Aromatic heterocyclic cyclohexylaminoalkylpiperidine derivatives, methods for preparation and uses thereof

Abstract

The present invention relates to aromatic heterocyclic cyclohexylaminoalkylpiperidine derivatives, methods for their preparation and their use. Specifically, the present invention relates to 5-HT 1A The present invention provides a compound represented by general formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, which is used for activating receptors and dopamine D2 and D3 receptor activity, and for use in the manufacture of a medicament for Parkinson's disease, as well as a method for producing the compound. [Formula 1] JPEG2025526807000132.jpg2058

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 2022109619064, filed on August 11, 2022. The entire text of the above Chinese patent application is incorporated herein by reference.

[0002] The present invention belongs to the field of medicine, and particularly relates to an aromatic heterocyclic cyclohexylaminoalkylpiperidine derivative, a preparation method thereof, and its use. More particularly, the present invention relates to an aromatic heterocyclic cyclohexylaminoalkylpiperidine derivative, a preparation method thereof, a pharmaceutical composition containing the aromatic heterocyclic cyclohexylaminoalkylpiperidine derivative, and the use of the aromatic heterocyclic cyclohexylaminoalkylpiperidine derivative or its pharmaceutical composition in the manufacture of a medicament for preventing and / or treating central nervous system diseases in mammals. [Background technology]

[0003] Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide after Alzheimer's disease. It frequently affects the elderly, with a prevalence of approximately 2% in people aged 60 years or older (Lilienfeld, DE Neuroepidemiology, 1993, 12, 219-228). Clinical features include resting tremor, muscle rigidity, bradykinesia, and postural balance disorders (Armstrong MJ JAMA. 2020;323(6):548-560). Concomitant symptoms include autonomic dysfunction (Jost WH J Neurol. 2003 Feb;250 Suppl 1:I28-30), cognitive impairment (Halliday, GM Mov. Disord. 2014, 29, 634-650), sleep and emotional disturbances (Gallagher, DA Neurobiol. Dis. 2012, 46, 2013). Pathologically, degeneration of dopamine neurons in the substantia nigra pars compacta leads to a significant decrease in dopamine content in the striatum, and α-synuclein accumulation leads to the formation of Lewy bodies (Schapira, AH Neurol. Clin. 2009, 27, 583-603), resulting in various motor disorders. In addition to the effects of dopamine pathways, non-motor disorders are associated with degeneration of cholinergic, noradrenergic, and serotonergic neural pathways (Titova N. Med J Aust 2018;208:404-409.) (Titova N. J Neural Transm (Vienna) 2017;124:907-914.).

[0004] Currently, pharmacotherapy for Parkinson's disease primarily focuses on dopamine-blocking drugs, including levodopa (L-DOPA), monoamine oxidase B inhibitors (MAOIs), catechol-O-methyltransferase inhibitors (COMTIs), and dopamine agonists (DAs). L-DOPA has long been the most commonly used drug for Parkinson's disease and remains the gold standard for its treatment. MAOIs and COMTIs are commonly used as adjuncts to levodopa, prolonging its therapeutic effect by blocking dopamine metabolism (Jankovic J. Journal of Neurology, Neurosurgery & Psychiatry 2020;91:795-808.) (Armstrong MJ. JAMA. 2020;323(6):548-560.). Although there is clear benefit in treating symptoms, long-term use of levodopa generally leads to motor fluctuations (on-off phenomena) and movement disorders (Marsden, CD Lancet 1976, 307,292-296.).

[0005] Dopamine agonists improve motor symptoms by directly stimulating D2-like receptors (D2, D3, and D4) or D1 receptors (Hisahara S. Int J Med Chem. 2011;2011:403039.). Although dopamine agonists are not as effective as levodopa, dopamine agonist monotherapy can adequately control early motor symptoms of Parkinson's disease, so most patients often choose dopamine agonists rather than levodopa as their first treatment (Jankovic J. Journal of Neurology, Neurosurgery & Psychiatry 2020;91:795-808.). In later stages of the disease, dopamine agonists are administered in combination with levodopa to reduce "off" time (Marsden, CD Lancet 1976, 307,292-296.). Dopamine agonists can also alleviate some non-motor symptoms. For example, pramipexole is effective in treating depressive symptoms, and ropinirole has beneficial effects on sleep, anxiety, and depression. Rotigotine has been shown to be effective in improving swallowing dysfunction, while apomorphine is effective in treating emotional, gastrointestinal, and urinary dysfunction (Torti M. Drugs. 2019 May;79(7):693-703.).

[0006] 5-HT 1A The 5-HT receptor also plays an important role in Parkinson's drug treatment, as demonstrated in three main ways: 1A Receptor agonists can improve extrapyramidal disorders caused by dopamine neuron degeneration and levodopa-induced movement disorders, such as eltoprazine and NLX-112 (Cerri S. Expert Opin Investig Drugs. 2017 Jul;26(7):777-791.). Next, 5-HT 1A Activation of the receptor helps improve cognitive impairment and produces anti-anxiety and antidepressant effects, such as aripiprazole (Ohno Y. Prog Neurobiol. 2015 Nov;134:104-21.). Furthermore, various models have demonstrated that 5-HT1A It has been shown that 5-HT receptor agonists can prevent neurotoxicity, meaning that they can control disease progression by protecting neurons from loss, such as BAY-639044. 1A It has been demonstrated that receptor activation can induce astrocyte proliferation and increase the levels of antioxidant molecules in the striatum, thereby preventing progressive dopaminergic neuron degeneration (Miyazaki I. Curr Med Chem. 2016;23(7):686-700.).

[0007] 5HT has also been found in the aqueous humor of the human eye (Martin et al., Ophthalmol., 95:1221-1226, 1988). 3 Receptor binding sites for [H]5HT have been demonstrated and pharmacologically characterized (Mallorga and Sugrue, Curr. Eye Res., 6:527-532, 1987 and Chidlow et al., Invest. Ophthalmol. Vis. Sci., 36:2238-2245, 1995). These 5HT binding sites were shown to be functionally coupled to second messengers generated by rabbits (Tobin and Osborne, J. Neurochem., 53:686-601, 1989 and Tobin et al., J. Neurosci., supra). In human ICB, these binding sites are functionally coupled to 5HT 1A and 5HT2 receptors (Barnet and Osborne, Exp. Eye Res., 57:209-216, 1993). Furthermore, 5HT 1A The existence of receptor mRNAs has been reported (Chidlow et al., Invest. Ophthalmol. Vis. Sci., supra and Osborne and Chidlow, Ophthalmologica, 210:308-314, 1996).

[0008] 8-hydroxyDPAT and MKC-242(5HT 1A Studies in rabbits using 5HT antagonists have shown that these 1A It has been shown that 5-methylpiperidine metolactin (5HT) agonists can reduce IOP (Osborne and Chidlow, Ophthalmology, 210:308-319, 1996, EP 0771563A2). 1A 5HT1 receptor agonists) can reduce IOP in glaucoma monkeys (Wang, et al., Curr. Eye Res., 16:679-775, 1997). U.S. Patent No. 5,693,654 discloses 5HT1 receptor agonists for reducing IOP. WO 92 / 20333 discloses several 5HT1 receptor agonists for treating glaucoma. 1A agonists are disclosed.

[0009] Eltoprazine is a 5HT 1A / 1B Agonist (EC 50 =148 nM) and was granted orphan drug status by the US FDA in 2016. It is used to treat levodopa-induced movement disorder (LID) and is currently undergoing phase II clinical trials, demonstrating excellent therapeutic efficacy and safety in the treatment of cognitive and movement disorders (Cabedo N. Journal of medicinal chemistry, 2001, 44(11):1794-1801.).

[0010] NLX-112 is a selective 5HT 1A Agonist (EC 50 = 3.3 nM, E max=84%) for the treatment of Parkinson's disease (PD) levodopa-induced dyskinesia (LID), and is currently undergoing Phase II clinical trials by Neurolixis. According to literature (Noureddine El Aouad, European Journal of Medicinal Chemistry, 44(11):4616-4621), NLX-112 exhibits novel therapeutic properties, including significant antidyskinetic activity without compromising the therapeutic efficacy of L-DOPA, as well as antidepressant and anti-anxiety effects on non-motor psychopathological symptoms.

[0011] In addition, 5-HT 1A Receptor agonists primarily alleviate movement and non-movement disorders through non-dopaminergic mechanisms. This means that a multi-target approach that binds to both dopaminergic and serotonergic receptors could provide a dual therapeutic effect in the treatment of Parkinson's disease. (Ohno Y. Prog Neurobiol. 2015 Nov;134:104-21.) (Shimizu S. Aging Dis. 2013 Feb;4(1):1-13.) Currently, molecules with such multi-target characteristics have demonstrated clinical efficacy.

[0012] SOMCL-171(D2:EC 50 =873 nM, E max =74%;5-HT 1A :EC 50 = 175 nM, E max = 83%) in the 6-OHDA-lesioned rat model 1A As an agonist, it exhibits effects against Parkinson's disease and can also delay the development of L-DOPA-induced dyskinesia (LID) without weakening the therapeutic effects of Parkinson's disease (Zhao R, Lu W, Fang X, et al. 2014 Sep;124:204-10.).

[0013] Bifeprunox(D2:EC 50 =39.8 nM, D3:IC50 =15.2 nM, 5-HT 1A :EC 50 =47.8 nM) is an investigational anti-Parkinson's disease drug developed by Solvay, currently in Phase III clinical trials. Clinical trials have shown that it has the effect of improving motor symptoms and alleviating psychiatric symptoms such as antidepressant and anti-anxiety (Wang, Q. Neuropharmacology, 2019, 148:1-10.).

[0014] Pardoprunox (SLV-308) (D2:EC 50 =10 nM, D3:EC 50 =0.6 nM, 5-HT 1A :EC 50 =500 nM) is a D2 / D3 / 5-HT inhibitor with antiparkinsonian, antidepressant, and anxiolytic effects. 1A It is a dopamine agonist (Jones CA. Eur Neuropsychopharmacol. 2010 Aug;20(8):582-93.). It is also less likely to cause side effects such as movement disorders than single-target dopamine agonists, and is currently in Phase III clinical trials for the treatment of Parkinson's disease (Glennon, JC Synapse 2006, 60, 599-608.).

[0015] Furthermore, Swati Biswas, in a 2008 publication (Biswas S. J Med Chem. 2008;51(10):3005-3019.), disclosed a class of 2-aminothiazole derivatives with selective D3 agonist activity, and the structures of compounds ((-)31, (-)33) closest to the patented compounds are as follows:

[0016] [ka]

[0017] The compound has a certain affinity for D2 and D3 receptors and is useful for the treatment of Parkinson's disease, among which D 2L and the binding affinity K of (-)31 to D3 receptorsi The values were 1979±567 nm and 44.0±10.6 nm, respectively, and the ratio was 58.6. 2L and the agonist potency EC of (-)33 for D3 receptors 50 were 13.4±2.4 (78.8±0.8%) and 0.06±0.015 (95.7±10.7%), respectively, and the ratio was 223.

[0018] JP2005104885A describes a compound that binds to dopamine D2 receptors and 5-serotonin 5-HT 1A Novel thiazole derivatives that exhibit agonistic activity against both receptors are disclosed. Among them, compound Example 19, which has a structure relatively close to that of the present patent compound, has the following structure, but the specification does not disclose the technical effect of this compound:

[0019] [ka]

[0020] In summary, dopamine D2, D3 receptors and / or 5-HT 1A In view of the existence of multi-target synergistic effects of receptors, dopamine D2, D3 receptors and / or 5-HT 1A Multi-target chemical small molecules with receptor activity are expected to treat the main motor symptoms of Parkinson's disease while overcoming motor impairments, improving cognitive impairment, and even exerting new clinical therapeutic properties in terms of improving mental mood, such as anxiolytic and antidepressant effects, particularly with respect to dopamine D2, D3 and / or 5-HT receptors. 1A In the field of drug development and application, multi-target agonists have become an important direction for the development of new drugs for Parkinson's disease, antidepressants, schizophrenia, and other diseases worldwide, and research in this field is novel, progressive, and of great scientific value. Summary of the Invention

[0021] The technical problem that the present invention aims to solve is to provide an aromatic heterocyclic cyclohexylaminoalkylpiperidine derivative, a preparation method and its use, and in particular, the present invention provides a method for producing aromatic heterocyclic cyclohexylaminoalkylpiperidine derivatives, D2, D3, 5-HT 1A The objective of this study is to develop a new type of anti-Parkinson's disease drug that simultaneously has receptor full agonist effects to effectively treat both movement disorders and non-movement disorders while reducing various toxicities and side effects. This aims to overcome the major deficiencies of existing drugs, such as the low therapeutic efficacy of D2 and D3 dual full agonist drugs for non-movement disorders and the presence of LID side effects, the limited anti-Parkinsonian movement disorder effects of selective D3 agonists, and the insufficient anti-Parkinsonian therapeutic effects of D2 and D3 dual partial agonists.

[0022] The present invention aims to provide a compound represented by general formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0023] [ka]

[0024] Among them, X is an amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, C 6-10 Aryl C 3-8 Cycloalkyl groups, C 6-10 Aryl 3-8 membered heterocyclyl group, C 6-10 Aryl 5-10 membered heteroaryl group, 5-10 membered heteroaryl C 3-8 a cycloalkyl group or a 5- to 10-membered heteroaryl or a 3- to 8-membered heterocyclyl group, optionally further substituted with one or more R; R is hydrogen, deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, C 1-6 Alkyl group, C1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, among which the above C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 The haloalkoxy group may optionally further comprise deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 substituted with one or more substituents selected from haloalkoxy groups; Z is a bond, -(CR aa R bb ) m -, -C(O)(CR aa R bb ) m -, -O(CR aa R bb ) m -, -(CR aa R bb ) m O-, -(CR aa R bb ) m N(R cc )-, -S(O)(CR aa R bb ) m -, -S(O)2(CR aa R bb ) m -, -C(O)(CR aa R bb ) m N(R cc )-, -C(S)(CR aa R bb ) m N(R cc )-or-C(S)(CR aa R bb ) m -Selected from M1 and M2 are each independently CR aa , N, O or S; R aa and R bbare each independently hydrogen, deuterium, halogen, hydroxy group, amino group, mercapto group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, among which the above C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 The haloalkoxy group may optionally further comprise deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 substituted with one or more substituents selected from haloalkoxy groups; R cc are hydrogen, deuterium, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, among which the above C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 The haloalkoxy group may optionally further comprise deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 substituted with one or more substituents selected from haloalkoxy groups; R1 is hydrogen, deuterium, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, among which the above C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 The haloalkoxy group may optionally further comprise deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 substituted with one or more substituents selected from haloalkoxy groups; R2 is a hydroxy group, an amino group, a mercapto group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, n is selected from 0, 1, 2, 3, or 4; m is selected from 0, 1, 2, 3, 4, 5 or 6.

[0025] In a further preferred embodiment of the present invention,

[0026] [ka] teeth,

[0027] [ka]

[0028] and preferably

[0029] [ka]

[0030] is.

[0031] In a further preferred embodiment of the present invention, X is an amino group, C 3-8Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group or C 6-10 aryl, 5-10 membered heteroaryl groups, optionally further substituted with one or more R, preferably an amino group, C 4-6 Cycloalkyl groups, 4- to 6-membered heterocyclyl groups, C 6-10 is selected from an aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 6-membered benzo heteroaryl group, and is optionally further substituted with one or more R.

[0032] In a further preferred embodiment of the present invention, the R is hydrogen, deuterium, halogen, a hydroxy group, an amino group, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, preferably hydrogen, deuterium, halogen, cyano group or C 1-6 is an alkyl group, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, a cyano group or C 1-3 It is an alkyl group, and more preferably hydrogen, deuterium, fluorine, chlorine, a cyano group or a methyl group.

[0033] In a further preferred embodiment of the present invention, Z is a bond, —(CH) m -, -C(O)-, -C(O)(CH2) m -, -S(O)2-, -S(O)2(CH2) m or —C(O)N(CH3)—, preferably a bond, —C(O)—, —S(O)2— or —C(O)N(CH3)—.

[0034] In a further preferred embodiment of the present invention, R1 is hydrogen, deuterium, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group or C 1-6 alkoxy groups, preferably hydrogen, deuterium or C 1-6is an alkyl group, more preferably hydrogen, deuterium or C 1-3 It is an alkyl group, and more preferably hydrogen, deuterium, a methyl group, an ethyl group, or a propyl group.

[0035] In a further preferred embodiment of the present invention, R2 is selected from the group consisting of a hydroxy group, an amino group, C 1-6 Alkyl group or C 1-6 haloalkyl groups, preferably hydroxy groups, amino groups, C 1-3 Alkyl group or C 1-3 It is a haloalkyl group, more preferably a hydroxy group or an amino group, and even more preferably an amino group.

