sequence. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography and preparative liquid chromatography (water / formic acid / acetonitrile) to obtain the target product (8.4 mg, yield 15.0%). 1H NMR (400 MHz, CD3OD): δ 8.46 (s, 1 H), 7.36 (d, J = 5.2 Hz, 1 H), 6.67 (d, J = 5.2 Hz, 1 H), 4.72 (s, 1 H), 4.02 (dd, J = 11.6, 1.6 Hz, 1 H), 3.60 (d, J = 11.6 Hz, 1 H), 2.59 (s, 3 H), 1.32 - 0.80 (m, 8 H). LC-MS [M+H] + : 236.1.

[0244] Example 22 2-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)pyrrolidine

[0245] [ka]

[0246] [ka]

[0247] To a solution of (1-(thiophen-3-yl)cyclopropyl)methanol (1.0 g, 6.48 mmol) in 2-methyltetrahydrofuran (40 mL), tert-butyl 2-formylpyrrolidine-1-carboxylate (1.42 g, 7.13 mmol) and trifluoromethanesulfonic acid (1.94 g, 12.96 mmol) were added and stirred at room temperature for 20 minutes. After the reaction was completed, the pH of the reaction solution was adjusted to 13 with a 15% aqueous sodium hydroxide solution, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), and the extract phase was concentrated to obtain a crude product, which was separated and purified by column chromatography and supercritical fluid chromatography (diethylamine / ethanol) to obtain a pair of diastereomers. Diastereomer 1 (20.1 mg, 1.32% yield). 1H NMR (400 MHz, CD3OD): δ 7.27 (d, J = 5.2 Hz, 1 H), 6.59 (d, J = 5.2 Hz, 1 H), 4.88 (d, J = 9.6 Hz, 1 H), 3.95 (d, J = 11.6 Hz, 1 H), 3.67 - 3.52 (m, 2 H), 3.20 - 3.06 (m, 1 H), 3.05 - 2.92 (m, 1 H), 2.30 - 2.14 (m, 1 H), 2.07 - 1.84 (m, 3 H), 1.13 - 0.75 (m, 4 H). LC-MS [M+H] + : 236.1. Diastereomer 2 (37.5 mg, yield 2.46%) 1 H NMR (400 MHz, CD3OD): δ 7.29 (d, J = 5.2 Hz, 1 H), 6.60 (d, J = 5.2 Hz, 1 H), 4.94 (d, J = 6.0 Hz, 1 H), 3.97 (dd, J = 11.6, 1.6 Hz, 1 H), 3.74 - 3.65 (m, 1 H), 3.61 (d, J = 11.6 Hz, 1 H), 3.24 - 3.14 (m, 1 H), 3.13 - 3.03 (m, 1 H), 2.36 - 2.19 (m, 1 H), 2.10 - 1.85 (m, 3 H), 1.11 - 0.76 (m, 4H). LC-MS [M+H] + : 236.1.

[0248] Example 23 1-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)azetidine

[0249] [ka]

[0250] [ka]

[0251] Step a: Synthesis of 7'-(bromomethyl)-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran Under ice bath conditions, trifluoromethanesulfonic acid (10.0 g, 66.6 mmol) was added to a solution of (1-(thiophen-3-yl)cyclopropyl)methanol (2.21 g, 14.3 mmol) and 2-bromo-1,1-dimethoxyethane (2.0 g, 11.9 mmol) in 2-methyltetrahydrofuran (25 mL), and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was adjusted to pH 13 with 15% aqueous sodium hydroxide solution, diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3), and the crude product obtained by concentrating the extract phase was purified by column chromatography to obtain the target product (2.6 g, yield 70.2%). 1 H NMR (400 MHz, CDCl3): δ 7.18 (d, J = 5.2 Hz, 1 H), 6.51 (d, J = 5.2 Hz, 1 H), 5.13 (dd, J = 8.0, 4.0 Hz, 1 H), 3.96 (d, J = 11.6 Hz, 1 H), 3.77 - 3.70 (m, 1 H), 3.67 - 3.57 (m, 2 H), 1.06 - 0.75 (m, 4 H). LC-MS [M+H] + : 258.9. Step b: Synthesis of 1-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)azetidine Potassium carbonate (4.2 g, 30.2 mmol) was added to a solution of 7'-(bromomethyl)-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran (2.6 g, 10.1 mmol) and azetidine (0.69 g, 12.1 mmol) in N,N-dimethylformamide (20 mL), and the mixture was stirred at 120 ° C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (200 mL), extracted with ethyl acetate (200 mL × 3), and the extract was washed with water (200 mL × 3) and saturated saline (200 mL) in sequence. After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated, and the crude product was purified by column chromatography and preparative liquid chromatography to obtain the target product (41.8 mg, yield 1.8%). 1 H NMR (400 MHz, CD3OD): δ 7.17 (d, J = 5.2 Hz, 1 H), 6.52 (d, J = 5.2 Hz, 1 H), 4.86 - 4.78 (m, 1 H), 3.84 (dd, J = 11.6, 1.2 Hz, 1 H), 3.51 (d, J = 11.6 Hz, 1 H), 3.40 - 3.30 (m, 4 H), 2.86 - 2.74 (m, 2 H), 2.17 - 2.05 (m, 2 H), 1.04 - 0.72 (m, 4 H). LC-MS [M+H] + : 236.1.

[0252] Example 24 5'H-Dispiro[cyclopropane-1,4'-thieno[2,3-c]pyran-7',3''-pyrrolidine]

[0253] [ka]

[0254] [ka]

[0255] To a solution of (1-(thiophen-3-yl)cyclopropyl)methanol (300.0 mg, 1.95 mmol) in 2-methyltetrahydrofuran (12 mL), tert-butyl 3-oxopyrrolidine-1-carboxylate (540.4 mg, 1.95 mmol) and trifluoromethanesulfonic acid (438.3 mg, 1.95 mmol) were added and stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was adjusted to pH 13 with 15% aqueous sodium hydroxide solution, then diluted with water (10 mL), the mixture was extracted with ethyl acetate (10 mL x 3), and the extract phase was concentrated to obtain a crude product, which was separated and purified by preparative liquid chromatography (water / formic acid / acetonitrile) to obtain the target product (6.2 mg, yield 1.2%). 1 H NMR (400 MHz, CD3OD): δ 8.54 (s, 1 H), 7.36 (d, J = 5.2 Hz, 1 H), 6.60 (d, J = 5.2 Hz, 1 H), 3.82 (d, J = 12.0 Hz, 1 H), 3.76 - 3.65 (m, 2 H), 3.64 - 3.47 (m, 2 H), 3.37 (d, J = 12.4 Hz, 1 H), 2.64 - 2.48 (m, 1 H), 2.41 - 2.27 (m, 1 H), 1.06 - 0.86 (m, 4 H). LC-MS [M+H] + : 222.1.

