Pyridine (pyrimidine) amine derivatives and their applications

Abstract

The present invention relates to the field of chemical medicine, and provides a compound represented by Formula I, which acts on 5-HT 2A and 5-HT 2C receptors, and has a selectivity for 5-HT 2A superior to or similar to pimavanserin. It is used for the treatment of schizophrenia or behavioral disorders and psychosis related to Parkinson's disease and dementia. The antipsychotic activity of the compound of the present application is equivalent to that of pimavanserin, and its cardiotoxicity is less than that of pimavanserin.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine, and particularly to pyridine (pyrimidine) amine derivatives and their applications. Background Art

[0002] Schizophrenia has a hidden onset and a low admission rate, with a relatively high lifetime prevalence. Currently, approximately 0.3-0.7% of the world's population is affected by schizophrenia in their lifetime, and it is estimated that there are more than 21 million schizophrenia patients globally in 2016. Currently, the main antipsychotic drugs for schizophrenia are typical antipsychotic drugs and atypical antipsychotic drugs. However, current schizophrenia treatment drugs strongly block dopamine receptors, resulting in adverse reactions such as extrapyramidal symptoms (EPS), tardive dyskinesia, and increased prolactin. In the medical field, although there are various types of active compounds acting on different targets available for the treatment of sleep disorder, adverse reactions such as addiction, drug resistance, and residual effects remain unsolved problems.

[0003] Traditionally, antipsychotic drugs that exert pharmacological effects by blocking dopamine D2 receptors are called first-generation antipsychotic drugs, that is, "typical" antipsychotic drugs (such as haloperidol). They have made breakthroughs in treating the positive symptoms of schizophrenia, but have failed to treat negative symptoms and cognitive impairments. Typical antipsychotic drugs generally have severe EPS side effects and are ineffective in one-third of schizophrenia patients.

[0004] After the 1960s, a series of new-generation antipsychotic drugs were successively developed, including ziprasidone, risperidone, etc., which are called second-generation antipsychotic drugs, that is, new antipsychotic drugs. Although their respective pharmacological effects are not completely the same, they have common pharmacological characteristics, that is, their affinities for 5-hydroxytryptamine (5-HT) receptors (5-HT 1A、2A、2C ) and norepinephrine (NA) receptors (α1, α2) are much higher than those for D2 receptors. Their clinical effects have more advantages compared with first-generation antipsychotic drugs. They are not only equally effective for positive symptoms as traditional antipsychotic drugs, but also effective for negative symptoms and cognitive deficit symptoms, with a wider spectrum of action. However, these drugs have adverse reactions such as QT interval prolongation, hyperprolactinemia, and weight gain. Therefore, finding drugs that are effective for the positive, negative symptoms and cognitive impairments of schizophrenia and have few side effects is a current research hotspot.

[0005] The serotonin system plays an important role in regulating the function of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. Pyramidal neurons and GABA interneurons in the PFC contain several serotonin receptor subtypes 5-HT 1A and 5-HT 2A . Recently, it has been demonstrated that the PFC and NMDA receptor channels are targets of 5-HT 1A R, and these two receptors regulate excitatory neurons in the cerebral cortex, thereby affecting cognitive function. In fact, various preclinical data indicate that 5-HT 1A R may be a new target for antipsychotic drug development. The high affinity of atypical antipsychotics (such as olanzapine, aripiprazole, etc.) for 5-HT 1A R and their low EPS side effects all illustrate that the serotonin system plays an important role in regulating the function of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. Pyramidal neurons and GABA interneurons in the PFC contain several serotonin receptor subtypes 5-HT 1A and 5-HT 2A . Recent studies have shown that 5-HT 1A agonists are related to the treatment of atypical antipsychotics and can improve negative symptoms and cognitive impairment. In the treatment of schizophrenia with the atypical antipsychotic clozapine, it has been found that 5-HT 2A plays a very important role, involving all aspects of perception, emotional regulation, and motor control. Blocking the 5-HT 2A receptor can normalize dopamine release and play an antipsychotic role. In addition, the 5-HT 2C receptor is closely related to weight gain.

[0006] Pimavanserin is an inverse agonist with high affinity for 5-HT 2A , a 5-HT 2C antagonist. In vitro experimental results show that its affinity for the 5-HT 2A receptor [inhibition constant (Ki) is 0.4 nM] is higher than that for 5-HT 2C (Ki = 16 nM), and it has no obvious affinity (Ki > 300 nM) for 5-HT 2B receptors, dopamine receptors (including D2 receptors), adrenergic receptors, muscarinic receptors, or calcium channel receptors. This drug was approved by the US Food and Drug Administration for marketing in April 2016, with the trade name Nuplazid TM , and is mainly used for the treatment of Parkinson's psychosis symptoms such as hallucinations and illusions.

[0007] Therefore, there is a need to find an antipsychotic drug that is effective against both positive and negative symptoms, can improve cognitive impairment, and can prevent extrapyramidal side effects, including tardive dyskinesia and Parkinson's disease; and can reduce weight gain. Summary of the Invention

[0008] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, an object of the present invention is to provide pyridine (pyrimidine) amine derivatives and their applications, such as the compounds of formula I or their pharmaceutically acceptable salts:

[0009]

[0010] Z and Q are each independently selected from C and N, and Z and Q are not both C at the same time;

[0011] R 13 is a straight-chain or branched-chain alkyl group having 1 to 5 carbon atoms;

[0012] R1 is selected from H and the structure of formula II,

[0013] R2 is absent, H or the structure of formula II,

[0014]

[0015] A is C or N;

[0016] R6 is H or a halogen; R7 is H or OH;

[0017] R5 is selected from H, R4 is H, a halogen or the structure of formula III, or R5 and R4 form a benzene ring;

[0018]

[0019] Wherein, in formula III, n1 is an integer from 0 to 3, and W3 is C or N;

[0020] R8 is a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms;

[0021] R3 is H, the structure of formula IV, V or VI:

[0022]

[0023] Wherein, in formula IV, n2 is an integer from 0 to 3, n4 and n5 are each independently selected from integers from 1 to 3; W1 and W2 are each independently selected from one of C and N;

[0024] R9 is H, a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms, a formyl group, an acetyl group, or a dimethylamino group;

[0025] In formula VI, n3 is an integer from 0 to 1;

[0026] In formula V, R 10 and R 11 are each independently selected from H, a straight-chain or branched-chain C1-C3 alkyl group.

[0027] In one embodiment, the compound of formula I as shown above is preferably formula I-1

[0028]

[0029] Z is selected from C, N.

[0030] In one embodiment, in the compound of formula I as shown above or a pharmaceutically acceptable salt thereof, the halogen is selected from fluorine, chlorine, bromine, iodine; the straight-chain or branched-chain C1-C5 alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl.

[0031] In a particularly specific embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from any one of the following compounds:

[0032] N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyrimidin-2-amine;

[0033] N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(1-methylpyrrolidin-3-yl)pyrimidin-2-amine;

[0034] N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(piperazin-1-yl)pyrimidin-2-amine;

[0035] 4-[2-[(4-Fluorobenzyl)(4-isobutoxybenzyl)amino]pyrimidin-4-yl]piperazine-1-carbaldehyde;

[0036] N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(piperidin-4-yl)pyrimidin-2-amine;

[0037] N-(4-Fluorobenzyl)-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(4-isobutoxybenzyl)pyrimidin-2-amine;

[0038] 4-(Azetidin-3-yl)-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyrimidin-2-amine; 5-fluoro-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyrimidin-2-amine; 5-chloro-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyrimidin-2-amine; 4-[3-(dimethylamino)azetidin-1-yl]-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyrimidin-2-amine;

[0039] N-benzyl-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyrimidin-2-amine;

[0040] N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(1-methylazetidin-3-yl)pyrimidin-2-amine; N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)quinazolin-2-amine;

[0041] 4-[3-(dimethylamino)cyclobutyl]-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyrimidin-2-amine; 4-[(dimethylamino)methyl]-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyridin-2-amine; 4-(aminomethyl)-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyridin-2-amine;

[0042] N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyridin-2-amine;

[0043] N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-6-(pyrrolidin-3-yl)pyridin-2-amine; 3-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(1-methylpyrrolidin-3-yl)pyridin-2-amine;

[0044] (4-fluorophenyl)[2-[(4-isobutoxybenzyl)amino]-4-(1-methylpyrrolidin-3-yl)pyridin-3-yl]methanol;

[0045] 3-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-5-(1-methylpiperidin-4-yl)pyridin-2-amine; 3-[(5-fluoropyridin-2-yl)methyl]-N-(4-isobutoxybenzyl)-5-(1-methylpiperidin-4-yl)pyridin-2-amine;

[0046] 3-[(5-fluoropyridin-2-yl)methyl]-N-(4-isobutoxybenzyl)-4-(1-methylpyrrolidin-3-yl)pyridin-2-amine.

[0047] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof and a medically acceptable carrier.

[0048] On the other hand, the present invention provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a medicament for treating mental diseases. The mental diseases are schizophrenia. The mental diseases are Parkinson's disease, dementia-related behavioral disorders and psychosis.

[0049] In a specific embodiment, in formula VI, when n3 is 0, the structure of formula I is the following specific structure Term Explanation:

[0050] The term "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other aspects. It should be understood that the term "comprising" can cover a closed meaning, that is, "consisting of".

[0051] As described in the present invention, the compounds of the present invention may optionally be substituted by one or more substituents, such as the general formula compounds above or specific examples and subclasses in the examples. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" can be used interchangeably. Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Unless otherwise indicated, the optionally substituted group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, then the substituents can be the same or different at each position.