[0036] In a further preferred embodiment of the present invention, n is selected from 0, 1, 2 or 3, preferably 0, 1 or 2.

[0037] In a further preferred embodiment of the present invention, X is

[0038] [ka]

[0039] It is selected from the following group: Among them, o is selected from 0, 1, 2, 3, 4 or 5, and R is defined as above.

[0040] In a further preferred embodiment of the present invention, X is

[0041] [ka]

[0042] It is selected from the group:

[0043] In a further preferred embodiment of the present invention, the above general formula (I) further has a structure represented by general formula (II):

[0044] [ka]

[0045] Among them, The definitions of X, Z, R1 and n are the same as above.

[0046] In a further preferred embodiment of the present invention, the above general formula (I) further has a structure represented by general formula (III):

[0047] [ka]

[0048] Among them, Ring A is C 6-10 Aryl group, 5- to 10-membered heteroaryl group or C 6-10 aryl 5-10 membered heteroaryl groups, preferably C 6-10 an aryl group or a 5-6 membered benzoheteroaryl group, more preferably a phenyl group or a benzothienyl group; The definitions of R, R1, n and o are the same as above.

[0049] In a further preferred embodiment of the present invention,

[0050] [ka] teeth,

[0051] [ka]

[0052] Preferably

[0053] [ka]

[0054] Selected from Among them, R3 and R4 each independently represent a halogen, a hydroxy group, an amino group, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, preferably halogen, cyano or C 1-6 It is an alkyl group, more preferably fluorine, chlorine or bromine, and even more preferably chlorine.

[0055] In a further preferred embodiment of the present invention,

[0056] [ka] teeth,

[0057] [ka]

[0058] It is selected from the group:

[0059] In a further preferred embodiment of the present invention, the above general formula (I) further has a structure represented by general formula (IV):

[0060] [ka]

[0061] Among them, Xa is an amino group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C6-10 aryl group or 5- to 10-membered heteroaryl group, optionally further comprising one or more R a and preferably an amino group, C 4-6 Cycloalkyl groups, 4- to 6-membered heterocyclyl groups, C 6-10 aryl group or 5- to 10-membered heteroaryl group, optionally further comprising one or more R a is replaced by R a represents hydrogen, deuterium, halogen, hydroxyl group, amino group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, preferably hydrogen, deuterium, halogen, cyano group or C 1-6 is an alkyl group, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, a cyano group or C 1-3 an alkyl group, more preferably hydrogen, deuterium, fluorine, chlorine, a cyano group, or a methyl group; n1 is selected from 0, 1, 2, 3, and 4, preferably 0, 1, or 2, and more preferably 1.

[0062] In a further preferred embodiment of the present invention, Xa is

[0063] [ka]

[0064] It is selected from the following group: Among them, y is selected from 0, 1, 2 or 3, and is preferably 0, 1 or 2.

[0065] In a further preferred embodiment of the present invention, Xa is

[0066] [ka]

[0067] Selected from wherein R5 and R6 each independently represent a halogen, a hydroxy group, an amino group, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, preferably halogen, cyano or C 1-6 alkyl group, more preferably fluorine, chlorine, bromine, cyano group or C 1-3 It is preferably an alkyl group, more preferably a fluorine group, a chlorine group, a cyano group or a methyl group.

[0068] In a further preferred embodiment of the present invention, Xa is

[0069] [ka]

[0070] It is selected from the group:

[0071] In a further preferred embodiment of the invention, the compound is

[0072] [ka]

[0073] [ka]

[0074] Selected from.

[0075] The present invention further provides a compound represented by general formula (V), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0076] [ka]

[0077] Among them, n1 is selected from 0, 1, 2, 3, and 4, preferably 0, 1, or 2, and more preferably 1.

[0078] The present invention further provides a process for preparing a compound of general formula (IV), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0079] [ka]

[0080] condensation reaction of a compound of general formula (V) with a substituted carboxylic acid or acid chloride to obtain a compound of general formula (IV), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof; wherein n1 and Xa are as defined in general formula (IV).

[0081] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by each of the above general formulas, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical additive selected from the group consisting of a pharmaceutically acceptable vector, diluent, and excipient.

[0082] In some embodiments of the present invention, the pharmaceutical composition can be prepared according to any method known in the art. The vectors include, for example, fillers or adhesives such as cellulose derivatives, gelatin, and polyvinylpyrrolidone, diluents such as water, excipients such as starch, disintegrants such as calcium carbonate and sodium bicarbonate, and lubricants such as calcium stearate or magnesium stearate, which are conventional in the pharmaceutical field. In addition, other auxiliary agents such as sweeteners, flavorings, or coloring agents can also be added to the composition.

[0083] In some embodiments of the present invention, the pharmaceutical composition can be administered orally, by spray inhalation, rectally, nasally, bucally, topically, parenterally, such as by subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or via an explanted reservoir, of which oral administration is preferred.

[0084] For oral administration, the compounds of the present application may be made into any orally acceptable dosage form, including, but not limited to, tablets, capsules, aqueous solutions or suspensions, and the like.

[0085] The present invention further provides preferred embodiments relating to the use of the compounds represented by the above general formulas, their stereoisomers, their tautomers or pharmaceutically acceptable salts thereof, or the above pharmaceutical compositions in the manufacture of drugs.

[0086] The present invention relates to the application of the compounds represented by the above general formulas, their stereoisomers, their tautomers or pharmaceutically acceptable salts thereof, or the above pharmaceutical compositions in the manufacture of drugs in which 5-serotonin receptors and / or dopamine receptors are involved or modulated, preferably 5-HT 1A A preferred embodiment is further provided for application in the manufacture of a drug in which the receptors, dopamine D2 receptors and / or dopamine D3 receptors, are involved or modulated.

[0087] The present invention further provides the application of the compound represented by each of the above general formulae, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the manufacture of a drug for treating a central nervous system disease.

[0088] The present invention further provides the application of the compound represented by each of the above general formulae, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the treatment of central nervous system diseases.

[0089] In a preferred embodiment of the present invention, the central nervous system disease is one or more selected from Parkinson's disease, schizophrenia, bipolar disorder, depression, anxiety disorder, mania, Huntington's disease, Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory impairment, loss of executive function, vascular dementia, neuropathic pain and neuropathic diseases related to intelligence, learning or memory, glaucoma, age-related macular degeneration, optic neuritis, ischemic disorder and retinal edema, more preferably Parkinson's disease.

[0090] Detailed Description of the Invention Unless specifically stated to the contrary, terms used in the specification and claims have the following meanings.

[0091] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention is intended to include cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, including enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Substituents such as alkyl groups may contain additional asymmetric carbon atoms. These isomers and mixtures thereof are all within the scope of the present invention. In some embodiments, preferred compounds are isomeric compounds that exhibit superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic or diastereomeric mixtures, are all within the scope of the present invention. Purification and separation of such materials can be achieved by standard techniques known in the art.

[0092] Unless otherwise specified, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of one another.

[0093] Unless otherwise specified, the terms "cis-trans isomers" or "geometric isomers" refer to the inability to freely rotate about double bonds or single bonds of ring carbon atoms.

[0094] Unless otherwise specified, the term "diastereomer" refers to stereoisomers that have two or more centers of chirality in the molecules and whose molecules are not mirror images of each other.

[0095] Certain compounds of the present invention may exist. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to different functional group isomers that are in dynamic equilibrium at room temperature and can rapidly interconvert. When tautomers are possible (e.g., in solution), chemical equilibrium of tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include intertransformations that occur via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include intertransformations that occur via rearrangement of some bond electrons. A specific example of keto-enol tautomerization is the intertransformation between the two tautomers pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0096] The term "alkyl group" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms connected to the rest of the molecule by a single bond. An "alkyl group" may have 1 to 8 carbon atoms, i.e., a "C1-C8 alkyl group," such as a C1-4 alkyl group, a C1-3 alkyl group, a C1-2 alkyl group, a C3 alkyl group, a C4 alkyl group, a C1-6 alkyl group, or a C3-6 alkyl group. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, and the like, or isomers thereof. The alkyl group may be optionally substituted or unsubstituted, and if substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from deuterium, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, mercapto, hydroxy, nitro, amino, or cyano, wherein the alkyl, haloalkyl, alkoxy, or haloalkoxy group is one or more groups optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy groups.

[0097] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl group contains 3 to 20 carbon atoms, i.e., a "C3-C20 cycloalkyl group", such as a C3-18 cycloalkyl group, a C3-16 cycloalkyl group, a C3-12 cycloalkyl group, a C3-8 cycloalkyl group, a C3-6 cycloalkyl group, a C3-5 cycloalkyl group, a C3-4 cycloalkyl group, a C4-8 cycloalkyl group, a C4-6 cycloalkyl group, or a C5-6 cycloalkyl group, preferably a C3-8 cycloalkyl group, a C3-6 cycloalkyl group, a C3-5 cycloalkyl group, or a C3-4 cycloalkyl group. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups. The cycloalkyl groups may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably independently selected from deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, mercapto, hydroxy, nitro, amino, or cyano, wherein the alkyl, haloalkyl, alkoxy, and haloalkoxy groups are optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy.

[0098] The term "heterocyclyl group" refers to a saturated or unsaturated monocyclic or polycyclic 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 of 0 to 2), but does not include a ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. That is, the "3- to 20-membered heterocyclyl group" is, for example, a 3- to 18-membered heterocyclyl group, a 3- to 16-membered heterocyclyl group, a 3- to 12-membered heterocyclyl group, a 3- to 8-membered heterocyclyl group, a 3- to 6-membered heterocyclyl group, a 3- to 5-membered heterocyclyl group, a 3- to 4-membered heterocyclyl group, a 4- to 8-membered heterocyclyl group, a 4- to 6-membered heterocyclyl group, or a 5- to 6-membered heterocyclyl group, preferably a 3- to 8-membered heterocyclyl group, a 3- to 5-membered heterocyclyl group, a 3- to 4-membered heterocyclyl group, a 4- to 8-membered heterocyclyl group, a 4- to 6-membered heterocyclyl group, or a 5- to 6-membered heterocyclyl group, which optionally contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms, and the heteroatoms are optionally N, O, S(O), m(wherein m is an integer of 0 to 2), but does not contain a ring moiety of -OO-, -OS-, or -SS-, and is preferably a 3- to 8-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O, or S, more preferably a 4- to 6-membered heterocyclyl group containing 1 to 3 heteroatoms selected from N, O, or S. Non-limiting examples of monocyclic heterocyclyl groups include an oxetanyl group, a thietanyl group, a pyrrolidinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a tetrahydropyranyl group, a dihydroimidazolyl group, a dihydrofuryl group, a dihydropyrazolyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a 1,3-dioxocyclopentyl group, a 2,2-difluoro-1,3-dioxocyclopentyl group, or an azepinyl group. Non-limiting examples of polycyclic heterocyclyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclyl groups. The heterocyclyl group may be optionally substituted or unsubstituted, and if substituted, the substituents may be at any available point of attachment, preferably independently selected from deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, mercapto, hydroxy, nitro, amino, or cyano groups, wherein the alkyl, haloalkyl, alkoxy, and haloalkoxy groups are one or more groups optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy groups.

[0099] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated electron system, preferably 6- to 10-membered, such as a phenyl or naphthyl group.

[0100] The aryl group may be fused to a heteroaryl group, a heterocyclyl group, or a cycloalkyl ring, where the ring bonded together to the parent structure is an aryl ring, such as an arylcycloalkyl group, an arylheterocyclyl group, or an arylheteroaryl group, preferably C 6-10 Aryl C 3-8 Cycloalkyl groups, C 6-10 aryl 3-8 membered heterocyclyl group or C 6-10 aryl is a 5-10 membered heteroaryl group, more preferably C 6-10 Aryl is a 5- to 10-membered heteroaryl group, more preferably a 5- to 6-membered benzo heteroaryl group, wherein the heterocyclyl group is a heterocyclyl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, and the heteroaryl group is a heteroaryl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, non-limiting examples of which (wherein the rings bonded together to the parent structure are aryl rings) include:

[0101] [ka]

[0102] The aryl, arylcycloalkyl, arylheterocyclyl, or arylheteroaryl groups may be substituted or unsubstituted; if substituted, the substituents are preferably independently selected from deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, mercapto, hydroxy, nitro, amino, or cyano groups, wherein the alkyl, haloalkyl, alkoxy, or haloalkoxy groups are one or more groups optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy groups.

[0103] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, or S, more preferably a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, or S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from benzo-N, O, or S, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, benzo ... Examples of the alkyl group include a benzoyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a thiadiazole group, a pyrazinyl group, or a benzo derivative thereof, and are preferably a furanyl group, a triazolyl group, a thienyl group, a thiazolyl group, an imidazolyl group, a pyrazolyl group, a pyrrolyl group, a pyridyl group, a pyrimidinyl group, a thiazolyl group, or a benzo derivative thereof, and more preferably a furanyl group, a thienyl group, a thiazolyl group, a pyrazolyl group, a pyrrolyl group, a pyridyl group, or a benzo derivative thereof. Non-limiting examples thereof include:

[0104] [ka]

[0105] Includes:

[0106] The heteroaryl group may be fused to a heterocyclyl group or a cycloalkyl ring, where the ring bonded together to the parent structure is a heteroaryl ring, such as a heteroarylcycloalkyl group, a heteroarylheterocyclyl group, and preferably a 5- to 10-membered heteroaryl C 3-8 It is a cycloalkyl group or a 5- to 10-membered heteroaryl 3- to 8-membered heterocyclyl group, wherein the heterocyclyl group is a heterocyclyl group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and the heteroaryl group is a heteroaryl group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.

[0107] The heteroaryl, heteroarylcycloalkyl, or heteroarylheterocyclyl groups may be optionally substituted or unsubstituted; if substituted, the substituents are preferably independently selected from deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, mercapto, hydroxy, nitro, amino, or cyano groups, wherein the alkyl, haloalkyl, alkoxy, or haloalkoxy groups are one or more groups optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy groups.

[0108] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where alkyl is as defined above, and is preferably an alkoxy group containing 1 to 8 carbon atoms, more preferably an alkoxy group containing 1 to 6 carbon atoms, and most preferably an alkoxy group containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. An alkoxy group may be optionally substituted or unsubstituted; if substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy groups.

[0109] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples of halomethyl groups include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, and the like, with fluoromethyl, difluoromethyl, and trifluoromethyl being preferred. Non-limiting examples of haloethyl groups include 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, Examples of haloalkyl groups include ethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, and 2-bromo-1,1,2,2-tetrafluoroethyl groups, and are preferably 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, and 2,2-difluoroethyl groups. Haloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, hydroxyl, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy groups.

[0110] The term "haloalkoxy group" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above. Non-limiting examples of halomethoxy groups include fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, and the like, with fluoromethoxy, difluoromethoxy, and trifluoromethoxy being preferred. Non-limiting examples of haloethoxy groups include 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, Examples of haloalkoxy groups include 1-chloroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, and 2-bromo-1,1,2,2-tetrafluoroethoxy groups, and are preferably 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, and 2,2-difluoroethoxy groups. The haloalkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy groups.

[0111] The term "alkenyl group" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and if substituted, the substituents are preferably independently selected from deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, mercapto, hydroxy, nitro, amino, or cyano, wherein the alkyl, haloalkyl, alkoxy, or haloalkoxy groups are optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy.

[0112] The term "alkynyl group" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the alkyl group is as defined above and has 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms (i.e., a C2-6 alkynyl group). Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. An alkynyl group can be substituted or unsubstituted; if substituted, the substituents are preferably independently selected from deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, mercapto, hydroxy, nitro, amino, or cyano, wherein the alkyl, haloalkyl, alkoxy, or haloalkoxy groups are optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy.

[0113] "Hydroxy" refers to an -OH group.

[0114] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0115] An "amino group" refers to -NH2.

[0116] A "cyano group" refers to -CN.

[0117] A "nitro group" refers to -NO2.

[0118] A "mercapto group" refers to -SH.

[0119] The terms "comprise," "include," "have," "contain," or "involve," and other variations thereof herein, are inclusive or open-ended and do not exclude other elements or method steps not recited. Those skilled in the art should understand that the above terms, such as "comprise," encompass the meaning of "consisting of."

[0120] The term "one or more species" or similar expression "at least one species" can mean, for example, one, two, three, four, five, six, seven, eight, nine, ten species, or more species.

[0121] When a lower and upper limit of a numerical range is disclosed, any number within that range and any encompassed range is specifically disclosed. In particular, each possible range of values disclosed herein should be understood to mean each value and range encompassing the broader range.

