Azaergoline derivative as well as pharmaceutical composition and application thereof

Abstract

The invention discloses an azaergoline derivative as well as a pharmaceutical composition and application of the azaergoline derivative. The invention provides a compound as shown in a formula I, pharmaceutically acceptable salt of the compound, a solvate of the compound or the solvate of the pharmaceutically acceptable salt of the compound. The compound disclosed by the invention has good affinity and agonistic activity on a dopamine D2 receptor or a dopamine D3 receptor. # imgabs0 #

Description

[0001] This application claims the priority of Chinese patent application No. 2023109928433 filed on August 8, 2023. This application cites the entire text of the above Chinese patent application. Technical Field

[0002] The present invention relates to an azaergoline derivative, a pharmaceutical composition thereof and application thereof. Background Art

[0003] The dopaminergic signaling pathway is related to many physiological functions of human beings, such as movement, behavior, emotion, memory, etc., and has been one of the focuses of neurobiological research in recent decades. The dysfunction of the dopaminergic signaling pathway is believed to be the cause of many diseases such as Parkinson's disease and schizophrenia. The dopaminergic signaling pathway consists of the neurotransmitter dopamine, dopamine receptors, and downstream signaling molecules associated with dopamine receptors. Dopamine receptors belong to the G protein-coupled receptor (GPCR) superfamily and are one of the most important central nervous system (CNS) drug targets. There are five subtypes of dopamine receptors (D 1-5 ), among which D1 and D5 are D1 receptors, which mainly interact with G s Protein coupling, after activation, increases the intracellular cAMP level; D2, D3, and D4 are D2 receptors, which mainly bind to G i Protein coupling, after activation, reduces the intracellular cAMP level. Different dopamine receptors have different expression levels and distributions in the central nervous system and play different physiological functions (Martel and McArthur, Front Pharmacol 2020, 11: 1003).

[0004] Among the five subtypes of dopamine receptors, the D2 receptor has been studied most extensively and in depth. Clinically used drugs such as pramipexole, ropinirole, and rotigotine are mainly used to treat Parkinson's disease and restless legs syndrome. These drugs mainly exert their therapeutic effects by activating dopamine D2 receptors, but they are also active on other dopamine receptors such as D3. Antipsychotic drugs such as haloperidol and olanzapine mainly exert their therapeutic effects by antagonizing D2 receptors, while the latest generation of drugs such as aripiprazole and cariprazine are partial agonists of dopamine D2 receptors (Frankel and Schwartz, Ther Adv Psychopharmacol 2017, 7(1): 29-41).

[0005] Dopamine D2 receptors have a certain degree of structural homology with other dopamine receptors and other monoamine GPCRs such as 5-hydroxytryptamine (5-HT) receptors. This homology results in the lack of target selectivity of most drugs. Most of the antipsychotic drugs targeting dopamine D2 receptors have no selectivity for 5-HT receptors such as 5-HT 2A receptors, all have a certain degree of affinity, and some drugs have a certain affinity for 5-HT 2A The affinity of D2 receptors is even stronger than that of 5-HT receptors. 2A The dual role of 5-HT receptors is a common feature of these drugs. In 2018, the US FDA approved the drug Pimavanserin, which is a 5-HT 2A Lumateperone, a selective inverse agonist for 5-HT receptors, was approved by the US FDA in 2019. 2A The affinity of the receptor is also about 60 times higher than that of the D2 receptor (Blair, Drugs, 2020, 80(4), 417-423). However, drugs with high selectivity for the D2 receptor are rarely reported in the literature (Fan and Tan et al., Nat Comm, 2020, 11, 1074).

[0006] Krogsgaard-Larsen et al. reported a compound A with an aza-ergoline skeleton, whose derivative A1 has binding activity to 5-HT6 receptors, derivative A2 has agonist activity to dopamine D2 receptors, and A3 has partial agonist activity to dopamine D2 receptors (Krogsgaard-Larsen et al., J. Med. Chem. 2014, 57, 5823-5828; WO2011088836; WO2011088838). The target selectivity, in vivo activity in animals and other drug properties of these compounds have not been reported.

[0007]

[0008] CN114835709A discloses a series of azaergoline derivatives having the following structural formula I-10:

[0009]

[0010] In CN114835709A, compounds such as I-10 have good affinity, agonist activity or selectivity for dopamine D2 receptors, and the development of compounds with higher activity remains a goal that researchers continue to pursue. Summary of the invention

[0011] The technical problem to be solved by the present invention is that there are few existing compounds with affinity and agonist activity for dopamine D2 receptors. To this end, the present invention provides an azaergoline derivative, a pharmaceutical composition thereof and an application thereof. The compound of the present invention has good affinity and agonist activity for dopamine D2 receptors or D3 receptors.

[0012] The present invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:

[0013]

[0014] in,

[0015] R 1 is hydrogen or C 1-6 alkyl;

[0016] R 2 is hydrogen or C 1-6 alkyl;

[0017] R 3 and R 4 The following conditions (1) or (2) are met:

[0018] Case (1): R 3 is hydrogen; R 4 is hydrogen or C 1-6 alkyl;

[0019] Case (2): R 3 C 2-6 Alkyl; R 4 is hydrogen or C 1-6 alkyl.

[0020] In a preferred technical scheme, in the compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, the definitions of certain groups may be as described below, and the definitions of the remaining groups are as described in any scheme of the present invention, hereinafter referred to as "in a preferred technical scheme".

[0021] In a preferred technical solution, the compound shown in Formula I is a compound shown in Formula Ia:

[0022]

[0023] In a preferred technical solution, the compound as shown in Formula I is a compound as shown in Formula Ib or Ib', preferably a compound as shown in Formula Ib;

[0024]

[0025] In a preferred technical solution, the compound shown in Formula I is a compound shown in Formula Ic or Ic', preferably a compound shown in Formula Ic;

[0026]

[0027] In a preferred technical solution, R 1 In the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0028] In a preferred technical solution, R 2 In the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0029] In a preferred technical solution, in situations (1) and (2), the R 4 C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl or ethyl.

[0030] In a preferred technical solution, in situation (2), the R 3 C 2-6 Alkyl is ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example ethyl.

[0031] In a preferred technical solution, R 1 For hydrogen.

[0032] In a preferred technical solution, R 2 For hydrogen.

[0033] In a preferred technical solution, in case (1), R 4 is hydrogen, methyl or ethyl.

[0034] In a preferred technical solution, in case (1), R 3 is hydrogen, R 4 is hydrogen, methyl or ethyl.

[0035] In a preferred technical solution, in situation (2), R 3 It is ethyl.

[0036] In a preferred technical solution, in situation (2), R 4 is hydrogen, methyl or ethyl.

[0037] In a preferred technical solution, in situation (2), R 3is ethyl; R 4 is hydrogen, methyl or ethyl.

[0038] In a preferred technical solution, R 3 is hydrogen; R 4 is hydrogen or C 1-6 Alkyl; for example, R 3 is hydrogen; R 4 C 1-6 alkyl.

[0039] In a preferred technical solution, R 1 is hydrogen; R 2 is hydrogen; R 3 is hydrogen; R 4 is hydrogen, methyl or ethyl.

[0040] In a preferred technical solution, the compound shown in Formula I is a compound shown in Formula Ia:

[0041]

[0042] R 1 is hydrogen; R 2 is hydrogen; R 3 is hydrogen; R 4 is hydrogen, methyl or ethyl.

[0043] In a preferred technical solution, R 3 C 2-6 Alkyl; R 4 is hydrogen or C 1-6 alkyl.

[0044] In a preferred technical solution, R 1 is hydrogen; R 2 is hydrogen; R 3 is ethyl; R 4 is hydrogen, methyl or ethyl.

[0045] In a preferred technical solution, the compound shown in Formula I is a compound shown in Formula Ia:

[0046]

[0047] R 1 is hydrogen; R 2 is hydrogen; R 3 is ethyl; R 4 is hydrogen, methyl or ethyl.