[0052] In addition, it should be noted that unless otherwise explicitly indicated, the description method "are each independently" adopted in the present invention should be understood in a broad sense, which can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0053] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or range. It should be specifically noted that the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C1-C5 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, and C5 alkyl independently disclosed. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), etc.

[0054] The ranges recited herein (such as numerical ranges) can cover each value within their range and each sub-range formed by the individual values. Thus, for example, the statement "n2 is any integer between 0 and 3" includes, for example, any integer from 0 to 2, any integer from 2 to 3, etc., such as 1, 2, 3.

[0055] The expression "one or more" can mean 1, 2, 3, 4, 5, 6 or more.

[0056] The term "hydrogen (H)" represents a single hydrogen atom. Such an atomic group can be connected to other groups, for example, connected to an oxygen atom to form a hydroxyl group.

[0057] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0058] The term "formyl" is "acetyl" is

[0059] The term "pharmaceutically acceptable salt" refers to an organic or inorganic salt of the compounds of the present invention.

[0060] Compound of formula I

[0061] The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof

[0062]

[0063] Among them, Z and Q are each independently selected from C and N, and Z and Q are not both C at the same time; R 13 is a straight-chain or branched-chain alkyl group having 1 to 5 carbon atoms;

[0064] R1 is selected from H and the structure of formula II,

[0065] R2 is absent, H or the structure of formula II,

[0066]

[0067] A is C or N;

[0068] R6 is H or a halogen, and R7 is H or OH;

[0069] R5 is H or R4 is H, a halogen or the structure of formula III, or R5 and R4 form a benzene ring,

[0070]

[0071] Among them, in formula III, n1 is an integer from 0 to 3, and W3 is C or N;

[0072] R8 is a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms;

[0073] R3 is H, the structure of formula IV, V or VI,

[0074]

[0075] Among them, in formula IV, n2 is an integer from 0 to 3, and n4 and n5 are each independently selected from integers from 1 to 3;

[0076] W1 and W2 are each independently selected from C and N;

[0077] R9 is selected from H, a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms, a formyl group, an acetyl group, and a dimethylamino group;

[0078] In formula VI, n3 is an integer from 0 to 1;

[0079] In formula V, R 10 and R 11 are each independently selected from H and a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms.

[0080] In one embodiment, the compound represented by formula I is formula I-1:

[0081]

[0082] Among them, Z is C or N.

[0083] In one embodiment, R1 is H or a structure of Formula II, and R2 is absent, H, or a structure of Formula II:

[0084] wherein A is C or N; R6 is H or a halogen, and R7 is H or OH. In a preferred embodiment, R1 is H. In yet another preferred embodiment, R1 is a compound of Formula II. In a preferred embodiment, R2 is H. In another preferred embodiment, R2 is absent. In yet another preferred embodiment, R2 is a structure of Formula II.

[0085] In one embodiment, the structure of Formula II is wherein A is C or N; R6 is H or a halogen, and R7 is H or OH. In a preferred embodiment, the structure of Formula II is wherein A is C or N; R6 is H, fluorine, chlorine, bromine, or iodine, and R7 is H or OH. In a particularly preferred embodiment, the structure of Formula II is wherein A is C or N; R6 is H or fluorine, and R7 is H or OH. In a specific embodiment, the structure of Formula II is In another specific embodiment, the structure of Formula II is In yet another specific embodiment, the structure of Formula II is In another specific embodiment, the structure of Formula II is

[0086] In one embodiment, R 13 is a straight-chain or branched-chain alkyl group having 1 to 5 carbon atoms. In a preferred embodiment, R 13 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl. In a more preferred embodiment, R 13 is isopropyl, butyl, isobutyl, or pentyl. In a particularly preferred embodiment, R 13 is isobutyl.

[0087] In one embodiment, R5 is H or In a specific embodiment, R5 is H. In another specific embodiment, R5 is

[0088] In one embodiment, R4 is H, a halogen, or a structure of Formula III: In Formula III, n1 is an integer from 0 to 3, W3 is C or N; R8 is a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms. In a preferred embodiment, R4 is selected from H, fluorine, chlorine, bromine, and the structure of Formula III In formula III, n1 is an integer of 0, 1, or 2, W3 is C or N; R8 is methyl, ethyl, propyl, or isopropyl. In a particularly preferred embodiment, R4 is selected from H, fluorine, chlorine, In formula III, n1 is 0, W3 is N; R8 is methyl.

[0089] In one embodiment, R5 and R4 form a benzene ring.

[0090] In one embodiment, R3 is H, a structure of formula IV, V, or VI;

[0091]

[0092] Among them, in formula IV, n2 is an integer of 0 - 3, n4, n5 are integers of 1 - 3;

[0093] W1 and W2 are each independently selected from C, N;

[0094] R9 is selected from H, a straight-chain or branched-chain alkyl of C1 - C3, formyl, acetyl, dimethylamino;

[0095] In formula VI, n3 is an integer of 0 - 1;

[0096] In formula V, R 10 、R 11 are each independently selected from H, a straight-chain or branched-chain alkyl of C1 - C3.

[0097] In a more preferred embodiment, R3 is H, a structure of formula IV, V, or VI;

[0098]

[0099] Among them, in formula IV, n2 is 0, n4 and n5 are each independently selected from 1, 2;

[0100] W1 and W2 are each independently selected from C, N;

[0101] R9 is H, methyl, ethyl, propyl, isopropyl, formyl, or dimethylamino;

[0102] In formula V, R 10 、R 11 are each independently selected from H, methyl;

[0103] In formula VI, n3 is 0 or 1.

[0104] In a particularly preferred embodiment, R3 is H, a structure of formula IV, V, or VI;

[0105]

[0106] Among them, in Formula IV, n2 is 0, and n4 and n5 are each independently selected from 1 and 2;

[0107] W1 and W2 are each independently selected from one of C and N;

[0108] R9 is selected from H, methyl, formyl, dimethylamino;

[0109] In Formula V, R 10 and R 11 are each independently selected from H and methyl;

[0110] In Formula VI, n3 is 0.

[0111] In one embodiment, the C1-C5 straight-chain or branched-chain alkyl and the C1-C3 straight-chain or branched-chain alkyl are each independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and isopentyl. In a more specific embodiment, the C1-C5 straight-chain or branched-chain alkyl and the C1-C3 straight-chain or branched-chain alkyl are each independently selected from methyl and isobutyl.

[0112] In one embodiment, the propyl includes but is not limited to n-propyl (n-Pr, -CH2CH2CH3) or isopropyl (i-Pr, -CH(CH3)2). The butyl includes but is not limited to n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3) or tert-butyl (t-Bu, -C(CH3)3). The pentyl includes but is not limited to n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2) or 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3).

[0113] In a specific embodiment, the halogen is selected from fluorine, chlorine, bromine and iodine. In a particularly specific embodiment, the halogen is selected from fluorine and chlorine.

[0114] Advantageous technical effects of the present invention:

[0115] The compound provided by the present invention acts on 5-HT2A and 5-HT2C receptors, and the selectivity for 5-HT2A is better than or similar to that of pimavanserin. It is used to treat schizophrenia or behavioral disorders and psychosis related to Parkinson's disease and dementia. The antipsychotic activity of the compound of the present application is equivalent to that of pimavanserin, and the cardiotoxicity is less than that of pimavanserin.

[0116] Specific implementation method

[0117] The present invention can be further described by the following examples. However, the scope of the present invention is not limited to the following examples. Those skilled in the art can understand that various changes and modifications can be made to the present invention without departing from the spirit and scope of the present invention.

[0118] Table 1 Compound structure and compound name

[0119]

[0120]

[0121]

[0122]

[0123] Specific implementation method

[0124] The following examples are for illustrative purposes only and are not intended as limitations on the present invention. General formula synthesis:

[0125]

[0126] The condensation reaction of a substituted 2-chloropyrimidine or pyridine derivative with a substituted 4-alkoxybenzylamine, followed by the condensation reaction with a substituted benzyl bromide, to obtain the structural formula of the general formula compound.

[0127] The general formula synthesis method is only used to simply summarize the synthesis methods of some compounds of the present invention. The specific synthesis route and synthesis steps are subject to the examples.

[0128] The synthesis examples are for illustrative purposes and should not be considered as limitations on the present invention.

[0129] Examples in terms of synthesis

[0130] Example 1. 4-(5-Benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)-1-methylpiperidine (1) Reaction formula 1

[0131]

[0132] 1.1 Preparation of tert-butyl 3-(2-chloropyrimidin-4-yl)-2,5-dihydropyrrole-1-carboxylate

[0133] 2,4-Dichloropyrimidine (1.00 g, 6.713 mmol), water (10 mL, 111.017 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (2.38 g, 8.055 mmol), Na2CO3 (1.42 g, 13.426 mmol) and Pd(dppf)Cl2 (0.25 g, 0.336 mmol) were added to 10 mL of dioxane. Under nitrogen protection, the temperature was raised to 80 °C and stirred for 2 hours. After the reaction was completed, the solid was removed by filtration. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine (1 x 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification by column chromatography (PE:EA = 2:1) gave 1.5 g of tert-butyl 3-(2-chloropyrimidin-4-yl)-2,5-dihydropyrrole-1-carboxylate, with a yield of 79.31%, as a pale yellow solid.

[0134] 1.2 Preparation of tert-butyl 3-(2-chloropyrimidin-4-yl)pyrrolidine-1-carboxylate

[0135] tert-Butyl 3-(2-chloropyrimidin-4-yl)-2,5-dihydropyrrole-1-carboxylate (1.50 g, 5.324 mmol), tetrahydrofuran (15.00 mL, 185.145 mmol) and Pd / C (0.15 g, 1.410 mmol) were added to a 50 mL round-bottom flask. Hydrogen was introduced into the system, and the reaction was carried out at room temperature overnight. After the reaction was completed, the mixture was filtered to obtain a solution, and the solvent was removed under reduced pressure to give 1.2 g of tert-butyl 3-(2-chloropyrimidin-4-yl)pyrrolidine-1-carboxylate, with a yield of 79.43%, as a yellow oil.