[0122] As used herein, "Z" and "-Z-" both represent the same specific group and may be used interchangeably.

[0123] As used herein, the expression m to n refers to the range of m to n and subscopes consisting of each point value therein, as well as each point value. For example, the expression "C2 to C8" or "C2-8" should be understood to encompass the range of 2 to 8 carbon atoms, and also encompass any subscopes and each point value therein, such as C2 to C5, C3 to C4, C2 to C6, C3 to C6, C4 to C6, C4 to C7, C4 to C8, etc., and C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3 to C10" or "C3-10" should be understood in a similar manner and may include any subscopes and point values contained therein, such as C3 to C9, C6 to C9, C6 to C8, C6 to C7, C7 to C10, C7 to C9, C7 to C8, C8 to C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C10, etc. Also, for example, the expression "C1 to C6" or "C1-6" should be understood to include the range of 1 to 6 carbon atoms and any subscopes and point values therein, such as C2 to C5, C3 to C4, C1 to C2, C1 to C3, C1 to C4, C1 to C5, C1 to C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. Also, for example, the expression "3-membered to 10-membered" should be understood to include any subscopes and respective 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 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, etc. Other similar expressions herein should be understood in a similar manner.

[0124] 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," and "X is A, B, and C" all mean the same thing, i.e., X may be any one or more of A, B, and C.

[0125] As used herein, the expression "-(CYY)-" means that each of Y or Y bonded to C may be the same or different, i.e., each of Y may be a different group, each of Y may be a different group, each of Y may be the same group, and each of Y may be the same group.

[0126] The term "optionally" or "optionally" refers to the subsequently described event or circumstance that may or may not occur, and the description includes cases where the described event or circumstance occurs and cases where it does not occur. For example, "a cycloalkyl group optionally substituted with an alkyl group" means that the alkyl group may be present, but is not necessarily so, 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" refer to the replacement of one or more (e.g., one, two, three, or four) hydrogens on a specified atom with one selected from the indicated group, provided that the specified atom's normal valences in its current context are not exceeded and that the substitution results in the formation of a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in the formation of stable compounds. When a substituent is described as being absent, it should be understood that the substituent may also be one or more hydrogen atoms, as long as the structure allows the compound to be stable. When it is described that each carbon atom in a group may optionally be replaced with a heteroatom, the proviso is that the normal valences of all atoms in the group in their current context are not exceeded and a stable compound is formed.

[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 that atom or group may be replaced with independently selected, optional substituents. When a substituent is oxo (i.e., =0), this means that two hydrogen atoms are replaced. Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position on the substituent.

[0129] When a bond of a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in that substitutable ring.

[0130] When any variable (e.g., R) and labeled variable (e.g., R, R, R, R, R, R, R, etc.) occurs more than one time in a composition or structure of a compound, its definition at each occurrence is independent at every other occurrence. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, then said group may optionally be substituted with up to 4 R substituents, and all options for each R substituent at each occurrence are independent of each other.

[0131] The term "pharmaceutically acceptable" refers to a substance that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, or the like, and that has a reasonable trade-off and can be effectively used for its intended use.

[0132] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is safe and effective when used in a mammalian body and possesses the desired biological activity.

[0133] The term "pharmaceutical composition" refers to a mixture containing one or more compounds described in the present invention or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, and other components such as physiologically / pharmaceutically acceptable vectors or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living body and contribute to the absorption of the active ingredients to further exert their biological activity.

[0134] The term "pharmaceutically acceptable vector" refers to a substance that has no appreciable irritating effect on an organism and does not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable vectors" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0135] Terms such as "administering" or "giving" refer to a method that allows a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, or intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.

[0136] As used herein, the term "treatment" includes, and extends to, alleviating, alleviating, or ameliorating a disease or symptom, preventing other symptoms, improving or preventing underlying metabolic factors of a symptom, inhibiting a disease or symptom, e.g., preventing the progression of a disease or symptom, alleviating a disease or symptom, promoting the alleviation of a disease or symptom, or arresting the symptoms of a disease or symptom. "Treatment" further includes achieving therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to the eradication or amelioration of the condition being treated. Furthermore, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disease, such that an improvement in the patient's disease may be observed even though the patient may still have the underlying disease. Prophylactic benefit refers to the patient using a composition to prevent the risk of a particular disease, or the patient taking the composition when one or more physiological symptoms of the disease appear, even though the disease has not yet been diagnosed.

[0137] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical substance that can effectively treat or prevent a target disorder, disease, or condition. The term "neuropsychiatric disorder" refers to a general term for neurological and psychiatric disorders, including neurological and / or psychiatric disorders.

[0138] The terms "effective amount," "therapeutically effective amount," or "prophylactically effective amount," with respect to a drug, drug unit, or active ingredient, refer to a dose of a drug or agent sufficient to achieve a desired effect while causing acceptable side effects. The effective amount is determined by the individual, and depends on the age and general condition of the individual, as well as the specific active substance; an appropriate effective amount for an individual can be determined by one skilled in the art through routine testing.

[0139] As used herein, an "individual" includes a human or a non-human animal. Exemplary human individuals include human individuals (referred to as patients) suffering from a disease (e.g., a disease described herein) or normal individuals. "Non-human animals" of the present invention include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, domestic animals, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0140] The following detailed description of the invention is intended to illustrate non-limiting embodiments, allowing those skilled in the art to better understand the technical solution of the present invention, its principles, and its practical applications, so that those skilled in the art can modify and implement the present invention in many ways, as may best suit the requirements of specific use. Beneficial effects The compound of the present invention has a novel structure and is a 5-HT 1A The compounds can be used as agonists for 5-HT receptors, dopamine D2 receptors and / or dopamine D3 receptors, and exhibit some agonist activity. 1A The majority of the compounds exhibit agonistic activity against at least two receptors: the dopamine D2 and D3 receptors, and the 5-HT 1A It exhibits triple agonist activity on the dopamine D2 and D3 receptors, and exhibits significant therapeutic effects on central nervous system disorders such as Parkinson's disease, and can be used to manufacture drugs for treating central nervous system disorders. [Brief explanation of the drawings]

[0141] [Figure 1] 1 shows the effect of Example 28 at various concentrations on rat mandibular tremor behavior induced by Tacrine. [Figure 2] 1 shows the effect of Example 32 at various concentrations on rat mandibular tremor behavior induced by Tacrine. [Figure 3] 1 shows the effect of Example 33 at various concentrations on rat mandibular tremor behavior induced by Tacrine. DETAILED DESCRIPTION OF THE INVENTION

[0142] Hereinafter, embodiments of the present invention will be described in detail with reference to examples. However, as will be understood by those skilled in the art, the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the present invention. Unless specific conditions are specified in the examples, they are carried out under general conditions or conditions recommended by the manufacturer. Unless the manufacturer of the reagents or equipment used is specified, they may be ordinary commercially available products. Unless otherwise specified, parts and percentages used herein are by weight. Example The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or / and liquid chromatography mass spectrometry (LC-MS).

[0143] NMR chemical shifts (δ) are reported in parts per million (ppm). NMR measurements were performed using an AVANCE III600 nuclear magnetometer in dimethyl sulfoxide (DMSO), deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0144] A Shimadzu LCMS2020 mass spectrometer (Japan) was used for liquid chromatography-mass spectrometry (LC-MS) measurements, and a Shimadzu LC20A liquid chromatograph (Japan) was used for HPLC measurements.

[0145] Yantai Jiangyou silica gel plates were used for thin-layer chromatography. TLC used 0.2 mm ± 0.03 mm silica gel plates, and thin-layer chromatography separated and purified products used 0.4 mm to 0.5 mm silica gel plates. Intermediate 1a (S)-N 6 -(piperidin-4-ylmethyl)-N 6-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine 1a

[0146] [ka]

[0147] Synthesis scheme:

[0148] [ka]

[0149] Step A: (S)-N 6 Synthesis of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (0.24 mol, 1 eq) was dissolved in 320 mL of NMP, and bromopropane (0.96 mol, 4 eq) was added. The mixture was stirred at room temperature for 18 h. After the reaction was completed, the mixture was suction filtered and washed with an appropriate amount of isopropanol to obtain a white solid. The solid was then dried in a ventilated oven at 70 °C. The dried sample was dissolved in an appropriate amount of water (30 mL), and the pH was adjusted to 10 with 20% aqueous NaOH solution. The solid was extracted with dichloromethane (400 mL x 3). The organic layers were combined, dried, and concentrated to give (S)-N 6 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was obtained. ESI-MS [M+H] + : m / z 212.1. Step B: Synthesis of tert-butyl (S)-4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carboxylate (S)-N 64-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (94.6 mmol, 1 eq) and tert-butyl 4-formylpiperidine-1-carboxylate (113.6 mmol, 1.2 eq) were dissolved in 1,2-dichloroethane (150 mL). 3 drops of acetic acid were added and the mixture was stirred for 30 min at -20 °C. Sodium triacetoxyborohydride (142.0 mmol, 1.5 eq) was then added and the mixture was stirred for 8 h at -20 °C. When the starting materials were essentially completely reacted or by-products began to form, the reaction was stopped and diluted with ethyl acetate (100 mL). The reaction was quenched by adding 10% hydrochloric acid (150 mL) at -20 °C, followed by the addition of saturated NaHCO3 solution (300 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (300 mL × 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to give tert-butyl (S)-4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carboxylate (15.2 g, 39.3%). ESI-MS [M+H] + : m / z 409.1. Step C: (S)-N 6 -(piperidin-4-ylmethyl)-N 6 Synthesis of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (S)-tert-Butyl 4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carboxylate (37.3 mmol, 1 eq) was dissolved in 20 mL of methanol, and 14 mL (1.5 eq) of 4 M hydrogen chloride in methanol was added. The mixture was stirred at room temperature for 12 h. The starting material was allowed to react completely, and the mixture was concentrated under reduced pressure. The solvent was removed, and 20 mL of water was added to disperse the sample. The aqueous phase was washed with 50 mL of ethyl acetate and then adjusted to pH 10 with 10% NaOH solution. The aqueous phase was extracted with dichloromethane (100 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Intermediate 1a (8.5 g, 73.9%). ESI-MS [M+H] + : m / z 309.1. Intermediate 1b 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)acetaldehyde 1b

[0150] [ka]

[0151] Synthesis scheme:

[0152] [ka]

[0153] Using the synthesis method for intermediate 1a, and replacing tert-butyl 4-formylpiperidine-1-carboxylate in step B with tert-butyl 4-(2-oxyethyl)piperidine-1-carboxylate, intermediate 1b was prepared by steps A to C. ESI-MS [M+H] + : m / z 323.1. Among them, the intermediate tert-butyl 4-(2-oxyethyl)piperidine-1-carboxylate was prepared by the following steps.

[0154] tert-Butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (21.8 mmol, 1 eq) was dissolved in 100 mL of dichloromethane, Dess-Martin reagent (21.8 mmol, 1 eq) was added, and the mixture was stirred at room temperature for 1.5 h. After the reaction was complete, 10% aqueous sodium thiosulfate (100 mL) and saturated aqueous sodium bicarbonate (100 mL) were added and the mixture was stirred at room temperature for 1 h. The layers were separated, and the aqueous layer was extracted with dichloromethane (100 mL x 2). The combined organic layer was washed with saturated aqueous sodium bicarbonate, dried, and concentrated to give tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate. ESI-MS [M+H] + : m / z 228.1. Example 1 (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its dihydrochloride salt

[0155] [ka]

[0156] (S)-N 6 Synthesis of -(1-(2,3-dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0157] [ka]

[0158] Step A: Synthesis of (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine The starting materials, 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (45.0 g, 0.266 mol) and L-(+)-tartaric acid (40.0 g, 0.266 mol), were added to a 1000 mL reaction flask, 450 mL of water was added, and the mixture was heated to 80 °C and stirred for 1 h. The mixture was then cooled to room temperature and stirred for 2 h until the solid was completely precipitated. The mixture was then suction filtered and dried to obtain 57.0 g of an off-white solid. The dried solid was then recrystallized three times, each time with 8 times the amount of water. The recrystallized product was dispersed in 80 mL of water, and 20% sodium hydroxide solution was added to adjust the pH to 12. The mixture was stirred at 0-5 °C for 2 h. The mixture was then suction filtered and dried to obtain 15.8 g of (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine in 62.0% yield.

[0159] ESI-MS [M+H] + : m / z 170.0. [α] D 20 -94.5°C (C=1, MeOH). The mother liquor was collected and purified by the same method using D-(-)-tartaric acid as a resolving agent to obtain (R)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (ESI-MS [M+H] + :m / z 170.0. [α] D 20 +99.4°C (C=1, MeOH).

[0160] Step B: Synthesis of 1-(2,3-dichlorophenyl)piperidin-4-one 1,2-Dichloro-3-iodobenzene (22.0 mmol, 1 eq), 4-piperidinone ethylene glycol (22.0 mmol, 1 eq), Pd(dba) (0.6 mmol, 0.025 eq), and Xantphos (2.2 mmol, 0.1 eq) were dissolved in toluene (60 mL). Sodium tert-butoxide (33.0 mmol, 1.5 eq) was added, and the mixture was purged with nitrogen gas. The mixture was heated to 80-110 °C and refluxed for 15 h. After the reaction was complete, the mixture was filtered through diatomaceous earth and the filtrate was rotary evaporated under reduced pressure to remove the solvent, yielding 5.1 g of the crude intermediate product (ESI-MS [M+H]). + : m / z 288.1. 1 H NMR (400 MHz, DMSO) δ 7.29 (d, J = 2.0 Hz, 1H), 7.28 (s, 1H), 7.16 (dd, J = 5.7, 3.9 Hz, 1H), 3.92 (s, 4H), 3.05 - 3.00 (m, 4H), 1.78 (t, J = 5.6 Hz, 4H)).

[0161] The crude intermediate product was dissolved in acetone (60 mL), 6N hydrochloric acid solution (70 mL) was added, and the mixture was stirred overnight at room temperature for complete hydrolysis. Water was added, and organic impurities were extracted with ethyl acetate to remove them. The aqueous layer was adjusted to pH 10 with NaHCO3, extracted with ethyl acetate (3 x 100 mL), and the organic layer was separated and concentrated. The crude product was purified by silica gel column chromatography to give 2.23 g of 1-(2,3-dichlorophenyl)piperidin-4-one in a 51.6% yield.

[0162] ESI-MS [M+H] + : m / z 244.0. Step C: (S)-N 6 Synthesis of -(1-(2,3-dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (3.7 mmol, 1 eq) and 1-(2,3-dichlorophenyl)piperidin-4-one (4.1 mmol, 1.1 eq) were dissolved in 1,2-dichloroethane (20 mL). One drop of acetic acid was added in an ice bath and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (5.5 mmol, 1.5 eq) was then added and the mixture was stirred at room temperature for 8 h. When the starting materials were essentially completely reacted or when by-products began to form, the reaction was stopped and ethyl acetate (100 mL) was added to dilute the reaction mixture. The reaction was quenched in an ice bath by adding 10% hydrochloric acid (10 mL), followed by the addition of saturated NaHCO3 solution (20 mL). After separation, the aqueous phase was extracted with dichloromethane, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target product.

[0163] ESI-MS [M+H] + : m / z 397.0. Preparation of the hydrochloride salt: (S)-N 6 Synthesis of -(1-(2,3-dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine dihydrochloride (S)-N 6 -(1-(2,3-Dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 2-5 h and then suction filtered to obtain the dihydrochloride salt of the compound.

[0164] ESI-MS [M+H] + : m / z 397.0. 1H NMR (400 MHz, DMSO) δ 9.63 (s, 1H), 9.44 (s, 1H), 9.17 (s, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.36 - 7.34 (m, 1H), 7.22 - 7.16 (m, 1H), 3.70 (s, 1H), 3.50 - 3.44 (m, 2H), 3.41 - 3.31 (m, 2H) 3.15 -3.04 (m, 1H), 2.87 - 2.78 (m, 2H), 2.78 - 2.72 (m, 1H), 2.71 -2.67 (m, 1H), 2.66 - 2.59 (m, 1H), 2.37 - 2.16 (m, 3H), 2.05 -1.97 (m, 1H), 1.95 - 1.74 (m, 2H). Example 2 (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride salt

[0165] [ka]

[0166] (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-N 6 Synthesis of -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0167] [ka]

[0168] Compound (S)-N 6-(1-(2,3-Dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (1.26 mmol, 1 eq) and propionaldehyde (1.26 mmol, 1 eq) were dissolved in 1,2-dichloroethane (10 mL). One drop of acetic acid was added in an ice bath and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (1.9 mmol, 1.5 eq) was then added and the mixture was stirred at room temperature for 6 h. When the starting material was essentially completely reacted or when by-products began to form, the reaction was stopped and ethyl acetate (20 mL) was added to dilute the reaction mixture. The reaction was quenched in an ice bath by adding 10% hydrochloric acid (5 mL), followed by the addition of saturated NaHCO3 solution (10 mL). After separation, the aqueous phase was extracted with dichloromethane, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target product.

