Aromatic heterocyclic cyclohexylaminoalkylpiperidine derivatives, method of production, and use 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 to Chinese Patent Application No. 2022109619064, filed on 11 August 2022. The entire text of the aforementioned Chinese Patent Application is incorporated herein by reference.

[0002] The present invention belongs to the pharmaceutical field and, more specifically, relates to aromatic heterocyclic cyclohexylaminoalkylpiperidine derivatives, methods for producing them, and their uses. More specifically, the present invention relates to aromatic heterocyclic cyclohexylaminoalkylpiperidine derivatives, methods for producing them, pharmaceutical compositions containing said aromatic heterocyclic cyclohexylaminoalkylpiperidine derivatives, and the use of said aromatic heterocyclic cyclohexylaminoalkylpiperidine derivatives or their pharmaceutical compositions in the manufacture of drugs for the prevention and / or treatment of mammalian central nervous system diseases. [Background technology]

[0003] Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, after Alzheimer's disease, and frequently affects the elderly, with a prevalence of approximately 2% in people over 60 years of age (Lilienfeld, DE Neuroepidemiology, 1993, 12, 219-228). Its clinical features mainly include resting tremor, muscle rigidity, bradykinesia, and postural balance disorders (Armstrong MJ. JAMA. 2020;323(6):548-560), along with autonomic dysfunction (Jost WH. J Neurol. 2003 Feb;250 Suppl 1:I28-30), cognitive impairment (Halliday, GM Mov. Disord. 2014, 29, 634-650), sleep disorders, and emotional disorders (Gallagher, DA Neurobiol. Dis. 2012, 46). Non-motor symptoms such as those described in 581-589. can occur. 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 forms Lewy bodies (Schapira, AH Neurol. Clin. 2009, 27, 583-603.), resulting in various motor disorders. Non-motor disorders are related to the degeneration of neural pathways such as cholinergic, noradrenergic, and serotonergic pathways, in addition to the effects of the dopamine pathway (Titova N. Med J Aust 2018;208:404-409.) (Titova N. J Neural Transm(Vienna)2017; 124:907-914.).

[0004] Currently, drug therapy for Parkinson's disease primarily focuses on a dopamine policy, 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, extending 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.). While there is a clear benefit in treating symptoms, long-term use of levodopa generally leads to motor variability (on-off phenomena) and motor impairment (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 the early motor symptoms of Parkinson's disease, so most patients choose dopamine agonists as their first-line treatment rather than levodopa (Jankovic J. Journal of Neurology, Neurosurgery & Psychiatry 2020;91:795-808). In the 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 several non-motor symptoms. For example, pramipexole is effective in treating depressive symptoms, and ropinirole has beneficial effects on sleep, anxiety, and depression. Rotigotine has demonstrated efficacy in improving dysphagia, while apomorphine is effective for emotional, gastrointestinal, and urinary tract dysfunction (Torti M. Drugs. 2019 May;79(7):693-703.).

[0006] 5-HT 1A Receptors also play an important role in Parkinson's drug therapy, as demonstrated in three main ways. First, 5-HT 1A Receptor agonists can improve extrapyramidal disorders caused by dopamine neuron degeneration and motor disorders caused by levodopa, such as eltoprazine and NLX-112 (Cerri S. Expert Opin Investig Drugs. 2017 Jul;26(7):777-791.). Next, 5-HT 1A Receptor activation helps improve cognitive impairment and produces anxiolytic and antidepressant effects, such as aripiprazole (Ohno Y. Prog Neurobiol. 2015 Nov;134:104-21.). Furthermore, various models have been found to be related to 5-HT1A They have shown that receptor agonists can prevent neurotoxicity, meaning that disease progression can be controlled by protecting nerves from loss, such as BAY-639044. Miyazaki et al. have shown that 5-HT 1A We have demonstrated that receptor activation induces astrocyte proliferation, increases antioxidant molecule levels in the striatum, and thereby prevents progressive dopaminergic neuronal degeneration (Miyazaki I. Curr Med Chem. 2016;23(7):686-700).

[0007] Furthermore, 5HT was found in the aqueous humor of the human eye (Martin et al., Ophthalmol., 95:1221-1226, 1988). In the iris ciliary body (ICB) of rabbits [ 3 The receptor binding sites of [H]5HT were identified and pharmacologically characterized (Mallorga and Sugrue, Curr. EyeRes., 6:527-532, 1987 and Chidlow et al., Invest. Ophthalmol. Vis. Sci., 36:2238-2245, 1995). These 5HT binding sites were shown to functionally couple to a second messenger produced 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 associated with 5HT 1A It is characterized as a 5HT2 receptor (Barnet and Osborne, Exp. Eye Res., 57:209-216, 1993). Furthermore, 5HT in rabbit ICB 1A The existence of receptor mRNAs has been reported (Chidlow et al., Invest. Ophthalmol. Vis. Sci., supra and osborne and Chidlow, Opthalmologica, 210:308-314, 1996).

[0008] 8-Hydroxy DPAT and MKC-242 (5HT 1A agonist) studies in rabbits have shown that these 5HT 1A agonists can reduce IOP (Osborne and Chidlow, Ophthalamologica, 210:308-319, 1996, EP 0771563A2.). Also, 5-methylpiperidine methoctramine (5HT 1A agonist) can reduce IOP in glaucomatous monkeys (Wang, et al., Curr. Eye Res., 16:679-775, 1997.). U.S. Patent 5693654 discloses 5HT1 receptor agonists for reducing IOP. WO 92 / 20333 discloses several 5HT 1A agonists for treating glaucoma.

[0009] Eltoprazine is a 5HT 1A / 1B agonist (EC 50 = 148 nM), was designated as an orphan drug by the U.S. FDA in 2016, is used for the treatment of levodopa-induced dyskinesia (LID), and is currently in Phase II clinical trials, which have shown excellent therapeutic effects 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 maxIt is used in the treatment of levodopa-induced movement disorder (LID) in Parkinson's disease (PD) at a rate of 84%, and a Phase II clinical trial with Neurolixis is currently underway. According to the literature (Noureddine El Aouad. European Journal of Medicinal Chemistry, 44(11):4616-4621.), NLX-112 exhibits novel therapeutic properties, possessing significant anti-movement disorder function without compromising the therapeutic performance of L-DOPA, and also showing improvement effects on non-motor psycho-mood symptoms such as antidepressant and anxiolytic effects.

[0011] Furthermore, 5-HT 1A Receptor agonists primarily alleviate motor and non-motor impairments through non-dopaminergic mechanisms. This means that a multi-target approach, which involves therapeutic effects by binding to both dopaminergic and serotonergic receptors, can provide a dual effect in treating 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 are demonstrating 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 D2 / 5-HT 1A It acts as an agonist against Parkinson's disease and can also delay the production of LID (L-DOPA-induced dyskinesia) without weakening the therapeutic effect 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 anti-Parkinson's disease research drug developed by Solvay, Inc., and is currently in Phase III clinical trials. Clinical trials have shown that it has effects that improve motor symptoms and alleviate psychiatric symptoms such as antidepressant and anxiolytic effects (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 D2 / D3 / 5-HT (=500 nM) has anti-Parkinsonian, antidepressant, and anxiolytic effects. 1A It is an agonist (Jones CA. Eur Neuropsychopharmacol. 2010 Aug;20(8):582-93). Furthermore, it has a lower tendency to cause side effects such as motor impairment compared to single-target dopamine agonists, and is currently progressing to Phase III clinical trials for the treatment of Parkinson's disease (Glennon, JC Synapse 2006, 60, 599-608).

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

[0016] [ka]

[0017] The compound has a certain affinity for D2 and D3 receptors and is useful in the treatment of Parkinson's disease, and among them D 2L and the binding affinity K of (-)31 to the D3 receptori The values ​​are 1979±567 nm and 44.0±10.6 nm, respectively, and the ratio is 58.6. 2L and the (-)33 agonist efficacy against the D3 receptor EC 50 These figures are 13.4±2.4 (78.8±0.8%) and 0.06±0.015 (95.7±10.7%), respectively, with a ratio of 223.

[0018] JP2005104885A contains dopamine D2 receptors and 5-serotonin 5-HT receptors. 1A Novel thiazole derivatives exhibiting agonist activity against both receptors have been disclosed, and among them, Compound Example 19, which has a structure relatively similar to the present patented compound, has the following structure, and the technical effects of this compound are not described in the specification:

[0019] [ka]

[0020] In summary, dopamine D2, D3 receptors and / or 5-HT 1A Given the existence of multi-target synergistic effects of receptors, dopamine D2, D3 receptors and / or 5-HT 1A Multitarget small molecules with receptor activity are expected to treat the main motor symptoms of Parkinson's disease, overcome motor impairment, improve cognitive impairment, and exhibit novel clinical therapeutic characteristics in terms of improving mental mood, such as anxiety and antidepressant effects. In particular, dopamine D2, D3 and / or 5-HT 1A Multi-target agonists are a key direction in drug development and application worldwide, particularly in the development of new drugs for novel anti-Parkinson's disease, antidepressants, and anti-schizophrenia conditions. Research in this field possesses novelty, inventiveness, and significant scientific value. [Overview of the Initiative]

[0021] The technical problem that this invention aims to solve is to provide aromatic heterocyclic cyclohexylaminoalkylpiperidine derivatives, methods for producing them, and their uses. In particular, this invention provides D2, D3, 5-HT 1A The aim is to develop a novel anti-Parkinson's disease drug that simultaneously possesses receptor full agonist activity to effectively treat both motor and non-motor disorders, while reducing various toxicities and side effects. This will overcome the main shortcomings of existing drugs, such as the low efficacy of D2 and D3 dual full agonist drugs in treating non-motor disorders, the presence of LID side effects, the limited anti-Parkinsonian motor disorder activity of selective D3 agonists, and the insufficient therapeutic effect of D2 and D3 dual partial agonists.