[0136] 1.3 Preparation of tert-butyl 3-[2-([[4-(2-methylpropoxy)phenyl]methyl]amino)pyrimidin-4-yl]pyrrolidine-1-carboxylate

[0137] tert-Butyl 3-(2-([[4-(2-methylpropoxy)phenyl]methyl]amino)pyrimidin-4-yl)pyrrolidine-1-carboxylate (1.00 g, 3.524 mmol), dimethyl sulfoxide (10.00 mL), 1-[4-(2-methylpropoxy)phenyl]methanamine (0.63 g, 3.524 mmol), and DIEA (0.91 g, 7.048 mmol) were added to a 40 mL round-bottom flask, and the temperature was raised to 150 °C and reacted for 2 hours. After the reaction was completed, the temperature was lowered to room temperature. 40 mL of ice water was added to the reaction solution, and it was extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated sodium chloride solution (1 x 30 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and purified by column chromatography (PE:EA = 1:1) to obtain 0.9 g of tert-butyl 3-[2-([[4-(2-methylpropoxy)phenyl]methyl]amino)pyrimidin-4-yl]pyrrolidine-1-carboxylate, with a yield of 59.87%, as a yellow solid.

[0138] 1.4 Preparation of tert-Butyl 3-(2-[[(4-Fluorophenyl)methyl]([[4-(2-methylpropoxy)phenyl]methyl])amino]pyrimidin-4-yl)pyrrolidine-1-carboxylate

[0139] tert-Butyl 3-(2-([[4-(2-methylpropoxy)phenyl]methyl]amino)pyrimidin-4-yl)pyrrolidine-1-carboxylate (300.00 mg, 0.703 mmol) and DMF (6.00 mL, 77.531 mmol) were added to a 50 mL round-bottom flask under nitrogen protection. The temperature was lowered to 0 °C, and NaH (33.76 mg, 1.407 mmol) was added. The reaction was carried out at 0 °C for 0.5 hour, and 1-(bromomethyl)-4-fluorobenzene (265.89 mg, 1.407 mmol) was added dropwise at 0 °C, and the reaction was continued for 2 hours. After the reaction was completed, 30 mL of ice water was added to quench the reaction, and it was extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine (1 x 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 320 mg of tert-butyl 3-(2-[[(4-fluorophenyl)methyl]([[4-(2-methylpropoxy)phenyl]methyl])amino]pyrimidin-4-yl)pyrrolidine-1-carboxylate, with a yield of 85.10%, as a yellow oil.

[0140] 1.5 Preparation of N-[(4-Fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]-4-(pyrrolidin-3-yl)pyrimidin-2-amine

[0141] tert-Butyl 3-(2-[[(4-fluorophenyl)methyl]([[4-(2-methylpropoxy)phenyl]methyl])amino]pyrimidin-4-yl)pyrrolidine-1-carboxylate (300.00 mg, 0.561 mmol) was added to 1,4-dioxane (5.00 mL, 137.134 mmol) of HCl and stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched by adding 30 mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (3 x 30 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and purified by column chromatography in batches (DCM:MeOH = 20:1) to obtain 76.3 mg of compound N-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]-4-(pyrrolidin-3-yl)pyrimidin-2-amine, with a yield of 28.86%. 1 H NMR (400 MHz, DMSO-d6): δ 9.36 (s, 1H), 9.20 (s, 1H), 8.35 (d, J = 5.0 Hz, 1H), 7.28 (dd, J = 8.4, 5.5 Hz, 2H), 7.18 (s, 1H), 7.19–7.08 (m, 3H), 6.86 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 5.0 Hz, 1H), 4.77 (t, J = 4.3 Hz, 4H), 3.71 (d, J = 6.5 Hz, 2H), 3.48 (q, J = 7.1, 6.5 Hz, 2H), 3.31 (s, 2H), 3.21 (d, J = 11.6 Hz, 2H), 2.27 (q, J = 6.7 Hz, 1H), 1.99 (dp, J = 13.3, 6.7 Hz, 2H), 0.97 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 435 [M+H] + 。

[0142] Example 2. N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(1-methylpyrrolidin-3-yl)pyrimidin-2-amine (2)

[0143] Reaction Scheme 2

[0144]

[0145] The target compound N-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]-4-(pyrrolidin-3-yl)pyrimidin-2-amine was prepared according to the method of Example 1.

[0146] N-[(4-Fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]-4-(pyrrolidin-3-yl)pyrimidin-2-amine (200.00 mg, 0.460 mmol) was added to 5.00 mL of methanol, followed by the addition of AcOH (55.28 mg, 0.921 mmol) and HCHO (69.10 mg, 2.301 mmol). The reaction was carried out at room temperature for 0.5 h, and then STAB (292.63 mg, 1.381 mmol) was added, and the reaction was continued at room temperature for 1 h. After the reaction was completed, the pH of the reaction mixture was adjusted to 8 with saturated NaHCO3 solution, extracted with ethyl acetate (2 × 10 mL), washed with saturated brine (1 × 10 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain 45.5 g of compound N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(1-methylpyrrolidin-3-yl)pyrimidin-2-amine, with a yield of 20.38%. 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.48 (s, 1H), 8.36 (dd, J = 5.0, 3.1 Hz, 1H), 7.28 (dt, J = 8.8, 5.3 Hz, 2H), 7.21–7.09 (m, 4H), 6.91–6.83 (m, 2H), 6.69 (dd, J = 5.0, 3.7 Hz, 1H), 4.78 (t, J = 5.3 Hz, 4H), 3.54 (d, J = 8.4 Hz, 1H), 3.38 (s, 1H), 3.01 (s, 1H), 2.84 (d, J = 5.0 Hz, 1H), 2.72 (d, J = 4.9 Hz, 2H), 2.29 (q, J = 8.1, 6.6 Hz, 1H), 1.99 (hept, J = 6.7 Hz, 1H), 0.97 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 449 [M+H] + 。

[0147] Example 3. N-[(4-Fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]-4-(piperazin-1-yl)pyrimidin-2-amine (3)

[0148] Reaction Scheme 2

[0149]

[0150] 3.1 Preparation of tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate

[0151] 2,4-Dichloropyrimidine (3.00 g, 20.138 mmol), DMSO (30.00 mL), tert-butyl piperazine-1-carboxylate (4125.94 mg, 22.152 mmol), and DIEA (5205.47 mg, 40.277 mmol) were added to a 100 mL reaction flask. Under nitrogen protection, the temperature was raised to 150 °C and stirred for 2 hours. After the reaction was completed, the temperature was lowered to room temperature, and the reaction was quenched with water. The mixture was extracted with ethyl acetate (3 x 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was purified by column chromatography (PE:EA = 3:2) to obtain 5.4 g of tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate, with a yield of 89.75%, as a pale yellow oil.

[0152] 3.2 Preparation of tert-butyl 4-[2-([[4-(2-methylpropoxy)phenyl]methyl]amino)pyrimidin-4-yl]piperazine-1-carboxylate

[0153] tert-Butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate (2.00 g, 6.694 mmol), dimethyl sulfoxide (20.00 mL), 1-[4-(2-methylpropoxy)phenyl]methanamine (1.32 g, 7.364 mmol), and DIEA (1.73 g, 13.388 mmol) were added to a 50 mL round-bottom flask. The temperature was raised to 150 °C and reacted for 2 hours. After the reaction was completed, the temperature was lowered to room temperature. 40 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated sodium chloride solution (1 x 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was purified by column chromatography (PE:EA = 1:1) to obtain 1 g of tert-butyl 4-[2-([[4-(2-methylpropoxy)phenyl]methyl]amino)pyrimidin-4-yl]piperazine-1-carboxylate, with a yield of 33.83%, as a yellow solid.

[0154] 3.3 Preparation of tert-butyl 4-(2-[(4-fluorophenyl)methyl]([[4-(2-methylpropoxy)phenyl]methyl])amino]pyrimidin-4-yl)piperazine-1-carboxylate

[0155] tert-Butyl 4-[2-([[4-(2-methylpropoxy)phenyl]methyl]amino)pyrimidin-4-yl]piperazine-1-carboxylate (1.00 g, 2.265 mmol) and DMF (10.00 mL) were added to a 25 mL round-bottom flask. Under nitrogen protection, the temperature was lowered to 0 °C, and then NaH (0.11 g, 4.529 mmol) was added. The reaction was carried out at 0 °C for 0.5 h. 1-(Bromomethyl)-4-fluorobenzene (265.89 mg, 1.407 mmol) was added dropwise at 0 °C, and the reaction was continued for 2 h. After the reaction was completed, 30 mL of ice water was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30 mL), and the organic phase was washed with saturated brine (1 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 1 g of tert-butyl 4-(2-[(4-fluorophenyl)methyl]([[4-(2-methylpropoxy)phenyl]methyl])amino]pyrimidin-4-yl)piperazine-1-carboxylate, with a yield of 80.33%, as a yellow solid.