[0169] ESI-MS [M+H] + : m / z 439.0. Preparation of the hydrochloride salt: (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-N 6 Synthesis of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-N 6 4,5,6,7-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, and a solid was precipitated. The mixture was stirred at room temperature for 2-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0170] ESI-MS [M+H] + : m / z 439.0. 1H NMR (400 MHz, DMSO) δ10.66 - 10.55 (m, 1H), 9.31 (s, 2H), 7.37 (d, J = 2.3 Hz, 1H), 7.36 - 7.35 (m, 1H), 7.23 -7.13 (m, 1H), 3.83 (s, 1H), 3.26 - 3.21 (m, 4H), 3.19 -2.89 (m, 1H), 2.84 - 2.74 (m, 2H), 2.73 - 2.60 (m, 2H), 2.52 -2.39 (m, 1H), 2.39 - 2.26 (m, 1H), 2.27 - 2.16 (m, 1H), 2.12 (s, 1H), 2.09 - 2.04 (m, 1H), 2.05 - 1.98 (m, 2H), 1.93 -1.83 (m, 1H), 1.83 - 1.77 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). Example 3 (S)-N 6 -(1-(benzo[b]thiophen-4-yl)piperidin-4-yl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride salt

[0171] [ka]

[0172] (S)-N 6 -(1-(benzo[b]thiophen-4-yl)piperidin-4-yl)-N 6 Synthesis of -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0173] [ka]

[0174] Using the synthesis method of Example 1, 1,2-dichloro-3-iodobenzene in step B is replaced with 4-bromobenzo[b]thiophene, and compound (S)-N 6-(1-(benzo[b]thiophen-4-yl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was obtained, and the raw material (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (S)-N 6 Substituting -(1-(benzo[b]thiophen-4-yl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine produced the desired product.

[0175] ESI-MS [M+H] + : m / z 427.0. Preparation of the hydrochloride salt: (S)-N 6 -(1-(benzo[b]thiophen-4-yl)piperidin-4-yl)-N 6 Synthesis of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride (S)-N 6 -(1-(benzo[b]thiophen-4-yl)piperidin-4-yl)-N 6 4,5,6,7-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, and a solid was precipitated. The mixture was stirred at room temperature for 2-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0176] ESI-MS [M+H] + : m / z 427.0. 1H NMR (600 MHz, DMSO) δ 10.57 (d, J = 18.2 Hz, 1H), 9.35 (s, 2H), 7.75 (d, J = 5.5 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 3.60 - 3.54 (m, 3H), 3.34 -3.09 (m, 3H), 3.08 - 2.91 (m, 1H), 2.91 - 2.79 (m, 2H), 2.78 -2.58 (m, 2H), 2.48 - 2.42 (m, 1H), 2.34 - 2.28 (m, 2H), 2.22 -2.18 (m, 3H), 2.14 - 2.03 (m, 1H), 1.89 - 1.80 (m, 2H), 0.97 (q, J = 7.1 Hz, 3H). Example 4 (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its dihydrochloride salt

[0177] [ka]

[0178] (S)-N 6 Synthesis of -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0179] [ka]

[0180] Step A: Synthesis of ethyl 1-(2,3-dichlorophenyl)piperidine-4-formate 1,2-Dichloro-3-iodobenzene (44.3 mmol, 1 eq), ethyl 4-piperidineformate (44.3 mmol, 1 eq), Pd(OAc) (1.1 mmol, 0.025 eq), BINAP (4.43 mmol, 0.1 eq), and CsCO (66.45 mmol, 1.5 eq) were dissolved in toluene (200 mL), purged with nitrogen, and heated to 110 °C under reflux for 15 h. After completion of the reaction, the mixture was suction filtered through diatomaceous earth. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography to give the intermediate 1-(2,3-dichlorophenyl)piperidine-4-ethylformate (6.1 g, 45.6%).

[0181] ESI-MS [M+H] + : m / z 302.1. 1 H NMR (600 MHz, DMSO-d6) δ 7.33 - 7.26 (m, 2H), 7.13 (dd, J = 7.0, 2.5 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.27 - 3.18 (m, 3H), 2.72 (td, J = 11.6, 2.5 Hz, 2H), 1.98 - 1.91 (m, 2H), 1.79 - 1.70 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H)).

[0182] Step B: Synthesis of 1-(2,3-dichlorophenyl)piperidine-4-carboxylic acid The intermediate 1-(2,3-dichlorophenyl)piperidine-4-ethyl formate (20.2 mmol, 1 eq) was dissolved in THF:MeOH (1:1, 60 mL) and a solution of LiOH·HO (30.3 mmol, 1.5 eq) in water (10 mL) was added. The mixture was stirred at room temperature for 18 h. After the reaction was complete, the solvent was evaporated, 10 mL of water was added to dissolve the solid, and the mixture was extracted with ethyl acetate to remove organic impurities. The aqueous layer was adjusted to pH 2 and extracted with dichloromethane (50 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and dried to give the intermediate 1-(2,3-dichlorophenyl)piperidine-4-carboxylic acid (5.3 g, 95.8%).

[0183] ESI-MS [M+H] + : m / z 274.1. Step C: Synthesis of (S)—N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-1-(2,3-dichlorophenyl)piperidine-4-formamide The intermediate product from the previous step, 1-(2,3-dichlorophenyl)piperidine-4-carboxylic acid (10.9 mmol, 1 eq), EDCI (13.1 mmol, 1.2 eq), HObt (13.1 mmol, 1.2 eq), and triethylamine (21.8 mmol, 2 eq) were dissolved in dichloromethane (50 mL) and stirred in an ice bath for 20 min. (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (21.8 mmol, 2 eq) was added and the mixture was stirred at room temperature for 4 h. After the reaction was completed, 20 mL of water was added and the mixture was extracted with dichloromethane (30 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the intermediate (S)-N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-1-(2,3-dichlorophenyl)piperidine-4-formamide (1.5 g, 32.6%).

[0184] ESI-MS[M+H]+: m / z 425.2. Step D: (S)-N 6 Synthesis of -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine The intermediate product from the previous step, (S)-N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-1-(2,3-dichlorophenyl)piperidine-4-formamide (1.8 g, 4.4 mmol), was dissolved in anhydrous THF (30 mL). 1 M BH3·THF (8.7 mL) was added in an ice bath and heated to 60°C with stirring for 3-5 days. After TLC showed the reaction was complete, the reaction mixture was cooled to room temperature, 10 mL of methanol was added at 0°C, and the mixture was concentrated. The sample was acidified with 4 M hydrogen chloride in methanol and stirred at room temperature for 2 h. The compound was then released with saturated sodium carbonate solution. The aqueous phase was extracted with DCM. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give the desired product.

[0185] ESI-MS [M+H] + : m / z 411.0. Preparation of the hydrochloride salt: (S)-N 6 Synthesis of -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine dihydrochloride (S)-N 6 -((1-(2,3-Dichlorophenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the dihydrochloride salt of the compound.

[0186] ESI-MS [M+H] + : m / z 411.0. 1H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 8.72 (s, 1H), 7.38 -7.34 (m, 1H), 7.33 (s, 1H), 7.20 (dd, J = 6.8, 2.9 Hz, 1H), 6.86 (s, 2H), 3.53 -3.48 (m, 1H), 3.13 - 2.92 (m, 3H), 2.79 - 2.65 (m, 4H), 2.65 -2.54 (m, 2H), 2.53 - 2.44 (m, 2H), 2.30 - 2.20 (m, 1H), 1.94 -1.86 (m, 4H), 1.52 - 1.42 (m, 2H). Example 5 (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its dihydrochloride salt

[0187] [ka]

[0188] (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine Synthesis scheme: Using the synthesis method of Example 4, ethyl 4-piperidine-formate in step A was replaced with ethyl 2-(piperidin-4-yl)acetate, and the target product was obtained by steps A to D.

[0189] ESI-MS [M+H] + : m / z 425.0. Preparation of the hydrochloride salt: (S)-N 6 Synthesis of -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine dihydrochloride (S)-N 6-(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the dihydrochloride salt of the compound.

[0190] ESI-MS [M+H] + : m / z 425.0. 1 H NMR (600 MHz, DMSO-d6) δ 7.33 -7.28 (m, 1H), 7.30 - 7.26 (m, 1H), 7.14 (dd, J = 7.6, 2.0 Hz, 1H), 6.71 (s, 2H), 3.29 - 3.24 (m, 3H), 2.91 - 2.88 (m, 3H), 2.67 -2.60 (m, 2H), 2.46 - 2.43 (m, 2H), 2.09 - 2.06 (m, 1H), 1.81 -1.76 (m, 2H), 1.72 - 1.69 (m, 1H), 1.61 - 1.46 (m, 3H), 1.41 -1.30 (m, 2H), 1.29 - 1.22 (m, 2H). Example 6 (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its dihydrochloride salt

[0191] [ka]

[0192] (S)-N 6 Synthesis of -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine : Using the synthesis method of Example 4, 1,2-dichloro-3-iodobenzene in step A was replaced with 4-bromobenzo[b]thiophene, and the target product was obtained by steps A to D.

[0193] ESI-MS [M+H] + : m / z 399.0. Preparation of the hydrochloride salt: (S)-N 6 Synthesis of -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine dihydrochloride (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the dihydrochloride salt of the compound.

[0194] ESI-MS [M+H] + : m / z 399.0. 1 H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 9.38 (s, 2H), 9.30 (s, 1H), 7.85 - 7.65 (m, 2H), 7.51 (s, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.11 - 7.07 (m, 1H), 3.62 - 3.53 (m, 3H), 3.53 - 3.50 (m, 1H), 3.50 - 3.42 (m, 3H), 3.15 - 3.06 (m, 1H), 2.98 - 2.78 (m, 2H), 2.77 - 2.68 (m, 1H), 2.64 - 2.57 (m, 1H), 2.38 - 2.31 (m, 1H), 2.10 - 2.03 (m, 4H), 1.79 - 1.53 (m, 2H). Example 7 (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride salt

[0195] [ka]

[0196] (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-N 6 Synthesis of -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0197] [ka]

[0198] Target product (S)-N of Example 4 6 The target product was obtained using the synthetic method of Example 2, starting from -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (1.6 mmol, 1 eq) and propionaldehyde (1.6 mmol, 1 eq).

[0199] ESI-MS [M+H] + : m / z 453.1. Preparation of the hydrochloride salt: (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-N 6 Synthesis of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-N 6 4,5,6,7-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, and a solid was precipitated. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0200] ESI-MS [M+H] + : m / z 453.1. 1H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 9.81 - 9.24 (m, 2H), 7.38 -7.30 (m, 2H), 7.18 (dd, J = 7.1, 2.6 Hz, 1H), 3.36 -3.22 (m, 3H), 3.17 - 3.12 (m, 2H), 3.09 - 2.81 (m, 2H), 2.80 -2.58 (m, 4H), 2.49 - 2.38 (m, 1H), 2.32 - 2.13 (m, 1H), 2.13 -1.79 (m, 6H), 1.63 - 1.30 (m, 3H), 1.01 - 0.91 (m, 3H). Example 8 (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride salt

[0201] [ka]

[0202] (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-N 6 Synthesis of -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0203] [ka]

[0204] Target product (S)-N of Example 5 6 The target product was obtained using -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (0.5 mmol, 1 eq) and propionaldehyde (0.5 mmol, 1 eq) as raw materials according to the synthesis method of Example 2.

[0205] ESI-MS [M+H]+ : m / z 467.3. Preparation of the hydrochloride salt: (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-N 6 Synthesis of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-N 6 4,5,6,7-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, and a solid was precipitated. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0206] ESI-MS [M+H] + : m / z 467.3. 1 H NMR (600 MHz, DMSO-d6) 9.27 - 8.86 (m, 2H), 7.33 - 7.27 (m, 2H), 7.15 (dd, J = 7.5, 2.1 Hz, 1H), 3.62 - 3.47 (m, 2H), 3.29 (s, 1H), 3.27 (s, 1H), 3.07 - 3.01 (m, 3H), 2.76 - 2.69 (m, 1H), 2.68 - 2.62 (m, 2H), 2.61 - 2.54 (m, 1H), 2.48 - 2.42 (m, 2H), 2.28 - 2.23 (m, 1H), 1.95 - 1.92 (m, 1H), 1.83 - 1.77 (m, 2H), 1.72 - 1.65 (m, 2H), 1.64 - 1.55 (m, 2H), 1.55 - 1.50 (m, 1H), 1.42 - 1.32 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). Example 9 (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride salt

[0207] [ka]

[0208] (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 Synthesis of -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0209] [ka]

[0210] Target product (S)-N of Example 6 6 The target product was obtained using -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (1.7 mmol, 1 eq) and propionaldehyde (1.7 mmol, 1 eq) as starting materials according to the synthesis method of Example 2.

[0211] ESI-MS [M+H] + : m / z 441.1. Preparation of the hydrochloride salt: (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 Synthesis of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 4,5,6,7-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, and a solid was precipitated. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0212] ESI-MS [M+H] + : m / z 441.1. 1H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 9.30 (s, 2H), 7.77 (d, J = 5.5 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.00 (s, 1H), 3.54 - 3.44 (m, 3H), 3.33 - 3.31 (m, 1H), 3.27 -3.07 (m, 5H), 2.85 - 2.81 (m, 4H), 2.77 - 2.67 (m, 1H), 2.44 -2.39 (m, 2H), 2.28 - 2.16 (m, 1H), 2.08 - 2.04 (m, 3H), 1.89 -1.84 (m, 2H), 1.02 - 0.94 (m, 3H). Example 10 (S)-N 6 -(2-(1-(benzo[b]thiophen-4-yl)piperidin-4-yl)ethyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride salt

[0213] [ka]

[0214] (S)-N 6 -(2-(1-(benzo[b]thiophen-4-yl)piperidin-4-yl)ethyl)-N 6 Synthesis of -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine: Using the synthesis method of Example 4, by replacing 1,2-dichloro-3-iodobenzene with 4-bromobenzo[b]thiophene in step A and ethyl 4-piperidineformate with ethyl 2-(piperidin-4-yl)acetate in step A to D, intermediate (S)-N 6-(2-(1-(benzo[b]thiophen-4-yl)piperidin-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was obtained. This intermediate (1.2 mmol, 1 eq) and propionaldehyde (1.2 mmol, 1 eq) were used as raw materials to produce the target product according to the synthesis method described in Example 2.

[0215] ESI-MS [M+H] + : m / z 455.1. Preparation of the hydrochloride salt: (S)-N 6 -(2-(1-(benzo[b]thiophen-4-yl)piperidin-4-yl)ethyl)-N 6 Synthesis of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride (S)-N 6 -(2-(1-(benzo[b]thiophen-4-yl)piperidin-4-yl)ethyl)-N 6 4,5,6,7-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, and a solid was precipitated. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0216] ESI-MS [M+H] + : m / z 455.1. 1H NMR (600 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.30 (s, 2H), 7.74 (s, 1H), 7.69 (s, 1H), 7.46 (s, 1H), 7.31 (s, 1H), 7.02 (s, 1H), 3.83 - 3.65 (m, 2H), 3.33 - 3.21 (m, 1H), 3.19 - 3.13 (m, 2H), 3.12 - 3.07 (m, 1H), 3.07 - 3.01 (m, 1H), 2.93 - 2.84 (m, 1H), 2.83 - 2.75 (m, 1H), 2.75 - 2.71 (m, 1H), 2.71 - 2.66 (m, 1H), 2.65 - 2.62 (m, 1H), 2.62 - 2.58 (m, 1H), 2.41 - 2.38 (m, 1H), 2.38 - 2.33 (m, 1H), 1.99 - 1.96 (m, 1H), 1.89 - 1.86 (m, 1H), 1.85 - 1.80 (m, 3H), 1.80 - 1.74 (m, 1H), 1.58 (m, 3H), 0.95 (t, J = 7.3 Hz, 3H). Example 11 (R)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride salt

[0217] [ka]

[0218] (R)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 Synthesis of -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine: Using the synthesis method of Example 4, 1,2-dichloro-3-iodobenzene in step A is replaced with 4-bromobenzo[b]thiophene, and (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine in step C is replaced with (R)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine, and intermediate (R)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was obtained. This intermediate (0.75 mmol, 1 eq) and propionaldehyde (0.75 mmol, 1 eq) were used as raw materials to prepare the target product according to the synthesis method described in Example 2.