[0048] In a preferred technical solution, the compound as shown in formula I is any of the following compounds:

[0049]

[0050] In a preferred technical solution, the compound shown in Formula 1 is Preferably, the for

[0051] In a preferred technical solution, the The compound with the earlier retention time under the following conditions;

[0052] The conditions are: the filler is a chromatographic column with amylose-tris(3-chloro-5-methylcarbamate) bonded to the surface of silica gel or cellulose-tris(3,5-dichlorophenylcarbamate) bonded to the surface of silica gel; the mobile phase includes an alcohol solvent (such as methanol) and a nitrile solvent (such as acetonitrile); or the mobile phase includes an alkane solvent (such as cyclohexane) and an alcohol solvent (such as methanol);

[0053] Preferably; The compound with a retention time of 3.044 min under the following conditions;

[0054] The conditions are as follows: chromatographic column: CHIRALPAKIG, 2.5cm*25cm*10μm; mobile phase: methanol / acetonitrile / diethylamine=80 / 20 / 0.1, the ratio is volume ratio; flow rate: 1.0mL / min; detection wavelength: UV210nm; column temperature: 25°C; HPLC instrument: ShimadzuLC-2010B;

[0055] or, It is a compound with a retention time of 8.46 min under the following conditions;

[0056] The conditions are: chromatographic column CHIRALPAK IC, 0.46cm*25cm*5μm; mobile phase: n-hexane / ethanol / diethanolamine=40 / 60 / 0.1, the ratio is volume ratio; flow rate: 1.0mL / min; wavelength: UV230nm; column temperature: 25°C; HPLC instrument: Agilent1260.

[0057] In a preferred technical solution, the A compound having a negative optical rotation value; preferably, a compound having an optical rotation value of -60.20° under the following test conditions;

[0058] The test conditions are as follows: measuring temperature: 20° C.; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: methanol; instrument: automatic polarimeter Rudolph V Plus.

[0059] In a preferred technical solution, the compound shown in Formula 2 is Preferably, the for

[0060] In a preferred technical solution, The compound with the earlier retention time under the following conditions;

[0061] The conditions are: the filler is a chromatographic column with amylose-tris(3-chloro-5-methylcarbamate) bonded to the surface of silica gel or cellulose-tris(3,5-dichlorophenylcarbamate) bonded to the surface of silica gel; the mobile phase includes an alcohol solvent (such as methanol) and a nitrile solvent (such as acetonitrile); or the mobile phase includes an alkane solvent (such as cyclohexane) and an alcohol solvent (such as methanol);

[0062] Preferably, the The compound with a retention time of 17.43 min under the following conditions is:

[0063] The conditions are: chromatographic column CHIRALPAK IC, 0.46cm*25cm*5μm; mobile phase: n-hexane / ethanol / diethanolamine=40 / 60 / 0.1, the ratio is volume ratio; flow rate: 1.0mL / min; wavelength: UV230nm; column temperature: 25°C; HPLC instrument: Agilent1260.

[0064] In a preferred technical solution, A compound having a negative optical rotation value; preferably, a compound having an optical rotation value of -60.00° under the following test conditions;

[0065] The test conditions are as follows: measuring temperature: 20° C.; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: methanol; instrument: automatic polarimeter Rudolph V Plus.

[0066] In a preferred technical solution, the compound shown in Formula 3 is Preferably, the for

[0067] In a preferred technical solution, the The compound having the earlier retention time under the following conditions: the chromatographic column is a chromatographic column whose filler is a silica gel surface bonded with amylose-tris(3-chloro-5-methylcarbamate) or a silica gel surface bonded with cellulose-tris(3,5-dichlorophenylcarbamate); the mobile phase includes an alcohol solvent (such as methanol) and a nitrile solvent (such as acetonitrile); or the mobile phase includes an alkane solvent (such as cyclohexane) and an alcohol solvent (such as methanol);

[0068] Preferably, the The compound with a retention time of 8.06 min under the following conditions is:

[0069] The conditions are: chromatographic column CHIRALPAK IC, 0.46cm*25cm*5μm; mobile phase: n-hexane / ethanol / diethanolamine=40 / 60 / 0.1, the ratio is volume ratio; flow rate: 1.0mL / min; wavelength: UV230nm; column temperature: 25°C; HPLC instrument: Agilent1260.

[0070] In a preferred technical solution, the A compound having a negative optical rotation value; preferably, a compound having an optical rotation value of -52.43° under the following test conditions;

[0071] The test conditions are as follows: measuring temperature: 20° C.; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: methanol; instrument: automatic polarimeter Rudolph V Plus.

[0072] In a preferred technical solution, the compound shown in Formula 4 is Preferably, the for

[0073] In a preferred technical solution, the The compound with the earlier retention time under the following conditions;

[0074] The conditions are: the filler is a chromatographic column with amylose-tris(3-chloro-5-methylcarbamate) bonded to the surface of silica gel or cellulose-tris(3,5-dichlorophenylcarbamate) bonded to the surface of silica gel; the mobile phase includes an alcohol solvent (such as methanol) and a nitrile solvent (such as acetonitrile); or the mobile phase includes an alkane solvent (such as cyclohexane) and an alcohol solvent (such as methanol);

[0075] Preferably, the The compound with a retention time of 7.08 min under the following conditions is:

[0076] The conditions are: chromatographic column CHIRALPAK IC, 0.46cm*25cm*5μm; mobile phase: n-hexane / ethanol / diethanolamine=40 / 60 / 0.1, the ratio is volume ratio; flow rate: 1.0mL / min; wavelength: UV230nm; column temperature: 25°C; HPLC instrument: Agilent1260.

[0077] In a preferred technical solution, the A compound having a negative optical rotation value; preferably, a compound having an optical rotation value of -60.40° under the following test conditions;

[0078] The test conditions are as follows: measuring temperature: 20° C.; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: MeOH; instrument: automatic polarimeter Rudolph V Plus.

[0079] In a preferred technical solution, the compound shown in Formula 5 is Preferably, the for

[0080] In a preferred technical solution, the The compound with the earlier retention time under the following conditions;

[0081] The conditions are: the filler is a chromatographic column with amylose-tris(3-chloro-5-methylcarbamate) bonded to the surface of silica gel or cellulose-tris(3,5-dichlorophenylcarbamate) bonded to the surface of silica gel; the mobile phase includes an alcohol solvent (such as methanol) and a nitrile solvent (such as acetonitrile); or the mobile phase includes an alkane solvent (such as cyclohexane) and an alcohol solvent (such as methanol);

[0082] Preferably, the The compound with a retention time of 8.70 min under the following conditions is:

[0083] The conditions are: chromatographic column CHIRALPAK IC, 0.46cm*25cm*5μm; mobile phase: n-hexane / ethanol / diethanolamine=40 / 60 / 0.1, the ratio is volume ratio; flow rate: 1.0mL / min; wavelength: UV230nm; column temperature: 25°C; HPLC instrument: Agilent1260.

[0084] In a preferred technical solution, the A compound having a negative optical rotation value; preferably, a compound having an optical rotation value of -57.43° under the following test conditions;

[0085] The test conditions are as follows: measuring temperature: 20° C.; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: MeOH; instrument: automatic polarimeter Rudolph V Plus.

[0086] The present invention also provides a pharmaceutical composition, comprising substance A and pharmaceutical excipients, wherein substance A is a compound as shown in Formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0087] The present invention provides a method for preparing a compound as shown in Formula I, which is the following method 1 or method 2:

[0088] Method 1 comprises the following steps: in a solvent, in the presence of a base, reacting a compound represented by formula I-S1 and a compound represented by formula I-S2 as shown in the following formula to obtain the compound represented by formula I;

[0089]

[0090] R 1 , R 2 , R 3 and R 4 is as defined in any one of the present invention; and R 3 and R 4 Not at the same time H;

[0091] Method 2 comprises the following steps: in a solvent, in the presence of a base and an amide condensation reagent, reacting a compound represented by formula I-S1 and a compound represented by formula I-S2' as shown in the following formula to obtain the compound represented by formula I;

[0092]

[0093] R 1 , R 2 , R 3 and R 4 The definition of is as described in any one of the present invention.

[0094] In method 1, the operation and conditions of the reaction are conventional operations and conditions for such reactions in the art. In a preferred technical scheme, the solvent may be N,N-dimethylformamide; the base may be triethylamine; the molar ratio of the base to the compound represented by formula I-S1 may be 5:1, and the molar ratio of the compound represented by formula I-S2 to the compound represented by formula I-S1 may be 3:1; the reaction temperature may be room temperature, and the compound represented by formula I may be compound 1.