[0156] 3. Preparation of N-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]-4-(piperazin-1-yl)pyrimidin-2-amine

[0157] tert-Butyl 4-(2-[(4-fluorophenyl)methyl]([[4-(2-methylpropoxy)phenyl]methyl])amino]pyrimidin-4-yl)piperazine-1-carboxylate (230.00 mg, 0.418 mmol) was added to 1,4-dioxane (2.00 mL) containing HCl. The mixture was stirred at room temperature for 1 h. After the reaction was completed, 30 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was purified by column chromatography in batches (DCM:MeOH = 20:1) to obtain 56.5 mg of N-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]-4-(pyrrolidin-3-yl)pyrimidin-2-amine, with a yield of 27.25%. 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.90 (d, J = 6.0 Hz, 1H), 7.29–7.21 (m, 2H), 7.18–7.06 (m, 4H), 6.88–6.81 (m, 2H), 6.10 (d, J = 6.1 Hz, 1H), 4.67 (s, 4H), 3.70 (d, J = 6.5 Hz, 2H), 3.47 (t, J = 5.0 Hz, 4H), 2.73 (t, J = 5.3 Hz, 4H), 1.99 (dp, J = 13.3, 6.6 Hz, 1H), 0.97 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 450 [M + H] + 。

[0158] Example 4. 4-(2-((4-Fluorobenzyl)(4-isobutoxybenzyl)amino)pyrimidin-4-yl)piperazine-1-carbaldehyde

[0159] Replace the reaction raw material tert-butyl piperazine-1-carboxylate with 1-formylpiperazine, and prepare the target compound according to the method of Example 3. The structural formula is shown as No. (4) in Table 1. 1 H NMR(400MHz,DMSO-d6):δ8.07(s,1H),7.95(d,J=6.0Hz,1H),7.34–7.19(m,2H),7.19–7.04(m,4H),6.89–6.80(m,2H),6.17(d,J=6.0Hz,1H),4.69(s,4H),3.70(d,J=6.5Hz,2H),3.55(d,J=20.3Hz,4H),3.37(d,J=6.5Hz,4H),1.99(dt,J=13.3,6.7Hz,1H),0.97(d,J=6.7Hz,6H).LCMS(ES,m / z):418[M+H] + 。

[0160] Example 5. N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(piperidin-4-yl)pyrimidin-2-amine

[0161] Replace the reaction raw material tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate, and prepare the target compound according to the method of Example 1. The structural formula is shown as No. (5) in Table 1. 1 H NMR(400MHz,DMSO-d6)δ8.31(d,J=5.0Hz,1H),7.28(dd,J=8.4,5.6Hz,2H),7.21–7.08(m,4H),6.90–6.82(m,2H),6.59(d,J=5.1Hz,1H),4.75(d,J=4.4Hz,4H),3.71(d,J=6.5Hz,2H),3.20(d,J=12.3Hz,2H),2.88–2.66(m,3H),1.99(dp,J=13.3,6.6Hz,1H),1.89(d,J=13.2Hz,2H),1.76(q,J=12.5Hz,2H),0.97(d,J=6.7Hz,6H).LCMS(ES,m / z):449[M+H] + 。

[0162] Example 6. N-(4-Fluorobenzyl)-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(4-isobutoxybenzyl)pyrimidin-2-amine

[0163] Replace the reaction raw material tert-butyl piperazine-1-carboxylate with octahydropyrrolo[1,2-a]pyrazine, and prepare the target compound according to the method of Example 1. The structural formula is shown as No. (6) in Table 1. 1 H-NMR(400MHz,Methanol-d4)δ7.88(d,J=6.2Hz,1H),7.27–7.17(m,2H),7.17–7.09(m,2H),7.06–6.96(m,2H),6.88–6.80(m,2H),6.14(d,J=6.2Hz,1H),4.80–4.65(m,4H),4.47(d,J=12.9Hz,1H),4.32(d,J=13.1Hz,1H),3.72(d,J=6.5Hz,2H),3.14–3.02(m,2H),2.99(ddd,J=14.9,11.8,3.3Hz,1H),2.63(dd,J=12.8,10.5Hz,1H),2.25–2.13(m,2H),2.10–1.94(m,1H),1.86(s,1H),1.84(dddd,J=20.8,16.1,12.7,9.3Hz,2H),1.51–1.33(m,1H),1.35(s,1H),1.31(d,J=3.6Hz,1H),1.04(d,J=6.7Hz,6H).LCMS(ES,m / z):490[M+H] + 。

[0164] Example 7. 4-(Azetidin-3-yl)-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyrimidin-2-amine

[0165] Replace the reaction raw material tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate with tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)azetidine-1-carboxylate, and prepare the target compound according to the method of Example 1. The structural formula is shown as No. (7) in Table 1. 11H NMR (400 MHz, Methanol-d4) δ 8.36 (d, J = 4.9 Hz, 1H), 7.31–7.23 (m, 2H), 7.21–7.14 (m, 2H), 7.08–6.98 (m, 2H), 6.89–6.82 (m, 2H), 6.58 (d, J = 4.9 Hz, 1H), 4.90 (s, 4H), 4.26 (qd, J = 10.1, 8.0 Hz, 4H), 4.17–4.04 (m, 1H), 3.73 (d, J = 6.5 Hz, 2H), 2.05 (dp, J = 13.3, 6.6 Hz, 1H), 1.04 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 421 [M+H] + 。

[0166] Example 8. 5-Fluoro-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyrimidin-2-amine

[0167] Replace the reaction raw material 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine, and prepare the target compound according to the method of Example 1. The structural formula is shown as No. (8) in Table 1. 1 1H NMR (400 MHz, Methanol-d4) δ 8.55 (s, 1H), 8.28 (d, J = 1.9 Hz, 1H), 7.24 (dd, J = 8.4, 5.4 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.02 (t, J = 8.6 Hz, 2H), 6.88–6.81 (m, 2H), 4.81 (d, J = 5.5 Hz, 4H), 3.88 (p, J = 7.5 Hz, 1H), 3.72 (d, J = 6.5 Hz, 2H), 3.60–3.46 (m, 2H), 3.33–3.24 (m, 2H), 2.39 (dq, J = 14.1, 7.1 Hz, 1H), 2.08 (ddq, J = 33.2, 13.3, 7.0 Hz, 2H), 1.03 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 453 [M+H] + 。

[0168] Example 9. 5-Chloro-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyrimidin-2-amine

[0169] Replace the reaction raw material 2,4-dichloropyrimidine with 2,4-dichloro-5-chloropyrimidine, and prepare the target compound according to the method of Example 1. The structural formula is shown as No. (9) in Table 1. 11H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H), 8.36 (s, 1H), 7.25 (dd, J = 8.4, 5.3 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 7.08–6.98 (m, 2H), 6.90–6.82 (m, 2H), 4.83 (d, J = 6.9 Hz, 4H), 3.96 (p, J = 7.2 Hz, 1H), 3.73 (d, J = 6.5 Hz, 2H), 3.53–3.46 (m, 2H), 3.25 (dp, J = 11.7, 4.3 Hz, 2H), 2.39 (dq, J = 14.5, 7.4 Hz, 1H), 2.06 (ddq, J = 17.0, 13.3, 6.8 Hz, 2H), 1.04 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 469 [M+H] + 。

[0170] Example 10. 4-(3-(Dimethylamino)azetidin-1-yl)-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyrimidin-2-amine

[0171] Replace the reaction raw material tert-butyl piperazine-1-carboxylate with N,N-dimethylazetidin-3-amine, and prepare the target compound according to the method of Example 1. The structural formula is shown as No. (10) in Table 1. 1 1H NMR (400 MHz, Methanol-d4) δ 8.28 (d, J = 1.9 Hz, 1H), 7.24 (dd, J = 8.4, 5.4 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.02 (t, J = 8.6 Hz, 2H), 6.88–6.81 (m, 2H), 4.81 (d, J = 5.5 Hz, 4H), 3.88 (p, J = 7.5 Hz, 1H), 3.72 (d, J = 6.5 Hz, 2H), 3.60–3.46 (m, 2H), 3.33–3.24 (m, 2H), 2.39 (dq, J = 14.1, 7.1 Hz, 1H), 2.08 (ddq, J = 33.2, 13.3, 7.0 Hz, 2H), 1.03 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 382 [M+H] + 。

[0172] Example 11. N-Benzyl-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyrimidin-2-amine

[0173] Replace the reaction raw material 1-(bromomethyl)-4-fluorobenzene with benzyl bromide, and prepare the target compound according to the method of Example 1. The structural formula is shown as No. (11) in Table 1. 11H NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 9.28 (s, 1H), 8.34 (d, J = 5.0 Hz, 1H), 7.36–7.28 (m, 2H), 7.28–7.15 (m, 5H), 6.90–6.80 (m, 2H), 6.71 (d, J = 5.0 Hz, 1H), 4.87–4.69 (m, 4H), 3.70 (d, J = 6.5 Hz, 2H), 3.51–3.44 (m, 2H), 3.31 (s, 2H), 3.24–3.15 (m, 2H), 2.26 (dd, J = 13.2, 6.8 Hz, 1H), 1.99 (dt, J = 13.2, 6.6 Hz, 1H), 1.94 (s, 1H), 0.96 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 417 [M+H] + 。

[0174] Example 12. N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(1-methylazetidin-3-yl)pyrimidin-2-amine

[0175] Replace the reaction raw material tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate with 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)azetidine, and prepare the target compound according to the method of Example 2. The structural formula is shown as No. (12) in Table 1. 1 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.29 (dd, J = 8.4, 5.6 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 7.16–7.07 (m, 2H), 6.90–6.83 (m, 2H), 6.62 (d, J = 5.0 Hz, 1H), 4.78 (d, J = 4.0 Hz, 4H), 3.70 (d, J = 6.5 Hz, 2H), 3.68–3.55 (m, 3H), 3.31 (d, J = 7.3 Hz, 2H), 2.27 (s, 3H), 1.99 (dp, J = 13.3, 6.6 Hz, 1H), 0.97 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 435 [M+H] + 。

[0176] Example 13. N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)quinazolin-2-amine