[0219] ESI-MS [M+H] + : m / z 441.1. Preparation of hydrochloride salt: (R)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 Synthesis of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride (R)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 4,5,6,7-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, and a solid was precipitated. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0220] ESI-MS [M+H] + : m / z 441.1. 1H NMR (600 MHz, DMSO-d6) δ 7.67 (d, J = 5.5 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.38 (dd, J = 5.5, 0.8 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 6.89 (dd, J = 7.7, 0.9 Hz, 1H), 6.59 (s, 2H), 3.42 (d, J = 11.5 Hz, 2H), 3.36 - 3.32 (m, 1H), 3.32 - 3.28 (m, 1H), 2.98 - 2.88 (m, 1H), 2.72 - 2.65 (m, 2H), 2.58 - 2.47 (m, 1H), 2.48 - 2.41 (m, 3H), 2.41 - 2.35 (m, 2H), 1.93 - 1.83 (m, 3H), 1.68 - 1.59 (m, 1H), 1.45 - 1.31 (m, 5H), 0.88 (t, J = 7.3 Hz, 3H). Example 12 N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride salt

[0221] [ka]

[0222] N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 Synthesis of -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine: Using the synthesis method of Example 11, by replacing (R)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine with 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine in step C, intermediate N 6-((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was obtained. This intermediate (0.5 mmol, 1 eq) and propionaldehyde (0.5 mmol, 1 eq) were used as raw materials to produce the target product according to the synthesis method of Example 2.

[0223] ESI-MS [M+H] + : m / z 441.1. Preparation of hydrochloride: N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 Synthesis of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 4,5,6,7-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, and a solid was precipitated. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0224] ESI-MS [M+H] + : m / z 441.1. 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.28 (s, 2H), 7.73 (d, J = 5.5 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.44 -7.39 (m, 1H), 7.30 (t, J = 7.8 Hz, 1H), 6.99 - 6.95 (m, 1H), 3.50 - 3.42 (m, 3H), 3.36 - 3.22 (m, 1H), 3.19 - 3.00 (m, 4H), 2.98 - 2.77 (m, 2H), 2.77 - 2.55 (m, 1H), 2.48 - 2.30 (m, 1H), 2.26 - 2.13 (m, 1H), 2.09 - 1.98 (m, 3H), 1.89 - 1.74 (m, 2H), 1.67 - 1.50 (m, 3H), 1.17 (t, J = 7.1 Hz, 1H), 0.98 - 0.90 (m, 3H). Example 13 (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -ethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0225] [ka]

[0226] (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 Synthesis of -ethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0227] [ka]

[0228] Target product (S)-N of Example 6 6The target product was obtained using -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (0.25 mmol, 1 eq) and acetaldehyde (0.25 mmol, 1 eq) as raw materials according to the synthesis method of Example 2.

[0229] ESI-MS [M+H] + : m / z 427.0. Preparation of the hydrochloride salt: (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 Synthesis of 4,5,6,7-ethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 1-Ethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, and a solid was precipitated. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0230] ESI-MS [M+H] + : m / z 427.0. 1H NMR (600 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.72 (dd, J = 5.5, 1.5 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 5.5 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 3.80 -3.68 (m, 1H), 3.49 - 3.44 (m, 3H), 3.32 - 3.20 (m, 1H), 3.11 -2.97 (m, 3H), 2.93 - 2.81 (m, 1H), 2.77 - 2.70 (m, 1H), 2.68 (s, 1H), 2.65 - 2.62 (m, 1H), 2.62 - 2.59 (m, 1H), 2.41 -2.39 (m, 1H), 2.37 - 2.33 (m, 1H), 2.15 - 2.08 (m, 1H), 2.04 -1.98 (m, 1H), 1.98 - 1.94 (m, 1H), 1.60 - 1.52 (m, 2H), 1.37 -1.33 (m, 3H). Example 14 (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0231] [ka]

[0232] (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis method:

[0233] [ka]

[0234] Target product (S)-N of Example 66 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (0.75 mmol, 1 eq) and 37% aqueous formaldehyde (1.5 mmol, 2 eq) were dissolved in formic acid (6 mL) and refluxed at 90 °C for 6 h. After the reaction was completed, the mixture was cooled to room temperature, 10 mL of water was added, and the reaction mixture was neutralized with saturated Na2CO3. The mixture was then extracted with ethyl acetate (10 mL × 2). The combined organic layer was washed with saturated brine, dried, concentrated, and purified by column chromatography to give the desired product.

[0235] ESI-MS [M+H] + : m / z 413.0. Preparation of the hydrochloride salt: (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 Synthesis of 2,6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 1-Methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, and a solid was precipitated. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0236] ESI-MS [M+H] + : m / z 413.0. 1H NMR (600 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.34 (s, 2H), 7.75 (d, J = 5.3 Hz, 1H), 7.70 - 7.67 (m, 1H), 7.46 - 7.43 (m, 1H), 7.32 (t, J = 7.03 - 7.00 (m, 1H), 3.50 - 3.46 (m, 6H), 3.28 - 3.25 (m, 1H), 3.17 - 2.96 (m, 1H), 2.93 - 2.86 (m, 1H), 2.86 - 2.81 (m, 4H), 2.76 - 2.69 (m, 1H), 2.67 - 2.57 (m, 1H), 2.26 - 2.19 (m, 1H), 2.09 - 2.06 (m, 1H), 2.00 - 1.90 (m, 2H), 1.62 - 1.59 (m, 2H). Example 15 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methyl ketone and its hydrochloride salt

[0237] [ka]

[0238] Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methyl ketone:

[0239] [ka]

[0240] 3-Chloro-4-fluorobenzoic acid (2.7 mmol, 1.0 eq), EDCI (3.2 mmol, 1.2 eq), HObt (3.2 mmol, 1.2 eq), and triethylamine (5.4 mmol, 2 eq) were dissolved in dichloromethane (20 mL) and stirred for 20 min in an ice bath. Intermediate 1a (3.2 mmol, 1.2 eq) was added and the mixture was allowed to react at room temperature for 1.5 h. After the reaction was complete, 20 mL of water was added and the mixture was extracted with dichloromethane (30 mL x 3). The organic layer was washed with water and saturated brine, dried over MgSO4, concentrated, and purified by column chromatography to give the desired product. ESI-MS [M+H] + : m / z 465.1. Preparation of Hydrochloride Salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methyl ketone was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0241] ESI-MS [M+H] + : m / z 465.1. 1H NMR (600 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.41 (s, 2H), 7.64 -7.60 (m, 1H), 7.54 - 7.48 (m, 1H), 7.43 - 7.39 (m, 1H), 4.45 -4.42 (m, 1H), 3.80 - 3.62 (m, 2H), 3.62 - 3.42 (m, 2H), 3.40 -3.34 (m, 1H), 3.23 - 3.11 (m, 2H), 3.11 - 2.98 (m, 2H), 3.00 -2.75 (m, 1H), 2.75 - 2.66 (m, 1H), 2.66 - 2.55 (m, 1H), 2.53 -2.49 (m, 3H), 2.44 - 2.31 (m, 1H), 2.23 - 1.90 (m, 2H), 1.90 -1.71 (m, 1H), 1.29 - 1.19 (m, 2H), 0.94 - 0.88 (m, 3H). Example 16 (S)-(4-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methyl ketone and its hydrochloride salt

[0242] [ka]

[0243] Synthesis of (S)-(4-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methyl ketone:

[0244] [ka]

[0245] 3-Chloro-4-fluorobenzoic acid (1.3 mmol, 1 eq), EDCI (1.6 mmol, 1.2 eq), HObt (1.6 mmol, 1.2 eq), and triethylamine (2.6 mmol, 2 eq) were dissolved in dichloromethane and stirred for 20 min in an ice bath. Intermediate 1b (1.6 mmol, 1.2 eq) was added and the mixture was allowed to react at room temperature for 1.5 h. After the reaction was complete, 20 mL of water was added and the mixture was extracted with dichloromethane (30 mL x 3). The organic layer was washed with water and saturated brine, dried over MgSO4, concentrated, and purified by column chromatography to give the desired product.

[0246] ESI-MS [M+H] + : m / z 479.1. Preparation of Hydrochloride Salt: Synthesis of (S)-(4-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methyl ketone hydrochloride (S)-(4-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methyl ketone was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0247] ESI-MS [M+H] + : m / z 479.1. 1H NMR (600 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.95 (s, 2H), 7.63 (dd, J = 7.2, 2.1 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.41 (ddd, J = 8.5, 4.7, 2.1 Hz, 1H), 4.44 -4.41 (m, 1H), 3.69 - 3.66 (m, 1H), 3.61 - 3.44 (m, 3H), 3.26 -3.17 (m, 1H), 3.17 - 3.07 (m, 1H), 3.07 - 3.04 (m, 1H), 3.04 -2.97 (m, 1H), 2.90 - 2.81 (m, 1H), 2.80 - 2.70 (m, 1H), 2.70 -2.65 (m, 1H), 2.65 - 2.52 (m, 1H), 2.34 - 2.31 (m, 1H),1.98 -1.90 (m, 1H), 1.87 - 1.67 (m, 5H), 1.67 - 1.53 (m, 2H), 1.33 -1.05 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). Example 17 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(phenyl)methyl ketone and its hydrochloride salt

[0248] [ka]

[0249] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(phenyl)methyl ketone :

[0250] [ka]

[0251] Using the synthetic method of Example 15, but substituting benzoic acid for the starting 3-chloro-4-fluorobenzoic acid, the desired product was prepared.

[0252] ESI-MS [M+H] + : m / z 413.1. Preparation of Hydrochloride Salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(phenyl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(phenyl)methyl ketone was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0253] ESI-MS [M+H] + : m / z 413.1. 1 H NMR (600 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.99 - 8.49 (m, 2H), 7.50 -7.42 (m, 3H), 7.40 - 7.34 (m, 2H), 4.55 - 4.39 (m, 1H), 3.70 -3.65 (m, 1H), 3.59 - 3.56 (m, 1H), 3.24 - 3.15 (m, 1H), 3.14 -3.03 (m, 3H), 3.00 - 2.72 (m, 1H), 2.72 - 2.55 (m, 1H), 2.42 -2.26 (m, 1H), 2.12 - 2.09 (m, 1H), 1.99 - 1.96 (m, 4H), 1.96 -1.89 (m, 2H), 1.87 - 1.77 (m, 2H), 1.26 - 1.23 (m, 1H), 1.22 -1.20 (m, 2H), 0.95 - 0.89 (m, 3H). Example 18 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-chloro-5-fluoropyridin-2-yl)methyl ketone and its hydrochloride salt

[0254] [ka]

[0255] Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-chloro-5-fluoropyridin-2-yl)methyl ketone:

[0256] [ka]

[0257] Using the synthetic method of Example 15, but substituting 2-chloro-3-fluoropyridine-6-formic acid for the starting material 3-chloro-4-fluorobenzoic acid, the desired product was prepared.

[0258] ESI-MS [M+H] + : m / z 466.0. Preparation of Hydrochloride Salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-chloro-5-fluoropyridin-2-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-chloro-5-fluoropyridin-2-yl)methyl ketone was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0259] ESI-MS [M+H] + : m / z 466.0. 1H NMR (600 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.07 (s, 2H), 8.07 (t, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.4, 3.4 Hz, 1H), 4.45 (d, J = 12.7 Hz, 1H), 3.69 -3.63 (m, 2H), 3.21 (s, 1H), 3.15 - 3.07 (m, 4H), 3.07 -3.02 (m, 1H), 3.02 - 2.93 (m, 1H), 2.93 - 2.74 (m, 1H), 2.70 -2.65 (m, 1H), 2.64 - 2.53 (m, 1H), 2.40 - 2.27 (m, 1H), 2.20 -2.06 (m, 1H), 2.05 - 1.89 (m, 1H), 1.90 - 1.71 (m, 2H), 1.27 -1.21 (m, 4H), 0.95 - 0.88 (m, 3H). Example 19 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-fluoropyridin-3-yl)methyl ketone and its hydrochloride salt

[0260] [ka]

[0261] Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-fluoropyridin-3-yl)methyl ketone:

[0262] [ka]

[0263] 6-Fluoronicotinic acid (2.7 mmol, 1 eq), EDCI (3.2 mmol, 1.2 eq), HObt (3.2 mmol, 1.2 eq), triethylamine (5.4 mmol, 2 eq), and intermediate 1a (3.2 mmol, 1.2 eq) were dissolved in DMF and reacted at -10°C for 5 h. After the reaction was complete, 20 mL of water was added and the mixture was extracted with dichloromethane (30 mL x 3). The organic layer was washed with water and saturated brine, dried over MgSO4, concentrated, and purified by column chromatography to give the desired product.

[0264] ESI-MS [M+H] + : m / z 432.1. Preparation of Hydrochloride Salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-fluoropyridin-3-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-fluoropyridin-3-yl)methyl ketone was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0265] ESI-MS [M+H] + : m / z 432.1. 1H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.31 (s, 2H), 8.30 (d, J = 2.4 Hz, 1H), 8.03 (td, J = 8.2, 2.4 Hz, 1H), 7.29 (dt, J = 8.6, 2.1 Hz, 1H), 4.61 -4.34 (m, 1H), 3.68 - 3.65 (m, 3H), 3.62 - 3.46 (m, 6H), 3.13 -3.03 (m, 3H), 3.00 - 2.75 (m, 1H), 2.72 - 2.57 (m, 1H), 2.43 -2.30 (m, 1H), 2.18 - 2.06 (m, 2H), 2.04 - 1.72 (m, 1H), 1.29 -1.18 (m, 3H), 0.91 (td, J = 7.3, 2.7 Hz, 3H). Example 20 (S)-5-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carbonyl)pyridinecarbonitrile and its hydrochloride

[0266] [ka]

[0267] Synthesis of (S)-5-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carbonyl)pyridinecarbonitrile:

[0268] [ka]

[0269] Using the synthesis method of Example 15, but substituting 6-cyanonicotinic acid for the starting material 3-chloro-4-fluorobenzoic acid, the desired product was prepared.

[0270] 6-Cyanonicotinic acid (4.0 mmol, 1 eq), EDCI (4.8 mmol, 1.2 eq), HObt (4.8 mmol, 1.2 eq), triethylamine (8 mmol, 2 eq), and intermediate 1a (4.8 mmol, 1.2 eq) were dissolved in DMF and reacted at -10°C for 4 h. After the reaction was complete, 20 mL of water was added and the mixture was extracted with dichloromethane (30 mL x 3). The organic layer was washed with water and saturated brine, dried over MgSO4, concentrated, and purified by column chromatography to give the desired product.

[0271] ESI-MS [M+H] + : m / z 439.1. Preparation of the hydrochloride salt: Synthesis of (S)-5-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carbonyl)pyridinecarbonitrile hydrochloride (S)-5-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carbonyl)pyridinecarbonitrile was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, causing a solid to precipitate. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0272] ESI-MS [M+H] + : m / z 439.1. 1H NMR (600 MHz, DMSO-d6) δ10.45 (s, 1H), 9.14 (s, 2H), 8.77 (d, J = 2.1 Hz, 1H), 8.15 (dt, J = 8.0, 1.2 Hz, 1H), 8.10 - 8.05 (m, 1H), 4.50 -4.45 (m, 1H), 3.77 - 3.62 (m, 1H), 3.24 - 3.16 (m, 1H), 3.16 -3.01 (m, 3H), 2.97 - 2.94 (m, 1H), 2.87 - 2.80 (m, 1H), 2.75 -2.54 (m, 1H), 2.41 - 2.33 (m, 1H), 2.21 - 2.07 (m, 2H), 2.07 -1.89 (m, 1H), 1.89 - 1.71 (m, 2H), 1.34 - 1.27 (m, 1H), 1.28 -1.22 (m, 5H), 1.21 - 1.15 (m, 1H), 0.95 - 0.89 (m, 3H). Example 21 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-indol-2-yl)methyl ketone and its hydrochloride salt

[0273] [ka]

[0274] Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-indol-2-yl)methyl ketone:

[0275] [ka]

[0276] Using the synthetic method of Example 15, but substituting 2-indoleformic acid for the starting material 3-chloro-4-fluorobenzoic acid, the desired product was prepared.