[0256] Example 25 N-Methyl-5'H-dispiro[cyclobutane-1,7'-thieno[2,3-c]pyran-4',1''-cyclopropane]-2-amine

[0257] [ka]

[0258] [ka]

[0259] LC-MS [M+H]+ : 236.1.

[0260] Example 26 N-Methyl-1-(4'H,6'H-spiro[cyclopropane-1,7'-pyrano[4,3-d]thiazol]-4'-yl)methanamine

[0261] [ka]

[0262] [ka]

[0263] LC-MS [M+H] + : 211.1.

[0264] Example 27 1-(5',6'-dihydro-8'H-spiro[cyclopropane-1,4'-thieno[2,3-c]oxepin]-8'-yl)-N-methylmethylamine

[0265] [ka]

[0266] [ka]

[0267] Step a: Synthesis of 3-(1-(2-methoxyvinyl)cyclopropyl)thiophene (Methoxymethyl)triphenylphosphine chloride (9.01g, 26.28mmol) was dissolved in tetrahydrofuran (80mL), and potassium tert-butoxide (2.95g, 26.28mmol) in tetrahydrofuran (20mL) was slowly added dropwise in an ice bath. After reacting for half an hour, 1-(thiophen-3-yl)cyclopropanecarbaldehyde (2g, 13.14mmol) in THF (20mL) was further added dropwise. After reacting for 1 hour, water (250mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (200mL x 2). The combined extract phase was dried over anhydrous sodium sulfate, filtered, and the solvent was dried with a spin evaporator to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target compound as a cis-trans mixture (1.8g, yield 76.0%). Cis products: 1 H NMR (CDCl3, 600 MHz): δ 7.20 - 7.17 (m, 1 H), 6.94 - 6.92 (m, 1 H), 6.85 - 6.82 (m, 1 H), 5.92 (d, J = 6.0 Hz, 1 H), 4.69 (d, J = 6.6 Hz, 1 H), 3.59 (s, 3 H), 1.15 - 1.11 (m, 2 H), 1.04 - 1.01 (m, 2 H). Trans products: 1 H NMR (CDCl3, 600 MHz): δ 7.24 - 7.21 (m, 1 H), 6.97 - 6.95 (m, 1 H), 6.90 - 6.87 (m, 1 H), 6.29 (d, J = 12.6 Hz, 1 H), 5.07 (d, J = 12.6 Hz, 1 H), 3.52 (s, 3 H), 1.00 - 0.92 (m, 4 H). Step b: Synthesis of 2-(1-(thiophen-3-yl)cyclopropyl)acetaldehyde 3-(1-(2-methoxyvinyl)cyclopropyl)thiophene (1.8 g, 9.99 mmol) was dissolved in tetrahydrofuran (20 mL), hydrochloric acid solution (20 mL, 2 M) was added, and the mixture was reacted at room temperature for 15 hours. The reaction mixture was then poured into water (60 mL), extracted twice with ethyl acetate (100 mL x 2), and the combined organic phase was washed with saturated aqueous sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound of interest (1.6 g, 96.3% yield), which was used directly in the next reaction without further purification. Step c: Synthesis of 2-(1-(thiophen-3-yl)cyclopropyl)ethanol 2-(1-(thien-3-yl)cyclopropyl)acetaldehyde (1.6 g, 9.62 mmol) was dissolved in tetrahydrofuran (30 mL), lithium aluminum tetrahydride (0.37 g, 9.62 mmol) was added little by little in an ice bath, and the reaction was allowed to proceed for 10 minutes. Anhydrous sodium sulfate (25 g) was then added to the reaction solution in an ice bath, and ice water was slowly added to quench the reaction. The reaction was then filtered and concentrated to obtain a crude product, which was then separated and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain the target compound (1.4 g, yield 86.5%). 1 H NMR (CDCl3, 600 MHz): δ 7.25 - 7.23 (m, 1 H), 6.98 - 6.96 (m, 2 H), 3.69 (t, J = 6.6 Hz, 2 H), 1.88 (t, J = 6.6 Hz, 2 H), 1.30 (brs, 1 H), 0.85 - 0.81 (m, 2 H), 0.75 - 0.72 (m, 2 H). Step d: Synthesis of 1-(5',6'-dihydro-8'H-spiro[cyclopropane-1,4'-thieno[2,3-c]oxepin]-8'-yl)-N-methylmethylamine 2-(1-(thiophen-3-yl)cyclopropyl)ethanol (800.0 mg, 4.75 mmol) and 2,2-dimethoxy-N-methylethylamine (566.0 mg, 4.75 mmol) were dissolved in dioxane (20 mL), and then trifluoromethanesulfonic acid (712.9 mg, 4.75 mmol) was added dropwise at room temperature and reacted at 110 ° C. for 2 hours in a microwave. After the reaction was completed, the reaction solution was poured into water (90 mL), alkalized with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate (80 mL × 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography (dichloromethane:methanol = 10:1) and preparative liquid chromatography to obtain the target product (22.0 mg, yield 11.4%). 1 H NMR (CDCl3, 600 MHz): δ 7.02 (d, J = 5.4 Hz, 1 H), 6.74 (d, J = 4.8 Hz, 1 H), 5.17 (dd, J = 11.4, 3.0 Hz, 1 H), 4.28 - 4.22 (m, 1 H), 4.04 - 3.97 (m, 1 H), 3.61 - 3.56 (m, 1 H), 3.39 - 3.31 (m, 1 H), 2.85 (s, 3 H), 2.18 - 2.08 (m, 1 H), 1.20 - 1.10 (m, 2 H), 0.82 - 0.68 (m, 3 H).