[0022] The present invention aims to provide compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof.

[0023] [ka]

[0024] Eventually, X is an amino group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Aryl group, 5-10 membered heteroaryl group, C 6-10 Aryl C 3-8 Cycloalkyl groups, C 6-10 Aryl 3-8 member heterocyclyl group, C 6-10 aryl 5-10 member heteroaryl group, 5-10 member heteroaryl C 3-8 Selected from cycloalkyl groups or 5-10 membered heteroaryl 3-8 membered heterocyclyl groups, and optionally further substituted with one or more R groups, R is hydrogen, deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, C 1-6 Alkyl alkyl group, C1-6 a haloalkyl group, C 1-6 an alkoxy group or C 1-6 a haloalkoxy group, and among them, the above C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group or C 1-6 haloalkoxy group is optionally further substituted with one or more substituents selected from 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 group, 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 -, and M1 and M2 are each independently selected from CR aa , N, O or S, R aa and R bbThese are, independently, hydrogen, deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 Selected from haloalkoxy groups, of which the above C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 The haloalkoxy group can optionally be further composed of deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, or C 1-6 Alkyl 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 is hydrogen, deuterium, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 Selected from haloalkoxy groups, of which the above C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 The haloalkoxy group can optionally be further composed of deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, or C 1-6 Alkyl 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 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 Selected from haloalkoxy groups, of which the above C 1-6 Alkyl 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 can optionally be further composed of deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, or C 1-6 Alkyl 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 consists of a hydroxyl group, an amino group, a mercapto group, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 Selected from 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, the above general formula (I)

[0026] [ka] teeth,

[0027] [ka]

[0028] Selected from the basis, preferably

[0029] [ka]

[0030] That is the case.

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

[0032] In a further preferred embodiment of the present invention, R is hydrogen, deuterium, halogen, hydroxyl group, amino group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 Selected from haloalkoxy groups, preferably hydrogen, deuterium, halogen, cyano group, or C 1-6 It is an alkyl group, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, cyano group or C 1-3 It is an alkyl group, 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, -(CH2) m -, -C(O)-, -C(O)(CH2) m -, -S(O)2-, -S(O)2(CH2) m Alternatively, selected from -C(O)N(CH3)-, preferably bonded, -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 alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group or C 1-6 Selected from alkoxy groups, preferably hydrogen, deuterium, or C 1-6It is 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 a hydroxyl group, an amino group, C 1-6 Alkyl or C 1-6 Selected from haloalkyl groups, preferably a hydroxyl group, an amino group, and C 1-3 Alkyl or C 1-3 It is a haloalkyl group, more preferably a hydroxyl 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 from 0, 1, or 2.

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

[0038] [ka]

[0039] Selected based on this principle, Eventually, o is selected from 0, 1, 2, 3, 4, or 5, and the definition of R is the same as above.

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

[0041] [ka]

[0042] It is selected based on this principle.

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

[0044] [ka]

[0045] Eventually, 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) has a structure represented by general formula (III):

[0047] [ka]

[0048] Eventually, Ring A is C 6-10 Aryl group, 5-10 membered heteroaryl group or C 6-10 Selected from aryl 5-10 member heteroaryl groups, preferably C 6-10 It is an aryl group or a benzo-5 to 6-membered heteroaryl 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, the above general formula (III)

[0050] [ka] teeth,

[0051] [ka]

[0052] Preferably

[0053] [ka]

[0054] Selected from, Eventually, R3 and R4 are, independently, halogen, hydroxyl group, amino group, cyano group, and C, respectively. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 Selected from haloalkoxy groups, preferably halogens, cyano groups, 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, the above general formula (III)

[0056] [ka] teeth,

[0057] [ka]

[0058] It is selected based on this principle.

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

[0060] [ka]

[0061] Eventually, Xa is an amino group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C6-10 Selected from aryl groups or 5-10 membered heteroaryl groups, and optionally one or more additional R a Substituted with, preferably an amino group, C 4-6 Cycloalkyl group, 4-6 membered heterocyclyl group, C 6-10 Selected from aryl groups or 5-10 membered heteroaryl groups, and optionally one or more additional R a Replaced by, R a These are hydrogen, deuterium, halogen, hydroxyl group, amino group, cyano group, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 Selected from haloalkoxy groups, preferably hydrogen, deuterium, halogen, cyano group, or C 1-6 It is an alkyl group, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, cyano group or C 1-3 It is an alkyl group, more preferably hydrogen, deuterium, fluorine, chlorine, cyano group or methyl group. n1 is selected from 0, 1, 2, 3, or 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] Selected based on this principle, Eventually, 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, Of these, R5 and R6 are, independently, halogen, hydroxyl group, amino group, cyano group, and C, respectively. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 Selected from haloalkoxy groups, preferably halogens, cyano groups, or C 1-6 It is an alkyl group, more preferably fluorine, chlorine, bromine, cyano group or C 1-3 It is an alkyl group, and more preferably fluorine, chlorine, 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 based on this principle.

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

[0072] [ka]

[0073] [ka]

[0074] They are selected from among them.

[0075] The present invention further provides compounds represented by general formula (V), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof.

[0076] [ka]

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

[0078] The present invention further provides a method for producing compounds of general formula (IV), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof.

[0079] [ka]

[0080] The process includes the step of condensing a compound of general formula (V) with a substituted carboxylic acid or acid chloride to obtain a compound of general formula (IV), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof. Of these, n1 and Xa are as described 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, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable vector, diluent, or excipient.

[0082] In some embodiments of the present invention, the pharmaceutical composition may be prepared according to any method known in the art. The vectors refer to conventional vectors in the pharmaceutical field, such as fillers or cellulose derivatives, adhesives such as 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. Other auxiliary agents, such as sweeteners, fragrances, or colorants, may also be added to the composition.

[0083] In some embodiments of the present invention, the pharmaceutical composition may be administered by any of the following methods: oral administration, spray inhalation, rectal administration, nasal administration, cheek administration, topical administration, parenteral administration such as injection or infusion into the subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, ventricular, sternal, or intracranial cavity, or administration via an explanted reservoir. Among these, oral administration is preferred.

[0084] For oral administration, the compound of the present invention may be manufactured in any orally acceptable formulation, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions.

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

[0086] The present invention relates to the application of 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 involving or modulating 5-serotonin receptors and / or dopamine receptors, preferably 5-HT 1A The present invention further provides a preferred form relating to applications in the manufacture of drugs involving or modulating receptors, dopamine D2 receptors and / or dopamine D3 receptors.

[0087] The present invention further provides applications of 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 for treating central nervous system disorders.

[0088] The present invention further provides applications of compounds represented by the above general formulas, their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, or the above pharmaceutical compositions, in the treatment of central nervous system disorders.

[0089] In one preferred embodiment of the present invention, the central nervous system disorder 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 disorders related to intelligence, learning or memory, glaucoma, age-related macular degeneration, optic neuritis, ischemic injury and retinal edema, and more preferably Parkinson's disease.

[0090] Detailed description of the present invention Unless otherwise specified, terms used in the specification and claims have the following meanings:

[0091] The compounds of the present invention may exist in the form of specific geometric isomers or stereoisomers. The present invention assumes the inclusion of cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the scope of the present invention. Substituents such as alkyl groups may have other chiral carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention. In some embodiments, preferred compounds are isomer compounds exhibiting superior biological activity. Purified or partially purified isomers and stereoisomers, or racemic or diastereomerized mixtures of the compounds of the present invention, are all within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.

[0092] Unless otherwise specified, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

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

[0094] Unless otherwise specified, the term "diastereomer" refers to stereoisomers that have two or more chiral centers in a molecule and are non-mirror images of each other.

[0095] Certain compounds may exist within the present invention. Unless otherwise specified, the term "tautomer" or "tautomer form" refers to a state in dynamic equilibrium at room temperature in which different functional isomers can rapidly transform into each other. If tautomerism is possible (e.g., in solution), then chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also called prototropic tautomers) include intertransformations carried out by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include intertransformations carried out by the rearrangement of several bond electrons. A specific example of keto-enol tautomerization is the intertransformation between two tautomers, pentane-2,4-dione and 4-hydroxypento-3-en-2-one.

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

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

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

[0099] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated electron system, preferably 6 to 10 members, for example, phenyl group or naphthyl group.

[0100] The above aryl group may be condensed with a heteroaryl group, a heterocyclyl group, or a cycloalkyl ring, of which the ring bonded together with the parent structure is an aryl ring, for example, 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 It is an aryl 5-10 member heteroaryl group, more preferably C 6-10 The group is an aryl 5-10 membered heteroaryl group, more preferably a benzo 5-6 membered heteroaryl group, where the heterocyclyl group is a heterocyclyl group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, and the heteroaryl group is a heteroaryl group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, and non-limiting examples thereof (where the ring bonded together to the parent structure is an aryl ring) include the following:

[0101] [ka]

[0102] The above-mentioned aryl group, arylcycloalkyl group, arylheterocyclyl group, or arylheteroaryl group may be substituted or unsubstituted. If substituted, the substituent is preferably independently selected from deuterium, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, mercapto group, hydroxy group, nitro group, amino group, or cyano group, and of which the above-mentioned alkyl group, haloalkyl group, alkoxy group, or haloalkoxy group may optionally be further substituted with one or more substituents selected from deuterium, halogen, hydroxy group, amino group, mercapto group, nitro group, cyano group, alkyl group, haloalkyl group, alkoxy group, or haloalkoxy group.

