Pyrimidine amine-containing compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention provides a pyrimidinamine compound with a structure as shown in a formula I, and a racemate, an R-isomer, an S-isomer, a pharmaceutically acceptable salt or a mixture of the racemate, the R-isomer, the S-isomer and the pharmaceutically acceptable salt. The compound can be used as a NaV1.2 inhibitor to play a role, has a relatively good protective effect in an in-vivo epilepsy model, and has relatively good blood-brain barrier penetration capability, so that the compound can be used for preparing medicines for treating NaV1.2-related diseases, such as benign familial neonatal convulsion (BFNIS), epileptic encephalopathy (EE) and the like # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry and pharmacotherapy, and in particular to a class of pyrimidine amine compounds, a preparation method thereof, a pharmaceutical composition containing such compounds, and a voltage-gated sodium ion channel 1.2 subtype (Na V 1.2) Inhibitors, especially for the preparation of drugs for treating central nervous system and mental system related diseases, such as benign familial neonatal seizures (BFNIS), epileptic encephalopathy (EE), etc. Background Art

[0002] Epilepsy is a common neurological disease characterized by repeated abnormal spontaneous discharges in the brain. According to the International League Against Epilepsy (ILAE), the following three situations can be considered epilepsy: 1. Two convulsive attacks without external influence occur within less than 24 hours; 2. After a convulsion without external influence, the diagnosis probability of a second convulsion is very high (the probability of a second convulsion within 10 years is more than 60%); 3. Direct diagnosis of epilepsy syndrome. Epilepsy is a complex disease with obvious genetic tendency, which is affected by multiple causes. Patients with epilepsy also suffer from other neurological diseases such as cognitive dysfunction, anxiety, autism and schizophrenia, which seriously affect the normal life of patients. According to WHO statistics, there are about 50 million epilepsy patients in the world, and there are about 9 million epilepsy patients in my country.

[0003] Traditional anti-epileptic drugs currently used generally have side effects such as neurotoxicity, teratogenicity, hepatotoxicity and bone marrow suppression, and often require very high dosages. For example, the commonly used anti-epileptic drug carbamazepine is generally believed to inhibit epileptic seizures by blocking sodium ion channels, and is the drug of choice for many epilepsy diseases; however, taking the drug may cause side effects such as blurred vision and abnormal liver function, which reduces the scope of use of the drug. In addition, most drugs only control the symptoms of epileptic seizures, and about 20-25% of epilepsy patients are still difficult to fully control and completely cure. Therefore, there is an urgent need to develop a class of broad-spectrum anti-epileptic drugs that are fast-acting, safer and have a new mechanism.

[0004] Voltage-gated sodium channels (VGSCs) are a class of membrane proteins that allow sodium ions to pass through the membrane surface. They are widely present in nerve, cardiovascular and skeletal muscle cells, and their activity is mainly determined by the voltage across the membrane. VGSCs mainly generate and propagate action potentials in neurons, and therefore play an important role in biological processes such as information transmission and skeletal muscle contraction.

[0005] In mammals, voltage-gated sodium channels have been separated into nine subtypes based on their primary sequence, tissue distribution, and gating characteristics, and are named Na V1.1-1.9, encoded by SCN(X)A gene. Among them, SCN2A gene encodes Na V 1.2 protein, mainly expressed in the cerebellar cortex. V 1.2 is the only Na+ expressed in the nodes of Ranvier and the axon initial segment V subtype, so it plays a vital role in the generation and propagation of early action potentials. Studies have found that Na V The abnormal function of SCN1.2 is closely related to epileptic seizures. The amino acid sequence caused by the missense mutation of the SCN2A gene can lead to functional changes in the sodium channel, causing the disruption of the excitatory / inhibitory balance and thus leading to epileptic seizures. In addition, SCN2A gene mutations have been found in patients with systemic epilepsy, infantile epilepsy (BFNIS), epileptic encephalopathy (EE) and autism spectrum disorder (ASD). V 1.2 inhibitors can inhibit this excitability and thus inhibit epileptic seizures. V 1.2 has become one of the effective targets for the treatment of epilepsy, attracting widespread attention from scientists.