[0095] In method 2, the operation and conditions of the reaction are conventional operations and conditions for such reactions in the art. In a preferred technical scheme, the solvent may be N,N-dimethylformamide; the base may be triethylamine; the molar ratio of the base to the compound represented by formula I-S1 may be 5:1, the amide condensation reagent may be N,N-carbonyldiimidazole (CDI), the molar ratio of the amide condensation reagent to the compound represented by formula I-S1 may be 2:1, and the molar ratio of the compound represented by formula I-S2' to the compound represented by formula I-S1 may be 2:1; the reaction temperature may be room temperature, and the compound represented by formula I may be compound 2, 3, 4 or 5.

[0096] In a preferred technical solution, the method for preparing the compound of formula I also includes a method for preparing the compound of formula I-S1, which comprises the following steps: in a solvent, in the presence of a deprotection agent, the compound of formula I-S1-1 is subjected to a deprotection reaction as shown in the following formula to obtain the compound of formula I-S1,

[0097]

[0098] Among them, R t is an amino protecting group, for example, tert-butyloxycarbonyl (-Boc).

[0099] The operation and conditions of the deprotection reaction are conventional operations and conditions for such reactions in the art. In a preferred technical scheme, the solvent may be methanol; the deprotection reagent may be hydrogen chloride; the molar ratio of the hydrogen chloride to the compound represented by the formula I-S1-1 may be 14:1; the reaction temperature may be the reflux temperature of the solvent; preferably, the hydrogen chloride and methanol participate in the deprotection reaction in the form of a hydrogen chloride methanol solution (for example, the molar concentration of hydrogen chloride is 4 mol / L).

[0100] In a preferred technical solution, the method for preparing the compound of formula I-S1 also includes a method for preparing the compound of formula I-S1-1, which comprises the following steps: in a solvent, in the presence of a base, reacting the compound of formula IA and the compound of formula IC as shown in the following formula to obtain the compound of formula I-S1-1,

[0101]

[0102] Among them, R t is an amino protecting group, such as tert-butyloxycarbonyl (-Boc); R s is a hydroxy-protecting group, for example, p-toluenesulfonyl (-Ts).

[0103] The operation and conditions of the reaction are conventional operations and conditions for such reactions in the art. In a preferred technical scheme, the solvent may be a mixed solvent of tetrahydrofuran and dimethyl sulfoxide, for example, the volume ratio of tetrahydrofuran to dimethyl sulfoxide is 4:1; the base may be potassium carbonate; the molar ratio of the base to the compound represented by formula IA may be 4:1, and the molar ratio of the compound represented by formula IC to the compound represented by formula IA may be 2:1; the reaction temperature may be 60°C.

[0104] The present invention provides a compound (an intermediate for preparing a compound represented by formula I), wherein the compound is any of the following compounds:

[0105]

[0106]

[0107] The present invention also provides a use of the substance A or the pharmaceutical composition in the preparation of a dopamine D2 receptor agonist or a D3 receptor agonist.

[0108] In a preferred technical solution, the dopamine D2 receptor is a dopamine D2L receptor and / or a dopamine D2S receptor, such as a dopamine D2L receptor.

[0109] The present invention also provides a use of the substance A or the pharmaceutical composition in preparing a drug for treating and / or preventing diseases associated with dopamine D2 receptors or D3 receptors.

[0110] The dopamine D2 receptor-related disease can be selected from one or more of neurodegenerative diseases, mental disorders and metabolic diseases related to mental disorders, such as Parkinson's disease, Alzheimer's disease, dementia, schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma or drug addiction.

[0111] The present invention also provides a use of the above-mentioned substance A or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing a disease; the disease can be selected from one or more of neurodegenerative diseases, mental disorders and metabolic diseases related to mental disorders.

[0112] In the application, the disease is preferably Parkinson's disease, Alzheimer's disease, dementia, schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma or drug addiction.

[0113] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0114] The terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" may exist in the form of a single stereoisomer or a mixture thereof (e.g., a racemate) if stereoisomers exist. The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be obtained by chiral separation by introduction of raw materials or separation, purification and enrichment by chiral separation. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.

[0115] The term "cis-trans isomers" in the present invention is caused by the fact that the single bonds of the carbon atoms of cyclohexane cannot rotate freely. It is the trans isomer.

[0116] The term "alkyl" refers to a group having a specified number of carbon atoms (e.g., C 1-6 or C 2-6 ) is a straight or branched chain alkyl group. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, etc.

[0117] When any variable appears multiple times in the definition of a compound, their definitions are independent of each other and do not affect each other.

[0118] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002).

[0119] The term "solvate" refers to a substance formed after crystallization of a compound with a solvent. Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

[0120] The term "solvate of a pharmaceutically acceptable salt" refers to a substance formed by combining a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base and a solvent, wherein the pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent is stoichiometric or non-stoichiometric. Pharmaceutically acceptable salt solvates include, but are not limited to, hydrochloride monohydrate.

[0121] The term "pharmaceutical excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0122] The term "treat" refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that initiates a disease; or (3) slowing the progression of one or more biological manifestations of a disease.

[0123] The term "prevention" refers to reducing the risk of developing a disease.

[0124] The term "patient" refers to any animal that has been or is about to be treated, preferably a mammal, most preferably a human. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0125] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0126] The reagents and raw materials used in the present invention are commercially available.

[0127] The positive and progressive effect of the present invention is that the compounds of the present invention have good affinity and agonistic activity to dopamine D2 receptors or D3 receptors. BRIEF DESCRIPTION OF THE DRAWINGS

[0128] Figure 1 This is the three-dimensional structural ellipsoid diagram of compound SA.

[0129] Figure 2 This is the three-dimensional structural ellipsoid diagram of compound RA. DETAILED DESCRIPTION

[0130] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0131] Preparation Example 1: Chiral separation of compound A

[0132]

[0133] Chiral analysis conditions: chiral column Daicel Chiralpak IG-3, column volume: 0.46 cm (diameter) x 10 cm (column length) (3 μm particle size filler); mobile phase: A is supercritical fluid CO2, B is MeOH (containing 0.1% isopropylamine); gradient: elution at a volume percentage of mobile phase B of 10% for 0.2 min, then within 2.2 min, the volume percentage of mobile phase B is increased from 10% to 50%, and the volume percentage of mobile phase B is continued to elute for 1 min, and finally within 0.6 min, the volume percentage of mobile phase B is reduced from to 10%; flow rate: 3.4 ml / min; wavelength: UV210 nm; temperature: 35°C; pressure 2000 psi; HPLC instrument: Waters Acquity UPC 2 ]peakl(front peak)t R =2.55min; peak2 (latter peak): t R =2.83min.

[0134] Chiral preparation conditions: chiral column Daicel Chiralpak IG, column volume: 5 cm (diameter) x 25 cm (column length) (10 μm particle size filler); mobile phase: A is supercritical fluid CO2, B is MeOH (containing 0.1% NH3H2O); gradient: B% = 50% isogradient elution; flow rate: 200 g / min; wavelength: UV210 nm; temperature: 40°C; pressure 100 bar; HPLC instrument: Waters SFC350preparative SFC]. peakl (front peak) t R =2.55min; peak2 (latter peak): t R =2.83min.

[0135] Sample preparation: Compound A was dissolved in tetrahydrofuran and methanol (3:1, V / V) to form a solution, and SFC separation was performed. After separation, the liquid was vacuum-rotated and evaporated to dryness at 35°C to obtain a sample. Racemic compound A (40 g), SA is the front peak (peak 1), )t R =2.55 min, yield 15 g, >98% ee. 1 H NMR (400 MHz, deuterated DMSO) δ 10.48 (s, 1H), 6.89 (t, J = 8.0 Hz, 1H), 6.80 (t, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.17 (t, J = 8.0 Hz, 1H), 3.70 (d, J = 12 Hz, 1H), 3.01 (m, 2H), 2.90 (m, 3H), 2.57–2.51 (m, 3H).

[0136] RA is the latter peak (peak2), tR =2.83 min, yield 14 g, >98% ee. 1 H NMR (400 MHz, deuterated DMSO) δ 10.49 (s, 1H), 6.88 (t, J = 8.0 Hz, 1H), 6.78 (t, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.18 (t, J = 8.0 Hz, 1H), 3.64 (d, J = 12 Hz, 1H), 3.01 (m, 2H), 2.89 (m, 3H), 2.57–2.50 (m, 3H).