[0103] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, of which the heteroatoms are selected from oxygen, sulfur, and nitrogen. A 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. Examples include imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, and triazolyl groups. These include zolyl groups, tetrazolyl groups, pyridyl groups, pyrimidinyl groups, thiadiazole groups, pyrazinyl groups, or benzo derivatives thereof, preferably furanyl groups, triazolyl groups, thienyl groups, thiazolyl groups, imidazolyl groups, pyrazolyl groups, pyrrolyl groups, pyridyl groups, pyrimidinyl groups, thiazolyl groups, or benzo derivatives thereof, and more preferably furanyl groups, thienyl groups, thiazolyl groups, pyrazolyl groups, pyrrolyl groups, pyridyl groups, or benzo derivatives thereof. Non-limiting examples include:

[0104] [ka]

[0105] Includes.

[0106] The above heteroaryl group may be condensed with a heterocyclyl group or a cycloalkyl ring, the ring bonded together with the parent structure being a heteroaryl ring, for example a heteroarylcycloalkyl group or a heteroarylheterocyclyl group, preferably a 5-10 membered heteroaryl C 3-8 The group is a cycloalkyl group or a 5-10 membered heteroaryl group, or a 3-8 membered heterocyclyl group, where the heterocyclyl group contains 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, and the heteroaryl group contains 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms.

[0107] The heteroaryl group, heteroarylcycloalkyl group, or heteroarylheterocyclyl group may be optionally substituted or unsubstituted. If substituted, the substituent is preferably independently selected from deuterium, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, mercapto group, hydroxy group, nitro group, amino group, or cyano group, and of which the alkyl group, haloalkyl group, alkoxy group, or haloalkoxy group may be optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy group, amino group, mercapto group, nitro group, cyano group, alkyl group, haloalkyl group, alkoxy group, or haloalkoxy group.

[0108] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), of which the definition of alkyl group is as described above, 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 group, ethoxy group, propoxy group, butoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, and cyclohexyloxy group. The alkoxy group may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, alkyl group, haloalkyl group, alkoxy group, or haloalkoxy group.

[0109] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, where 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, and dibromofluoromethyl groups, with fluoromethyl, difluoromethyl, and trifluoromethyl groups being preferred. Non-limiting examples of haloethyl groups include 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2-chloro-2-fluoroethyl group, 2,2-dichloroethyl group, 2-bromo-2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-chloro-2,2-difluoroethyl group, 2,2,2-dichloro-2-fluoroethyl group, 2,2,2-trichloroethyl group, 2-bromo-2,2-difluoroethyl group, and 2-bromo-2-chloro-2-fluoroethyl group. The haloalkyl group includes ethyl group, 2-bromo-2,2-dichloroethyl group, 1,1,2,2-tetrafluoroethyl group, pentafluoroethyl group, 1-chloro-1,2,2,2-tetrafluoroethyl group, 2-chloro-1,1,2,2-tetrafluoroethyl group, 1,2-dichloro-1,2,2-trifluoroethyl group, 2-bromo-1,1,2,2-tetrafluoroethyl group, and preferably 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, and 2,2-difluoroethyl group. The haloalkyl group may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, alkyl group, haloalkyl group, alkoxy group, or haloalkoxy group.

[0110] The term "haloalkoxy group" refers to an alkoxy group substituted with one or more halogens, where 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, and dibromofluoromethoxy, with fluoromethoxy, difluoromethoxy, and trifluoromethoxy being preferred. Non-limiting examples of haloethoxy groups include 2-fluoroethoxy group, 2-chloroethoxy group, 2-bromoethoxy group, 2,2-difluoroethoxy group, 2-chloro-2-fluoroethoxy group, 2,2-dichloroethoxy group, 2-bromo-2-fluoroethoxy group, 2,2,2-trifluoroethoxy group, 2-chloro-2,2-difluoroethoxy group, 2,2-dichloro-2-fluoroethoxy group, 2,2,2-trichloroethoxy group, 2-bromo-2,2-difluoroethoxy group, and 2-bromo-2-chloro-2-fluorinated group. The haloalkoxy group includes a roethoxy group, a 2-bromo-2,2-dichloroethoxy group, a 1,1,2,2-tetrafluoroethoxy group, a pentafluoroethoxy group, a 1-chloro-1,2,2,2-tetrafluoroethoxy group, a 2-chloro-1,1,2,2-tetrafluoroethoxy group, a 1,2-dichloro-1,2,2-trifluoroethoxy group, a 2-bromo-1,1,2,2-tetrafluoroethoxy group, and preferably a 2-fluoroethoxy group, a 2-chloroethoxy group, a 2-bromoethoxy group, or a 2,2-difluoroethoxy group. The haloalkoxy group may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from deuterium, a halogen, a hydroxyl group, an amino group, a mercapto group, a nitro group, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group, or a haloalkoxy group.

[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 a vinyl group, a 1-propenyl group, a 2-propenyl group, or a 1-, 2-, or 3-butenyl group. The alkenyl group may be substituted or unsubstituted. If substituted, the substituent is preferably independently selected from deuterium, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, halogens, mercapto groups, hydroxyl groups, nitro groups, amino groups, or cyano groups, of which the alkyl groups, haloalkyl groups, alkoxy groups, or haloalkoxy groups may be optionally further substituted with one or more substituents selected from deuterium, halogens, hydroxyl groups, amino groups, mercapto groups, nitro groups, cyano groups, alkyl groups, haloalkyl groups, alkoxy groups, or haloalkoxy groups.

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

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

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

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

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

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

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

[0119] The terms "comprising", "including", "having", "containing", or "involving" and other variations thereof in this specification are inclusive or open-ended and do not exclude other elements or method steps not recited. One skilled in the art should understand that the above terms such as "comprising" include the meaning of "consisting of".

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

[0121] When the lower and upper limits of a numerical range are disclosed, any numerical value within that range and any included range are specifically disclosed. In particular, the range of each possible value of the values disclosed herein should be understood to mean each value and range that encompasses a wider range.

[0122] In this specification, both "Z" and "-Z-" represent the same specific group and they can be used interchangeably.

[0123] As used herein, the expression m~n refers to the range from m to n, the subscopes consisting of each point value within that range, and each point value. For example, the expression "C2~C8" or "C2-8" should be understood to encompass the range of 2 to 8 carbon atoms, and any subscope and each point value within that range, such as C2~C5, C3~C4, C2~C6, C3~C6, C4~C6, C4~C7, C4~C8, etc., as well as C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3~C10" or "C3-10" should be understood in a similar manner, encompassing any subscope and point values ​​within it, such as C3~C9, C6~C9, C6~C8, C6~C7, C7~C10, C7~C9, C7~C8, C8~C9, and C3, C4, C5, C6, C7, C8, C9, C10, etc. Similarly, the expression "C1~C6" or "C1-6" should be understood to encompass the range of 1 to 6 carbon atoms, and also include any subscope and point values ​​within it, such as C2~C5, C3~C4, C1~C2, C1~C3, C1~C4, C1~C5, C1~C6, and C1, C2, C3, C4, C5, C6, etc. For example, the expression "3 to 10 members" should be understood to encompass any subscope and point values ​​within it, such as 3 to 5 members, 3 to 6 members, 3 to 7 members, 3 to 8 members, 4 to 5 members, 4 to 6 members, 4 to 7 members, 4 to 8 members, 5 to 7 members, 5 to 8 members, 6 to 7 members, 6 to 8 members, 9 to 10 members, etc., as well as 3, 4, 5, 6, 7, 8, 9, 10 members, etc. Other similar expressions in this specification should be understood in a similar manner.

[0124] The different terms used herein, 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 have the same meaning, that is, X may be one or more of A, B, or C.

[0125] As used herein, the expression "-(CY1Y2)n-" means that each of the Y1 or Y2 groups bonded to C may be the same or different, that is, each of the Y1 groups may be a different group, each of the Y2 groups may be a different group, each of the Y1 groups may be the same group, and each of the Y2 groups may be the same group.

[0126] The terms “optionally” or “optionally” refer to whether the event or situation described thereafter may or may not occur, and such description includes cases in which the event or situation described may or may not occur. For example, “optionally alkyl-substituted cycloalkyl group” means that an alkyl group may be present, but is not necessarily so, and such description includes cases in which the cycloalkyl group is substituted with an alkyl group and cases in which the cycloalkyl group is not substituted with an alkyl group.

[0127] The terms “substitution” and “substituted” refer to the substitution of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom with a selection from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in its current state, and that the substitution forms a stable compound. A combination of substituents and / or variables is permitted only if such a combination forms a stable compound. Where it is stated that a substituent is absent, it should be understood that the substituent may be one or more hydrogen atoms, provided that the structure allows the compound to be stable. Where it is stated that each carbon atom in a group may be optionally substituted with a heteroatom, the condition is that the substitution does not exceed the normal valence of all atoms in the group in its current state, and that a stable compound is formed.

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

[0129] If the substituent's bond penetrates a bond connecting two atoms within the ring, such substituent may be bonded to any of the ring-constituting atoms within the substituteable ring.

[0130] When any variable (e.g., R) and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear one or more times in the composition or structure of a compound, the definition in each case is independent for each occurrence. For example, when a group is substituted with 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted with at most 4 R substituents, and all options for each R substituent in each case are independent of one another.

[0131] The term "pharmaceutically acceptable" refers to a substance that, within the bounds of normal medical judgment, is suitable for use in contact with a patient's tissue without causing inappropriate toxicity, irritation, or allergic reactions, has a reasonable cost-benefit ratio, and can be effectively used for its intended purpose.

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

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

[0134] The term "pharmaceutically acceptable vector" refers to a substance that does not have an apparent irritant 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, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0135] Terms such as "administer" or "give" refer to methods that enable a compound or composition to be delivered to the desired site of action. These methods include, but are not limited to, oral or parenteral (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, and rectal administration, particularly injection or oral administration.