[0277] ESI-MS [M+H] + : m / z 452.2. Preparation of Hydrochloride Salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-indol-2-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-indol-2-yl)methyl ketone was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0278] ESI-MS [M+H] + : m / z 452.2. 1 H NMR (600 MHz, D2O) δ 7.75 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 6.94 (s, 1H), 4.83 -4.82 (m, 1H), 4.82 - 4.79 (m, 3H), 4.76 - 4.74 (m, 1H), 4.52 (d, J = 13.2 Hz, 2H), 3.84 - 3.81 (m, 1H), 3.41 - 3.27 (m, 1H), 3.28 -3.04 (m, 1H), 3.02 - 2.97 (m, 1H), 2.86 - 2.83 (m, 1H), 2.78 -2.73 (m, 1H), 2.39 - 2.13 (m, 2H), 2.04 - 1.87 (m, 3H), 1.82 -1.75 (m, 2H), 1.43 - 1.29 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). Example 22 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(benzo[b]thiophen-2-yl)methyl ketone and its hydrochloride salt

[0279] [ka]

[0280] Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(benzo[b]thiophen-2-yl)methyl ketone:

[0281] [ka]

[0282] Using the synthesis method of Example 15, but substituting benzothiophene-2-carboxylic acid for the starting material 3-chloro-4-fluorobenzoic acid, the target product was prepared.

[0283] ESI-MS [M+H] + : m / z 469.1. Preparation of Hydrochloride: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(benzo[b]thiophen-2-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(benzo[b]thiophen-2-yl)methyl ketone was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3. A solid was precipitated, which was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0284] ESI-MS [M+H] + : m / z 469.1. 1H NMR (600 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.06 (s, 2H), 8.05 -8.00 (m, 1H), 7.96 - 7.91 (m, 1H), 7.70 (s, 1H), 7.49 -7.42 (m, 2H), 4.42 - 4.24 (m, 3H), 3.71 - 3.66 (m, 1H), 3.33 -3.15 (m, 1H), 3.14 - 3.05 (m, 4H), 3.01 - 2.96 (m, 1H), 2.92 -2.79 (m, 1H), 2.73 - 2.55 (m, 1H), 2.41 - 2.30 (m, 1H), 2.23 -2.07 (m, 2H), 2.05 - 1.89 (m, 2H), 1.87 - 1.72 (m, 2H), 1.31 -1.22 (m, 3H), 0.92 (td, J = 7.3, 2.4 Hz, 3H). Example 23 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(naphthalen-2-yl)methyl ketone and its hydrochloride salt

[0285] [ka]

[0286] Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(naphthalen-2-yl)methyl ketone:

[0287] [ka]

[0288] Using the synthesis method of Example 15, but substituting 2-naphthoic acid for the starting material 3-chloro-4-fluorobenzoic acid, the desired product was prepared.

[0289] ESI-MS [M+H] + : m / z 463.2. Preparation of Hydrochloride Salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(naphthalen-2-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(naphthalen-2-yl)methyl ketone was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0290] ESI-MS [M+H] + : m / z 463.2. 1 H NMR (600 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.27 (s, 2H), 8.00 -7.98 (m, 3H), 7.95 (d, J = 1.6 Hz, 1H), 7.61 - 7.58 (m, 2H), 7.49 (dd, J = 8.4, 1.7 Hz, 1H), 4.63 - 4.42 (m, 1H), 3.76 - 3.61 (m, 3H), 3.43 -3.37 (m, 3H), 3.22 - 3.19 (m, 1H), 3.12 - 3.06 (m, 4H), 2.99 -2.96 (m, 1H), 2.90 - 2.80 (m, 1H), 2.77 - 2.54 (m, 1H), 2.45 -2.26 (m, 1H), 2.23 - 2.07 (m, 1H), 2.08 - 1.89 (m, 1H), 1.89 -1.71 (m, 1H), 1.39 - 1.19 (m, 3H), 0.92 (td, J = 7.3, 2.6 Hz, 3H). Example 24 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiophen-2-yl)methyl ketone and its hydrochloride salt

[0291] [ka]

[0292] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiophen-2-yl)methyl ketone :

[0293] [ka]

[0294] Using the synthesis method of Example 15, but substituting 2-thiopheneformic acid for the starting material 3-chloro-4-fluorobenzoic acid, the desired product was prepared.

[0295] ESI-MS [M+H] + : m / z 419.1. Preparation of Hydrochloride Salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiophen-2-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiophen-2-yl)methyl ketone was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0296] ESI-MS [M+H] + : m / z 419.1. 1 H NMR (400 MHz, DMSO) δ 9.97 (s, 1H), 8.93(s, 2H), 7.79 (dd, J = 5.0, 1.1 Hz, 1H), 7.41 (dd, J = 3.7, 1.2 Hz, 1H), 7.20 - 7.14 (m, 1H), 4.39 -4.21 (m, 2H), 3.79 - 3.64 (m, 1H), 3.33 - 3.19 (m, 3H), 3.18 -3.05 (m, 4H), 3.05 - 2.97 (m, 2H), 2.94 - 2.56 (m, 1H), 2.15 -2.07 (m, 2H), 1.99 - 1.92 (m, 2H), 1.84 - 1.78 (m, 2H), 1.33 -1.27 (m, 1H), 1.27 - 1.23 (m, 2H), 0.99 - 0.92 (m, 3H). Example 25 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(furan-2-yl)methyl ketone and its hydrochloride salt

[0297] [ka]

[0298] Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(furan-2-yl)methyl ketone:

[0299] [ka]

[0300] Using the synthetic method of Example 15, but substituting 2-furancarboxylic acid for the starting material 3-chloro-4-fluorobenzoic acid, the desired product was prepared.

[0301] ESI-MS [M+H] + : m / z 403.0. Preparation of Hydrochloride Salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(furan-2-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(furan-2-yl)methyl ketone was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, and a solid was precipitated. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0302] ESI-MS [M+H] + : m / z 403.0. 1H NMR (600 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.84 (d, J = 1.6 Hz, 1H), 6.96 (d, J = 3.4 Hz, 1H), 6.63 (dt, J = 3.0, 1.2 Hz, 1H), 4.35 -4.32 (m, 2H), 3.76 - 3.63 (m, 1H), 3.23 - 3.18 (m, 1H), 3.16 -3.02 (m, 1H), 3.01 - 2.94 (m, 1H), 2.90 - 2.78 (m, 1H), 2.70 -2.65 (m, 1H), 2.65 - 2.54 (m, 1H), 2.42 - 2.32 (m, 1H), 2.30 -2.27 (m, 1H), 2.12 - 2.10 (m, 2H), 2.10 - 2.04 (m, 1H), 1.97 -1.94 (m, 1H), 1.94 - 1.89 (m, 1H), 1.83 - 1.78 (m, 2H), 1.78 -1.75 (m, 1H), 1.26 - 1.20 (m, 3H), 0.93 (td, J = 7.3, 2.3 Hz, 3H). Example 26 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-pyrrol-2-yl)methyl ketone and its hydrochloride salt

[0303] [ka]

[0304] Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-pyrrol-2-yl)methyl ketone:

[0305] [ka]

[0306] Using the synthesis method of Example 15, but substituting 2-pyrrolecarboxylic acid for the starting material 3-chloro-4-fluorobenzoic acid, the desired product was prepared.

[0307] ESI-MS [M+H] + : m / z 402.0. Preparation of Hydrochloride Salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-pyrrol-2-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-pyrrol-2-yl)methyl ketone was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0308] ESI-MS [M+H] + : m / z 402.0. 1 H NMR (600 MHz, DMSO-d6) δ 11.41 (s, 1H), 10.11 (s, 1H), 8.86 (s, 2H), 6.90 -6.85 (m, 1H), 6.48 - 6.44 (m, 1H), 6.14 - 6.10 (m, 1H), 4.45 -4.40 (m, 2H), 3.71 - 3.67 (m, 1H), 3.24 - 3.17 (m, 1H), 3.14 -3.06 (m, 2H), 3.01 - 2.94 (m, 2H), 2.91 - 2.79 (m, 1H), 2.71 -2.65 (m, 1H), 2.64 - 2.53 (m, 1H), 2.39 - 2.29 (m, 1H), 2.13 -2.05 (m, 2H), 2.02 - 1.90 (m, 2H), 1.88 - 1.70 (m, 3H), 1.27 -1.19 (m, 2H), 1.19 - 1.14 (m, 1H), 0.93 (td, J = 7.3, 2.2 Hz, 3H). Example 27 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiazol-5-yl)methyl ketone and its hydrochloride salt

[0309] [ka]

[0310] Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiazol-5-yl)methyl ketone:

[0311] [ka]

[0312] Using the synthetic method of Example 15, but substituting 5-thiazolecarboxylic acid for the starting material 3-chloro-4-fluorobenzoic acid, the desired product was prepared.

[0313] ESI-MS [M+H] + : m / z 420.1. Preparation of Hydrochloride Salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiazol-5-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiazol-5-yl)methyl ketone was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to <3, resulting in the precipitation of a solid. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0314] ESI-MS [M+H] + : m / z 420.1. 1H NMR (600 MHz, DMSO-d6) δ 10.49 (s, 1H), 9.45 - 9.38 (m, 2H), 9.24 (s, 1H), 8.17 (s, 1H), 4.43 - 4.40 (m, 1H), 3.46 - 3.42 (m, 1H), 3.23 -3.17 (m, 1H), 3.16 - 3.03 (m, 3H), 3.01 - 2.93 (m, 1H), 2.93 -2.80 (m, 1H), 2.74 - 2.67 (m, 1H), 2.66 - 2.58 (m, 1H), 2.42 -2.34 (m, 1H), 2.21 - 2.10 (m, 2H), 2.05 - 1.88 (m, 2H), 1.88 -1.75 (m, 2H), 1.30 - 1.20 (m, 5H), 0.92 (t, J = 7.4 Hz, 3H). Example 28 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1-methyl-1H-pyrazol-4-yl)methyl ketone

[0315] [ka]

[0316] Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1-methyl-1H-pyrazol-4-yl)methyl ketone:

[0317] [ka]

[0318] Using the synthetic method of Example 15, but substituting 1-methylpyrazole-4-formic acid for the starting material 3-chloro-4-fluorobenzoic acid, the desired product was prepared.

[0319] 1-Methylpyrazole-4-formic acid (2.7 mmol, 1 eq), EDCI (3.2 mmol, 1.2 eq), HObt (3.2 mmol, 1.2 eq), triethylamine (5.4 mmol, 2 eq), and intermediate 1a (3.2 mmol, 1.2 eq) were dissolved in DMF and reacted at -10°C for 8 h. After the reaction was complete, 20 mL of water was added and the mixture was extracted with dichloromethane (30 mL x 3). The organic layer was washed with water and saturated brine, dried over MgSO4, concentrated, and purified by column chromatography to give the desired product.

[0320] ESI-MS [M+H] + : m / z 417.1. 1 H NMR (600 MHz, CDCl3) δ 7.58 (s, 1H), 7.50 (s, 1H), 4.53 (s, 2H), 3.82 (s, 3H), 3.79 - 3.67 (m, 1H), 2.93 -2.85 (m, 1H), 2.64 - 2.57 (m, 1H), 2.55 - 2.50 (m, 1H), 2.50 -2.37 (m, 2H), 2.37 - 2.30 (m, 2H), 2.29 - 2.24 (m, 1H), 2.24 -2.16 (m, 1H), 1.87 - 1.82 (m, 1H), 1.81 - 1.73 (m, 2H), 1.62 -1.52 (m, 2H), 1.37 - 1.28 (m, 3H), 1.16 (s, 2H), 1.02 -0.99 (m, 2H), 0.78 (t, J = 7.3 Hz, 3H). Example 29 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(cyclohexyl)methyl ketone and its hydrochloride salt

[0321] [ka]

[0322] Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(cyclohexyl)methyl ketone:

[0323] [ka]

[0324] Using the synthetic method of Example 15, but substituting cyclohexylformic acid for the starting material 3-chloro-4-fluorobenzoic acid, the desired product was prepared.

[0325] ESI-MS [M+H] + : m / z 419.2. Preparation of Hydrochloride Salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(cyclohexyl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(cyclohexyl)methyl ketone was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, causing the solid to precipitate. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0326] ESI-MS [M+H] + : m / z 419.2. 1H NMR (600 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.30 (s, 2H), 4.47 -4.30 (m, 1H), 4.03 - 3.85 (m, 1H), 3.58 - 3.44 (m, 5H), 3.18 -3.15 (m, 1H), 3.12 - 3.03 (m, 2H), 3.02 - 2.76 (m, 1H), 2.72 -2.66 (m, 1H), 2.65 - 2.53 (m, 1H), 2.49 - 2.41 (m, 1H), 2.38 -2.32 (m, 1H), 2.19 - 2.11 (m, 1H), 2.08 - 1.96 (m, 1H), 1.88 -1.79 (m, 2H), 1.74 - 1.63 (m, 2H), 1.63 - 1.58 (m, 3H), 1.38 -1.23 (m, 5H), 1.20 - 1.07 (m, 3H), 1.03 - 0.99 (m, 1H), 0.91 (td, J = 7.3, 2.2 Hz, 3H). Example 30 (S)-N 6 -((1-(phenylsulfonyl)piperidin-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride salt

[0327] [ka]

[0328] (S)-N 6 -((1-(phenylsulfonyl)piperidin-4-yl)methyl)-N 6 Synthesis of -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0329] [ka]

[0330] Intermediate 1a (0.65 mmol, 1 eq) was dissolved in DCM (6 mL), and triethylamine (1.95 mmol, 3 eq), DMAP (2 mg, catalytic amount), and benzenesulfonyl chloride (0.65 mmol, 1 eq) were added under ice-bath conditions. The mixture was stirred for 2 h to complete the reaction, and then 10 mL of water was added. The mixture was extracted with dichloromethane (20 mL × 3). The organic layer was washed with water and saturated brine, dried over MgSO4, concentrated, and purified by column chromatography to obtain the desired product.

[0331] ESI-MS [M+H] + : m / z 449.0. Preparation of the hydrochloride salt: (S)-N 6 -((1-(phenylsulfonyl)piperidin-4-yl)methyl)-N 6 Synthesis of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride (S)-N 6 -((1-(phenylsulfonyl)piperidin-4-yl)methyl)-N 6 4,5,6,7-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, and a solid was precipitated. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0332] ESI-MS [M+H] + : m / z 449.0. 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.00 (s, 2H), 7.77 -7.71 (m, 3H), 7.66 (t, J = 7.6 Hz, 2H), 3.71 - 3.58 (m, 3H), 3.18 -3.09 (m, 1H), 3.05 - 2.99 (m, 3H), 2.93 - 2.88 (m, 1H), 2.85 -2.75 (m, 1H), 2.69 - 2.53 (m, 1H), 2.34 - 2.25 (m, 1H), 2.20 -2.13 (m, 1H), 2.16 - 2.05 (m, 1H), 1.96 - 1.89 (m, 1H), 1.82 -1.63 (m, 4H), 1.33 - 1.19 (m, 4H), 0.87 (td, J = 7.5, 2.1 Hz, 3H). Example 31 (S)-N 6 -((1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride salt

[0333] [ka]

[0334] (S)-N 6 -((1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-N 6 Synthesis of -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0335] [ka]

[0336] Using the synthesis method of Example 30, but substituting 3-chloro-4-fluorobenzenesulfonyl chloride for the starting benzenesulfonyl chloride, the desired product was prepared.

[0337] ESI-MS [M+H]+ : m / z 501.0. Preparation of the hydrochloride salt: (S)-N 6 -((1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-N 6 Synthesis of 4,5,6,7-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride (S)-N 6 -((1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-N 6 4,5,6,7-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken and dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3, and a solid was precipitated. The mixture was stirred at room temperature for 1-5 h and then suction filtered to obtain the hydrochloride salt of the compound.

[0338] ESI-MS [M+H] + : m / z 501.0. 1 H NMR (600 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.56 (s, 2H), 8.00 -7.95 (m, 1H), 7.82 - 7.77 (m, 1H), 7.72 (t, J = 8.8 Hz, 1H), 3.70 -3.60 (m, 4H), 3.17 - 3.11 (m, 1H), 3.10 - 2.95 (m, 2H), 2.95 -2.89 (m, 1H), 2.85 - 2.75 (m, 1H), 2.69 - 2.51 (m, 1H), 2.37 -2.15 (m, 3H), 2.14 - 2.03 (m, 1H), 1.98 - 1.84 (m, 2H), 1.81 -1.78 (m, 2H), 1.75 - 1.71 (m, 2H), 1.29 - 1.24 (m, 2H), 0.88 (td, J = 7.3, 2.3 Hz, 3H). Example 32 (S)-4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)-N,N-dimethylpiperidine-1-formamide

[0339] [ka]

[0340] Synthesis of (S)-4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)-N,N-dimethylpiperidine-1-formamide:

[0341] [ka]

[0342] Using the synthesis method of Example 30, the starting material benzenesulfonyl chloride was replaced with dimethylcarbamoyl chloride to produce the desired product.