[0177] Replace the reaction raw material 2,4-dichloropyrimidine with 2,4-dichloroquinazoline, and prepare the target compound according to the method of Example 1. The structural formula is shown as No. (13) in Table 1. 1 H NMR(400MHz,Methanol-d4)δ8.04(dd,J=8.4,1.3Hz,1H),7.70(ddd,J=8.3,6.7,1.4Hz,1H),7.62(dd,J=8.5,1.2Hz,1H),7.29(td,J=6.7,3.2Hz,3H),7.19(d,J=8.1Hz,2H),7.07–6.95(m,2H),6.88–6.78(m,2H),4.94(t,J=5.3Hz,4H),4.24(ddd,J=10.9,8.0,5.4Hz,1H),3.71(d,J=6.5Hz,2H),3.31–3.23(m,1H),2.99(t,J=7.2Hz,2H),2.38–2.24(m,1H),2.06(ddp,J=26.5,13.2,6.6,6.0Hz,2H),1.30(s,1H),1.02(d,J=6.7Hz,6H).LCMS:(ES,m / z):485[M+H] + 。

[0178] Example 14. 4-(3-(Dimethylamino)cyclobutyl)-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyrimidin-2-amine

[0179] Replace the reaction raw material 2,4-dichloropyrimidine with 2,3-dichloropyrimidine, and replace tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate with N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclobutan-1-amine. Prepare the target compound according to the method of Example 1. The structural formula is shown as No. (14) in Table 1. 1 H NMR:(400MHz,Methanol-d4)δ8.28(d,J=6.4Hz,1H),7.34(dd,J=8.3,5.2Hz,2H),7.23(d,J=8.3Hz,2H),7.19–7.06(m,3H),7.02–6.86(m,2H),4.95(s,4H),3.85(p,J=8.3Hz,1H),3.75(d,J=6.5Hz,2H),3.70–3.52(m,1H),2.95–2.65(m,10H),2.07(dh,J=13.2,6.6Hz,1H),1.04(d,J=6.7Hz,6H).

[0180] Example 15. 4-[(Dimethylamino)methyl]-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyridin-2-amine

[0181] Reaction Scheme 3

[0182]

[0183] 15.1 Preparation of N-(4-Isobutoxybenzyl)-4-isocyanatopyridin-2-amine

[0184] 2-Fluoro-4-isocyanatopyridine (5.00 g, 40.98 mmol), (4-isobutoxyphenyl)methanamine (8.07 g, 45.08 mmol), DIEA (10.57 g, 81.94 mmol) and 30 mL of DMSO were placed in a 100 mL round-bottom flask, and the temperature was raised to 150 °C and reacted for 2 hours. After the reaction was completed, the temperature was lowered to room temperature, 100 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine (1 x 50 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and purified by column chromatography (PE:EA = 1:1) to obtain 4.6 g of the compound N-(4-isobutoxybenzyl)-4-isocyanatopyridin-2-amine, with a yield of 39.97%.

[0185] 15.2 Preparation of N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-isocyanatopyridin-2-amine

[0186] N-(4-Isobutoxybenzyl)-4-isocyanatopyridin-2-amine (2.00 g, 7.12 mmol) was added to 10 mL of DMF, and the temperature was lowered to 0 °C. 60% sodium hydride (0.34 g, 8.52 mmol) was slowly added thereto. After the addition was completed, the mixture was stirred for 10 minutes, and 4-fluorobenzyl bromide (1.48 g, 7.83 mmol) was added thereto. After the addition was completed, the temperature was raised to room temperature and reacted for 1 hour. After the reaction was completed, 40 mL of water was slowly added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine (1 x 30 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (PE:EA = 5:1) to obtain 2.1 g of the compound N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-4-isocyanatopyridin-2-amine, with a yield of 75.81%.

[0187] 15.3 Preparation of 4-(Aminomethyl)-N-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine

[0188] N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-isocyanatopyridin-2-amine (2.00 g, 5.14 mmol) and Raney Ni (198.00 mg, 2.31 mmol) were added to 50.00 mL of tetrahydrofuran. Hydrogen gas was introduced into the system, and the reaction was carried out overnight at room temperature. After the reaction was completed, filtration was performed by suction to obtain a solution. The solvent was removed by evaporation under reduced pressure to obtain 1.4 g of the compound 4-(aminomethyl)-N-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine, with a yield of 69.31%.

[0189] 15.4 Preparation of 4-[(dimethylamino)methyl]-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyridin-2-amine

[0190] 4-(Aminomethyl)-N-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine (0.6 g, 1.53 mmol) was added, and then AcOH (184.33 mg, 3.06 mmol) and HCHO (229.73 mg, 7.65 mmol) were added. The reaction was carried out at room temperature for 0.5 hour, and then STAB (972.61 mg, 4.59 mmol) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (2 x 10 mL). The organic phase was washed with saturated brine, and the solvent was removed by evaporation under reduced pressure. Purification was carried out by column chromatography (DCM:MeOH = 30:1) to obtain 0.2 g of the compound 4-[(dimethylamino)methyl]-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyridin-2-amine, with a yield of 31.25%. 1 H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.14 (d, J = 6.1 Hz, 1H), 7.56 (s, 1H), 7.41–7.33 (m, 2H), 7.28–7.21 (m, 2H), 7.21–7.09 (m, 3H), 6.93–6.85 (m, 2H), 4.93 (s, 2H), 4.88 (s, 2H), 4.31 (d, J = 4.6 Hz, 2H), 3.71 (d, J = 6.5 Hz, 2H), 2.67 (d, J = 3.8 Hz, 6H), 1.99 (dp, J = 13.3, 6.7 Hz, 1H), 0.96 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 422 [M+H] + 。

[0191] Example 16. 4-(Aminomethyl)-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyridin-2-amine

[0192] The target compound was prepared according to the method of Example 15, and its structural formula is shown as No. (16) in Table 1. 1 HNMR(400MHz,DMSO-d6)δ8.64(s,3H),8.12(d,J=5.8Hz,1H),7.35–7.28(m,2H),7.26(s,1H),7.23–7.11(m,4H),6.96–6.85(m,3H),4.82(d,J=17.7Hz,4H),4.02(q,J=5.8Hz,2H),3.72(d,J=6.5Hz,2H),1.99(hept,J=6.7Hz,1H),0.97(d,J=6.7Hz,6H).LCMS(ES,m / z):394[M+H] + 。

[0193] Example 17. N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyridin-2-amine Reaction Scheme 4

[0194]

[0195] 17.1 Preparation of 4-Bromo-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine

[0196] 4-Bromo-2-fluoropyridine (1100.00 mg, 6.250 mmol) and 1-[4-(2-methylpropoxy)phenyl]methanamine (1232.52 mg, 6.875 mmol) were added to 11.00 mL of DMSO, and the temperature was raised to 80 °C. DIEA (2423.48 mg, 18.751 mmol) was added, and the reaction was carried out overnight. After the reaction was completed, 5.00 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 5 mL). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (PE:EtOAc = 5:1) to obtain 900 mg of 4-bromo-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine, with a yield of 42.95%, as a colorless oil. 17.2 Preparation of 4-Bromo-N-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine

[0197] 4-Bromo-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine (900.00 mg, 2.685 mmol) and NaH (96.64 mg, 4.027 mmol) were separately added to 10.00 mL of DMF. The temperature was lowered below 0 °C and the reaction was carried out for 1 hour. 1-(Bromomethyl)-4-fluorobenzene (608.96 mg, 3.222 mmol) was added. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out for 2 hours. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with ethyl acetate (10 ml × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification by column chromatography (DCM:MeOH = 9:1) gave 800 mg of 4-bromo-N-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine, with a yield of 67.21%, as a white solid.

[0198] Preparation of tert-butyl 3-(2-[[(4-fluorophenyl)methyl]([[[4-(2-methylpropoxy)phenyl]methyl])amino]pyridin-4-yl)-2,5-dihydropyrrole-1-carboxylate

[0199] 4-Bromo-N-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine (800.00 mg, 1.804 mmol) and sodium tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (870.83 mg, 2.165 mmol) were added to 8.00 mL of dioxane. Then Pd(dppf)Cl2 (132.03 mg, 0.180 mmol), Na2CO3 (382.49 mg, 3.609 mmol) and H2O (2.00 mL, 0.111 mmol) were added. Under nitrogen protection, the temperature was raised to 80 °C and the reaction was carried out for 2 hours. After the reaction was complete, 5.00 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (3 x 5 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification by column chromatography (PE:EtOAc = 5:1) gave 900 mg of tert-butyl 3-(2-[[(4-fluorophenyl)methyl]([[4-(2-methylpropoxy)phenyl]methyl])amino]pyridin-4-yl)-2,5-dihydropyrrole-1-carboxylate, with a yield of 93.81%, as a white solid.

[0200] Preparation of tert-butyl 3-(2-[[(4-fluorophenyl)methyl]([[4-(2-methylpropoxy)phenyl]methyl])amino]pyridin-4-yl)pyrrolidine-1-carboxylate

[0201] Raney nickel (85.00 mg) was added to 10.00 mL of tetrahydrofuran, and then tert-butyl 3-(2-[[(4-fluorophenyl)methyl]([[4-(2-methylpropoxy)phenyl]methyl])amino]pyridin-4-yl)-2,5-dihydropyrrole-1-carboxylate (850.00 mg) was added. Hydrogen was introduced into the mixture, and the reaction was carried out overnight at room temperature. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 800 mg of tert-butyl 3-(2-[[(4-fluorophenyl)methyl]([[4-(2-methylpropoxy)phenyl]methyl])amino]pyridin-4-yl)pyrrolidine-1-carboxylate, with a yield of 93.76%.