[0136] As used herein, the term “treatment” includes, and extends to, alleviating, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of a symptom; suppressing a disease or symptom, for example, preventing the progression of a disease or symptom; reducing a disease or symptom; promoting the relief of a disease or symptom; or ceasing the signs of a disease or symptom. “Treatment” further includes achieving therapeutic and / or preventive benefits. A therapeutic benefit means the eradication or improvement of the medical condition being treated. Furthermore, a therapeutic benefit may be achieved by eradicating or improving one or more physiological signs associated with an underlying disease, and an improvement in the patient’s condition may be observed, even though the patient may still have the underlying disease. A preventive benefit means the patient using the composition to prevent the risk of a particular disease, or the patient taking one or more physiological symptoms of a disease when the disease manifests, even though the disease has not yet been diagnosed.

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

[0138] With respect to drugs, drug units, or active ingredients, the terms “effective dose,” “therapeutic effective dose,” or “preventive effective dose” refer to a dose of the drug or medication sufficient to achieve the desired effect with tolerable side effects. The effective dose is determined by the individual, depending on the individual’s age and general condition, and also on the specific active substance. A suitable effective dose for an individual can be determined by a person skilled in the art through ordinary testing.

[0139] As used herein, “individual” includes humans and non-human animals. An exemplary human individual includes a human individual suffering from a disease (e.g., a disease described herein) (referred to as a patient) or a healthy individual. “Non-human animals” in this invention include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cattle, pigs, etc.).

[0140] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling those skilled in the art to better understand the technical concept of the invention, its principles, and its practical applications, thereby allowing the invention to be modified and implemented in many ways so as to best suit the requirements of a particular use. Beneficial effects The compound of the present invention has a novel structure and is 5-HT 1A It can be used as a receptor, dopamine D2 receptor and / or dopamine D3 receptor, and exhibits certain agonist activity. Some compounds are 5-HT 1A These compounds exhibit agonist activity against at least two receptors, including dopamine D2 and D3 receptors, and in particular, most of the compounds are 5-HT receptors. 1A It exhibits triple agonist activity against receptors, dopamine D2 and D3 receptors, shows remarkable therapeutic effects against central nervous system disorders such as Parkinson's disease, and can be used in the manufacture of drugs that treat central nervous system disorders. [Brief explanation of the drawing]

[0141] [Figure 1] This shows the effects of Tacrine-induced mandibular tremor behavior in rats at various concentrations, as shown in Example 28. [Figure 2] This shows the effects of Tacrine-induced mandibular tremor behavior in rats at various concentrations, as shown in Example 32. [Figure 3] This shows the effects of Tacrine-induced mandibular tremor behavior in rats at various concentrations in Example 33. [Modes for carrying out the invention]

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

[0143] NMR chemical shifts (δ) are expressed in parts per million (ppm). An AVANCE III600 nuclear magnetometer was used for the NMR measurements, with dimethyl sulfoxide (DMSO), deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.

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

[0145] For thin-layer chromatography, Yantai Jiangyou silica gel plates were used. TLC plates with a specification of 0.2 mm ± 0.03 mm were used, and plates with a specification of 0.4 mm to 0.5 mm were used for separating and purifying the products from the thin-layer chromatography. Intermediate 1a (S)-N 6 -(piperidine-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 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 taken, dissolved in 320 mL of NMP, and bromopropane (0.96 mol, 4 eq) was added. The mixture was stirred at room temperature for 18 hours. After complete reaction, the mixture was filtered by suction, and the filter cake was washed with an appropriate amount of isopropanol to obtain a white solid, which was dried in a forced-air drying box at 70°C. The dried sample was dissolved in an appropriate amount of water (30 mL), the pH was adjusted to 10 by adding 20% ​​NaOH aqueous solution, and the mixture was extracted with dichloromethane (400 mL x 3). The organic layers were combined, dried, and concentrated to obtain (S)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was obtained. ESI-MS[M+H] + : m / z 212.1. Step B: Synthesis of (S)-4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-carboxylate tert-butyl (S)-N 6-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (94.6 mmol, 1 eq) and 4-formylpiperidine-1-carboxylate tert-butyl (113.6 mmol, 1.2 eq) were taken and dissolved in 1,2-dichloroethane (150 mL), and the mixture was stirred for 30 minutes with 3 drops of acetic acid at -20°C. Then sodium triacetoxyborohydride (142.0 mmol, 1.5 eq) was added, and the mixture was stirred for 8 hours at -20°C. When the starting materials had reacted almost completely or when by-products began to form, the reaction was stopped, and the reaction mixture was diluted with ethyl acetate (100 mL). The reaction was quenched with 10% hydrochloric acid (150 mL) at -20°C, and then saturated NaHCO3 solution (300 mL) was added. The liquid-liquid layers were separated, the aqueous layer was extracted with dichloromethane (300 mL x 2), the organic layers were combined, the organic layers were 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 (S)-4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-carboxylate tert-butyl (15.2 g, 39.3%). ESI-MS[M+H] + : m / z 409.1. Step C:(S)-N 6 -(piperidine-4-ylmethyl)-N 6 Synthesis of propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (S)-4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-carboxylate tert-butyl (37.3 mmol, 1 eq) was taken and dissolved in 20 mL of methanol. 14 mL (1.5 eq) of 4 M hydrogen chloride methanol solution was added, and the mixture was stirred at room temperature for 12 hours. After complete reaction of the starting materials, the mixture was concentrated under reduced pressure, the solvent was removed, and the sample was dispersed by adding 20 mL of water. The aqueous phase was washed with 50 mL of ethyl acetate, and then the pH was adjusted to 10 with 10% NaOH solution. The aqueous phase was extracted with dichloromethane (100 mL x 3), the organic phase was combined, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain intermediate 1a (8.5 g, 73.9%). ESI-MS[M+H] + : m / z 309.1. Intermediate 1b 2-(4-(5-fluoropyridine-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetaldehyde 1b

[0150] [ka]

[0151] Synthesis scheme:

[0152] [ka]

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

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

[0155] [ka]

[0156] (S)-N 6 Synthetic method for -(1-(2,3-dichlorophenyl)piperidine-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 at 80°C and stirred for 1 hour. After cooling to room temperature, stirring was continued for 2 hours until the solid had completely precipitated. The mixture was then filtered by suction, dried, and yielded 57.0 g of a grayish-white solid. The dried solids were taken and recrystallized three times with 8 times the volume of water. The recrystallized products were dispersed in 80 mL of water, 20% sodium hydroxide solution was added, the pH was adjusted to 12, and the mixture was stirred at 0-5°C for 2 hours. The mixture was then filtered by suction, dried, and yielded 15.8 g of (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine. The yield was 62.0%.

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

[0160] Step B: Synthesis of 1-(2,3-dichlorophenyl)piperidine-4-one 1,2-Dichloro-3-iodobenzene (22.0 mmol, 1 eq), 4-piperidinone ethylene glycol (22.0 mmol, 1 eq), Pd2(dba)3 (0.6 mmol, 0.025 eq), and Xantphos (2.2 mmol, 0.1 eq) were taken, dissolved in toluene (60 mL), sodium tert-butoxide (33.0 mmol, 1.5 eq) was added, and after purging with nitrogen gas, the mixture was heated to 80-110°C and reacted under reflux for 15 hours. After complete reaction, the mixture was filtered by suction through diatomaceous earth, and the filtrate was evaporated under reduced pressure using rotary evaporation to remove the solvent and obtain 5.1 g of the crude intermediate (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 was dissolved in acetone (60 mL), 6 N hydrochloric acid solution (70 mL) was added, and the mixture was stirred overnight at room temperature to completely hydrolyze it. Water was added, and organic impurities were extracted and removed with ethyl acetate. The aqueous layer was adjusted to pH=10 with NaHCO3, extracted with ethyl acetate (3 × 100 mL), and separated. The organic layer was concentrated, and the crude product was obtained by silica gel column chromatography to yield 2.23 g of 1-(2,3-dichlorophenyl)piperidine-4-one, with a yield of 51.6%.

[0162] ESI-MS[M+H] + : m / z 244.0. Step C:(S)-N 6 Synthesis of -(1-(2,3-dichlorophenyl)piperidine-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)piperidine-4-one (4.1 mmol, 1.1 eq) were taken and dissolved in 1,2-dichloroethane (20 mL). One drop of acetic acid was added under ice bath conditions, and the mixture was stirred for 30 minutes. Then sodium triacetoxyborohydride (5.5 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature for 8 hours. When the starting materials had reacted almost completely or when by-products began to form, the reaction was stopped, and the reaction mixture was diluted with ethyl acetate (100 mL). The reaction was quenched under ice bath conditions with 10% hydrochloric acid (10 mL), and then saturated NaHCO3 solution (20 mL) was added. After liquid-liquid 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. Hydrochloride salt production: (S)-N 6 Synthesis of -(1-(2,3-dichlorophenyl)piperidine-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine dihydrochloride (S)-N 6 -(1-(2,3-dichlorophenyl)piperidine-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken, dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to < 3. The solid was precipitated, stirred at room temperature for 2-5 hours, and filtered by suction 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)piperidine-4-yl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0165] [ka]

[0166] (S)-N 6 -(1-(2,3-dichlorophenyl)piperidine-4-yl)-N 6 Synthetic method for propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0167] [ka]

[0168] Compound (S)-N 6-(1-(2,3-dichlorophenyl)piperidine-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 taken and dissolved in 1,2-dichloroethane (10 mL). One drop of acetic acid was added under ice bath conditions, and the mixture was stirred for 30 minutes. Then sodium triacetoxyborohydride (1.9 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature for 6 hours. When the starting materials had reacted almost completely or when by-products began to form, the reaction was stopped, and the reaction mixture was diluted with ethyl acetate (20 mL). The reaction was quenched under ice bath conditions with 10% hydrochloric acid (5 mL), and then saturated NaHCO3 solution (10 mL) was added. After liquid-liquid 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. Hydrochloride salt production: (S)-N 6 -(1-(2,3-dichlorophenyl)piperidine-4-yl)-N 6 Synthesis of propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride (S)-N 6 -(1-(2,3-dichlorophenyl)piperidine-4-yl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken, dissolved in ethyl acetate (5-10 mL), and HCl·EA (2 M) was added dropwise to adjust the pH to < 3. The solid precipitated, the mixture was stirred at room temperature for 2-5 hours, and the hydrochloride salt of the compound was obtained by suction filtration.