[0268] Example 28 N-Methyl-1-(7'-methyl-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methylamine

[0269] [ka]

[0270] [ka]

[0271] Step a: Synthesis of 2,2,2-trifluoro-N-methyl-N-((2-methyl-1,3-dioxolan-2-yl)methyl)acetamide N-methyl-1-(2-methyl-1,3-dioxolan-2-yl)methanamine (300.0 mg, 2.29 mmol) was dissolved in dichloromethane (10 mL), triethylamine (578.6 mg, 5.72 mmol) was added, trifluoroacetic anhydride (624.5 mg, 2.97 mmol) was added dropwise at 0 ° C, the mixture was slowly warmed to room temperature, and stirred overnight. The next day, the mixture was poured into saturated aqueous sodium bicarbonate solution (50 mL), extracted twice with dichloromethane (30 mL × 2), and the collected organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of the target compound (500 mg, yield 96.1%). Step b: Synthesis of 2,2,2-trifluoro-N-methyl-N-((7'-methyl-5'H,7'H spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)acetamide (1-(thiophen-3-yl)cyclopropyl)methanol (100.0 mg, 0.65 mmol) and 2,2,2-trifluoro-N-methyl-N-((2-methyl-1,3-dioxolan-2-yl)methyl)acetamide (221.0 mg, 0.97 mmol) were dissolved in dioxane (10 mL), trifluoromethanesulfonic acid (291.9 mg, 1.95 mmol) was slowly added dropwise at 0 ° C, and the mixture was reacted at room temperature overnight. The next day, the reaction solution was poured into an aqueous sodium bicarbonate solution (30 mL), extracted twice with ethyl acetate (30 mL × 2), and the collected 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 = 10: 1) to obtain the target compound (53 mg, yield 25.6%). LC-MS [M+H] + : 319.9. Step c: Synthesis of N-methyl-1-(7'-methyl-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methylamine 2,2,2-Trifluoro-N-methyl-N-((7'-methyl5'H,7'H spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)acetamide (53.0 mg, 0.17 mmol) was dissolved in a mixed solvent of methanol and water (3 mL / 0.3 mL), potassium carbonate (45.9 mg, 0.33 mmol) was added, and the mixture was stirred at 70 ° C for 3 hours. The mixture was then filtered and concentrated to obtain a crude product, which was separated and purified by preparative liquid chromatography to obtain the target compound (30 mg, yield 53.6%). 1 H NMR (600MHz ,DMSO-d6) δ 7.47 (d, J = 4.8 Hz, 1 H), 6.66 (d, J = 4.8 Hz, 1 H), 3.76 (d, J = 12.0 Hz, 1 H), 3.68 (d, J = 12.0 Hz, 1 H), 3.43 (d, J = 13.2 Hz, 1 H), 3.36 (d, J = 13.2 Hz, 1 H), 2.58 (s, 3 H), 1.57 (s, 3 H), 1.00 - 0.87(m, 4 H). LC-MS [M+H] + : 223.95.

[0272] Example 29 N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)-2,2,2-trifluoroethyl-1-amine

[0273] [ka]

[0274] N-((5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)-2,2,2-trifluoroacetamide (200.0 mg, 0.65 mmol) was dissolved in tetrahydrofuran (10 mL), and borane-tetrahydrofuran solution (1.98 mL, 1.98 mmol, 1 M in THF) was added dropwise. The mixture was reacted at 70°C for 2 hours, cooled to room temperature, and concentrated to obtain a crude product. The crude product was separated and purified by preparative liquid chromatography to obtain the desired product (32.9 mg, 17.2% yield). 1 H NMR (400 MHz, CD3OD) δ 7.31 (dd, J = 5.2 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 4.88 - 4.82 (m, 1H), 4.21 (d, J = 11.2 Hz, 1H), 3.66 (d, J = 11.2 Hz, 1H), 3.41 - 3.25 (m, 2H), 3.00 (d, J = 6.0 Hz, 2H), 2.52 - 2.39 (m, 1H), 2.29 - 1.92 (m, 5H). LC-MS [M+H] + : 292.1.

[0275] Example 30 1-(3'-Bromo-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine

[0276] [ka]

[0277] [ka]

[0278] Step a: Synthesis of 3-bromo-4-(bromomethyl)thiophene 3-Bromo-4-methylthiophene (2.0 g, 11.3 mmol), N-bromosuccinimide (2.02 g, 11.36 mmol), and azobisisobutyronitrile (93.0 mg, 0.57 mmol) were dissolved in carbon tetrachloride (30 mL) and the reaction was refluxed under nitrogen protection for 2 h. The reaction mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by column chromatography to give the product (2.3 g, 79.5% yield). 1 H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 4.4 Hz, 1 H), 7.29 (d, J = 4.4 Hz, 1 H), 4.48 (s, 2 H). Step b: Synthesis of 2-(4-bromothien-3-yl)acetonitrile 3-Bromo-4-(bromomethyl)thiophene (2.3 g, 8.99 mmol) was dissolved in acetonitrile (30 mL), trimethylsilyl cyanide (2.7 g, 27.2 mmol) and tetrabutylammonium fluoride (2.7 mL, 27.2 mmol) were slowly added, and the mixture was stirred at room temperature overnight. The reaction mixture was then cooled to 0° C., water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL×3). The combined extracts were washed with water (100 mL×2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give the product (1.25 g, 68.8% yield). 1 H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 4.4 Hz, 1 H), 7.34 (d, J = 4.4 Hz, 1 H), 3.68 (s, 2 H). Step c: Synthesis of 1-(4-bromothiophen-3-yl)cyclopropanenitrile Sodium hydride (597.0 mg, 14.93 mmol) was slowly added to dimethyl sulfoxide (20 mL), then 2-(4-bromothien-3-yl)acetonitrile (1.2 g, 5.97 mmol) and 1-bromo-2-chloroethane (2.12 g, 14.93 mmol) were slowly added to the mixture. The reaction mixture was stirred at room temperature overnight. Then, after cooling to 10° C., water (100 mL) was added and extracted with ethyl acetate (100 mL×3). The extract phases were combined, washed with water (100 mL×2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give the product (1.13 g, 82.9% yield). 1 H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 4.4 Hz, 1 H), 7.22 (d, J = 4.0 Hz, 1 H), 1.75 - 1.63 (m, 2 H), 1.37 - 1.23 (m, 2 H). Step d: Synthesis of 1-(4-methylthiophen-3-yl)cyclopropanecarbaldehyde 1-(4-Bromothiophen-3-yl)cyclopropanecarbonitrile (1.1 g, 4.85 mmol) was dissolved in tetrahydrofuran (15 mL) and diisobutylaluminum hydride (1M in hexane, 9.8 mL, 9.8 mmol) was added slowly to the reaction mixture at 0° C. and under nitrogen protection. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was cooled to 0° C., water (50 mL) was added, and extracted with ethyl acetate (50 mL×3). The extracts were combined, washed with water (50 mL×3) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the product (930 mg, 83.8% yield). 1 H NMR (400 MHz, CDCl3): δ 9.21 (s, 1 H), 7.32 (d, J = 4.4 Hz, 1 H), 7.15 (d, J = 4.4 Hz, 1 H), 1.72 -1.60 (m, 2 H), 1.42 - 1.30 (m, 2 H). Step e: Synthesis of (1-(4-bromothiophen-3-yl)cyclopropyl)methanol 1-(4-Bromothiophen-3-yl)cyclopropanecarbaldehyde (930.0 mg, 4.04 mmol) was dissolved in methanol (10 mL), sodium borohydride (169.0 mg, 4.45 mmol) was added slowly at 0° C., and the reaction mixture was warmed to room temperature and stirred for 3 h. Water (50 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (30 mL×3). The combined extract phase was washed with water (30 mL×3) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to give the desired product (800.0 mg, yield 84.9%). 1 H NMR (400 MHz, CDCl3): δ 7.27 (d, J = 3.2 Hz, 1 H), 7.18 (d, J = 4.0 Hz, 1 H), 3.66 (s, 2 H), 0.89 (d, J = 14.4 Hz, 4 H). Step f: N-((3'-bromo-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)-2,2,2-trifluoro-N-methylacetamide (1-(4-bromothien-3-yl)cyclopropyl)methanol (800.0 mg, 3.45 mmol) and N-(2,2-dimethoxyethyl)-2,2,2-trifluoro-N-methylacetamide (1.3 g, 6.21 mmol) were dissolved in 2-methyltetrahydrofuran (10 mL), and trifluoromethanesulfonic acid (3.1 g, 20.7 mmol) was slowly added to the solution at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 hours, then cooled to 0° C., diluted with dichloromethane (50 mL), washed with 5% sodium hydroxide (50 mL×3) and brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give the product (500.0 mg, yield 37.6%). LC-MS [M+H] +: 384.2. Step g: Synthesis of 1-(3'-bromo-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)-N-methylmethylamine N-((3'-bromo-5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methyl)-2,2,2-trifluoro-N-methylacetamide (250.0 mg, 0.65 mmol) was dissolved in methanol (10 mL), and potassium carbonate (270.0 mg, 1.95 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, and then the residue obtained by filtering and concentrating the reaction mixture was separated and purified by preparative liquid chromatography (water / formic acid / acetonitrile) to obtain the target product (62.4 mg, yield 28.8%). 1 H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1 H), 7.50 (s, 1 H), 4.95 - 4.85 (m, 1 H), 3.85 (d, J = 15.6 Hz, 1 H), 3.38 (d, J = 15.6 Hz, 1 H), 3.06 - 2.78 (m, 2 H), 2.41 (s, 3 H), 1.95 - 1.80 (m, 1 H), 1.40 - 1.30 (m, 1 H), 0.90 - 0.76 (m, 1 H), 0.65 - 0.50 (m, 1 H). LC-MS [M+H] + : 288.0.