[0006] There are currently multiple Na V 1.2 Inhibitor small molecules are in clinical and preclinical research. Compound GW273293 is a derivative of lamotrigine and exhibits good anti-epileptic activity. It is used to treat localized epileptic seizures, primary and secondary tonic-clonic seizures. It is currently in Phase II clinical trials. JNJ26990990 has the function of limiting the spread of epilepsy and raising the epilepsy threshold. It exhibits broad-spectrum anticonvulsant activity in rodents and is currently in Phase I clinical trials.

[0007] Na V 1.2 As a new anti-epileptic target, its drugability and effectiveness have been well verified. V 1.2 After treatment with the inhibitor, the patient's epileptic seizures were significantly improved; due to the high homology of the voltage-gated sodium channel subtype structure, it is easy to produce off-target effects, which in turn cause a series of side effects, such as inhibiting Na V 1.5 can cause arrhythmia and block Na V 1.1 May cause hereditary epilepsy syndrome.

[0008] In summary, the development of a new generation of Na V 1.2 Inhibitors are used to treat central nervous system and mental system related diseases and have very important research significance and clinical value. Summary of the invention

[0009] One object of the present invention is to provide pyrimidine amide compounds, and their R-isomers, S-isomers or pharmaceutically acceptable salts thereof.

[0010] Another object of the present invention is to provide a method for preparing the compound of the present invention.

[0011] Another object of the present invention is to provide novel Na V 1.2 Agonists can be used for the treatment and / or prevention of Na V 1.2 Diseases and drugs for various central nervous system diseases.

[0012] The present invention provides a class of pyrimidine amide compounds having a structure shown in the following formula I, and their R-isomers, S-isomers or pharmaceutically acceptable salts thereof:

[0013]

[0014] in:

[0015] X is N, O, S or CH2;

[0016] n is an integer from 0 to 3;

[0017] R 1 Each is independently hydrogen, halogen, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3-7 membered heterocyclyl, substituted or unsubstituted 5-7 membered aromatic-methylene, each heterocyclyl independently contains 1-4 heteroatoms selected from oxygen and nitrogen;

[0018] In another preferred embodiment, R 2 , R 3 , R 4 and R 5 Each is independently hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C3-C8 cycloalkyl;

[0019] In another preferred embodiment, R 4 and R 5 Connected to form a five-membered, six-membered, seven-membered, or eight-membered aromatic or heteroaromatic ring;

[0020] In another preferred embodiment, R 6 Each is independently hydrogen, halogen, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3-7 membered heterocyclyl, substituted or unsubstituted 5-7 membered aromatic-methylene, each heterocyclyl independently contains 1-4 heteroatoms selected from oxygen and nitrogen;

[0021] The substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, cyano, amino, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C6-C10 aryl and 3-12 membered heterocyclic group; wherein the heterocyclic group each independently contains 1-4 heteroatoms selected from oxygen and nitrogen;

[0022] The pyrimidine ring can also be selected from the following groups:

[0023]

[0024] The preparation method of the pyrimidine amide compound I of the present invention is as follows:

[0025] First, we used the cheap and readily available compound 1 as the starting material, and reacted it with aniline 2 through a nucleophilic substitution reaction to obtain intermediate 3. Then, intermediate 3 and phenylboronic acid 4 underwent a Suzuki coupling reaction to obtain pyrimidine amine-containing compounds.

[0026]

[0027] a: DIPEA, ethanol, 100℃, overnight.; b: K2CO3, Pd(PPh3)4, 1.4-dioxane, 100℃, overnight.

[0028] In another preferred embodiment, the compound is a compound as shown in Table A.