[0343] ESI-MS [M+H] + : m / z 380.2. 1 H NMR (600 MHz, CDCl3) δ 4.80 (s, 2H), 3.60 -3.54 (m, 2H), 2.92 - 2.84 (m, 1H), 2.71 (s, 6H), 2.66 -2.56 (m, 2H), 2.55 - 2.49 (m, 1H), 2.44 - 2.37 (m, 1H), 2.37 -2.27 (m, 2H), 2.27 - 2.21 (m, 1H), 2.21 - 2.15 (m, 1H), 1.88 -1.81 (m, 1H), 1.77 - 1.74 (m, 1H), 1.72 - 1.66 (m, 1H), 1.61 -1.51 (m, 1H), 1.48 - 1.37 (m, 1H), 1.36 - 1.27 (m, 2H), 1.25 -1.09 (m, 2H), 1.03 - 0.92 (m, 2H), 0.78 (t, J = 7.3 Hz, 3H). Example 33 (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(morpholino)methyl ketone

[0344] [ka]

[0345] Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(morpholino)methyl ketone:

[0346] [ka]

[0347] Using the synthesis method of Example 30, but substituting 4-morpholinecarbonyl chloride for the starting benzenesulfonyl chloride, the desired product was prepared.

[0348] ESI-MS [M+H] + : m / z 422.1. 1 H NMR (600 MHz, CDCl3) δ 4.86 (s, 2H), 3.67 - 3.53 (m, 8H), 3.16 -3.13 (m, 4H), 2.91 - 2.83 (m, 1H), 2.68 - 2.62 (m, 2H), 2.62 -2.55 (m, 1H), 2.54 - 2.49 (m, 1H), 2.49 - 2.37 (m, 1H), 2.37 -2.27 (m, 2H), 2.27 - 2.22 (m, 1H), 2.21 - 2.15 (m, 1H), 1.87 -1.81 (m, 1H), 1.74 - 1.66 (m, 2H), 1.61 - 1.51 (m, 1H), 1.36 -1.26 (m, 2H), 1.03 - 0.91 (m, 2H), 0.78 (t, J = 7.3 Hz, 3H). Comparative Example 1 (S)-N 6 -(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0349] [ka]

[0350] Synthesis scheme:

[0351] [ka]

[0352] Comparative Example 1 was produced according to the above route with reference to the literature (Biswas S. J Med Chem. 2008;51(10):3005-3019.).

[0353] The following Comparative Examples 2 and 3 were prepared with reference to Example 30 or Example 19 of JP2005104885A. Comparative Example 2 4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-formate methyl ester hydrochloride

[0354] [ka]

[0355] Comparative Example 3 (R)-4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-formate methyl ester hydrochloride

[0356] [ka]

[0357] Biological Testing and Evaluation The present invention will be further explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present invention.

[0358] Test Example 1: In vitro 5HT 1A Receptor function experiments 1.1 Experimental materials 1.1.1 Cell information: HEK293 / 5HT 1A, 5HT 1A The recipient lentivirus was infected into HEK293 cells, and the stably transformed cell line HEK293 / 5HT 1A Construct growth medium: DMEM, 10% FBS, 0.6 µg / mL puromycin; cryopreservation medium: 70% culture medium, 20% FBS, 10% DMSO.

[0359] 1.1.2 Experimental Reagents and Consumables

[0360] TIFF2025526807000096.tif43114

[0361] 1.1.3 Experimental equipment

[0362] TIFF2025526807000097.tif44119

[0363] 1.2 Experimental Method (1) Preparation of compounds: Test compounds and 5HT were diluted to 0.1 mM with stimulation buffer and prepared for use.

[0364] (2) Preparation of experimental buffer: 5x stimulation buffer was diluted to 1x with ddH2O, IBMX was added to a final concentration of 0.5 mM, and the mixture was mixed uniformly for use.

[0365] (3) Cells were digested with pancreatin and centrifuged. The cell pellet was resuspended in 10 mL of preheated HBSS, centrifuged, and resuspended in 1 mL of stimulation buffer. 20 μL of the digested material was then taken and counted.

[0366] (4) Take an appropriate amount of cell suspension and measure 0.6 × 10 6 The cells were diluted to cells / mL, and 5 μL of the cell suspension was added per well to a cell plate, followed by centrifugation at 1000 rpm for 1 minute.

[0367] (5) Dilute and transfer the compounds using Bravo™ to a compound plate, diluting the compounds 4-fold in eight spots. Then, use Bravo™ to transfer the entire diluted compound plate to a 384-well white plate and centrifuge at 1000 rpm for 1 minute.

[0368] (6) The experimental plate was blocked and incubated at room temperature for 15 minutes.

[0369] (7) Forskolin prepared in DMSO was added using a Tecan D300e to a mother solution of 0.2 mM and a final concentration of 1 μM, and the mixture was centrifuged at 1000 rpm for 1 minute.

[0370] (8) The plate was blocked and incubated at room temperature for 45 minutes.

[0371] (9) Preparation of cAMP standard curve: The starting concentration was 2848 nM, and 8 points were serially diluted 4-fold. 10 μL was added to the experimental plate to give a peak concentration of 712 nM.

[0372] (10) 5 μL of cAMP-d2 solution (diluted 1:20 with lysis buffer) was added to the experimental plate and centrifuged at 1000 rpm for 1 minute.

[0373] (11) Next, 5 μL of Anti-cAMP-Cryptate solution (diluted 1:20 from the stock solution with lysis buffer) was further added to the experimental plate, followed by centrifugation at 1000 rpm for 1 min.

[0374] (12) The experimental plates were incubated at room temperature for 1 h and centrifuged at 1000 rpm for 1 min before reading.

[0375] (13) Plate reading was performed using Envision. The excitation light was 320 nm, and the emission light was 620 nm and 665 nm. The derived data was analyzed and processed to determine the maximum activation rate of the compound, E max and E.C. 50 was calculated.

[0376] 1.3 Experimental results: shown in Table 1.

[0377] Table 1 5-HT 1A Experimental results of the function of the compounds of the present invention on receptors

[0378] [Table 1]

[0379] Note: In the above table, a indicates the free base form of the compound, the rest indicate the hydrochloride / dihydrochloride forms of the compound.

[0380] 1.4 Experimental conclusions: As can be seen from the results in Table 1 above, the compounds of the present invention inhibit the activity of 5-HT 1A It can act on receptors and has good 5-HT 1A It showed receptor agonist activity.

[0381] Test Example 2: In vitro dopamine D 2L Receptor function test 2.1 Experimental materials 2.1.1 Cell information

[0382] TIFF2025526807000099.tif17101

[0383] 2.1.2 Experimental Reagents and Consumables

[0384] TIFF2025526807000100.tif43114

[0385] 2.1.3 Experimental equipment

[0386] TIFF2025526807000101.tif44114

[0387] 2.2 Experimental method (1) Preparation of compounds: Test compounds and dopamine were diluted to 200 nM and prepared for use.

[0388] (2) Preparation of experimental buffer: 5x stimulation buffer was diluted to 1x with ddH2O, IBMX was added to a final concentration of 0.5 mM, and the mixture was mixed uniformly for use.

[0389] (3) Cells were digested with pancreatin and centrifuged. The cell pellet was resuspended in 10 mL of preheated HBSS, centrifuged, and resuspended in 1 mL of stimulation buffer. 20 μL of the digested material was then taken and counted.

[0390] (4) Take an appropriate amount of cell suspension and measure 0.4 × 10 6 The cells were diluted to cells / mL, and 5 μL of the cell suspension was added per well to a cell plate, followed by centrifugation at 1000 rpm for 1 minute.

[0391] (5) Dilute and transfer the compounds using Bravo™ to a compound plate, diluting the compounds 4-fold in eight spots. Then, use Bravo™ to transfer the entire diluted compound plate to a 384-well white plate and centrifuge at 1000 rpm for 1 minute.

[0392] (6) The experimental plate was blocked and incubated at room temperature for 15 minutes.

[0393] (7) Forskolin prepared in DMSO was added using a Tecan D300e, with the mother solution being 0.2 mM and the final concentration being 0.25 μM. 25.1 nL of forskolin was added per well, and the plate was centrifuged at 1000 rpm for 1 minute.

[0394] (8) The plate was blocked and incubated at room temperature for 45 minutes.

[0395] (9) Preparation of cAMP standard curve: The starting concentration was 2848 nM, and 8 points were serially diluted 4-fold. 10 μL was added to the experimental plate to give a peak concentration of 712 nM.

[0396] (10) 5 μL of cAMP-d2 solution (diluted 1:20 with lysis buffer) was added to the experimental plate and centrifuged at 1000 rpm for 1 minute.

[0397] (11) Next, 5 μL of Anti-cAMP-Cryptate solution (diluted 1:20 from the stock solution with lysis buffer) was further added to the experimental plate, followed by centrifugation at 1000 rpm for 1 min.

[0398] (12) The experimental plates were incubated at room temperature for 45 min and centrifuged at 1000 rpm for 1 min before reading.

[0399] (13) Plate reading was performed using Envision. The excitation light was 320 nm, and the emission light was 620 nm and 665 nm. The derived data was analyzed and processed to determine the maximum activation rate of the compound, E max and E.C. 50 was calculated.

[0400] 2.3 Experimental results: shown in Table 2.

[0401] Table 2. Functional experiment results of the compounds of the present invention on D2 receptors

[0402] [Table 2]

[0403] Note: In the above table, a indicates the free base form of the compound, the rest indicate the hydrochloride / dihydrochloride forms of the compound.

[0404] 2.4 Experimental conclusions: As can be seen from the results in Table 2 above, the compounds of the present invention were able to act on dopamine D2 receptors and exhibited good dopamine D2 receptor (partial) agonist activity.

[0405] Test Example 3: In vitro dopamine D3 receptor function test of the compounds of the present invention 3.1 Experimental materials 3.1.1 Cell information: CHO-K1 / D3 / CRE, CN114369578A, constructed according to the method in Example 5.

[0406] 3.1.2 Experimental Reagents and Consumables

[0407] TIFF2025526807000103.tif43114

[0408] 3.1.3 Experimental equipment

[0409] TIFF2025526807000104.tif44114

[0410] 3.2 Experimental method Day 1: Cell plating (1) The cultured cells were digested with pancreatin and the digestion was completed with the medium. The cell suspension was then transferred to a centrifuge tube and centrifuged at 750 rpm for 5 minutes.

[0411] (2) The supernatant was discarded, the precipitate was resuspended in an appropriate amount of plating medium, and 20 μL was taken and counted using a cell counter.

[0412] (3) Take an appropriate amount of cell suspension and measure 0.5 × 10 6 The cells were diluted to cells / mL, and 20 μL of the cell suspension was added to each well of a cell plate (cell density: 10,000 cells / well).

[0413] (4) The cell plate was incubated overnight at 5% CO2 / 37°C.

[0414] Day 2: Experimental detection (1) Test compounds were diluted to 0.2 mM in DMSO, and the reference compound Dopamine was diluted to 0.02 mM.

[0415] (2) Compounds were diluted in Bravo (4-fold dilutions with 8 concentration points). The starting concentration of the test compound was 5 μM, and the reference compound was 500 nM. 5 μL was then added to the cell plate. The final reaction concentration of the test compound was 1 μM, and the final reaction concentration of the reference compound was 100 nM. The positive control wells contained 100 nM Dopamine, and the negative control wells contained an equal volume of DMSO.

[0416] (3) The mixture was centrifuged at 1000 rpm for 1 minute and incubated at 5% CO2 / 37°C for 30 minutes.

[0417] (4) Using a Tecan-D300e, 40 nL of 0.2 mM forskolin DMSO solution was transferred to the cell plate to a final concentration of 0.4 μM. To the blank group (Blank), cells were added without adding forskolin.

[0418] (5) The mixture was centrifuged at 1000 rpm for 1 minute and incubated at 5% CO2 / 37°C for 4 hours.

[0419] (6) 30 minutes before use, remove the dissolving solution, thaw it in a water bath at room temperature, and return it to room temperature. Take out an appropriate amount of substrate, dilute it with the dissolving solution at a ratio of 1:50, and mix it evenly to prepare it for use.

[0420] (7) 20 μL of detection reagent was added and centrifuged at 1000 rpm for 1 minute.

[0421] (8) After incubation at room temperature for 3 minutes, the plate was read using Envision. The ultra-sensitive chemiluminescence detection program was selected. The derived data was analyzed and processed to determine the maximum activation rate of the compound, E max and E.C. 50 was calculated.

[0422] 3.3. Experimental results: Shown in Table 3.

[0423] Table 3. Functional experiment results of the compounds of the present invention on D3 receptors

[0424] [Table 3]

[0425] Note: In the above table, a indicates the free base form of the compound, the rest indicate the hydrochloride / dihydrochloride forms of the compound.

[0426] 3.4 Experimental conclusions: As can be seen from the results in Table 3 above, the compounds of the present invention can act on dopamine D3 receptors and exhibit good dopamine D3 receptor (partial) agonist activity. Test Example 4: In vitro liver microsome experiment using the compound of the present invention 4.1 Experimental Objectives The monophasic metabolic stability of compounds of the present invention was evaluated in CD-1 mice, SD rats and human liver microsomes.

[0427] 4.2 Experimental materials 4.2.1 Experimental Reagents

[0428] TIFF2025526807000106.tif79138

[0429] 4.2.2 Experimental equipment

[0430] TIFF2025526807000107.tif27124

[0431] 4.3 Experimental method (1) Preparation of buffer solution: Dissolve 73.21 g of dipotassium hydrogen phosphate trihydrate and 10.78 g of potassium dihydrogen phosphate in 4000 mL of ultrapure water. Adjust the pH of the solution to 7.40 ± 0.10 with 10% phosphoric acid or 1 M potassium hydroxide to a final concentration of 100 mM.

[0432] (2) Solution preparation and dilution: A 10 mM stock solution of the test compound was prepared in dimethyl sulfoxide (DMSO), stored at 4°C, and diluted with pure acetonitrile to a working solution concentration of 100 μM before use. A 10 mM stock solution of the control compound testosterone was prepared in DMSO and stored at -20°C. It was diluted with pure acetonitrile to a working solution concentration of 400 μM before use.

[0433] (3) Preparation of stop solution: Acetonitrile containing the internal standard buspirone was used as the stop solution. The prepared stop solution was stored in a refrigerator at 2 to 8°C.

[0434] (4) Preparation of liver microsome solution: Microsomes from various genera (CD-1 mice, SD rats, and humans) were diluted to a working solution of 20x with 100 mM potassium phosphate buffer. The final concentration of microsomes in the reaction system was 0.5 mg / mL.

[0435] (5) Preparation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) regenerating system: Nicotinamide adenine dinucleotide phosphate (NADP), glucose-6-phosphate (G6P), magnesium chloride (MgCl2), and glucose-6-phosphate dehydrogenase (G6PDH) were weighed appropriately to prepare stock solutions with concentrations of 65.33 mM, 330 mM, 300 mM, and 250 units / mL, respectively. The four stock solutions were added to an appropriate amount of buffer and mixed uniformly by gently inverting the solution. The final concentrations in the NADPH regenerating system were 2.65 mM NADP, 10.2 mM G6P, 6.12 mM MgCl2, and 2.45 units / mL G6PDH, respectively.

[0436] (6) Incubation process: The incubation was completed in a 96-well plate. Several incubation plates, designated T0, T5, T10, T20, T40, T60, PB60, and NCF60, were prepared. The corresponding reaction time points for the first six plates were 0, 5, 10, 20, 40, and 60 minutes, respectively. In the NCF60 plate, the NADPH regenerating system solution was replaced with potassium phosphate buffer and incubated for 60 minutes. In the PB60 plate, liver microsomes were replaced with potassium phosphate buffer and incubated for 60 minutes. All condition samples were in triplicate.

[0437] 2 μL of test compound or control compound and 100 μL of microsomal working solution (containing 1 mg / mL of liver microsomal protein) were added to the T0, T5, T10, T20, T40, T60, and NCF60 plates, respectively. 2 μL of test compound and 100 μL of potassium phosphate buffer were added to the PB60 plate. The incubation plates were then placed in a 37°C water bath and pre-incubated for approximately 5 minutes.

[0438] After preincubation, 600 μL of stop solution was added to the TO sample, followed by 98 μL of NADPH-regenerating working solution. The plate was blocked and shaken before being processed simultaneously with subsequent samples. Except for the addition of 98 μL of potassium phosphate buffer to each sample well of the NCF60 incubation plate, 98 μL of NADPH-regenerating working solution was added to each sample well of the other incubation plates to initiate the reaction. The final reaction concentrations of the test compound and control compound in the reaction system were 1 μM and 4 μM, respectively. The liver microsome concentration was 0.5 mg / mL. The final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively.