[0279] Example 32 N-((4',6'-dihydrospiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)methyl)methyl-D3-amine

[0280] [ka]

[0281] [ka]

[0282] Step a: Synthesis of N-((4',6'-dihydrospiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)methyl)2,2,2-trifluoro-N-(methyl-D3)acetamide

[0283] [ka]

[0284] To a solution (10 mL) of N-((4',6'-dihydrospiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)methyl)2,2,2-trifluoroacetamide (1.0 g, 3.43 mmol), potassium carbonate (950 mg, 6.86 mmol) and deuterated iodomethane (1.5 g, 10.3 mmol) were added in sequence and stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (70 mL), extracted with ethyl acetate (30 mL x 3), and the crude product obtained by concentrating the extract phase was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the target compound (600 mg, yield 56%). LC-MS [M+H] + : 308.9. 1 H NMR (600 MHz, CDCl3): δ 7.02 (d, J = 4.8 Hz, 1 H), 6.83 (d, J = 5.4 Hz, 1 H), 5.06 (dd, J = 9.0, 2.4 Hz, 1H), 4.12 (dd, J = 14.4, 2.4 Hz, 1H), 3.81 (d, J = 11.4 Hz, 1 H), 3.61 (d, J = 11.4 Hz, 1 H), 3.54 - 3.48 (m, 1 H), 1.07 - 0.93(m, 4 H). Step b: Synthesis of N-((4',6'-dihydrospiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)methyl)methyl-D3-amine

[0285] [ka]

[0286] Potassium carbonate (540 mg, 3.9 mmol) was added to a methanol (6 mL) solution of N-((4',6'-dihydrospiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)methyl)2,2,2-trifluoro-N-(methyl-D3)acetamide (600 mg, 1.95 mmol) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered and concentrated, and the obtained crude product was separated and purified by preparative liquid chromatography (acetonitrile:water = 25:75) to obtain the target product (340 mg, yield 53.5%). LC-MS [M+H] + : 212.9. 1 H NMR (600 MHz, CDCl3): δ 7.00 (d, J = 4.8 Hz, 1 H), 6.75 (d, J = 4.8 Hz, 1 H), 4.91 (dd, J = 9.0, 3.0 Hz, 1 H), 3.93 (d, J = 11.4 Hz, 1 H), 3.56 (d, J = 11.4 Hz, 1 H), 3.01 (dd, J = 12.6, 3.0 Hz, 1 H), 2.92 (dd, J = 12.6, 9.0 Hz, 1 H), 1.06 - 0.89 (m, 4 H).

[0287] Example 32-S and Example 32-R (S)-N-((4',6'-dihydrospiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)methyl)methyl-D3-amine and (R)-N-((4',6'-dihydrospiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)methyl)methyl-D3-amine

[0288] [ka]

[0289] Example 32 was resolved by chiral chromatography to give Example 32-S and Example 32-R. Liquid Chromatography Method: Chromatography column: DAICEL CHIRALPAK IG column; Mobile phase A: supercritical CO2, Mobile phase B: methanol (containing 0.1% diethylamine); Detection wavelength: 214 nm; Flow rate: 1.5 mL / min, Column temperature: 35° C.; Background column pressure: 1800 psi. Mobile phase gradient:

[0290] [Table 3]

[0291] Example 32-S: RT: 3.236 min; [α]D 23 = 63 (c 0.10, MeOH); LC-MS [M+H] + : 212.9. 1 H NMR (600 MHz, CDCl3): δ 7.00 (d, J = 5.4 Hz, 1 H), 6.75 (d, J = 5.4 Hz, 1 H), 4.91 (dd, J = 9.0, 3.0 Hz, 1 H), 3.93 (dd, J = 11.4, 1.2 Hz, 1 H), 3.56 (d, J = 11.4 Hz, 1 H), 3.01 (dd, J = 12.6, 3.0 Hz,1H), 2.92 (dd, J = 12.6, 9.0 Hz, 1 H), 1.06 - 0.90 (m, 4 H). Example 32-R: RT: 3.624 min; [α]D 23 = -60 (c 0.11, MeOH); LC-MS [M+H] + : 212.9. 1H NMR (600 MHz, CDCl3): δ 7.00 (d, J = 4.8 Hz, 1 H), 6.75 (d, J = 4.8 Hz, 1 H), 4.91 (dd, J = 8.4, 3.0 Hz, 1 H), 3.93 (d, J = 11.4 Hz, 1 H), 3.56 (d, J = 11.4 Hz, 1 H), 3.00 (dd, J = 12.6, 3.0 Hz, 1 H), 2.91 (dd, J = 12.6, 8.4 Hz, 1 H), 1.06 - 0.90 (m, 4 H).