[0202] Preparation of 17.4 N-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]-4-(pyrrolidin-3-yl)pyridin-2-amine

[0203] tert-Butyl 3-(2-[[(4-fluorophenyl)methyl]([[4-(2-methylpropoxy)phenyl]methyl])amino]pyridin-4-yl)pyrrolidine-1-carboxylate (500.00 mg, 0.937 mmol) was added to a 5.00 mL dioxane solution of HCl, and the reaction was carried out at room temperature for 0.5 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (DCM:MeOH = 20:1) to obtain 300 mg of N-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]-4-(pyrrolidin-3-yl)pyridin-2-amine, with a yield of 73.92%. 1 H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 1H), 8.08 (d, J = 5.3 Hz, 1H), 7.29–7.21 (m, 2H), 7.18–7.10 (m, 2H), 7.08–6.98 (m, 2H), 6.90–6.81 (m, 2H), 6.61 (dd, J = 5.3, 1.5 Hz, 1H), 6.49 (t, J = 0.9 Hz, 1H), 4.79 (s, 2H), 4.73 (s, 2H), 3.72 (d, J = 6.5 Hz, 2H), 3.54 (dd, J = 11.4, 7.9 Hz, 1H), 3.42–3.34 (m, 1H), 3.33–3.18 (m, 1H), 3.02 (dd, J = 11.4, 9.8 Hz, 1H), 2.39–2.27 (m, 1H), 2.06 (dq, J = 13.3, 6.6 Hz, 1H), 2.02–1.87 (m, 1H), 1.33 (d, J = 17.7 Hz, 1H), 1.03 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 434 [M+H] + 。

[0204] Example 18. N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-6-(pyrrolidin-3-yl)pyridin-2-amine

[0205] Replace the reaction raw material 4-bromo-2-fluoropyridine with 2-bromo-6-chloropyridine, and prepare the target compound according to the method of Example 17. The structural formula is shown as No. (18) in Table 1. 1 H NMR(400MHz,DMSO-d6):δ7.35(t,J=7.8Hz,1H),7.26(dd,J=8.4,5.5Hz,2H),7.13(q,J=8.1Hz,4H),6.86(d,J=8.2Hz,2H),6.51(t,J=7.3Hz,1H),6.38(d,J=8.5Hz,1H),4.74(s,2H),4.69(s,2H),3.70(d,J=6.5Hz,2H),3.23–3.14(m,4H),3.00–2.87(m,2H),1.99(tq,J=13.2,7.1,6.6Hz,2H),1.92–1.79(m,1H),0.96(d,J=6.7Hz,6H).LCMS(ES,m / z):434[M+H] + 。

[0206] Example 19. 3-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(1-methylpyrrolidin-3-yl)pyridin-2-amine

[0207] Reaction Scheme 5

[0208]

[0209] 19.1 Preparation of 4-bromo-2-fluoro-3-(4-fluorobenzoyl)pyridine

[0210] Add 4-bromo-2-fluoropyridine (3.00 g, 17.047 mmol) and LDA (2.01 g, 18.763 mmol) to 30.00 mL of THF, protect with nitrogen, cool down to -78 °C, add 4-fluoro-N-methoxy-N-methylbenzamide (3.12 g, 17.047 mmol) thereto, and react for 1 hour. After the reaction is completed, quench the reaction with saturated NH4Cl solution, extract with ethyl acetate (3x10 mL), wash the organic phase with saturated brine (1x10 ml), dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and purify by column chromatography (PE:EtOAc = 3:1) to obtain 3 g of the compound with a yield of 59.04%, a pale yellow solid.

[0211] 19.2 Preparation of 4-bromo-3-(4-fluorobenzoyl)-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine

[0212] 4-Bromo-2-fluoro-3-(4-fluorobenzoyl)pyridine (3.60 g, 12.077 mmol), 1-[4-(2-methylpropoxy)phenyl]methanamine (2.60 g, 14.504 mmol) and DIEA (3.12 g, 24.154 mmol) were added to 36.00 mL of DMSO. Under nitrogen protection, the temperature was raised to 80 °C and the reaction was carried out for 3 hours. After the reaction was completed, the temperature was lowered to room temperature, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated brine (2 x 10 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the product was purified by column chromatography (PE:EtOAc = 3:1) to obtain 3.1 g of 4-bromo-3-(4-fluorobenzoyl)-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine, with a yield of 56.13%, as a yellow solid.

[0213] 19.3 Preparation of tert-butyl 3-[3-(4-fluorobenzoyl)-2-([[4-(2-methylpropoxy)phenyl]methyl]amino)pyridin-4-yl]-2,5-dihydropyrrole-1-carboxylate

[0214] 4-Bromo-3-(4-fluorobenzoyl)-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine (4.40 g, 9.621 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3.57 g, 11.545 mmol), Na2CO3 (2.04 g, 19.242 mmol) and Pd(dppf)Cl2CH2Cl2 (0.39 g, 0.481 mmol) were added to 40.00 mL of 1,4-dioxane and 10.00 mL of water. Under nitrogen protection, the temperature was raised to 80 °C and the reaction was carried out for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine (1 x 10 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the product was purified by column chromatography (PE:EtOAc = 3:1) to obtain 3.5 g of tert-butyl 3-[3-(4-fluorobenzoyl)-2-([[4-(2-methylpropoxy)phenyl]methyl]amino)pyridin-4-yl]-2,5-dihydropyrrole-1-carboxylate, with a yield of 94.63%, as a yellow solid.

[0215] Preparation of tert-butyl 3-[3-[(4-fluorophenyl)(hydroxy)methyl]-2-([[4-(2-methylpropoxy)phenyl]methyl]amino)pyridin-4-yl]-2,5-dihydropyrrole-1-carboxylate

[0216] tert-Butyl 3-[3-(4-fluorobenzoyl)-2-([[4-(2-methylpropoxy)phenyl]methyl]amino)pyridin-4-yl]-2,5-dihydropyrrole-1-carboxylate (2.00 g, 3.665 mmol) was added to a mixed solution of 14.00 mL of THF and 7.00 mL of water. Under nitrogen protection, the temperature was lowered to 0 °C, and NaBH4 (208.01 mg, 5.498 mmol) was added. The reaction was carried out for 2 hours. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with ethyl acetate (3 x 10 mL), and the organic phase was washed with saturated brine (1 x 10 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was purified by column chromatography (PE:EtOAc = 3:1) to obtain 1.9 g of tert-butyl 3-[3-[(4-fluorophenyl)(hydroxy)methyl]-2-([[4-(2-methylpropoxy)phenyl]methyl]amino)pyridin-4-yl]-2,5-dihydropyrrole-1-carboxylate, with a yield of 94.65%, as a yellow solid.

[0217] Preparation of 3-[chloro(4-fluorophenyl)methyl]-4-(2,5-dihydro-1H-pyrrol-3-yl)-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine

[0218] tert-Butyl 3-[3-[(4-fluorophenyl)(hydroxy)methyl]-2-([[4-(2-methylpropoxy)phenyl]methyl]amino)pyridin-4-yl]-2,5-dihydropyrrole-1-carboxylate (500.00 mg, 0.890 mmol) was added to DCM (5.00 mL). Under nitrogen protection, the temperature was lowered to 0 °C, and SOCl2 (529.51 mg, 4.451 mmol) was slowly added dropwise. After the reaction was completed, the solvent was removed under reduced pressure to obtain 1 g of 3-[chloro(4-fluorophenyl)methyl]-4-(2,5-dihydro-1H-pyrrol-3-yl)-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine.

[0219] Preparation of 3-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]-4-(pyrrolidin-3-yl)pyridin-2-amine

[0220] 3-[Chloro(4-fluorophenyl)methyl]-4-(2,5-dihydro-1H-pyrrol-3-yl)-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine (1.00 g, 2.146 mmol) and Pd / C (0.20 g, 1.888 mmol) were added to CH3COOH (10.00 mL), and hydrogen was introduced thereto. The reaction was carried out overnight at room temperature. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 500 mg of 3-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]-4-(pyrrolidin-3-yl)pyridin-2-amine, with a yield of 53.74%, as a pale yellow solid.

[0221] 19.7 Preparation of 3-[(4-fluorophenyl)methyl]-5-(1-methylpiperidin-4-yl)-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine

[0222] 3-[(4-fluorophenyl)methyl]-N-[[4-(2-methylpropoxy)phenyl]methyl]-4-(pyrrolidin-3-yl)pyridin-2-amine (500.00 mg, 1.153 mmol), HCHO (86.57 mg, 2.883 mmol) and AcOH (207.76 mg, 3.460 mmol) were added to 5.00 mL of methanol. Under nitrogen protection, the reaction was carried out at room temperature for 30 minutes, and then STAB (293.30 mg, 1.384 mmol) was added. After completion of the reaction, the reaction was quenched with water, extracted with CH2Cl2 (3 x 5 mL), the organic phase was washed with saturated brine (1 x 5 mL), dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (DCM:MeOH = 20:1) to obtain 37.3 mg of 3-[(4-fluorophenyl)methyl]-5-(1-methylpiperidin-4-yl)-N-[[4-(2-methylpropoxy)phenyl]methyl]pyridin-2-amine, with a yield of 7.23%. 1 H NMR (400 MHz, Methanol-d4) δ 7.93 (d, J = 6.6 Hz, 1H), 7.18–7.03 (m, 7H), 6.88–6.80 (m, 2H), 4.61–4.56 (m, 2H), 4.24 (s, 2H), 3.88 (s, 2H), 3.72 (d, J = 6.5 Hz, 2H), 3.42 (s, 1H), 3.01 (s, 4H), 2.34 (s, 1H), 2.23 (s, 2H), 2.05 (dp, J = 13.3, 6.7 Hz, 1H), 1.03 (d, J = 6.8 Hz, 6H). LCMS (ES, m / z): 434 [M+H] + 。