[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)piperidine-4-yl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0171] [ka]

[0172] (S)-N 6 -(1-(benzo[b]thiophen-4-yl)piperidine-4-yl)-N 6 Synthetic method for 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 is produced by steps A to C. 6-(1-(benzo[b]thiophen-4-yl)piperidine-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was obtained, and then, using the synthesis method of Example 2, starting material (S)-N 6 -(1-(2,3-dichlorophenyl)piperidine-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine(S)-N 6 The target product was prepared by substituting -(1-(benzo[b]thiophen-4-yl)piperidine-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine.

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

[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)piperidine-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its dihydrochloride

[0177] [ka]

[0178] (S)-N 6 Synthetic method for -((1-(2,3-dichlorophenyl)piperidine-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-piperidine-formate (44.3 mmol, 1 eq), Pd(OAc)2 (1.1 mmol, 0.025 eq), BINAP (4.43 mmol, 0.1 eq), and Cs2CO3 (66.45 mmol, 1.5 eq) were taken, dissolved in toluene (200 mL), purged with nitrogen gas, heated to 110°C, refluxed, and reacted for 15 hours. After complete reaction, the mixture was filtered by suction through diatomaceous earth, and the filtrate was concentrated. The crude product was obtained by silica gel column chromatography to yield the intermediate ethyl 1-(2,3-dichlorophenyl)piperidine-4-formate (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 ethyl 1-(2,3-dichlorophenyl)piperidine-4-formate (20.2 mmol, 1 eq) was dissolved in THF:MeOH (1:1, 60 mL), and an aqueous solution of LiOH·H2O (30.3 mmol, 1.5 eq) (10 mL) was added. The mixture was stirred at room temperature for 18 hours. After complete reaction, the solvent was evaporated and removed. 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 taken and adjusted to pH=2. Extraction was performed with dichloromethane (50 mL × 3), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and dried to obtain 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]thiazole-6-yl)-1-(2,3-dichlorophenyl)piperidine-4-formamide The intermediates 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 taken, dissolved in dichloromethane (50 mL), and stirred under ice bath conditions 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. The mixture was allowed to react completely, 20 mL of water was added, and it was extracted with dichloromethane (30 mL x 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The mixture was purified by column chromatography to obtain the intermediate (S)-N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-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)piperidine-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine The intermediate (S)-N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)-1-(2,3-dichlorophenyl)piperidine-4-formamide (1.8 g, 4.4 mmol) from the product of the previous step was taken, dissolved in anhydrous THF (30 mL), and 1 M BH3·THF (8.7 mL) was added under ice bath conditions. The mixture was heated at 60°C and stirred for 3-5 days. Complete reaction was confirmed by TLC detection. The reaction mixture was cooled to room temperature, and 10 mL of methanol was added under 0°C conditions to concentrate the reaction mixture. The sample was acidified with a 4 M hydrogen chloride methanol solution and stirred at room temperature for 2 hours. The compound was then liberated with saturated sodium carbonate solution, the aqueous phase was extracted by DCM, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target product.

[0185] ESI-MS[M+H] + : m / z 411.0. Hydrochloride salt production: (S)-N 6 Synthesis of -((1-(2,3-dichlorophenyl)piperidine-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine dihydrochloride (S)-N 6 -((1-(2,3-dichlorophenyl)piperidine-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, a solid was precipitated, the mixture was stirred at room temperature for 1-5 hours, and the mixture was filtered by suction 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)piperidine-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its dihydrochloride

[0187] [ka]

[0188] (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidine-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-(piperidine-4-yl)ethyl acetate, and the product was prepared by steps A to D to obtain the target product.

[0189] ESI-MS[M+H] + : m / z 425.0. Hydrochloride salt production: (S)-N 6 Synthesis of -(2-(1-(2,3-dichlorophenyl)piperidine-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine dihydrochloride (S)-N 6-(2-(1-(2,3-dichlorophenyl)piperidine-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, and the solid precipitated. The mixture was stirred at room temperature for 1-5 hours and then filtered by suction 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)piperidine-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its dihydrochloride

[0191] [ka]

[0192] (S)-N 6 Synthetic method for -((1-(benzo[b]thiophen-4-yl)piperidine-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 product was prepared by steps A to D to obtain the target product.

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

[0195] [ka]

[0196] (S)-N 6 -((1-(2,3-dichlorophenyl)piperidine-4-yl)methyl)-N 6 Synthetic method for propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0197] [ka]

[0198] Target product of Example 4 (S)-N 6 The target product was obtained by using -((1-(2,3-dichlorophenyl)piperidine-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) as starting materials and the synthesis method of Example 2.

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

[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)piperidine-4-yl)ethyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0201] [ka]

[0202] (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidine-4-yl)ethyl)-N 6 Synthetic method for propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0203] [ka]

[0204] Target product of Example 5: (S)-N 6 The target product was obtained by using -(2-(1-(2,3-dichlorophenyl)piperidine-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 starting materials and the synthesis method of Example 2.

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

[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)piperidine-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0207] [ka]

[0208] (S)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidine-4-yl)methyl)-N 6 Synthetic method for propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0209] [ka]

[0210] Target product of Example 6: (S)-N 6 The target product was obtained by using -((1-(benzo[b]thiophen-4-yl)piperidine-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 and the synthesis method of Example 2.

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

[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)piperidine-4-yl)ethyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0213] [ka]

[0214] (S)-N 6 -(2-(1-(benzo[b]thiophen-4-yl)piperidine-4-yl)ethyl)-N 6 Synthetic method for 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 ethyl 4-piperidine-formate is replaced with ethyl 2-(piperidine-4-yl)ethyl acetate, and the intermediate (S)-N is produced by steps A to D. 6-(2-(1-(benzo[b]thiophen-4-yl)piperidine-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was obtained. Using this intermediate (1.2 mmol, 1 eq) and propionaldehyde (1.2 mmol, 1 eq) as starting materials, the product was prepared by the synthesis method of Example 2 to obtain the target product.

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

[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)piperidine-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0217] [ka]

[0218] (R)-N 6 -((1-(benzo[b]thiophen-4-yl)piperidine-4-yl)methyl)-N 6 Synthetic method for 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 the intermediate (R)-N is produced by steps A to D. 6 -((1-(benzo[b]thiophen-4-yl)piperidine-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was obtained. The intermediate (0.75 mmol, 1 eq) and propionaldehyde (0.75 mmol, 1 eq) were used as starting materials to produce the target product by the synthesis method of Example 2.

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

[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)piperidine-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0221] [ka]

[0222] N 6 -((1-(benzo[b]thiophen-4-yl)piperidine-4-yl)methyl)-N 6 Synthetic method for propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine: Using the synthesis method of Example 11, (R)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine in step C is replaced with 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine, and intermediate N is produced by steps A to D. 6-((1-(benzo[b]thiophen-4-yl)piperidine-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was obtained. The intermediate (0.5 mmol, 1 eq) and propionaldehyde (0.5 mmol, 1 eq) were used as starting materials to produce the target product by the synthesis method of Example 2.

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

[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)piperidine-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)piperidine-4-yl)methyl)-N 6 Synthetic method for ethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0227] [ka]

[0228] Target product of Example 6: (S)-N 6-((1-(benzo[b]thiophen-4-yl)piperidine-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) were used as starting materials and the target product was obtained by the synthesis method of Example 2.

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

[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)piperidine-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)piperidine-4-yl)methyl)-N 6 Synthetic method for methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0233] [ka]

[0234] Target product of Example 6: (S)-N6 -((1-(benzo[b]thiophen-4-yl)piperidine-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 solution (6 mL) and refluxed at 90°C for 6 hours. After complete reaction, 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 x 2). The combined organic layers were washed with saturated brine, dried, concentrated, and purified by column chromatography to obtain the target product.

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

[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]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(3-chloro-4-fluorophenyl)methyl ketone and its hydrochloride

[0237] [ka]

[0238] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-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 taken, dissolved in dichloromethane (20 mL), and stirred under ice bath conditions for 20 min. Intermediate 1a (3.2 mmol, 1.2 eq) was added, and the mixture was reacted at room temperature for 1.5 h. After complete reaction, 20 mL of water was added, and the mixture was extracted with dichloromethane (30 mL × 3). The organic layer was washed with water and saturated brine, dried over MgSO4, concentrated, and purified by column chromatography to obtain the target product. ESI-MS[M+H] + : m / z 465.1. Preparation of hydrochloride: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(3-chloro-4-fluorophenyl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(3-chloro-4-fluorophenyl)methyl ketone was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, and the solid was precipitated. The mixture was stirred at room temperature for 1-5 hours and then filtered by suction 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]thiazole-6-yl)(propyl)amino)ethyl)piperidine-1-yl)(3-chloro-4-fluorophenyl)methyl ketone and its hydrochloride

[0242] [ka]

[0243] Synthetic method for (S)-(4-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)ethyl)piperidine-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 taken, dissolved in dichloromethane, and stirred under ice bath conditions for 20 minutes. Intermediate 1b (1.6 mmol, 1.2 eq) was added, and the mixture was reacted at room temperature for 1.5 hours. After complete reaction, 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 obtain the target product.