[0137] Confirmation of SA chiral configuration:

[0138] Single crystal preparation of the compound represented by formula SA

[0139] Cultivate single crystals by evaporation method: weigh 10 mg of compound SA product in 10 mL of dichloromethane, then add 1 mL of methanol. Place the test tube at room temperature to slowly evaporate and crystallize.

[0140] Detection method: X-ray single crystal diffraction

[0141] Instrument information:

[0142] instrument model brand Single Crystal X-ray Diffractometer SMART APEX-II Bruker

[0143] Test conditions: CuKα radiation, φ / ω scanning

[0144] After testing, the direct method (Shelxs97) was used to analyze the crystal structure. The crystal belongs to the orthorhombic system, the space group is P212121, and the unit cell parameters are: α=β=γ=90.00°; unit cell volume The number of asymmetric units in the unit cell is Z = 4. The least square method is used to correct the structural parameters and determine the atomic types, and the geometric calculation method is used to obtain the position of hydrogen atoms. The final reliability factor R1 = 0.0393, wR2 = 0.1105, S = 1.103. The chemical formula of the asymmetric unit is finally determined to be C13H15N3, the calculated molecular weight is 213.28, and the calculated crystal density is 1.305g / cm3.

[0145] The results show that the molecular arrangement in the crystalline state belongs to the first type of space group, the sample should be optically active, and the Flack coefficient is 0.1(5), which can determine the absolute configuration of the compound in the crystal. Figure 1 In the crystalline state, the molecules are stabilized in space by van der Waals forces and hydrogen bonds.

[0146] Confirmation of RA chiral configuration:

[0147] Single crystal preparation of the compound represented by formula RA

[0148] Cultivate single crystals by evaporation method: weigh 10 mg of compound RA product in 10 mL of dichloromethane, then add 1 mL of methanol. Place the test tube at room temperature to slowly evaporate and crystallize.

[0149] Detection method: X-ray single crystal diffraction

[0150] Instrument information:

[0151] instrument model Production Unit Single Crystal X-ray Diffractometer Bruker D8 Venture Bruker

[0152] Test conditions: CuKα radiation, φ / ω scanning

[0153] The crystal structure was analyzed by direct method (Shelxs97). The crystal belongs to orthorhombic system, the space group is P212121, and the unit cell parameters are: α=β=γ=90.00°; unit cell volume The number of asymmetric units in the unit cell is Z = 4. The least square method is used to correct the structural parameters and determine the atomic types, and the geometric calculation method is used to obtain the position of hydrogen atoms. The final reliability factor R1 = 0.0409, wR2 = 0.1140, S = 1.063. The chemical formula of the asymmetric unit is finally determined to be C13H15N3, the calculated molecular weight is 213.28, and the calculated crystal density is 1.329g / cm3.

[0154] The results show that the molecular arrangement in the crystalline state belongs to the first type of space group, the sample should be optically active, and the Flack coefficient is -0.1(5), which can determine the absolute configuration of the compound in the crystal. Figure 2 In the crystalline state, the molecules are stabilized in space by van der Waals forces and hydrogen bonds.

[0155] Example 1: Preparation of Compound 1-2

[0156] Method 1: The synthetic route of compound 1-2 is as follows:

[0157]

[0158] Step 1: Add trans-2-(4-aminocyclohexyl)ethyl acetate hydrochloride C3 (2.00 g, 9.0 mmol), solvent dichloromethane (20 ml) and triethylamine (3.10 g, 30.6 mmol) to the reaction flask, then add methylcarbamoyl chloride (1.26 g, 13.5 mmol) at 0-5°C, protect with nitrogen, and stir at room temperature for 8 hours. After the reaction is completed, the reaction solution is washed with water (20 ml) and saturated brine (20 ml) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness and slurried with methyl tert-butyl ether (15 ml) to obtain the target compound D1 (1.69 g, yield 77.5%) as a white solid.

[0159] 1 H NMR (400 MHz, deuterated chloroform) δ 4.09 (q, 2H), 3.56 (m, 1H), 2.70 (s, 3H), 2.28 (d, 2H), 2.15 (m, 2H), 1.77 (m, 3H), 1.26 (t, 3H), 1.15-1.08 (m, 4H).

[0160] 13 C NMR (400 MHz, deuterated chloroform) δ 173.97, 157.92, 61.17, 53.48, 40.50, 33.17, 29.72, 14.20.

[0161] Step 2: Add D1 (0.50 g, 2.06 mmol) and solvent tetrahydrofuran (5 ml) to the reaction flask, start stirring, then add sodium borohydride (0.63 g, 16.5 mmol), heat to reflux, and stir for 1 hour. Then cool to room temperature, slowly drop methanol (1 ml), and reflux for 16 hours. After the reaction is completed, add water (1 ml) to quench the reaction, then add 0.5 ml hydrochloric acid and stir for 1 hour. Filter by suction, wash the filter cake with 4 ml dichloromethane, separate the filtrate, extract the aqueous layer twice with 2 ml dichloromethane, dry it with anhydrous sodium sulfate, and evaporate to dryness to obtain the target product D2 (0.364 g, yield 88.1%), a white solid.

[0162] 1 H NMR (400 MHz, deuterated chloroform) δ 3.54 (t, 2H), 3.49 (m, 1H), 2.70 (s, 3H), 2.07-1.98 (m, 2H), 1.82-1.70 (m, 2H), 1.62 (m, 1H), 1.50-1.45 (q, 1H), 1.42-1.31 (m, 1H), 1.14-1.03 (m, 4H).

[0163] 13 C NMR (400 MHz, deuterated chloroform) δ 157.77, 60.66, 50.84, 39.72, 33.99, 33.54, 31.98, 27.11.

[0164] Step 3: D2 (0.35 g, 1.75 mmol), solvent dichloromethane (3.5 ml) and triethylamine (0.53 g, 5.24 mmol) were added to the reaction flask. After cooling to 0-5°C, p-toluenesulfonyl chloride (0.48 g, 1.75 mmol) was added and stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was washed with water (3.5 ml), dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, slurried with methyl tert-butyl ether (3.5 ml) for 12 h, filtered and dried in vacuo to obtain the target product D3 (0.52 g, 83.5%) as a white solid.

[0165] 1 H NMR (400 MHz, deuterated chloroform) δ 7.78 (d, J = 12 Hz, 2H), 7.38 (d, J = 12 Hz, 2H), 4.04 (t, 2H), 2.69 (s, 3H), 3.53 (t, 1H) 2.45 (s, 3H), 1.96 (d, 2H), 1.67 (d, 2H), 1.54 (q, 2H), 1.38-1.30 (m, 1H), 1.09-0.91 (m, 4H).

[0166] 13 C NMR (400 MHz, deuterated chloroform) δ 157.75, 147.73, 133.16, 130.82, 127.88, 70.10, 50.68, 35.49, 33.13, 32.93, 30.42, 27.13, 21.63.

[0167] Step 4: Add intermediate A (100 mg, 0.47 mmol), intermediate D3 (220 mg, 0.61 mmol) and K2CO3 (0.19 g, 1.41 mmol) to the reaction flask in sequence, and then add solvent THF (6 mL) and DMSO (2 ml). The reaction system was heated and stirred at 60 ° C for 16 hours. After the reaction, the solvent was removed and purified by rapid silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to obtain compound 1-1 (170 mg, 92%) as an off-white solid.

[0168] Step 5: Preparation of compound 1-2

[0169] Chiral preparation conditions: chiral column CHIRALPAKIG (Dacel), column volume: 2.5 cm (diameter) x 25 cm (column length) (10 μm particle size filler); mobile phase: methanol / acetonitrile / diethylamine = 80 / 20 / 0.1 (V / V / V); flow rate: 1.0 mL / min; wavelength: UV210 nm; column temperature: 25°C; HPLC instrument: Shimadzu LC-2010B.

[0170] peak1 (front peak) t=3.044 min is compound 1-2; obtained is 72 mg, >98% ee.

[0171] Chiral analysis and optical rotation determination: chiral column CHIRALPAK IC (Dacel), column volume: 0.46 cm (diameter) * 25 cm (column length) (5 μm particle size filler); mobile phase: n-hexane (Hexane) / EtOH / diethanolamine (DEA) = 40 / 60 / 0.1 (V / V / V); flow rate: 1.0 mL / min; wavelength: UV230 nm; column temperature: 25°C; HPLC instrument: Agilent 1260.