[0223] Example 20. (4-Fluorophenyl)(2-((4-isobutoxybenzyl)amino)-4-(1-methylpyrrolidin-3-yl)pyridin-3-yl)methanol

[0224] The target compound was prepared according to the method of Example 19, and its structural formula is shown as No. (20) in Table 1. 1 H NMR(400MHz,DMSO-d6)δ7.88(d,J=5.4Hz,1H),7.22(td,J=6.9,5.8,2.0Hz,2H),7.18–7.03(m,2H),6.94–6.84(m,2H),6.74(dd,J=8.8,2.7Hz,2H),6.67(dd,J=6.5,5.4Hz,1H),6.51–6.37(m,2H),6.23(d,J=3.6Hz,1H),4.42(dd,J=14.9,5.8Hz,1H),4.29(dt,J=14.8,5.0Hz,1H),3.69(s,1H),3.67(s,2H),2.77–2.52(m,4H),2.28(d,J=1.9Hz,3H),1.97(dh,J=13.0,6.5Hz,2H),1.72(dq,J=14.4,7.3Hz,1H),0.96(d,J=6.6Hz,6H).LCMS(ES,m / z):464[M+H] + 。

[0225] Example 21. 3-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-5-(1-methylpiperidin-4-yl)pyridin-2-amine

[0226] The reaction raw material tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, and the target compound was prepared according to the method of Example 19, and its structural formula is shown as No. (21) in Table 1. 11H NMR (400 MHz, Methanol-d4) δ 7.78 (d, J = 2.3 Hz, 1H), 7.21–7.13 (m, 3H), 7.07–6.97 (m, 4H), 6.82–6.74 (m, 2H), 4.46 (s, 2H), 3.85 (s, 2H), 3.71 (d, J = 6.5 Hz, 2H), 2.99 (dt, J = 12.2, 3.2 Hz, 2H), 2.44 (tt, J = 12.0, 4.0 Hz, 1H), 2.33 (s, 3H), 2.17 (td, J = 12.0, 2.8 Hz, 2H), 2.05 (dq, J = 13.3, 6.7 Hz, 1H), 1.85–1.77 (m, 2H), 1.77–1.63 (m, 2H), 1.03 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 462 [M+H] + 。

[0227] Example 22. 3-((5-Fluoropyridin-2-yl)methyl)-N-(4-isobutoxybenzyl)-5-(1-methylpiperidin-4-yl)pyridin-2-amine

[0228] Replace the reaction raw material 4-fluoro-N-methoxy-N-methylbenzamide with 5-fluoro-N-methoxy-N-methylpyridine-2-carboxamide, and prepare the target compound according to the method of Example 19. The structural formula is shown as No. (22) in Table 1. 1 1H NMR (400 MHz, Methanol-d4) δ 8.24 (d, J = 2.9 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.53 (td, J = 8.6, 3.0 Hz, 1H), 7.39–7.31 (m, 2H), 7.17–7.09 (m, 2H), 6.88–6.79 (m, 2H), 4.46 (s, 2H), 3.99 (s, 2H), 3.74 (d, J = 6.5 Hz, 2H), 3.04–2.96 (m, 2H), 2.45 (ddt, J = 11.9, 8.1, 4.2 Hz, 1H), 2.34 (s, 3H), 2.17 (td, J = 11.9, 2.9 Hz, 2H), 2.06 (dp, J = 13.3, 6.6 Hz, 1H), 1.86–1.66 (m, 4H), 1.04 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 463 [M+H] + 。

[0229] Example 23. 3-[(5-Fluoropyridin-2-yl)methyl]-N-(4-isobutoxybenzyl)-4-(1-methylpyrrolidin-3-yl)pyridin-2-amine

[0230] Replace the reaction raw material 4-fluoro-N-methoxy-N-methylbenzamide with 5-fluoro-N-methoxy-N-methylpyridine-2-carboxamide, and replace tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. Prepare the target compound according to the method of Example 19, and the structural formula is shown as No. (23) in Table 1. 1 H NMR(400MHz,Methanol-d4)δ8.26(d,J=2.9Hz,1H),7.91(d,J=5.5Hz,1H),7.50(td,J=8.6,3.0Hz,1H),7.22(dd,J=8.7,4.4Hz,1H),7.17–7.09(m,2H),6.87–6.78(m,2H),6.74(d,J=5.6Hz,1H),4.47(s,2H),4.14(s,2H),3.89–3.76(m,1H),3.72(d,J=6.5Hz,2H),2.96(dd,J=9.8,8.1Hz,1H),2.92–2.81(m,1H),2.76(td,J=8.9,5.9Hz,1H),2.56(dd,J=9.8,8.0Hz,1H),2.44(s,3H),2.27(dddd,J=17.2,15.0,10.5,6.7Hz,1H),2.05(hept,J=6.6Hz,1H),1.88(dtd,J=13.5,8.1,6.3Hz,1H),1.04(d,J=6.7Hz,6H).LCMS(ES,m / z):449[M+H] + 。

[0231] Pharmacological Example:

[0232] In vitro receptor binding experiment

[0233] 1 Experimental method

[0234] 1.1 Preparation of solutions required for the experiment

[0235] A: (For the preparation of 5-HT 2C receptor membrane): 50 mM Tris-HCl buffer: Dissolve 96.8 g of Tris in double-distilled water with a total volume of 4000 ml, adjust the pH to 7.5 with HCl, and dilute to 16000 mL, pH = 7.4

[0236] B: (For the preparation of 5-HT 2AReceptor membrane): Weigh 11.7 mg of EDTA and 380.84 mg of MgCl2, add them to 50 mM Tris-HCl buffer with a total volume of 400 mL, and adjust the pH to 7.4. The final concentrations are 0.1 mM of EDTA and 10 mM of MgCl2 respectively.

[0237] C: (For preparing Dopamine receptor membrane): Weigh 2.978 g of HEPES, 1.17 g of NaCl, 0.119 g of MgCl2, and 36.5 mg of EDTA, add them to pure water with a total volume of 250 ml, and adjust the pH to 7.4. The final concentrations are 50 mM of HEPES, 50 mM of NaCl, 5 mM of MgCl2, 0.5 mM of EDTA, and pH 7.4 respectively.

[0238] 1.2 Preparation of receptor membrane

[0239] 1) CHO-5-HT 2A Preparation of receptor membrane

[0240] CHO-5-HT 2A The cells are taken out of the -80°C refrigerator and thawed naturally, centrifuged at 2000 g and 4°C for 15 minutes. Take the precipitate and discard the supernatant. Add solution B to the precipitate. Mix the cells for 20 - 30 seconds, then centrifuge at 50000 g and 4°C for 25 min. Carefully discard the upper layer of liquid, add solution B again to mix, and centrifuge at 50000 g and 4°C for 25 min. Store the precipitate at -80°C.

[0241] 2) 5-HT 2C Preparation of membrane

[0242] The rat cortex is taken out of the -80°C refrigerator and thawed naturally, added with solution A, homogenized at 4 gears for 3 - 4 s, homogenized 4 times, centrifuged at 50000 g and 4°C for 25 min, discard the supernatant, add solution A, mix with a vortex mixer, centrifuge at 50000 g and 4°C for 25 min, repeat the centrifugation twice. After centrifugation, discard the supernatant, and store the precipitate at -80°C for standby.

[0243] 3) Preparation of CHO-D2 receptor membrane

[0244] The cells CHO-D2 are taken out of the -80°C refrigerator and thawed naturally, centrifuged at 2000 g for 15 min. Add the homogenate C to the precipitate, mix with a vortex mixer, centrifuge at 50000 g and 4°C for 25 min, discard the supernatant, take the precipitate, add C buffer again to wash, resuspend and centrifuge. After centrifugation, discard the supernatant, and store the precipitate at -80°C for standby.

[0245] 1.3 Receptor competition binding experiment

[0246] 1) 5-HT 2AReceptor competition binding assay

[0247] Step 1: First, prepare a suspension of the prepared membrane with homogenate B at a concentration of 10 mg / mL for later use.

[0248] Step 2: Add 100 μL of the membrane preparation to each reaction tube.

[0249] Step 3: Add 100 μL of solution B to the total binding tube (TB), add 100 μL of Methysergide (final concentration 1.0×10 -5 M) to the non-specific binding tube (NB), and add 100 μL of the test compound to each test compound tube (CB).

[0250] Step 4: Add the radioactive ligand 3 10 μL of 3H-Ketanserin to each reaction tube, with a final concentration of 2.98 nM.

[0251] Step 5: Incubate each reaction tube at 37 °C for 25 min. After the reaction is completed, the bound ligand is rapidly filtered under reduced pressure through Whatman filter paper GF / C plate (previously soaked in 0.5% PEI for more than 1 h). After filtration, dry the filter membrane at 60 °C, stick on the bottom film, add 40 μL of scintillation fluid, seal the top film, and let it stand.

[0252] Step 6: Place the scintillation vial into a liquid scintillation counter for counting.

[0253] 2) 5-HT 2C Receptor competition binding assay

[0254] Step 1: First, prepare a suspension of the prepared membrane with homogenate B at a concentration of 210 mg / mL for later use.

[0255] Step 2: Add 100 μL of the membrane preparation to each reaction tube.

[0256] Step 3: Add 100 μL of solution B to the total binding tube (TB), add 100 μL of Ketanserin (final concentration 1.0×10 -5 M) to the non-specific binding tube (NB), and add 100 μL of the test compound to each test compound tube (CB).

[0257] Step 4: Add the radioactive ligand 3 10 μL of 3H-Mesulergine to each reaction tube, with a final concentration of 3 nM.