[0029] Table A

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063] The above is only a preferred embodiment of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and modifications without departing from the concept of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A pyrimidineamine compound having a structure as shown in the following formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof: in, X is N, O, S or CH2; n is an integer from 0 to 4; R 1 Each is independently hydrogen, halogen, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3-7 membered heterocyclyl, substituted or unsubstituted 5-7 membered aromatic-methylene, each heterocyclyl independently contains 1-4 heteroatoms selected from oxygen and nitrogen; R 2 , R 3 , R 4 and R 5 Each is independently hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C3-C8 cycloalkyl; R 4 and R 5 Connected to form a five-membered, six-membered, seven-membered, or eight-membered aromatic or heteroaromatic ring; R 6 Each is independently hydrogen, halogen, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3-7 membered heterocyclyl, substituted or unsubstituted 5-7 membered aromatic-methylene, each heterocyclyl independently contains 1-4 heteroatoms selected from oxygen and nitrogen; The substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, cyano, amino, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C6-C10 aryl and 3-12 membered heterocyclic group; wherein the heterocyclic group each independently contains 1-4 heteroatoms selected from oxygen and nitrogen; The pyrimidine ring can also be selected from the following groups:

2. The compound according to claim 1, characterized in that The R 1 Selected from the following group: each independently hydrogen, halogen, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3-7 membered heterocyclic group, substituted or unsubstituted 5-7 membered aromatic-methylene, each heterocyclic group independently containing 1-4 heteroatoms selected from oxygen and nitrogen; wherein, the definition of substitution is the same as above.

3. The compound according to claim 1, characterized in that The R4 and R5 are connected to form a five-membered, six-membered, seven-membered, or eight-membered aromatic ring or heteroaromatic ring.