[0172] The main peak (front) t = 8.46min is compound 1-2, optical rotation value [a] 0 25 =-60.20°; instrument: automatic polarimeter Rudolph V Plus; measurement temperature: 20°C; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: methanol (MeOH).

[0173] 1 H NMR (400 MHz, deuterated chloroform) δ7.91 (s, 1H), 7.29 (s, 1H), 7.10 (t, 1H), 6.82 (d, J = 12 Hz, 1H), 6.74 (s, 1H), 6.35 (d, J = 12 Hz, 1H), 4.24 (d, J = 6 Hz, 1H), 4.14 (d, J = 12 Hz, 1H), 3.82 (d, J = 18 Hz, 1H), 3.52-3.4 5(m,1H),3.24-3.19(m,1H),3.09(t,2H),3.02-2.91(m,2H),2.79(m,3H),2.44(m,2H),2.36-2 .30(m,1H),2.12-2.02(m,3H),1.82(m,2H),1.52-1.46(m,2H),1.28(s,1H),1.16-1.05(m,4H).

[0174] 13 C NMR (400 MHz, deuterated chloroform) δ 158.18, 142.23, 134.33, 124.05, 118.06, 114.91, 109.44, 101.93, 60.21, 56.61, 56.16, 53.10, 49.69, 46.25, 35.56, 33.91, 33.82, 32.03, 27.63, 27.26.

[0175] C 24 H 29 D6N5O+ [M+H]+, calculated: 395.5510, found: 395.6168.

[0176] Method 2: Preparation of Compound 1-2A or 1-2B

[0177] The synthetic route of compound 1-2A is as follows:

[0178]

[0179] Step 1: Add intermediate SA (10 g, 46.89 mmol), intermediate C8 (37.30 g, 93.77 mmol) and K2CO3 (25.88 g, 187.5 mmol) to the reaction flask in sequence, and then add solvent THF (80 mL) and DMSO (20 ml). Heat and stir the reaction system at 60°C for 16 hours. After the reaction, the solvent was removed and the product was purified by flash silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to obtain compound M1 (12.3 g, 60%) as a gray foamy solid with >98% ee (chiral column: Daicel Chiralpak IC, column volume: 0.46 cm (diameter) x 25 cm (column length) (5 μm particle size filler); mobile phase: hexane: ethanol: diethylamine = 50:50:0.1; running time: 15 minutes; flow rate: 1 ml / min; detection wavelength: UV 230 nm; column temperature: 25°C; injection volume: 10 μL).

[0180] Optical rotation value [a] 0 25 =-49.80° (c=0.1, methanol); (Instrument: automatic polarimeter Rudolph V Plus

[0181] Measurement temperature: 25°C, sample concentration: 1 mg / ml, selected wavelength: 589 nm, dilution solvent: MeOH).

[0182] 1 H NMR (400MHz, DMSO) δ10.50(s,1H),6.89(t,J=8Hz,1H),6.79(s,1H),6.70(d,J=8Hz,1H),6.20(d,J=8Hz,1H),3.70(d,1H),3.14 -2.91(m,5H),2.71-2.65(m,2H),2.36-2.32(m,2H),2.18-2.09(m,1H),1.96-1.91(m,1 H),1.77-1.72(m,4H),1.93(t,1H),1.38(s,12H),1.25-1.14(m,2H),1.00–0.92(m,3H).

[0183] Step 2: Add M1 (10 g, 22.83 mmol) and 4 mol / L methanolic hydrogen chloride solution (80 ml) to the reaction flask, start stirring, heat to reflux, and stir for 5 hours. Then cool to room temperature and filter. The filter cake is freed with aqueous sodium carbonate solution. Filter, wash the filter cake with 40 ml of water, and dry it in vacuo at 50 ° C to obtain the target product M2 (6.80 g, yield 88.1%), gray-green solid, >98% ee (chiral column Daicel Chiralpak IC, column volume: 0.46 cm (diameter) x 25 cm (column length) (5 μm particle size filler); mobile phase: hexane: ethanol: diethylamine = 40:60:0.1; running time: 20 minutes; flow rate: 1 ml / min; detection wavelength: UV230nm; column temperature: 25 ° C; injection volume: 5 microliters).

[0184] Optical rotation value [a] 0 25 =-67.00° (c=0.1, methanol).

[0185] 1 H NMR (400MHz, DMSO) δ10.50(s,1H),6.87(t,1H),6.78(s,1H),6.69(d,1H),6.18(d,1H),3.69(d,1H),3.10–2.88(m,8 H),2.71–2.60(m,2H),2.38–2.29(m,2H),2.13(td,1H),1.93(t,1H),1.73(dd,4H),1.37(dd,2H),1.05–0.88(m,4H).

[0186] 13 C NMR (101MHz, DMSO) δ142.45,134.45,123.39,118.30,115.95,108.13,102.46,98. 39,60.15,56.54,56.30,53.04,50.83,46.40,36.03,35.44,34.00,32.12,27.58.

[0187] Step 3: Add M2 (1.0 g, 2.96 mmol), solvent DMF (10 ml), and then triethylamine (1.50 g, 14.80 mmol) to the reaction flask, cool to 0-5 ° C, add N-methylformyl chloride (0.83 g, 8.88 mmol), stir at room temperature for 12 hours, after the reaction is completed, add water (50 ml) to the reaction solution for crystallization, and purify by rapid silica gel column chromatography (eluent is 0-10% methanol / dichloromethane) to obtain compound 1-2A (0.818 g, 70%), gray solid powder, >98% ee (chiral HPLC method is the same as M2). Optical rotation value [a] 0 25 =-60.20° (c=0.1, methanol).

[0188] After testing, under the chiral analysis conditions in method 1, the retention time of compound 1-2 in method 1 is consistent with the retention time of compound 1-2A prepared in method 2; and the optical rotation values ​​of the compound with a retention time of t=8.46min in method 1 and compound 1-2A prepared in method 2 are 1 H NMR, 13 The C NMR data were consistent, and the compound with a retention time of t = 8.46 min in method 1 was determined to be 1-2A.

[0189] The synthetic route of compound 1-2B is as follows:

[0190]

[0191] Following the method for compound 1-2A, the starting material was replaced with RA, which was reacted with c8 to obtain R-M1, and then R-M2 was obtained by removing the Boc protecting group, and then reacted with N-methylformyl chloride to obtain compound 1-2B, an off-white solid, >98% ee (same HPLC analysis method as 1-2).

[0192] Optical rotation value [a] 0 25 =+58.90° (c=0.1, methanol).

[0193] 1H NMR (400 MHz, deuterated chloroform) δ7.93 (s, 1H), 7.29 (s, 1H), 7.12 (t, 1H), 6.82 (d, J = 12 Hz, 1H), 6.74 (s, 1H), 6.34 (d, J = 12 Hz, 1H), 4.25 (d, J = 6 Hz, 1H), 4.14 (d, J = 12 Hz, 1H), 3.82 (d, J = 18 Hz, 1H), 3.52-3.4 5(m,1H),3.23-3.21(m,1H),3.09(t,2H),3.02-2.91(m,2H),2.79(m,3H),2.45(m,2H),2.36-2 .30(m,1H),2.12-2.02(m,3H),1.82(m,2H),1.52-1.46(m,2H),1.28(s,1H),1.16-1.04(m,4H).

[0194] 13 C NMR (400 MHz, deuterated chloroform) δ 158.18, 142.25, 134.33, 124.05, 118.06, 114.93, 109.45, 101.93, 60.21, 56.61, 56.16, 53.10, 49.69, 46.25, 35.56, 33.91, 33.82, 32.03, 27.63, 27.26.

[0195] C24H29D6N5O+[M+H]+, calculated: 395.5510, found: 395.6165.

[0196] Example 2

[0197] Method 1: Preparation of compound 2-2

[0198]

[0199] The preparation method is as in Example 1.

[0200] Chiral analysis and optical rotation determination: chiral column CHIRALPAK IC (Dacel), column volume: 0.46 cm (diameter) * 25 cm (column length) (5 μm particle size filler); mobile phase: n-hexane (Hexane) / EtOH / diethanolamine (DEA) = 40 / 60 / 0.1 (V / V / V); flow rate: 1.0 mL / min; wavelength: UV230 nm; column temperature: 25°C; HPLC instrument: Agilent 1260.