[0292] Biological Test Evaluation The present invention will be further described below in combination with test examples, but these examples are not intended to limit the scope of the present invention.

[0293] The following SEP-363856 of the present invention is as shown below and was prepared with reference to the method of Example 129 of patent PCT / US2010 / 058884.

[0294] [ka]

[0295] The following Comparative Example 1 of the present invention is as shown below, which was prepared with reference to the method of Example 89 of patent PCT / US2010 / 058884.

[0296] [ka]

[0297] Test Example 1: Test method for TAAR1 receptor cAMP agonists 1.1 Experimental materials: The cAMP detection kit was purchased from Cisbio, the HE3K293 cell line stably expressing the TAAR1 receptor was constructed by Shanghai Shujing Biotechnology Co., Ltd., IBMX was purchased from Sigma, Phenethylamine (PEA); ProxiPlate-384 well plates were purchased from PerkinElmer, and HBSS was purchased from Thermo Fisher Scientific Company. A PerkinElmer Envision 2105 multifunction microplate reader, an Agilent Bravo liquid workstation, and a Countstar BioTech cell counter were used.

[0298] 1.2 Experimental Method: (1) Preparation of experimental buffer: 5× stimulation buffer was diluted to 1× with ddH2O, and IBMX was added to a final concentration of 0.5 mM and mixed evenly for subsequent use. (2) Thaw the cryopreserved cells quickly in a 37 °C water bath, wash the cell suspension with HBSS buffer, centrifuge at 200 x g to remove the cryopreservation solution, resuspend the pellet in an appropriate volume of experimental buffer, take 20 µL, count using a cell counter, and obtain a cell count of 1.5 × 10 6 Diluted to cells / mL. (3) Add 5 μL of cell suspension (1.5 × 10 per well) to a ProxiPlate-384 well plate. 4 cells) were added. (4) Test compounds were serially diluted in experimental buffer and 5 μL was transferred to the reaction plate using a Bravo. Negative control wells received 5 μL of experimental buffer and positive control wells received 5 μL of PEA (final concentration 10 -2 M). (5) Incubate at 37°C for 1 hour. (6) 10 μL of detection reagent was added to the reaction plate and incubated in the dark at room temperature for 1 hour. (7) Detection was performed using an Envision 2105 multifunction microplate reader. The excitation light was 340 nm, and the emission light was 620 nm and 665 nm. The 665 nm / 620 nm ratio of each test well was calculated. Activity% = (negative control ratio - compound ratio) / (negative control ratio - positive control ratio) x 100% EC of the compound 50 Values ​​were calculated using a four-parameter fitting model log(agonist) vs. response-variable slope(four parameters) in GraphPad Prism.

[0299] 1.3 Experimental results: According to the above scheme, the specific results of the compounds of the present invention in the test of agonist activity of the TAAR1 receptor are shown in Table 1.

[0300] [Table 4]

[0301] 1.4 Experimental Conclusions: The results of in vitro experiments show that the compounds of the present invention have agonistic effects on the TAAR1 receptor.

[0302] Test Example 2, 5-HT 1A Testing methods for receptor cAMP agonists 2.1 Experimental materials: The cAMP detection kit was purchased from Cisbio, and 5-HT 1AHEK293 cell lines stably expressing the receptors were constructed by Shanghai Pivot Biotechnology Co., Ltd. Serotonin, Forskolin, and IBMX were purchased from Sigma, ProxiPlate-384-well plates were purchased from PerkinElmer, and HBSS was purchased from Thermo Fisher Scientific. A PerkinElmer Envision 2105 multifunction microplate reader, Tecan D300e picoliter micropipette, Agilent Bravo liquid workstation, and Countstar BioTech cell counter were used.

[0303] 2.2 Experimental Method: (1) Preparation of experimental buffer: 5× stimulation buffer was diluted to 1× with ddH2O, and IBMX was added to a final concentration of 0.5 mM and mixed evenly for subsequent use. (2) Digest the cultured cells with trypsin. After digestion is complete, wash the cell suspension with HBSS buffer, centrifuge at 200 x g to remove the medium, resuspend the pellet in an appropriate amount of experimental buffer, take 20 μL, count using a cell counter, and find a cell count of 0.4 × 10 6 Diluted to cells / mL. (3) Add 5 μL of cell suspension (2 × 10 per well) to a ProxiPlate-384 well plate. 3 cells) were added. (4) Test compounds were serially diluted with the experimental buffer and 5 μL was transferred to the reaction plate using a Bravo. 5 μL of experimental buffer was added to the negative control wells and 5 μL of Serotonin (final concentration 10 -6 M). (5) Incubate at room temperature for 15 minutes. (6) Using a Tecan D300e picoliter microdispenser, add Forskolin (final concentration 1.5 × 10 -7 M) was added to the reaction plate. (7) Incubate at room temperature for 45 minutes. (8) 10 μL of detection reagent was added to the reaction plate and incubated in the dark at room temperature for 1 hour. (9) Detection was performed using an Envision 2105 multifunction microplate reader. The excitation light was 340 nm, and the emission light was 620 nm and 665 nm. The 665 nm / 620 nm ratio of each test well was calculated. Activity% = (negative control ratio - compound ratio) / (negative control ratio - positive control ratio) x 100% EC of the compound 50 Values ​​were calculated using a four-parameter fitting model log(agonist) vs. response-variable slope(four parameters) in GraphPad Prism.

[0304] 2.3 Experimental results: According to the above scheme, 5-HT 1A Specific results of the compounds of the present invention in the receptor agonist activity test are shown in Table 2.

[0305] [Table 5]

[0306] 2.4 Experimental Conclusions: In vitro experiments have shown that the compounds of the present invention inhibit 5-HT 1A These results indicate that the compounds of the present invention have an agonistic effect on the receptor, suggesting that the compounds of the present invention can improve negative symptoms and cognitive impairment.

[0307] Test Example 3: Inhibitory effect of the compound of the present invention on MK-801-induced hyperlocomotor activity in mice 3.1 Experimental materials: Test compounds: self-made compounds of the examples of the present invention. (+)-MK-801 Aminomethylbenzodiazepine (also known as 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-methanamine dimaleate): purchased from Sigma-Aldrich Company, catalog number: M107-50MG. Experimental animals: 18-22g male C57Bl / 6J mice, purchased from SHANGHAI SLAC LABORATORY ANIMAL CO. LTD.