4. The compound according to claim 1, characterized in that R6 is independently hydrogen, halogen, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3-7 membered heterocyclyl, substituted or unsubstituted 5-7 membered aromatic-methylene, each heterocyclyl independently containing 1-4 heteroatoms selected from oxygen and nitrogen.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 4-(Benzo[d][1,3]dioxin-5-ylmethoxy)-6-(3-methoxyphenyl)pyrimidin-2-amine, N-(Benzo[d][1,3]dioxin-5-methyl)-6-(3-methoxyphenyl)pyrimidin-4-amine, N-(Benzo[d][1,3]dioxin-5-methyl)-6-(4-fluorophenyl)pyrimidin-4-amine, N-(Benzo[d][1,3]dioxin-5-methyl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine, N 4 -(3,4-dimethoxybenzyl)-6-(3-methoxyphenyl)pyrimidine-2,4-diamine, N 4 -(3,4-dimethoxybenzyl)-6-(p-tolyl)pyrimidine-2,4-diamine, N 4 -(3,4-dimethoxybenzyl)-6-(4-fluorophenyl)pyrimidine-2,4-diamine, N 4 -(3,4-dimethoxybenzyl)-6-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine, N4 -(3,4-dimethoxyphenethyl)-6-(3-methoxyphenyl)pyrimidine-2,4-diamine, 4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, 4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, 4-(4-chlorophenyl)-6-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine, 4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(6-methoxypyridin-3-yl)pyrimidin-2-amine, 4-(Benzo[d][1,3]dioxin-5-yl)-6-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine, 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(3-methoxyphenyl)pyrimidin-4-amine, 6-(4-chlorophenyl)-2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-4-amine, 4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(3-methoxyphenyl)-1,3,5-triazine-2-amine, 4-(4-chlorophenyl)-6-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-1,3,5-triazine-2-amine, 4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(3-methoxyphenyl)pyrimidine-2,5-diamine, 4-(4-chlorophenyl)-6-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidine-2,5-diamine, 4-(3-methoxyphenyl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)pyrimidin-2-yl, 2-(4-(3-methoxyphenyl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)pyrimidin-2-yl]ethyl-1-amine, 4-(3-methoxyphenyl)-6-(phenethylthio)pyrimidin-2-amine, 4,6-bis((3,4-dimethoxybenzyl)oxy)pyrimidin-2-amine, N-(2-amino-6-(3-methoxyphenyl)pyrimidin-4-yl)benzo[d][1,3]dioxin-5-carboxamide, (4-(3-methoxyphenyl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepinepyridin-2-yl)pyrimidin-2-yl, 4-(3-methoxyphenyl)-6-(2-methyl-6,7-dihydrothiazol[5,4-c]pyridin-5(4H)-yl)pyrimidin-2-amine, 4-(3-methoxyphenyl)-6-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H-yl)pyrimidin-2-amine, 4-(3-methoxyphenyl)-6-morpholinopyrimidin-2-amine, 4-(1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-yl)-6-(thiophen-3-yl)pyrimidin-2-amine, 5-(3-methoxyphenyl)-4-(1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-yl)pyrimidin-2-amine, 2-(2-amino-6-(3-methoxyphenyl)pyrimidin-4-yl)isoquinolin-1(2H)-one, 4-(3-methoxyphenyl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepinepyridin-2-yl)pyridin-2-amine, 3′-methoxy-5-(1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-[1,1′-biphenyl]-3-amine, 1-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)isoquinolin-3-amine, 6,7-dimethoxy-4-(1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-yl)quinazolin-2-amine, N 4 -(3-(3,4-dimethoxyphenyl)propyl)-6-(3-methoxyphenyl)pyrimidine-2,4-diamine, N 4 -(4-(3,4-dimethoxyphenyl)butyl)-6-(3-methoxyphenyl)pyrimidine-2,4-diamine, (4-(3-methoxyphenyl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)pyrimidin-2-yl)methanethiol, 4-(3-methoxyphenyl)-6-(1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-yl)pyrimidin-2-amine, 4-(4,4-difluoroazacyclo-1-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, 4-(3-methoxyphenyl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine, 4-(2-(Aza-1-yl)ethoxy)-6-(3-methoxyphenyl)pyrimidin-2-amine, 1-(2-amino-6-(3-methoxyphenyl)pyrimidin-4-yl)-N,N-dimethylazepine-3-amine, 2-(2-amino-6-(3-methoxyphenyl)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepinepyridin-1-one, 4-(8-methoxy-1,3,4,5-tetrahydro-2H-benzazepin-2-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, 4-(isoindol-2-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, 4-(6,8-dimethoxy-1,3,4,5-tetrahydro-2H-benzazepin-2-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, 1-(2-amino-6-(3-methoxyphenyl)pyrimidin-4-yl)azepine-4-amine, 4-(azetidin-1-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, N 4 -(azetidin-3-ylmethyl)-6-(3-methoxyphenyl)pyrimidine-2,4-diamine, 4-(3-methoxyphenyl)-6-(5-methylisoindol-2-yl)pyrimidin-2-amine, 2-(2-amino-6-(3-methoxyphenyl)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepinepyridin-8-yl, 4-((1S,5R)-6-azabicyclo[3.2.1]octan-6-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, (1-(2-amino-6-(3-methoxyphenyl)pyrimidin-4-yl)azetidin-3-yl)methanol, 4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, 4-(8-Fluoro-1,3,4,5-tetrahydro-2H-benzazepin-2-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, 