[0201] The main peak (front peak) t = 17.43min is 2-2, and the optical rotation value [a] 0 25=-60.00°; instrument: automatic polarimeter Rudolph V Plus; measurement temperature: 20°C; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: methanol (MeOH).

[0202] 1 H NMR(400MHz,DMSO-d6)δ10.51(s,1H),6.89(t,1H),6.79(s,1H),7.10(t,1H),6.70( d,J=8Hz,1H),6.20(d,J=8Hz,1H),5.77(d,J=8Hz,1H),5.29(s,2H),3.71(d,J=8Hz,1 H),3.06-2.92(m,4H),2.71-2.62(m,2H),2.37-2.33(m,2H),2.18-2.12(m,1H),1.97 -1.92(m,1H),1.82-1.73(m,4H),1.42-1.37(m,2H),1.25(s,2H),1.09-0.92(m,4H).

[0203] 13 C NMR (400MHz, DMSO-d6) δ158.46,142.48,134.47,123.42,118.32,115.98,108.17,102.48,98.42,6 0.14,56.57,56.28,53.06,48.85,46.43,35.35,33.95,33.75,32.25,32.22,27.60,22.57,14.42.

[0204] C 24 H 31 N5O + [M+H]+, calculated: 381.5240, found: 381.5233.

[0205] Method 2: The synthetic route of compound 2-2A is as follows:

[0206]

[0207] M2 (1.0 g, 2.96 mmol) prepared in accordance with Preparation Example 1, solvent DMF (10 ml), and triethylamine (1.50 g, 14.80 mmol) were added to the reaction flask. After cooling to 0-5 ° C, CDI (0.96 g, 5.92 mmol) was added, and the mixture was stirred at room temperature for 1 h. Ammonia water (0.4 ml, 2 eq) was then added and stirred at room temperature for 4 h. After the reaction was completed, water (50 ml) was added to the reaction solution for crystallization, and the mixture was purified by rapid silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to obtain compound 2-2 (0.677 g, 60%), a gray solid powder, >98% ee.

[0208] Optical rotation value [a] 0 25 =-60.00° (c=0.1, methanol).

[0209] After testing, under the chiral analysis conditions in method 1, the retention time of compound 2-2 in method 1 is consistent with the retention time of compound 2-2A prepared in method 2; and the optical rotation values ​​of the compound with a retention time of t=17.43min in method 1 and compound 2-2A prepared in method 2 are 1 H NMR, 13 The C NMR data were consistent, and the compound with a retention time of t = 17.43 min in method 1 was determined to be 2-2A.

[0210] Example 3

[0211] Method 1: Preparation of compound 3-2

[0212]

[0213] The preparation method is as in Example 1.

[0214] Chiral analysis and optical rotation test: chiral column CHIRALPAK IC (Dacel), column volume: 0.46 cm (diameter) * 25 cm (column length) (5 μm particle size filler); mobile phase: n-hexane (Hexane) / EtOH / diethanolamine (DEA) = 40 / 60 / 0.1 (V / V / V); flow rate: 1.0 mL / min; wavelength: UV230 nm; column temperature: 25°C; HPLC instrument: Agilent 1260.

[0215] The main peak (front peak) t = 8.06min is 3-2, and the optical rotation value [a] 0 25 =-52.43°; instrument: automatic polarimeter Rudolph V Plus; measurement temperature: 20°C; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: methanol (MeOH).

[0216] 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),6.89(t,1H),6.79(s,1H),6.70(d,J=8Hz,1H) ,6.20(d,J=8Hz,1H),5.72(d,J=8Hz,1H),3.72(d,J=12Hz,1H),3.41-3.28(m,4H),3. 06-2.91(m,4H),2.71-2.63(m,2H),2.38-2.34(m,2H),2.19-2.14(m,1H),1.98-1.93 (m,1H),1.77-1.74(m,4H),1.41-1.37(s,2H),1.25-1.21(m,4H),1.01-0.96(m,8H).

[0217] 13 C NMR (400MHz, DMSO-d6) δ156.58,142.46,134.48,123.42,118.33,115.98,108.16,102.49,98.4 3,60.14,56.56,56.23,53.06,49.76,46.42,35.49,34.01,33.48,32.55,32.50,27.60,14.31.

[0218] C 26 H 39 N5O + [M+H]+, calculated: 437.6320, found: 437.7128.

[0219] Method 2:

[0220] Preparation of compound 3-2A

[0221]

[0222] Following the method of compound 2-2A, M2 was reacted with CDI and diethylamine to obtain compound 3-2 (0.84 g, yield 65%), a white solid, >98% ee. Optical rotation value [a] 0 25 =-52.43° (c=0.1, methanol).

[0223] After testing, under the chiral analysis conditions in method 1, the retention time of compound 3-2 in method 1 is consistent with the retention time of compound 3-2A prepared in method 2; and the optical rotation values ​​of the compound with a retention time of t=8.06min in method 1 and compound 3-2A prepared in method 2 are 1H NMR, 13 The C NMR data were consistent, and the compound with a retention time of t = 8.06 min in method 1 was determined to be 3-2A.

[0224] Example 4

[0225] Method 1: Preparation of compound 4-2

[0226]

[0227] The preparation method is as in Example 1.

[0228] Chiral analysis and optical rotation test: chiral column CHIRALPAK IC (Dacelide), column volume: 0.46 cm (diameter) * 25 cm (column length) (5 μm particle size filler); mobile phase: n-hexane (Hexane) / EtOH / diethanolamine (DEA) = 40 / 60 / 0.1 (V / V / V); flow rate: 1.0 mL / min; wavelength: UV230 nm; temperature: 25°C; HPLC instrument: Agilent 1260.

[0229] The main peak (front peak) t = 7.08min is 4-2, and the optical rotation value [a] 0 25 =-60.40°; instrument: automatic polarimeter Rudolph V Plus; measurement temperature: 20°C; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: methanol (MeOH). 1 HNMR(400MHz,DMSO-d6)δ10.49(s,1H),6.89(t,1H),6.79(s,1H),6.70(d,J=8Hz, 1H),6.20(d,J=8Hz,1H),5.62-5.58(m,2H),3.72(d,J=12Hz,1H),3.30-3.22(m,4 H),3.02-2.96(m,6H),2.72-2.62(m,2H),2.35(t,2H),2.18-2.15(m,1H),1.97-1 .92(m,1H),1.82-1.72(m,4H),1.42-1.36(s,2H),1.25(s,1H),1.09-0.95(m,7H).

[0230] 13C NMR (400MHz, DMSO-d6) δ157.78,142.47,134.47,123.42,118.32,115.99,108.16,102.48,98.4 3,60.13,56.56,56.27,53.05,48.88,46.42,35.35,34.41,33.92,33.82,32.24,27.59,16.19.

[0231] C 24 H 35 N5O + [M+H]+, calculated: 409.5780, found: 409.5769.

[0232] Method 2: Preparation of compound 4-2A

[0233]

[0234] Following the preparation method of compound 2-2A, M2 was reacted with CDI and ethylamine to obtain compound 4-2 (0.76 g, yield 63%), a white solid, >98% ee. Optical rotation value [a] 0 25 =-60.40° (c=0.1, methanol).

[0235] After testing, under the chiral analysis conditions in method 1, the retention time of compound 4-2 in method 1 is consistent with the retention time of compound 4-2A prepared in method 2; and the optical rotation values ​​of the compound with a retention time of t=7.08min in method 1 and compound 4-2A prepared in method 2 are 1 H NMR, 13 The C NMR data were consistent, and the compound with a retention time of t = 7.08 min in method 1 was determined to be 4-2A.

[0236] Example 5

[0237] Method 1: Preparation of compound 5-2

[0238]

[0239] The preparation method is as in Example 1.

[0240] Chiral analysis and optical rotation test: chiral column CHIRALPAK IC (Dacel), column volume: 0.46 cm (diameter) * 25 cm (column length) (5 μm particle size filler); mobile phase: n-hexane (Hexane) / EtOH / diethanolamine (DEA) = 40 / 60 / 0.1 (V / V / V); flow rate: 1.0 mL / min; wavelength: UV230 nm; column temperature: 25°C; HPLC instrument: Agilent 1260.