[0246] ESI-MS[M+H] + : m / z 479.1. Preparation of hydrochloride: Synthesis of (S)-(4-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)ethyl)piperidine-1-yl)(3-chloro-4-fluorophenyl)methyl ketone hydrochloride (S)-(4-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)ethyl)piperidine-1-yl)(3-chloro-4-fluorophenyl)methyl ketone was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, and the solid was precipitated. The mixture was stirred at room temperature for 1-5 hours and then filtered by suction 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]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(phenyl)methyl ketone and its hydrochloride

[0248] [ka]

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

[0250] [ka]

[0251] The target product was produced by using the synthesis method of Example 15, replacing the starting material 3-chloro-4-fluorobenzoic acid with benzoic acid.

[0252] ESI-MS[M+H] + : m / z 413.1. Preparation of hydrochloride: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(phenyl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(phenyl)methyl ketone was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, and the solid was precipitated. The mixture was stirred at room temperature for 1-5 hours and then filtered by suction 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]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(6-chloro-5-fluoropyridine-2-yl)methyl ketone and its hydrochloride

[0254] [ka]

[0255] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(6-chloro-5-fluoropyridine-2-yl)methyl ketone:

[0256] [ka]

[0257] Using the synthesis method of Example 15, the starting material 3-chloro-4-fluorobenzoic acid was replaced with 2-chloro-3-fluoropyridine-6-formic acid to produce the target product.

[0258] ESI-MS[M+H] + : m / z 466.0. Preparation of hydrochloride: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(6-chloro-5-fluoropyridine-2-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(6-chloro-5-fluoropyridine-2-yl)methyl ketone was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, and the solid was precipitated. The mixture was stirred at room temperature for 1-5 hours and then filtered by suction 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]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(6-fluoropyridine-3-yl)methyl ketone and its hydrochloride

[0260] [ka]

[0261] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(6-fluoropyridine-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 for 5 hours at -10°C. After complete reaction, 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 obtain the target product.

[0264] ESI-MS[M+H] + : m / z 432.1. Preparation of hydrochloride: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(6-fluoropyridine-3-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(6-fluoropyridine-3-yl)methyl ketone was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, and the solid was precipitated. The mixture was stirred at room temperature for 1-5 hours and then filtered by suction 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]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-carbonyl)pyridinecarbonnitrile and its hydrochloride

[0266] [ka]

[0267] Synthetic method for (S)-5-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-carbonyl)pyridinecarbonitrile:

[0268] [ka]

[0269] Using the synthesis method of Example 15, the starting material 3-chloro-4-fluorobenzoic acid was replaced with 6-cyanonicotinic acid to produce the target product.

[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 for 4 hours at -10°C. After complete reaction, 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 obtain the target product.

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

[0273] [ka]

[0274] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(1H-indole-2-yl)methyl ketone:

[0275] [ka]

[0276] Using the synthesis method of Example 15, the starting material 3-chloro-4-fluorobenzoic acid was replaced with 2-indoleformic acid to produce the target product.

[0277] ESI-MS[M+H] + : m / z 452.2. Preparation of hydrochloride: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(1H-indole-2-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(1H-indole-2-yl)methyl ketone was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, and the solid was precipitated. The mixture was stirred at room temperature for 1-5 hours and then filtered by suction 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]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(benzo[b]thiophene-2-yl)methyl ketone and its hydrochloride

[0279] [ka]

[0280] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(benzo[b]thiophen-2-yl)methyl ketone:

[0281] [ka]

[0282] Using the synthesis method of Example 15, the starting material 3-chloro-4-fluorobenzoic acid was replaced with benzothiophene-2-carboxylic acid to produce the target product.

[0283] ESI-MS[M+H] + : m / z 469.1. Preparation of hydrochloride: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(benzo[b]thiophen-2-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(benzo[b]thiophen-2-yl)methyl ketone was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, and the solid was precipitated. The mixture was stirred at room temperature for 1-5 hours and then filtered by suction 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]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(naphthalene-2-yl)methyl ketone and its hydrochloride

[0285] [ka]

[0286] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(naphthalene-2-yl)methyl ketone:

[0287] [ka]

[0288] Using the synthesis method of Example 15, the starting material 3-chloro-4-fluorobenzoic acid was replaced with 2-naphthoic acid to produce the target product.

[0289] ESI-MS[M+H] + : m / z 463.2. Preparation of hydrochloride: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(naphthalene-2-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(naphthalen-2-yl)methyl ketone was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, and the solid was precipitated. The mixture was stirred at room temperature for 1-5 hours and then filtered by suction 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]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(thiophene-2-yl)methyl ketone and its hydrochloride

[0291] [ka]

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

[0293] [ka]

[0294] Using the synthesis method of Example 15, the starting material 3-chloro-4-fluorobenzoic acid was replaced with 2-thiopheneformic acid to produce the target product.

[0295] ESI-MS[M+H] + : m / z 419.1. Preparation of hydrochloride: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(thiophen-2-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(thiophen-2-yl)methyl ketone was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, and the solid was precipitated. The mixture was stirred at room temperature for 1-5 hours and then filtered by suction 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]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(furan-2-yl)methyl ketone and its hydrochloride

[0297] [ka]

[0298] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(furan-2-yl)methyl ketone:

[0299] [ka]

[0300] Using the synthesis method of Example 15, the starting material 3-chloro-4-fluorobenzoic acid was replaced with 2-furanic acid to produce the target product.

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

[0303] [ka]

[0304] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(1H-pyrrole-2-yl)methyl ketone:

[0305] [ka]

[0306] Using the synthesis method of Example 15, the starting material 3-chloro-4-fluorobenzoic acid was replaced with 2-pyrrolecarboxylic acid to produce the target product.

[0307] ESI-MS[M+H] + : m / z 402.0. Preparation of hydrochloride: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(1H-pyrrole-2-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(1H-pyrrole-2-yl)methyl ketone was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, and the solid was precipitated. The mixture was stirred at room temperature for 1-5 hours and then filtered by suction 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]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(thiazole-5-yl)methyl ketone and its hydrochloride

[0309] [ka]

[0310] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(thiazole-5-yl)methyl ketone:

[0311] [ka]

[0312] Using the synthesis method of Example 15, the starting material 3-chloro-4-fluorobenzoic acid was replaced with 5-thiazole carboxylic acid to produce the target product.

[0313] ESI-MS[M+H] + : m / z 420.1. Preparation of hydrochloride: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(thiazole-5-yl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(thiazole-5-yl)methyl ketone was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, and the solid was precipitated. The mixture was stirred at room temperature for 1-5 hours and then filtered by suction 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]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(1-methyl-1H-pyrazole-4-yl)methyl ketone

[0315] [ka]

[0316] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(1-methyl-1H-pyrazole-4-yl)methyl ketone:

[0317] [ka]

[0318] Using the synthesis method of Example 15, the starting material 3-chloro-4-fluorobenzoic acid was replaced with 1-methylpyrazole-4-formic acid to produce the target product.

[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 for 8 hours at -10°C. After complete reaction, 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 obtain the target 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]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(cyclohexyl)methyl ketone and its hydrochloride

[0321] [ka]

[0322] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(cyclohexyl)methyl ketone:

[0323] [ka]

[0324] Using the synthesis method of Example 15, the starting material 3-chloro-4-fluorobenzoic acid was replaced with cyclohexylformic acid to produce the target product.

[0325] ESI-MS[M+H] + : m / z 419.2. Preparation of hydrochloride: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(cyclohexyl)methyl ketone hydrochloride (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(cyclohexyl)methyl ketone was taken, dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to < 3, and the solid was precipitated. The mixture was stirred at room temperature for 1-5 hours and then filtered by suction 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)piperidine-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0327] [ka]

[0328] (S)-N 6 -((1-(phenylsulfonyl)piperidine-4-yl)methyl)-N 6 Synthetic method for propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0329] [ka]

[0330] Intermediate 1a (0.65 mmol, 1 eq) was taken and dissolved in DCM (6 mL). Under ice bath conditions, triethylamine (1.95 mmol, 3 eq), DMAP (2 mg, catalytic amount), and benzenesulfonyl chloride (0.65 mmol, 1 eq) were added, and the mixture was stirred for 2 hours to allow it to react completely. 10 mL of water was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic layer was washed with water and saturated brine, dried over MgSO4, concentrated, and purified by column chromatography to obtain the target product.

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

[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)piperidine-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0333] [ka]

[0334] (S)-N 6 -((1-((3-chloro-4-fluorophenyl)sulfonyl)piperidine-4-yl)methyl)-N 6 Synthetic method for propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine:

[0335] [ka]

[0336] The target product was prepared by using the synthesis method of Example 30, replacing the starting material benzenesulfonyl chloride with 3-chloro-4-fluorobenzenesulfonyl chloride.

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

[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]thiazole-6-yl)(propyl)amino)methyl)-N,N-dimethylpiperidine-1-formamide

[0339] [ka]

[0340] Synthetic method for (S)-4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-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 target 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]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(morpholino)methyl ketone

[0344] [ka]

[0345] Synthetic method for (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)(propyl)amino)methyl)piperidine-1-yl)(morpholino)methyl ketone:

[0346] [ka]

[0347] The target product was prepared by using the synthesis method of Example 30, replacing the starting material benzenesulfonyl chloride with 4-morpholine carbonyl chloride.