[0439] After incubation for an appropriate period (e.g., 5, 10, 20, 40, or 60 minutes), 600 μL of stop solution containing the internal standard was added to each test compound sample and control compound well to terminate the reaction. The plate was blocked, shaken uniformly, and then centrifuged at 4000 × g for 15 minutes at 4°C. The supernatant was transferred to a 96-well sample receiving plate, diluted with an appropriate amount of pure water, shaken uniformly, and used for LC-MS / MS analysis. Data were processed using Analyst 7.1 software (Sciex, Framingham, Massachusetts, USA).

[0440] 4.4 Experimental results: shown in Table 4.

[0441] Table 4. In vitro liver microsome stability test results

[0442] [Table 4]

[0443] Note: The clearance classification criteria are shown in the table below.

[0444] TIFF2025526807000109.tif27165

[0445] 4.5 Experimental Conclusions As can be seen from the results in Table 4 above, the compounds of the present invention have a medium clearance rate in SD rat and CD-1 mouse liver microsomes, and a medium-low clearance rate in human liver microsomes. Based on the pharmacological activity and pharmacological mechanism of this series of compounds, a slower metabolic rate contributes to the exertion of the compound's pharmacological activity, so the compounds of the present invention are superior in terms of metabolic rate.

[0446] Test Example 5: In vitro hERG experiment of the compound of the present invention 5.1 Experimental materials 5.1.1 Experimental Reagents

[0447] TIFF2025526807000110.tif111147

[0448] 5.1.2 Experimental equipment

[0449] TIFF2025526807000111.tif49145

[0450] 5.1.3 Electrophysiological detection solutions Extracellular solution: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 10 mM glucose, 10 mM HEPES, 1.25 mM NaH2PO4, adjusted to pH 7.4 with NaOH.

[0451] Intracellular solution: 20 mM KCl, 115 mM K-Aspartic, 1 mM MgCl2, 5 mM EGTA, 10 mM HEPES, 2 mM Na2-ATP, adjusted to pH 7.2 with KOH.

[0452] 5.2 Patch clamp detection method Using an inverted microscope, a glass electrode micromanipulator was manipulated (micromanipulation) to contact the recording electrode with the cell, and then negative pressure was applied to the cell to encourage the formation of a GΩ seal. After the GΩ seal was formed, rapid capacitance compensation was performed, followed by continuous negative pressure to rupture the cell membrane, forming the whole-cell recording mode. In the whole-cell recording mode, slow capacitance compensation was performed, and values of membrane capacitance and series resistance were recorded.

[0453] The voltage stimulation protocol for cellular hERG potassium current was as follows: the membrane clamp voltage was -80 mV, then depolarized from -80 mV to +30 mV for 2.5 seconds, and then immediately held at -50 mV for 4 seconds to excite the tail current of the hERG channel. Data collection was repeated every 10 seconds. Leak current was detected at -50 mV.

[0454] The cell-seeded coverslip was placed in the recording chamber of an inverted microscope, and negative control and test compounds were rapidly perfused into the recording chamber by gravity perfusion, from low to high concentrations. The external fluid was continuously circulated using a vacuum pump during recording. The detection current of the negative control for each cell served as a control for the cell itself. Each drug concentration was applied for 5 minutes or until the current stabilized. All experiments were performed at room temperature.

[0455] 5.3 Data analysis First, the post-action currents for each drug concentration were normalized ((Peak tail current compound) / (Peak tail current vehicle)), and then the corresponding inhibition rate was calculated (1-(Peak tail current compound) / (Peak tail current vehicle)). Basic statistics, including mean (Mean), standard deviation (SD), standard error (SE), and number of duplicates (n), were calculated for each concentration. The dose-response curve was fitted with the following equation to determine the half-inhibitory concentration (IC) of the test compound. 50 ) was calculated: inhibition=1 / (1+(IC 50 / C)^h) where C represents the test compound concentration and IC 50 where σ represents the half-maximal inhibitory concentration, and h represents the Hill coefficient. Curve fitting and IC were performed using GraphPad Prism 5.0 software. 50 The calculation was performed.

[0456] 5.4 Experimental results: shown in Table 5.

[0457] Table 5. Experimental results of the inhibitory activity of the compounds of the present invention against hERG potassium channel receptor

[0458] [Table 5]

[0459] Note: In the above table, a indicates the free base form of the compound, the rest indicate the hydrochloride / dihydrochloride forms of the compound.

[0460] 5.5 Experimental Conclusions The hERG inhibition test results in Table 5 above show that most of the compounds described in this invention have relatively weak or essentially no inhibitory activity against the hERG potassium channel. Among them, the hERG inhibition IC of Examples 28, 32, and 33 50 The functional activity of each compound was 20 μM, which was more than 1000 times lower than that of the target compound. Therefore, the compounds of the present invention have an extremely low risk of potential cardiotoxicity.

[0461] Test Example 6: Test of the effect of the compound of the present invention on tacrine-induced mandibular tremor behavior in rats 6.1 Experimental design 6.1.1 Experimental materials Test compounds: free bases of Examples 28, 32, 33 of the present invention prepared in-house.

[0462] Positive control compound: Rotigotine.

[0463] Modeling drug: Tacrine, SIGMA, A3773-1G.

[0464] Solvent: Physiological saline, Chenxin Pharmaceutical Co., Ltd., 2111060723.

[0465] 6.1.2 Experimental equipment

[0466] TIFF2025526807000113.tif28145

[0467] 6.1.3 Experimental animals Sprague Dawley rats, male, 10 rats / group, Shanghai Slack Laboratory Animal Co., Ltd.

[0468] 6.1.4 Administration Information Drug preparation: Test compound was taken, solvent was added and sonicated.

[0469] Route and method of administration: intraperitoneal injection.

[0470] Dosage frequency and duration: Single dose.

[0471] 6.2 Experimental Method The rats were stratified according to body weight and randomly divided into a model group, a treatment group, and a control group. Three days before the experiment, the rats underwent adaptation training. On the day of the experiment, the rats were first intraperitoneally injected with vehicle or drug, followed 60 minutes later by intraperitoneal injection of tacrine at 5 mg / kg body weight. After administration, the rats were placed in a transparent observation box and their jaw trembling behavior was counted 10 minutes later. The duration of the count was 5 minutes, and the number of jaw trembling behaviors within 5 minutes was recorded.

[0472] 6.3 Data Processing and Statistics The experimental data is JPEG2025526807000114.jpg53

[0473] The results are expressed as ±SEM, and the inhibition rate % = 100% × (number of mandibular tremors in model group rats - number of mandibular tremors in treatment group rats) / number of mandibular tremors in model group rats, where *: p<0.05, **: p<0.01, ***: p<0.001 vs vehicle.

[0474] 6.4 Experimental results: As shown in Figure 1 (amelioration of Tacrine-induced mandibular tremor in rats by the compounds of the present invention at various concentrations).

[0475] 6.5 Experimental Conclusions The free bases of Examples 28, 32, and 33 were tested in a tacrine-induced rat mandibular tremor model, using the anti-Parkinson's drug rotigotine as the active agent to investigate their potential anti-Parkinson's tremor symptoms. The results are shown in Figures 1-3. Compared with the model group, the positive control rotigotine group (10 mg / kg), Example 28 (1 mg / kg, 3 mg / kg, 10 mg / kg), Example 32 (1 mg / kg, 3 mg / kg, 10 mg / kg), and Example 33 (1 mg / kg, 3 mg / kg, 10 mg / kg) were able to significantly inhibit the mandibular tremor behavior in tacrine-induced rats. The minimum effective doses of Examples 28, 32, and 33 were lower than those of the active agent. The results demonstrated that a series of compounds of the present invention have the effect of improving Parkinson's tremor symptoms.

[0476] Although the specific embodiments of the present invention have been described in detail above, based on all the teachings disclosed, those skilled in the art can make various modifications and substitutions to the details of the technical solutions of the present invention, and all of these changes fall within the protection scope of the present invention. The full scope of the present invention is defined by the appended claims and any equivalents thereof.

Claims

1. A compound represented by general formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, [Chemical Formula 1] Among them, X is an amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O, or S, C 6-10 aryl groups, 5- to 10-membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, or S; C 6-10 Aryl C 3-8 Cycloalkyl groups, C 6-10 aryl 3-8 membered heterocyclyl group containing 1-4 heteroatoms selected from N, O or S, C 6-10 aryl; 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, or S; 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, or S; 3-8 a cycloalkyl group or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, or S; a 3- to 8-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O, or S, optionally further substituted by one or more R; R is deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, among which the C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 The haloalkoxy group may optionally further comprise deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 substituted with one or more substituents selected from haloalkoxy groups; Z is a bond, -(CR aa R bb ) m -, -C(O)(CR aa R bb ) m -, -O (CR aa R bb ) m -,-(CR aa R bb ) m O-, - (CR aa R bb ) m N (R cc ) -, -S(O)(CR aa R bb ) m -, -S(O) 2 (CR aa R bb ) m -, -C(O)(CR aa R bb ) m N (R cc ) -, -C(S)(CR aa R bb ) m N (R cc ) - or - C (S) (CR aa R bb ) m -Selected from M 1 and M 2 are each independently CR aa , N, O or S; R aa and R bb are each independently hydrogen, deuterium, halogen, hydroxy group, amino group, mercapto group, nitro group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, among which the C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 The haloalkoxy group may optionally further comprise deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 substituted with one or more substituents selected from haloalkoxy groups; R cc are hydrogen, deuterium, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, among which the C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 The haloalkoxy group may optionally further comprise deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 substituted with one or more substituents selected from haloalkoxy groups; R 1 are hydrogen, deuterium, and C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, among which the C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 The haloalkoxy group may optionally further comprise deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 substituted with one or more substituents selected from haloalkoxy groups; R 2 is a hydroxy group, amino group, mercapto group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, n is selected from 0, 1, 2, 3, or 4; m is selected from 0, 1, 2, 3, 4, 5 or 6; A compound, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

2. Meets one or more of the following criteria: （1） 【Chemistry 2-1】 teeth, 【Chemistry 2-2】 and preferably 【Chemistry 2-3】 and (2) X is an amino group, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O, or S, C 6-10 an aryl group, a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, or S, or C 6-10 aryl is selected from 5-10 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O or S, optionally further substituted with one or more R, preferably an amino group, C 4-6 a cycloalkyl group, a 4- to 6-membered heterocyclyl group containing 1 to 3 heteroatoms selected from N, O, or S; C 6-10 The aryl group, the 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S, or the 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from benzoN, O or S, is optionally further substituted with one or more R, more preferably X is 【Chemistry 3】 wherein o is selected from 0, 1, 2, 3, 4, or 5; (3) R is hydrogen, deuterium, halogen, hydroxyl group, amino group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 Haloalkoxy groups, preferably hydrogen, deuterium, halogen, cyano groups or C 1-6 alkyl group, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, cyano group or C 1-3 alkyl groups, more preferably hydrogen, deuterium, fluorine, chlorine, cyano groups or methyl groups; (4) Z is a bond, -(CH 2 ) m -, -C(O)-, -C(O)(CH 2 ) m -, -S(O) 2 -, -S(O) 2 (CH 2 ) m - or -C(O)N(CH 3 )-, preferably a bond, -C(O)-, -S(O) 2 - or -C(O)N(CH 3 ) - selected from (5) R 1 are hydrogen, deuterium, and C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group or C 1-6 Alkoxy groups, preferably hydrogen, deuterium or C 1-6 alkyl group, more preferably hydrogen, deuterium or C 1-3 alkyl groups, more preferably hydrogen, deuterium, methyl, ethyl or propyl groups; (6) R 2 is a hydroxy group, an amino group, C 1-6 Alkyl group or C 1-6 Haloalkyl groups, preferably hydroxy groups, amino groups, C 1-3 Alkyl group or C 1-3 a haloalkyl group, more preferably a hydroxy group or an amino group, and even more preferably an amino group; (7) n is selected from 0, 1, 2 or 3, preferably 0, 1 or 2; (8) m is selected from 0, 1, 2 or 3, preferably 0 or 1; 2. The compound according to claim 1, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof.

3. General formula (I) further has a structure represented by general formula (II): 【Chemistry 4】 Among them, X, Z, R 1 and n is defined as in claim 1 or 2.

3. The compound according to claim 1, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

4. General formula (I) further has a structure represented by general formula (III): 【Chemistry 5】 Among them, Ring A is C 6-10 an aryl group, a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, or S, or C 6-10 aryl A 5-10 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O or S, preferably C 6-10 an aryl group or a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms selected from benzoN, O or S, more preferably a phenyl group or a benzothienyl group; R is hydrogen, deuterium, halogen, hydroxyl group, amino group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 Haloalkoxy groups, preferably hydrogen, deuterium, halogen, cyano groups or C 1-6 alkyl group, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, cyano group or C 1-3 alkyl groups, more preferably hydrogen, deuterium, fluorine, chlorine, cyano groups or methyl groups; o is selected from 0, 1, 2 or 3, preferably 0, 1 or 2; R 1 and n is defined as in claim 3.

4. The compound according to claim 3, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof.

5. In the general formula (III), 【Chemistry 6】 teeth, 【Chemistry 7-1】 Preferably, 【Chemistry 7-2】 Selected from Among them, R 3 and R 4 are each independently a halogen, a hydroxy group, an amino group, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, preferably halogen, cyano or C 1-6 an alkyl group, more preferably fluorine, chlorine or bromine, and even more preferably chlorine; 5. The compound according to claim 4, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof.

6. General formula (I) further has a structure represented by general formula (IV): 【Chemistry 8】 Among them, Xa is an amino group, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O, or S, C 6-10 aryl group or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, or S, and optionally further containing one or more R a and preferably an amino group, C 4-6 a cycloalkyl group, a 4- to 6-membered heterocyclyl group containing 1 to 3 heteroatoms selected from N, O, or S; C 6-10 aryl group or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, or S, and optionally further containing one or more R a and more preferably, Xa is 【Chemistry 9】 wherein y is selected from 0, 1, 2 or 3, preferably 0, 1 or 2; R a represents hydrogen, deuterium, halogen, hydroxyl group, amino group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, preferably hydrogen, deuterium, halogen, cyano group or C 1-6 is an alkyl group, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, a cyano group or C 1-3 an alkyl group, more preferably hydrogen, deuterium, fluorine, chlorine, a cyano group, or a methyl group; n1 is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 1; 4. The compound according to claim 3, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof.

7. The Xa is 【Chemistry 10】 It is selected from the following group: Among them, R 5 and R 6 are each independently a halogen, a hydroxy group, an amino group, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 haloalkoxy groups, preferably halogen, cyano or C 1-6 alkyl group, more preferably fluorine, chlorine, bromine, cyano group or C 1-3 an alkyl group, more preferably a fluorine group, a chlorine group, a cyano group, or a methyl group; 7. The compound according to claim 6, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof. 【Request 8】 【Chemical 11-1】 【Chemistry 11-2】 is selected from the compounds 8. The compound according to any one of claims 1 to 7, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof.

9. A compound represented by general formula (V), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 12】 Among them, n1 is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 1; A compound, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

10. 10. A method for preparing the compound of claim 6, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, comprising: 【Chemistry 13】 condensation reaction of a compound of general formula (V) with a substituted carboxylic acid or acid chloride to obtain a compound of general formula (IV), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof; wherein n1 and Xa are as defined in claim 6; A method characterized by:

11. A therapeutically effective amount of a compound according to any one of claims 1 to 8, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical additive selected from the group consisting of a pharmaceutically acceptable vector, diluent or excipient. Pharmaceutical compositions.

12. The use of the compound according to any one of claims 1 to 8, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the manufacture of a drug in which 5-serotonin receptors and / or dopamine receptors are involved or modulated, preferably 5-HT 1A Receptor, dopamine D 2 Receptors and / or dopamine D 3 Applications in the production of receptor-mediated or receptor-modulated drugs.

13. 12. Use of the compound according to any one of claims 1 to 8, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11, in the manufacture of a drug for treating a central nervous system disease.

14. 14. The application of claim 13, wherein the central nervous system disease is one or more selected from Parkinson's disease, schizophrenia, bipolar disorder, depression, anxiety disorder, mania, Huntington's disease, Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory impairment, loss of executive function, vascular dementia, neuropathic pain and neuropathic diseases related to intelligence, learning or memory, glaucoma, age-related macular degeneration, optic neuritis, ischemic disorders and retinal edema, preferably Parkinson's disease.

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