[0308] 3.2 Experimental Method: 3.2.1 Animal grouping: Before the start of the experiment, the animals were randomly assigned to groups according to body weight. 3.2.2 Animal adaptation: Before the experiment, the mice were first adapted to the experimental environment for at least 1 h, i.e., the animals were transferred from the breeding room to the experimental room and allowed to move freely within their cages. 3.2.3 Drug Administration: Preparation of drugs: The test compound was taken, pure water was added, and ultrasonic treatment was performed. The animals were randomly divided into blank group, model group, and drug administration group according to body weight, with 9 animals per group. Detailed drug administration information is shown in the table below:

[0309] [Table 6]

[0310] T-30 min Oral administration of compound: The test compound or solvent (pure water) was orally administered by force. Immediately after administration, the mouse was placed in a test box (test box size: length x width x height = 27 x 27 x 40 cm) and the spontaneous movement of the mouse was recorded for 30 minutes. T0 min Intraperitoneal injection of modeling drugs: 30 min after compound administration, the mice were removed and intraperitoneally injected with MK-801 (0.3 mg / kg). The blank control group was injected with saline. The animals were returned to the test box immediately after MK-801 administration, and recordings were continued for 150 min. 3.2.4 Data recording and analysis. The animal's movement (distance traveled in the test box) was automatically recorded by a camera and analyzed with the ANY MAZE software. 50 was calculated.

[0311] 3.3 Experimental results: As shown in Table 3.

[0312] [Table 7]

[0313] 3.4 Experimental conclusions: From the above scheme, it can be concluded that the compound of the present invention can significantly inhibit the high spontaneous movement of mice induced by MK-801, and with the increase in the dose of the compound, the inhibitory effect is gradually enhanced, and has a good dose-dependency relationship.In addition, compared with SEP-363856, the minimum effective dose of the compound of the present invention is lower, and the inhibitory effect is stronger.

[0314] Test Example 4: Inhibitory experiment of the compound of the present invention on the hypervoluntary movement of PCP-induced mice 4.1 Experimental materials: Test compounds: self-made compounds of the examples of the present invention. Phencycliding hydrochloride (PCP): purchased from Shanghai Yuansi Pharmaceutical Technology Co., Ltd., specification: 5g. Experimental animals: 18-22g male C57Bl / 6J mice, purchased from SHANGHAI SLAC LABORATORY ANIMAL CO. LTD.

[0315] 4.2 Experimental Method: 4.2.1 Animal grouping: Before the start of the experiment, the animals were randomly assigned to groups according to body weight. 4.2.2 Animal adaptation: Before the experiment, the mice were first adapted to the experimental environment for at least 1 h, i.e., the animals were transferred from the breeding room to the experimental room and allowed to move freely within their cages. 4.2.3 Drug Administration: Preparation of drugs: The test compound was taken, pure water was added, and ultrasonic treatment was performed. The animals were randomly divided into blank group, model group, and drug administration group according to body weight, with 9 animals per group. Detailed drug administration information is shown in the table below:

[0316] [Table 8]

[0317] T-30 min Oral administration of compound: The compound of the present invention or a solvent (pure water) was orally administered by force. Immediately after administration, the mouse was placed in a test box (test box size: length x width x height = 27 x 27 x 40 cm) and the spontaneous movement of the mouse was recorded for 30 minutes. T0 min Intraperitoneal injection of modeling drugs: 30 min after compound administration, the mice were removed and injected intraperitoneally with PCP (5 mg / kg). The blank control group was injected with ultrapure water. The animals were returned to the test box immediately after PCP administration, and recording was continued for 60 min. 4.2.4 Data recording and analysis. The activity of the animals (distance traveled in the test box) was automatically recorded by a camera and analyzed with the ANY MAZE software. 50 was calculated.

[0318] 4.3 Experimental results: As shown in Table 4.

[0319] [Table 9]

[0320] 4.4 Experimental Conclusions: From the above scheme, it can be concluded that the compound of the present invention can obviously inhibit the PCP-induced hyperlocomotor activity in mice, and as the dose of the compound increases, the inhibitory effect gradually increases, and there is a good dose-dependent relationship.In addition, compared with SEP-363856, the minimum effective dose of the compound of the present invention is lower, and the inhibitory effect is stronger.

Claims

1. General formula (I): 【Chemistry 1】 [In the formula, M １ is -(CH2) ｎ - and M ２ is O; or M 1 is O and M 2 is --(CH 2 ) n --; M ３ is S and M ４ is CR ｂ And M ５ is CR ｃ or M 3 is CR a , M 4 is S and M 5 is CR c ; or M 3 is CR a , M 4 is CR b and M 5 is S; R a, R ｂ , and R ｃ are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C １～６ Alkyl, C １～６ Deuterated alkyl, C １～６ Haloalkyl, C １～６ Alkoxy or C １～６ alkylamino; R １ and R ２ are connected to the carbon atom to which they are attached, ３～８ forming a cycloalkyl group or a 3- to 8-membered heterocyclic group, the 3- to 8-membered heterocyclic group containing 1 to 4 atoms selected from N, O or S; R ３ and R ４ are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, C １～６ Alkyl, C １～６ Deuterated alkyl or C １～６ haloalkyl; Or, R ３ and R ４ combine with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing heterocyclic group; R ５ and R ６ are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, C １～６ Alkyl, C １～６ Deuterated alkyl or C １～６ haloalkyl; Or, R ５ and R ６ are connected to the carbon atom to which they are attached, ３～８ forming a cycloalkyl group or a 3- to 8-membered heterocyclic group, the 3- to 8-membered heterocyclic group containing 1 to 4 atoms selected from N, O or S; Or, R ５ Or R ６ is R ３ Or R ４ and link them to form a 3-8 membered nitrogen-containing heterocyclic group; R ７ is hydrogen, deuterium, halogen, hydroxyl, cyano, C １～６ Alkyl, C １～６ Deuterated alkyl or C １～６ haloalkyl; Or, R ７ is R ３ Or R ４ and link them to form a 4-8 membered nitrogen-containing heterocyclic group; Or, R ７ is R ５ Or R ６ Combined with C ３～８ forming a cycloalkyl group or a 3- to 8-membered heterocyclic group, the 3- to 8-membered heterocyclic group containing 1 to 4 atoms selected from N, O or S; and n is an integer from 0 to 2. 【Chemistry 2】 A compound not containing, its stereoisomer or a pharma- ceutically acceptable salt thereof. 【Request 2】 【Chemistry 3】 teeth 【Chemistry 4】 Selected from: R a, R ｂ , and R ｃ are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C １～６ Alkyl, C １～６ Deuterated alkyl, C １～６ Haloalkyl, C １～６ Alkoxy or C １～６ alkylamino; R １ and R ２ are connected to the carbon atom to which they are attached, ３～８ forming a cycloalkyl group or a 3- to 8-membered heterocyclic group, the 3- to 8-membered heterocyclic group containing 1 to 4 atoms selected from N, O or S; R ３ and R ４ are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, C １～６ Alkyl, C １～６ Deuterated alkyl or C １～６ haloalkyl; Or, R ３ and R ４ combine with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing heterocyclic group; R ５ and R ６ are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, C １～６ Alkyl, C １～６ Deuterated alkyl or C １～６ haloalkyl; Or, R ５ and R ６ are connected to the carbon atom to which they are attached, ３～８ forming a cycloalkyl group or a 3- to 8-membered heterocyclic group, the 3- to 8-membered heterocyclic group containing 1 to 4 atoms selected from N, O or S; Or, R ５ Or R ６ is R ３ Or R ４ and link them to form a 3-8 membered nitrogen-containing heterocyclic group; R ７ is hydrogen, deuterium, halogen, hydroxyl, cyano, C １～６ Alkyl, C １～６ Deuterated alkyl or C １～６ haloalkyl; Or, R ７ is R ３ Or R ４ and link them to form a 4-8 membered nitrogen-containing heterocyclic group; Or, R ７ is R ５ Or R ６ Combined with C ３～８ forming a cycloalkyl group or a 3- to 8-membered heterocyclic group, the 3- to 8-membered heterocyclic group containing 1 to 4 atoms selected from N, O or S; 2. A compound represented by the general formula (I) according to claim 1, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