[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)piperazine-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 prepared according to the above route, referring to the literature (Biswas S. J Med Chem. 2008;51(10):3005-3019.).

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

[0354] [ka]

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

[0356] [ka]

[0357] Biological testing and evaluation The present invention will be further described 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: 5HT of the compound of the present invention in vitro 1A Receptor function experiment 1.1 Experimental Materials 1.1.1 Cell Information: HEK293 / 5HT 1A, 5HT 1A The receptor lentivirus was used to infect HEK293 cells, resulting in the stable transformed cell line HEK293 / 5HT. 1A The growth medium was constructed as follows: DMEM, 10% FBS, 0.6 μg / mL puro; cryopreservation medium: 70% culture medium, 20% FBS, 10% DMSO.

[0359] 1.1.2 Experimental Reagents and Consumables

[0360] TIFF0007870402000095.tif43114

[0361] 1.1.3 Laboratory Equipment

[0362] TIFF0007870402000096.tif44119

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

[0364] (2) Preparation of experimental buffer: Dilution of 5× stimulation buffer to 1× with ddH2O, adding IBMX to a final concentration of 0.5 mM, and mixing uniformly to prepare for use.

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

[0366] (4) Take an appropriate amount of cell suspension and divide it into 0.6 × 10 6 The cells were diluted to cells / mL, and 5 μL of the cell suspension was added to each well of a cell plate. The plates were then centrifuged at 1000 rpm for 1 minute.

[0367] (5) The compound was diluted and transferred using Bravo, and the compound was diluted fourfold by making eight dots on the compound plate. Then, using Bravo, the entire diluted compound plate was transferred to a 384-well white plate and centrifuged at 1000 rpm for 1 minute.

[0368] (6) Block the experimental plate and incubate it at room temperature for 15 minutes.

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

[0370] (8) Block the plate and incubate at room temperature for 45 minutes.

[0371] (9) Preparation of the cAMP standard curve: The starting concentration was 2848 nM, and it was sequentially diluted fourfold at eight points. 10 μL was added to the experimental plate so that the highest concentration at point 712 nM.

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

[0373] (11) Next, 5 μL of Anti-cAMP-Cryptate solution (diluted 1:20 with lysis buffer) was added to the experimental plate and centrifuged at 1000 rpm for 1 minute.

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

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

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

[0377] Table 1 5-HT 1A Functional experimental results of the compound of the present invention on receptors

[0378] [Table 1]

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

[0380] 1.4 Conclusions of the experiment: As can be seen from the results in Table 1 above, the compound of the present invention is 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] TIFF0007870402000098.tif17101

[0383] 2.1.2 Experimental Reagents and Consumables

[0384] TIFF0007870402000099.tif43114

[0385] 2.1.3 Laboratory Equipment

[0386] TIFF0007870402000100.tif44114

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

[0388] (2) Preparation of experimental buffer: Dilution of 5× stimulation buffer to 1× with ddH2O, adding IBMX to a final concentration of 0.5 mM, and mixing uniformly to prepare for use.

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

[0390] (4) Take an appropriate amount of cell suspension and divide it into 0.4 × 10 6 The cells were diluted to cells / mL, and 5 μL of the cell suspension was added to each well of a cell plate. The plates were then centrifuged at 1000 rpm for 1 minute.

[0391] (5) The compound was diluted and transferred using Bravo, and the compound was diluted fourfold by making eight dots on the compound plate. Then, using Bravo, the entire diluted compound plate was transferred to a 384-well white plate and centrifuged at 1000 rpm for 1 minute.

[0392] (6) Block the experimental plate and incubate it at room temperature for 15 minutes.

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

[0394] (8) Block the plate and incubate at room temperature for 45 minutes.

[0395] (9) Preparation of the cAMP standard curve: The starting concentration was 2848 nM, and it was sequentially diluted fourfold at eight points. 10 μL was added to the experimental plate so that the highest concentration at point 712 nM.

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

[0397] (11) Next, 5 μL of Anti-cAMP-Cryptate solution (diluted 1:20 with lysis buffer) was added to the experimental plate and centrifuged at 1000 rpm for 1 minute.

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

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

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

[0401] Table 2. Experimental results of the functional effects of the present compound on the D2 receptor.

[0402] [Table 2]

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

[0404] 2.4 Conclusions of the experiment: 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 showed good dopamine D2 receptor (partial) agonist activity.

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

[0406] 3.1.2 Experimental Reagents and Consumables

[0407] TIFF0007870402000102.tif43114

[0408] 3.1.3 Laboratory Equipment

[0409] TIFF0007870402000103.tif44114

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

[0411] (2) Discard the supernatant, resuspend the precipitate in an appropriate amount of plating medium, take 20 μL and count with a cell counter.

[0412] (3) Take an appropriate amount of cell suspension and 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 of 10,000 cells / well).

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

[0414] Day 2: Experimental detection (1) The test compound was diluted to 0.2 mM with DMSO, and the reference compound Dopamine was diluted to 0.02 mM.

[0415] (2) The compounds were diluted with Bravo (four-fold dilution at eight concentration points), with a starting concentration of 5 μM for the test compound and 500 nM for the reference compound. Next, 5 μL was taken and added to the cell plate, with a final reaction concentration of 1 μM for the test compound and 100 nM for the reference compound. The positive control well contained 100 nM dopamine, and the negative control well contained an equal volume of DMSO.

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

[0417] (4) 40 nL of 0.2 mM Forskolin DMSO solution was transferred to a cell plate using Tecan-D300e, and the final concentration was 0.4 μM. Cells were added to the blank group 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) Thirty minutes prior, the dissolution was removed, melted in a water bath at room temperature, and returned to room temperature. An appropriate amount of substrate was taken out, diluted with the dissolution according to a ratio of 1:50, and mixed uniformly to prepare for use.

[0420] (7) Add 20 μL of detection reagent and centrifuge at 1000 rpm for 1 minute.

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

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

[0423] Table 3. Experimental results of the function of the present invention compound against the D3 receptor.

[0424] [Table 3]

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

[0426] 3.4 Conclusions of the experiment: As can be seen from the results in Table 3 above, the compounds of the present invention can act on dopamine D3 receptors and showed good dopamine D3 receptor (partial) agonist activity. Test Example 4: In vitro liver microsome experiment with the compound of the present invention 4.1 Experimental Objectives The one-phase metabolic stability of the compound 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] TIFF0007870402000105.tif79138

[0429] 4.2.2 Laboratory Equipment

[0430] TIFF0007870402000106.tif27124

[0431] 4.3 Experimental Method (1) Preparation of buffer solution: 73.21 g of dipotassium hydrogen phosphate trihydrate and 10.78 g of potassium dihydrogen phosphate were dissolved in 4000 mL of ultrapure water. The pH of the solution was adjusted to between 7.40 ± 0.10 with 10% phosphoric acid or 1 M potassium hydroxide, and the final concentration was 100 mM.

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

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

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

[0435] (5) Preparation of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) regeneration system: Appropriate amounts of nicotinamide adenine dinucleotide phosphate (NADP), glucose-6-phosphate (G6P), magnesium chloride (MgCl2), and 6-phosphate glucose dehydrogenase (G6PDH) were weighed out, and stock solutions with concentrations of 65.33 mM, 330 mM, 300 mM, and 250 Units / mL were prepared. Appropriate amounts of the four stock solutions were added to buffer solutions, and the mixture was gently inverted to ensure uniformity. The final concentrations in the NADPH regeneration 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: Incubation was completed in 96-well plates. Multiple incubation plates were prepared, each named T0, T5, T10, T20, T40, T60, PB60, and NCF60. The reaction time points corresponding to the first six plates were 0, 5, 10, 20, 40, and 60 minutes, respectively. In the NCF60 plate, the NADPH regeneration 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 three parallel pairs.

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

[0438] After pre-incubation, 600 μL of stop solution was first added to the T0 sample, followed by 98 μL of NADPH regeneration system working solution. The plate was then blocked and shaken, and then awaited simultaneous processing with subsequent samples. Except for adding 98 μL of potassium phosphate buffer to each sample well of the NCF60 incubation plate, 98 μL of NADPH regeneration system 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, and 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 time (e.g., 5, 10, 20, 40, and 60 minutes), the reaction was stopped by adding 600 μL of stop solution containing an internal standard to each well of the test compound sample and the control compound. The plate was then blocked, shaken uniformly, and centrifuged at 4°C and 4000 × g for 15 minutes. 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 processing was performed using Analyst 7.1 software (Sciex, Framingham, Massachusetts, USA).

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

[0441] Table 4 Results of liver microsome stability tests in vitro

[0442] [Table 4]

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

[0444] TIFF0007870402000108.tif27165

[0445] 4.5 Conclusions of the Experiment As can be seen from the results in Table 4 above, the compounds of the present invention exhibit moderate clearance rates in SD rat and CD-1 mouse liver microsomes, and moderate to low clearance rates in human liver microsomes. Based on the pharmacokinetic activity and pharmacological mechanism of this series of compounds, a slower metabolic rate contributes to the exertion of the pharmacokinetic activity of the compounds; therefore, 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] TIFF0007870402000109.tif111147

[0448] 5.1.2 Laboratory Equipment

[0449] TIFF0007870402000110.tif49145

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

[0451] The intracellular fluid was adjusted to pH 7.2 with 20 mM KCl, 115 mM K-Aspartic, 1 mM MgCl2, 5 mM EGTA, 10 mM HEPES, 2 mM Na2-ATP, and KOH.