[0258] Step 5: Incubate each reaction tube at 37 °C for 25 min. After the reaction is completed, the bound ligand is quickly filtered under reduced pressure. The Whatman filter paper GF / C is saturated with 0.5% PEI solution 1 h in advance, washed thoroughly with ice-cold Tris buffer, the filter disc is taken out and placed in a 4 mL scintillation vial, and 1 mL of toluene scintillation fluid is added and mixed well.

[0259] Step 6: Place the scintillation vial into a liquid scintillation counter for counting.

[0260] 3) CHO-D2 receptor competitive binding assay

[0261] Step 1: First, prepare the membrane into a suspension of 8 mg / mL membrane with homogenate C for standby.

[0262] Step 2: Add 100 μL of the membrane preparation to each reaction tube.

[0263] Step 3: Add 100 μL of solution C to the total binding tube (TB), add 100 μL of Haloperidol (final concentration 1.0×10 -5 M) to the non-specific binding tube (NB), and add 100 μL of the test compound to each test compound binding tube (CB).

[0264] Step 4: Add 10 μL of radioactive ligand 3 H-Spiperone to each reaction tube, with a final concentration of 1.176 nM.

[0265] Step 5: Incubate each reaction tube at 37 °C for 25 min. After the reaction is completed, the bound ligand is quickly filtered under reduced pressure. The Whatman filter paper GF / B plate is soaked with 0.5% PEI for more than 1 h in advance. After filtration, the filter membrane is dried at 60 °C, a bottom film is pasted on, 40 μL of scintillation fluid is added, the top film is sealed, and it is left standing.

[0266] Step 6: Place the suction filtration plate into a liquid scintillation counter for counting.

[0267] 2 Experimental results

[0268] Pimaserine 5-HT 2A 、5-HT 2C receptor Ki values are 0.036 and 2.94 nM respectively. Compound 1 and 5-HT 2A 、5-HT 2C receptor Ki values are 0.005 and 8.19 nM respectively, superior to pimaserine; Compound 7 and 5-HT 2A 、5-HT 2C receptor Ki values are 0.0064 and 162.1 nM respectively, superior to pimaserine. See the following table for details.

[0269] Table 2 In vitro receptor binding activity (Ki value, nM) of each compound

[0270]

[0271]

[0272] In vitro hERG experiment

[0273] Seed the stably transfected cells onto a glass slide at a cell density of less than 50% and culture overnight. Transfer the experimental cells to a bath of approximately 1 ml embedded in the stage of an inverted microscope, and perfuse the extracellular fluid at a perfusion rate of 2.7 ml / min. After stabilizing for 5 minutes, the experiment can be started. Record the membrane current using a HEKA EPC-10 patch clamp amplifier and PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany). All experiments were completed at room temperature (22 - 24 °C).

[0274] In the experiment, a P-97 microelectrode puller (Sutter Instrument Company, One Digital Drive, Novato, CA 94949) was used to pull the electrodes (BF150-110-10). The inner diameter of the electrode was 1 - 1.5 mm, and the access resistance after filling with the internal solution was 2 - 4 MΩ.

[0275] The electrophysiological stimulation protocol for the hERG potassium channel is to first clamp the membrane voltage at -80 mV, apply a +20 mV voltage stimulation to the cell for 2 s to activate the hERG potassium channel, and then repolarize to -50 mV for 5 s to generate an outward tail current, with a stimulation frequency of once every 15 s. The current value is the peak value of the tail current.

[0276] In the experiment, the whole-cell recording mode was used to record the channel current. First, perfuse the extracellular fluid (about 2 ml per minute) and continuously record, and wait for the current to stabilize (the current decay (Run-Down) is less than 5% within 5 minutes). At this time, the peak value of the tail current is the control current value. Then, perfuse the extracellular fluid containing the test drug and continuously record until the inhibitory effect of the drug on the hERG current reaches a steady state. At this time, the peak value of the tail current is the current value after adding the drug. The standard of the steady state is judged by whether the last three consecutive current recording lines coincide. After reaching the steady state, if the hERG current recovers or approaches the size before adding the drug after perfusing and rinsing with the extracellular fluid, other concentrations or drugs can be perfused and tested.

[0277] Experimental results:

[0278] The hERG experiment IC50 of pimaserine is 208 nM. The cardiotoxicity of Compound 6, Compound 10, Compound 11, Compound 15, and Compound 23 is less than that of pimaserine. The results are shown in the following table.

[0279] Table 3 Results of in vitro hERG tests of compounds

[0280] Compound number hERG (nM) 6 564 10 319 11 355 15 643 23 356 Pimavanserin 208

[0281] Animal experiment

[0282] Mouse head-tossing test

[0283] 1 Test method

[0284] After stratifying mice by body weight, they were randomly divided into a model control group, a blank control group, and each dosing group. 1 h after intragastric administration of the vehicle or drug to the animals, the animals were placed in a beaker (13 cm in diameter and 19 cm in height) lined with fresh bedding. DOI ((±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride, (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride), a modeling drug, was intraperitoneally injected at a dose of 1 mg / kg, and the number of head tosses of the mice within 0 - 20 minutes after intraperitoneal injection of DOI was recorded. Head-tossing behavior was defined as rapid rotational twitching or wet dog-like shaking of the mouse's head, and this movement should be distinguished from normal grooming or exploratory behavior.

[0285] 2 Test results

[0286] The results of this test showed that the ED50 of pimaserine in inhibiting DOI-induced head-tossing behavior in mice was 0.39 mg / kg, and the ED50 of Compound 7 in inhibiting DOI-induced head-tossing behavior in mice was 0.83 mg / kg, indicating that the compounds of the present invention have a good effect in treating mental diseases, and the results of the animal model are comparable to those of pimaserine. The detailed results are shown in the following table.

[0287] Table 4 ED50 of pimaserine and other compounds in inhibiting DOI-induced head-tossing behavior in mice

[0288] Compound number ED50 (mg / kg) Pimavanserin 0.39 7 0.83

[0289] Note: ED50 is the median effective dose.

Claims

1. A compound of formula I-1 or a pharmaceutically acceptable salt thereof Z is C, N; R 13 is a straight-chain or branched-chain alkyl group having 2 to 5 carbon atoms; R1 is selected from H or a structure of formula II, R2 is absent, H or R2 is a structure of formula II, and R1 and R2 are not both H or a structure of formula II; when Z is N, R2 is absent and R1 is selected from a structure of formula II; A is C or N; R6 is H or a halogen; R7 is H or OH; R5 is H or R4 is H, a halogen or a structure of formula III, or R5 and R4 form a benzene ring; In formula III, n1 is an integer from 0 to 3, and W3 is C or N; R8 is a straight-chain or branched-chain alkyl having 1 to 3 carbon atoms; R3 is H, a structure of formula IV, V or VI: Among them, In formula IV, n2 is an integer from 0 to 3, and n4, n5 are each independently selected from integers from 1 to 3; W1, W2 are each independently selected from C, N; R9 is selected from H, a straight-chain or branched-chain alkyl having 1 to 3 carbon atoms; In formula VI, n3 is an integer from 0 to 1; In formula V, R 10 , R 11 are each independently selected from H, straight-chain or branched-chain alkyl having 1 to 3 carbon atoms.

2. The compound of formula I-1 or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The halogen is selected from fluorine, chlorine, bromine, iodine.

3. The compound of formula I-1 or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The straight-chain or branched-chain alkyl having 2 to 5 carbon atoms is selected from ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl.

4. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from any one of the following compounds: N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyrimidin-2-amine; N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(1-methylpyrrolidin-3-yl)pyrimidin-2-amine; N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(piperazin-1-yl)pyrimidin-2-amine; 4-[2-[(4-Fluorobenzyl)(4-isobutoxybenzyl)amino]pyrimidin-4-yl]piperazine-1-carbaldehyde; N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(piperidin-4-yl)pyrimidin-2-amine; N-(4-Fluorobenzyl)-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(4-isobutoxybenzyl)pyrimidin-2-amine; 4-(Azetidin-3-yl)-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyrimidin-2-amine; 5-Fluoro-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyrimidin-2-amine; 5-Chloro-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyrimidin-2-amine; 4-[3-(Dimethylamino)azetidin-1-yl]-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyrimidin-2-amine; N-Benzyl-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyrimidin-2-amine; N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(1-methylazetidin-3-yl)pyrimidin-2-amine; N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)quinazolin-2-amine; 4-[3-(Dimethylamino)cyclobutyl]-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyrimidin-2-amine; 4-[(Dimethylamino)methyl]-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyridin-2-amine; 4-(Aminomethyl)-N-(4-fluorobenzyl)-N-(4-isobutoxybenzyl)pyridin-2-amine; N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(pyrrolidin-3-yl)pyridin-2-amine; N-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-6-(pyrrolidin-3-yl)pyridin-2-amine; 3-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-4-(1-methylpyrrolidin-3-yl)pyridin-2-amine; (4-Fluorophenyl)[2-[(4-isobutoxybenzyl)amino]-4-(1-methylpyrrolidin-3-yl)pyridin-3-yl]methanol; 3-(4-Fluorobenzyl)-N-(4-isobutoxybenzyl)-5-(1-methylpiperidin-4-yl)pyridin-2-amine; 3-[(5-Fluoropyridin-2-yl)methyl]-N-(4-isobutoxybenzyl)-5-(1-methylpiperidin-4-yl)pyridin-2-amine; 3-[(5-Fluoropyridin-2-yl)methyl]-N-(4-isobutoxybenzyl)-4-(1-methylpyrrolidin-3-yl)pyridin-2-amine.

5. A pharmaceutical composition, characterized in that A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.

6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 5, in the preparation of a medicament for treating mental diseases.

7. The application according to claim 6, wherein The mental disease is schizophrenia.

8. The application according to claim 7, wherein The mental diseases are Parkinson's disease, behavioral disorders associated with dementia and psychosis.

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