3. The following conditions: (1) R a, R ｂ and R ｃ are each independently hydrogen, halogen or C １～６ being selected from alkyl; (2) R １ and R ２ are connected to the carbon atom to which they are attached, ３～６ forming a cycloalkyl group or a 3- to 6-membered heterocyclic group, the 3- to 6-membered heterocyclic group containing 1 to 3 atoms selected from N, O or S; (3) R ３ and R ４ are each independently hydrogen, C １～６ Alkyl, C １～６ Deuterated alkyl or C １～６ haloalkyl; (4) R ３ and R ４ combine with the nitrogen atom to which they are attached to form a 4- to 6-membered nitrogen-containing heterocyclic group; (5) R ５ and R ６ are each independently hydrogen or C １～６ being selected from alkyl; (6) R ５ and R ６ are connected to the carbon atom to which they are attached, ３～５ forming a cycloalkyl or 3- to 5-membered heterocyclic group, said 3- to 5-membered heterocyclic group containing 1 to 3 atoms selected from N, O or S; (7) R ５ Or R ６ is R ３ Or R ４ linking with to form a 4-6 membered nitrogen-containing heterocyclic group; (8) R ７ is hydrogen or C １～６ being selected from alkyl; (9) R ７ is R ３ Or R ４ linking with to form a 5-6 membered nitrogen-containing heterocyclic group; (10) R ７ is R ５ Or R ６ Combined with C ４～６ forming a cycloalkyl group or a 4- to 6-membered heterocyclic group, the 4- to 6-membered heterocyclic group containing 1 to 3 atoms selected from N, O or S; (11) The compound represented by the general formula (I) is 【Chemistry 5】 To be selected from 3. The compound represented by the general formula (I) according to claim 1 or 2, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, which satisfies one or more of the following requirements:

4. The following conditions: (1) R a , R b and R c are each independently selected from hydrogen, fluorine, chlorine, bromine or C 1-3 alkyl; (2) R 1 and R 2 , taken together with the carbon atom to which they are attached, form a C 3-4 cycloalkyl group or a 3-4 membered heterocyclic group, which contains 1 to 2 atoms selected from N, O, or S; (3) R 3 and R 4 are each independently selected from hydrogen, C 1-3 alkyl, C 1-3 deuterated alkyl, or C 1-3 haloalkyl; (4) R 3 and R 4 combine with the nitrogen atom to which they are attached to form a 4-membered nitrogen-containing heterocyclic group; (5) R 5 and R 6 are each independently selected from hydrogen or C 1-3 alkyl; (6) R 5 and R 6 combine with the carbon atom to which they are attached to form a C 3-5 cycloalkyl; (7) R 5 or R 6 combines with R 3 or R 4 to form a 5-membered nitrogen-containing heterocyclic group; (8) R 7 is selected from hydrogen or C 1-3 alkyl; (9) R 7 combines with R 3 or R 4 to form a 5-membered nitrogen-containing heterocyclic group; (10) R 7 combines with R 5 or R 6 to form a C 4-6 cycloalkyl group.

4. The compound represented by the general formula (I) according to claim 3, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, which satisfies one or more of the following conditions:

5. The following conditions: (1) R a , R b and R c are each independently selected from hydrogen, fluorine, chlorine, bromine or methyl; (2) R 1 and R 2 combine with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, or oxetanyl; (3) R 3 and R 4 are each independently selected from hydrogen, methyl, ethyl, isopropyl, -CD 3 , or -CH 2 CF 3 ; (4) R 3 and R 4 are joined with the nitrogen atom to which they are attached to form an azetidinyl; (5) R 5 and R 6 are each independently selected from hydrogen or methyl; (6) R 5 and R 6 are joined with the carbon atom to which they are attached to form a cyclopropyl; (7) R 5 or R 6 combines with R 3 or R 4 to form tetrahydropyrrolyl; (8) R 7 is selected from hydrogen or methyl; (9) R 7 is linked with R 3 or R 4 to form tetrahydropyrrolyl; (10) R 7 is linked with R 5 or R 6 to form a cyclobutyl group; 5. The compound represented by the general formula (I) according to claim 4, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, which satisfies one or more of the following conditions:

6. In the general formula (I), 【Chemistry 6】 is the following group: 【Chemistry 7】 is selected from Where: Rb and R ｃ are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C １～６ Alkyl, C １～６ Deuterated alkyl, C １～６ Haloalkyl, C １～６ Alkoxy or C １～６ 3. The compound represented by the general formula (I) according to claim 1 or 2, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, wherein the aryl group is selected from the group consisting of aryl, arylamino, arylalkylamino, aryl ...