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

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

[0454] Cells seeded on coverslips were placed in the recording chamber of an inverted microscope, and negative controls and test compounds were rapidly introduced into the recording chamber from low to high concentrations using gravity perfusion to rapidly act on the cells. During recording, an external fluid was continuously circulated using a vacuum pump. The detection current in the negative control of each cell was used as the control group for the cells themselves. 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 current for each drug concentration was standardized ((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 the mean, standard deviation (SD), standard error (SE), and overlapping cases (n), were calculated for each concentration. The dose-dependent curve was fitted using the following equation to determine the median inhibitory concentration (IC) of the test compound. 50 ) was calculated: ∇ = 1 / (1 + (IC) 50 / C)^h) In the formula, C represents the concentration of the test compound, IC 50 represents the half-number 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: These are shown in Table 5.

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

[0458] [Table 5]

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

[0460] 5.5 Conclusions of the Experiment The results of the hERG inhibition tests in Table 5 above showed that most of the compounds described in the present invention have relatively weak inhibitory activity against hERG potassium channels, or essentially no effect. Among these, the hERG inhibition IC of Examples 28, 32, and 33 50 All of these concentrations were 20 μM, and their functional activity was more than 1000 times lower than that of the therapeutic target. Therefore, the series of compounds of the present invention had an extremely low potential risk of cardiotoxicity.

[0461] Test Example 6: Study on the effect of the compound of the present invention on tacrine-induced mandibular tremor behavior in rats. 6.1 Experimental Plan 6.1.1 Experimental Materials Test compound: Free bases of Examples 28, 32, and 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 Laboratory Equipment

[0466] TIFF0007870402000112.tif28145

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

[0468] 6.1.4 Administration Information Drug preparation: The test compound was taken, a solvent was added, and sonication was performed.

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

[0470] Frequency and duration of administration: Single dose.

[0471] 6.2 Experimental Method After stratifying the rats according to their body weight, they were randomly divided into a model group, a treatment group, and a control group. Three days prior to the experiment, the rats underwent adaptive training. On the day of the experiment, a solvent or drug was first injected intraperitoneally, followed 60 minutes later by intraperitoneal injection of tacrine at a dose of 5 mg / kg (body weight). After administration, the rats were placed in a transparent observation box, and mandibular tremor behavior was counted after 10 minutes. The duration of the count was 5 minutes, and the number of mandibular tremor behaviors within 5 minutes was recorded.

[0472] 6.3 Data Processing and Statistics The experimental data is, JPEG0007870402000113.jpg53

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

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

[0475] 6.5 Experimental Conclusion Examples 28, 32, and 33 free bases were subjected to a Tacrine-induced rat mandibular tremor model test, and their potential anti-Parkinsonian tremor effect was investigated using rotigotine, an antiparkinsonian drug, as the positive agent. The results are shown in Figures 1-3. Compared to 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 clearly able to inhibit mandibular tremor behavior in Tacrine-induced rats, and the minimum effective doses for Examples 28, 32, and 33 were lower than those for the positive agent. The results indicate that the series of compounds of the present invention have the effect of improving Parkinsonian tremor symptoms.

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

Claims

1. Compounds represented by general formula (I), their stereoisomers, their tautomers, or their pharmaceutically appropriate properties A permissible salt, 【Chemistry 1】 Eventually, X is an amino group, C 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups containing 1-4 heteroatoms selected from N, O, or S, C 6-10 An aryl group, a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O, or S, or C 6-10 Selected from 5-10 membered heteroaryl groups containing 1-4 heteroatoms selected from aryl N, O, or S, and optionally further substituted with one or more R atoms, R is hydrogen, deuterium, halogen, cyano group, or C 1-6 Selected from alkyl groups, Z is selected from bonding, -C(O)(CR aa R bb ), -S(O) m (CR 2 R aa ), or -C(O)(CR bb R m )(CR aa R bb ), or -C(O)(CR m N(R cc ), and M 1 and M 2 Each is independently selected from N or S. R aa and R bb These are, independently, hydrogen or deuterium, and R cc is hydrogen, deuterium, or C 1-6 Selected from alkyl groups, R 1 is hydrogen, deuterium, or C 1-6 Selected from alkyl groups, R 2 It is an amino group, n is selected from 0, 1, or 2. m is 0. Compounds, their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof.

2. One or more of the following conditions must be met: （1） 【Chemistry 2-1】 teeth, [Chemistry 2-3] And, (2) X is a C1-6 alkyl group, an amino group, C 4-6 Cycloalkyl groups, 4-6 membered heterocyclyl groups containing 1-3 heteroatoms selected from N, O, or S, C 6-10 A 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from an aryl group, N, O, or S, or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from benzo-N, O, or S, is optionally further substituted with one or more R groups. (3) R is selected from C1-3 alkyl groups, hydrogen, deuterium, fluorine, chlorine, or cyano groups. (4) Z is a bond, -C(O)-, -S(O) 2 -or -C(O)N(CH 3 ) - Selected from, (5) R 1 It is selected from hydrogen, deuterium, methyl group, ethyl group or propyl group, (6) R 2 It is an amino group, (7) n is selected from 0, 1 or 2, (8) m is 0, The compound described in feature 1, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof.

3. General formula (I) has the structure shown by general formula (II): 【Chemistry 4】 Eventually, X, Z, R 1 The definitions of n are as described in claim 1 or 2. A compound according to feature 1 or 2, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

4. General formula (I) has the structure shown by general formula (III): 【Transformation 5】 Eventually, Ring A is C 6-10 A 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from an aryl group, N, O, or S, or C 6-10 Selected from 5-10 membered heteroaryl groups containing 1-4 heteroatoms selected from aryl N, O, or S, R is hydrogen, deuterium, halogen, cyano group or C 1-6 Selected from alkyl groups, o is selected from 0, 1, 2, or 3. R 1 The definitions of n are as described in claim 3. The compound according to feature 3, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, characterized in that ring A is a C6-10 aryl group or a benzo5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S.

6. The compound according to claim 4, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that ring A is a phenyl group or a benzothienyl group.

7. The compound according to claim 4, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, characterized in that R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, a cyano group, or a C1-3 alkyl group.

8. The compound according to claim 4, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, characterized in that R is selected from hydrogen, deuterium, fluorine, chlorine, a cyano group, or a methyl group.

9. X 【Chemistry 9-1】 A compound according to claim 2, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, selected from, where o is selected from 0, 1, 2, 3, 4, or 5.

10. In the above general formula (III) 【Transformation 6】 teeth, 【Chemistry 7-1】 Selected based on this principle, Eventually, R 3 and R 4 These are, independently, halogen, cyano group, or C 1-6 It is an alkyl group. The compound according to feature 4, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof.

11. In formula (III) 【Chemistry 6-1】 teeth, 【Chemistry 6-2】 The compound according to feature 10, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 10, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt, characterized in that R3 and R4 are each independently selected from fluorine, chlorine, or bromine.

13. General formula (I) has the structure shown by general formula (IV): 【Transformation 8】 Eventually, Xa is an amino group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups containing 1-4 heteroatoms selected from N, O, or S, C 6-10 Selected from aryl groups or 5-10 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, or S, and optionally further one or more R a It is replaced by, where y is chosen from 0, 1, 2 or 3, R a is hydrogen, deuterium, halogen, cyano group or C 1-6 It is an alkyl group, n1 is 0, 1, or 2. The compound according to feature 3, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, characterized in that Xa is selected from an amino group, a C4-6 cycloalkyl group, a 4-6 membered heterocyclyl group containing 1-3 heteroatoms selected from N, O, or S, a C6-10 aryl group, or a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O, or S, and is optionally further substituted with one or more Ra.

15. Xa is based on the following basis 【Chemistry 14】 A compound according to feature 13, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from among.

16. The compound according to claim 13, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt, characterized in that Ra is selected from fluorine, chlorine, a cyano group, or a methyl group.

17. The compound according to claim 13, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt, characterized in that Ra is selected from fluorine, chlorine, bromine, a cyano group, or a C1-3 alkyl group.

18. The aforementioned Xa is, 【Chemistry 10】 Selected based on this principle, Eventually, R 5 and R 6 These are, independently, halogen, cyano group, or C 1-6 The compound according to claim 13, characterized in that it is an alkyl group, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 18, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt, characterized in that R 5 and R 6 are each independently selected from fluorine, chlorine, bromine, a cyano group, or a C1-3 alkyl group.

20. The compound according to claim 18, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt, characterized in that R 5 and R 6 are each independently selected from fluorine, chlorine, a cyano group, or a methyl group. 【Request Item 21】 【Chemistry 11-1】 【Chemistry 11-2】 Selected from the following compounds: A compound according to feature 1 or 2, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

22. A compound represented by general formula (V), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, 【Chemistry 12】 Eventually, n1 is 0, 1, or 2. Compounds, their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof.

23. A method for producing the compound described in claim 13, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, 【Chemistry 13】 The process includes the step of condensing a compound of general formula (V) with a substituted carboxylic acid or acid chloride to obtain a compound of general formula (IV), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof. Of these, n1 and Xa are as described in claim 13. A method characterized by the following:

24. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or 2, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable vector, diluent, or excipient.

25. The pharmaceutical composition according to claim 24, wherein the pharmaceutical composition is used to be involved in or modulate 5-serotonin receptors and / or dopamine receptors.

26. The pharmaceutical composition according to claim 25, wherein the pharmaceutical composition is used to be involved with or modulate 5-HT1A receptors, dopamine D2 receptors, and / or dopamine D3 receptors.

27. ​​The pharmaceutical composition according to claim 24, wherein the pharmaceutical composition is used for the treatment of a central nervous system disorder.

28. The pharmaceutical composition according to claim 27, wherein the central nervous system disorder 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 disorders related to intelligence, learning or memory, glaucoma, age-related macular degeneration, optic neuritis, ischemic disorder and retinal edema.

29. The pharmaceutical composition according to claim 27, wherein the central nervous system disorder is Parkinson's disease.

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