[0241] The main peak (front peak) t = 8.70min is 5-2, and the optical rotation value [a] 0 25 =-57.43° (Instrument: automatic polarimeter Rudolph V Plus; measurement temperature: 20°C; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: MeOH).

[0242] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),6.89(t,1H),6.79(s,1H),6.70(d,J=8Hz,1H),6.20( d,J=8Hz,1H),5.78(d,J=8Hz,1H),3.72(d,J=12Hz,1H),3.42-3.35(m,1H),3.22-3.17(m,2 H),3.06-2.96(m,3H),2.73(m,4H),2.69-2.62(m,1H),2.36(t,2H),2.19-2.13(m,1H),1.9 8-1.92(m,1H),1.77-1.72(m,4H),1.42-1.37(s,2H),1.25-1.19(m,4H),1.01-0.92(m,5H).

[0243] 13 C NMR (400MHz, DMSO-d6) δ157.32,142.47,134.48,123.42,118.32,115.99,108.16,102.48,98.42,6 0.14,56.57,56.27,53.05,49.84,46.42,42.75,35.49,34.01,33.65,33.47,32.47,27.59,13.12.

[0244] C 25 H 37 N5O + [M+H]+, calculated: 423.6050, found: 423.6162.

[0245] Method 2 Preparation of Compound 5-2A

[0246]

[0247] Following the method of Example 2, M2 was reacted with CDI and methylethylamine to obtain compound 4-2 (0.74 g, yield 59%), a white solid, >98% ee. Optical rotation value [a] 0 25 =-57.43° (c=0.1, methanol).

[0248] After testing, under the chiral analysis conditions in method 1, the retention time of compound 5-2 in method 1 is consistent with the retention time of compound 5-2A prepared in method 2; and the optical rotation values ​​of the compound with a retention time of t=8.70min in method 1 and compound 5-2A prepared in method 2 are 1 H NMR, 13 The C NMR data were consistent, and the compound with a retention time of t = 8.70 min in method 1 was determined to be 5-2A.

[0249] The compound 1-2 in the following effect example 1 is the compound with a retention time of t=8.46 min under the chiral analysis conditions in example 1; the compound 5-2 is the compound with a retention time of t=8.70 min under the chiral analysis conditions in example 5; the compound (-)-I-10 is prepared according to example 10 in patent application CN114835709A.

[0250] Effect Example 1

[0251] The D2L gene, Gα15 gene and D3 gene can all be retrieved through commonly used biological databases (such as NCBI, National Center for Biotechnology Information, US National Center for Biotechnology Information).

[0252] Plasmids and CHO cells are routine in the art.

[0253] 1. Reaction system: 100 μL cell membrane, 1 μL test compound, 100 μL corresponding isotope.

[0254] The construction of D2L and D3 high-expressing cells and cell membrane extraction were completed by Shanghai WuXi AppTec New Drug Development Co., Ltd. The construction method of the overexpression cell line is as follows:

[0255] 1) Plasmid construction: The D2L gene (NM_000795) and the Gα15 gene (NM_002068) were co-inserted into the vector plasmid pcDNA3.1; the D3 gene (NM_000796.3) was inserted into the vector plasmid pcDNA3.1.

[0256] 2) The vector plasmid was transfected into CHO cells using liposome transfection method.

[0257] 3) Use selective antibiotics to screen the successfully transfected cells.

[0258] 4) Perform monoclonal screening on the cells obtained by antibiotic screening.

[0259] 5) Use the FLIPR (D2L) or cAMP (D3) method to verify the screened monoclonal cells and obtain cell lines that successfully express D2L and D3.

[0260] 6) D2L and D3 cell lines were amplified in large quantities and cell membranes were extracted for later use.

[0261] The specific steps of the receptor affinity test are as follows:

[0262] 1) Cell membrane preparation: D2L and D3 cell membranes were diluted with Assay buffer (50 mM Tris-HCl, pH 7.4). The final concentrations of cell membranes were as follows:

[0263] Target Working concentration (μg / well) <![CDATA[D2L]]> 20 <![CDATA[D3]]> 4

[0264] 2) Isotope preparation: dilute the corresponding isotope with Assay buffer. The final isotope concentration of the experimental system is as follows:

[0265]

[0266] 3) Dilution of positive compounds and test compounds: The two test compounds are diluted 4-fold in 10 points with DMSO, and the positive compound is diluted 4-fold in 10 points with DMSO. Transfer 1 μL of the diluted positive compound and test compound to the designated position in the experimental plate. For the D2L receptor, the starting concentration of compound 1-2 was 1000nM, the starting concentration of compound 5-2 was 10000nM, the starting concentration of compound (-)-I-10 was 1000nM, and the starting concentration of the positive compound 7-OH-DPAT (Sigma, H8653) was 1μM; for the D3 receptor, the starting concentration of 1-2 was 1000nM, the starting concentration of compound 5-2 was 10000nM, the starting concentration of (-)-I-10 was 10000nM, and the starting concentration of the positive compound NGB2904 (Sigma, SML0066) was 0.1μM; transfer 1μL of nonspecific binding compound to the experimental plate as nonspecific binding well Low control (LC), and transfer 1μL of DMSO to the experimental plate as total binding well High control (HC).

[0267]

[0268] 2. Test steps:

[0269] 1) According to the experimental compound arrangement, add 100 μL of prepared cell membrane to each well of the reaction plate.

[0270] 2) According to the arrangement of experimental compounds, add 100 μL of prepared isotope to the reaction plate.

[0271] 3) Seal the reaction plate with a sealing film and then incubate it on a shaker at room temperature for 1 hour. At the same time, soak the GF / C filter plate with 50 μL of 0.3% PEI soaking solution for at least 0.5 hour.

[0272] 4) After the reaction plate is incubated, the reaction solution is collected onto the GF / C filter plate using a cell collector, washed 4 times with wash buffer, and dried in an oven at 50°C for 1 hour.

[0273] 5) Seal the bottom of the dried GF / C filter plate with a film, add 50 μL MicroScint-O scintillation fluid to each well, and seal.

[0274] 6) Use Microbeta2 readouts.

[0275] 7) Result analysis: The inhibitory activity of the sample was calculated using Excel (% = (1-(sample well signal-Low control signal) / (High control signal-Low control signal)) × 100%). The IC50 was calculated using the "log (inhibitor) vs. response--Variable slope" model in GraphPad Prism 5.0.

[0276] 8) Perform the above experimental steps three times independently.

[0277] 3: Affinity test of the compounds of the present invention for D3 and D2L receptors

[0278] The results are shown in the following table:

[0279]

[0280] The results show that the compounds of the present application have stronger affinity activities for both dopamine D3 receptors and D2L receptors.

[0281] Effect Example 2

[0282] Both D2L receptor and D2R receptor can be retrieved through commonly used biological databases (such as NCBI, National Center for Biotechnology Information, US National Center for Biotechnology Information).

[0283] Plasmids and HEK 293T cells are routine in the art.

[0284] 1. Reaction system:

[0285] On the first day, 6 cm culture dishes were incubated with 1 μg dopamine D2L or D2R receptor, 1 μg Gα containing C-terminal algal luciferase i1 (Gα i1 ), 1 μg G β3 , 1 μg of Gγ9 containing C-terminal green fluorescent protein (Gγ9) and 16 μL PEI were used for transfection.

[0286] On the next day, the confluent cells were digested and the amount of cells from a confluent 6-cm culture dish was plated on a 96-well plate, with 100 μL of culture medium per well.

[0287] On the third day, drug addition test. Take out the 96-well plate from the cell room and remove the culture medium. Add 40 μL of substrate coelenterazine 400a (final concentration 5 μM) to each well, and then add 20 μL of different drugs from left to right to ensure that the final drug concentration decreases from bottom to top. Each treatment is repeated twice. Finally, the machine is used for detection to determine the agonist effect of various compounds on dopamine D2 receptors.

[0288] 2. The cell function parameters of the compounds of the present invention on D2L and D2S number

[0289] <![CDATA[D2S]]> Dopamine 1-2A (-)-I-10 <![CDATA[EC 50 ,nM]]> 22.47 2.41 6.63 <![CDATA[D2L]]> Dopamine 1-2A (-)-I-10 <![CDATA[EC 50 ,nM]]> 19.87 1.64 5.70

[0290] The results show that the compounds of the present application have stronger agonist activity on both dopamine D2S and D2L receptors.