7. The compound represented by the general formula (I) according to claim 6, characterized in that R b and R c are each independently selected from hydrogen, halogen or C 1-6 alkyl, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

8. The compound represented by the general formula (I) according to claim 7, characterized in that R b and R c are each independently selected from hydrogen, fluorine, chlorine, bromine or C 1-3 alkyl, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

9. The compound represented by the general formula (I) according to claim 8, characterized in that R b and R c are each independently selected from hydrogen, fluorine, chlorine, bromine or methyl, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

10. General formula (I) can be further represented by general formula (II-A): 【Chemistry 8】 [In the formula, R ３ and R ４ are each independently hydrogen, C １～６ Alkyl, C １～６ Deuterated alkyl or C １～６ haloalkyl; Or, R ３ and R ４ combine with the nitrogen atom to which they are attached to form a 4- to 6-membered nitrogen-containing heterocyclic group; R ５ and R ６ are each independently hydrogen or C １～６ alkyl; Or, R ５ and R ６ are connected to the carbon atom to which they are attached, ３～５ Forms a cycloalkyl group or a 3- to 5-membered heterocyclic group; Or, R ５ Or R ６ is R ３ Or R ４ together with to form a 4-6 membered nitrogen-containing heterocyclic group; R ７ is hydrogen or C １～６ alkyl; Or, R ７ is R ３ Or R ４ together with to form a 5-6 membered nitrogen-containing heterocyclic group; Or, R ７ is R ５ Or R ６ Combined with C ４～６ Forms a cycloalkyl group or a 4- to 6-membered heterocyclic group; R ｂ and R ｃ are each independently hydrogen, halogen or C １～６ alkyl, and and m is 0 or 1. The compound represented by the general formula (I) according to claim 1 or 2, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

11. R 3 and R 4 are each independently selected from hydrogen, C 1-3 alkyl, C 1-3 deuterated alkyl, or C 1-3 haloalkyl; or R 3 and R 4 taken together with the nitrogen atom to which they are attached form a 4-membered nitrogen-containing heterocyclic group; R 5 and R 6 are each independently selected from hydrogen or C 1-3 alkyl; or R 5 and R 6 taken together with the carbon atom to which they are attached form a cyclopropyl group; Alternatively, R 5 or R 6 joins with R 3 or R 4 to form tetrahydropyrrolyl; R 7 is selected from hydrogen or C 1-3 alkyl; Alternatively, R 7 is linked with R 3 or R 4 to form tetrahydropyrrolyl; Alternatively, R 7 is linked with R 5 or R 6 to form a cyclobutyl group; R b and R c are each independently selected from hydrogen, fluorine, chlorine, bromine or C 1-3 alkyl; 11. The compound represented by the general formula (II-A) according to claim 10, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

12. R 3 and R 4 are each independently selected from hydrogen, methyl, ethyl, isopropyl, -CD 3 or -CH 2 CF 3 ; or R 3 and R 4 taken together with the nitrogen atom to which they are attached form an azetidinyl; R 5 and R 6 are each independently selected from hydrogen or methyl; R 7 is selected from hydrogen or methyl; R b and R c are each independently selected from hydrogen, fluorine, chlorine, bromine or methyl; 12. The compound represented by the general formula (II-A) according to claim 11, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

13. General formula (I) can be further represented by general formula (II): 【Chemistry 9】 [In the formula, R ｂ , R ｃ , R ３ , R ４ , R ５ , R ６ and R ７ is as defined in claim 1 or 2. The compound represented by the general formula (I) according to claim 1 or 2, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, characterized in that:

14. General formula (I) can be further represented by general formula (III): 【Chemistry 10】 [In the formula, R ａ , R ｂ , R ３ , R ４ , R ５ , R ６ and R ７ is as defined in claim 1 or 2. The compound represented by the general formula (I) according to claim 1 or 2, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, wherein:

15. R ３ and R ４ The compound represented by the general formula (I) according to claim 1 or 2, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, wherein is not simultaneously hydrogen.

16. A compound represented by general formula (I) according to claim 15, characterized in that R 3 is hydrogen and R 4 is selected from C 1-3 alkyl, C 1-3 deuterated alkyl or C 1-3 haloalkyl, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

17. The compound represented by the general formula (I) according to claim 16, wherein R 4 is methyl, ethyl, isopropyl, -CD 3 or -CH 2 CF 3 , a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

18. The compound represented by the general formula (I) according to claim 17, wherein R 4 is methyl or -CD 3 , a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

19. The compound: 【Chemistry 11】 【Chemistry 12】 The compound represented by the general formula (I) according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

20. 【Chemical 13】 The method comprises reacting a compound of general formula (II-A1) with a compound of general formula (II-2) to obtain a compound represented by general formula (II-A), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, During the ceremony, R ｂ , R ｃ , m, R ３ , R ４ , R ５ , R ６ and R ７ A method for preparing a compound represented by general formula (II-A) according to claim 10, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, wherein the compound is as described in claim 10.

21. 【Chemical 14】 The method comprises reacting a compound of general formula (II-1) with a compound of general formula (II-2) to obtain a compound represented by general formula (II), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, During the ceremony, R ｂ , R ｃ , R ３ , R ４ , R ５ , R ６ and R ７ A method for preparing a compound represented by general formula (II) as claimed in claim 13, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, characterized in that:

22. 【Chemical 15】 The method comprises reacting a compound of general formula (III-1) with a compound of general formula (II-2) to obtain a compound represented by general formula (III), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, During the ceremony, R ａ , R ｂ , R ３ , R ４ , R ５ , R ６ and R ７ A method for preparing a compound represented by general formula (III) as claimed in claim 14, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

23. 20. A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 19, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers.

24. Use of a compound according to any one of claims 1 to 19, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, in the manufacture of a medicament for the prevention and / or treatment of a neuropsychiatric disorder in a mammal.

25. The use according to claim 24, characterized in that the neuropsychiatric disorder is a central nervous system disorder associated with 5-hydroxytryptamine receptors and / or trace amine associated receptors and / or dopamine receptors.

26. The neuropsychiatric disorder is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizophrenic personality disorder, delusional disorder, psychosis, psychotic disorder, transient psychotic disorder, shared psychotic disorder, psychotic disorder due to physical illness, drug-induced psychosis, psychoemotional disorder, aggression, delirium, Parkinson's psychosis, irritable psychosis, Tourette's 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 psychosis, depression.

26. The use of claim 25, wherein the indication is one or more of the following: chronic inflammatory disease, major depressive disorder, dysthymia, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, dizziness, epilepsy, pain, neuropathic pain, neuropathic pain predisposition, inflammatory pain, fibromyalgia, migraine, cognitive impairment, movement disorder, restless legs syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, medication-induced sleepiness side effect, insomnia, substance abuse dependency, addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesch-Nyharn disease, Wilson's disease, autism, Huntington's chorea and premenstrual dysphoria.

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