4-(8-azabicyclo[5.1.0]octan-8-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, 4-(2-chloro-7,8-dihydro-1,6-naphthylthiodine-6(5H)-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, 4-(8-Chloro-1,3,4,5-tetrahydro-2H-benzazepin-2-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine N 4 -(Benzo[d][1,3]dioxin-5-yl)-6-(3-methoxyphenyl)pyrimidine-2,4-diamine, 4-(3-azabicyclo[3.2.0]heptane-3-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, 1-(2-amino-6-(3-methoxyphenyl)pyrimidin-4-yl)pyrrolidin-3-ol, 4-(4-fluoroazacyclyl-1-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, 4-(3-fluoropyrrolidin-1-yl)-6-(3-methoxyphenyl)pyrimidin-2-amine, 2-(2-amino-6-(3-methoxyphenyl)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine-8-carbonitrile, 1-(2-amino-6-(3-methoxyphenyl)pyrimidin-4-yl)azepin-4-one, 4-(3-methoxyphenyl)-6-(8-nitro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)pyrimidin-2-amine, 4-(3-methoxyphenyl)-6-(piperidin-1-yl)pyrimidin-2-amine, 6-(3-methoxyphenyl)-N 4 -phenethylpyrimidine-2,4-diamine, 1-(2-amino-6-(3-methoxyphenyl)pyrimidin-4-yl)azepin-4-ol, 4-(3-methoxyphenyl)-6-morpholinopyrimidin-2-amine, N 4 -(2-(dihydrofuran-6-yl)ethyl)-6-(3-methoxyphenyl)pyrimidine-2,4-diamine, 4-(4-(cyclohexyloxy)phenyl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)pyrimidin-2-amine, 4-(Benzo[d][1,3]dioxin-5-yl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-yl)pyrimidin-2-amine, 4-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)-6-(3-(trifluoromethoxy)phenyl)pyrimidin-2-amine, 4-(4-isopropoxyphenyl)-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-2-amine, 4-phenyl-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-2-amine, 4-(3-methoxyphenyl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-yl)pyrimidin-2-amine, 4-(4-chlorophenyl)-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-2-amine, 4-(4-phenoxyphenyl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)pyrimidin-2-amine, 4-(1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-6-(m-tolyl)pyrimidin-2-amine, 4-(pyridin-2-yl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-alkyl)pyrimidin-2-amine, 4-(chroman-7-yl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)pyrimidin-2-amine, 4-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)-6-(1,3,4,15-tetrahydro-2H-benzo[c]azepin-2-yl)pyrimidin-2-amine, 4-(1H-pyrrol-2-yl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepinepyridin-2-yl]pyrimidin-2-amine, 4-(1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-6-(1-(tetrahydro-2H-pyran))-2-yl, 4-(5-methylpyridin-2-yl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-alkyl)pyrimidin-2-amine, 4-(4-phenoxyphenyl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)pyrimidin-2-amine, 4-methyl-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-2-amine, 4-methoxy-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-2-amine, 4-ethyl-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-2-amine, 4-propyl-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-2-amine, (2-amino-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-4-yl)methanol, 4-isopropyl-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-2-amine, 4,5-dimethyl-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-2-amine, 2-amino-4-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidine-5-carbonitrile, 4-(methoxymethyl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)pyrimidin-2-amine, 5-allyl-4-methyl-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)pyrimidin-2-amine, 4-cyclopentyl-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-2-amine, 4-(pyrrolidin-1-yl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepinepyridin-2-yl)pyrimidin-2-amine, 7-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-amine, 4-(1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-2-amine, 4-(1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine, 4-(1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-yl)-5,6,7,8-tetrahydroquinazolin-2-amine, 4-cyclopropyl-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-2-amine, 4-isopropoxy-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-2-amine, 4-cyclohexyl-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)pyrimidin-2-amine, 4-(4-methylpiperazin-1-yl)-6-(1,3,4,5-tetrahydro-2H-benzo[c]azepinedin-2-yl)pyrimidin-2-amine.

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, R-isomer, S-isomer, or a combination thereof.

7. A drug for activating Nav1.2, comprising the compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, R-isomer, S-isomer, or a combination thereof.

8. A medicament for treating and / or preventing a disease involving Nav1.1, the medicament comprising a compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, an R-isomer, an S-isomer, or a combination thereof; Preferably, the disease is of the central nervous system; more preferably, it is a disease selected from the group consisting of benign familial neonatal seizures (BFNIS) and epileptic encephalopathy (EE).

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