Claims

1. A compound as shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof: in, R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen or C 1-6 alkyl; R 3 and R 4 The following conditions (1) or (2) are met: Case (1): R 3 is hydrogen; R 4 is hydrogen or C 1-6 alkyl; Case (2): R 3 C 2-6 Alkyl; R 4 is hydrogen or C 1-6 alkyl.

2. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1)R 1 In the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (2)R 2 In the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (3) In cases (1) and (2), the R 4 C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl or ethyl; and (4) In case (2), the R 3 C 2-6 Alkyl is ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example ethyl.

3. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1)R 1 is hydrogen; (2)R 2 is hydrogen; (3) In case (1), R 4 is hydrogen, methyl or ethyl; (4) In case (2), R 3 is ethyl; and (5) In case (2), R 4 is hydrogen, methyl or ethyl.

4. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It is either Scheme I or Scheme II below: Option I: R 3 is hydrogen; R 4 is hydrogen or C 1-6 alkyl; Option II: R 3 C 2-6 Alkyl; R 4 is hydrogen or C 1-6 alkyl.

5. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound shown in Formula I is a compound shown in Formula Ia, Ib or Ib': Preferably, the compound as shown in formula I is a compound as shown in formula Ic or Ic', 6. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It is the following option 1 or option 2: Scheme 1: The compound shown in Formula I is a compound shown in Formula Ia: R 1 is hydrogen; R 2 is hydrogen; R 3 is hydrogen; R 4 is hydrogen, methyl or ethyl; Scheme 2: The compound shown in Formula I is a compound shown in Formula Ia: R 1 is hydrogen; R 2 is hydrogen; R 3 is ethyl; R 4 is hydrogen, methyl or ethyl.

7. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound as shown in formula I is any of the following compounds: Preferably, The compound shown in Formula 1 is For example Or, the compound as shown in Formula 2 is For example Or, the compound as shown in Formula 3 is For example Or, the compound as shown in Formula 4 is For example Or, the compound as shown in Formula 5 is For example 8. The compound of formula I according to claim 7, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: Said are independently the compounds with the preceding retention times under the following conditions; The conditions are: the filler is a chromatographic column with amylose-tris(3-chloro-5-methylcarbamate) bonded to the surface of silica gel or cellulose-tris(3,5-dichlorophenylcarbamate) bonded to the surface of silica gel; the mobile phase includes an alcohol solvent (such as methanol) and a nitrile solvent (such as acetonitrile); or the mobile phase includes an alkane solvent (such as cyclohexane) and an alcohol solvent (such as methanol); Preferably: Said The compound with a retention time of 3.044 min under the following conditions; The conditions are as follows: chromatographic column: CHIRALPAKIG, 2.5cm*25cm*10μm; mobile phase: methanol / acetonitrile / diethylamine=80 / 20 / 0.1, the ratio is volume ratio; flow rate: 1.0mL / min; detection wavelength: UV210nm; column temperature: 25°C; HPLC instrument: ShimadzuLC-2010B; or, It is a compound with a retention time of 8.46 min under the following conditions; The conditions are: chromatographic column CHIRALPAK IC, 0.46cm*25cm*5μm; mobile phase: n-hexane / ethanol / diethanolamine=40 / 60 / 0.1, the ratio is volume ratio; flow rate: 1.0mL / min; Wavelength: UV230nm; Column temperature: 25℃; HPLC instrument: Agilent1260; or, The compound with a retention time of 17.43 min under the following conditions is: The conditions are: chromatographic column CHIRALPAK IC, 0.46cm*25cm*5μm; mobile phase: n-hexane / ethanol / diethanolamine=40 / 60 / 0.1, the ratio is volume ratio; flow rate: 1.0mL / min; Wavelength: UV230nm; Column temperature: 25℃; HPLC instrument: Agilent1260; or, The compound with a retention time of 8.06 min under the following conditions is: The conditions are: chromatographic column CHIRALPAK IC, 0.46cm*25cm*5μm; mobile phase: n-hexane / ethanol / diethanolamine=40 / 60 / 0.1, the ratio is volume ratio; flow rate: 1.0mL / min; Wavelength: UV230nm; Column temperature: 25℃; HPLC instrument: Agilent1260; or, The compound with a retention time of 7.08 min under the following conditions is: The conditions are: chromatographic column CHIRALPAK IC, 0.46cm*25cm*5μm; mobile phase: n-hexane / ethanol / diethanolamine=40 / 60 / 0.1, the ratio is volume ratio; flow rate: 1.0mL / min; Wavelength: UV230nm; Column temperature: 25℃; HPLC instrument: Agilent1260; or, The compound with a retention time of 8.70 min under the following conditions is: The conditions are: chromatographic column CHIRALPAK IC, 0.46cm*25cm*5μm; mobile phase: n-hexane / ethanol / diethanolamine=40 / 60 / 0.1, the ratio is volume ratio; flow rate: 1.0mL / min; Wavelength: UV230nm; column temperature: 25°C; HPLC instrument: Agilent1260.

9. The compound of formula I according to claim 7, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: Said independently a compound having a negative optical rotation value; Preferably: Said The compound with an optical rotation value of -60.20° under the following test conditions; The test conditions are: measurement temperature: 20°C; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: methanol; Instrument: Automatic polarimeter Rudolph V Plus; or, The compound with an optical rotation value of -60.00° under the following test conditions; The test conditions are: measurement temperature: 20°C; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: methanol; Instrument: Automatic polarimeter Rudolph V Plus; or, The compound having an optical rotation value of -52.43° under the following test conditions; The test conditions are: measurement temperature: 20°C; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: methanol; Instrument: Automatic polarimeter Rudolph V Plus; or, A compound having an optical rotation value of -60.40° under the following test conditions; The test conditions are: measurement temperature: 20°C; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: MeOH; Instrument: Automatic polarimeter Rudolph V Plus; or, The compound having an optical rotation value of -57.43° under the following test conditions; The test conditions are: measurement temperature: 20°C; sample concentration: 1 mg / ml; selected wavelength: 589 nm; dilution solvent: MeOH; Instrument: Automatic polarimeter Rudolph V Plus.

10. A method for preparing a compound represented by formula I, characterized in that: It is either method 1 or method 2 below: Method 1 comprises the following steps: in a solvent, in the presence of a base, reacting a compound represented by formula I-S1 and a compound represented by formula I-S2 as shown in the following formula to obtain the compound represented by formula I; R 1 , R 2 , R 3 and R 4 is defined as in any one of claims 1 to 9; and R 3 and R 4 Not at the same time H; Method 2 The method comprises the following steps: in a solvent, in the presence of a base and an amide condensation reagent, reacting a compound represented by formula I-S1 and a compound represented by formula I-S2' as shown in the following formula to obtain a compound represented by formula I; R 1 , R 2 , R 3 and R 4 The definition as described in any one of claims 1 to 9.

11. A compound, which is any of the following compounds:

12. A pharmaceutical composition comprising substance A and pharmaceutical excipients, wherein substance A is a compound of formula I as described in any one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

13. Use of a substance A or a pharmaceutical composition as claimed in claim 12 in the preparation of a dopamine D2 receptor agonist or a D3 receptor agonist; the substance A is a compound of formula I as claimed in any one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; The dopamine D2 receptor may be a dopamine D2L receptor and / or a dopamine D2S receptor, such as a dopamine D2L receptor.

14. Use of a substance A or a pharmaceutical composition as claimed in claim 12 in the preparation of a drug for treating and / or preventing diseases associated with dopamine D2 receptors or D3 receptors, wherein the substance A is a compound as shown in formula I as claimed in any one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; The dopamine D2 receptor-related disease can be selected from one or more of neurodegenerative diseases, mental disorders and metabolic diseases related to mental disorders, such as Parkinson's disease, Alzheimer's disease, dementia, schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma or drug addiction.

15. Use of a substance A or a pharmaceutical composition as claimed in claim 12 in the preparation of a drug for treating and / or preventing a disease; the substance A is a compound of formula I as claimed in any one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; The disease is selected from one or more of neurodegenerative diseases, mental disorders and metabolic diseases related to mental disorders; The disease may be Parkinson's disease, Alzheimer's disease, dementia, schizophrenia, bipolar disorder, depression, ADHD, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma or drug addiction.

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